Cardiovascular events occur most frequently in the early morning. Similarly, the release of reticulated platelets (RP) by megakaryocytes has a peak in the late night and early morning. Which... Show moreCardiovascular events occur most frequently in the early morning. Similarly, the release of reticulated platelets (RP) by megakaryocytes has a peak in the late night and early morning. Which aspirin regimen most effectively inhibits platelets during these critical hours is unknown. Hence, the primary objective of this trial was to assess platelet function and RP levels at 8.00 AM, in stable cardiovascular (CVD) patients, during three different aspirin regimens. In this open-label randomized cross-over study subjects were allocated to three sequential aspirin regimens: once-daily (OD) 80 mg morning; OD-evening, and twice-daily (BID) 40 mg. Platelet function was measured at 8.00 AM & 8.00 PM by serum Thromboxane B-2(sTxB(2)) levels, the Platelet Function Analyzer (PFA)-200 (R) Closure Time (CT), Aspirin Reaction Units (ARU, VerifyNow (R)), and RP levels. In total, 22 patients were included. At 8.00 AM, sTxB(2)levels were the lowest after OD-evening in comparison with OD-morning (p= <0.01), but not in comparison with BID. Furthermore, RP levels were similar at 8.00 AM, but statistically significantly reduced at 8.00 PM after OD-evening (p= .01) and BID (p= .02) in comparison with OD-morning. OD-evening aspirin intake results in higher levels of platelet inhibition during early morning hours and results in a reduction of RP levels in the evening. These findings may, if confirmed by larger studies, be relevant to large groups of patients taking aspirin to reduce cardiovascular risk. Show less
ObjectiveRecently, salivary alpha-amylase (sAA) has been proposed as a suitable index for sympathetic activity and dysregulation of the autonomic nervous system (ANS). Although determinants of sAA... Show moreObjectiveRecently, salivary alpha-amylase (sAA) has been proposed as a suitable index for sympathetic activity and dysregulation of the autonomic nervous system (ANS). Although determinants of sAA have been described, they have not been studied within the same study with a large sample size without potential disturbances of psychopathology. In this paper, we report about correlates of evening sAA in saliva. MethodsIn 487 participants (mean age=42.9years, 59.8% female) without lifetime psychiatric disorders from the Netherlands Study of Depression and Anxiety (NESDA), sociodemographic, health and sampling determinants of sAA levels were examined using multivariable linear regression analysis. sAA was measured in two saliva samples that participants collected in the late evening, at 22:00h and 23:00h, after which these were averaged. ResultsIn multivariate analysis, age (β=0.20, p<0.001) and daily alcohol intake (β=−0.13, p=0.01) were independent determinants of evening sAA levels. Gender, allergy or lung disease, and the use of oral contraceptives were univariate correlates, but no longer associated with sAA in the multivariate model. ConclusionsAge and alcohol use were identified as potential confounding factors that should be taken into account in epidemiologic studies that examine the ANS function using sAA. Show less
OBJECTIVE: Recently, salivary alpha-amylase (sAA) has been proposed as a suitable index for sympathetic activity and dysregulation of the autonomic nervous system (ANS). Although determinants of... Show moreOBJECTIVE: Recently, salivary alpha-amylase (sAA) has been proposed as a suitable index for sympathetic activity and dysregulation of the autonomic nervous system (ANS). Although determinants of sAA have been described, they have not been studied within the same study with a large sample size without potential disturbances of psychopathology. In this paper, we report about correlates of evening sAA in saliva. METHODS: In 487 participants (mean age=42.9years, 59.8% female) without lifetime psychiatric disorders from the Netherlands Study of Depression and Anxiety (NESDA), sociodemographic, health and sampling determinants of sAA levels were examined using multivariable linear regression analysis. sAA was measured in two saliva samples that participants collected in the late evening, at 22:00h and 23:00h, after which these were averaged. RESULTS: In multivariate analysis, age (β=0.20, p<0.001) and daily alcohol intake (β=-0.13, p=0.01) were independent determinants of evening sAA levels. Gender, allergy or lung disease, and the use of oral contraceptives were univariate correlates, but no longer associated with sAA in the multivariate model. CONCLUSIONS: Age and alcohol use were identified as potential confounding factors that should be taken into account in epidemiologic studies that examine the ANS function using sAA. Show less
Cortisol affects the acute-phase response, but it is unknown whether C-reactive protein (CRP), an acute-phase reactant, also affects hypothalamus?pituitary?adrenal axis activity. In the present... Show moreCortisol affects the acute-phase response, but it is unknown whether C-reactive protein (CRP), an acute-phase reactant, also affects hypothalamus?pituitary?adrenal axis activity. In the present study, associations were explored between CRP haplotypes with plasma CRP concentrations and basal salivary cortisol level. We included 266 physically healthy Caucasian subjects (103 females and 163 males) aged between 18 and 65 years of whom 94 had a psychiatric disorder in a genetic association study. Six tag single-nucleotide polymorphisms capturing the common genetic variation of the CRP gene were genotyped (i.e. rs2808628, rs2808630, rs1205, rs1800947, rs1417938, and rs3091244) to yield common CRP haplotypes. Plasma CRP concentrations, the salivary cortisol awakening response (CAR) (0, 30, 45, and 60?min after awakening), and the diurnal cortisol decline (11:00, 15:00, 19:00, and 23:00?h) were assessed for 2 days. rs2808628, rs1205, rs1417938, and rs3091244 showed expected associations not only with CRP concentrations, but also with salivary cortisol levels during the CAR. Five well-characterized CRP haplotypes were arranged in ascending order according to increasing CRP levels. There was an inverse linear association between CRP haplotypes and cortisol levels during the CAR, but no association with the diurnal cortisol decline. Hence, genetic variants in the CRP gene that are associated with lifetime plasma CRP levels were also associated with salivary cortisol levels after awakening, in basal, non-inflammatory conditions. Show less
The Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV classification may fail to adequately distinguish neuroendocrine factors involved in the etiology of depressive and anxiety... Show moreThe Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV classification may fail to adequately distinguish neuroendocrine factors involved in the etiology of depressive and anxiety disorders. Continuous phenotypic dimensions may correlate better with underlying neuroendocrine dysregulations. We compared the categorical DSM-IV diagnoses with a dimensional approach in the same group of outpatients with depressive (n=36), anxiety (n=18), and comorbid depressive and anxiety (n=19) disorders, who were free of psychotropic medication, and in 36 healthy controls. The Mood and Anxiety Symptom Questionnaire (MASQ) was used to measure the three dimensions of the tripartite model, i.e., anhedonic depression, anxious arousal, and general distress. The salivary cortisol awakening response (CAR) (0, 30, 45, and 60 min after awakening), and diurnal cortisol decline (11:00 h, 15:00 h, 19:00 h, and 23:00 h) were analyzed for linear and nonlinear associations. The CAR showed statistically significant nonlinear relationships with two MASQ dimensions, i.e., anhedonic depression and general distress, but no differences between DSM-IV categories. The diurnal cortisol decline was linearly related to the MASQ dimensions anhedonic depression and general distress and significantly higher AUC(diurnal) levels and a steeper slope were found in depressive patients compared to controls using DSM-IV categories. The present study shows that linear and nonlinear associations with salivary cortisol are detected when using phenotypic dimensions and may be complementary to phenotypic DSM-IV categories when doing neuroendocrine research. Show less
Background: Dysregulation of the hypothalamic pituitary adrenal (HPA)-axis is hypothesized to underlie stress-related psychiatric disorders such as post-traumatic stress disorder (PTSD). We aimed... Show moreBackground: Dysregulation of the hypothalamic pituitary adrenal (HPA)-axis is hypothesized to underlie stress-related psychiatric disorders such as post-traumatic stress disorder (PTSD). We aimed to explore whether trauma exposure is associated with alterations in HPA-axis functioning in the absence of lifetime psychiatric morbidity. Method: We included 39 trauma-exposed healthy male subjects (mean age = 47 years; SD = 9.2) and 24 non-exposed healthy male controls (mean age = 47.4 years; SD = 14.5). All subjects were free of lifetime psychopathology. Basal salivary cortisol levels (on two consecutive days) as well as the cortisol and adrenocorticotropic hormone (ACTH) response to the combined dexamethasone/corticotropin releasing hormone (Dex/CRH) challenge test were analyzed using general linear models (GLM) adjusted for body mass index, age and smoking status. Results: A blunted salivary cortisol awakening response was found in the exposed group compared to the non-exposed group (F(1,57) = 5.46, p = .02). Consistent with these findings, salivary diurnal cortisol was lower in the trauma-exposed versus non-exposed group (F(1,57) = 4.04, p =.05). No differences, however, were found between both groups for plasma cortisol or ACTH responses to the Dex/CRH test. Conclusion: Low basal cortisol levels were found in trauma-exposed men, suggesting that HPA-axis alterations in men are associated with trauma exposure during adulthood, also in the absence of psychopathology. (C) 2009 Elsevier Ltd. All rights reserved. Show less
In this thesis, we provide evidence in research on endophenotypes of psychopathology that it is fruitful not to take the clinical picture central, but the hypothalamus-pituitary-adrenal (HPA) axis... Show moreIn this thesis, we provide evidence in research on endophenotypes of psychopathology that it is fruitful not to take the clinical picture central, but the hypothalamus-pituitary-adrenal (HPA) axis as a core stress system underlying psychopathophysiology in stress-related disorders. Homeostatic systems, including the HPA axis, are by nature nonlinear in their function, with suboptimal states of function at both sides of the curve, e.g. hyper- versus hypofunction. By taken the HPA axis as starting point, we were able redefine the clinical phenotype in relation to both dysfunctional states, i.e., hyper- and hypocortisolism. Furthermore, starting with the stress system enabled us to investigate the effects of HPA axis dysfunction on the metabolic and immune system. Based on the studies presented in this thesis, we hypothesize that the nonlinear aspect of HPA axis function reflects different time points during the stress process, from a hyperactive HPA axis when the stress begins to, eventually, a hypoactive HPA axis when stress holds on. Secondly, we hypothesize that both dysfunctional states of the HPA axis, i.e., hyper- and hypocortisolism, differ in their effects on the metabolic and immune system. Show less
