Дисертації з теми "Hypercholesteremia"

The National Cholesterol Education Program Adult Treatment Panel II (NCEP ATP II) unequivocally advocates an initial trial of dietary modification in both primary and secondary prevention prior to the institution of pharmacotherapy. Perhaps the rationale for this delay rests in the inherent, yet unsubstantiated, fear among clinicians that lifestyle change will be compromised in the presence of concurrent pharmacotherapy. However, the question of adherence to diet and exercise interventions following the initiation of lipid-lowering drug therapy has seemingly never been addressed scientifically.
It was therefore hypothesized that pharmacologically-treated patients with untreated hypercholesterolemia started on a program of lifestyle modification would achieve relatively less reduction in dietary fat intake and body weight, and participate less often in physical activity, if a pharmacologic agent was simultaneously prescribed. This was tested by a protocol in which these and related variables were assessed in participants who thought they were taking a lipid-lowering medication at diagnosis, compared to conventional initial treatment of diet and exercise alone. (Abstract shortened by UMI.)

Plant sterols (PS) lower total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), and inflammatory markers, and decrease risk of atherosclerotic cardiovascular disease (CVD). Exercise increases high density lipoprotein cholesterol (HDL-C) levels and decreases triglycerides (TG) and inflammation, also reducing the risk of CVD. The study objective was to investigate the combined effects of PS and exercise on apolipoproteins (apo) A and B, adiponectin, growth hormone (GH) and ghrelin, in context of previously obtained lipid data. In an 8-wk, placebo-controlled, parallel-arm clinical trial, 84 subjects were randomly assigned to: (1) combination of PS and exercise, (2) exercise, (3) PS, or (4) control group. PS increased (P=0.04) adiponectin values by 15%. ApoA was associated with HDL and apoB with LDL values at baseline. ApoA %change was correlated to HDL %change in the exercise group. ApoB, GH and ghrelin were unchanged. The capability of PS to increase adiponectin values reinforce their role in preventing inflammation, atherosclerosis, and CVD.

Thesis (MSc)--Stellenbosch University, 2000.
ENGLISH ABSTRACT: Familial hypercholesterolaemia (FH) contributes significantly to the high death rate from cardiovascular disease worldwide. FH is a common autosomal co-dominant disease characterised by raised cholesterol levels and premature coronary heart disease (CHD). Whilst these features usually are very prominent in homozygotes the clinical diagnosis of heterozygotes is complicated by variable phenotypic expression. Specific founder genes in the low-density lipoprotein receptor (LDLR) gene have increased the prevalence of FH in South African Afrikaners, Indians, Jews and Coloureds, and screening for these known mutations allows unequivocal diagnosis of FH-affected individuals. The systematic molecular analysis of FH resulted in the identification of at least ten founder-type LDLR gene mutations among the 56 different gene defects described to date in the diverse South African population. DNA screening of 792 at-risk family members for the FH-related mutations identified in 379 index cases, allowed accurate disease diagnosis in an additional 340 relatives and exclusion of the relevant mutation in 452 individuals. This effort forms part of the MED PED FH initiative, a collaborative project to "Make Early Diagnosis and Prevent Early Deaths in MEDical PEDigrees with FH". Evaluation of clinical criteria versus DNA diagnosis of three founder-related mutations (D154N, D206E and V408M) in the South African population demonstrated that the sensitivity and specificity of diagnoses, based on total cholesterol values measured in family members of index cases recruited for this study, were 88% and 77%, respectively. A population-directed DNA diagnosis of FH is therefore justified in South Africa on a routine basis, since expression of the defective gene measured in biochemical tests does not allow accurate diagnosis of FH in all cases. The application of mutation detection was illustrated by prenatal diagnosis of FH performed for a couple who are both heterozygous for the most common Afrikaner mutation, D206E. The mutation was absent in the foetus and a normocholesterolaemic infant was born. Prenatal diagnosis of FH, aimed at the detection of homozygous cases, is particularly applicable in populations and families with molecularly defined LDLR gene mutations. The MED-PED approach resulted in accurate diagnosis and subsequent treatment of FH in more patients, and referral to lipid clinics where they could receive the intensive care their condition justifies. Molecularly diagnosed FH patients will be the first to benefit from future treatment approaches based on mutation type.
AFRIKAANSE OPSOMMING: Familiële hiprcholesterolemie dra grootliks by tot die wêreldwye hoë sterftesyfer van kardiovaskulêre siekte. FH is 'n algemene outosomale ko-dominante siekte wat gekenmerk word deur verhoogde cholesterolvlakke en vroeë koronêre hartsiekte. Terwyl hierdie kenmerke prominent is in homosigote, word die kliniese diagnose van heterosigote bemoeilik deur variasie in fenotipiese uitdrukking. Spesifieke stigtergene in die lae-digtheids lipoproteien reseptor (LDLR) geen het die voorkomssyfer van FH verhoog in Suid Afrikaanse Afrikaners, Indiërs, Jode en Kleurlinge. Sifting vir hierdie bekende mutasies maak akkurate diagnose van FH geaffekteerde individue moontlik. Die sistematiese molekulêre analise van FH het aangetoon dat ten minste tien van die 56 verskillende geen defekte wat tot dusver beskryf is in die Suid-Afrikaanse populasie stigtertipe LDLR geen mutasies is. DNA sifting van 792 familielede vir die FH-verwante mutasie in 379 indeksgevalle geïdentifiseer is, het akkurate diagnose moontlik gemaak in 340 addisionele familielede, en uitsluiting daarvan in 452 individue. Hierdie poging vorm deel van die MED-PED FH ("Make Early Diagnosis and Prevent Early Deaths in MEDical PEDigrees with FH) inisiatief. Evaluering van kliniese kriteria teenoor DNA diagnose van drie stigter verwante mutasies (D154N, D206E en V408M) in die Suid Afrikaanse populasie het getoon dat die sensitiwiteit en spesifisiteit van die diagnose, wat gebasseer is op totale cholesterol waardes in familielede van indeksgevalle, onderskeidelik 88% en 77% was. 'n Populasie gerigte DNA diagnose van FH is dus geregverdig in Suid-Afrika op "n roetine basis, omdat die defektiewe geen nie altyd in biochemiese toetse uitgedruk word nie. Die waarde van mutasie opsporing is geillustreer deur 'n voorgeboortelike diagnose van FH wat aangevra is vir ouers wat beide heterosigoties is vir die mees algemene Afrikaner mutasie, D206E. Die mutasie was afwesig in die fetus en 'n normocholesterolemiese baba is gebore. Voorgeboortelike diagnose van FH, wat gemik is op die opsporing van homosigotiese gevalle, is veral van toepassing in populasies en families met bekende LDLR geen mutasies. Die MED-PED benadering het gelei tot akkurate diagnose en daaropvolgende behandeling van FH in meer pasiënte, en verwysings na lipiedklinieke waar hulle intensiewe aandag kan geniet. Molekulêre gediagnoseerde FH pasiënte sal die eerste wees om baat te vind by toekomstige behandeling wat moontlik gebasseer sal word op mutasie status.

The expression of two phenotypically-contrasting LDL receptor mutations was characterized in cultured fibroblasts from the genetically-homozygous Afrikaner subjects, FH1a and lb, and FH3a and 3b, respectively. Surface receptor expression and functional activity were studied by ligand (¹²⁵I-LDL) and monoclonal antibody (¹²⁵I-IgG-C7) binding, and c35s]-methionine pulse-chase experiments were used to analyze biosynthesis, processing and degradation of IgG-C7- immunoprecipitable mutant receptors. Cells from the "receptor-negative" subjects, FH3a and 3b exhibited reduced, but significant (40-60% of normal) LDL receptor synthesis rates. Newly-synthesized precursors were processed slowly (t½ 1.5 hours versus normal t½ of approximately 15 minutes) to mature receptors which reached the cell-surface, but were rapidly degraded thereafter with a half-life of approximately 1.7 hours (normal value 12.6 hours) thus representing a new type of LDL receptor defect. Lysosomotropic weak bases such as ammonium chloride partially inhibited rapid degradation of the mutant receptors, suggesting the involvement of proteolysis in acidic compartments such as lysosomes or endosomes. Fibroblasts from FH1a and lb exhibited normal synthesis rates of LDL receptor precursors that were processed at a severely reduced rate (t½ approximately 5 hours) to functionally heterogeneous mature surface receptors. Onethird of the receptors (20% of normal levels) bound ¹²⁵I-LDL with normal affinity at 4°C and 37°C, whereas the majority were able to recognize only ¹²⁵I-IgG-C7, and apparently showed defective internalisation and subsequent degradation of the bound IgG-C7 at 37°C. The existence of the two receptor populations was further supported by selective intracellular trapping and degradation of only the active, LDL-binding population, in the presence of ammonium chloride and LOL. The abnormal form predominated even in newly-synthesized receptors and reached a maximum of 50-70% of normal levels after 48 hours of upregulation. Upregulation kinetics and degradation rates (t½ = 10-11 hours) of both functionally-active and abnormal receptor populations were similar to normal. A progressive increase in apparent molecular weight of the slowly-processed precursor receptors suggested a possible role for abnormal glycosylation in the formation of both "normal" and abnormal conformations of the same receptor molecule.

To evaluate the relative efficacy of plant sterols (PS) esterified with the fatty acids from fish oil (PS-FO), olive oil (PS-OO) and sunflower oil (PS-SO) on blood lipid and PS concentrations, 21 hyperlipidemic subjects were randomly assigned to each of five treatments for 28 days using a cross-over design. The results showed that: (1) in a comparison of olive oil (OO), fish oil (FO), PS-FO and PS-SO subgroup, PS-FO reduced triacylglycerols (TG) relative to PS-SO. Total cholesterol (T-C)/high-density lipoprotein cholesterol (HDL-C) ratio was reduced with PS-FO compared with FO. Plasma PS levels were increased with PS-SO and PS-FO. (2) in a comparison of OO, PS-SO and PS-OO subgroup, PS-OO had a larger decrease in T-C than OO, while PS-SO and OO reduced T-C equally. Both PS-SO and PS-OO elevated plasma PS levels. Overall, PS-FO and PS-OO have a higher potential for decreasing the risk of cardiovascular disease in hyperlipidemic subjects than PS-SO and OO supplementations.

Plant sterols are effective cholesterol-lowering agents; however, recent evidence suggests that this treatment may not be safe and beneficial in all individuals. This study determined whether high and low baseline circulating plasma campesterol and sitosterol are related to subsequent changes in plasma LDL-C, plant sterol or CRP levels, after accounting for plant sterol supplementation in hypercholesterolemic men (n=82). This trial was a 2-phase randomized cross-over design consisting of a controlled diet with and without a dose of 2.0 g/d of plant sterols over 4 weeks. There was no significant difference in plasma LDL-C, in the elevation of plasma plant sterol or in the changes of CRP levels for high and low groups, respectively. In view of these data, a supplement of 2.0 g/d of plant sterols should be viewed as a safe and beneficial cholesterol-lowering therapy for all individuals, with respect to their baseline plasma plant sterol levels.

Orientador: Eros Antonio de Almeida
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
Made available in DSpace on 2018-08-10T01:47:47Z (GMT). No. of bitstreams: 1 Hernandes_DorivalBlaquer_M.pdf: 1038635 bytes, checksum: f87a9f0cf9cca81b3827e6b7fefdbb9b (MD5) Previous issue date: 2007
Resumo: Objetivo: este estudo teve como objetivo detectar o efeito da rosuvastatina sobre os lípides plasmáticos, peroxidação lipídica, colesterol tecidual e disfunção endotelial e comparar seus efeitos com a atorvastatina em coelhos hipercolesterolêmicos. Métodos: Quarenta coelhos machos da raça Nova Zelândia foram distribuídos aleatoriamente em quatro grupos: Grupo Hipercolesterolêmico (GH), Grupo não Hipercolesterolêmico (GN), Grupo Atorvastatina (GA) e Grupo Rosuvastatina (GR) (N = 10). Todos os animais foram alimentados com dieta complementada com gordura de côco 10% e colesterol 0,5% por 45 dias e água a vontade. Após 15 dias amostras de sangue foram colhidas dos grupos através de punção venosa para determinação do colesterol plasmático total. A rosuvastatina era administrada por gavagem, na dose de 2,5 mg/dia/animal e a atorvastatina na dose de 10 mg/dia/animal aos Grupos GR e GA. No final do experimento, novas amostras de sangue foram coIbidas para determinação do colesterol total e isolamento de LDL. Os animais foram sacrificados por deslocamento cervical, êra realizada Toracotomia, a aorta era removido e preparado anéis de 5mm para o estudo da função endotelial, medindo colesterol tecidual, MDA na parede da aorta e LDLs. Os resultados foram comparados por métodos estatísticos não - paramétricos. Resultados: Ao analisar os resultados deste trabalho, podem ser observadas redução dos níveis de CT, 44,1 % e 66%, TG 53,16%, 23,11 %, LDL 53% e de, 40,68%, e um aumento de 17,23%, 36,98% do HDL e uma melhora na função endotelial de 33,09%, 22,37%, respectivamente, em relação a comparação GA e GR. Com o GH. Conclusão: Os resultados mostraram que rosuvastatina e atorvastatina foram equivalentes na redução das susceptibilidades de LDL de sofrer peroxidação, diminuindo o colesterol tecidual e melhorando a função endotelial
Abstract: Objective: The aim of this study was to detect the effect of the rosuvastatin on plasmatic lipids, lipidic peroxidation, tis sueI cholesterol, and endothelium disfunction and to compare its effect with the atorvastatin in hypercholesterolemic rabbits. Methods: Forty male New Zealand white rabbits were randomized in Four Groups: Group Hypercholesterolemic (GH), Group No Hypercholesterolemic (GN), Group Atorvastatin (GA) and Group Rosuvastatin (GR). (N=lO). AlI the animaIs were fed with diet supplemented with fat of coconut 10% and cholesterol 0.5% w/w per 45 days. After 15 days samples of blood were removed from the groups through venous punction for total plasmatic cholesterol determination. Then the rosuvastatin was managed by gavage, in the dose of 2,5mg and Atorvastatin in the dose of 10mg per day to each animal of Groups GR. and GA. In the end of the experiment, new samples of blood were renioved for determination of the cholesterol and isolation pf LDL. The animals were sacrificed by displacement of the cervical column. Medium Toracotomia was carried out and the aorta was removed for ring preparation for study of the endothelium function, measured of tissue cholesterol, MDA in the walI of aorta and LDLs. The results were compared by not-parametric statistical methods. Results: When analyzing the results of this work, a reduction in the CT levels can be observed, of 44,1 % and 66%, TG 53.16%, 23.11%, LDL 53% and of, 40.68%, and an increase of 17,23%, 36.98% of HDL, 33.09%, 22.37% in the endothelium function respectively for the compared GA and GR. with the GH. Conclusion: The results have sh6wn that rosuvastatin and atorvastatin were equivalent in reducing the susceptibilities of LDL to suffer peroxidation, in decreasing the tecidual cholesterol and improving the endothelium function
Mestrado
Ciencias Basicas
Mestre em Clinica Medica

Background. A high ratio of total cholesterol to high-density lipoprotein (HDL) cholesterol, in addition to increased levels of small low-density lipoprotein (LDL) particles, are important indicators of cardiovascular disease risk. Therefore, interventions that combine the lowering of total cholesterol and raising of HDL cholesterol concentrations that also increase LDL particle size, may be preventive against cardiovascular disease. Plant sterols decrease total cholesterol and LDL cholesterol levels by 10-15%, while exercise increases HDL cholesterol levels by 4-22%. In view of their complementary effects, combining plant sterols with exercise would appear to be an effective lifestyle therapy to decrease the risk of future cardiovascular disease.
Objective. The aim of this study was to examine the independent and combined effects of plant sterols and exercise on blood lipid levels, and LDL particle size in previously sedentary, hypercholesterolemic adults. An additional objective of this trial was to assess the underlying mechanism by which this combination therapy modulates whole body cholesterol metabolism, to in turn improve lipid profiles.
Methods. In an 8-week, parallel-arm trial, 84 subjects were randomized to 1 of 4 interventions: (1) plant sterols and exercise,(2) plant sterols alone, (3) exercise alone, or (4) control. Blood lipid concentrations were measured using enzymatic kits, and LDL particle size was assessed using polyacrylamide gel electrophoresis. Cholesterol absorption and synthesis were determined using the single isotope single tracer technique and the deuterium incorporation approach, respectively.
Results. Plant sterol supplementation decreased (P < 0.01) total cholesterol concentrations by 8.2% when compared to baseline. Exercise increased (P < 0.01) HDL cholesterol levels by 7.5% while decreasing (P < 0.01) triglyceride concentrations by 13.3% when compared to baseline. Exercise reduced (P < 0.05) post-treatment LDL peak particle size from 255 to 253 A, and decreased (P < 0.05) the proportion of large LDL particles by 13.1%. Plant sterols had no effect on particle size distribution. Plant sterol supplementation decreased (P < 0.01) intestinal cholesterol absorption by 18%, while exercise had no effect on cholesterol absorption. Non-significant increases in cholesterol synthesis rates of 63%, 59%, and 57%, were observed in the combination, exercise, and plant sterol groups, respectively, relative to control.
Conclusion. These findings suggest that this combination therapy yields the most favourable alterations in lipid profiles when compared to each intervention alone. This combined intervention exerts its beneficial effects on lipid profiles by suppressing intestinal cholesterol absorption. Therefore, this lifestyle therapy may be an effective means of decreasing the risk of cardiovascular disease in hypercholesterolemic adults.

The objective of this research was to examine the effects of sitosterol and sitostanol supplementation on plasma cholesterol levels and cholesterol metabolism in hypercholesterolemic subjects consuming a fixed foods diet in a four-phase crossover design. It was hypothesized that addition of either phytosterols, phytostenols, or a 50:50 mixture of sterols and stanols to butter would reduce circulating cholesterol levels, despite butter's hypercholesterolemic effect, through actions involving cholesterol absorption, synthesis, and turnover rates. The data obtained indicate that in their free, unesterified form, plant sterols and stanols lower plasma LDL cholesterol equivalently in hypercholesterolemic subjects. Results of this study provide new data that phytosterols and stanols function by suppressing cholesterol absorption while increasing cholesterol synthesis, however, the de-suppression in synthesis cannot fully compensate for the decrease in absorption making the treatment effective, thus may assist in the development of a food which offers health-promoting advantages related to the prevention of cardiovascular disease.

Discovery of cheap, nontoxic and readily available antiatherosclerotic drugs is an extraordinary challenge in this modern world. Atherosclerosis and cardiovascular diseases have been predicted to be the leading cause of death by the year 2030. Hence, this thesis was designed to search for plant (s) with anti-atherogenic properties, investigate its possible side effects and extrapolate its likely mechanism(s) of action. An ethnobotanical survey was employed in identification of locally important plants used for the management and treatment of cardiovascular diseases and its predisposing factors in Nkonkobe Municipality, Eastern Cape in South Africa. Information on the names of plants, their parts used and methods of preparation was collected through a questionnaire which was administered to herbalists, traditional healers and rural dwellers. The most frequently used plant (Rhizomes of Tulbaghia violacea Harv.) was investigated for toxicity using brine shrimp lethality (in vitro) and in vivo toxicity test (acute and subchronic) on rats to determine safety dosage. The in vitro antioxidant and free radical scavenging activity of the plant was investigated using models such as 1,1-diphenyl-2- picrylhydrazyl (DPPH), superoxide anions, hydrogen peroxide (H2O2), nitric oxide (NO), 2,2’- azinobis [3-ethylbenzothiazoline-6-sulfonic acid] diammonium salt (ABTS), lipid peroxidation inhibition and the ferric reducing agent. Phytochemical content and the effect of oral administration of fresh methanolic extract rhizomes of Tulbaghia violacea (250, 500 mg/kg. bwt/day) on Lipid peroxidation (TBARS), serum and tissue antioxidant enzymes in normal, hypercholesterolemic and diet induced atherogenic rats were also assessed. More so, the potential of the extract (250 and 500 mg/kg. bwt) to protect against atherogenic diet (4 percentage cholesterol 1 pecentage cholic acid and 0.5 percentage thiouracil) induced fatty streaks formation, dyslipidemia, oxidative stress and endothelial dysfunction was also investigated. Ethnobotanical study revealed that 19 plant species are used for the treatment of heart related diseases in the Municipality. 53 percentage of the plants mentioned were used for the management of chest pain, 47 percentage for high blood pressure, 42 percent for heart disease, 16 percentage for stroke and 11 percentage for the treatment of hypercholesterolemia. Tulbaghia violacea was repeatedly mentioned as the plant species used for the treatment of high blood pressure and predisposing factors in the study area. The brine shrimp cytotoxicity test revealed that fresh, dried methanolic extracts and essential oil of the T. violacea exhibited a high degree of cytotoxic activity with IC50 values of 18.18 (fresh) and 19.24 (dried) μg/ml. An IC50 value of 12. 59 μg/ml was obtained for the essential oil of the plant. The low cytotoxicity values obtained, suggested that rhizome of T. violacea may serve as a potential source of antimicrobial and anticancer agents. In vivo acute study of single oral administration of 5g/kg dose does not produce mortality or significant behavioral changes during 14 days observation. In the sub-chronic study, the extract (250, 500 mg/kg/bwt/ day) administered for a period of 28 days showed no mortality or morbidity. The weekly body and organ weight of the rats showed no significant differences between the control and the rats treated with the extract. The extract at all doses does not show any effect on of biomarkers of liver or renal damage. However, a significant decrease in the activity of ƔGT was observed in the extract treated groups. Hematological evaluation revealed that oral administration of fresh methanolic extracts of rhizomes of T. violacea does not cause anaemia or leucocytosis in the animals. Furthermore, histopathology results of the internal organs revealed no detectable inflammation. These results demonstrated that the rhizome extract of T. violacea was potentially safe for consumption orally even in chronic concentration. In vitro antioxidant evaluation showed that the essential oil, fresh and dried methanolic extracts exhibited potent antioxidant activities in a concentration dependent manner. Phytochemical investigation reveals that the fresh and the dry extract of RTV are rich in flavonoid, flavonol, phenols, tannin and proanthocyanidin, while the essential oil contained dimethy disulfide, dimethyl trisulfide, (methyl methylthio) methyl, 2,4-dithiapentane (11.35 percent) and (methylthio) acetic acid, 2- (methylthio) ethanol, 3-(methylthio) - and propanenitrile (7.20 percent). The fresh extract had higher radicals scavenging activity than the essential oil or dried extract, with 50 percentage inhibition of DPPH, hydrogen peroxide and lipid peroxidation at a concentration of 35.0 ± 0.12, 19.3 ± 0.11 and 17.9 ± 0.15 μg/ml respectively. Oral administration of methanolic extract of RTV in 125, 250 and 500 mg/kg to female Wistar rats significantly inhibited reduction of glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT). The extracts also inhibited (p< 0.05) lipid peroxidation in normal, high cholesterol and diet induced atherosclerosis fed rats in a dose dependant manner. Also the extract (250 and 500 mg/kg/bwt/day) caused a significant (p<0.05) improvement in body weight of treated animals compared with untreated hypercholesterolemia control rats. The extracts also protected significantly (p<0.05) against atherogenic diet induced liver damage or fatty streaks formation in the aorta as revealed by histological examination. The anti-cholesterolemia and anti-atherosclerotic activities of the extract compared favorably well with standard drugs Gemfibrozil and Atorvastatin respectively. Conclusively, rhizomes of T. violacea possess significant anti-atherogenic activity and its mechanism of action(s) may be due to its antioxidant and anti-hypercholesterolemia properties. The results of this study also suggested that rhizome of T. violacea is relatively safe for human consumption and it may be used as an alternative to garlic.

Familial hypercholesterolemia (FH) is an autosomal dominant disorder in which the primary defect is a mutation in the LDL receptor. Heterozygous FH is among the most common inborn errors of metabolism and remains as the best example of an inherited defect causing premature coronary artery disease (CAD). This thesis describes the physical and biochemical characteristics of heterozygous FH in a large cohort consisting of 208 women and 156 men. The influence of both genetic and environmental factors on the clinical expression of FH were investigated to better understand the phenotypic variation within FH and thus improve the prediction and treatment of CAD in affected individuals. The general incidence of CAD in this population was lower compared to previous reports but the differences between the sexes were expected. It was shown that men had a much higher frequency of CAD (31%) compared to women (13%) despite having lower concentrations of total and LDL cholesterol. In addition, the average age of onset of coronary symptoms was delayed in females, 55 years compared to 48 years for males. A greater risk of developing CAD for men was associated with low levels of HDL cholesterol and a history of smoking. In women, however, CAD was associated with elevated triglyceride levels and the presence of hypertension. In order to efficiently assess the influence of the co-inheritance of the apolipoprotein E polymorphism in this large FH population, a novel apo E phenotyping procedure was developed. Phenotypes were determined directly from plasma which was neuraminidase treated, delipidated and focused in polyacrylamide minigels. The accuracy of this method was confirmed by making a comparison to the established procedure of phenotyping by isoelectric focusing of delipidated VLDL. The low cost, speed and simplicity of the minigel methodology provided ideal conditions to phenotype a large patient population. The frequencies of the ɛ2, ɛ3 and ɛ4 alleles of apolipoprotein E in 125 unrelated FH subjects did not differ significantly from the normal population. In addition, there was no apparent relationship between apo E4 and the concentration of any of the parameters in the plasma lipid profile. However, the presence of the E2 isoform was associated with significantly elevated triglycerides in both sexes. From this study, it is evident that the mutant FH gene exerts its effect within a system of interacting environmental and polygenic factors that are known to modify atherosclerotic risk. It has been established that the dissimilarity in the frequency of CAD between men and women is related to differences between the impact of known risk factors and the incidence of CAD. Therefore, the importance of the influence of these risk factors and the differences between men and women should be emphasized when treating and predicting the development of CAD in patients with FH.
Medicine, Faculty of
Pathology and Laboratory Medicine, Department of
Graduate

The objective of this study was to compare the effect of phytosterols (PS) on lipid profiles and cholesterol kinetics of hypercholesterolemic individuals with or without type 2 diabetes. It was hypothesised that the response to PS would differ between both groups due to different lipid metabolism. During this randomised, double blind, crossover trial, participants consumed a controlled diet with placebo or PS for 21 days.
Plasma total cholesterol (TC) decreased with placebo and PS (10.9% and 9.7% in non-diabetic versus 11.6% and 13.6% in diabetic participants, p < 0.05). Plasma low-density lipoprotein cholesterol (LDL) significantly decreased with PS in both groups. The reduction in LDL with PS was greater in diabetic compared to non-diabetic individuals (29.8% versus 14.9%, p < 0.05). Cholesterol absorption decreased on average (p = 0.06) by 26.5% with PS compared with placebo in the diabetic group only. Therefore, a controlled heart healthy diet reduced TC and LDL concentrations in non-diabetic and diabetic individuals. Adding PS as adjuncts to a hypocholesterolemic dietary treatment was associated with lower LDL concentrations and cholesterol absorption in hypercholesterolemic participants with type 2 diabetes.

Statins are widely used to treat hypercholesterolemia. Statins inhibit cholesterol biosynthesis, thereby activating genes involved in cholesterol homeostasis, which are under the control of the Sterol Regulatory Element (SRE). Statins also have cholesterol-independent beneficial cardiovascular effects mediated through the phosphoinositide 3-kinase (PI3-K) / Akt signaling pathway and by inhibition of protein prenylation. Because statins inhibit the synthesis of isoprenoids, they can act by inhibiting the small signaling GTPases Ras and Rho, which require post-translational prenylation to become membrane-anchored and functional. We showed that simvastatin-mediated inhibition of protein prenylation does not appear to play a role in activation of SRE transcriptional activity in HepG2 cells. We also found that when isoprenoids were replenished, basal phospho-Akt decreased, suggesting that inhibition of prenylation by simvastatin mediates Akt phosphorylation. Future studies will be needed to investigate the role that inhibition of protein prenylation plays in the activation of the PI3-K/Akt pathway by simvastatin.
Department of Biology

Thesis (PhD) -- University of Stellenbosch, 2001.
ENGLISH ABSTRACT: The advent of the new millennium saw the complete sequencing of the entire human genome. Only approximately 30 000 genes, much less than was initially predicted, have been identified to be responsible for the genetic diversity in humans. This discovery has prompted a shift in the approach to disease research, since one gene can be involved in numerous diseases. This phenomenon seems to be especially true for the low-density lipoprotein receptor (LDLR) gene. Various substances beside sterols can induce transcription of the LDLR gene. Non-communicable diseases (e.g. hypertension) are common in the developing world and contribute significantly to mortality rates. The fmding that a promoter variant (-175 g~t) in the LDLR gene is associated with elevated diastolic blood pressure may explain the phenomenon of high LDL-cholesterollevels in hypertensive individuals. Studies have demonstrated that the lowering of cholesterol, especially LDL-cholesterol, can reduce the incidence of hypertension. The -175 g~t variant is located in a newly described cis-acting regulatory element which contains a putative binding site for Yin Yang (YY)-l and also demonstrates great homology to the cAMP response element (CRE) which bind the Ca2+- dependent transcription factor, CRE binding protein (CREB). The fact that Ca2+ can induce transcription of the LDLR gene may, at least in part, explain the association between the - 175g~t variant and elevated diastolic blood pressure. Cholesterol is important for various processes, such as apoptosis, maintenance of cellular membranes and immune function. The -59 c-ot mutation in repeat 2 of the LDLR gene abolishes binding of the sterol regulatory element binding protein(SREBP) to the SRE-l site. SREBP is proteolytically activated during apoptosis by two caspases (CPP32 and Mch3) to induce cholesterol levels. Our results imply that the -59C/T mutation, in repeat 2 of the LDLR gene promoter, may inhibit apoptosis under normal immunological conditions. Atherosclerosis can be considered an immunological disease, since various humoral and cellular immune processes can be detected throughout the course of the disease. The fmding that certain lipoproteins can protect against infection by binding and lysing of pathogens, or competing with pathogens for cellular receptors, prompted the investigation into the potential role of variation in the LDLR gene promoter in immune function. A significant difference in allelic distribution was detected between asymptomatic HIY -infected subjects and fast progressors for the -124 c-ot variant (P=O.006), shown to increase (~160%) transcriptional activity of the LDLR gene. Of relevance to this particular study is the fact that human herpesvirus (HHV) 6 can transactivate CD4 promoters through a partial CRE site. It has been shown that the CREB and YYl can regulate viral and cellular promoters, and these transcription factors can potentially bind to the LDLR promoter at the FP2 site. The mutation enrichment in the LDLR gene promoter seen in the South African Black and Coloured population groups can possibly provide insight into the pathogenesis of various diseases. This could also potentially, provide novel targets for treatment, since manipulation of cholesterol levels may affect the pathogenesis of various diseases.
AFRIKAANSE OPSOMMING: Die volledige DNA volgorde bepaling van die mensgenoom is voltooi vroeg in die nuwe millennium. Slegs ongeveer 30 000 gene is geidentifiseer, heelwat minder as wat in die verlede voorspel is, wat verantwoordelik is vir die genetiese diversiteit in die mens. Hierdie ontdekking het gelei tot 'n verandering in die benadering van navorsing ten opsigte van siektes, aangesien een geen 'n rol by verskeie siektes kan speel. Hierdie gewaarwording blyk veral waar te wees vir die lae digtheids lipoproteien reseptor (LDLR) geen. Verskeie stimuli, buiten sterole, kan transkripie van die LDLR geen inisieer. Verskeie siektes soos hipertensie is algemeen in die ontwikkelende wereld, en dra by tot die hoe mortaliteit syfers. Die bevinding dat 'n promoter variant in die LDLR geen (-175g-H) geassosieer is met verhoogde diastoliese bloeddruk, kan moontlik verhoogde lipiedvlakke in hipertensiewe individue verklaar. Studies het aangetoon dat die verlaging van cholesterol, veral LDL-cholesterol, die voorkorns van hipertensie kan verlaag. Die -175 g~t variant is gelee in 'n cis-regulerende element wat na bewering 'n bindingsetel vir die Yin Yang (YY)-l transkripsie faktor bevat asook sterk homologie met die cAMP respons element (CRE) toon, wat bind aan die Ca2 +_ afhanklike transkripie faktor, CRE bindings proteiene (CREB). Die feit dat Ca2+ transkripsie van die LDLR geen kan inisieer, kan dalk tot 'n mate, 'n verklaring bied vir die assosiasie tussen die -175 (g~t) variant en verhoogde diastoliese bloeddruk. Cholesterol is noodsaaklik vir verskeie prosesse soos apoptose, die instandhouding van selmembrane sowel as immuun funksies. Die -59 c-ot mutasie in die sterol regulerende element 1 (SRE-l) van die LDLR geen vernietig binding van die sterol regulerende element bindingsprotei'en (SREBP) aan SRE-l. SREBP word proteolities geaktiveer tydens apoptose deur twee kaspases (CPP32 en Mch3) om cholesterolvlakke te induseer. Ons resultate impliseer dat die -59C/T mutasie, in herhaling-2 van die LDLR-geen promoter, apoptose kan inhibeer onder normale immunologiese toestande. Aterosklerose kan beskou word as 'n immunologiese siekte, aangesien verskeie humorale en sellulere immuun prosesse deur die verloop van die siekte waargeneem kan word. Die feit dat Iipoproteiene beskermend kan wees teen infeksies, deur binding en lisering van virusse of kompeteer met patogene vir sellulere reseptore, het aanleiding gegee tot 'n ondersoek na die potensiele rol van variasies in die promoter area van die LDLR geen in immuun funksie. Betekenisvolle verskille in alleel verspreiding vir die -124c~t variant (P=0.006) is waargeneem tussen asimptomatiese MIV -geinfekteerde pasiente en individue met vinnige siekte progressie. In vitro studies het voorheen getoon dat die -124c~t 'n verhoging in LDLR geen transkripsie (160%) tot gevolg het. Dit is noemenswaardig dat 'n vroee studie getoon het dat die mens like herpesvirus-6 (MHV6) transaktivering van die CD4 promoters deur 'n gedeeltelike CRE bindingsetel kan bewerkstellig. Beide CREB en YYl kan virus en sellulere promotors reguleer, en hierdie transkripsie faktore toon bindingshomologie met die FP2 element van die LDLR promotor Die mutasie verryking van die LDLR geen promoter soos waargeneem in Suid Afrikaanse Swart en Kleurling populasies, kan moontlik lig werp op die patogenese van verskeie siektetoestande. Hierdie bevindinge kan potensieel nuwe teikens vir behandeling identifiseer, aangesien manipulasie van cholesterolvlakke 'n effek mag he op die patogenese van verskeie siektes.

Two studies were conducted to determine how HDL cholesteryl ester and apoprotein catabolism might contribute to the observed hypercholesterolemia of copper-deficient rats. Weanling male Sprague-Dawley rats were divided into two dietary treatments; copper-adequate (control, 5-7 mg Cu/kg diet) and copper-deficient (0.6-0.8 mg Cu/kg diet). Deionized water and diet were provided ad libitum. Dietary copper deficiency resulted in enlarged intravascular pools of HDL cholesteryl esters and total protein. HDL were isolated from rats of both treatment groups, radiolabeled, and injected into animals of the respective groups. In Study I, HDL apoproteins were labeled by iodination, whereas HDL in Study II were doubly labeled by additionally incorporating into the particle core [³H]cholesteryl linoleyl ether, which served as a nondegradable analog of HDL cholesteryl ester. At specific time intervals up to 12 hours after injection, blood and tissue samples were removed and analyzed for radioactivity. Plasma disappearance curves indicated that HDL cholesteryl esters were preferentially catabolized 1.6-fold faster than HDL protein in controls and 2.5-fold faster in copper-deficient animals. Clearance of individual apoproteins did not occur at significantly different rates in either treatment group. Absolute mass removal of HDL cholesteryl ester and total protein from the plasma was significantly increased in copper-deficient rats. Virtually all of the increased removal of HDL cholesteryl ester was attributed to the liver, whereas most of the increased uptake of HDL protein was attributed to the bulk tissues and not the liver. Since previous studies indicate that copper deficiency may not result in increased cholesterol excretion, these data suggest that cholesteryl esters delivered to the liver of copper-deficient rats are possibly reassembled into new HDL particles at an increased rate. The observed hypercholesterolemia in this animal model, then, appears to be the result of an imbalance in the net flux of cholesterol between the tissues and the plasma.

The current study examined the impact of plant sterols, stanols, sterol esters, and stanol esters on (i) cholesterol-lowering efficiency, (ii) gene expression of ABCG5 and ABCG8 sterol transporters in the liver and small intestine, and (iii) colon mucosal cell proliferation in hamsters. After 5 weeks on experimental diets, plasma total cholesterol levels were reduced ( P<0.05) by stanols, sterol esters and stanol esters compared to cholesterol-control diet. Different PS analogs did not alter ABCG5 and ABCG8 mRNA levels in small intestine and liver as compared to cholesterol control. In addition, colon mucosal cell proliferation was 21.4% lower (P<0.01) in group fed 0.7% stanol esters relative to cholesterol control. Results suggest that hypocholesterolemic effects of PS analogs are not associated with changes of liver and small intestine ABCG5 and ABCG8 sterol transporters. Data also indicated that plant stanol ester may possess anticarcinogenic properties.

Plant sterols (PS) are effective in reducing plasma lipid concentrations, however, few studies have examined their cholesterol lowering effects in type 2 diabetics. The objective was to assess whether PS consumption alters blood lipid profile in hypercholesterolemic subjects with and without type 2 diabetes. Fifteen control subjects (age = 55.1 +/- 8.5 yr and BMI = 26.9 +/- 3.0kg/m2) and fourteen diabetic subjects (age = 54.5 +/- 6.7 yr and BMI = 30.2 +/- 3.0kg/m2) participated in a double-blinded, randomized, crossover, placebo-controlled feeding trial. The Western diet included either 1.8g/d of PS or cornstarch placebo each provided over 21 d separated by a 28 d washout period. Subjects consumed only foods prepared in Mary Emily Clinical Nutrition Research Unit of McGill University. Total cholesterol (TC) decreased (p < 0.05) from baseline with PS for control and diabetic subjects by 9.7% and 13.6%, respectively. TC decreased (P < 0.05) from baseline with placebo for control and diabetic subjects by 10.9% and 11.6%, respectively. Non high density lipoprotein cholesterol (non-HDL-C) decreased (p < 0.05) from baseline with PS for diabetic subjects by 18.5%. Low density lipoprotein cholesterol (LDL-C) levels were reduced (p < 0.05) from baseline with PS for control and diabetic subjects by 14.9% and 29.8%, respectively. The reduction of LDL-C due to PS alone is greater with type 2 diabetics. There were no significant changes in HDL-C and TG across diets or treatments. It is thus concluded that PS consumption with diet enhances non-HDL-C and LDL-C reduction compared with diet alone in hypercholesterolemic individuals with and without type 2 diabetes. Demonstration for the first time that PS alone are more efficacious in lowering LDL-C and non-HDL-C in diabetic individuals compared to non-diabetics confirm the beneficial effects of PS to help prevent cardiovascular disease (CVD) for this high risk population.

The objective of this study was to examine the effects of plant sterols and/or glucomannan on lipid profiles and cholesterol kinetics in hyperlipidemic individuals with or without type 2 diabetes. It was hypothesized that plant sterols and glucomannan reduce circulating cholesterol levels and may have an additive or synergistic effect when combined by reducing cholesterol absorption. Thirteen type 2 diabetics and sixteen non-diabetics all mildly hypercholesterolemic free living subjects participated in a randomized crossover trial consisting of 4 phases, 21 days each. Subjects consumed plant sterols and glucomannan during the trial. Overall reductions in total and LDL-cholesterol levels were greater (P<0.05) after consumption of the combination supplement. Effects of supplements were not different between diabetics and non-diabetics. No significant changes were observed in cholesterol absorption or synthesis in both diabetics and non-diabetics. The intake of plant sterols and glucomannan together may be an alternative approach in reducing blood cholesterol levels.

Localised accumulation of body fat significantly influences the development of obesity related co-morbidities and cardiovascular disease (CVD) risk. Medium chain triglycerides (MCT) have been suggested to modulate body fat distribution. Phytosterols (PS) have demonstrated unequivocal cholesterol-lowering effects. A healthy dietary solution combining MCT and PS could thus become first-line obesity and CVD prevention. The aim of this study was therefore to investigate the effects of a functional oil (FctO) rich in MCT and PS on blood lipid levels and body adiposity, compared to olive oil. Twenty-three hypercholesterolemic, overweight men, were randomly assigned, in a single-blind crossover study, to consume a FctO, or olive oil, incorporated into a 40% fat diet for 6 wks. Blood lipid levels were measured and body composition was assessed. Total and LDL cholesterol were significantly reduced in subjects consuming the FctO versus the control oil. No significant differences for weight or adiposity loss of subjects were observed between the two oils. Results support the cardio-protective role of this FctO.

The objective of this research was to examine the effects of plant sterols and glucomannan on lipid profiles, plasma plant sterol levels and glycemic control in mildly hypercholesterolemic subjects. Thirteen type 2 diabetic and sixteen non-diabetic individuals participated in a randomized crossover trial consisting of 4 phases, of 21 days each. During the study period, subjects were supplemented with plant sterols and/or glucomannan. Overall reductions of total cholesterol and low-density lipoprotein (LDL) cholesterol concentrations were greater after consumption of plant sterols and glucomannan compared to plant sterol or glucomannan supplementation alone. Plasma lathosterol levels, indicators of cholesterol biosynthesis, were decreased after combination treatment. The results suggest that a combination of glucomannan and plant sterols substantially improve plasma lipids by reducing cholesterol absorption and synthesis simultaneously. Supplementation of plant sterols and glucomannan can thus be used as an effective treatment for management of circulating cholesterol levels and prevention of cardiovascular disease.

La enfermedad cardiovascular sigue siendo la principal causa de morbilidad y mortalidad en todo el mundo. La inmensa mayoría de los eventos cardiovasculares incluyendo los síndromes coronarios y accidente cerebrovascular son la causa por la rotura o erosión de las placas de ateroma en la pared arterial. La aterosclerosis es una enfermedad compleja dinámica caracterizada por la infiltración de lípidos en la pared arterial y una respuesta inflamación crónica por las células del sistema inmune innato, principalmente monocitos y macrófagos. Los altos niveles circulantes de lipoproteínas de baja densidad (LDL) son uno de los principales factores de riesgo cardiovasculares en sujetos con hipercolesterolemia familiar (FH), causada principalmente por mutaciones en LDLR afectando el metabolismo de los lípidos, que están en alto riesgo de eventos cardiovasculares prematuros. Actualmente está bien establecida la relevancia de la inflamación en el desarrollo de las placas ateroscleróticas, sin embargo, los efectos de la LDL sobre el fenotipo y la función de las células de la inmunidad innata, como monocitos y macrófagos, no son completamente entendidos. Además, la respuesta inflamatoria en los macrófagos de pacientes con HF (de SAFEHEART cohorte) y su asociación con la exposición de por vida a niveles altos de LDLc no se ha estudiado. En esta tesis, nosotros investigamos el efecto de los niveles aterogénicas LDL sobre los monocitos humanos y se demostró que la LDL facilita la diferenciación de los monocitos en macrófagos a través de un proceso que implica una expresión potenciada de moléculas de adhesión celular y la regulación disminuida de efectores de apoptosis que regulan la anoikis en el estadio temprano del macrófago. Esto sugiere un papel relevante de la LDL en la relación entre los lípidos, la inmunidad innata y la aterosclerosis. En pacientes FH, hemos demostrado que LRP5, receptor activo de internalización de lípidos, está incrementado en las células de la inmunidad innata que tiene una baja expresión del LDLR pero que conservan la función de internalización de LDL. La expresión reducida de CD163 en estos macrófagos FH también sugiere menos ateroprotección. También muestran que los macrófagos derivados de monocitos de pacientes con FH tratados de acuerdo a las guías tienen un fenotipo pro-inflamatorio sostenido, que se caracteriza por un aumento de la expresión de receptores de quimioquinas CCR3, CCR4, CXCR1 y una baja regulación de miR-505-3p, moléculas relacionadas con respuesta inflamatoria. El efecto es dependiente de la edad del paciente, lo que sugiere un patrón inflamatorio crónica en las células de la inmunidad innata que está relacionado con los cambios epigenéticas inducidos por la exposición de por vida a niveles altos de LDL.
Cardiovascular disease remains a leading cause of morbidity and mortality worldwide. The vast majority of cardiovascular events including coronary syndromes and stroke are cause by the rupture or erosion of atherosclerotic plaques in the arterial wall. Atherosclerosis is a complex dynamic disease characterized by lipid infiltration in arterial wall and a chronic inflammation response by cells of the innate immune system, mainly monocytes and macrophages. High levels of circulating low-density lipoproteins (LDL) are one of the major cardiovascular risk factors and subjects with Familial Hypercholesterolemia (FH), mainly caused by LDLR mutations affecting lipid metabolism, are at high risk of premature cardiovascular events. Currently it is well established the relevance of inflammation in the development of the atherosclerotic plaques, however, the effects of LDL on the phenotype and function of cells of the innate immunity, as monocyte and macrophage, are not fully understood. Further, the inflammatory response in macrophages of FH patients (from SAFEHEART Cohort) and its association with lifetime exposure to high LDLc levels has not been studied. In this thesis, we investigated the effect of atherogenic levels LDL on human monocyte and demonstrated that LDL facilitate monocyte differentiation into macrophage through a process that involves enhanced expression of cell-adhesion molecules and downregulation of apoptosis- effectors regulating anoikis in the early stage macrophages. This suggests a relevant role of LDL in the link between lipids, innate immunity and atherosclerosis. In patients FH, we demonstrated that LRP5, active lipid-internalizing receptor, is upregulated in innate immunity cells that have downregulated LDLR but retain the LDL internalization function. The reduced CD163 expression in these FH-macrophages also suggests less atheroprotection. We also show that monocyte-derived macrophages from FH patients treated according to guidelines have a sustained pro-inflammatory phenotype, characterized by an increased expression of chemokine receptors CCR3, CCR4, CXCR1 and a down-regulation of miR-505-3p, molecules related with inflammatory response. The effect is dependent on the age of the patient, suggesting a chronic inflammatory pattern in innate immunity cells that is related to epigenetic changes induced by lifetime exposure to high levels of LDL.

This study looked at how cholesterol levels of students, ages 11-15, who participated in the NSLP and the SBP would be affected compared with those students who only participated in the NSLP. Fasting blood samples (lOmL) were analyzed from 15 students who ate lunch only (L) and 15 students who ate both breakfast and lunch (BL) from the Driver Middle School food service at least 3 times a week. Blood was analyzed for changes in total cholesterol, HDL, LDL, and Triglycerides from baseline to 4 months. Results showed a significant decrease in total cholesterol and LDL, and a significant increase in triglycerides from baseline to 4 months in both the L group and the BL group. This may be attributable to hormone levels during sexual maturation in prepubescent and pubescent students.
Department of Family and Consumer Sciences

This thesis shows the research carried out on two specific diseases: familial hypercholesterolemia, which is included within the cardiovascular diseases group, and cancer. These diseases are the major cause of deaths in Spain and worldwide. The study of familial hypercholesterolemia is of great interest, as it is mainly caused by a protein called PCSK9 whose atypical functioning leads to an increase of LDL-C in blood. Thus, the study of new diseases results in the study of new therapeutic targets. Therefore, a thorough investigation on the PCSK9 protein has been conducted by means of molecular modelling analysis. Also, the synthesis of potentially PCSK9 inhibitors new compounds has been performed. The modelling studies have been based on the research of new binding sites and in de novo synthesis of new inhibitors. On the other side, the experimental synthesis of new compounds has been conducted by the preparation of pyrrolo[2,3-d]pyrimidines and finally, by the preparation of a series of compounds analogues of Combretastatin A4 through modification in the two aromatic rings and the fixation of its configuration with the introduction of a cycle. In the case of cancer, the study is based mainly on the research of a key protein in cell proliferation, growth and cell signalling. KRAS protein is either active or mutated in most common cancers, being the main cause of pancreas and colorectal cancer. Research on this target is of high chemical and biological relevance since no drugs have been found to act directly on said target. Molecular modelling studies are performed in order to find the binding site of a reference product whose inhibiting capacity over the protein is known. Furthermore, the synthesis of a series of symmetric pyrazoles with different structural modifications has also been carried out. Additionally, biological WST-8 / CCK8 assay have been performed on some of the synthetized compounds, specifically on two Combretastatin A4 analogues, in an endothelial cell line that allows studying both endothelial dysfunction and cardiovascular diseases. Research on the MAPK signalling pathway has been performed with pyrazoles structure derivatives.

Introduction: Cardiovascular disease affects a greater proportion of females than it does males, and is responsible for an estimated 52 percent of female deaths per annum, globally. Due to the loss of oestrogen associated with the menopause, post-menopausal females are at elevated risk for hypercholesterolaemia which is a primary risk factor for cardiovascular disease. It has not yet been conclusively established whether resistance training can be used to ameliorate hypercholesterolaemia. Aim: This randomized controlled trial investigated what effect 12 weeks of progressive resistance training would have on plasma lipoproteins in a sample of post-menopausal females. Methods: Caucasian women (n=30 intervention and n=18 control) between the ages of 55 and 65 years who were not taking hormone replacement therapy were recruited. Participants did not smoke, were sedentary, were not taking any form of cholesterol-lowering medication, had at least one cholesterol abnormality at baseline but were otherwise healthy and able to participate in a strength training programme. Following extensive medical pre-screening, information dissemination and voluntary consent, the sample was divided into two groups. The exercise sample undertook 12 weeks of resistance training on five days of the week. The control group received no intervention. Measurements were obtained at baseline and every four weeks thereafter and included measures of strength, biochemistry (oestradiol, testosterone, full blood lipid profile, glycated haemoglobin and sex hormone binding globulin), anthropometry, morphology and self-reports (dietary intake, energy expenditure and the profile of mood states questionnaire). Results: There was no change to low density lipoprotein cholesterol, high density lipoprotein cholesterol, triglyceride content or total cholesterol as a result of the intervention. Back, chest and leg strength increased significantly (p<0.01) (increases of 51 percent, 35 percent and 43 percent respectively from baseline); waist circumference dropped (p<0.01) by 5 percent overall and diastolic blood pressure decreased significantly (-9 percent, p<0.01) in the exercise cohort but no change was noted in the matched control. Dietary intake, energy expenditure and body mass remained unchanged in both samples. Morphology (sum of skinfolds, estimated body fat content and girth measures) did not change and nor did other biochemical measures (HbA1c and sex hormone binding globulin) or hormone levels (oestradiol and testosterone). Despite the lack of overall change, an important finding was noted in individual results where a clear indication of ‘responders’ and ‘non-responders’ emerged. Conclusion: Overall mean results suggest that 12 weeks resistance training undertaken five days of the week was ineffective in reducing hypercholesterolaemia in this sample. Despite there being no identifying characteristics determined in this sample, evidence of responders and non-responders to the intervention indicates that reliance on mean data may not be sufficient when analysing data from exercise interventions. Therefore, while progressive resistance training had a positive effect on strength, waist circumference and diastolic blood pressure, it did not positively influence the plasma lipoproteins in this cohort of post-menopausal women.
Maiden name: Kelly, Janet Erica

Atherosclerosis is an inflammatory process characterized by the accumulation of lipids and fibrous elements in large arteries. It is the main underlying pathological process leading to heart attack and stroke. Low-density-lipoprotein Receptor-related Protein 5 (LRP5) functions as a co-receptor with Frizzled for extracellular Wnt glycoproteins to trigger the canonical Wnt pathway. It regulates multiple cellular processes including cell differentiation, inflammation, carcinogenesis, fibrosis, and angiogenesis. We studied the role of LRP5 and the canonical Wnt signaling pathway in atherosclerosis progression. First we analyzed cultured human macrophages and demonstrated that the canonical Wnt pathway can be activated by extracellular lipids binding to LRP5 and that the motility of macrophages is severely impaired in LRP5-deficient inflammatory cells. We showed that high levels of LRP5 impaired monocyte to macrophage differentiation through ß-catenin sequestering at the plasma membrane. We then moved to an “in vivo” mice model where we found that hypercholesterolemic LRP5 knockout mice (LRP5-/-) have larger atherosclerotic lesions compared with their WT littermates indicating a protective role for LRP5 in atherosclerosis progression. Furthermore, in the absence of LRP5 there is an increase in the leukocyte-driven inflammatory response as the canonical Wnt signaling pathway cannot be activated. Thus, we conclude that LRP5 and the canonical Wnt signaling pathway are a defense mechanism against hyperlipidemia and inflammation during atherosclerotic lesion progression. In summary, this work describes the role of LRP5 and the canonical Wnt signaling pathway in different key cellular processes during atherosclerosis progression, including differentiation, cellular adhesion, migration and infiltration of inflammatory cells. We also demonstrate that the absence of LRP5 under hypercholesterolemic conditions impairs the inflammatory response. These results show an atheroprotective and pro-survival role for LRP5 and the canonical Wnt signaling pathway during atherosclerosis progression.
Las enfermedades cardiovasculares (CVD) son la primera causa de discapacidad y muerte prematura en el mundo. La aterosclerosis, caracterizada por la acumulación de lípidos y elementos fibrosos en las arterias, es el principal proceso patológico que da lugar a las CVD. En el desarrollo de esta patología participan la diferenciación, la proliferación y la migración celular, dando lugar a diferentes respuestas celulares y moleculares, que son características de una enfermedad inflamatoria. La vía de señalización por Wnt es un regulador de la proliferación, la supervivencia y la diferenciación celular y es una de las primeras repuestas celulares al daño. En esta tesis quisimos discernir si la vía canónica de señalización por Wnt tiene un papel anti- o pro-inflamatorio durante la progresión de la lesión aterosclerótica, así como la implicación de su activación mediante LRP5 en los estados iniciales de la aterosclerosis. Con este fin, analizamos la expresión de LRP5 en los tipos celulares implicados en la formación de la lesión aterosclerótica y su modulación por los lípidos extracelulares. Estudiamos la implicación del LRP5 en la diferenciación y proliferación de las células inflamatorias que participan en la formación de la lesión aterosclerótica y caracterizamos la función de LRP5 y la vía canónica de señalización por Wnt en un modelo de ratones hipercolesterolémicos deficientes para LRP5. Nuestros resultados demuestran que los lípidos extracelulares aumentan la expresión de LRP5 en cultivos de macrófagos humanos provocando la activación de la vía de de señalización por Wnt, mientras que el silenciamiento de LRP5 provoca una menor migración de los macrófagos. La sobreexpresión de LRP5 en monocitos induce una menor diferenciación a macrófagos, una disminución de la proliferación y un aumento de la apoptosis. En ratones hipercolesterolémicos deficientes para LRP5 la vía canónica de señalización por Wnt se encuentra bloqueada empeorando el perfil dislipémico de los ratones Lrp5-/- mediante el aumento de la infiltración de monocitos en la pared vascular y de la respuesta inflamatoria de los leucocitos. Además, demostramos que los efectos proaterogénicos ocasionados por el exceso de lípidos en el plasma están mediamos en parte por la modulación de la expresión de LRP5 en la aorta y que LRP5 y la vía canónica de señalización por Wnt ejercen un mecanismo de defensa contra de la hiperlipidemia y la progresión de las lesiones ateroscleróticas. Así, este trabajo describe la implicación de LRP5 en diferentes procesos celulares claves durante la formación de la lesión, como son la infiltración y diferenciación de las células monocíticas, la adhesión y migración celular y la captación de lípidos. Además, demostramos que la ausencia de este receptor durante la hipercolesterolemia ocasiona una deficiencia en la respuesta inflamatoria y en el metabolismo de las lipoproteínas a nivel sistémico. En conjunto, nuestros resultados demuestran la participación de LRP5 en el desarrollo de la lesión aterosclerótica y evidencian un papel ateroprotector y de supervivencia para LRP5 y la vía canónica de señalización por Wnt.

The aim of this research project was to assess and compare cardiovascular disease (CVD) risk in black males and females from an urban, working population in the Makana (Grahamstown) region of the Eastern Cape, South Africa. Two-hundred and ninety one individuals (males: n = 143, females: n = 148) with a mean age of 42.6 (±8.1) years were voluntarily recruited from the greater urban Makana (Grahamstown) area. Eight Cardiovascular disease (CVD) risks were assessed: stature and mass were obtained in order to calculate body mass index (BMI) (mass/stature2). Obesity, defined as a morphological risk, was classified according to the World Health Organisation (WHO) BMI criteria (BMI>30kg.m-2), as well as according to measures of waist circumference (WC) and body composition. Hypertension, hypercholesterolemia and type II diabetes, were grouped as cardiovascular (CV) risks. Hypertension was defined as a blood pressure greater than 140/90mmHg (JNC-7); hypercholesterolemia, as total cholesterol greater than 6.2mmol.L-1 (NCEP); and type II diabetes, as total glucose greater than 12mmol.L-1 (WHO). Physical activity, diet, tobacco use, and alcohol consumption and dependence were grouped as lifestyle-related risks. These were assessed by means of self-reporting through the use of various validated questionnaires. Finally, self-reporting of obesity, hypertension, hypercholesterolemia and type II diabetes was assessed, in addition to perception questions on individuals’ perceived body shape and size (Ziebland figures). Self-reported and perceived responses were then compared to actual measures. Females were significantly (p<0.001) heavier than the males (92.7kg compared to 72.1kg) and had significantly (p<0.001) higher BMIs than their male counterparts (37.6kg.m-2 compared to 25.7 kg.-2). They also recorded significantly (p<0.001) higher waist circumference (WC) values and had significantly (p<0.001) higher percentage and total body fat. Significantly (p<0.001) more females were obese (81%) compared to males (17%). While a higher percentage of males (25 % compared to 22%) presented with stage I hypertension (≥140/90mmHg, <160/95mmHg), significantly (p<0.05) more females (14% compared to 8%) presented with stage II hypertension (>160/95mmHg). The prevalence of hypercholesterolemia at a high level of risk (>6.2mmol.L-1) was relatively low (2.1 % of males, 3.4% of females), but notably more participants (22% of males and 26% of females) presented with the condition at a moderate level of risk (>5mmol.L-1). Type II diabetes was the least prevalent CV risk factor, with no males and only 3% of females presenting with the condition. Males consumed significantly (p<0.05) more in terms of total energy intake (9024 vs. 7234 kJ) and were significantly (p<0.05) more active (3315 compared to 2660 MET-mins.week). A significantly (p<0.05) higher percentage of males smoked (51.1% compared to 3.4%), consumed alcohol (73.4% compared to 46.6%) and were alcohol dependent (40% compared to 33.5%). Both males and females tended to be ignorant of their health status, with both samples under-reporting obesity, hypertension and hypercholesterolemia, while over-reporting type II diabetes. Furthermore, obesity was significantly (p<0.05) underestimated, with both male and female individuals perceiving themselves to be notably smaller than they actually were. Physical activity and diet were important determinants of CVD risk in this black urban sample of individuals. Obesity, in particular central adiposity, was the most notable risk (particularly in females), followed by hypertension (particularly in males). Although some risks presented at a moderate level of risk, a clustering of risk factors was evident in both samples, with 12.6% and 41.2% of males and females presenting with two risk factors, and 2.8% and 8.1% of males and females respectively presenting with three risks.

碩士
靜宜大學
食品營養研究所
97
Several researchs pointed out that the cactus fruit (Opuntia dillenii fruit), which contained abundant antioxidants, might lessen the imbalance of oxidative status and complication of chronic disease. The purpose of this study was to examine the effect of Opuntia dillenii fruit (ODF) in hypercholesteremia rats. Four-week-old male Wistar rats were randomly assigned into four experimental groups, inclouding normal control, normal diet with ODF (100mg/Kg BW), high cholesterol diet (2% cholesterol+15% soy oil), high cholesterol diet with ODF (2% cholesterol+15% soy oil +100mg/Kg BW). After 12 weeks feeding, food intake, body weight, plasma biochemical parameters, malondiadehyde (MDA), superoxide dismutase (SOD) and catalase (CAT) were measured. Liver histopathological examination were performed after sacrificed, and the Interleukin-6 (IL-6) and tumor necrosis factor α (TNF α) mRNA espressions of liver were also evaluated. The results showed that the supplementation of ODF could significantly reduce the plasma concentrations of total cholesterol, low density lipoprotein cholesterol, triglyceride, GOT and MDA and increase the activity of CAT in hyperlipidemia rats (p＜0.05) , whereas the SOD activity did not be affected. The liver of the hypercholesteremia rats presented serious fatty liver, inflammation and swellen status. ODF supplementation significantly decreased the TNF-α but not IL-6 mRNA espressions of liver. In summary, our results showed that the supplementation of ODF could improve the dyslipidemia status of rats, promote the antioxidative defense system, and decreased the mRNA espressions of proinflammatory cytokines of liver.

碩士
中國醫藥大學
醫學研究所
92
Hypercholesterolemia is an important pathogenic factor in atherogenesis. In hypercholesterolemia, nitric oxide (NO) production was enhanced. Over production of NO was found to attenuate baroreflex function. This is consistent with the findings that baroreflex sensitivity (BRS) was depressed in hypercholesterolemia. The Chinese herb, Magnolia officinalis, was shown to improve hypercholesterolemia. However, whether the Magnolia officinalis could also improve BRS is not known. In some pathophysiological states, such as in hemorrhage, BRS was also depressed and could be attributed to NO. Whether the BRS depression in hypercholesterolemia in hemorrhage is also related to NO or whether it could be ameliorated by Magnolia officinalis remains unknown. The present study, therefore, was undertaken to investigate the following hypotheses: 1. the BRS in hypercholesterolemia may be attenuated in severe hemorrhage, 2. the attenuation of BRS may be mediated by NO, 3. besides improvement of hypercholesterolemia, Magnolia officinalis could also improve BRS in normal state as well as in severe hemorrhagic state, and 4. the action of Magnolia officinalis on BRS in hypercholesterolemia may be mediated by NO. Male New Zealand white rabbits were divided into 3 groups: 1. Control group (normal diet), 2. Cholesterol group (0.5% w/w cholesterol diet), or 3. Magnolia group (same as Cholesterol group but plus 1% w/w magnolia officiralis crude methanol extract). The animals were continuously treated under the designated diet for 4 or 8 weeks. BRS in the control of heart rate was determined by linear regression method. Hemorrhage was induced by bleeding from the arterial catheter, until a paradoxical decrease of heart rate from peak tachycardia and a drop of mean arterial blood pressure below 70 mmHg were both observed. The results demonstrated that arterial blood pressure (BP), heart rate (HR), and BRS were not different among groups after 4 weeks of diet treatment. However, after 8 weeks of treatment, plasma total cholesterol was significantly elevated in the Cholesterol and Magnolia groups. The BP was also increased in the Cholesterol and Magnolia groups. The BRS of the Cholesterol and Magnolia groups was both significantly depressed. However, the BRS of the Magnolia group was significantly greater than that of the Cholesterol group. After L-NAME (Nω-nitro-Larginine methyl ester, 20mg/kg, iv.), the BRS of the Cholesterol group was significantly improved. In response to hemorrhage, BRS was depressed in all 3 groups. But BRS was improved by L-NAME treatment in all 3 groups. In hemorrhage, the BRS of the Magnolia group was greater than that of the Cholesterol. The data suggested that BRS was depressed in hypercholesterolemia, and it can be related to NO. Hemorrhage also caused decrease in BRS in hypercholesterolemia, and it may also be attributed to the NO. Magnolia apparently improved the BRS of the hypercholesterolemia group, but it is likely that it is not related to NO.

M.Tech.
It is estimated that 4.5 million South Africans have hypercholesterolaemia. Atherosclerosis and stroke-related conditions have been identified by the South African Department of Health as priority diseases (South African Department of Health, 1998). Hypercholesterolaemia was estimated to have caused 4.6% of all deaths in South Africa in 2000 and is therefore an important cardiovascular risk factor in all population groups in South Africa (Norman et al, 2007). Panax ginseng is the botanical name for the plant commonly known as Korean ginseng. It is part of the Araliaceae botanical family. Korean ginseng has pharmacological actions including lowering serum cholesterol, improved functioning of the pituitary adrenal axis, enhanced protein synthesis and protection of the liver from hepatotoxins (Murray and Pizzorno, 2000a). The aim of the research was to evaluate the effect of Panax ginseng 1X on the total plasma cholesterol level of adult males between the ages of eighteen and fifty years. A sample group of thirty participants was recruited. Interested participants attended an initial interview where they were screened using a questionnaire and physical examinations and were instructed to have a blood test done to determine whether they qualified to take part in the study. Inclusion criteria comprised: adult males between the ages of eighteen and fifty years, total plasma cholesterol level between 4.0 and 6.19 mmol/l and not more than one major cardiovascular risk factor as classified by the U.S Department of Health and Human Services (U.S Department of Health and Human Services, 2001). Participation in the study was voluntary and participants were free to refuse treatment or withdraw from the study at any time. Since standardised Panax ginseng in normal therapeutic doses is rarely associated with side-effects, the anticipated risk for participants in the study was minimal (Murray and Pizzorno, 2000a). The total plasma cholesterol levels were measured by Lancet Laboratories. Body weight was measured and a clinical cardiovascular examination was performed by the researcher. Reliability and validity of clinical investigations was ensured by adherence to procedural documentation. The study was performed in a randomised, double-blind, placebo controlled manner. Participants were divided into two groups of fifteen. For the first four weeks of the trial no treatment was given to either group. After the first four weeks the participants attended a follow-up visit and the total plasma cholesterol level of each participant was retested. The experimental group then received Panax ginseng 1X and the control group received a placebo. Sufficient treatment for a period of eight weeks was issued to both groups. Participants were instructed to take 1.5 ml three times daily in 100 ml of water fifteen minutes before meals and were informed not to make any substantial changes to their lifestyle that could affect plasma cholesterol levels. Such lifestyle changes included alterations of diet, amount of exercise, alcohol or tobacco consumption, sleep pattern and stress levels. Patients attended a follow-up visit after taking the treatment for four weeks and the total plasma cholesterol levels were determined again at the end of the study. Collected data was analysed using descriptive statistics (frequencies and percentages). The total plasma cholesterol level of the experimental group was compared to the total plasma cholesterol level of the placebo group as obtained at the initial consultation, after four weeks and at the conclusion of the study. Groups were compared using independent samples t-tests within each sample group. Differences over time were analysed using dependent samples t-tests and repeated measures ANOVA. Panax ginseng 1X did not provide a statistically significant change in the total plasma cholesterol levels. The use of Panax ginseng is rarely associated with side-effects and in this particular study none were experienced by the participants.

碩士
中國醫藥學院
醫學研究所
91
Atherosclerosis is a chronic inflammatory disease. New Zealand White (NZW) rabbits were assigned randomly into six and eleven treated groups. The normal group was fed regular rabbit chow and the cholesterol group was fed a chow containing 0.5% cholesterol. 8-hydroxy-deoxyguanosine (8-OH-dG) is a main index of oxidatively damage DNA. We extracted DNA in the liver tissues and blood vessel of NZW rabbits. Sample analysis was performed using high-performance liquid chromatography /electrochemical detector (HPLC-ECD). These data revealed that 8-OHdG increased significantly in liver and blood vessels of high cholesterol-fed rabbits than other treated groups. The levels of 8-OHdG between the cholesterol group and the normal group was highest for 17 folds. Treatment with various Chinese herb essences significantly decrease the levels of 8-OHdG, as compared to the cholesterol group. These results suggest that the antioxidant and antiatherogenic effects of Chinese herb essences can be useful in the prevention of atherogenesis. We also investigated the expression of proteins in DNA repair system. This may provide a possible tool to modulate the mechanism against DNA damage in human.

M.Tech. (Homoeopathy)
South Africa is a diverse and multi-cultured country where coronary vascular disease has become a leading cause of mortality among all sub-cultures. According to the South African Dyslipidaemia Guidelines Consensus Statement published in 2012 it is estimated that every day 80 people die of myocardial infarcts and 60 people die of strokes. Hypercholesterolaemia is associated with the accumulation of atherosclerotic plaques which lead to the condensing and restriction of vessel walls. This in turn leads to an increased risk of developing cardiovascular disease which can present itself in the form of hypertension and coronary heart disease (Knox, 2008). This product Vasostate™ proposes to lower total serum cholesterol levels in a variety of ways ranging from aiding and increasing the transport of cholesterol to the liver while decreasing the amount of cholesterol synthesised by the liver to reducing cholesterol uptake from the intestines (Foodstate, n.d.). The aim of this study was to determine the efficacy of Vasostate™ on modifying elevated lipid and CRP levels in males with fasting total serum cholesterol levels greater than 4.5mmol/l utilising blood measures including Lipogram and ultra-sensitive CRP within a 12 week period. This was a double-blind placebo controlled study conducted over a 13 week period utilising 40 male participants 30 to 55 years of age. Participants qualified for participation in the study with two rapid total plasma cholesterol test results averaging between 4.5-6.5mmol/l and no more than two Category 2 cardiovascular risk factors or a plasma cholesterol greater than 6.5mmol/l with no more than one Category 2 cardiovascular risk factors in individuals who are unwilling or unable to take conventional dyslipidaemia medicine. Participants were divided into 2 groups of 20 each. The control group was given the placebo (an identical form to the active in appearance), while the experimental group received Vasostate™. In order to ensure uniform distribution of participants across both groups stratification of participants between each group took place according to race and cigarette smoking. To guarantee the double blinded aspect of the study the researcher was not informed which group was the active or the placebo until the statistical results were released...

Lee Chung-hung.
Thesis (M.Phil.)--Chinese University of Hong Kong, 2003.
Includes bibliographical references (leaves 113-133).
Abstracts in English and Chinese.
Chapter Chapter 1 --- General Introduction
Chapter 1.1 --- History of soybean --- p.1
Chapter 1.2 --- Health benefits of soybean --- p.2
Chapter 1.3 --- Introduction to flavonoids --- p.3
Chapter 1.4 --- Bioavailability of flavonoids --- p.5
Chapter 1.5 --- Chemistry of isoflavones --- p.6
Chapter 1.6 --- Estrogenic property of isoflavones --- p.8
Chapter 1.7 --- Nutritional significance of isoflavones and their glycosides --- p.8
Chapter 1.7.1 --- Anticarcinogenic activity --- p.9
Chapter 1.7.2 --- Antioxidative activity --- p.10
Chapter 1.7.3 --- Cardioprotective activity --- p.13
Chapter 1.7.4 --- Osteoprotective activity --- p.14
Chapter 1.7.5 --- Neuroprotective activity --- p.15
Chapter 1.7.6 --- Antiangiogenic activity --- p.16
Chapter Chapter 2 --- Composition of Soybean Isoflavones
Chapter 2.1 --- Introduction --- p.17
Chapter 2.2 --- Objective --- p.19
Chapter 2.3 --- Materials and Methods --- p.20
Chapter 2.3.1 --- Extraction and isolation --- p.20
Chapter 2.3.1.1 --- Preparation of soybean butanol extract --- p.20
Chapter 2.3.1.2 --- Preparation of isoflavones and their glycosides from soybean butanol extract --- p.20
Chapter 2.3.2 --- HPLC analysis --- p.21
Chapter 2.3.2.1 --- Sample preparation for the HPLC analysis --- p.21
Chapter 2.3.2.2 --- HPLC analysis --- p.22
Chapter 2.3.2.3 --- Quantification of the flavonoids and their glycosides --- p.24
Chapter 2.4 --- Results --- p.25
Chapter 2.4.1 --- Structural identification --- p.25
Chapter 2.4.1.1 --- Compound 1 --- p.25
Chapter 2.4.1.2 --- Compound 2 --- p.26
Chapter 2.4.1.3 --- Compound 3 --- p.26
Chapter 2.4.1.4 --- Compound 4 --- p.27
Chapter 2.4.1.5 --- Compound 5 --- p.27
Chapter 2.4.1.6 --- Compound 6 --- p.28
Chapter 2.4.1.7 --- Compound 7 --- p.28
Chapter 2.4.1.8 --- Compound 8 --- p.29
Chapter 2.4.2 --- Quantification of isoflavones in traditional Chinese foods --- p.29
Chapter 2.5 --- Discussion --- p.32
Chapter Chapter 3 --- Hypocholesterolemic Effects of Soymilkin Hamsters
Chapter 3.1 --- Introduction --- p.35
Chapter 3.1.1 --- Lipoproteins and their functions --- p.35
Chapter 3.1.2 --- Risk factors of cardiovascular disease --- p.36
Chapter 3.1.3 --- Hamster as an animal model of cholesterol metabolism --- p.38
Chapter 3.2 --- Objective --- p.39
Chapter 3.3 --- Materials and Methods --- p.40
Chapter 3.3.1 --- Preparation of soymilk --- p.40
Chapter 3.3.2 --- Animals --- p.40
Chapter 3.3.2.1 --- Experiment one - Hypocholesterolemic effect of soymilk in hamsters --- p.40
Chapter 3.3.2.1 --- Experiment two 一 The effect of fluid cross-over between soymilk and cow´ة s milk on serum cholesterol in hamsters --- p.41
Chapter 3.3.3 --- Serum lipid and lipoprotein determinations --- p.42
Chapter 3.3.4 --- Determination of cholesterol in organs --- p.42
Chapter 3.3.5 --- Statistics --- p.43
Chapter 3.4 --- Results --- p.46
Chapter 3.4.1 --- Experiment one-Hypocholesterolemic effect of soymilk in hamsters --- p.46
Chapter 3.4.1.1 --- Growth and food intake --- p.46
Chapter 3.4.1.2 --- "Effect of SM and CM on TG, TC and HDL-C" --- p.46
Chapter 3.4.1.3 --- Effect of SM and CM on non-HDL-C and ratio of non-HDL-C to HDL-C --- p.46
Chapter 3.4.1.4 --- Effect of SM and CM on concentration of hepatic cholesterol --- p.47
Chapter 3.4.1.5 --- "Effect of SM and CM on brain, heart and kidney cholesterol" --- p.47
Chapter 3.4.2 --- Experiment two - The effect of fluid cross-over between soymilk and cow´ةs milk on serum cholesterol in hamsters --- p.52
Chapter 3.4.2.1 --- Growth and food intake --- p.52
Chapter 3.4.2.2 --- Effect of fluid cross-over on serum TC --- p.52
Chapter 3.5 --- Discussion --- p.55
Chapter Chapter 4 --- Antioxidant Activities of Soybean Isoflavones and Their Glycosides
Chapter 4.1 --- Introduction --- p.58
Chapter 4.1.1 --- Role of low density lipoprotein oxidation in the development of atherosclerosis --- p.59
Chapter 4.1.2 --- LDL oxidation --- p.61
Chapter 4.1.3 --- Thiobarbituric acid reactive substances (TBARS) as an index of LDL oxidation --- p.62
Chapter 4.1.4 --- "The ferric reducing ability of plasma (FRAP) as a measure of “antioxidant power""" --- p.65
Chapter 4.1.5 --- "1,1-diphenyl-2-picrylhydrazyl (DPPH) as a measure of free radical scavenging capacity" --- p.65
Chapter 4.1.6 --- Antioxidant and LDL oxidation --- p.65
Chapter 4.2 --- Objective --- p.67
Chapter 4.3 --- Materials and Methods --- p.68
Chapter 4.3.1 --- Preparation of samples --- p.68
Chapter 4.3.2 --- Isolation of LDL from human serum --- p.68
Chapter 4.3.3 --- LDL oxidation --- p.69
Chapter 4.3.4 --- TBARS assay --- p.69
Chapter 4.3.5 --- FRAP assay --- p.70
Chapter 4.3.6 --- DPPH assay --- p.71
Chapter 4.3.7 --- Statistics --- p.72
Chapter 4.4 --- Results --- p.73
Chapter 4.4.1 --- Effects of seven individual soybean isoflavones and their glycosides on LDL oxidation --- p.73
Chapter 4.4.2 --- The antioxidant power of individual soybean isoflavones and their glycosides in the FRAP assay --- p.73
Chapter 4.4.3 --- Activity of individual soybean isoflavones and their glycosides as radical scavenging antioxidants --- p.74
Chapter 4.5 --- Discussion --- p.78
Chapter Chapter 5 --- Hypocholesterolemic Effects of Soybean Isoflavones in Ovariectomized Golden Syrian Hamsters
Chapter 5.1 --- Introduction --- p.83
Chapter 5.1.1 --- Coronary heart disease in women --- p.83
Chapter 5.1.2 --- Menopause as a risk factor in CHD --- p.84
Chapter 5.1.3 --- Dietary soy in treating postmenopausal hypercholesterolemia --- p.85
Chapter 5.2 --- Objective --- p.87
Chapter 5.3 --- Materials and Methods --- p.88
Chapter 5.3.1 --- Preparation of soymilk --- p.88
Chapter 5.3.2 --- Preparation of soybean extract --- p.88
Chapter 5.3.3 --- Animals --- p.89
Chapter 5.3.4 --- Serum lipid determinations --- p.90
Chapter 5.3.5 --- Determination of tissue cholesterol content --- p.90
Chapter 5.3.6 --- Extraction of neutral and acidic sterols from fecal samples --- p.90
Chapter 5.3.6.1 --- Determination of neutral sterols --- p.91
Chapter 5.3.6.2 --- Determination of acidic sterols --- p.92
Chapter 5.3.6.3 --- GLC analysis of neutral and acidic sterols --- p.92
Chapter 5.3.7 --- Statistics --- p.93
Chapter 5.4 --- Results --- p.96
Chapter 5.4.1 --- Growth and food intake --- p.96
Chapter 5.4.2 --- Effect of ovariectomy on serum TC --- p.96
Chapter 5.4.3 --- "Effect of soymilk and soybean extract on serum TC,TG and HDL-C" --- p.96
Chapter 5.4.4 --- Effect of soymilk and soybean extract on non-HDL-C and ratio of non- HDL-C to HDL-C --- p.97
Chapter 5.4.5 --- Effect of soymilk and soybean extract on concentration of hepatic cholesterol --- p.97
Chapter 5.4.6 --- Effect of soymilk and soybean extract on heart and kidney cholesterol --- p.97
Chapter 5.4.7 --- Effect of soymilk and soybean extract on fecal neutral and acidic sterols --- p.103
Chapter 5.5 --- Discussion --- p.106
Chapter Chapter 6 --- Conclusion --- p.110
References --- p.113

Guan, Lei.
Thesis (M.Phil.)--Chinese University of Hong Kong, 2005.
Includes bibliographical references (leaves 123-145).
Abstracts in English and Chinese.
ACKNOWLEDGEMENT --- p.I
ABSTRACT --- p.II
LIST OF ABBREVIATIONS --- p.VII
TABLE OF CONTENT --- p.IIX
Chapter Chapter 1 --- General Introduction --- p.1
Chapter 1.1 --- Introduction --- p.1
Chapter 1.2 --- Distribution and Origins --- p.1
Chapter 1.3 --- History of Use --- p.2
Chapter 1.4 --- Chemical Structure --- p.3
Chapter 1.5 --- Physiologic Properties --- p.5
Chapter 1.6 --- Absorption and Metabolism --- p.7
Chapter 1.6.1 --- Concentration of Isoflavones in Plasma --- p.10
Chapter 1.6.2 --- Urinary Excretion --- p.10
Chapter 1.7 --- Healthy Effects --- p.11
Chapter 1.7.1 --- Menopausal Symptom --- p.11
Chapter 1.7.2 --- Cardiovascular Disease --- p.12
Chapter 1.7.3 --- Osteoporosis --- p.13
Chapter 1.7.4 --- Tumors --- p.14
Chapter 1.7.4.1 --- Breast Cancer --- p.14
Chapter 1.7.4.2 --- Prostate Cancer --- p.15
Chapter 1.7.5 --- Alcohol Addiction --- p.16
Chapter 1.7.6 --- Potential Adverse Effects --- p.16
Chapter 1.8 --- Summary --- p.17
Chapter Chapter 2 --- Determination of Isoflavones in Soybean and Gegen --- p.19
Chapter 2.1 --- Introduction --- p.19
Chapter 2.1.1 --- Classification and Structure of Phytoestrogens --- p.19
Chapter 2.1.2 --- Isoflavones in Soybeans and Gegen --- p.21
Chapter 2.1.3 --- Methods of Determination --- p.26
Chapter 2.1.3.1 --- Isolation and Purification of Isoflavones --- p.26
Chapter 2.1.3.2 --- Analytical Methods for Isoflavones in Soybeans and Gegen --- p.26
Chapter 2.2 --- Objective --- p.28
Chapter 2.3 --- Materials and Methods --- p.29
Chapter 2.3.1 --- Extraction and Isolation of Soybean and Gegen Isoflavone Extracts --- p.29
Chapter 2.3.2 --- HPLC Analysis --- p.29
Chapter 2.3.2.1 --- Sample Preparation for the HPLC Analysis --- p.29
Chapter 2.3.2.2 --- HPLC Analysis --- p.30
Chapter 2.3.3.3 --- Qualitative Analysis of the Isoflavones and Their Glycosides in Soybean and Gegen --- p.30
Chapter 2.4 --- Results --- p.31
Chapter 2.4.1 --- Isoflavone Identification of Soybean Extract --- p.31
Chapter 2.4.2 --- Isoflavone Identification of Gegen Extract --- p.33
Chapter 2.5 --- Discussion --- p.35
Chapter Chapter 3 --- Hypocholesterolemic Effects of Soybean and Gegen Isoflavone Extracts in Ovariectomized，Intact Male and Castrated Golden Syrian Hamsters --- p.38
Chapter 3.1 --- Introduction --- p.38
Chapter 3.2 --- Objective --- p.41
Chapter 3.3 --- Materials and Methods --- p.42
Chapter 3.3.1 --- Preparation of Soybean and Gegen Isoflavone Extracts --- p.42
Chapter 3.3.2 --- Animals and Diets --- p.42
Chapter 3.3.3 --- Serum Lipid and Lipoprotein Determinations --- p.45
Chapter 3.3.4 --- Determination of Cholesterol Concentration in the Organs --- p.45
Chapter 3.3.5 --- Statistics --- p.46
Chapter 3.4 --- Results --- p.48
Chapter 3.4.1 --- Food Intake and Body and Relative Organ Weights --- p.48
Chapter 3.4.2 --- Effects of Soybean and Gegen Isoflavone Extracts on Serum and Organ Cholesterol in Ovariectomized and Intact Male and Castrated Hamsters --- p.56
Chapter 3.5 --- Discussion --- p.61
Chapter Chapter 4 --- Possible Developmental and Reproductive Toxicity of Soybean Isoflavones on SD Rats --- p.67
Chapter 4.1 --- Introduction --- p.67
Chapter 4.2 --- Objective --- p.70
Chapter 4.3 --- Materials and Methods --- p.71
Chapter 4.3.1 --- Diet --- p.71
Chapter 4.3.2 --- Animals --- p.73
Chapter 4.3.3 --- Study Design --- p.73
Chapter 4.3.4 --- Measurement of Reproductive Hormones --- p.74
Chapter 4.3.5 --- Measurement of Sperm Number --- p.74
Chapter 4.3.6 --- Statistics --- p.75
Chapter 4.4 --- Results --- p.77
Chapter 4.4.1. --- Food Intake and Food Efficiency Ratio --- p.77
Chapter 4.4.2 --- Growth Trend --- p.79
Chapter 4.4.3 --- Organ Weight --- p.82
Chapter 4.4.3.1 --- Absolute Organ Weight --- p.82
Chapter 4.4.3.2 --- Relative Organ Weight --- p.84
Chapter 4.4.4 --- Reproductive Hormone Levels --- p.86
Chapter 4.4.5 --- Epididymis Parameters of Male Rats --- p.88
Chapter 4.5 --- Discussion --- p.90
Chapter Chapter 5 --- Possible Developmental and Reproductive Toxicity of Gegen Isoflavones on SD Rats --- p.97
Chapter 5.1 --- Introduction --- p.97
Chapter 5.2 --- Objective --- p.99
Chapter 5.3 --- Materials and Methods --- p.100
Chapter 5.3.1 --- Animals and Diets --- p.100
Chapter 5.3.2 --- Study Design --- p.100
Chapter 5.3.3 --- Statistics --- p.101
Chapter 5.4 --- Results --- p.103
Chapter 5.4.1 --- Food Consumption and Food Efficiency Ratio --- p.103
Chapter 5.4.2 --- Growth Trend --- p.105
Chapter 5.4.3 --- Organ Weights --- p.108
Chapter 5.4.3.1 --- Absolute Organ Weights --- p.108
Chapter 5.4.3.2 --- Relative Organ Weight --- p.110
Chapter 5.4.4 --- Reproductive Hormone Levels --- p.112
Chapter 5.4.5 --- Epididymis Parameters of Male Rats --- p.114
Chapter 5.5 --- Discussion --- p.116
Chapter Chapter 6 --- Conclusions --- p.121
References --- p.123

目的：針對心血管初級預防，世界各國均推薦某一年齡段人群全部測量膽固醇以估算心血管病發病風險。此舉耗費高且非必須，本研究旨在建立並驗證一個新型的选择性膽固醇篩查模型，用以篩查需藥物治療之高危人群，并在成本效益方面與其它篩查模型相比較。
方法：本模型具體采用兩步法：首先利用一個足夠高的假設膽固醇值代入心血管病風險預測方程，用以系統性的高估絶大多數人的心血管病風險；其次只有假設心血管病風險高於推薦治療閾值時，該個體才需要測量膽固醇，並進行實際心血管病風險分析。
英国健康调查和中国营养与健康调查是本次研究的合适数据。我們首先探索最優的假設膽固醇值，尋找到最後膽固醇值之後，我們將繼續測試我們的新型膽固醇篩查模型，在不同的治療閾值下，表現是否穩定。我們以靈敏度，特異度和徐篩查人群為指標，比較我們模型與全民篩查模型和英國NICE 選擇篩查模型相比較。之後我們估算在中英人群中應用該篩查模型，所需耗費的成本和可預防心血管事件數。
结果：與全名篩查模型相比，我們的模型靈敏度相若但可以節省80%左右的篩查費用。模型的靈敏度主要取決於所採用的假設膽固醇值，與所用風險預測方程，治療閾值和人群心血管風險分佈無關。當以均數加2 倍標準差作為假設膽固醇值時，靈敏度可達到97.5%左右，特異度可以達到90%左右，符合預期。模型應用於中國人群得到的結果類似。值得註意的是，在中國人群中，即使不測量膽固醇，模型靈敏度亦接近95%。此外，將膽固醇篩查項目限制于男性50-84歲，女性60-84 歲年齡段可以進一步減少篩檢費用。在人群影響方面，我們模型可預防心血管事件數比全名篩查模型略少，但成本大大降低。英國NICE 模型適用於某些特定情況，但並非全部。
結論：我們的新型篩查模型靈敏度與全民篩查模型相若，但可以節省大量篩查費用。在资源匮乏地区，可考虑在某一特定年龄段运用我们的模型已达到进一步减少费用的效果。如果本研究结果得到进一步数据证实，對於中國人群而言，膽固醇測量可能並非心血管風險評估所必須。
Objectives
Since the mid 1990s, most guidelines on primary prevention of cardiovascular disease (CVD) have recommended regular cholesterol measurement for all adults or those above a certain age (which is known as mass screening). Cholesterol measurement comprises a large cost of CVD prevention and is not necessarily required in those who do not need drug intervention. In order to reduce this cost, we have developed a new selective cholesterol screening model in order to determine whose cholesterol should be measured for drug prevention. The model was evaluated and compared with other widely adopted models in basic model performance as well as cost effectiveness.
Methods
The new model has two steps. In the first step, we purposely over-estimated the majority of respondents’ CVD risk by substituting a sufficiently high hypothetical cholesterol value in the risk estimation. We then recommend cholesterol measurement only to those with the estimated CVD risk above a predetermined risk threshold for drug treatment. In the second step, the CVD risk is re-estimated based on the individual’s real cholesterol consentration. Those with a risk above the treatment threshold are recommended for drug treatment.
We evaluated the performance of our two-step model with data from the Health Survey for England and re-evaluated it with data from the China Nutrition and Health Survey 2002. By varying the hypothetical cholesterol values and treatment thresholds in CVD risk, we assessed the sensitivity, specificity and proportion of the population who need to measure cholesterol and compared it with the US mass screening model and the UK NICE selective screening model. We further compared the costs and CVD events avoided in the compared screening programmes. We also examined how the age restriction should be set in cholesterol screening programmes.
Results
As compared to mass screening, our new model can achieve a high sensitivity and save some 80% the cost of cholesterol measurements. The sensitivity depends mainly on the hypothetical cholesterol level used and seems independent of population’s CVD risk, treatment cut-off values and risk prediction model. The model performed well in almost all the conditions tested. When the hypothetical cholesterol was set at MEAN+2SD, the resulting sensitivity of our selective screening model was almost always above 95% and close to the expected 97.5%. The sensitivity was only compromised slightly if cholesterol is not measured at all for the Chinese population. Furthermore, in order to save more costs, cholesterol measurement could be better restricted to men aged 50-84 and women 60-84 years regardless of the screening model used. In CVD events prevented, mass screening is always the best but our model can prevent almost as many. In costs, mass screening is always the most expensive but our model can save all or most of the cost. The NICE selective model can perform as well as our model only when it is used in an appropriate manner and in certain circumstances.
Conclusion
Our new cholesterol screening model has a high sensitivity which is comparable to that of universal screening programs but can save most of the cost on cholesterol measurements. In where resources are particular sparse, our model can also perform well by applying it only to certain age groups, which will further save cholesterol measurement costs. Cholesterol measurement could even be completely avoided for the Chinese population if our findings can be re-confirmed correct with more updated data.
Detailed summary in vernacular field only.
Detailed summary in vernacular field only.
Detailed summary in vernacular field only.
Detailed summary in vernacular field only.
Detailed summary in vernacular field only.
Hu, Xuefeng.
Thesis (Ph.D.)--Chinese University of Hong Kong, 2012.
Includes bibliographical references (leaves 114-121).
Abstract also in Chinese.
Abstract (in English) --- p.i
Abstract (in Chinese) --- p.iv
Acknowledgements --- p.vi
Abbreviations used in the thesis --- p.viii
List of Tables --- p.xvi
List of Figures --- p.xviii
List of Boxes --- p.xix
Chapter 1. --- Introduction --- p.1
Chapter 1.1 --- The burden of cardiovascular disease --- p.1
Chapter 1.2 --- Primary prevention of CVD --- p.2
Chapter 1.3 --- The high-risk individual strategy for CVD primary prevention --- p.3
Chapter 1.3.1 --- The high risk individual strategy is effective --- p.4
Chapter 1.3.2 --- The high risk individual strategy is cost-effective --- p.4
Chapter 1.4 --- Who should be treated with drugs? --- p.5
Chapter 1.4.1 --- The single risk factor strategy --- p.5
Chapter 1.4.2 --- The overall CVD risk strategy --- p.7
Chapter 1.4.3 --- Scope of CVD primary prevention --- p.8
Chapter 1.5 --- Methods for assessing the CVD risk --- p.9
Chapter 1.6 --- Current strategies for cholesterol measurements --- p.10
Chapter 1.6.1 --- United States National Cholesterol Education Program --- p.13
Chapter 1.6.2 --- American Heart Association CVD and Stroke prevention guideline --- p.14
Chapter 1.6.3 --- The U.S. Preventive Services Task Force guideline --- p.15
Chapter 1.6.4 --- New Zealand guideline 2003 --- p.16
Chapter 1.6.5 --- Australian guideline 2009 --- p.17
Chapter 1.6.6 --- The Joint British Society guideline-2 --- p.17
Chapter 1.6.7 --- UK Department of Health guideline on vascular check --- p.18
Chapter 1.6.8 --- China Blood Lipid Modification Guideline 2007 --- p.18
Chapter 1.6.9 --- Summary of the reviewed guidelines --- p.19
Chapter 1.7 --- Rationale for a selective screening model --- p.20
Chapter 1.8 --- The UK NICE model --- p.22
Chapter 1.9 --- Objectives of this study --- p.24
Chapter 2 --- Methods --- p.25
Chapter 2.1 --- The new cholesterol screening model --- p.25
Chapter 2.2 --- Framework for evaluating the new screening model --- p.27
Chapter 2.3 --- Indexes for evaluating the basic performance of screening models --- p.28
Chapter 2.3.1 --- Sensitivity, specificity and % need cholesterol measurement --- p.28
Chapter 2.3.2 --- Sensitivity analysis for model performance --- p.29
Chapter 2.3.2.1 --- Using different hypothetical cholesterol values --- p.29
Chapter 2.3.2.2 --- Using different treatment cut-off thresholds --- p.30
Chapter 2.3.2.3 --- Using different populations --- p.30
Chapter 2.3.2.4 --- Using different risk equations --- p.31
Chapter 2.4 --- Data --- p.31
Chapter 2.4.1 --- The Health Survey for England --- p.31
Chapter 2.4.1.1 --- Background and aim of the survey --- p.31
Chapter 2.4.1.2 --- Survey design --- p.32
Chapter 2.4.1.2.1 --- Sampling Frame --- p.32
Chapter 2.4.1.2.2 --- Weighting variables --- p.33
Chapter 2.4.1.3 --- Data collection --- p.33
Chapter 2.4.1.3.1 --- Blood cholesterol --- p.34
Chapter 2.4.1.3.2 --- Blood pressure --- p.34
Chapter 2.4.1.3.3 --- Smoking --- p.34
Chapter 2.4.1.3.4 --- History of CVD and diabetes --- p.34
Chapter 2.4.1.3.5 --- Treatment history --- p.35
Chapter 2.4.2 --- The 2002 China National Nutrition and Health Survey --- p.35
Chapter 2.4.2.1 --- Survey design --- p.36
Chapter 2.4.2.2 --- Data collection --- p.36
Chapter 2.4.2.2.1 --- Blood pressure --- p.36
Chapter 2.4.2.2.2 --- Blood cholesterol --- p.38
Chapter 2.4.2.2.3 --- Smoking --- p.38
Chapter 2.4.2.2.4 --- History of CVD, diabetes and drug treatment --- p.38
Chapter 2.4.3 --- Subjects eligible for analysis in this study --- p.38
Chapter 2.5 --- CVD risk prediction --- p.43
Chapter 2.5.1 --- The Framingham risk equation for the UK population --- p.43
Chapter 2.5.2 --- The Asian equation for the Chinese population --- p.44
Chapter 2.5.3 --- Adjusting for cholesterol and blood pressure --- p.45
Chapter 2.5.4 --- Deriving the hypothetical cholesterol --- p.46
Chapter 2.6 --- Identifying the appropriate age ranges for cholesterol measurement --- p.47
Chapter 2.7 --- Comparing various screening models and options --- p.47
Chapter 2.7.1 --- Compared screening models and options --- p.47
Chapter 2.7.1 --- Indices for the performance of the screening options --- p.49
Chapter 2.7.2 --- Costs of different screening options --- p.50
Chapter 2.7.2.1 --- Components of screening cost from societal perspective --- p.50
Chapter 2.7.2.1.1 --- Cost for inviting people for data collection --- p.50
Chapter 2.7.2.1.2 --- Cost for the full risk assessment --- p.51
Chapter 2.7.2.1.3 --- Treatment cost --- p.51
Chapter 2.7.2.1.4 --- Cost saved for avoided CVD events --- p.52
Chapter 2.7.2.2 --- Components of screening cost from health system’s perspective --- p.52
Chapter 2.7.3 --- Number of CVD events avoidable --- p.53
Chapter 2.8 --- Statistical analysis --- p.54
Chapter 2.8.1 --- Descriptive analysis --- p.54
Chapter 2.8.2 --- Cross-tabulation analysis --- p.54
Chapter 2.8.3 --- Survey data analysis --- p.54
Chapter 3 --- Results --- p.57
Chapter 3.1 --- Description of data --- p.57
Chapter 3.1.1 --- The UK population --- p.57
Chapter 3.1.1.1 --- Sumamry of CVD risk and risk factors --- p.57
Chapter 3.1.1.2 --- Distribution of age --- p.57
Chapter 3.1.1.3 --- Distribution of blood pressure and blood cholesterol --- p.58
Chapter 3.1.1.4 --- Distribution of the predicted 10-year CVD risk --- p.62
Chapter 3.1.1.5 --- Relation between the risk threshold and age --- p.63
Chapter 3.1.2 --- The Chinese population --- p.65
Chapter 3.1.2.1 --- Summary of CVD risk and risk factors --- p.65
Chapter 3.1.2.2 --- Distribution of age --- p.65
Chapter 3.1.2.3 --- Distribution of blood pressure and blood cholesterol --- p.66
Chapter 3.1.2.4 --- Distribution of the predicted 10-year CVD risk --- p.69
Chapter 3.1.2.5 --- Relation between the risk threshold and age --- p.70
Chapter 3.2 --- Performance of our new screening model --- p.72
Chapter 3.2.1 --- Performance according to cholesterol values in the UK population --- p.72
Chapter 3.2.2 --- Performance according to treatment cut-offs in the UK population --- p.73
Chapter 3.2.3 --- Performance according to cholesterol values in the Chinese population --- p.73
Chapter 3.2.4 --- Performance according to the risk cut-offs in the Chinese population --- p.74
Chapter 3.2.4 --- Performance using different risk equations --- p.76
Chapter 3.3 --- Comparison with other existing screening models --- p.77
Chapter 3.3.1 --- Performance of the 3 models within an age-restricted UK population --- p.79
Chapter 3.3.2 --- Performance of the 3 models within an age-restricted Chinese population --- p.81
Chapter 3.3.3 --- Performance of the 3 models in the entire UK population --- p.83
Chapter 3.3.4 --- Performance of the 3 models in the entire Chinese population --- p.84
Chapter 3.3.5 --- Costs of various screening options --- p.87
Chapter 3.3.6 --- Number of CVD events avoidable of the screening programmes --- p.92
Chapter 4 --- Discussion --- p.96
Chapter 4.1.1 --- Performance at different hypothetical cholesterol values --- p.96
Chapter 4.1.2 --- Performance at various treatment cut-off thresholds --- p.97
Chapter 4.1.3 --- Performance with different risk equations --- p.98
Chapter 4.1.4 --- Performance in different populations --- p.99
Chapter 4.1.5 --- Performance with different survival functions --- p.99
Chapter 4.2 --- Further modifications of the model --- p.100
Chapter 4.2.1 --- A model without any cholesterol measurement --- p.100
Chapter 4.2.2 --- Age restriction for selective models --- p.102
Chapter 4.2.3 --- Our model with potential personalized treatment cut-off --- p.103
Chapter 4.2.4 --- Three key things to ensure model performance in other population --- p.104
Chapter 4.3 --- CVD events preventable --- p.105
Chapter 4.3.1 --- Importance of age restriction --- p.105
Chapter 4.3.2 --- Limitations of the NICE model --- p.106
Chapter 4.4 --- Costs of different screening models --- p.107
Chapter 4.4.1 --- Cost from different perspectives --- p.107
Chapter 4.4.2 --- Cholesterol measurement cost and routine data collection --- p.108
Chapter 4.4.3 --- Cost components --- p.109
Chapter 4.4.4 --- Ways to reduce cholesterol measurement costs --- p.109
Chapter 4.4.5 --- Costs and gain of the missing 2.5% high risk individuals --- p.109
Chapter 4.5 --- Strengths and limitations of this study --- p.110
Chapter 4.6 --- Recommendations --- p.113
References --- p.114

A total of 146 Chinese patients with various degrees of hyperlipidaemia and high cardiovascular risk, suitable for treatment with rosuvastatin 10 mg daily and in whom it was possible to obtain baseline lipid profiles measured on no lipid lowering drug, were enrolled in to the study. The drug compliance was assessed by personal interview and 9 patients were excluded from the efficacy analysis because they stated their compliance was less than 80%. From the remaining 137 subjects, 62 had a clinical diagnosis of familial hypercholesterolaemia. Data for dietary intake were available in 121 of the 137 subjects. The average reduction in LDL-cholesterol in these subjects was 48.8 +/- 12.8% and as anticipated there was a wide range between individuals. The percentage reductions in LDL-cholesterol were significantly greater in the female than in the male subjects (-51.35 +/-10.89% vs. -46.38 +/-13.96%; p = 0.025), but this was no longer significant after adjustment for body weight. In patients with familial hypercholesterolaemia the absolute reductions in total cholesterol and LDL-cholesterol were significantly greater (p<0.001) than in those without familial hypercholesterolaemia, but the percentage reductions were not significantly different in the two groups. The increases in HDL-cholesterol and the decreases in triglycerides were significantly greater in the subjects with familial hypercholesterolaemia than in those without familial hypercholesterolaemia, both for the absolute changes and for the percentage changes. There were no significant effects on the percentage changes in lipids with rosuvastatin treatment due to age, measurements of body fatness, smoking or alcohol drinking status, or having hypertension or diabetes.
Polymorphisms in the CYP2D6 gene were analyzed and the subjects were divided into 4 groups as wild-type or extensive metabolisers, heterozygotes for CYP2D6*10 and wild-type, homozygotes for CYP2D6*10, and subjects with one allele for poor metaboliser status. The groups in this order would be expected to have decreasing activity of the CYP2D6 enzyme. There was a tendency for greater reduction in LDL-cholesterol in groups with lower CYP2D6 activity, most obvious in male subjects and this was significant in the patients with familial hypercholesterolaemia comparing the first 3 groups. The fourth group had a low number of subjects, which may have biased that result. In the subjects without familial hypercholesterolaemia, the % change in LDL-cholesterol was similar in all genotype groups, but the % reduction in triglycerides was numerically higher in the wild-type group than in groups with CYP2D6*10 alleles and the group with poor metaboliser status showed a lower % reduction. These differences were not significant and may be influenced by the baseline levels of triglycerides, which were not corrected for in this analysis.
The daily calorie intake and percentage of different macronutrient intake was obtained by using seven days food recall records. Dietary intake of most nutrients with higher in male than in female patients and was higher in the patients compared to gender-matched population data. Higher intake of most nutrients was associated with higher baseline triglyceride levels, but not LDL-cholesterol levels in all patients, and in lower HDL-cholesterol levels in the patients without familial hypercholesterolaemia. Higher intake of total calories was associated with less percentage reduction in LDL-cholesterol with rosuvastatin in the patients without familial hypercholesterolaemia and a similar non-significant tendency was seen with higher intake of total fat, saturated fat and cholesterol.
The study described in this thesis examined the role of the CYP2D6*10 polymorphism on the lipid response to rosuvastatin in addition to a number of phenotypic factors such as diet, gender, measures of obesity and other medical conditions.
These findings suggest that the CYP2D6 genotype may have some influence on the lipid response to rosuvastatin, but it appears to interact with other factors including, gender, diet and the presence of familial hypercholesterolaemia. (Abstract shortened by UMI.)
Lui, Siu Hung.
"February 2007."
Adviser: Brian Tomlinson.
Source: Dissertation Abstracts International, Volume: 69-01, Section: B, page: 0248.
Thesis (Ph.D.)--Chinese University of Hong Kong, 2007.
Includes bibliographical references (p. 165-190).
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.

Indiana University-Purdue University Indianapolis (IUPUI)
Obesity increases cardiovascular disease risk and is associated with factors of the “metabolic syndrome” (MetS), a disorder including hypertension, hypercholesterolemia and/or impaired glucose tolerance. Expanding adipose and subsequent inflammation is implicated in vascular dysfunction in MetS. Perivascular adipose tissue (PVAT) surrounds virtually every artery and is capable of releasing factors that influence vascular reactivity, but the effects of PVAT in the coronary circulation are unknown. Accordingly, the goal of this investigation was to delineate mechanisms by which lean vs. MetS coronary PVAT influences vasomotor tone and the coronary PVAT proteome. We tested the hypothesis that MetS alters the functional expression and vascular contractile effects of coronary PVAT in an Ossabaw swine model of the MetS. Utilizing isometric tension measurements of coronary arteries in the absence and presence of PVAT, we revealed the vascular effects of PVAT vary according to anatomical location as coronary and mesenteric, but not subcutaneous adipose tissue augmented coronary artery contractions to KCl. Factors released from coronary PVAT increase baseline tension and potentiate constriction of isolated coronary arteries relative to the amount of adipose tissue present. The effects of coronary PVAT are elevated in the setting of MetS and occur independent of endothelial function. MetS is also associated with substantial alterations in the coronary PVAT proteome and underlying increases in vascular smooth muscle Ca2+ handling via CaV1.2 channels, H2O2-sensitive K+ channels and/or upstream mediators of these ion channels. Rho-kinase signaling participates in the increase in coronary artery contractions to PVAT in lean, but not MetS swine. These data provide novel evidence that the vascular effects of PVAT vary according to anatomic location and are influenced by the MetS phenotype.