The present dissertation investigated adolescents’ overall stress and perceived stressors, the effectiveness of a universal psychoeducational program about stress, the Stress Lessons, and... Show moreThe present dissertation investigated adolescents’ overall stress and perceived stressors, the effectiveness of a universal psychoeducational program about stress, the Stress Lessons, and adolescents’ self-referral to a targeted school-based intervention. Another aim was to examine whether adolescents from different demographic groupings vary in their experience of stressors and the effect of psychoeducation. A large and heterogeneous sample was recruited from schools with variation in educational tracks and self-perceived ethnic backgrounds. The sample consisted of 1613 predominantly young adolescents with an average age of 13 years old. Most adolescents have to maneuver through a world of stressors, mostly related to the school environment, their health, and future uncertainty, while adolescents experience less stress from social pressure and financial pressure. Furthermore, our results indicate that the Stress Lessons were effective regarding improving adolescents’ knowledge about stress, but not in terms of stress levels. Finally, we found that adolescents who reported higher levels of test anxiety were generally more likely to show interest in an intervention targeting reduction of performance anxiety after the Stress Lessons. However, we did not find that adolescents with lower levels of social skills were more interested in an intervention targeting improvement of social skills. Show less
From an evolutionary perspective, stress is an adaptive system that is necessary togenerate appropriate responses to stochastic and unpredictable events, and copeaccordingly with the environment.... Show moreFrom an evolutionary perspective, stress is an adaptive system that is necessary togenerate appropriate responses to stochastic and unpredictable events, and copeaccordingly with the environment. The physiological response to stress has beenremarkably conserved in vertebrate evolution. However, the threats to ourinternal “equilibrium” have changed between our ancestral environments and ourcurrent modern societies, and the demands for survival have evolved. Theglucocorticoid receptor (GR) is a timeless component of stress adaptation, as it is atthe intersection between the environmental stressors (i.e., physical, or psychosocial)and the genome. Therefore, the GR represents a valuable therapeutic target instress- and glucocorticoid-related disorders. This thesis provides new insightsinto the molecular mechanisms underlying GR signaling in metabolic diseases andbrain function and highlights the promise and importance of selectivity in novel GRtargeting treatments. Show less
This thesis addresses the pathophysiology of stress related diseases, taking two rare diseases, in which the hypothalamic-pituitary-adrenal axis and cortisol play a key role, as a model for stress... Show moreThis thesis addresses the pathophysiology of stress related diseases, taking two rare diseases, in which the hypothalamic-pituitary-adrenal axis and cortisol play a key role, as a model for stress vulnerability of the brain and the eye. The second aim of this thesis is to describe the organization of thromboprophylaxis management, and the outcome evaluation and quality of care for patients treated for Cushing’s syndrome. For more informatie, please refer tot he summary in the pdf of the thesis. Show less
Our research group recently published a positive association between early postoperative pain and 30-day postoperative complications in a broad surgical population. To investigate whether... Show moreOur research group recently published a positive association between early postoperative pain and 30-day postoperative complications in a broad surgical population. To investigate whether heterogeneity of the population and surgical procedures influenced these results, we explored this association in a homogenous surgical population. A secondary analysis of the LEOPARD-2 (NCT02146417) and RELAX-1 study (NCT02838134) in laparoscopic donor nephrectomy patients (n = 160) was performed. Pain scores on the postanesthesia care unit and postoperative day (POD) 1 and 2 were compared between patients with infectious, noninfectious, and no complications 30 days after surgery. Patients who developed infectious complications had significantly higher pain scores on POD1 and 2 (6.7 +/- 2.1 and 6.4 +/- 2.8) than patients without complications (4.9 +/- 2.2 and 4.1 +/- 1.9), respectively (P= 0.006 andP= 0.000). Unacceptable pain (numeric rating scale [NRS] >= 6) on POD1 was reported by 72% of patients who developed infectious complications, compared to 38% with noninfectious complications and 30% without complications (P= 0.018). This difference was still present on POD2 at 67% with infectious complications, 21% with noninfectious, and 40% without complications (P= 0.000). Multiple regression analysis identified unacceptable pain (numeric rating scale >= 6) on POD2 as a significant predictor for 30-day infectious complications (odds ratio 6.09,P= 0.001). Results confirm the association between early postoperative pain and 30-day infectious complications in a separate, homogenous surgical population. Further clinical trials should focus on finetuning of postoperative analgesia to elucidate the effects on the endocrine and immune response, preserve immune homeostasis, and prevent postoperative infectious complications. Show less
The forced swim test (FST) for rodents does not model despair or helplessness. It also is not a read-out for depression, anxiety, psychomotor retardation or autism, because these are... Show moreThe forced swim test (FST) for rodents does not model despair or helplessness. It also is not a read-out for depression, anxiety, psychomotor retardation or autism, because these are anthropomorphic interpretations of the rodent's acquired immobility. Rather, the transition from swimming to immobility allows to examine the mechanistic underpinning of coping with inescapable stressors. However, in a recent detailed analysis of the FST application over the past 40 years, we noted a dramatic surge in the use of this test to phenotype animals as 'depressed'. As a follow up to that report, we now present an analysis of the use of the FST over the past three years. This literature analysis shows that the popularity of the EST is still increasing and that the majority of researchers qualifies the rodent's floating response as depressive-like behavior. However, over the past few years we also note a trend to interpret immobility rather as the expression of a coping strategy. In view of this result, we have sent a poll to the relevant authors to learn how consistent they are in naming FST behavior. Remarkably, we find a dramatic inverse correlation between their first qualification of acquired immobility as depressive-like behavior towards their current interpretation as coping strategy. In this contribution we have embedded our literature analysis and poll results in an update on the management of coping with inescapable stressors by processing in prefrontal cortical circuitry and glucocorticoid feedback. Show less
Corticosteroid hormones act in the brain to support adaptation to stress via binding to mineralocorticoid and glucocorticoid receptors (MR and GR). These receptors act in large measure as... Show moreCorticosteroid hormones act in the brain to support adaptation to stress via binding to mineralocorticoid and glucocorticoid receptors (MR and GR). These receptors act in large measure as transcription factors. Corticosteroid effects can be highly divergent, depending on the receptor type, but also on brain region, cell type, and physiological context. These differences ultimately depend on differential interactions of MR and GR with other proteins, which determine ligand binding, nuclear translocation, and transcriptional activities. In this review, we discuss established and potential mechanisms that confer receptor and cell type-specific effects of the MR and GR-mediated transcriptional effects in the brain. Show less
Psychotic depression is characterized by elevated circulating cortisol, and high daily doses of the glucocorticoid/progesterone antagonist mifepristone for 1 week are required for significant... Show morePsychotic depression is characterized by elevated circulating cortisol, and high daily doses of the glucocorticoid/progesterone antagonist mifepristone for 1 week are required for significant improvement. Using a rodent model, we find that such high doses of mifepristone are needed because the antagonist is rapidly degraded and poorly penetrates the blood-brain barrier, but seems to facilitate the entry of cortisol. We also report that in male C57BL/6J mice, after a 7-day treatment with a high dose of mifepristone, basal blood corticosterone levels were similar to that of vehicle controls. This is surprising because after the first mifepristone challenge, corticosterone remained elevated for about 16 h, and then decreased towards vehicle control levels at 24 h. At that time, stress-induced corticosterone levels of the 1xMIF were sevenfold higher than the 7xMIF group, the latter response being twofold lower than controls. The 1xMIF mice showed behavioral hyperactivity during exploration of the circular hole board, while the 7xMIF mice rather engaged in serial search patterns. To explain this rapid reset of corticosterone secretion upon recurrent mifepristone administration, we suggest the following: (i) A rebound glucocorticoid feedback after cessation of mifepristone treatment. (ii) Glucocorticoid agonism in transrepression and recruitment of cell-specific coregulator cocktails. (iii) A more prominent role of brain MR function in control of stress circuit activity. An overview table of neuroendocrine MIF effects is provided. The data are of interest for understanding the mechanistic underpinning of stress system reset as treatment strategy for stress-related diseases. Show less
Acute stress and elevated glucocorticoid hormone levels are well known to impair the retrieval of hippocampus-dependent 'declarative' memory. Recent findings suggest that stress might also impair... Show moreAcute stress and elevated glucocorticoid hormone levels are well known to impair the retrieval of hippocampus-dependent 'declarative' memory. Recent findings suggest that stress might also impair the retrieval of non-hippocampal memories. In particular, stress shortly before retention testing was shown to impair the retrieval of striatal stimulus-response associations in humans. However, the mechanism underlying this stress-induced retrieval impairment of non-hippocampal stimulus-response memory remains elusive. In the present study, we investigated whether an acute elevation in glucocorticoid levels mediates the impairing effects of stress on retrieval of stimulus-response memory. Male Sprague-Dawley rats were trained on a stimulus-response task in an eight-arm radial maze until they learned to associate a stimulus, i.e., cue, with a food reward in one of the arms. Twenty-four hours after successful acquisition, they received a systemic injection of vehicle, corticosterone (1 mg/kg), the corticosterone-synthesis inhibitor metyrapone (35 mg/kg) or were left untreated I h before retention testing. We found that the corticosterone injection impaired the retrieval of stimulus-response memory. We further found that the systemic injection procedure per se was stressful as the vehicle administration also increased plasma corticosterone levels and impaired the retrieval of stimulus-response memory. However, memory retrieval was not impaired when rats were tested 2 min after the systemic vehicle injection, before any stress-induced elevation in corticosterone levels had occurred. Moreover, metyrapone treatment blocked the effect of injection stress on both plasma corticosterone levels and memory retrieval impairment, indicating that the endogenous corticosterone response mediates the stress-induced memory retrieval impairment. None of the treatments affected rats' locomotor activity or motivation to search for the food reward within the maze. These findings show that stress may affect memory processes beyond the hippocampus and that these stress effects are due to the action of glucocorticoids. (C) 2016 Elsevier Ltd. All rights reserved. Show less
Fitzsimons, C.P.; Herbert, J.; Schouten, M.; Meijer, O.C.; Lucassen, P.J.; Lightman, S. 2016
