Effect of redox conditions on the DNA-binding efficiency of the retinoic acid receptor zinc-finger

All 24-hour endocrine rhythms partially reflect the interaction of circadian rhythmicity with sleep-wake homeostasis but their relative contributions vary from one system to another. In older adults, many 24-hour rhythms are dampened and/or advanced, including those of cortisol and GH. Amplitude reduction and phase advance of 24-hour rhythms may represent age-related changes in the central nervous systems underlying circadian rhythmicity and sleep-wake homeostasis. Age-related alterations in circadian function could also reflect decreased exposure and/or responsivity to the synchronizing effects of both photic (e.g. light exposure) and nonphotic (e.g. social cues) inputs. There are pronounced age-related alterations in sleep quality in aging which consist primarily of a marked reduction of slow-wave sleep, a reduction in REM stages and a marked increase in the number and duration of awakenings interrupting sleep. Alterations in slow-wave sleep occur abruptly in young adulthood (30-40 years of age) whereas disturbances in amounts of REM and wake appear more gradually. This article reviews evidence indicating that deficits in characteristics of sleep-wake homeostasis and circadian function may mediate age-related alterations in somatotropic and corticotropic function. Because sleep loss in young subjects results in endocrine disturbances which mimic those observed in aging, it is conceivable that the decrease in sleep quality which characterizes aging may contribute to age-related alterations in hormonal function and their metabolic consequences.     

The roles of time of day and sleep quality in modulating glucose regulation: clinical implications

Consistent variations in glucose regulation across the 24-hour cycle are present in normal subjects. These diurnal variations are altered in various states of impaired glucose tolerance (aging, obesity, diabetes). Changes in insulin secretion, clearance and/or action across the day have been demonstrated. Studies in subjects receiving continuous intravenous glucose infusion have shown that major alterations of glucose tolerance occur during sleep and that sleep quality markedly influences glucose utilization. Diurnal variations in glucose tolerance result from the alternation of wake and sleep states as well as from intrinsic effects of circadian rhythmicity. The important roles of physiological variations in levels of counterregulatory hormones which are markedly dependent on sleep (i.e. growth hormone) or circadian rhythmicity (i.e. cortisol) have only begun to be appreciated. The modulatory effects of sleep and circadian rhythmicity on glucose regulation may have important clinical implications for the diagnosis and treatment of abnormalities of carbohydrate metabolism.     

The role of melatonin in the human fetus (review)

Melatonin, an indole amine, primarily derived from the pineal gland is secreted during the hours of darkness. Melatonin acts as a hormonal transduction of photoperiod influencing the timing of seasonal and daily (circadian) physiological rhythms. Maternal melatonin crosses the placenta and enters the fetal circulation providing photoperiodic information to the fetus influencing the subsequent circadian and seasonal rhythms of the offspring. The function of melatonin in humans is more obscure. However, melatonin has attained prominence as a treatment for disturbed circadian rhythms and sleep patterns which occur as a result of transmeridian travel, shift work or blindness. The biological clock, the hypothalamic suprachiasmatic nuclei (SCN), possesses melatonin receptors, in both the adult and fetal human. This concurs with the reported influence of melatonin on human circadian rhythmicity and indicates that this influence may begin in utero. Melatonin receptors are widespread in the human fetus and occur in both central and peripheral tissue from early in fetal development. Thus, the influence of melatonin on the developing human fetus may not be limited to entraining circadian rhythmicity. Considering the transplacental availability of melatonin to the fetus the ingestion of melatonin by pregnant women may be inadvisable.     

Chronopharmacological effects on nicotine repeated administration on heart rate, body temperature and locomotor activity circadian rhythms in rats

The aim of this study was to compare morning and evening repeated nicotine administration on the circadian rhythms of heart rate (H), body temperature (T) and locomotor activity (A) in unrestrained rats by using implanted radio-telemetry transmitters. The study was divided into three 7-day periods: a control period (P1), a treatment period (P2) and a recovery period (P3). During P2, four rats received nicotine (1mg.kg(-1)) subcutaneously at 09.00 h and four rats received nicotine in the same conditions at 21.00 h. For P1, P2 and P3, a power spectrum analysis was applied in order to determine the dominant period of rhythmicity. If H, T and A circadian rhythms were detected, the characteristics of these rhythms were determined by cosinor analysis, expressed as means+/-SEM and compared by ANOVA. Our results indicated: (1) a lack of detection of A circadian rhythm during P2 for the morning group while H and T circadian rhythms were detected for the morning and evening group whatever the period. (2) alterations of mesors, amplitudes and acrophases of H and T circadian rhythms for the morning and evening group during P2 and alterations of mesor, amplitude and acrophase of A circadian rhythm for the evening group. Furthermore these alterations were significantly different for the morning and evening group during P2. These results showed that the time of administration of nicotine differently affect H, T and A rhythms. The authors suggest that these effects can be mediated by central cholinergic and/or monoaminergic mechanisms.     

Neurons of the rat suprachiasmatic nucleus show a circadian rhythm in membrane properties that is lost during prolonged whole-cell recording

The suprachiasmatic nucleus is commonly considered to contain the main pacemaker of behavioral and hormonal circadian rhythms. Using whole-cell patch-clamp recordings, the membrane properties of suprachiasmatic nucleus neurons were investigated in order to get more insight in membrane physiological mechanisms underlying the circadian rhythm in firing activity. Circadian rhythmicity could not be detected either in spontaneous firing rate or in other membrane properties when whole-cell measurements were made following an initial phase shortly after membrane rupture. However, this apparent lack of rhythmicity was not due to an unhealthy slice preparation or to seal formation, as a clear day/night difference in firing rate was found in cell-attached recordings. Furthermore, in a subsequent series of whole-cell recordings, membrane properties were assessed directly after membrane rupture, and in this series we did find a significant day/night difference in spontaneous firing rate, input resistance and frequency adaptation. As concerns the participation of different subpopulations of suprachiasmatic nucleus neurons expressing circadian rhythmicity, cluster I neurons exhibited strong rhythmicity, whereas no day/night differences were found in cluster II neurons. Vasopressin-containing cells form a subpopulation of cluster I neurons and showed a more pronounced circadian rhythmicity than the total population of cluster I neurons. In addition to their strong rhythm in spontaneous firing rate they also displayed a day/night difference in membrane potential.     

Circadian rhythms during gradually delaying and advancing sleep and light schedules

The circadian rhythms of the night shift worker show very little phase shift in response to the daytime sleep and night work schedule. One strategy for producing circadian adaptation may be to use appropriately timed exposure to high-intensity light. We attempted to shift the circadian temperature rhythms of seven normal subjects while they followed a sleep schedule that gradually delayed (2 h per day) until sleep occurred during the daytime, as is customary for workers during the night shift. After 5 days, the sleep schedule was gradually advanced back to baseline. High illuminance light (2 h per day) and the attenuation or avoidance of sunlight were timed to facilitate temperature rhythm phase shifts. In general, the temperature rhythm did not shift along with the sleep-wake schedule, but appeared either to free run or remain entrained to the natural 24-h zeitgebers. This study showed how difficult it can be to shift human circadian rhythms in the field, when subjects are exposed to competing 24-hr zeitgebers.     

Beneficial effect of risperidone on sleep disturbance and psychosis following traumatic brain injury

Severe disturbances of sleep architecture and circadian rhythms are common in traumatic brain injured patients; however, complete absence of the rapid eye movement sleep stage is very rare. We describe a brain injured patient with cognitive disturbances who developed severe alterations of sleep architecture, accompanied by paranoid and jealousy delusions. Following several trials with conventional antipsychotics his psychotic state stabilized but he continued to complain of insomnia and daytime fatigue. When treated with risperidone 2 mg/day, both his sleep and the delusional thoughts improved markedly and his daytime alertness increased. Severe deterioration of his support system brought about discontinuation of treatment with re-emergence of all symptoms.     

Changes in cortisol secretion during shiftwork: implications for tolerance to shiftwork?

The present study was conducted to determine the size of changes and the time point of those changes in biological rhythms during night-shift and whether they are associated with tolerance to shiftwork. The adrenal hormone cortisol has frequently been investigated in the field of shiftwork since it follows a pronounced circadian variation and has been demonstrated to be affected by night-work. However, studies are restricted with respect to sample size, number of measurements or duration of sampling periods. Therefore, a sample of 24 night-shift workers was investigated in a cardiac emergency unit for seven nights. Saliva samples were collected frequently for determination of cortisol. A total of 28 cortisol measurements in each subject were made in order to decide whether the circadian rhythm changed, and if so at which time point. A clear reversal of circadian function could be observed for the total group (mean cortisol concentrations) after the fifth night. However, inspection of individual patterns revealed that six out of 24 subjects did not change in circadian function. These subjects exhibited lower durations of and less consistency in recovery sleep across the following days after night-work. With respect to personality dimensions a pattern associated with neuroticism can be observed in subjects without appropriate changes in cortisol rhythm. However, owing to the small sample size of non-adapters these results are preliminary and should be replicated with larger samples. The overall relationship between neuroticism and low adaptability has been discussed.     

An improved sample packing device for rapid freeze-trap electron paramagnetic resonance spectroscopy kinetic measurements

Circadian rhythms are generated by the suprachiasmatic nuclei (SCN) and synchronized (entrained) to environmental light-dark cycles by the retinohypothalamic tract (RHT), a direct pathway from the retina to the suprachiasmatic nuclei. In anophthalmic mice, the optic primordia are resorbed between embryonic days 11.5 and 13, before retinal ganglion cells emerge. Thus the retinohypothalamic tract, which is the primary "zeitgeber" for circadian rhythms in sighted animals, never forms, and there is no retinal or photic input to the circadian system. We have used wheel running activity, a highly consistent and reliable measure of circadian rhythmicity in rodents, to establish the properties of endogenous locomotor rhythms of anophthalmic mice. We have identified three subpopulations of anophthalmic mice: a) rhythmic with strong stable circadian period but significantly increased period length; b) rhythmic with unstable circadian period; and c) arrhythmic. Future correlation of locomotor rhythms with properties of the suprachiasmatic nuclei in these mice will clarify the relationship between generation and properties of circadian rhythms and the neuroanatomical, neurochemical, and molecular organization of the circadian clock.     

Effect of bedrest on circadian rhythms of plasma renin, aldosterone, and cortisol

Previous studies of normal men after 5 d of bedrest showed that circulatory instability on head-up tilt or standing is preceded by increased plasma renin activity (PRA) at bedrest. In the present study, the circadian rhythms of PRA, aldosterone, and cortisol have been observed in five normal men on a constant diet. In ambulatory controls, PRA and aldosterone increased normally after standing. On the third morning of bedrest, PRA was higher than before, and at noon, PRA was higher than in standing controls. The nocturnal peaks of PRA resulting from episodic renin secretion during sleep were higher after bedrest. Plasma aldosterone was also increased by bedrest. The findings are compatible with the theory that intermittent beta-adrenergic nerve activity during sleep is increased after bedrest, but other factors, such as loss of body sodium and a lower plasma volume, may also be involved.     

Ocular bubble formation as a method of assessing decompression stress

Human well-being depends on the entrainment of endogenous circadian rhythms of biological functions and the sleep-wake rhythm. Although the incidence of otherwise healthy subjects with chronically altered sleep-wake rhythms is rather low, the investigation of these patients provides new sights into circadian entrainment mechanisms. We therefore examined the circadian rhythm of circulating melatonin and the sleep-wake rhythm in five patients with chronic sleep-wake rhythm disorders and ten age-matched healthy controls. All patients showed altered circadian melatonin rhythm parameters in relation to their sleep-wake cycle compared to age-matched controls. These alterations were random, i.e., independent of the type, the duration, and the age of onset of the disorder. The melatonin onset to sleep onset interval varied between the patients and the melatonin acrophase to sleep offset interval was prolonged in four patients. These findings indicate individual phase relations between the circadian melatonin rhythm and the sleep-wake cycle in patients with chronic sleep-wake rhythm disorders. Since the prolonged melatonin acrophase to sleep offset interval was the most consistent finding independent of aetiological origins, this abnormality may be one possible maintaining factor in chronic sleep-wake rhythm disorders due to reduced phase-resetting properties of the circadian pacemaker. Furthermore, rather low circadian melatonin amplitudes and a subsensitivity to daylight may maintain the disorder in at least some patients.     

A chronobiological approach to circulating levels of renin, angiotensin-converting enzyme, aldosterone, ACTH, and cortisol in Addison's disease

This study deals with a chronobiological approach to the circadian rhythm of the renin-angiotensin-aldosterone system (RAAS) and the ACTH-cortisol axis (ACA) in patients with Addison's disease (PAD). The aim is to explore the mechanism(s) for which the circadian rhythmicity of the RAAS and ACA takes place. The study has shown that both the RAAS and ACA are devoid of a circadian rhythm in PAD. The lack of rhythmicity for renin and ACTH provides indirect evidence that their rhythmic secretion is in some way related to the circadian oscillation of aldosterone and cortisol. This implies a new concept: a positive feedback may be included among the mechanisms which chronoregulate the RAAS and ACA.     

Polysomnography and other methods for the assessment of sleep disorders

Polysomnography is an essential tool in the assessment of sleep disorders. However, PSG alone not always sufficient to evaluate various sleep disorders patients. For instance, in patients with suspected inadequate sleep hygiene, sleep logs or questionnaires on sleep habits may, be helpful in making the diagnosis. Patients who complain of excessive daytime sleepiness as a result of insomnia should be evaluated with the Epworth sleepiness scale and/or polysomnographic nap studies such as the multiple sleep latency test. In patients with suspected circadian rhythm sleep disorder, continuous temperature monitoring together with sleep log and actigraphy may establish the phase relationship between sleep-wake rhythms and other biological rhythms. Because polysomnographic measurements are cumbersome and expensive, it is necessary to select the suitable methods for the assessment of sleep disorders by the careful examination of the patients' complain.     

Circadian rhythms

1997 marks the 25th anniversary of the discovery of the master circadian pacemaker in mammals in the hypothalamic suprachiasmatic nucleus. Remarkable progress has been made over the last 25 years in elucidating the physiological mechanisms involved in the entrainment, generation and expression of circadian rhythms at the cellular and systems levels. The recent discovery and cloning of the first mammalian clock gene is expected to lead to rapid advances in the understanding of the genetic and molecular mechanisms underlying circadian rhythmicity in mammals. Indeed, the impressive and extensive database on circadian rhythms in mammals obtained over the past 25 years provides a foundation for making rapid progress in utilizing future genetic and molecular findings for discovering the fundamental mechanisms controlling 24-hour temporal organization.     

Ultradian pulsatility of plasma glucose and insulin secretion rate: circadian and sleep modulation

Insulin release is a complex oscillatory process with rapid pulses (10 min) superimposed on slower circhoral oscillations (50-100 min). The exact mechanism of the circhoral oscillations, which are probably in part the consequence of a negative feedback loop linking glucose and insulin secretion rate, remains unclear. Stimulatory effects of sleep on insulin secretion are achieved by an enhancement of the oscillation amplitude which could be partly mediated by GH. The different patterns observed after acute or chronic shift of sleep suggest however an interaction between sleep influence and circadian rhythmicity, as described for numerous pituitary hormones. The intra-sleep awakenings have a modulatory effect on glucose levels but no systematic relationship exists between glucose or insulin secretion rate oscillations and the REM-NREM sleep cycles. Irrespective of the mechanisms involved, sleep or GH stimulatory effects result from a modulation of the oscillation amplitude rather than of their frequency which is probably an important feature of insulin efficacy.     

Circadian clock functions localized in xenopus retinal photoreceptors

A circadian oscillator that regulates visual function is located somewhere within the vertebrate eye. To determine whether circadian rhythmicity is generated by retinal photoreceptors, we isolated and cultured photoreceptor layers from Xenopus retina. On average, 94% of the viable cells in these preparations were rod or cone photoreceptors. Photoreceptor layers produced melatonin rhythmically, with an average period of 24.3 hr, in constant darkness. The phase of the melatonin rhythm was reset by in vitro exposure of the photoreceptor layers to cycles of either light or quinpirole, a D2 dopamine receptor agonist. These data indicate that other parts of the eye are not necessary for generation or entrainment of retinal circadian melatonin rhythms and suggest that rod and/or cone photoreceptors are circadian clock cells.     

The chronobiology of human cytokine production

Cytokine production in human whole blood exhibits diurnal rhythmicity. Peak production of the pro-inflammatory cytokines IFN-gamma, TNF-alpha, IL-1 and IL-12 occurs during the night and early morning at a time when plasma cortisol is lowest. The existence of a causal relationship between plasma cortisol and production is suggested by the finding that elevation of plasma cortisol within the physiological range by the administration of cortisone acetate results in a corresponding fall in pro-inflammatory cytokine production. Cortisol may not be the only neuroendocrine hormone that entrains cytokine rhythms; other candidates include 17-hydroxy progesterone, melatonin and dihydroepiandrostene dione (DHEAS). The finding of diurnal cytokine rhythms may be relevant to understanding why immuno-inflammatory disorders such as rheumatoid arthritis or asthma exhibit night-time or early morning exacerbations and to the optimisation of treatment for these disorders. Diurnal rhythmicity of cytokine production also has implications for the timing of blood samples drawn for diagnostic T-cell assays. Finally, diurnal rhythmicity of immune function suggests that the nature of an immune response, for example in response to vaccination, may be modified by the time of day of antigen administration and raises the possibility that immune responses could be therapeutically manipulated by co-administration of immuno-regulatory hormones such as glucocorticoids.