Background: Harnessing cold-induced thermogenesis (CIT) and brown adipose tissue (BAT) activity has been proposed as a means of counteracting a positive energy balance, and thus of combating... Show moreBackground: Harnessing cold-induced thermogenesis (CIT) and brown adipose tissue (BAT) activity has been proposed as a means of counteracting a positive energy balance, and thus of combating obesity and its related comorbidities. However, it has remained unclear whether CIT and BAT activity show diurnal variation in humans -knowledge that might allow treatments based on these factors to be time-optimized.Methods: A randomized crossover experiment was designed to examine whether CIT shows morning/evening variation in young, healthy adults (n = 14, 5 women). On the first experimental day, subjects' shivering thresholds were determined following a cooling protocol. After z96 h had elapsed, the sub-jects then returned on two further days (approx. 48 h apart) at 08:00 h or 18:00 in random order. On both the latter days, the resting energy expenditure (REE) was measured before the subjects underwent personalized cold exposure (i.e., according to their shivering threshold). CIT was then assessed for 60 min by indirect calorimetry. In an independent cross-sectional study (n = 133, 88 women), subjects came to the laboratory between 8:00 and 18:00 h and their BAT F-18-fluordeoxyglucose (F-18-FDG) uptake was assessed after personalized cold stimulation.Results: Both the REE and CIT were similar in the morning and evening (all P > 0.05). Indeed, 60 min of personalized-mild cold exposure in the morning or evening elicited a similar change in energy expen-diture (16.8 +/- 12.8 vs. 15.7 +/- 15.1% increase above REE, P = 0.72). BAT F-18-FDG uptake was also similar in the morning, evening and afternoon (all P > 0.05).Conclusion: CIT does not appear to show morning/evening variation in young healthy adults, with the current study design and methodology. BAT F-18-FDG uptake appears not to change across the day either, although experiments with a within-subject study design are needed to confirm these findings. (C) 2021 The Author(s). Published by Elsevier Ltd. Show less
Objectives Rheumatoid arthritis (RA) patients show an earlier circadian rhythm (i.e. serum melatonin peaks earlier during the night, indicating an earlier timing of the internal circadian pacemaker... Show moreObjectives Rheumatoid arthritis (RA) patients show an earlier circadian rhythm (i.e. serum melatonin peaks earlier during the night, indicating an earlier timing of the internal circadian pacemaker). In the current study, we examined whether the chronotype, which is influenced by the circadian rhythm, is also earlier. In addition, we explored whether chronotype is related to disease activity and patient-reported outcomes.Methods The chronotype (Munich Chronotype Questionnaire) of patients with RA (n = 121; mean age 60 years, 73% female) was compared with that of subjects from the general population (norm group; n = 1695) with a one-sample t test. In addition, we investigated chronotype in relation to disease activity (Disease Activity Score; DAS), reported morning stiffness, fatigue (Checklist Individual Strength), and health-related quality of life (RAND-36).Results The chronotype of patients with RA was, on average, 23 min (95% CI, 15 to 31 min) earlier than that of the norm group (t(115) = - 5.901, p < 0.001, d = 0.55). Chronotype was not related to disease activity or patient-reported outcomes (p > 0.05).Conclusion As expected, chronotype was earlier in RA patients. However, in this correlational study, chronotype was not related to disease activity or patient-reported outcomes. An experimental study is needed to examine whether delaying the circadian rhythm has a positive influence on these outcomes. This insight could improve our understanding of the pathophysiology of RA and contribute to exploring new treatment possibilities.Key Points This is the first study examining chronotype in patients with rheumatoid arthritis, and how chronotype relates to disease activity and patient-reported outcomes.We found an earlier chronotype in patients with rheumatoid arthritis than in subjects from the general population.In this correlational study, chronotype was not related to disease activity or patient-reported outcomes. An experimental study is needed to examine whether delaying the circadian rhythm positively influences these outcomes. Show less
This thesis provides an insight in the clinical aspects and therapy with neurostimulation in cluster headache patients. An unique cohort of Dutch cluster headache patients (LUCA - Leiden University... Show moreThis thesis provides an insight in the clinical aspects and therapy with neurostimulation in cluster headache patients. An unique cohort of Dutch cluster headache patients (LUCA - Leiden University Cluster headache neuro-Analysis programme) has been used to analyse different clinical aspects like drug-use, chronobiology and aura symptoms in cluster headache patients. Regarding neuromodulation: a case-report about occipital nerve stimulation and pregnancy is described here and a meta-analysis of non-invasive vagal nerve stimulation as acute treatment in both episodic and chronic cluster headache. Show less
Background: The role of chronotype, the individual timing of sleep/activity, has been studied in relation todepressive and anxiety disorders. A cross-sectional association between a depressive... Show moreBackground: The role of chronotype, the individual timing of sleep/activity, has been studied in relation todepressive and anxiety disorders. A cross-sectional association between a depressive episode and evening-typehas been identified. However, until now the predicting capacity of chronotype concerning persistence of psy-chiatric disorders remains unclear. Our aim is to examine whether a later chronotype in patients with a de-pressive and/or anxiety disorder can serve as a predictor of a persistent course.Methods: A subsample of patients with a depressive and/or anxiety disorder diagnosis and chronotype data ofthe longitudinal Netherlands Study of Depression and Anxiety (NESDA) was used. Diagnosis of depressive andanxiety disorders (1-month DSM-IV based diagnosis) were determined at baseline (n = 505). From this grouppersistence was determined at 2-year (FU2) (persistent course: n = 248, non-persistent course: n = 208) and 4-year follow-up (FU4) (persistent course: n = 151, non-persistent course: n = 264). Chronotype was assessed atbaseline with the Munich Chronotype Questionnaire.Results: A later chronotype did not predict a persistent course of depressive and/or anxiety disorder at FU2 (OR(95% CI) = 0.99 (0.83–1.19), P = 0.92) or at FU4 (OR (95% CI) = 0.94 (0.77–1.15), P = 0.57).Limitations: Persistence was defined as having a diagnosis of depressive and/or anxiety disorder at the two-yearand four-year follow-up, patients may have remitted and relapsed between assessments.Conclusion: Chronotype, measured as actual sleep timing, of patients with a depressive or anxiety disorder didnot predict a persistent course which suggests it might be unsuitable as predictive tool in clinical settings. Show less
Many physiological processes, including those involved in the absorption, distribution, metabolism, elimination, pharmacodynamics and toxicity of therapeutic drugs, show profound fluctuations... Show moreMany physiological processes, including those involved in the absorption, distribution, metabolism, elimination, pharmacodynamics and toxicity of therapeutic drugs, show profound fluctuations over the course of the day and night. This may lead to time-of-day dependent changes in the exposure and effect of therapeutic drugs. The aim of this thesis is to provide a structured framework for chronopharmacological studies, while concurrently touching upon several critical issues encountered during the development and optimization of new and existing drug treatments. Firstly, we studied 24-hour variation in the pharmacokinetics of both midazolam and levofloxacin in healthy male subjects and found that for both drugs, absorptive processes show time-of-day dependency. Moreover, the magnitude of QT prolongation induced by levofloxacin, a common side-effect induced by many types of drugs, varied considerably and systematically over the course of the day. Furthermore, we investigated daily variation of drug distribution to the brain and found that time of day can be a considerable source of variation that could influence the effectiveness of drugs targeted to the brain. Taken together, these studies show that chronopharmacological aspects should not be overlooked in order to benefit from the systematic fluctuations in physiological processes during the development and optimization of drug treatments. Show less
In modern society, circadian rhythms and sleep are often disturbed, which may negatively affect health. This thesis examines these associations and focuses on the basic functioning of sleep and the... Show moreIn modern society, circadian rhythms and sleep are often disturbed, which may negatively affect health. This thesis examines these associations and focuses on the basic functioning of sleep and the circadian system in mice and in humans. Circadian rhythms are orchestrated by ~20,000 neurons in the central clock in the suprachiasmatic nuclei (SCN) in the brain. In mice, a complete abolishment of central clock-driven rhythms resulted in obesity and severe hepatic insulin resistance. An attenuation of rhythms resulted in decreased muscle strength, osteoporosis-like bone changes and transient changes in the immune system. In humans, short sleeping obese individuals with a preference for evening activities ("evening chronotypes") had increased cardiovascular risk factors. Their neurocognitive function was often impaired and could be improved with sleep extension. Insufficient sleep was also associated with an increased risk for osteopenia and sarcopenia. Taken together, disrupted circadian rhythms and insufficient sleep associate with a spectrum of unfavorable health outcomes. Studies described in the thesis provide insight in potential strategies to improve rhythms and sleep: by appropriately timed behavior (active behavior during the active phase; rest during the rest phase), light exposure (light during the subjective day; darkness at night) as well as caffeine intake. Show less
We have developed an integrated PK/PD model that adequately captures the disposition kinetics of benazeprilat, as well as the time-varying changes of systemic renin-angiotensin aldosterone (RAA)... Show moreWe have developed an integrated PK/PD model that adequately captures the disposition kinetics of benazeprilat, as well as the time-varying changes of systemic renin-angiotensin aldosterone (RAA) biomarkers without, and with ACE inhibition therapy. This mechanistic representation provides a quantitative framework for better understanding the effect of ACE inhibition on the RAAS in dogs, but also in humans. Our data show that benazepril influences the dynamics of the renin-angiotensin-aldosterone cascade, resulting in a profound but temporary decrease in angiotensin II (AII) and aldosterone (ALD), while increasing RA for about 24 hours. Based on recent literature in human heart failure (HF) patients (G_der et al., 2007), the reduction of AII and ALD may be one of the drivers of increased survival and improved quality of life in benazepril-treated dogs. To support and consolidate this hypothesis, additional efforts should be directed towards collection of circulating RAA peptides in spontaneous cases of canine HF. If such a link can be established, profiling of these peptides could support the determination of the severity of heart failure, complement clinical and echocardiographic findings, and be used for therapeutic drug monitoring purposes. Show less
