Sleep and chronobiology: recommendations for nursing education

The discipline of nursing is concerned with human responses in illness and wellness at individual, family, and community levels of practice. Sleep and circadian rhythms are biological processes that can influence wellness and illness, or can be altered by illness and adverse environments. As yet, however, there is no established curriculum for sleep or chronobiology in undergraduate or graduate nursing education. This paper provides a consensus by expert nurses in the field of sleep and circadian rhythm disorders that can be used for undergraduate and graduate levels of nursing education as well as a basis for beginning research and practice on sleep and health consequences of sleep loss.     

Measuring circadian temperature rhythm

Experimental control and mathematical techniques increase confidence that results of circadian temperature rhythm studies reflect true changes in the circadian timing system versus coupling with exogenous synchronizers. Masking effects represent confounding influences in studies that are concerned with the endogenous temperature rhythm. Because it is technically difficult to measure directly the behavior of the endogenous timing system, marker rhythms are used as proxy measures. However in addition to entraining, the external environment exerts a direct masking effect on the monitored rhythm. Methods for measuring circadian temperature rhythm are reviewed in this article. Constant routine, forced desynchrony, and purification methods represent attempts, at an experimental or mathematical level, to remove masking effects and more accurately capture the endogenous circadian temperature rhythm. Exogenous factors have not been subjected to the same scrutiny as the endogenous features of circadian temperature rhythm. But it is the environmental context, the extent to which the endogenous features are adaptively modified by the field environment, that will ultimately determine the biological value of circadian temperature rhythm to the organism. Thus, nurse investigators are encouraged to use rigorous methods to study both endogenous circadian temperature rhythm and exogenous rhythms.     

Reducing disruption of circadian temperature rhythm following surgery

Temperature and other circadian rhythms are disrupted following surgery and other traumatic events. During recovery, coordination between temperature rhythms and other rhythmic physiologic processes is reduced. Studies of animals and humans have shown that return of synchrony is not immediate, but that it is important in the recovery process. The purpose of this study was to test a combination of cues that have been shown to adjust the timing of circadian temperature rhythm. The combined cues consisted of timed ingestion of caffeine and protein foods and adjustment of the sleep/wake cycle. The intervention was tested in 26 age- and gender-matched maxillofacial surgery patients. Patients were randomly assigned to control or experimental groups. Circadian temperature rhythm was measured by continuous monitoring with axillary probes and miniature recorders before and after surgery. Following surgery, both experimental and control subjects displayed 24-hour circadian temperature rhythms; however, the peak-to-trough difference was decreased more following surgery in the control subjects than in the subjects who had prepared for surgery by practicing the intervention. Control subjects also had less day-to-day stability in the phase of their rhythms following surgery. These results suggest that the intervention reduced circadian disruption following surgery and provides a way for patients to prepare themselves to resist rhythm changes.     

Timing treatment to the rhythm of disease. A short course in chronotherapeutics.

The recognition of circadian rhythms in both normal human biologic function and disease has heightened the awareness that the timing of drug regimens may have an important impact on effectiveness of treatment. Outcomes in several diseases that have predictable circadian variations (e.g., arthritis, asthma, allergies, pepticulcer disease, dyslipidemia, cancer) have been improved by matching the timing of medication use to the circadian rhythm of the illness. Results of the ongoing CONVINCE study may provide evidence that chronotherapy for hypertension and angina pectoris may be more effective than traditional homeostatic treatment.     

Circadian regulation of cardiac metabolism

Circadian rhythm evolved to allow organisms to coordinate intrinsic physiological functions in anticipation of recurring environmental changes. The importance of this coordination is exemplified by the tight temporal control of cardiac metabolism. Levels of metabolites, metabolic flux, and response to nutrients all oscillate in a time-of-day–dependent fashion. While these rhythms are affected by oscillatory behavior (feeding/fasting, wake/sleep) and neurohormonal changes, recent data have unequivocally demonstrated an intrinsic circadian regulation at the tissue and cellular level. The circadian clock — through a network of a core clock, slave clock, and effectors — exerts intricate temporal control of cardiac metabolism, which is also integrated with environmental cues. The combined anticipation and adaptability that the circadian clock enables provide maximum advantage to cardiac function. Disruption of the circadian rhythm, or dyssynchrony, leads to cardiometabolic disorders seen not only in shift workers but in most individuals in modern society. In this Review, we describe current findings on rhythmic cardiac metabolism and discuss the intricate regulation of circadian rhythm and the consequences of rhythm disruption. An in-depth understanding of the circadian biology in cardiac metabolism is critical in translating preclinical findings from nocturnal-animal models as well as in developing novel chronotherapeutic strategies.     

The circadian rhythm of body temperature is preserved during malarial fever

Body temperature follows a circadian rhythm with a low around 6 a.m. and a peak about 12 hours later. The effect of fever on this endogenous oscillation is unknown. We obtained hourly measurements of the rectal temperature of 66 children with Plasmodium falciparum malaria. Even at febrile temperatures, the temperature followed a clear circadian rhythm. 33 patients (50%) had fever above 38 degrees C at 6 p.m. on the first day compared to only 9 (14%) at 6 a.m. the next morning. This considerable difference was also found on the second day of observation. Since in clinical practice antipyretics are often given above a certain fever threshold, the time of day should be taken into account when antipyretics are applied.     

Desynchronization of daily rest-activity rhythm in the days following light propofol anesthesia for colonoscopy

Anesthesia and surgery are associated with fatigue and sleep disorders, suggestive of disturbance of the circadian rest-activity rhythm. Previous studies on circadian rhythm disturbance were focused on patients undergoing general anesthesia associated with surgery. This does not permit one to draw valid conclusions about the effects of general anesthesia per se on circadian rhythms. Our study was set up to determine the impact of a hypnotic dose of propofol on the circadian rest-activity rhythm in humans under real-life conditions. Seventeen healthy subjects scheduled to receive light propofol anesthesia for ambulatory colonoscopy were investigated. Their rest-activity rhythms were assessed using actigraphic monitoring. Diurnal rest was increased, whereas nocturnal sleep was unchanged in the days following anesthesia. Nonparametric analyses showed a decrease in the strength of coupling of the rhythm to stable environmental zeitgebers and increase of fragmentation of the rhythm after anesthesia. Light general anesthesia itself impairs synchronization of the circadian rest-activity rhythm to local time in patients by acting directly on the circadian clock.     

The Circadian Clock: From Molecules to Behaviour

Circadian rhythms are a cardinal feature of living organisms. The stereotypical organization of homeostatic, endocrine and behavioural variables around the 24-hour cycle constitutes one of the most conserved attributes among species. It is now well established that circadian rhythmicity is not a learned behaviour, but is genetically transmitted and therefore subject to genetic manipulations. Recent advances in the circadian field have demonstrated that circadian oscillations are cell autonomous, that the circadian mechanism operates through a negative feedback loop and that a growing number of genes is under circadian control. Furthermore, single-gene mutations have been isolated in mammals that have profound effects on circadian behaviour. The production and mapping of one of these mutations in the mouse, an organism about which there exists a wealth of genetic information, should accelerate the elucidation of the molecular events involved in the generation of circadian rhythms in mammals.     

Chronic headache and potentially modifiable risk factors: screening and behavioral management of sleep disorders

Sleep-related variables have been identified among risk factors for frequent and severe headache conditions. It has been postulated that migraine, chronic daily headache, and perhaps other forms of chronic headache are progressive disorders. Thus, sleep and other modifiable risk factors may be clinical targets for prevention of headache progression or chronification. The present paper is part of the special series of papers entitled "Chronification of Headache" describing the empirical evidence, future research directions, proposed mechanisms, and risk factors implicated in headache chronification as well as several papers addressing individual risk factors (ie, sleep disorders, medication overuse, psychiatric disorders, stress, obesity). Understanding the link between risk factors and headache may yield novel preventative and therapeutic approaches in the management of headache. The present paper in the special series reviews epidemiological research as a means of quantifying the relationship between chronic headache and sleep disorders (sleep-disordered breathing, insomnia, circadian rhythm disorders, parasomnias) discusses screening for early detection and treatment of more severe and prevalent sleep disorders, and discusses fundamental sleep regulation strategies aimed at headache prevention for at-risk individuals.     

Eosinophils in Health and Disease: A State-of-the-Art Review

Eosinophils play a homeostatic role in the body’s immune responses. These cells are involved in combating some parasitic, bacterial, and viral infections and certain cancers and have pathologic roles in diseases including asthma, chronic rhinosinusitis with nasal polyps, eosinophilic gastrointestinal disorders, and hypereosinophilic syndromes. Treatment of eosinophilic diseases has traditionally been through nonspecific eosinophil attenuation by use of glucocorticoids. However, several novel biologic therapies targeting eosinophil maturation factors, such as interleukin (IL)-5 and the IL-5 receptor or IL-4/IL-13, have recently been approved for clinical use. Despite the success of biologic therapies, some patients with eosinophilic inflammatory disease may not achieve adequate symptom control, underlining the need to further investigate the contribution of patient characteristics, such as comorbidities and other processes, in driving ongoing disease activity. New research has shown that eosinophils are also involved in several homeostatic processes, including metabolism, tissue remodeling and development, neuronal regulation, epithelial and microbiome regulation, and immunoregulation, indicating that these cells may play a crucial role in metabolic regulation and organ function in healthy humans. Consequently, further investigation is needed into the homeostatic roles of eosinophils and eosinophil-mediated processes across different tissues and their varied microenvironments. Such work may provide important insights into the role of eosinophils not only under disease conditions but also in health. This narrative review synthesizes relevant publications retrieved from PubMed informed by author expertise to provide new insights into the diverse roles of eosinophils in health and disease, with particular emphasis on the implications for current and future development of eosinophil-targeted therapies.     

Challenges facing islet transplantation for the treatment of type 1 diabetes mellitus

Islet transplantation represents a most impressive recent advance in the search for a type 1 diabetes mellitus cure. While several hundred patients have achieved at least temporary insulin independence after receiving the islet "mini-organs" (containing insulin-producing beta cells), very few patients remain insulin independent beyond 4 years after transplantation. In this review, we describe historic as well as technical details about the procedure and provide insight into clinical and basic research efforts to overcome existing hurdles for this promising therapy.     

Therapy of circadian rhythm disorders in chronic fatigue syndrome: no symptomatic improvement with melatonin or phototherapy

BACKGROUND: Patients with chronic fatigue syndrome (CFS) show evidence of circadian rhythm disturbances. We aimed to determine whether CFS symptoms were alleviated by melatonin and bright-light phototherapy, which have been shown to improve circadian rhythm disorders and fatigue in jet-lag and shift workers. DESIGN: Thirty patients with unexplained fatigue for > 6 months were initially assessed using placebo and then received melatonin (5 mg in the evening) and phototherapy (2500 Lux for 1 h in the morning), each for 12 weeks in random order separated by a washout period. Principal symptoms of CFS were measured by visual analogue scales, the Shortform (SF-36) Health Survey, Mental Fatigue Inventory and Hospital Anxiety and Depression Scale. We also determined the circadian rhythm of body temperature, timing of the onset of melatonin secretion, and the relationship between these. RESULTS: Neither intervention showed any significant effect on any of the principal symptoms or on general measures of physical or mental health. Compared with placebo, neither body temperature rhythm nor onset of melatonin secretion was significantly altered by either treatment, except for a slight advance of temperature phase (0.8 h; P = 0.04) with phototherapy. CONCLUSION: Melatonin and bright-light phototherapy appear ineffective in CFS. Both treatments are being prescribed for CFS sufferers by medical and alternative practitioners. Their unregulated use should be prohibited unless, or until, clear benefits are convincingly demonstrated.     

Depression and sleep

More than 80% of depressive patients have complaints about sleepiness and insomnia. Physiological researches demonstrate changes in sleep architecture and circadian rhythm in depressive patients. These researches suggest the enhancement of arousal function in daytime and nighttime and circadian changes in cholinergic and catecholaminergic neural system. Pharmacological therapy might be selected in considering the mechanism of these neural changes. The research about sleep deprivation therapy may give us the new advances in the further treatment.     

Diagnosis and treatment in circadian rhythm sleep disorders

Circadian rhythm sleep disorders (CRSD) are characterized by misalignment between major sleep episode and desired sleep phase, or symptoms associated with internal desynchronization between endogenous circadian rhythm and overt sleep-wake rhythm. Endogenous circadian rhythm is mainly regulated by master circadian clock located in the suprachiasmatic nucleus. Light entrains the circadian clock according to a phase-response curve. Furthermore, social time cue affects human sleep-wake rhythm. Instructions concerning sleep hygiene including light environment play fundamental role for the treatment in CRSD. In addition, light therapy and oral melatonin administration have application to delayed sleep phase type. Diagnostic classification and treatment in each types of CRSD are reviewed in this article.     

Serotonin and the regulation of mammalian circadian rhythmicity

The suprachiasmatic nucleus (SCN), the site of the primary mammalian circadian clock, contains one of the densest serotonergic terminal plexes in the brain. Although this fact has been appreciated for some time, only in the last decade has there been substantial approach toward the understanding of the function of serotonin in the circadian rhythm system. The intergeniculate leaflet, which projects to the SCN via the geniculohypothalamic tract, receives serotonergic innervation from the dorsal raphe nucleus, and the SCN receives its serotonergic input from the median raphe nucleus. This separation of serotonergic origins provides the opportunity to investigate the function of the two projections. Loss of serotonergic neurones of the median raphe yields earlier onset and later offset of the nocturnal activity phase, longer duration of the activity phase, and increased sensitivity of circadian rhythm response to light. Despite the simplicity of the origins of serotonergic anatomy with respect to the circadian rhythm system, the actual involvement of serotonin in rhythm modulation is not so obvious. A variety of pharmacological studies have clearly implicated serotonin as a direct regulator of circadian rhythm phase, but others employing different methods suggest that simple elevation of SCN serotonin concentrations does not modify rhythm phase. The most convincing role of serotonin is its apparent ability to modulate sensitivity of the circadian rhythm to light. The putative method for such modulation is via a presynaptic 5-HT1B receptor on the retinohypothalamic tract, the activation of which attenuates photic input to the SCN thereby reducing phase response to light. Serotonin may modulate phase response to benzodiazepines, but does not appear to modify such response to environmentally induced locomotor activity. Current interest in serotonergic modulation of circadian rhythmicity is strong and the research is vigorous. There is an abundance of information about serotonin and circadian rhythm function that lacks a satisfactory framework for its interpretation. The next decade is likely to see the gradual evolution of this framework as the role of serotonin in circadian rhythm regulation is further elucidated.     

Axillary and thoracic skin temperatures poorly comparable to core body temperature circadian rhythm: results from 2 adult populations

Data from 2 separate studies were used to examine the relationships of axillary or thoracic skin temperature to rectal temperature and to determine the phase relationships of the circadian rhythms of these temperatures. In study 1, axillary skin and rectal temperatures were recorded in 19 healthy women, 21 to 36 years of age. In study 2, thoracic skin and rectal temperatures were recorded in 74 healthy women, 39 to 59 years of age. In both studies, temperatures were recorded continuously for 24 h while subjects carried out normal activities. Axillary and thoracic probes were insulated purposely to prevent ambient effects. Cosinor analysis was employed to estimate circadian rhythm mesor, amplitude, and acrophase. In addition, correlations between temperatures at various measurement sites were calculated and agreement determined. The circadian timing of axillary and skin temperature did not closely approximate that of rectal temperature: the mean acrophase (clock time) for study 1 was 18:57 h for axillary temperature and 16:12 h for rectal; for study 2, it was 03:05 h for thoracic and 15:05 h for rectal. Across individual subjects, the correlations of axillary or thoracic temperatures with rectal temperatures were variable. Results do not support the use of either axillary or skin temperature as a substitute for rectal temperature in circadian rhythm research related to adult women.     

Interconnections between circadian clocks and metabolism

Circadian rhythms evolved through adaptation to daily light/dark changes in the environment; they are believed to be regulated by the core circadian clock interlocking feedback loop. Recent studies indicate that each core component executes general and specific functions in metabolism. Here, we review the current understanding of the role of these core circadian clock genes in the regulation of metabolism using various genetically modified animal models. Additionally, emerging evidence shows that exposure to environmental stimuli, such as artificial light, unbalanced diet, mistimed eating, and exercise, remodels the circadian physiological processes and causes metabolic disorders. This Review summarizes the reciprocal regulation between the circadian clock and metabolism, highlights remaining gaps in knowledge about the regulation of circadian rhythms and metabolism, and examines potential applications to human health and disease.

To adapt to daily environmental changes caused by our Earth’s rotation, most organisms on the planet evolved near-24-hour cycles of behavioral, physiological, and metabolic rhythms (1). In addition to the entrained environmental stimuli, the internal timekeeping system of the circadian clock has evolved to anticipate external changes (2, 3). These conserved rhythms synchronize internal biological and behavioral processes to the external temporal environment, presumably providing organisms with selective advantages for survival. However, over the past century, modern industrialized society has profoundly changed our external environment (4). For example, the boundaries between day and night have been blurred by electric light and travel across different time zones. Disrupted circadian rhythms are highly associated with metabolic disorders (5). Conversely, obesity induced by overeating or overnutritional environment leads to circadian remodeling (6, 7). Understanding the reciprocal regulation of circadian rhythm and metabolism may provide mechanistic insights into circadian physiology and advance new chronotherapy approaches and therapeutic targets for metabolic disorders.     

Melatonin: therapeutic and clinical utilization

Melatonin, acting through melatonin receptors, is involved in numerous physiological processes including circadian entrainment, blood pressure regulation, oncogenesis, retinal physiology, seasonal reproduction, ovarian physiology, immune function and most recently in inducing osteoblast differentiation. Moreover, melatonin was proved to be a potent-free radical scavenger and a broad-spectrum antioxidant. More research is required into the effects of therapeutically modulating the melatoninergic system on circadian haemodynamics and rhythm under varying physiopathological conditions and the possible impact on morbidity and mortality in humans.     

Seasonal affective disorder. Shedding light on a dark subject

Seasonal affective disorder (SAD) appears to be a disturbance of circadian rhythm caused by desynchronization between the solar clock and the human biologic clock during seasons of short photoperiods. The supplemental bright light of phototherapy resynchronizes the disturbed rhythm; however, a comprehensive theory to explain the mechanism of phototherapy is lacking. Future research on the action of melatonin and serotonin and the photochemical effect of light in relation to possible circadian rhythm disorders should help us to better understand and treat not only SAD but other conditions such as jet lag, premenstrual syndrome, eating disorder, and carbohydrate-craving obesity.