Circadian rhythms of food and 1% NaCl intake, urine and electrolyte excretion, plasma renin activity and insulin concentration in adrenalectomized rats

The circadian rhythms of food and 1% NaCl intake, and urine, Na+, Cl- and K+ excretion were followed up in male Wistar rats before and one week after bilateral adrenalectomy at 4-hour intervals during two consecutive days. The circadian rhythms of plasma renin activity (PRA) and plasma immunoreactive insulin (IRI) were evaluated after decapitation of both intact and adrenalectomized rats at 08, 16 and 24 h. To all rats 1% NaCl was offered instead of drinking water. Adrenalectomy did not cause any significant phase shift in the cosine curves approximating the data collected at 4-hour intervals. The circadian rhythms showed the same relationships before and after the operation: the rhythms of food intake, K+ excretion and saline intake preceded significantly the rhythms of urine, Na+ and Cl- excretion. Adrenalectomy induced an increase in mean PRA and shifted its minimal value from 08 to 24 h. After the operation mean IRI decreased and the minimal value shifted from 16 to 24 h. It was concluded that adrenal glands do not play an important role in the synchronization of the circadian rhythms of food and 1% NaCl intake, urine and synchronization of the circadian rhythms of food and 1% NaCl intake, urine and electrolyte excretion with the illumination cycle, but play a relevant role in the synchronization of the circadian rhythms of PRA and IRI in the rat.     

Effect of octreotide on 24-hour growth hormone and prolactin secretory patterns in acromegalics.

Four adult patients with active acromegaly underwent studies of their 24-hour secretory pattern of hGH and Prl prior to and at the end of 3 months of treatment with the octreotide (somatostatin analog SMS 201-995) 100 micrograms s.c. every 8 h. Blood was withdrawn at 30-min intervals with the aid of a constant withdrawal pump. The best fit cosinor method was used to define the following rhythm parameters: mesor, amplitude, acrophase and periodicity. Prior to treatment, hGH secretion was increased in all patients. The mean 24-hour ranged from 9-47 ng/ml with amplitude 5.2-23 and observed maximal pulse 41-95 ng/ml. Computed rhythms were circadian in 3 patients and ultradian in 1; in 2 patients the acrophases were shifted to daytime. hPrl secretion was altered in 3 of the patients. Two had elevated mean 24-hour of 17.7 and 22.2 ng/ml, while computed rhythms showed semicircadian periodicity in 1 of them and circadian periodicity with a shift of acrophase to daytime in the other. The third patient who had normal hPrl levels, showed ultradian 8-hour periodicity. At the end of treatment there was a marked reduction in hGH secretion in 1 patient and a lesser reduction in the other 3. The rhythm was influenced by the masking effect of the drug, to yield an 8-hour period with acrophases related to injection clock time having equal amplitudes.(ABSTRACT TRUNCATED AT 250 WORDS)     

Development and validation of computational models for mammalian circadian oscillators

Circadian rhythms are endogenous rhythms with a cycle length of approximately 24 h. Rhythmic production of specific proteins within pacemaker structures is the basis for these physiological and behavioral rhythms. Prior work on mathematical modeling of molecular circadian oscillators has focused on the fruit fly, Drosophila melanogaster. Recently, great advances have been made in our understanding of the molecular basis of circadian rhythms in mammals. Mathematical models of the mammalian circadian oscillator are needed to piece together diverse data, predict experimental results, and help us understand the clock as a whole. Our objectives are to develop mathematical models of the mammalian circadian oscillator, generate and test predictions from these models, gather information on the parameters needed for model development, integrate the molecular model with an existing model of the influence of light and rhythmicity on human performance, and make models available in BioSpice so that they can be easily used by the general community. Two new mammalian models have been developed, and experimental data are summarized. These studies have the potential to lead to new strategies for resetting the circadian clock. Manipulations of the circadian clock can be used to optimize performance by promoting alertness and physiological synchronization.     

Melatonin in circadian sleep disorders in the blind

Assessment of sleep patterns in blind people demonstrates a high prevalence of sleep disorders. Our studies have shown that subjects with no conscious light perception (NPL) have a higher occurrence and more severe sleep disorders than those with some degree of light perception (LP). A detailed study of 49 blind individuals showed that those with NPL are likely to have free-running (FR) circadian rhythms (aMT6s, cortisol) including sleep. Non-24-hour (or FR) sleep-wake disorder, characterised by periods of good and bad sleep is a condition that may benefit from melatonin treatment. Melatonin has been administered to NPL subjects with FR circadian rhythms and compared with placebo (or the no-treatment baseline) sleep parameters improved. The results suggest that prior knowledge of the subject's type of circadian rhythm, and timing of treatment in relation to the individual's circadian phase, may improve the efficacy of melatonin.     

Effects of 24-Hour Shift Work with Nighttin Napping on Circadian Rhythm Characteristi in Ambulance Personnel

Forty-two ambulance personnel engaged in a 24-h shift system participated in a chronobiological field study to study the effects of 24-h shift work on circadian rhythm characteristics. Autorhythmometry of circadian rhythms of oral temperature, right and left grip strengths, and heart rate plus subjective assessment of drowsiness, fatigue, and attention was performed every ～ 4 h except during sleep for 7 days. Cosinor and power spectral analyses were applied to the longitudinal data of each individual. Changes in circadian period different from 24 h of oral temperature, grip strengths, and heart rate plus subjective drowsiness, fatigue, and attention were observed in ambulance personnel. The incidence of circadian periodicity different from 24 h in oral temperature and right and left grip strength was 28.6%, 35.7%, and 47.6%, respectively. The incidence was relatively lower than that of shift workers engaged in a discontinuous 8-h shift system we reported on previously. Working conditions allowing ambulance personnel to nap when not called for emergency (for > 4 h) might contribute to a stabilization of circadian rhythms. Furthermore, long nighttime ambulance service amounting to >100 min was significantly associated with a high incidence of at least one prominent circadian period among oral temperature and right and left grip strength rhythms different from 24 h. In conclusion, 24-h shift work altered the characteristics of circadian rhythms of ambulance personnel; nighttime naps seemed to have a favorable effect on averting changes in circadian rhythms.     

On analyzing circadian rhythms data using nonlinear mixed models with harmonic terms

Wang, Ke, and Brown (2003, Biometrics59, 804-812) developed a smoothing-based approach for modeling circadian rhythms with random effects. Their approach is flexible in that fixed and random covariates can affect both the amplitude and phase shift of a nonparametrically smoothed periodic function. In motivating their approach, Wang et al. stated that a simple sinusoidal function is too restrictive. In addition, they stated that "although adding harmonics can improve the fit, it is difficult to decide how many harmonics to include in the model, and the results are difficult to interpret." We disagree with the notion that harmonic models cannot be a useful tool in modeling longitudinal circadian rhythm data. In this note, we show how nonlinear mixed models with harmonic terms allow for a simple and flexible alternative to Wang et al.'s approach. We show how to choose the number of harmonics using penalized likelihood to flexibly model circadian rhythms and to estimate the effect of covariates on the rhythms. We fit harmonic models to the cortisol circadian rhythm data presented by Wang et al. to illustrate our approach. Furthermore, we evaluate the properties of our procedure with a small simulation study. The proposed parametric approach provides an alternative to Wang et al.'s semiparametric approach and has the added advantage of being easy to implement in most statistical software packages.     

Changing the dosing schedule minimizes the disruptive effects of interferon on clock function

The effectiveness and toxicity of many drugs vary depending on the relationship between the dosing schedule and the 24-hour rhythms of biochemical, physiological and behavioral processes. In addition, several drugs can cause alterations to the 24-hour rhythms leading to illness and altered homeostatic regulation. However, the mechanisms of this drug-based disruption of circadian 'clock' genes remain unclear. Here, we show the disruptive effect of interferon-alpha on the rhythm of locomotor activity, body temperature and clock-gene mRNA expression in the periphery and suprachiasmatic nuclei, a primary circadian pacemaker. The rhythmicity of clock genes and the photic induction of the Per gene in suprachiasmatic nuclei were disturbed by the repetitive administration of interferon-alpha. Moreover, alteration of clock function, a new concept of adverse effects, can be overcome by optimizing the dosing schedule to minimize adverse drug effects.     

Reproducibility of the circadian rhythms of serum cortisol and melatonin in healthy subjects: a study of three different 24-h cycles over six weeks

Plasma melatonin and cortisol are characterized by a marked circadian rhythm, but little information is available about the reproducibility and stability of these rhythms over several weeks in the same subjects. This study examined the characteristics of these rhythms in 31 healthy human subjects 20 to 30 years of age. They were synchronized with a diurnal activity from 0800 to 2300 and nocturnal rest. They participated in three 24-hour sessions (S1, S2, and S3): S2 took place two weeks after S1 and S3 4 weeks after S2. Blood samples were taken during each session at 3-hour intervals from 1100 to 2000 and hourly from 2200 to 0800. Comparison of the circadian rhythms between groups used repeated measures 2-way ANOVA, the cosinor method, and Bingham's test. Intraindividual variations were compared by the cosinor method and Bingham's test. The groups did not differ, but a slight difference in the amplitude or acrophase of individual circadian rhythms was observed in 5 of 31 subjects for melatonin and 1 of 31 for cortisol. The circadian means did not differ over the three sessions. These results show that the circadian profile of cortisol and melatonin are highly reproducible over a six-week period, in both individuals and groups. Our study clearly shows that these hormones can be considered to be stable markers of the circadian time structure and therefore useful tools to validate rhythms' synchronisation of human subjects.     

Circadian temperature rhythms in clockwise and counter-clockwise rapidly rotating shift schedules

The purpose of this study was to examine the circadian temperature rhythm in clockwise (CW) and counter-clockwise (CCW) rapidly rotating shift schedules. Arguments against the CCW rotation of shifts are that they result in shortened sleep and promote greater disruption of circadian rhythms. The 3-week study included a week of day shifts (0800-1600) and 2 weeks of shiftwork. The CW 2-2-1 schedule rotated from two early mornings (0600-1400) to two evenings (1400-2200) to one midnight shift (2200-0600) allowing 24 hours off at each shift rotation and a 48-hour weekend. The CCW schedule rotated from two evenings to two early mornings to one midnight shifts allowing only 8 hours off at each shift rotation and an 80-hour weekend. Analysis of the 72-hr periods at the end of each workweek, including the midnight shifts and recovery periods during weeks 2 and 3 were compared to the same 72-hour period at the end of week 1 (baseline). A cosine function that fit the temperature curves by minimizing the sums of squares produced parameters that underwent analysis of covariance procedures. Significant differences were found between rotation conditions for amplitude and acrophase. An attenuation of amplitude and a delay in the acrophase was the found for the counter-clockwise condition. Features inherent in this schedule might explain these effects, particularly, the increased opportunity for "sleeping in" at the beginning of the week and an expanded (2-shift) workday at the end of the week.     

Acute exposure to 2G phase shifts the rat circadian timing system

The circadian timing system (CTS) provides internal and external temporal coordination of an animal's physiology and behavior. In mammals, the generation and coordination of these circadian rhythms is controlled by a neural pacemaker, the suprachiasmatic nucleus (SCN), located within the hypothalamus. The pacemaker is synchronized to the 24 hour day by time cues (zeitgebers) such as the light/dark cycle. When an animal is exposed to an environment without time cues, the circadian rhythms maintain internal temporal coordination but exhibit a "free-running" condition in which the period length is determined by the internal pacemaker. Maintenance of internal and external temporal coordination are critical for normal physiological and psychological function in human and non-human primates. Exposure to altered gravitational environments has been shown to affect the amplitude, mean, and timing of circadian rhythms in species ranging from unicellular organisms to man. However, it has not been determined whether altered gravitational fields have a direct effect on the neural pacemaker, or affect peripheral physiological systems that express these circadian parameters. In previous studies, the ability of a stimulus to phase shift circadian rhythms was used to determine whether a stimulus has a direct effect on the neural pacemaker. The present experiment was performed in order to determine whether acute exposure to a hyperdynamic field could phase shift circadian rhythms.     

Nonphotic entrainment in humans?

Although light is accepted as the dominant zeitgeber for entrainment of the human circadian system, there is evidence that nonphotic stimuli may play a role. This review critically assesses the current evidence in support of nonphotic entrainment in humans. Studies involving manipulations of sleep-wake schedules, exercise, mealtimes, and social stimuli are re-examined, bearing in mind the fact that the human circadian clock is sensitive to very dim light and has a free-running period very close to 24 h. Because of light confounds, the study of totally blind subjects with free-running circadian rhythms represents the ideal model to investigate the effects of nonphotic stimuli on circadian phase and period. Strong support for nonphotic entrainment in humans has already come from the study of a few blind subjects with entrained circadian rhythms. However, in these studies the nonphotic stimulus(i) responsible was not identified. The effect of appropriately timed exercise or exogenous melatonin represents the best proof to date of an effect of nonphotic stimuli on human circadian timing. Phase-response curves for both exercise and melatonin have been constructed. Given the powerful effect of feeding as a circadian zeitgeber in various nonhuman species, studies of meal timing are recommended. In conclusion, the available evidence indicates that it remains worthwhile to continue to study nonphotic effects on human circadian timing to identify treatment strategies for shift workers and transmeridian travelers as well as for the blind and possibly the elderly.     

Circadian disorganization in experimental arthritis

This review discusses the experimental evidence indicating that arthritis disrupts circadian organization, which was mainly derived from animal studies employing Freund's complete mycobacterial adjuvant (FCA). The defense response to antigenic challenge, mediated in part by cytokines, includes changes in chronobiological central nervous system function, like depressed daily activity, superficial sleep or anorexia. Interferon (IFN)-gamma receptors are detectable in the central circadian pacemaker, the hypothalamic suprachiasmatic nuclei, at a time when the capacity for photic entrainment of the pacemaker became established. The disruptive effects of the systemic injection of IFN on the circadian rhythms of locomotor activity, body temperature and clock-gene mRNA expression have been documented. In the last few years we have examined a number of immune and neuroendocrine circadian rhythms in FCA-injected rats, both in the preclinical phase of arthritis (2-3 days after FCA injection) as well as in the acute phase of the disease (18 days after FCA injection). In arthritic rats, the 24-hour organization of immune and neuroendocrine responses becomes altered. A hormonal pathway involving the circadian secretion of melatonin and a purely neural pathway including, as a motor leg, the autonomic nervous system innervating the lymph nodes were identified. The significant effects of the immune-mediated inflammatory response on the diurnal rhythmicity of adenohypophysial and hypophysiotropic hormones occurred in arthritic rats. Melatonin treatment prevented the alteration in 24-hour rhythms of serum ACTH, prolactin and luteinizing hormone in rats injected with FCA. In addition, melatonin pretreatment prevented the alteration in the 24-hour variation in hypothalamic serotonin and dopamine turnover during the preclinical phase of Freund's adjuvant arthritis in rats. Some pinealectomy-induced immune changes in arthritic rats were also prevented by physiological concentrations of melatonin. Melatonin may play the role of an 'internal synchronizer' for the immune system.     

Circadian disruption accelerates tumor growth and angio/stromagenesis through a Wnt signaling pathway

Epidemiologic studies show a high incidence of cancer in shift workers, suggesting a possible relationship between circadian rhythms and tumorigenesis. However, the precise molecular mechanism played by circadian rhythms in tumor progression is not known. To identify the possible mechanisms underlying tumor progression related to circadian rhythms, we set up nude mouse xenograft models. HeLa cells were injected in nude mice and nude mice were moved to two different cases, one case is exposed to a 24-hour light cycle (L/L), the other is a more "normal" 12-hour light/dark cycle (L/D). We found a significant increase in tumor volume in the L/L group compared with the L/D group. In addition, tumor microvessels and stroma were strongly increased in L/L mice. Although there was a hypervascularization in L/L tumors, there was no associated increase in the production of vascular endothelial cell growth factor (VEGF). DNA microarray analysis showed enhanced expression of WNT10A, and our subsequent study revealed that WNT10A stimulates the growth of both microvascular endothelial cells and fibroblasts in tumors from light-stressed mice, along with marked increases in angio/stromagenesis. Only the tumor stroma stained positive for WNT10A and WNT10A is also highly expressed in keloid dermal fibroblasts but not in normal dermal fibroblasts indicated that WNT10A may be a novel angio/stromagenic growth factor. These findings suggest that circadian disruption induces the progression of malignant tumors via a Wnt signaling pathway.     

Familial advanced sleep-phase syndrome: A short-period circadian rhythm variant in humans.

Biological circadian clocks oscillate with an approximately 24-hour period, are ubiquitous, and presumably confer a selective advantage by anticipating the transitions between day and night. The circadian rhythms of sleep, melatonin secretion and body core temperature are thought to be generated by the suprachiasmatic nucleus of the hypothalamus, the anatomic locus of the mammalian circadian clock. Autosomal semi-dominant mutations in rodents with fast or slow biological clocks (that is, short or long endogenous period lengths; tau) are associated with phase-advanced or delayed sleep-wake rhythms, respectively. These models predict the existence of familial human circadian rhythm variants but none of the human circadian rhythm disorders are known to have a familial tendency. Although a slight 'morning lark' tendency is common, individuals with a large and disabling sleep phase-advance are rare. This disorder, advanced sleep-phase syndrome, is characterized by very early sleep onset and offset; only two cases are reported in young adults. Here we describe three kindreds with a profound phase advance of the sleep-wake, melatonin and temperature rhythms associated with a very short tau. The trait segregates as an autosomal dominant with high penetrance. These kindreds represent a well-characterized familial circadian rhythm variant in humans and provide a unique opportunity for genetic analysis of human circadian physiology.     

Melatonin and circadian rhythms in autism: Case report

Among the most co-occurring conditions in autism spectrum disorders (ASD), there are sleep disorders which may exacerbate associated behavioral disorders and lead to intensification of existing autistic symptoms. Several studies investigating the use of melatonin in the treatment of sleep disorders in ASD have shown comparative efficiency in sleep with little or no side effects. Here we report a case of ASD with non-24-hour rhythm and the effect of melatonin in circadian parameters by actigraphy. Visual analysis of the first 10 days recorded and the periodogram suggest that this patient showed a non-24-hour rhythm. This ASD subject showed before melatonin administration an activity/rest rhythm lower than 24 hours. The results show that melatonin increased approximately 4.7 times the regularity of circadian activity rhythm and resting staying on average between 00:00 and 06:00 and showed positive effects in improving the quality of sleep and behavior. So, the actigraphy showed an ASD subject with a non-24-hour activity/rest rhythm which changed this rhythm to a 24-hour rhythm after melatonin administration. This result reinforces the prospect of therapy with melatonin for synchronization (increased regularity) of endogenous rhythms and improve sleep quality and hence behavior and indicates the actigraphy as a choice tool to characterize several parameters of the activity/rest rhythm of ASD individuals.     

Chronobiology in hematology and immunology

The hematopoietic and the immune systems in all their components are characterized by a multifrequency time structure with prominent rhythms in cell proliferation and cell function in the circadian, infradian, and rhythms in cell proliferation and cell function in the circadian, infradian, and circannual frequency ranges. The circulating formed elements in the peripheral blood show highly reproducible circadian rhythms. The timing and the extent of these rhythms were established in a clinically healthy human population and are shown as chronograms, cosinor summaries and, for some high-amplitude rhythms, as time-qualified reference ranges (chronodesms). Not only the number but also the reactivity of circulating blood cells varies predictably as a function of time as shown for the circadian rhythm in responsiveness of human and murine lymphocytes in vitro to lectin mitogens (phytohemagglutinin and pokeweed mitogen). Some circadian rhythms of hematologic functions appear to be innate and are presumably genetically determined but are modulated and adjusted in their timing by environmental factors, so-called synchronizers. Phase alterations in the circadian rhythms of hematologic parameters of human subjects and of mice by manipulation of the activity-rest or light-dark schedule and/or of the time of food uptake are presented. Characteristically these functions do not change their timing immediately after a shift in synchronizer phase but adapt over several and in some instances over many transient cycles. The circadian rhythm of cell proliferation in the mammalian bone marrow and lymphoid system as shown in mice in vivo and in vitro may lend itself to timed treatment with cell-cycle-specific and nonspecific agents in an attempt to maximize the desired and to minimize the undesired treatment effects upon the marrow. Differences in response, and susceptibility of cells and tissues at different stages of their circadian and circaseptan (about 7-day) rhythms and presumably of cyclic variations in other frequencies are expected to lead to the development of a chronopharmacology of the hematopoietic and immune system. Infradian rhythms of several frequencies have been described for numerous hematologic and immune functions. Some of these, i.e., in the circaseptan frequency range, seem to be of importance for humoral and for cell mediated immune functions including allograft rejection. Infradian rhythms with periods of 19 to 22 days seem to occur in some hematologic functions and are very prominent in cyclic neutropenia and (with shorter periods) in its animal model, the grey collie syndrome.(ABSTRACT TRUNCATED AT 400 WORDS)     

Circadian rhythm of activity and sleep‐wakefulness in elderly institutionalized persons

Abstract

The circadian rhythms of blood pressure (BP) and heart rate (HR) were documented in 30 patients for a 24‐hour period before and during the 24 hours that included unilateral surgery for senile cataract or retinal detachment. The patients were premedicated with diazepam. Anaesthesia was induced at a fixed time (09.00) in all patients with thiopentone, and muscle relaxation was with pancuronium. Maintenance was with enflurane in 15 patients and with fentanyl and droperidol in the rest. Though the intraoperative changes in haemodynamic parameters were dissimilar with the two types of maintenance agents, but both types had a similar effect on the circadian rhythms of blood pressure and heart rate. Whereas preoperatively the BP and HR circadian rhythms were nearly in phase, with their peaks in the late morning to early afternoon, the postoperative rhythms underwent a dissociation to a phase shift in the BP 24‐h pattern. The phase effect may be hypothetically attributed to direct pharmacological actions or to masking effects.