Statement of the problem: Many methods for surrogate outcome validation require individual patient data which is often inaccessible by clinical trialists. Methods: A review was performed to identify statistical methods for surrogate outcome validation that may be implemented using summary data from published clinical trials. The methods were used to evaluate carotid intima-media thickness (CIMT) as a surrogate outcome for cardiovascular events in a systematic review of randomized trials of interventions for atherosclerosis. Results: the review of methods identified five procedures. At two or more years of follow-up, there was a marginally significant association of CIMT with myocardial infarction and a statistically significant association with cardiovascular mortality. At ≥ four years of follow-up, a statistically significant, negative relationship was observed between CIMT and stroke. Conclusions: CIMT may be a valid surrogate outcome for myocardial infarction and cardiovascular mortality. Additional data is needed to evaluate CIMT in specific drug classes.

Cellular Inhibitor of Apoptosis 2 (cIAP2) belongs to the IAP family, a group of endogenous proteins that inhibit apoptosis. However, the physiological role of cIAP2 remains poorly defined. Knock-out (KO) and wild type (WT) mice were used to examine the effect of cIAP2 protein on the progression of atherosclerosis in apoE -/- mice. Following the high-fat diet period of 4 and 12 wks, tissues were harvested and analysis focused on the aortic root, the aortic arch, the descending aorta, and the blood. Ex vivo results show a significant decrease in aortic arch lesion area in KO vs. WT in both study groups. Results also show a decrease in aortic root lesion size in KO vs. WT in both study groups. These results support that cIAP2 is an important survival factor for lesion-associated macrophages, since loss of cIAP2 expression in this mouse model reduced atherosclerotic lesion development.

Atheroma, heart attacks and strokes continue to be a major cause of morbidity and mortality in our community. Atherosclerosis is a chronic inflammatory vascular disease, characterised by thickening of the vascular wall due to lipid accumulation, infiltration by circulating monocytes and T cells and proliferation of smooth muscle cells. Leukocyte adherence to the blood vessel wall is promoted by the up-regulation of cell adhesion molecules (CAM) by atherogenic substances such as tumour necrosis factor (TNF-α) and oxidised low density lipoprotein (oxidised-LDL). Recently our group has synthesised a novel polyunsaturated fatty acid, β-oxa 23:4n-6 which inhibits CAM up-regulation in blood vessel walls. It was therefore the objective of this thesis to determine whether this fatty acid protects against atherosclerosis. Advantage was taken of an experimental model of this disease, the apoE deficient mouse (apoE [superscript -/-]) which spontaneously develop atherosclerosis. To assist our studies on MP3, we established an appropriate classification of different stages of atherosclerotic lesions and defined the kinetics of development of the disease in this model. By examining of the sections at the level of aortic roots the atherosclerotic lesions were classified into six categories. This classification was based on the histological characteristics of the plaque component including the degree of macrophage infiltration and foam cells formation, the presence of cholesterol clefts and confluent lipid cores, calcification and ossification, the composition of the fibrous cap, the media involvement and the incipient/actual aneurysm formation and inflammation, including neutrophils. Kinetics of plaque development under the influence of a high fat and high cholesterol diet followed an exponential relationship of y= -e [ superscript -x ]. The asymptotic characteristic of this lesion development was however a function of compensatory aortic enlargement which accompanied the increase in lesion development and size. Thus it is concluded that the level of atherosclerosis needs to be gauged by the size of the lesion per se. This may be particularly important for the assessment of anti-atherogenic effects of drugs. Therefore attempts to develop a quantitative system to assess plaques revealed that expression of plaque size as % of occupation of blood vessel had limitations. Using this model we were able to demonstrate that injections of the novel polyunsaturated fatty acid, MP3 led to a significant reduction/inhibition (70%) of plaque area and a corresponding 60% inhibition of aortic size. As expected this inhibition was not as evident when results were expressed as % of aortic lumen size. The results also suggested that protection by MP3 was dependent on conditions which promoted increased uptake into tissues by, for example, preloading animals with MP3 prior to commencing the high fat high cholesterol diet. The protective effects of MP3 are consistent with a role for the activation of the transcriptional factor, NFkB and up-regulation of cell adhesion molecules in this disease, and the ability of MP3 to inhibit these targets. Thus the objective of this research has been achieved and the hypothesis proven. / Thesis (M.Med.Sc.)--Univesity of Adelaide, School of Paediatrics & Reproductive Health, 2005.

Proefschrift Maastricht. / Lit. opg. - Met een samenvatting in het Nederlands.

Proefschrift Universiteit van Amsterdam. / Met bibliogr., lit. opg. - Met samenvatting in het Nederlands.

Proefschrift Universiteit van Amsterdam. / Met lit. opg. - Met samenvatting in het Nederlands.

Proefschrift Universiteit van Amsterdam. / Met lit. opg. - Met samenvatting in het Nederlands.

Proefschrift Universiteit van Amsterdam. / Auteursnaam op rug: Paula Martins. Met bibliogr., lit. opg. - Met samenvatting in het Nederlands en Portugees.

Thesis (M. Med. Sc.)--University of Hong Kong, 2007.

Thesis (M.Sc.)--University of Western Australia, 2004.