This thesis describes the use of MRI contrast agents and vessel wall parameters to image different stages of atherosclerosis. Chapter 2 summerizes different MRI contrast agents targeted towards... Show moreThis thesis describes the use of MRI contrast agents and vessel wall parameters to image different stages of atherosclerosis. Chapter 2 summerizes different MRI contrast agents targeted towards vulnerable plaques that have been presented in literature. Chapter 3 illustrates accumulation of paramagnetic micelles and liposomes in atherosclerosis, yet have complex kinetics when followed over time. In chapter 4 the use of self-gated MRI was validated to detect contrast agent accumulation in atherosclerotic plaques and assess the vessel wall compliance. The potential of both techniques to monitor plaque progression and anti-atherosclerotic therapy was assessed. In chapter 5 we developed a scavenger receptor-A1 targeted USPIO to detect vulnerable lesions. Chapter 6 describes the application of VCAM-1 targeted USPIO. Imaging at different time points, allows to discriminate early plaques from advanced lesions and can be used to monitor treatment response in ApoE-/- mice. In Chapter 7 an E-selectin targeted USPIO was validated. This USPIO allowed discrimination of lesions rich in macrophages from early lesions. In Chapter 8 we developed a micelle encapsulating rosiglitazone. Targeted delivery to the plaque lead to an anti-atheroscle rotic response without cardiac side-effects. Finally in Chapter 9 the potentials and pitfalls of histological validation of MRI contrast agents are illustrated. Show less
Women diagnosed with a sexual dysfunction often suffer from marked distress and interpersonal difficulty that arise from unwanted, persistent or recurrent low sexual desire (hypoactive sexual... Show moreWomen diagnosed with a sexual dysfunction often suffer from marked distress and interpersonal difficulty that arise from unwanted, persistent or recurrent low sexual desire (hypoactive sexual desire disorder, HSDD). An imbalance of excitatory and inhibitory neurotransmitters has been proposed to underlie certain forms of HSDD. Serotonin (5-HT) is a key neurotransmitter involved in female sexual inhibition. Animal studies that apply 5-HT receptor subtype specific ligands permit mechanistic examination of 5-HT mediated effects on sexual behavior. The aim of this thesis was to investigate the serotonergic regulation of female sexual behavior in the common marmoset (Callithrix jacchus), a nonhuman primate that is characterized by a pairmate social setting comparable to humans. The experimental agents employed in the study were (1) flibanserin, a 5-HT1A agonist, 5-HT2A antagonist and putative pharmacotherapeutic treatment for HSDD in women, and (2) 8-OH-DPAT, a prototype 5-HT1A agonist. Neuroendocrine, PET imaging and genetic experiments were conducted to explore hormonal, brain activity and gene expression patterns that underlie female sexual behavior. While flibanserin, administered daily to the female for several weeks, enhanced the male pairmate’s sexual interest and increased pro-social interactions between pairmates, 8-OH-DPAT reduced female sexual receptivity and increased aggressive interactions between pairmates. HPA responses to restraint stress were enhanced after both flibanserin and 8-OH-DPAT. Furthermore, 8-OH-DPAT treated females showed reduced glucose uptake to the medial occipital cortex that correlated with sexual rejection behavior, while gene transcription of the serotonin transporter in the dorsal raphé nucleus, and of oxytocin in the medial preoptic area of the hypothalamus, was increased. Gene cluster analysis of microarray data indicated brain region-specific alterations in neural development, neurotransmission and energy production after 8-OH-DPAT. The results presented in this thesis demonstrate that pair-bond quality between partners and sexual behavior are closely linked and suggest that oxytocin may be the pivot of serotonergic regulation of female sexual behavior, pair-bond and pharmacotherapy of HSDD. Show less
