The project described in this thesis was designed to test if genetic variation in the mineralocorticoid receptor (MR) gene is a risk factor for developing major depression. First the MR-gene was... Show moreThe project described in this thesis was designed to test if genetic variation in the mineralocorticoid receptor (MR) gene is a risk factor for developing major depression. First the MR-gene was screened for genetic variation. Two selected single nucleotide polymorphisms (SNPs) were tested for in vitro functionality at different levels including: protein and mRNA expression, transactivational capacity and ligand binding. Functionality in vitro was confirmed leading us to test their influence on electrolyte regulation, stress responsiveness and personality. First, in three different cohorts one SNP influenced blood pressure and salt regulation, as could be expected for the MR. Second, the SNPs were associated with the cortisol awaking response (CAR) after dexamethasone administration and with the cortisol and autonomic response following psychosocial stress. This indicates an important role for the MR in the regulation of the stress-response. Third in a relatively small cohort (n=150) the SNPs were not associated with mood and/or anxiety disorders but in the patient group there was an association with the personality trait neuroticism. We hypothesize that genetic variants in the MR-gene are determinants of vulnerability for psychiatric disorders. Show less
Pronounced ultradian and circadian rhythms in the hormones of the hypothalamic-pituitary-adrenal (HPA) axis (i.e. glucocorticoids), one of the body__s major neuroendocrine axes, were already... Show morePronounced ultradian and circadian rhythms in the hormones of the hypothalamic-pituitary-adrenal (HPA) axis (i.e. glucocorticoids), one of the body__s major neuroendocrine axes, were already demonstrated several decades ago. Until now, the clinical relevance of the pulsatile nature of glucocorticoids was poorly understood or sometimes even regarded as not important. Its evolutionary conservation across many species however implies biological significance. Indeed, glucocorticoids have been proven to be crucial for a plethora of bodily functions, e.g. emotion, cognition and the central mechanism underlying the adaptation to stress. Furthermore, disturbances in the characteristic temporal pattern of glucocorticoid exposure have often been described in stress-related pathology. However, the significance of glucocorticoids secretory patterns for physiology, stress responsiveness and nuclear receptor signalling is still largely unexplored and is accordingly addressed in this thesis. A new concept in the endocrinology of glucocorticoids has evolved from the data presented here showing that pulsatile release of glucocorticoids is a major determinant in __resilience__ of glucocorticoid signalling in neuronal cells and stress responsiveness. Moreover, we show that particularly the glucocorticoid receptor is affected after disrupting glucocorticoid pulsatility and could thus provide an excellent target for therapy to normalise the downstream effects of disturbances in glucocorticoid rhythms in stress-related disease. Show less
For a majority of people worries about upcoming stressful events are a common experience in daily life. The aim of this thesis was to examine the effects of common worries on somatic health. In... Show moreFor a majority of people worries about upcoming stressful events are a common experience in daily life. The aim of this thesis was to examine the effects of common worries on somatic health. In particular, the effects of worry on somatic health complaints, like headache and back pain, and on cardiac activity after stressful events were tested. Furthermore, the mechanisms by which worry was hypothesized to affect somatic health were investigated. The studies in this thesis add to the accumulating number of studies testing the perseverative cognition hypothesis stating that only perseverative cognitive representations of stressful events (worries) lead to prolonged stress-related physiological activity which, in turn, can lead to somatic disease. Taken together, the studies reported in this thesis provide evidence for the perseverative cognition hypothesis, that is, worry predicted adverse somatic health outcomes. In addition, the results of the studies presented in the second part of this thesis yielded several new and more specific hypotheses concerning the mechanisms behind the health effects of worry and the effects of worry on stress management therapies. All in all, evidence from real life and laboratory studies makes clear that worry might play a substantial role in somatic health. Show less
In this thesis, determinants, risk and protective factors of parental reactions to childhood cancer are described and research areas that are understudied until now have been identified. Chapter 2... Show moreIn this thesis, determinants, risk and protective factors of parental reactions to childhood cancer are described and research areas that are understudied until now have been identified. Chapter 2 contains a review study on stress and adaptation in parents of pediatric cancer patients. Chapter 3 describes the results of a multicenter study among parents of children with cancer with the aim to evaluate the psychometric qualities of the Dutch version of a disease-related instrument measuring parental stress. Chapter 4 is a review article on parental stress and adaptation among parents of children undergoing stem cell transplantation (SCT). Chapter 5 contains the results of a longitudinal study on child- and parent reported health related quality of life and parenting stress in parents of children undergoing SCT. In Chapter 6, the results of a cross-sectional study on parental stress and perceptions of child vulnerability in parents of children who underwent SCT either 5 or 10 years ago are reported. In Chapter 7, cognitive problems, behavior problems and health related quality of life of children with LCH are described. Show less
