iLib08 - Citavi Buijs, Ruud M.; Scheer, Frank A.; Kreier, Felix; Yi, Chunxia; Bos, Nico; Goncharuk, Valeri D.

; Kalsbeek, Andries (2006): Organization of circadian functions: interaction with the body. In: Progress in brain research, Jg. 153, S. 3 13 0 Onn v r g a u t d i01 1 /0 7 -1 30 )3 2 -. 4 – 6 . le ef b r ne o: . 6S 0 96 2 (65 0 01 i ü r 1 0 Abstract The hypothalamus integrates information from the brain and the body; this activity is essential for survival of the individual (adaptation to the environment) and the species (reproduction). As a result, countless functions are regulated by neuroendocrine and autonomic hypothalamic processes in concert with the appropriate behaviour that is mediated by neuronal influences on other brain areas. In the current chapter attention will be focussed on fundamental hypothalamic systems that control metabolism, circulation and the immune system. Herein a system is defined as a physiological and anatomical functional unit, responsible for the organisation of one of these functions. Interestingly probably because these systems are essential for survival, their function is highly dependent on each other's performance and often shares same hypothalamic structures. The functioning of these systems is strongly influenced by (environmental) factors such as the time of the day, stress and sensory autonomic feedback and by circulating hormones. In order to get insight in the mechanisms of hypothalamic integration we have focussed on the influence of the biological clock; the suprachiasmatic nucleus (SCN) on processes that are organized by and in the hypothalamus. The SCN imposes its rhythm onto the body via three different routes of communication: 1.Via the secretion of hormones; 2. via the parasympathetic and 3.via the sympathetic autonomous nervous system. The SCN uses separate connections via either the sympathetic or via the parasympathetic system not only to prepare the body for the coming change in activity cycle but also to prepare the body and its organs for the hormones that are associated with such change. Up till now relatively little attention has been given to the question how peripheral information might be transmitted back to the SCN. Apart from light and melatonin little is known about other systems from the periphery that may provide information to the SCN. In this chapter attention will be paid to e.g. the role of the circumventricular organs in passing info to the SCN. Herein especially the role of the arcuate nucleus (ARC) will be highlighted. The ARC is crucial in the maintenance of energy homeostasis as an integrator of long- and short-term hunger and satiety signals. Receptors for metabolic hormones like insulin, leptin and ghrelin allow the ARC to sense information from the periphery and signal it to the central nervous system. Neuroanatomical tracing studies using injections of a retrograde and anterograde tracer into the ARC and SCN showed a reciprocal connection between the ARC and the SCN which is used to transmit feeding related signals to the SCN. The implications of multiple inputs and outputs of the SCN to the body will be discussed in relation with metabolic functions. Schlagwörter Animals; Autonomic Pathwaysphysiology; Biological Clocksphysiology; Circadian Rhythmphysiology; Endocrine Systemphysiology; Humans; Hypothalamuscytologyphysiology; Neuronsphysiology; Neuropeptidesmetabolism Hu, K.; Scheer, F. A. J. L.; Ivanov, P. Ch; Buijs, R. M.; Shea, S. A. (2007): The suprachiasmatic nucleus fn t n b y n cc da ry m g n rtn I: e rsi c , g 1 9 H 3 S 5 8 5 7 O levr g a u co s e o d i a i h t i r n h e eai .n N uo c n e J . 4 , . , . 0 – 1 . nn ef b r o e i ü unter doi:10.1016/j.neuroscience.2007.03.058. Abstract We recently discovered that human activity possesses a complex temporal organization characterized by scale-invariant/self-similar fluctuations from seconds to approximately 4 h-(statistical properties of fluctuations remain the same at different time scales). Here, we show that scale-invariant activity patterns are essentially identical in humans and rats, and exist for up to approximately 24 h: sixtimes longer than previously reported. Theoretically, such scale-invariant patterns can be produced by a neural network of interacting control nodes-system components with feedback loops-operating at different time scales. However such control nodes have not yet been identified in any neurophysiological model of scale invariance/self-similarity in mammals. Here we demonstrate that the endogenous

iLib08 - Citavi circadian pacemaker (suprachiasmatic nucleus; SCN), known to modulate locomotor activity with a periodicity of approximately 24 h, also acts as a major neural control node responsible for the generation of scale-invariant locomotor patterns over a broad range of time scales from minutes to at least 24 h (rather than solely at approximately 24 h). Remarkably, we found that SCN lesion in rats completely abolished the scale-invariant locomotor patterns between 4 and 24 h and significantly altered the patterns at time scales <4 h. Identification of the control nodes of a neural network responsible for scale invariance is the critical first step in understanding the neurophysiological origin of scale invariance/self-similarity. Activity Cyclesphysiology; Adult; Animals; Circadian Rhythmphysiology; Darkness; Data Interpretation, Statistical; Female; Humans; Light; Male; Motor Activityphysiology; Rats; Rats, Wistar; Suprachiasmatic Nucleusphysiology

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Hu, Kun; Scheer, Frank A. J. L.; Buijs, Ruud M.; Shea, Steven A. (2008): The endogenous circadian pacemaker imparts a scale-invariant pattern of heart rate fluctuations across time scales spanning minutes to 24 hours. In: J un l f io i lh t , g 2 , . , . 6 – 7 . nn vr g a u t d i01 7 / 4 7 0 0 3 6 6 . o rao bo g a ryh J. 3 H 3 S 2 52 3 O le ef b r ne o 1 . 70 8 3 4 8 1 1 6 l c ms i ü r : 1 7 Abstract Heartbeat fluctuations in mammals display a robust temporal structure characterized by scale-invariant/fractal patterns. These scale-invariant patterns likely confer physiological advantage because they change with cardiovascular disease and these changes are associated with reduced survival. Models of physical systems imply that to produce scale-invariant patterns, factors influencing the system at different time scales must be coupled via a network of feedback interactions. A similar cardiac control network is hypothesized to be responsible for the scale-invariant pattern in heartbeat dynamics, although the essential network components have not been determined. Here is shown that scale-invariant cardiac control occurs across time scales from minutes to approximately 24 h, and that lesioning the mammalian circadian pacemaker (suprachiasmatic nucleus; SCN) completely abolishes the scale-invariant pattern at time scales>or approximately 4 h. At time scales<or approximately 4 h, the scale invariance persisted following SCN lesion but with a different pattern. These results indicate previously unrecognized multiscale influences of the SCN on heart rate fluctuations that cannot be explained by a simple pacemaker of 24-h rhythmicity. The conclusion is that the SCN serves as a major node in the cardiac control network and imparts scale-invariant cardiac control across a wide range of time scales with strongest effects between approximately 4 and 24 h. These results demonstrate that experimental manipulations (e.g., SCN lesion) can be used to begin to model and understand the origin of scale-invariant behavior in a neurophysiological system. Schlagwörter Animals; Biological Clocks; Circadian Rhythm; Heart Rate; Rats; Rats, Wistar; Suprachiasmatic Nucleusphysiology Hu, Kun; Scheer, Frank A. J. L.; Buijs, Ruud M.; Shea, Steven A. (2008): The circadian pacemaker generates similar circadian rhythms in the fractal structure of heart rate in humans and rats. In: Cardiovascular research, J . 0 H 1 S 6 – 8 O lev r g a u tr o 1 .0 3cr v 1 0 g 8 , . , . 2 6 . ni ef b r ne d i 0 9 / / n 5 . n ü : 1 vc Abstract AIMS: Adverse cardiovascular events in humans occur with a day/night pattern, presumably related to a daily pattern of behaviours or endogenous circadian rhythms in cardiovascular variables. Healthy humans possess a scaleinvariant/fractal structure in heartbeat fluctuations that exhibits an endogenous circadian rhythm and changes towards the structure observed in cardiovascular disease at the circadian phase corresponding to the time of the broad peak of adverse cardiovascular events (at about 10 AM). To explore the relationship between the rest/activity cycle, endogenous circadian rhythmicity, and cardiac vulnerability, we tested whether the fractal structure of heart rate exhibits a similar circadian rhythm in a mammalian species that is nocturnally active (Wistar rats) compared with diurnally active humans, and how this fractal structure changes after lesioning the circadian pacemaker (suprachiasmatic nucleus, SCN) in rats. METHODS AND RESULTS: Analysis of heart rate data collected over 10 days in

iLib08 - Citavi eight intact and six SCN-lesioned Wistar rats during constant darkness revealed that: (i) as with humans, rats exhibit an endogenous circadian rhythm in the scaling exponent characterizing the hourly fractal structure of heart rate (P = 0.0005) with larger exponents during the biological day (inactive phase for rats; active phase for humans); (ii) SCN lesioning abolished the rhythm in the fractal structure of heart rate and systematically increased the scaling exponent (P = 0.01). CONCLUSION: Rats possess a circadian rhythm of fractal structure of heart rate with a similar temporal pattern as previously observed in humans despite opposite rest/activity cycles between the two species. The SCN imparts this endogenous rhythm. Moreover, lesioning the SCN in rats results in a larger scaling exponent, as occurs with cardiovascular disease in humans. Animals; Biological Clocks; Circadian Rhythm; Fractals; Heart Rate; Humans; Rats; Rats, Wistar; Suprachiasmatic Nucleusphysiology

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Kalsbeek, A.; Palm, I. F.; La Fleur, S. E.; Scheer, F. A. J. L.; Perreau-Lenz, S.; Ruiter, M. et al. (2006): SCN o t ta dte yoh l cb l c o l .n J un l f io i lh t , g 2 , . , . 5 – 6 . nn up s n h h p t a u a mi aa e ff I o ra o b l c ry ms J . 1 H 6 S 4 8 4 9 O le n i : e oga h i verfügbar unter doi:10.1177/0748730406293854. Abstract The circadian clock in the suprachiasmatic nucleus (SCN) is composed of thousands of oscillator neurons, each dependent on the cell-autonomous action of a defined set of circadian clock genes. Still, the major question remains how these individual oscillators are organized into a biological clock producing a coherent output able to time all the different daily changes in behavior and physiology. In the present review, the authors discuss the anatomical connections and neurotransmitters used by the SCN to control the daily rhythms in hormone release. The efferent SCN projections mainly target neurons in the medial hypothalamus surrounding the SCN. The activity of these preautonomic and neuroendocrine target neurons is controlled by differentially timed waves of, among others, vasopressin, GABA, and glutamate release from SCN terminals. Together, the data on the SCN control of neuroendocrine rhythms provide clear evidence not only that the SCN consists of phenotypically (i.e., according to neurotransmitter content) different subpopulations of neurons but also that subpopulations should be distinguished (within phenotypically similar groups of neurons) based on the acrophase of their (electrical) activity. Moreover, the specialization of the SCN may go as far as a single body structure, that is, the SCN seems to contain neurons that specifically target the liver, pineal, and adrenal. Schlagwörter Animals; Autonomic Nervous Systemphysiology; Biological Clocksphysiology; Circadian Rhythmphysiology; Humans; Neuronsphysiology; Suprachiasmatic Nucleusphysiologysecretion; Vasopressinsphysiology Scheer, F. A.; Buijs, R. M. (1999): Light affects morning salivary cortisol in humans. In: The Journal of clinical e d cio g a dme b lm, g 8 , . , . 3 5 3 9 . n or l y n no t oi J . 4 H 9 S 3 9 – 3 8 a s Abstract The effect of light on the morning-cortisol peak in humans was investigated in fourteen healthy men by exposing them to darkness and to light of 800 lux during a 1-h period on two subsequent mornings. In the early morning, we demonstrated a temporary increase of salivary cortisol levels after awakening, while light exposure resulted in a +/- 35% further increase in cortisol levels. Cortisol levels 20 and 40 min after waking were significantly higher during 800 lux exposure than during darkness. In order to investigate the time-dependency, the experiment was repeated in the late evening. In the evening, light had no effect on cortisol levels. These results demonstrate that light conditions in the early morning have a strong impact on the morning-cortisol peak, but that evening cortisol levels are unaffected by light. The possible role of the circadian pacemaker as mediator of the light effect on cortisol level is discussed. Schlagwörter Adult; Circadian Rhythm; Humans; Hydrocortisonemetabolism; Light; Male; Salivametabolism

iLib08 - Citavi Scheer, F. A.; Ter Horst, G. J.; van der Vliet, J.; Buijs, R. M. (2001): Physiological and anatomic evidence for regulation of the heart by suprachiasmatic nucleus in rats. In: American journal of physiology. Heart and circulatory physiology, Jg. 280, H. 3, S. H1391-9. Abstract The suprachiasmatic nucleus (SCN) is the mammalian biological clock that generates the daily rhythms in physiology and behavior. Light can phase shift the rhythm of the SCN but can also acutely affect SCN activity and output, e.g., output to the pineal. Recently, multisynaptic SCN connections to other organs were also demonstrated. Moreover, they were shown to affect those organs functionally. The aim of the present study was to investigate the role of the SCN in the regulation of the heart. First, we demonstrated that heart rate (HR) in SCN-intact, but not SCNlesioned (SCNx), male Wistar rats had a clear circadian rhythm, which was not caused by locomotor activity. Second, we demonstrated that light at night reduces HR in intact but not in SCNx rats. Finally, we demonstrated the presence of a multisynaptic autonomic connection from SCN neurons to the heart with the retrograde pseudorabies virus tracing technique. Together, these results demonstrate that the SCN affects the heart in rats and suggest that this is mediated by a neuronal mechanism. Schlagwörter Animals; Autonomic Nervous Systemphysiology; Circadian Rhythmphysiology; Heartinnervationphysiology; Heart Ratephysiology; Herpesvirus 1, Suid; Lighting; Male; Rats; Rats, Wistar; Suprachiasmatic Nucleusanatomy & histologyphysiology Scheer, F. A.; van Doornen, L. J.; Buijs, R. M. (1999): Light and diurnal cycle affect human heart rate: possible rl frh cc da p cma e.n J un l f io i lh t , g 1 , . , . 0 – 1 . oe o te i a i a e k rI:o ra o b l c ry ms J . 4 H 3 S 2 2 2 2 r n oga h Abstract Humans and animals demonstrate diurnal rhythms in physiology and behavior, which are generated by the circadian pacemaker, located in the supra-chiasmatic nucleus (SCN). The endogenous diurnal rhythm of the SCN is synchronized to the diurnal cycle most effectively by light. However, light also influences the SCN and its output instantaneously, as is demonstrated for the immediate effects of light on SCN neuronal firing frequency and on the output of the SCN to the pineal, inhibiting melatonin secretion. In addition to this, the circadian pacemaker modulates neuronally also other organs such as the adrenal. Therefore, the authors investigated the effect of this light input to the SCN on human heart rate, using light at different phases of the day-night cycle and light of different intensities. Resting heart rate (HR) was measured in volunteers between 20 and 40 years of age during supine, awake, resting conditions, and after 2 hours of fasting. In Experiment 1, HR was measured at different times over the day-night cycle at 0 lux and at indoor light. In Experiment 2, HR was measured at different times over the day-night cycle at controlled light intensities of 0 lux, 100 lux, and 800 lux. The authors demonstrate a clear diurnal rhythm in resting HR in complete darkness, similar to that measured under constant routine conditions. Second, it is demonstrated that light increases resting HR depending on the phase of the day-night cycle and on the intensity of light. These data strongly suggest that the circadian pacemaker modulates human HR. Schlagwörter Adult; Analysis of Variance; Biological Clocksphysiology; Circadian Rhythmphysiology; Dose-Response Relationship, Radiation; Heart Ratephysiologyradiation effects; Humans; Light; Male Scheer, F. A. J. L.; Pirovano, C.; van Someren, E. J. W.; Buijs, R. M. (2005): Environmental light and suprachiasmatic nucleus interact in the regulation of body temperature. In: Neuroscience, Jg. 132, H. 2, S. 4 54 7 Onn v r g a u t d i01 1 / e rsi c . 0 .20 2 6 – 7 . le ef b r ne o: . 6j uo c n e2 41 .1 . i ü r 1 0 . n e 0 Abstract The mammalian biological clock, located in the suprachiasmatic nucleus (SCN), is crucial for circadian rhythms in physiology and behavior. However, equivocal findings have been reported on its role in the circadian regulation of body temperature. The goal of the present studies was to investigate the interaction between the SCN and environmental light in the regulation of body temperature. All recordings were performed by telemetry in free moving male Wistar rats. Firstly, we

iLib08 - Citavi demonstrated an endogenous circadian rhythm in body temperature independent of locomotor activity. This rhythm was abolished by stereotactic lesioning of the SCN. Secondly, we demonstrated a circadian phase-dependent suppressive effect of light ('negative masking') on body temperature. Light suppressed body temperature more at the end of the subjective night (circadian time [CT] 22) than in the middle (CT 6) and at the end (CT 10) of the subjective day. This circadian-phase dependent suppression was not demonstrated in SCN-lesioned animals. Surprisingly, after half a year of recovery from lesioning of the SCN, light regained its suppressing action on body temperature, resulting in a daily body temperature rhythm only under light-dark conditions. In contrast to body temperature, light could not substantially mimic a daytime inhibitory SCN-output in the regulation of heart rate and locomotor activity. The present results suggest that, after lesioning of the SCN as main relay station for the immediate body temperature-inhibition by light, secondary relay nuclei can fully take over this function of the SCN. These findings provide a possible explanation for the controversy in literature over the question whether the SCN is required for the diurnal rhythm in body temperature. Furthermore, they show that light may have an acute effect on behavior and physiology of the organism via the SCN, which extends beyond the generally acknowledged effect on melatonin secretion. Analysis of Variance; Animals; Body Temperaturephysiology; Chi-Square Distribution; Circadian Rhythmphysiology; Heart Ratephysiology; Light; Male; Motor Activityphysiology; Photic Stimulation; Rats; Rats, Wistar; Suprachiasmatic Nucleusphysiology; Time Factors

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Scheer, Frank A.; Kalsbeek, Andries; Buijs, Ruud M. (2003): Cardiovascular control by the suprachiasmatic nucleus: neural and neuroendocrine mechanisms in human and rat. In: Biological chemistry, Jg. 384, H. 5, S. 6 77 9 Onn v r g a u t d i01 1 /C2 0 . 8 9 – 0 . le ef b r ne o: . 5B .0 30 . i ü r 1 5 7 Abstract The risk for cardiovascular incidents is highest in the early morning, which seems partially due to endogenous factors. Endogenous circadian rhythms in mammalian physiology and behavior are regulated by the suprachiasmatic nucleus (SCN). Recently, anatomical evidence has been provided that SCN functioning is disturbed in patients with essential hypertension. Here we review neural and neuroendocrine mechanisms by which the SCN regulates the cardiovascular system. First, we discuss evidence for an endogenous circadian rhythm in cardiac activity, both in humans and rats, which is abolished after SCN lesioning in rats. The immediate impact of retinal light exposure at night on SCN-output to the cardiovascular system, which signals 'day' in both diurnal (human) and nocturnal (rat) mammals with opposite effects on physiology, is discussed. Furthermore, we discuss the impact of melatonin treatment on the SCN and its potential medical relevance in patients with essential hypertension. Finally, we argue that regional differentiation of the SCN and autonomous nervous system is required to explain the multitude of circadian rhythms. Insights into the mechanisms by which the SCN affects the cardiovascular system may provide new strategies for the treatment of disease conditions known to coincide with circadian rhythm disturbances, as is presented for essential hypertension. Schlagwörter Animals; Autonomic Nervous Systemphysiology; Cardiovascular Physiological Phenomena; Circadian Rhythmphysiology; Heart Ratephysiology; Humans; Light; Melatoninphysiology; Neurosecretory Systemsphysiology; Rats; Suprachiasmatic Nucleusphysiology Scheer, Frank A. J. L.; van Doornen, Lorenz J. P.; Buijs, Ruud M. (2004): Light and diurnal cycle affect autonomic cardiac balance in human; possible role for the biological clock. In: Autonomic neuroscience : basic & cnc l g 1 0 H 1 S 4 – 8 O lev r g a u tr o1 .0 6j un u2 0 . . 1 li , . 1 , . , . 4 4 . ni ef b r ne d i 0 1 / te .0 30 0 . i aJ n ü : 1 . a 30 Abstract The morning shift in cardiac sympatho-vagal balance seems involved in the increased risk of cardiovascular incidents at that time. To investigate the contribution of the biological clock in autonomic cardiac control, we investigated the

iLib08 - Citavi presence of a diurnal rhythm independent of external factors, and of a circadian phase-dependent effect of moderate light in healthy volunteers. Recordings of heart rate (HR) and vagal and sympathetic cardiac tone were performed at different times over the day-night cycle during supine, awake, resting conditions, during exposure to different light intensities. The similarity between the diurnal rhythm in resting HR and that during previous constant routine conditions, demonstrated that our setup allowed accurate estimation of the endogenous circadian rhythm in HR. The present study suggests that, while a circadian rhythm in vagal cardiac tone is the main cause for the circadian rhythm in resting heart rate, the increase in sympathetic cardiac tone participates in the HR increase caused by early morning light. Adult; Biological Clocksphysiologyradiation effects; Circadian Rhythmphysiologyradiation effects; Female; Heartinnervationphysiologyradiation effects; Heart Ratephysiology; Humans; Light; Male; Photic Stimulation; Photoperiod; Sympathetic Nervous Systemphysiologyradiation effects; Vagus Nervephysiologyradiation effects

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Scheer, Frank A. J. L.; van Montfrans, Gert A.; van Someren, Eus J. W.; Mairuhu, Gideon; Buijs, Ruud M. (2004): Daily nighttime melatonin reduces blood pressure in male patients with essential hypertension. In: H p r n in J. 3 H 2 S 1 21 7 O le efg a u tr o 1 . 6 /1H P0 0 1 3 9 . 1 6 b y et s , g 4 , . , . 9 – 9 . nn v r b r ne d i01 10 .Y .0 0 1 2 31 8 . . e o i ü : 1 5 3 Abstract Patients with essential hypertension have disturbed autonomic cardiovascular regulation and circadian pacemaker function. Recently, the biological clock was shown to be involved in autonomic cardiovascular regulation. Our objective was to determine whether enhancement of the functioning of the biological clock by repeated nighttime melatonin intake might reduce ambulatory blood pressure in patients with essential hypertension. We conducted a randomized, double-blind, placebo-controlled, crossover trial in 16 men with untreated essential hypertension to investigate the influence of acute (single) and repeated (daily for 3 weeks) oral melatonin (2.5 mg) intake 1 hour before sleep on 24-hour ambulatory blood pressure and actigraphic estimates of sleep quality. Repeated melatonin intake reduced systolic and diastolic blood pressure during sleep by 6 and 4 mm Hg, respectively. The treatment did not affect heart rate. The day-night amplitudes of the rhythms in systolic and diastolic blood pressures were increased by 15% and 25%, respectively. A single dose of melatonin had no effect on blood pressure. Repeated (but not acute) melatonin also improved sleep. Improvements in blood pressure and sleep were statistically unrelated. In patients with essential hypertension, repeated bedtime melatonin intake significantly reduced nocturnal blood pressure. Future studies in larger patient group should be performed to define the characteristics of the patients who would benefit most from melatonin intake. The present study suggests that support of circadian pacemaker function may provide a new strategy in the treatment of essential hypertension. Schlagwörter Adult; Aged; Antihypertensive Agentsadministration & dosagetherapeutic use; Blood Pressuredrug effects; Blood Pressure Monitoring, Ambulatory; Circadian Rhythm; Cross-Over Studies; Double-Blind Method; Humans; Hypertensiondrug therapy; Male; Melatoninadministration & dosagetherapeutic use; Middle Aged; Sleep; Wakefulness Scheer, Frank A. J. L.; van Paassen, Barbara; van Montfrans, Gert A.; Fliers, Eric; van Someren, Eus J. W.; van Heerikhuize, Joop J.; Buijs, Ruud M. (2002): Human basal cortisol levels are increased in hospital compared to h m s t g I: e rsi c l tr J . 3 , . , . 9 8 . o e et .n N uo c n ee es g 3 3 H 2 S 7 – 2 i n e t , Abstract The impact of study-environment on experimental outcome is mostly not realized and certainly not demonstrated. In the present study, a comparison was made between free salivary cortisol levels in healthy young men in a carefully controlled hospital setting versus a home setting. Cortisol levels during rest were increased in hospital compared to home environment: 2-fold at awakening, 3-fold at the morning peak, and 5-fold late in the evening. Early morning light increased cortisol

iLib08 - Citavi concentrations only in the home setting, while this effect was absent in the hospital setting. The data of the present study show that study-environment has a major impact on basal hypothalamo-pituitary-adrenal (HPA)-axis activity, which is of particular relevance in future studies in which small changes in HPA-axis activity are subject of study. Adrenocorticotropic Hormoneblood; Adult; Circadian Rhythm; Hospitals; Humans; Hydrocortisoneblood; Hypothalamo-Hypophyseal Systemphysiology; Inpatients; Male; Outpatients; Pituitary-Adrenal Systemphysiology; Salivametabolism; Sleep; Specimen Handlingpsychology

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