Osteoarthritis (OA) mainly affects the articular cartilage covering the bones. In this thesis we investigated the relation between levels of inflammatory mediators, genes involved in their... Show moreOsteoarthritis (OA) mainly affects the articular cartilage covering the bones. In this thesis we investigated the relation between levels of inflammatory mediators, genes involved in their regulation and the disease status of OA. We investigated the role of genetic variation at the interleukin(IL)-1 gene cluster in the innate bio-availability of IL-1beta. A haplotype that associated to low innate bio-availability also associated to higher hand OA scores. Although this is counterintuitive with respect to the generally accepted hypothesis that a pro-inflammatory status is detrimental to the cartilage it underlines a complex relationship between inflammation and OA. For the C-reactive protein we identified a haplotype associated to high CRP levels as well as to severe hand OA, which is more in line with expected directions of associations. Analysis of baseline cytokine and chemokine levels indicated that chemokine levels associated to hand OA scores, again with low levels associated to high OA scores. In a follow up functional genomic analysis of a previously identified OA susceptibility gene (DIO2) in our studies we show that the risk allele of this gene is transcribed at higher levels as compared to the non-risk allele. Furthermore, we showed increased DIO2 protein presence in OA affected cartilage. Show less
In the first of this thesis, results are summarized of a randomised crossover trial on the effects of aspirin on markers of inflammation, coagulation and number of endothelial progenitor cells in... Show moreIn the first of this thesis, results are summarized of a randomised crossover trial on the effects of aspirin on markers of inflammation, coagulation and number of endothelial progenitor cells in type 2 diabetic patients without cardiovascular disease. In the second part, results of two systematic reviews on prevalence and clinical relevance of aspirin resistance are reported. Furthermore, we describe time-dependent mechanisms by which aspirin may reduce bloodpressure. Show less
The aim of this thesis was to explore the relation between visceral obesity and the accompanying metabolic disturbances, systemic inflammation and the atherosclerotic process. A newly developed... Show moreThe aim of this thesis was to explore the relation between visceral obesity and the accompanying metabolic disturbances, systemic inflammation and the atherosclerotic process. A newly developed magnetic resonance vessel wall imaging technique was implemented in phenotyping patients and as a therapeutic endpoint in a randomised controlled setting. A three step approach was chosen for this purpose. First, the magnetic resonance black blood vessel wall imaging technique at the magnetic field strength of 3 Tesla was developed and validated. Secondly, phenotyping of viscerally obese subjects was performed with special attention for the role of systemic inflammation and atherosclerosis. Finally, in the setting of a randomised controlled trial, the impact of reducing visceral obesity and systemic inflammation with lifestyle intervention and rosiglitazone treatment (PPARg agonist) on the progression of atherosclerosis was assessed. Show less
Ischemia-reperfusion injury (IRI) is a pathophysiological event that occurs in many clinical conditions, ranging from surgery, acute artery occlusion to transplantation. Complement activation is... Show moreIschemia-reperfusion injury (IRI) is a pathophysiological event that occurs in many clinical conditions, ranging from surgery, acute artery occlusion to transplantation. Complement activation is thought to be a crucial step in IRI, because complement inhibition and complement deficiency considerably attenuate irreversible injury. However, the specific complement pathway remains unclear. All three complement pathways: the classical, the alternative, and the mannose-binding lectin dependent pathway may be involved in the development of IRI, depending on the model, the tissue, and the time course of inflammation. Ischemia leads to the exposition of neoantigens on the jeopardized tissues, which could be recognized by C-reactive protein (CRP) and natural IgM antibodies. The binding of CRP and IgM to these neoepitopes is followed by complement activation. In this thesis, we demonstrated that both proteins bind to jeopardized tissues and activate the complement system, in particular intestines from rats subjected to IRI. Furthermore, it was shown that IgM levels against altered phospholipids correlated with the levels of inflammatory mediators in patients subjected to tissue damage suggesting that IgM participates in amplification of inflammation. The development of strategies to prevent binding of CRP and/or IgM is an attractive approach for a therapy for reducing IRI. Show less
