Natural Circadian Rhythm Research Articles

Sleep improvement in an insomniac patient with global pituitary insufficiency after change from triple to quadruple cortisol replacement therapy

Although cortisol has a distinct circadian rhythm, patients with adrenal insufficiency usually receive diurnal hydrocortisone replacement therapy (HRT), disregarding possible consequences for sleep quality. The case reported here concerns the resolution of severe insomnia in a patient with global hypopituitary insufficiency upon adjustment of triple HRT to quadruple HRT. The data show a strong influence of cortisol on total sleep time and slow wave sleep (SWS) as well as rapid eye movement (REM) sleep. Clinically, the data are suggestive of the need to assimilate HRT to the natural circadian cortisol rhythm and not restrict it to the active part of the day.

The Riskiest Time for the Brain

The natural circadian rhythm of blood pressure (BP) typically includes a nocturnal decrease of 10% to 20% in BP compared with daytime, awake values.1,2 However, in as many as 25% to 35% of hypertensive patients, there is a moderate-to-marked loss of this decline in nocturnal BP, a phenomenon that has been associated with excessive cardiac,3 renal,4 and cerebrovascular5 target organ damage. In addition, patients with hypertension who exhibit a nocturnal BP increase compared with daytime BP (so-called “risers”) have the worst prognosis for future stroke and cardiac events.6 In contrast, there is also some evidence that patients with marked nocturnal BP declines (so-called “extreme dippers”) are at greater risk for ischemic strokes and silent myocardial ischemia than patients whose decline in BP during sleep is normal.7 Both the etiologies and the consequences of an elevated nocturnal BP are diverse. Since Shimada et al8 first reported a study evaluating ambulatory BP monitoring in older patients with hypertension using MRI 15 years ago, there has been an ongoing issue with our general understanding of BP variability and the brain as a target organ, because most studies have had small sample sizes and have been performed in homogenous populations. In this issue of Hypertension , Schwartz et al9 have provided us with a large cross-sectional study from Minnesota and Mississippi of 263 black and 343 white subjects who underwent clinic …

Psychostimulants and Military Operations

Sleep-deprived individuals appear to have decreased psychological and physical capabilities. Studies have shown how major psychological aspects, such as alertness, complex mental performance, and memory, are strongly affected by sleep deprivation. Military use of psychostimulants dates back many years, especially in units that operate over long hours and deprive soldiers of sleep. During prolonged military operations, pilots are regularly kept awake for hours and days without fulfilling their biological sleep requirements. This consequently affects their natural circadian rhythm. This article deals with both the benefits and the side effects of two kinds of psychostimulants, namely, dextroamphetamine, which is more popular and is most widely used, and modafinil, which is a relatively newer type. There is growing evidence that modafinil has fewer side effects, in comparison with its predecessor dextroamphetamine, while still maintaining all of the latter's beneficial characteristics.

The potential of melatonin in reducing morbidity–mortality after craniocerebral trauma

Craniocerebral trauma (CCT) is the most frequent cause of morbidity-mortality as a result of an accident. The probable origins and etiologies are multifactorial and include free radical formation and oxidative stress, the suppression of nonspecific resistance, lymphocytopenia (disorder in the adhesion and activation of cells), opportunistic infections, regional macro and microcirculatory alterations, disruptive sleep-wake cycles and toxicity caused by therapeutic agents. These pathogenic factors contribute to the unfavorable development of clinical symptoms as the disease progresses. Melatonin (N-acetyl-5-methoxytryptamine) is an indoleamine endogenously produced in the pineal gland and in other organs and it is protective agent against damage following CCT. Some of the actions of melatonin that support its pharmacological use after CCT include its role as a scavenger of both oxygen and nitrogen-based reactants, stimulation of the activities of a variety of antioxidative enzymes (e.g. superoxide dismutase, glutathione peroxidase, glutathione reductase and catalase), inhibition of pro-inflammatory cytokines and activation-adhesion molecules which consequently reduces lymphocytopenia and infections by opportunistic organisms. The chronobiotic capacity of melatonin may also reset the natural circadian rhythm of sleep and wakefulness. Melatonin reduces the toxicity of the drugs used in the treatment of CCT and increases their efficacy. Finally, melatonin crosses the blood-brain barrier and reduces contusion volume and stabilizes cellular membranes preventing vasospasm and apoptosis of endothelial cells that occurs as a result of CCT.

Night Eating Syndrome: Impact on Bariatric Surgery

Individuals with night eating syndrome (NES) display a time-delayed pattern of food intake, outside the natural circadian rhythm. High prevalence estimates have been reported among bariatric surgery candidates, and some evidence suggests that NES is positively associated with obesity, negatively associated with weight loss efficacy, and follows a chronic course. In order to evaluate current NES theory, and the association between NES and bariatric surgery, literature searches were conducted to identify relevant literature published in English up to 2005. Because of inconsistencies in NES characterization, and significant heterogeneity in study design and methods, a qualitative assessment of NES and its relation to bariatric surgery was then undertaken. Within the literature, variable NES definitions highlight the distinct lack of clarity as to which behavioral features constitute a clinically meaningful entity. Prevalence estimates appear high among persons seeking bariatric surgery; however, no consistent pre- or postoperative demographic, clinical, or psychological factors reliably differentiate NES from non-NES. Further examination of the clinical significance, correlates, and course of NES in general and surgical samples is important, given the link with obesity. The ways in which NES departs from "normal" eating behavior must be clarified. Behavioral and psychological traits of NES need elucidation, and the establishment of agreed diagnostic criteria is essential for research to move forward. Therapy options should focus on aspects of the syndrome that cause greatest impairment, distress, or health risk.

Proliferative activity of cells in mouse thymus and spleen under different diurnal regimens of interleukin-2 administration

Circadian variations in spontaneous and concanavalin A-stimulated proliferation of mouse thymocytes and splenocytes were studied after administration of recombinant interleukin-2 at different times of day. Differences were revealed in the effect of morning and evening treatment with the cytokine. The time of injection corresponded to various phases of the natural circadian rhythm of endogenous interleukin-2 production, which probably contributes to diurnal differences in the influence of this cytokine.

Management of patients with glucocorticoid deficiency

At present, patients with hypoadrenalism are treated with hydrocortisone replacement regimens which aim to mimic the natural circadian rhythms of glucocorticoid secretion. As current knowledge regarding glucocorticoid biology increases, however, it is becoming clear that replacement therapies are nonphysiologic and could affect patients' quality of life.

Sleep and Cardiovascular Disease

Sleep is an important modulator of cardiovascular function, both in physiological conditions and in disease states. In individuals without a primary sleep disorder, sleep may exert significant effects on the autonomic nervous system, systemic hemodynamics, cardiac function, endothelial function, and coagulation. Some of these influences can be directly linked to specific modulatory effects of sleep stages per se; others result from the natural circadian rhythm of various physiological processes. There is a temporal association between physiological sleep and occurrence of vascular events, cardiac arrhythmias, and sudden death. Epidemiological and pathophysiological studies also indicate that there may be a causal link between primary sleep abnormalities (sleep curtailment, shift work, and sleep-disordered breathing) and cardiovascular and metabolic disease, such as hypertension, atherosclerosis, stroke, heart failure, cardiac arrhythmias, sudden death, obesity, and the metabolic syndrome. Finally, sleep disturbances may occur as a result of several medical conditions (including obesity, chronic heart failure, and menopause) and may therefore contribute to cardiovascular morbidity associated with these conditions. Further understanding of specific pathophysiological pathways linking sleep disorders to cardiovascular disease is important for developing therapeutic strategies and may have important implications for cardiovascular chronotherapeutics.

Foal behaviour in a loose housing/paddock environment during winter

The aim of this study was to establish some basic facts about weanling horse ( Equus caballus) behaviour in a loose housing/paddock environment during winter. The behaviour of 10 foals (seven American Standardbred and three Finnish cold-blooded foals) was observed in a cold loose housing/paddock environment from December 2002 to March 2003. The time budget, circadian rhythm and effect of weather conditions on behaviour were examined. The foals were observed for a total of 23 24-h periods by video recording. The method used was instantaneous sampling ( Martin and Bateson, 1993), where the locations of foals were noted at every 15 min along with the behaviour performed at that time. Temperature, humidity and wind speed were recorded three times a day. The foals spent 43.2 ± 6.6% of the time in the sleeping hall (an insulated building with a deep-litter bed), 51.4 ± 5.8% in the open paddock and 5.2 ± 2.7% in the shelter (a two-sided, roofed entrance shelter in front of the sleeping hall). The time spent outdoors was greatest between the hours of 08:00 and 20:00, but the foals spent some time outdoors also at night. They spent most of the day eating hay (27.6 ± 3.0%) (offered ad libitum), standing (25.5 ± 2.8%) and resting (32.1 ± 2.4%). The proportion of locomotive behaviour patterns was 5% of the observations. The foals in this study were able to perform species-specific behaviour patterns (resting, eating, being active) and to follow the natural circadian rhythm of these patterns. The behaviour of the foals did not change much as the temperature dropped from 0 to −20 °C. The time spent in the sleeping hall did not increase greatly, nor the time spent eating, resting or lying close to each other (huddling). On the basis of their behaviour, the weanling horses did not seem to suffer from the cold environment.

Pharmacological Mechanisms of Clinically Favorable Properties of a Selective β1‐Adrenoceptor Antagonist, Nebivolol

Nebivolol is a racemic mixture of d- and l-enantiomers. The drug is characterized by beta(1)-adrenoceptor selectivity and long-acting beta-blockade exerted predominantly by d-enantiomer. Nebivolol is devoid of intrinsic sympathomimetic activity and has no relevant membrane stabilizing action. Antiproliferative properties of nebivolol were demonstrated in endothelial and smooth muscle cell cultures. Infusion of nebivolol causes a vasodilation in all vascular beds by endothelial-dependent mechanism involving stimulation of beta(3)-adrenoceptors as well as by endothelial-independent mechanism. Nebivolol possesses not only direct vasodilator properties but also augments the action of endothelium-dependent vasodilators. The antioxidant property of nebivolol can at least in part explain why treatment with this drug enhances eNOS activity and minimizes the reperfusion-induced myocardial injury. The systemic effects of nebivolol in humans have an unusual hemodynamic profile. In contrast to traditional beta-adrenoceptor antagonists, nebivolol reduces preload and afterload due to systemic vasodilation and improves arterial distensibility. At 5 mg daily nebivolol effectively reduces systolic and diastolic blood pressure over a 24-h period. During treatment with nebivolol arterial pressure follows the natural circadian rhythm. Trough-to-peak ratio for nebivolol is 0.9. It has been demonstrated in numerous placebo-controlled studies that exercise tolerance is not reduced during nebivolol therapy. By chronic administration to patients with left ventricular dysfunction nebivolol increases myocardial contractility. Nebivolol produced no significant changes in lipid levels, insulin sensitivity or glucose tolerance. These findings make nebivolol a promising therapeutic tool for the treatment of arterial hypertension and chronic heart failure.

A circadian oscillator in Aspergillus spp. regulates daily development and gene expression.

We have established the presence of a circadian clock in Aspergillus flavus and Aspergillus nidulans by morphological and molecular assays, respectively. In A. flavus, the clock regulates an easily assayable rhythm in the development of sclerotia, which are large survival structures produced by many fungi. This developmental rhythm exhibits all of the principal clock properties. The rhythm is maintained in constant environmental conditions with a period of 33 h at 30 degrees C, it can be entrained by environmental signals, and it is temperature compensated. This endogenous 33-h period is one of the longest natural circadian rhythms reported for any organism, and this likely contributes to some unique responses of the clock to environmental signals. In A. nidulans, no obvious rhythms in development are apparent. However, a free running and entrainable rhythm in the accumulation of gpdA mRNA (encoding glyceraldehyde-3-phosphate dehydrogenase) is observed, suggesting the presence of a circadian clock in this species. We are unable to identify an Aspergillus ortholog of frequency, a gene required for normal circadian rhythmicity in Neurospora crassa. Together, our data indicate the existence of an Aspergillus circadian clock, which has properties that differ from that of the well-described clock of N. crassa.

A Circadian Rhythm in Mice that is Unaffected by the Period Mutation at Clock

Circadian rhythms of locomotor behavior were induced in mice using chronic d-amphetamine. The periods of the rhythms at various doses of amphetamine were unaffected by a mutation at the clock locus that lengthens circadian period. Amphetamine-induced rhythms were superimposed on the hostÕs natural circadian rhythm that is driven by the pacemaker in the suprachiasmatic nucleus. The results demonstrate the existence of an alternative mechanism for generating circadian rhythms that does not require the activity of canonical clock genes.

Varying responses to the rat forced-swim test under diurnal and nocturnal conditions

The paradox that experiments in behavioural pharmacology employing nocturnal rodent species are carried out almost exclusively in the resting phase of the animals' circadian cycle has remained largely unexamined and unquestioned. This is despite the fact that all major physiological systems in the body are intrinsically aligned with its natural circadian rhythm. The forced-swim test (FST) is a rodent model that is used extensively as a screening test for antidepressant activity. The objectives of the present study were to examine the behaviour of rats in the FST under diurnal and nocturnal conditions and, in addition, to profile the response of neurochemical, neuroendocrine, and cellular indices of stress at time points up to 120 min following exposure to the FST. The time spent in escape-oriented activity was significantly less when animals were tested in the dark phase. The profile of serum corticosterone and adrenal ascorbic acid concentrations indicates that the animals were less stressed by the test situation during the active (i.e., dark) phase of their circadian cycle. Similarly, increases in blood enzymatic markers of stress-induced cellular damage were less marked following FST exposure in the nocturnal period. Characteristic stress-induced increases in 5-HT turnover in the frontal cortex and amygdala observed in the diurnal phase were reversed in the nocturnal period. In conclusion, circadian differences in behaviour in the FST may be related to parallel alterations in the ability of animals to adapt to exposure to stress.

Optimizing delivery systems to tailor pharmacotherapy to cardiovascular circadian events.

The role of chronotherapeutics--agents that match drug delivery to the natural circadian rhythms of the cardiovascular system--in antihypertensive and antianginal therapy is discussed. Hypertension and angina remain two of the most important risk factors for cardiovascular morbidity and mortality. Early-morning increases in blood pressure do not seem to be attenuated by many currently available sustained-release and extended-dosing formulations of anti-hypertensive agents, such as atenolol, enalapril, sustained-release verapamil, nitrendipine, nifedipine, diltiazem, and long-acting propranolol. A 24-hour controlled-onset, extended-release delivery system (COER-24) for verapamil hydrochloride has recently been developed to address the pharmacokinetic and circadian challenges to controlling blood pressure and angina. COER-24 for verapamil hydrochloride, the first chronopharmacologic agent approved for the treatment of both hypertension and angina, is designed for bedtime administration. It provides the highest concentration of drug in the blood during the early hours of the day, when blood pressure and heart rate are rising rapidly. COER-24 for verapamil hydrochloride has a more favorable adverse-effect profile than is seen with immediate-release verapamil. COER-24 for verapamil hydrochloride provides effective blood pressure reduction for 24 hours and protects against the early-morning increase in blood pressure; the drug has a more favorable adverse-effect profile than immediate-release verapamil.

Effect of biological time on the determination of the LD50 of 5-fluorouracil in mice.

The LD50 was determined for 5-fluorouracil (FU) in mice at 11.00 and 23.00 h during one 24-hour period. These times were chosen because in mice kept on a light-dark cycle, with lights on from 06.00 to 18.00 h, the natural circadian rhythm in DNA synthetic activity in many different normal organs attains peak levels around 24.00 h (mid-dark) and through levels around 12.00 h (mid-light). The LD50 of FU, in milligrams per kilogram body weight, was much higher (450-500 mg/kg) at 11.00 than at 23.00 h (250-300 mg/kg). Since the biology of the living animal oscillates significantly on a daily or circadian basis, it is understandable that the degree of susceptibility or resistance to drugs should also fluctuate over the circadian period. Determination of the LD50 of a drug at that point in time when the animal is naturally resistant to that drug will result is a false appraisal of the toxic effects to the drug. To assess correctly the risk a drug poses, it should be tested at its time of maximal susceptibility in the living animal.

Mediation of diurnal fluctuations in pain sensitivity in the rat by food intake patterns: reversal by naloxone.

Rats maintained on a 12-hour light-dark cycle were tested for pain sensitivity after being deprived of food during either the dark or the light phase of the cycle. Diurnal fluctuations in pain sensitivity were observed. The fluctuations followed food intake patterns rather than a natural circadian rhythm, with food deprivation producing a decrease in pain sensitivity. The analgesic response produced by this mild food deprivation was strongly attenuated by naloxone or feeding, suggesting that endogenous opioid systems may be related to patterns of food intake.

Experimental Studies of Shift-Work I: A Comparison of ‘ Rotating ’ and ‘ Stabilized ’ 4-hour Shift Systems

Abstract Efficiency at ‘ mental ’ tasks was observed when performed according to a time schedule imposed by following one of two different 4-hour shift systems for a period of 12 consecutive days. Twenty-eight subjects were assigned either to a ‘ rotating ’ system, in which each 4-hour period of the 24 hours was worked once every 72 hours in a repeating cycle, or to a ‘ stabilized ’ system, in which the work periods were from 1230 to 1630 and 2400-0400 each day. In the rotating system, alterations in the level of several aspects of performance at different times of day were found to be related quite closely to concurrent fluctuations in body temperature arising from its natural circadian rhythm. A shift in the phase of this rhythm in response to the now sleep/waking cycle imposed by the stabilized system was accompanied by a corresponding change in the relative levels of performance observed in the two work periods. Thus in both systems body temperature was, in effect, a predictor of performance efficienc...