Atherosclerosis is a complex inflammatory disease in which oxidative stress is a major protagonist in the development and progression of the atherosclerotic plaque. All biochemical analysis studies of plaque over the past fifteen years have been carried out on whole plaque with no attempt to localise sites of differing biochemical conditions. This study set out to identify in oxidation levels and inflammatory markers in relation to spatial localisation within the plaque. Advanced plaque samples removed during endarectomy were obtained from the Christchurch Hospital Department of surgery and were dissected into 3-5 mm sections along the longitudinal axis prior to analysis. Samples were analysed for vitamin E, neopterin, total cholesterol and markers of oxidative damage to protein and lipids. Neopterin is a marker of inflammation as it is released by activated macrophages yet it has never been measured in plaques. Initial analysis showed that the acid precipitation method for removing protein from samples prior to HPLC neopterin analysis was causing a significant loss in neopterin. A new acetonitrile based protein removal procedure was developed. Markers of oxidative stress and inflammation where shown to vary across the length of an atherosclerotic plaque. This variation allows for localized incidences of high and low radical flux and microenvironments of depleted antioxidants or areas in which the prooxidative actions of molecular components are favoured. Significant correlations were rarely seen in more then one plaque and trends found in the combined data set generally did not hold true in individual plaques. This reflects upon the complexity of the disease, especially at this advanced stage in which the biochemical morphology of individual plaques is extremely diverse. Separation of the plaques into pre-, post-, and bifurcation areas did produce some trends. These can be related to shear stress variations in the blood flow; further investigations into the biochemical differences between these areas may provide a better understanding of the growth and development of the atherosclerotic plaque.

No description available.

No description available.

This study investigated the expression and activity of tissue transglutaminase (tTG) in human umbilical vein endothelial cells (HUVEC) and vessel wall. tTG was located in the SMC and sub-endothelium of normal vessels. Cross-linking activity was also in this area. Vessels with atherosclerotic plaque showed increased staining for tTG and cross-links. Positive staining for tTG was located in the SMC, neointima, macrophages and the fibrous cap. Most cross-linking activity was observed in the fibrous cap, and cross-linking was observed around macrophages and smooth muscle cells. Cross-linking activity was also observed with incorporation of a labelled cross-linking substrate into vessel sections. Free tTG could be extracted from the vessel wall. HUVEC expressed 10 g tTG/mg total protein. tTG was detected in cell lysate and extracellular matrix, but not in the culture supernatant. Thrombin up-regulated tTG expression at both the mRNA and protein level. Optimal up-regulation was at a thrombin concentration of 1 U/ml The up-regulation by thrombin was dependent on thrombin activity, and was mediated through the thrombin receptor, protease-activated receptor 1 (PAR-1). Cross-linking activity was also increased after thrombin treatment, measured with a microtitre plate assay and an in situ assay. The specific activity of tTG increased after thrombin treatment. Thrombin treatment increased the level of tTG in the HUVEC ECM. Treatment of HUVEC with PMA reduced the expression of tTG mRNA, reduced the level of tTG protein, but increased the tTG cross-linking activity compared to untreated cells.

Orbital pseudotumor, also known as idiopathic orbital inflammatory disease (IOID), is an idiopathic inflammatory process within the orbit. The potential for permanent visual impairment makes this disease important to diagnose and treat. While oral corticosteroids are the mainstay of therapy, they can have significant toxicity when used for long periods of time. We present a case of IOID that was successfully treated with leflunomide after methotrexate was discontinued for toxicity-related issues. To our knowledge, use of leflunomide for this condition has not previously been reported in the literature.

No description available.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2006. / Härtill 5 uppsatser.

This diploma thesis is about the illness called multiple sclerosis. The theoretic part describes this illness, its history, types of multiple sclerosis and refers to economic costs. The practical part detected the position of patients and evaluates their quality of life. The most important in this part are economic costs of patient and economic costs of insurance companies.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24493号 / 医博第4935号 / 新制||医||1063(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 浅野 雅秀, 教授 万代 昌紀, 教授 上杉 志成 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Lipopolysaccharide (LPS), a Gram-negative endotoxin, has been well-established as the trigger for the effects of sepsis and septic shock through its binding with the innate immune receptor, Toll-like receptor 4 (TLR4). High doses of LPS signal through TLR4 to produce a massive release of pro-inflammatory cytokines including IL-6, TNFα, and other. Additionally, several recent publications have demonstrated severe metabolic alterations after LPS challenge, suppressing lipid oxidation and concurrently up-regulating glucose oxidation. Unfortunately, this switch in metabolism is inefficient for the great energy demands of the host during a systemic microbial infection which can result in vital organ failure. Meanwhile, a novel concept in several chronic disease pathologies also implicates LPS, although at very low doses. The presence of subclinically elevated circulating endotoxin levels has been termed metabolic endotoxemia and is beginning to be investigated in disease pathologies including insulin resistance and type II diabetes, atherosclerosis, cancer metastasis and Parkinson's disease. These disease phenotypes all possess a component of chronic inflammation whose source has not largely been understood, but examining the effects of very low doses of LPS may provide vital information in understanding their etiologies. However, most information on LPS signaling has been obtained using high doses of LPS (10-200ng/ml) while little to no studies have been published regarding the effects of very low doses of LPS (1pg-100pg/ml) on inflammatory and metabolic alterations. Thus, we use in vivo and in vitro models to determine that both IRAK1 and JNK are critical points of crosstalk downstream of TLR4 for the metabolic and inflammatory alterations associated with metabolic endotoxemia. Additionally, we observed significant down-regulation of nuclear receptors responsible for fatty acid metabolism, including PGC1α, PPARα, and PPARγ after very low dose LPS challenge. Further, we observe phenotypic changes in fatty acid oxidation and glucose oxidation, as well as subsequent changes in cytosolic acetyl-CoA levels and acetylation of pro-inflammatory transcription factor ATF2. Overall our studies point to several mechanisms of cross-talk between metabolism and inflammation and offer significant support to the concept of metabolic endotoxemia in the development of chronic disease. / Ph. D.