Search tips
Search criteria 


Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Sleep Med Clin. Author manuscript; available in PMC 2010 June 1.
Published in final edited form as:
Sleep Med Clin. 2009 June 1; 4(2): 143–163.
doi:  10.1016/j.jsmc.2009.02.005
PMCID: PMC2733366

Influence of the Circadian System on Disease Severity


The severity of many diseases varies across the day and night. For example, adverse cardiovascular incidents peak in the morning, asthma is often worse at night and temporal lobe epileptic seizures are most prevalent in the afternoon. These patterns may be due to the day/night rhythm in environment and behavior, and/or endogenous circadian rhythms in physiology. Furthermore, chronic misalignment between the endogenous circadian timing system and the behavioral cycles could be a cause of increased risk of diabetes, obesity, cardiovascular disease and certain cancers in shift workers. Here we describe the magnitude, relevance and potential biological basis of such daily changes in disease severity and of circadian/behavioral misalignment, and present how these insights may help in the development of appropriate chronotherapy.

Keywords: sleep, circadian, asthma, cardiovascular, epilepsy, chronotherapy


The severity of many diseases varies across the 24-hour period. For example, myocardial infarction occurs most frequently in the morning a few hours after waking up, epileptic seizures of the brain's temporal lobe usually occur in the late afternoon or early evening, and asthma is generally worse at night (Figure 1). There are also differences across the 24-hour period in cancer development and on chemotherapeutic effectiveness. In addition, shift work is generally associated with chronic misalignment between the endogenous circadian timing system and the behavioral cycles, including sleep/wake and fasting/feeding cycles, and this misalignment could be a cause of the increased risk of diabetes, obesity, cardiovascular disease and certain cancers in shift workers. Here we describe the existence and magnitude of such daily changes in disease severity. We also describe what is known regarding the mechanisms underlying these time-variant changes in disease severity, in particular in terms of whether or not these changes are caused by the circadian pacemaker or due to behaviors that occur on a regular daily basis, including the sleep/wake cycle. Understanding the biological basis of these changes across the day and night can lead to better therapy e.g. appropriately timed medication to target specific phases of the body clock or to coincide with specific behaviors that cause vulnerability, while avoiding higher doses at other times when deleterious side effects could outweigh the benefits. Thus, current and future chronotherapeutic practices and targets are presented where appropriate.

Figure 1
The day/night patterns of disease severity

Cardiovascular Disease

Day/night rhythm in adverse cardiovascular events, arrhythmias and blood pressure

Cardiovascular disease is the leading cause of death in the US. Myocardial ischemia (insufficient supply of oxygenated blood relative to the demand of the cardiac muscle) can be caused by rupture of an atherosclerotic plaque and subsequent thrombosis affecting the coronary circulation, by hypoxia, or by coronary vasospasm. In extreme cases `sudden cardiac death' can result from an ischemic event in association with severe myocardial infarction and/or ventricular tachycardia/fibrillation. There exists robust epidemiological evidence that the peak incidence of cardiac ischemic events, including angina, acute myocardial infarction and sudden cardiac death occurs around 9-11 AM1-6, The reasons for this day/night pattern are not yet known, although triggering behaviors occurring at specific times of day have been suggested as a cause. It is equally possible that endogenous circadian rhythms in an array of hemodynamic, hemostatic, endothelial and autonomic variables could cause a day/night pattern in adverse events6.

Ventricular tachyarrhythmias are the most common cause of sudden cardiac death. Studies of patients undergoing 24-h electrocardiographic monitoring have revealed a robust and prominent peak in ventricular tachyarrhythmias during the morning and a trough at night7-16. For example, Mallavarapu et al.13 analyzed the electrocardiograms from 390 implantable cardioverter-defibrillator recipients who sustained a total of 2692 episodes of ventricular tachycardia or ventricular fibrillation. The peak incidence of the arrhythmias occurred between 10 and 11 AM, with a nadir between 2 and 3 AM. This day/night pattern persisted regardless of age, gender, ejection fraction, or ventricular tachycardia cycle length. Further evidence of the morning increase in susceptibility to serious arrhythmias comes from defibrillation thresholds in patients with implantable cardioverter-defibrillators: Venditti et al.17 found that the defibrillation threshold was higher when implantation occurred in the morning than when implanted at other times of day (thus greater energy is required for termination of morning tachyarrhythmias), and in ambulant patients they found a significant peak in failed first shocks in the morning compared with other times.

Arterial blood pressure (BP) generally falls during sleep and rises during activity, contributing to a day/night pattern in BP in most normotensive people as well as those with uncomplicated essential hypertension. However, a `non-dipping' hypertensive phenotype exists without much of a decline during sleep, and this presents an independent predictor of cardiovascular morbidity and mortality18. Mechanisms for this phenotype could include enhanced sodium sensitivity19-22, underlying circadian rhythmicity, and theoretically the presence of sleep disorders, such as insomnia and obstructive sleep apnea, and more sleep during the daytime which would blunt the day/night pattern.

Circadian rhythm vs. behavioral influences on cardiovascular risk markers

Sympathetic nervous activity is modulated in most circumstances as a protective homeostatic response. However, in some individuals with underlying pathophysiology or susceptibility, sympathetic activation can provoke adverse cardiovascular events, for instance by increasing blood pressure and arterial wall sheer forces that could potentially rupture vulnerable atherosclerotic plaques in coronary arteries. Thus, a day/night pattern in the activity of the sympathetic nervous system might underlie the day/night pattern of adverse events in vulnerable individuals. The day/night pattern could occur simply from a day/night pattern of behaviors, such as a surge of sympathetic activity upon standing up and becoming active in the morning or during REM sleep23-25,26, 27,28. Indeed, Deedwania et al. found that the morning increase in heart rate (HR) and blood pressure (BP) may cause a 40% increase in cardiac oxygen demand29. Andrews et al. found that about 80% of ambulatory ischemic events are accompanied by tachycardia30. Tachycardia, while normally promoting blood supply to peripheral tissues, actually decreases blood supply to the myocardium due to a relative reduction in diastole (when coronary arterioles receive most flow) vs. systole. In addition, platelets are a cornerstone of the hemostatic system and facilitate thrombus formation, which could impede coronary blood flow. Several in vivo and in vitro studies have found day/night variation in a number of functional platelet factors, with peaks in both activation and adhesiveness between 6 and 9 AM31-35. The increased morning platelet activation possibly could be caused by increased circulating catecholamines36, 37 or decreasing plasma melatonin38.

Most of the evidence demonstrating the existence of a 24-hour pattern in adverse cardiovascular events is epidemiological, which cannot attribute the underlying behavioral or circadian causes. Laboratory studies clearly show marked systematic changes in most hemodynamic and hemostatic variables with changes in behavior, such as exercise. Usually people sleep at the same phase of the circadian cycle so the relative contribution of behavioral and circadian influences on cardiovascular vulnerability cannot be determined. Such separation can be examined when keeping people awake and in the same conditions across at least 24 h or by shifting the time-relationship between the endogenous circadian clock and the behaviors (as occurs with shift work and during jet lag, which can be simulated in the laboratory) and examining the changes in relevant variables. A few laboratory studies have examined the existence of endogenous circadian influences on cardiovascular variables, principally be employing a `constant routine' protocol in which subjects remain in the same posture and awake for over 24 hours in dim light and with regular small snacks rather than larger irregular meals39-41. For example, Burgess et al.40 studied 16 subjects during a 26-hour constant routine protocol (to reveal underlying circadian rhythmicity) and a similar study in which sleep was permitted (to assess the additional effect of sleep beyond underlying circadian rhythmicity). They found that sympathetic activity was reduced during sleep (estimated from cardiac isvolumetric contraction time), whereas parasympathetic nervous system activity (estimated from heart rate variability) increased during the circadian `night' with little additional effect of sleep itself. Kerkhof et al.41, were unable to find a circadian fluctuation in BP in 12 healthy normotensive adults, but found significant circadian variation in HR (7 beats/min range, peak around 11 AM). Hu et al.42 found in healthy humans, the scale invariance of HR fluctuations changes toward an `unhealthy' state at a circadian phase corresponding to the peak in adverse events in other studies and populations. Experiments on rats discovered that circadian fluctuations in HR as well as the scale invariance of HR fluctuations were abolished upon lesioning of suprachiasmatic nucleus (SCN)43, 44. To quantify both circadian and behavioral effects as well as any interactions, Scheer et al. performed a forced desynchrony protocol that scheduled all behaviors evenly across all phases of the circadian cycle. They found robust circadian-related increases in HR and plasma epinephrine throughout the circadian `morning', with maxima occurring later than the time when cardiovascular risk is highest (~9 AM), raising the untested hypothesis that the rate of change of some sympathetic markers may be more relevant than the absolute level for the timing of adverse cardiovascular events45. These same authors found that certain behavioral stressors (mental stress, postural tilt or exercise) resulted in similar autonomic, hemostatic or hemodynamic effects when these stressors were presented at different phases of the circadian cycle. This result suggests that there is little functional interaction between the behavioral stressors and the circadian system, suggesting that these factors are additive in terms of affecting vulnerability to an adverse cardiovascular event46.

Chronotherapy for cardiovascular disorders

Although pharmacology for cardiovascular disease is a rapidly moving field, the current standard of care often includes utilization of a number of medications depending on each individual's disease[s] (e.g., coronary artery disease, congestive heart failure, arrhythmias, and/or hypertension), disease severity, and presence of co-morbidities (e.g., diabetes mellitus, renal insufficiency). The main classes of medications include: (a) Beta-adrenoreceptor antagonists (beta-blockers), which block the effects of endogenous catecholamines to decrease cardiac output and heart rate, and prolong diastole leading to improved myocardial blood supply; (b) Nitrates, which increase coronary artery diameter and blood flow to alleviate angina; (c) Calcium channel blockers (CCB), which are strong arterial vasodilators, and/or may have negative inotropic effects (decreasing the force of myocardial contractions) and negative chronotropic effects (decreasing heart rate); (d) Anti-hemostatic drugs that reduce platelet aggregation and thrombus formation, such as aspirin; (e) Angiotensin converting enzyme inhibitors and angiotensin receptor blockers, used primarily for reducing blood pressure; (f) Cholesterol lowering medications (e.g. statins) to reduce circulating low density lipoprotein, and thereby reduce the risk of atheroma formation on arterial walls; and (g) Experimental drugs, such as use of melatonin in hypertension.

Chronotherapy refers to the appropriately timed medication to achieve the most efficacious therapeutic levels in the body at the most needed times, while avoiding higher doses at other times when side effects could outweigh the benefits. For instance, rather than perpetually giving patients the maximum tolerated dose of beta-blocker, it may be better to time the beta blockade to coincide with the periods of greatest sympatho-excitation. This strategy may improve exercise tolerance in those with chronotropic incompetence (inadequate heart rate response) by allowing periods of reduced beta blockade during lower risk periods. Similarly, anti-platelet agents in cardiovascular disease could specifically target the periods of greatest platelet aggregability to reduce thrombotic complications, while minimizing hemorrhagic complications during periods of reduced platelet aggregation. Furthermore, by determining if certain behaviors alter disease severity (e.g., exercise-induced angina), timed medication can be planned to coincide with those behaviors, or such triggering behaviors could be scheduled outside periods of greater vulnerability.

Calcium channel blockers

CCBs are commonly used in hypertension, Prinz-Metal angina, supraventricular tachyarrhythmias (e.g. atrial fibrillation) and `non-Q wave' myocardial infarction. For example, Verapamil has potent negative inotropic and negative chronotropic effects and has a relatively weak arterial vasodilatory effect compared to Nifedipine. Chronotherapy with CCBs has been designed to achieve the highest plasma concentration during the most vulnerable time period while maintaining an adequate therapeutic dose throughout the remainder of the 24 hour period and has been marketed in the US since 1996. A variety of CCB delivery formulations (e.g., with controlled-onset and/or extended release) have been approved by the FDA47, 48, 49, and may be beneficially prescribed to lower BP, HR and rate-pressure product between 6:00 AM and noon depending on the time of administartion50, 51, 52. Another study demonstrated an improvement in the duration of exercise with evening doses of this Diltiazem preparation vs. morning dosing53.

Beta-adrenoreceptor antagonists

Beta-adrenoreceptor blockers are associated with an overall decrease in adverse cardiovascular events as well as the abolition of the day/night pattern of adverse coronary events54-56. Andrews et al. also found that beta-blockers decrease the incidence of coronary events associated with tachycardia, but not with a normal heart rate, suggesting that this effect of beta blockers is mediated via decreased myocardial demand (reduced tachycardia) and/or improved myocardial blood supply (prolonged diastole).30 An evening dose of propranolol extended release results in peak levels that are sustained throughout the most vulnerable time for ischemic events. Such propranolol chronotherapy was approved by the FDA in 2003 for treating systemic hypertension, although this also seems to possess optimal pharmacokinetics properties for treating ischemic heart disease57. A potential setback for beta-blocker chronotherapy is that it can suppress nighttime melatonin production and could disrupt normal circadian rhythms58


Short acting nitrates control angina most effectively when administered in the morning59. In contrast, long acting nitrates are designed for once per day dosing and should normally be administered at bedtime to maintain a therapeutic concentration in the plasma throughout the night and the subsequent vulnerable morning hours60.


Aspirin inhibits cyclooxygenase in platelets, which normally induces thromboxane B to promote platelet aggregation and thrombus formation. Aspirin has reduced the incidence of myocardial infarction in males by 59% during morning hours and only 34% during the rest of the 24 hour cycle61. However, low dose aspirin in females decreased risk for ischemic stroke but not myocardial infarction62, and the mechanisms for this gender difference are currently unknown. Although the effect of aspirin on platelets is irreversible (lasting throughout the thrombocyte's lifespan, ~12 days), some data shows that the effect of aspirin has marked diurnal variation with a peak during morning63, possibly due to day/night variation in pharmacodynamics, bioavailability and rate of elimination63-65.

Angiotensin converting enzyme inhibitors and cholesterol lowering medication

So far there is no solid evidence for the benefit of chronotherapy with ACE inhibitors in patients with hypertension or coronary artery disease was found66-68. For example, Kohno et al67 found no significant difference in BP decrease between morning and evening doses of imidaprol in either “dipping” and “non-dipping” hypertensive patients. Similarly, to the best of our knowledge there is no evidence for the benefit of chronotherapy with cholesterol lowering medication.

Melatonin and hypertension

Generally used therapeutic strategies for sub-optimally controlled arterial hypertension include increasing the dose of current medications, or switching to or adding another medication with a different mechanism of action. A recent review69 indicates that most hypertensive patients take their medications once a day in the morning, which would likely prove sufficient for patients with a normal nighttime fall in BP. However, this strategy may be inadequate for the `non-dipper' phenotype as effective medication levels are still needed across the night. Thus, sustained release preparations, or twice a day dosing may be better suited for `non-dipping' hypertensive patients who are at higher risk for cardiovascular complications70. One paper found that `non-dippers' have impaired nocturnal melatonin secretion71. Moreover, a randomized placebo controlled crossover trial in men with uncontrolled essential hypertension found that melatonin administration for 3 weeks (2.5 mg orally 1 hour before sleep) decreased nighttime systolic and diastolic blood pressure by 6 and 4 mmHg, respectively72. These results have recently been extended to females, in whom 3 weeks of melatonin significantly decreased nocturnal systolic and diastolic blood pressure73. Thus, the approach of supplementing the traditional management of hypertension with melatonin therapy appears promising, but requires more investigation into both the mechanism and the clinical use.


Day/night rhythm in asthma severity

A hallmark of bronchial asthma's natural course is that it is rarely stable. The highest frequency of asthmatic events occurs during the night74. More severe asthma is associated with more nocturnal symptoms75. Patients with nocturnal asthma demonstrate increased morbidity and mortality relative to patients without noticeable worsening of asthma at night76. There are three defining components of asthma; chronic inflammation, airway hyper-responsiveness and reversible airway obstruction77. Each of these parameters exhibit 24-hour fluctuations with worsening around 4 AM compared to 4 PM78, 79,80, 81,82-84. Such changes could be caused by the physiological consequences of sleep (e.g., increased vagal tone, decreased sympathetic activity, decreased temperature), the supine posture (e.g., causing reduced functional residual capacity of the lungs affecting the lower airway caliber), the environment (e.g., allergies to dust mites in the bedding) or factors related to the endogenous circadian system (e.g., increased pulmonary vagal bronchoconstrictive tone during the biological night). The relative contributions of these varied factors is not firmly established and these potentially change from patient-to patient and even within a patient from one day to the next, although some general findings may be applicable. For example, Hetzel et al. studied airway obstruction as indicated by peak expiratory flow (PEF) in 221 healthy and asthmatic subjects and found that even though the timing of the 24 hour rhythm in PEF was similar between these two groups, with more obstruction during the night, the amplitude of the fluctuation was 51% larger in asthma patients81. In patients with nocturnal worsening of asthma, airway-provoking agents (e.g., histamine, methacholine, house dust) had a greater effect on indices of airway obstruction during the night than during the day. For instance, Bonnet et al. found 24 hour oscillations in the pulmonary sensitivity to histamine and methacholine, with at least doubling concentrations required for the same effect at certain times of day82. There is day/night variability in sympathetic activity, related to sleep and/or circadian rhythms85-89. The lowest plasma epinephrine concentration generally occurs at ~4 AM corresponding to the nadir of PEF, suggesting that these may be linked86, 90. Patients with symptoms and signs of `nocturnal asthma' (i.e., disturbed sleep, nocturnal wheeze, overnight decreases in pulmonary function), exhibit significantly higher concentrations of inflammatory markers in the distal airways (e.g., leukocyte, neutrophil and eosinophil counts) at 4 AM compared to 4 PM79. The increase in neutrophils and eosinophils correlates with the overnight change in PEF79, 91. There is some evidence suggesting that patients with nocturnal asthma have abnormal functioning of hypothalamo-pituitary adrenal axis (HPA) and/or impaired cortisol binding and steroid responsiveness92, 93.

Circadian rhythm vs. behavioral influences on pulmonary function and asthma severity

Many studies of nocturnal asthma have relied on making assessments when awake at 4 PM and comparing these measurements when subjects are awoken to make assessments at 4 AM. There are obvious limitations with such approaches - such as measurements at two time points likely underestimates the underlying peaks and troughs in a rhythmic signal, and the fact that the arousal provoked by waking someone to make measurements can presumably affect pulmonary function. Furthermore, there may be a carry-over effect from the differences in posture, state and environmental conditions preceding the measurements at 4 AM versus 4 PM on the subsequent assessments of pulmonary function. The separate contributions of behavioral and circadian influences on asthma severity can be examined by keeping people awake and in the same conditions for at least 24 hours or by shifting the time-relationship between the endogenous circadian clock and the behaviors, as occurs relatively uncontrolled with shift work. While such designs are well-suited to assess the separate circadian influence on pulmonary function and asthma severity assessed during wakefulness, assessments of asthma during sleep within these protocols is difficult because most indices of asthma severity (e.g., from forced spirometry or bronchoalveolar lavage) can only be performed when awake. To specifically assess the contribution of the endogenous circadian system to the day/night pattern of pulmonary function, Spengler et al. studied 10 healthy subjects during continuous wakefulness throughout a `constant routine' protocol performed in the same posture for 40 hours in dim light, with small evenly distributed meals, and with pulmonary function measured every two hours. There was a significant circadian variation in forced expired volume in 1 second (FEV1), with a trough during the biological night at the time when sleep would normally occur94. To further explore this in patients with asthma, Shea et al. examined endogenous circadian variations in pulmonary function throughout a `forced desynchrony' protocol conducted over 10 days in the laboratory, during which the behavioral sleep/wake cycles were adjusted systematically to occur across all phases of the endogenous circadian cycle, enabling analytical separation of the circadian and behavioral cycle effects on pulmonary function. PEF and airway resistance exhibited circadian rhythms, with worsening asthma during the biologic night, and an additional worsening caused by sleep itself (independent of the phase of the circadian cycle)95. The same authors found an endogenous circadian rhythm in rescue inhaler use in asthma, peaking during the biological night96. Although most people usually sleep at night, many people occasionally or even systematically stay awake throughout the biological night due to the high prevalence of jet lag, sleep disorders and shift work in today's society. So it is important to determine the extent to which the severity of asthma is affected by being awake and active across the night (as well as the effect on asthma of sleep during the day). Assuming that the behavioral and circadian cycle effects summate, these data suggest that when sleep occurs at night, asthma severity will be highest in some individuals due to a combined effect of sleep and the circadian system. Moreover, the severity of bronchoconstriction across the night can be masked by sleep due to lack or awakenings, reduced sensations upon awakening (e.g., due to `sleep inertia' upon awakening), and/or reduced ventilatory demands at night.

Chronotherapy for asthma

Despite substantial advances in our knowledge of the pathogenesis of bronchial asthma, as well as in the development of therapeutic measures, morbidity and mortality related to asthma remains high97. Asthma is usually classified based on severity of symptoms and pulmonary function97. Thus, mild intermittent asthma (daytime symptoms less than once a week and nocturnal less than twice a month) does not require daily medication, while short acting beta-2 agonist inhalers are used as sporadic `rescue' medication. Mild persistent asthma (daytime symptoms on 1-6 days/week, with nocturnal symptoms >twice/month) is commonly treated with low dose inhaled corticosteroids. Prior to the wide availability of inhaled corticosteroids, oral Theophylline was a mainstream therapy for moderate asthma. Nowadays, moderate persistent asthma requires higher doses of inhaled corticosteroids with or without sporadic `rescue' use inhaled beta2 adrenoreceptor agonists. In severe asthma (daily and frequent nocturnal symptoms) and for asthma exacerbations, systemic corticosteroids might be indicated. To counter the daily variation in asthma severity, chronotherapy has been attempted. Theophylline was prescribed as a chronotherapy for asthma as early as 198098. The recommended daily pattern of dosing is either a single evening dose, or one-third of the daily dose in the morning and two-thirds in the evening. Several studies have shown that the bioavailability of Theophylline is greater if administered in the evening than in the morning, and that such chronotherapy is more effective in preventing the nighttime dip in FEV1 than the conventional Theophylline administration (equally divided daily dose between morning and evening administration)99-101, although this effect may be concentration dependent102. Kraft et al. have also shown that administration of Theophylline to subjects with asthma in the evening improved the inflammatory profile of the distal airways, and this was correlated with improved nocturnal FEV1103.

A series of investigations has revealed that: (1) administration of corticosteroids in the mid afternoon (3 PM) is the most effective in preventing a nocturnal drop of FEV1 and improving the respiratory inflammatory profile in patients with nocturnal asthma104, 105; (2) glucocorticoids given in the morning or late at night did not prevent the drop of FEV1 during the nighttime105, 106; and (3) systemic glucocorticoids in healthy subjects during the daytime (8 AM - 3 PM) minimized suppression of the hypothalamo-pituitary-adrenal axis (HPA) activity104, 107. Thus, by administering systemic corticosteroids around 3 PM one might achieve the best therapeutic effect across the night while avoiding HPA suppression. Similar results were obtained for inhaled corticosteroids108-110. For example, Pincus et al.109 studied the effects in asthma of inhaled Triamcinolone given four times per 24-hour (QID), once at 8 AM, or once at 5 PM. There were clear improvements in FEV1, PEF, use of beta2-agonists rescue medication, nocturnal awakenings, and quality of life score in the QID group and the 5 PM group, but not in the 8 AM group.

Several studies have investigated the benefits of chronotherapy of beta2-agonist medication in the management of nocturnal asthma. Gaultier et al. measured total lung resistance in 6 children with asthma at 7:30 AM, 11:30 AM, 4:30 PM and 10:30 PM, each before and 10 min after 2 mg Orciprenaline (beta-adrenoreceptor agonist) aerosol. Inhaled Orciprenaline was mainly effective around 7:30 AM and to a lesser extent around 10:30 AM, whereas there was no detectable effect at the other times111. The effect of time of 20 mg oral Bambuterol (a long acting beta adrenoreceptor agonist) was assessed in a double blind cross-over design study in 30 adult patients with asthma, and a trend toward higher FEV1 throughout 24 hr period was found when Bambuterol was administered in the evening compared with the morning112. In a double blind randomized cross-over designed study, Salmeterol aerosol 100 mg inhaled at night is as effective as 50 mg inhaled twice a day in improving PEF and FEV1113. Montelukast-leukotriene inhibitors, which are widely used as add-on therapy for treating asthma particularly in patients with a prominent allergic component to asthma and co-morbid allergic rhinitis, improve FEV1 more effectively when dosed in the evening compared with the morning114, 115. These studies demonstrate that varied modes of chronotherapy remain potentially useful in some patients with nocturnal worsening of asthma. While the role of Theophylline has decreased over the last few decades, it still is an add-on therapy or used for patients who are unable to tolerate inhaled corticosteroids. Some data suggest positive effects of Theophylline on diaphragmatic function as well as mucociliary clearance116, 117, which may be of particular importance in asthma patients suffering from respiratory muscle fatigue and excessive mucus. The emergence of a new generation of inhaled corticosteroids was recently heralded by the appearance of Ciclesonide (approved by the FDA in 2008 for maintenance treatment and prophylactic therapy of bronchial asthma in adults). The most remarkable feature of Ciclesonide is that it becomes activated by intracellular esterases located in the lower airways, therefore the side effects in the upper airways (such as oropharyngeal candidiasis and hoarseness) may potentially be less prominent compared with other inhaled corticosteroids. Anticholinergic agents represent another class of agents that theoretically may be useful in the management of nocturnal asthma, as these cause bronchodilation by opposing the effects of the parasympathetic nervous system, and such vagal effects are greatest at night (including during sleep).


Existing epidemiological data indicate a link between various physiologic parameters having well-established day/night rhythms and carcinogenesis. For example, Rafnsson et al. found a higher rate of breast cancer in shift working and flight attendant females118. Severely disrupted rest/activity cycles in patients with metastatic colorectal cancer is accompanied by decreased survival compared with patients with a well-preserved rest/activity pattern119. There are a number of biomolecular and genetic factors that might be responsible for the relationship between the circadian system and carcinogenesis. First, circadian clock proteins play an important role in regulating cell apoptosis, proliferation and differentiation, DNA repair and the cell cycle, by influencing the expression of numerous genes. For example, c-Myc is a proto-oncogen that regulates cell differentiation and proliferation, has a day/night rhythm120, and is over-expressed in cells of many human cancers. mPER2 and CLOCK knock-out mice have over-expressed c-Myc, are cancer prone and more susceptible to gamma radiation with reduced survival when compared to their wild-type counterparts121, 122. PER2 has a tumor suppressor effect, depletion of PER2 protein was observed in varied types of cancer cells in humans123, 124, and induction of PER2 expression in cancer cells inhibits growth, arrests the cell cycle and reduces apoptosis (at least partially through inhibiting c-Myc gene transcription). Such effects of PER2 induction do not occur in normal human cell lines125. Some data suggests that CCAAT/enhancer binding protein (C/EBP) alfa, a transcription factor that is ubiquitous in human tissues and plays a role in regulation of cell growth and differentiation, mediates part of its influence through up-regulation of PER2 protein expression123. Gery et al., induced expression of C/EBP alfa genes in chronic myeloid leukemia, Burkitt's lymphoma and murine fibroblast cell lines. Using microarray analysis these authors showed that induction of the C/EBP alfa gene increased expression of the PER2 gene, which may explain C/EBP's inhibitory effect on c-Myc expression in cancer cells126. Circadian clock proteins, such as PER1, also participate in cell apoptosis via modulation of the `checkpoint' proteins: ataxia telangiectasia mutated (ATM), kinase-1 and kinase-2124. Clock proteins modulate the cell cycle by affecting the expression of cell-cycle related genes cyclin B1, cyclin D1 and WEE1 transcription127. The c-Myc oncogene participates in G0/G1 cell phase transition in normal and tumor cells128, 129, such that circadian clock proteins may influence the cell cycle through expression of the c-Myc gene as well. Thus, each aspect of a cell's life cycle, including proliferation, differentiation, cell cycle phase shifting and apoptosis, is affected by circadian clock genes, providing the theoretical basis for cancer chronotherapy. It is becoming more recognized that chemotherapy for different types of malignancy at specific points of the molecular clock cycle and cell cycle can minimize adverse effects, increase tolerable doses, and help achieve better therapeutic responses and survival130. In addition, gene therapy is now being used in some field, including oncology131. Thus, in the future, modulating the expression of certain clock genes could be a therapeutic target in treating and/or preventing certain types of cancer132, 133 both in the general population as well as populations at risk, such as night shift workers. Finally, there is need for future studies on the potential therapeutic value of melatonin as anti-oncogenic therapy134


Epilepsy is another disorder that often exhibits a day/night variation in clinical presentation. Pavlova et al.135, found that temporal lobe epileptic seizures occur more frequently between 3 PM and 7 PM, whereas the peak incidence for extra temporal lobe epileptic seizures occurs between 7 PM and 11 PM. Among those seizures that occurred during sleep, the majority originated in the temporal lobe135. Similarly, analysis of 131 adults with localized epilepsy revealed that the day/night distribution of epileptiform activity depended on brain area involved: most frontal and parietal seizures occurred between 4-7 AM whereas temporal lobe seizures had two peaks (4-7 PM and 7-10 AM). Seizures of occipital origin occurred mostly between 4-7 PM.136 Whether these patterns are caused by the behavioral sleep/wake cycle and/or by a circadian rhythm in vulnerability is unknown. Some preliminary data indicate an endogenous circadian rhythm in epileptiform inter-ictal discharges while awake in some subjects with generalized epilepsy, with a peak in the beginning of habitual sleep period (11 PM - 3 AM)137. However considering all inter-ictal discharges - regardless of sleep/wake state - the distribution appeared random137. Sleep is well known to activate some seizures, including benign Rolandic epilepsy of childhood and autosomal dominant nocturnal frontal lobe epilepsy, but the mechanism of interaction between sleep physiology and cryptogenic and localization-related epilepsy is yet to be clarified138.

Yegnaranayan et al. randomized 103 epileptic subjects who were receiving subtherapeutic plasma levels of anti-epileptic medications (Phenytoin/Carbamazepin) to two treatment groups: one was allowed to increase the dose but not the timing of medication, the second group maintained the same dose but potentially altered the time of administration to 8 PM (regardless of when it was previously scheduled). This latter `chronotherapy' was better as it achieved more therapeutic levels of plasma medication and improved clinical outcomes (no seizures within 1 year), whereas symptoms of toxicity were more often observed in the conventional dose scheduling group (p<0.05)139. Thus, while data on chronotherapy for epilepsy is quite limited, there may be clinical utility in investigating this more.

Gastroesophageal reflux disease

Gastroesophageal reflux disease that occurs during wakefulness is usually postprandial and rapidly cleared. Nocturnal gastroesophageal reflux events occur less frequently than during the daytime but are associated with longer acid clearance time140 due to sleep and/or circadian-related decreases in swallowing141, saliva production (saliva contains mucous and bicarbonates that neutralize any acid from the stomach)142, peristalis143 and reduced symptoms of heartburn such that protective mechanisms are not as quickly initiated144. These all may potentially be paired with decreased gastric emptying during NREM sleep. While sleep and the supine posture can promote some of these deleterious effects, currently there are no studies that have determined whether the endogenous circadian system also contributes to any of these effects, and no consistent data on chronotherapy for gastroesophageal reflux disease.

Alzheimer Disease

Alzheimer disease (AD) affects about 15 million people worldwide, and is most commonly seen after age of 50, with progressive cognitive decline, circadian rhythm disturbances and sleep disturbances, including insomnia. It is tragic for the patient, causes major physical and emotional burden for primary caregivers, and represents a large economic burden for society. Altered sleep/wake regulation is the most common reason for institutionalizing patients with AD due to increased locomotor activity and need for care during the night145. “Sundowning” is a feature of AD, characterized by a late afternoon/evening predominance of activity146, which some authors attribute to insufficient melatonin production147. A pathoanathomical sign of AD is the deposition of beta-amyloid in certain areas of the brain, including the SCN148. Beta-amyloid is a potent generator of free radicals, which may cause neuronal damage and cell loss in the SCN and other brain structures, mediating circadian rhythm disruption149 and cognitive deficits in AD150. There is a significant decrease in vasoactive intestinal peptide (VIP) expressing neurons within the SCN of patients with AD151, 152. VIP plays an important role in the synchronization of clock gene expression across the SCN153. Lack of VIP or its receptors eliminates diurnal fluctuations of corticosteroids secretion in rats154. Disruption of the SCN neuronal output and/or the lack of a 24-hour fluctuation in beta1 adrenoreceptor expression in the pineal gland155, 156 are thought underlie the observed decrease in melatonin secretion in AD. Moreover, melatonin deficiency might also be implicated in the pathogenesis of AD as melatonin is a potent anti-oxidant that may protect neural tissue from the effects of reactive oxygen species157. A series of studies also support the notion that melatonin may decrease beta-amyloid related neurotoxicity158-160. The peak of melatonin serum concentration at night is decreased with age.161 Some data suggest that exogenous melatonin administration may improve sleep, decrease sundowning and slow the progression of cognitive deficit in AD patients162, 163. The anti-inflammatory effect of melatonin164, 165 as well as its protective effect on the cholinergic system demonstrated in rats166, 167 may have a therapeutic effect on some aspects of AD pathogenesis in humans. In a recent, double-blind, placebo-controlled trial on the effects of light and melatonin (Latin square) in 189 elderly subjects, it was shown that increased daytime environmental light exposure resulted in decreased cognitive deterioration, improved depressive symptoms, and attenuated the increase in functional limitations168. In this same study, melatonin supplementation shortened sleep onset latency and increased total sleep time. However, melatonin also decreased affect ratings and increased withdrawn behavior which was counteracted by light. Combined treatment reduced aggressive behavior, increased sleep efficiency and improved nocturnal restlessness.

Effect of Circadian Misalignment on Health

About 10 percent of the US labor force works rotating, irregular or permanent night shifts. Shift work is generally associated with chronic misalignment between the endogenous circadian timing system and the behavioral cycles, including sleep/wake and fasting/feeding cycles. Thus, such people may be attempting to sleep during the daytime at a circadian phase better `designed' for optimal activity, and conversely, attempting to remain awake during the night at a circadian phase better designed for sleep and fasting. The effect of Jet lag is similar but results from rapid travel across a number of time zones, and is characterized by insomnia or hypersomnolence, fatigue, behavioral symptoms, headaches, and gastrointestinal disturbances. Symptoms of jet lag syndrome usually last not more than a week, but with shift work there can be chronic circadian misalignment together with increased risk of diabetes, obesity, cardiovascular disease, gastrointestinal disorders and certain cancers. These adverse consequences of working night shifts could be mediated by direct effects of the misalignment between the endogenous circadian cycle and behavioral cycles (i.e., sleep/wake, feed/fast and rest/activity schedule), or secondary effects of such misalignment including altered family and society schedules, leading to generalized stress and the potential development of mood disorders, such as depression and anxiety, as well as chronic partial sleep deprivation, which can cause a number of adverse cardiovascular, endocrine and neurocognitive outcomes169-171. For instance, some surveys suggest that night shift workers sleep 10 fewer hours per week than those who work day shifts172. Gander et al. found that during long haul flights crew operators were sleep deprived with only 6.5 hours sleep over a 24 hour period173. Mittler et al. found that truck drivers had on average 3.8 hours sleep over a 24 hour period174. Similar data have emerged for other professions that require night shifts, including police officers and medical residents. The direct effects of misalignment are presented below.

Night shift work and cardiovascular disorders

From a study of 79,109 female nurses, the relative risk (RR) for development of coronary heart disease in women working night shifts >6 years was 1.51 (95% Confidence Interval: 1.12-2.03) compared with those who had never worked night shifts.175 The risk persisted after adjustment for smoking, alcohol intake, history of hypertension, diabetes mellitus, hypercholesterolemia, postmenopausal status, hormone replacement therapy, aspirin use and family history of myocardial infarction. From a study of 2,354 shift workers and 3,088 day workers, shift workers demonstrated increased mortality from coronary heart disease after adjusting for age, lifestyle, blood pressure and lipid profile (Odds ratio 1.83; 1.01-3.32)176. However, Boggild et al. found no increased risk for ischemic heart disease with night shifts in a prospective study with a 22-year follow-up period (RR=1.0; CI 95%=0.9-1.2; n=5,249 Danish males), whether or not adjusting for age and social class177. The authors discuss the potential of “healthy worker effect” and “survival bias” leading to a relatively healthy population among these middle-aged shift workers as a potential explanation for the lack of an effect. There were several cross-sectional and longitudinal prospective studies confirming the higher prevalence of cardiovascular disorders in people working rotating or night shifts178-181. There are a number of autonomic consequences of circadian misalignment that could be implicated in the adverse cardiovascular effects, such as increased cortisol, increased catecholamine output, increased cardiac sympathetic predominance and reduced parasympathetic activity182. For instance, there is less of a drop in blood pressure during the sleep periods of shift workers183, 184.

Night shift work and metabolic disorders

A cross-sectional study found that among 6,676 workers, night shift work was associated with a higher body mass index and higher waist-to-hip ratio185. A longitudinal study found that weight gains that exceeded 7 kg were more frequent among nurses on night work than on daytime work186. In a study of 27,485 individuals, obesity was more prevalent in shift workers than in day workers even after adjustment for age and socio-economic status (Odds ratio 1.41; 1.25-1.59).187 Obesity is a risk factor for insulin resistance and diabetes mellitus, and it was found that markers associated with insulin resistance, including hyperglycemia, increased triglyceride concentrations, low HDL cholesterol and hypertension, were more prevalent among night shifter workers than among day workers188. In the study of female nurses noted above, the risk of developing diabetes also rose with increasing duration of night shift work.175 In a study by Mikuni et al., the prevalence of diabetes in rotating shift workers was 2.1% versus 0.9% in day shift workers189. Night shift work increases the likelihood of developing insulin resistance190. These adverse metabolic effects of night shift work could be mediated via deleterious effects on glucose regulation or indirectly via increased appetite, leading to weight gain and obesity, a major risk factor for insulin resistance and type 2 diabetes191. Leptin is secreted by adipocytes and inhibits appetite and food intake to produce energy balance in normal weight individuals. Low leptin levels have been associated with chronic short habitual sleep duration in epidemiological studies192, 193, following acute sleep deprivation in laboratory studies (e.g., two nights of 4 hours sleep/night)194 and following reduced sleep for one week195. Reduced leptin signals a negative energy balance, leading to increased appetite. Leptin resistance eventually appears in obesity and has been implicated in sympathetic activation196 and insulin resistance197, 198. There is a significant circadian rhythm in leptin secretion, and circadian misalignment was predicted to alter the day/night range in circulating leptin, which could increase appetite199. Other hormones that are secreted by adipose tissue and exhibit day/night patterns that could be affected by shift work include adiponectin which is positively correlated with insulin sensitivity (adiponectin concentrations are high during the day and low at night200), and resistin which causes insulin resistance in rodents201 (concentrations are high during the dark/feeding phase in nocturnal rodents). Furthermore, ghrelin, an appetite-stimulating hormone primarily secreted from the gastric fundic mucosa202, is associated with type 2 diabetes203, may have a direct effect on the SCN204, and is increased by sleep loss193. Complementary epidemiologic evidence links short sleep with reduced leptin and increased ghrelin levels with increased body mass index205. Since these hormones are affected by day/night, food intake/fasting and in some cases circadian rhythms, misalignment of these factors due to shift work may cause prominent metabolic affects. Indeed, circadian misalignment leads to a suppression of leptin levels, which may play a role in explaining the increased risk for obesity in shift workers206.

Night shift work and cancer

An early study by Taylor and Pocock found higher cancer-attributed mortality in night shift workers compared with day shift ones207. A series of more recent investigations have confirmed and extended these findings, showing a higher risk for breast cancer in females whose job involves shift and/or night work, such as flight attendants118, nurses208, radio operators and telegraph operators209. In a study of 7,565 women with breast cancer, past employment requiring work at night for >6 months was associated with higher risk of development of breast cancer compared with a daytime working schedule (Odds ratio 1.5; CI 1.3-1.7), after adjusting for age, social class, age at birth of last child and number of children210. In a prospective, 10 year longitudinal study of 78,586 women, working at least 3 nights per month for >15 years increased risk of developing colon cancer compared to those who never worked rotating night shifts (RR 1.35; 1.03-1.77)211. A higher risk for prostate cancer was reported among those whose profession requires working rotating night shifts at least at some point in time, including police officers, firefighters, physicians and pilots212, 213. The International Agency for Research of Cancer (IARC), a unit of World Health Organization (WHO) recently announced that night shift work is probably carcinogenic. The underlying pathological mechanism could include exposure to light during the biological night which suppresses melatonin secretion by pineal gland. This is because melatonin has growth inhibitory and oncostatic properties. For example, melatonin: (i) inhibited breast cancer cells proliferation in vitro by 60-78%214; (ii) inhibited invasive and metastatic properties of breast cancer cells in vitro by decreasing attachment to basal membrane and counteracting the stimulatory effect of estradiol on cell adhesiveness215; (iii) enhanced apoptosis of breast cancer cells216; (iv) increased expression of p53 and p21WAF1 genes (tumor suppression genes) in breast cells culture217; (v) reversed the mammary tumor promoting effects of pinealectomy in rats218; and (vi) had an anti-tumor effect on prostate cancer in vitro. Interestingly, Zhu et al. found that a polymorphism in PER3 might be linked to breast cancer219; several animal experiments demonstrate the modulating effect of light exposure on PER2 gene expression in the SCN220, 221 which may affect its neurohumoral output, leading to alteration in clock genes expression in peripheral tissues. Finally, alteration in PER2 affects the DNA damage response and tumor suppression in mice and may play a role in apoptosis of cancerous cells121. Thus, it is plausible that light exposure during night shift work may affect clock gene expression and alter the regulatory effects of clock genes on cell proliferation, differentiation, apoptosis and DNA damage responses.

Night shift and gastrointestinal and reproductive disorders

In a study of 11,657 employees, there were significant increases in both gastric and duodenal ulcers in shift workers compared to day workers222. Many gastrointestinal variables exhibit robust day/night fluctuations that may be affected by shift work. For example: (i) in rats there are day/night fluctuations in gastrin receptor expression223, acid, bicarbonate secretion, gastric mucus efflux and gastric mucosa blood flow during fasting224, 225; and prostacyclin activity in gastric tissue during fasting226; (ii) in humans there are day/night rhythms in gastric mucosa vulnerability for aspirin and ethanol related injury227, 228, gastric emptying (longer at 8 PM vs. 8 AM)229; gastrointestinal motor propagation speed (slower during the night)230; and basal gastric secretion (highest from 9 PM until midnight)231. Studies on rats indicated that the peak of gastric acid secretion in rats is out of phase with that of bicarbonate secretion by about 7 hours232, creating a period of gastric mucosa vulnerability to injury. Thus, it is reasonable to speculate that an imbalance between acid secretion and protective factors as well as alterations in the inflammatory profile and activation of stress responses due to circadian and rest/activity and fasting/feeding rhythm misalignment might cause gastrointestinal morbidity in night shift workers compared to day workers.

It is also noteworthy that there have been a number of reports of increased reproductive function abnormalities in those who work night or rotating shifts, including irregular menstruation, increased risk of miscarriage, premature birth, and low birth weight233, 234.

Summary and Future Directions

We have reviewed: (i) how interactions between the circadian and behavioral systems affect disease severity, notably, the day/night pattern of adverse cardiovascular events, seizures and asthma exacerbations; (ii) how a disease can affect circadian rhythmicity, notably the circadian disruption of Alzheimer's disease; and (iii) the adverse health consequences of circadian misalignment, typical of chronic shift work. In each case, chronotherapeutic considerations are presented. With a few notable exceptions described above, chronotherapy is probably currently underused in most fields of medicine considering the very prominent day/night variation in disease severity. This reticence may be due to a need for improved physician education, availability of suitable medications with appropriate pharmacodynamics, and greater understanding of whether the vulnerable periods are produced by specific behaviors and/or the circadian phase. This last point is important when determining the therapeutic target, which becomes particularly relevant to consider when circadian rhythms and behaviors become differently aligned, as with sleep deprivation, shift work, jet lag and certain sleep disorders. While there are numerous options to improve neurocognitive function and sleep in conditions of circadian misalignment, less is known about the therapeutic countermeasures to the many physiological changes that accompany circadian misalignment that might underlie the increased hypertension, cardiovascular disease, diabetes, obesity, cancer, gastroesophageal and reproductive problems in shift workers. However, there is growing recognition of these problems. In addition, researchers are now beginning to study how functional circadian clocks exist in many peripheral tissues (e.g., heart, liver, lung, circulating blood) which potentially can become desynchronized from the central circadian pacemaker in the SCN. The consequences of peripheral-central desynchronization are not well understood, but may have implications for physiological function, metabolism, sleep, neurocognitive function and health. The molecular and genetic underpinnings of this rhythmicity are currently being studied in numerous animal models, laying the groundwork for future translational research to the bedside. The practical implementation of chronotherapy for many disorders warrants further exploration. Finally, determination of useful biomarkers or genetic analyses that can be reliably used to identify individuals at particular risk for adverse circadian disease-related effects, or adverse consequences of circadian misalignment would have numerous far-reaching consequences.


This work was supported by Grant K24 HL76446 from the National Institutes of Health to SA Shea, by Grant R21 AT002713 from the National Institutes of Health to FAJL Scheer and by grant 43-PA-08 from the American Sleep Medicine Foundation (a foundation of the American Academy of Sleep Medicine) to M Litinski.


Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.


1. Cohen MC, Rohtla KM, Lavery CE, Muller JE, Mittleman MA. Meta-analysis of the morning excess of acute myocardial infarction and sudden cardiac death. Am J Cardiol. 1997;79(11):1512–1516. [PubMed]
2. Ogawa H, Yasue H, Oshima S, Okumura K, Matsuyama K, Obata K. Circadian variation of plasma fibrinopeptide A level in patients with variant angina. Circulation. 1989;80(6):1617–1626. [PubMed]
3. Deedwania PC. Circadian rhythms of cardiovascular disorders. Futura Publishing Company, Inc; Armonk, NY: 1997.
4. Rocco MB, Barry J, Campbell S, et al. Circadian variation of transient myocardial ischemia in patients with coronary artery disease. Circulation. 1987;75(2):395–400. [PubMed]
5. Arntz HR, Willich SN, Oeff M, et al. Circadian variation of sudden cardiac death reflects age-related variability in ventricular fibrillation. Circulation. 1993;88(5 Pt 1):2284–2289. [PubMed]
6. Shea SA, Hilton MF, Muller JE. Day/Night Patterns of Myocardial Infarction and Sudden Cardiac Death: Interacting Roles of the Endogenous Circadian System and Behavioral Triggers. In: White WB, editor. Blood Pressure Monitoring in Cardiovascular Medicine and Therapeutics. 2nd ed. Humana Press Inc.; Totowa, NJ: 2007. pp. 251–289.
7. Canada WB, Woodward W, Lee G, et al. Circadian rhythm of hourly ventricular arrhythmia frequency in man. Angiology. 1983;34(4):274–282. [PubMed]
8. Twidale N, Taylor S, Heddle WF, Ayres BF, Tonkin AM. Morning increase in the time of onset of sustained ventricular tachycardia. Am J Cardiol. 1989;64(18):1204–1206. [PubMed]
9. Valkama JO, Huikuri HV, Linnaluoto MK, Takkunen JT. Circadian variation of ventricular tachycardia in patients with coronary arterial disease. Int J Cardiol. 1992;34(2):173–178. [PubMed]
10. Rebuzzi AG, Lucente M, Lanza GA, Coppola E, Manzoli U. Circadian rhythm of ventricular tachycardia. Prog Clin Biol Res. 1987;227B:153–158. [PubMed]
11. d'Avila A, Wellens F, Andries E, Brugada P. At what time are implantable defibrillator shocks delivered? Evidence for individual circadian variance in sudden cardiac death. Eur Heart J. 1995;16(9):1231–1233. [PubMed]
12. Behrens S, Galecka M, Bruggemann T, et al. Circadian variation of sustained ventricular tachyarrhythmias terminated by appropriate shocks in patients with an implantable cardioverter defibrillator. Am Heart J. 1995;130(1):79–84. [PubMed]
13. Mallavarapu C, Pancholy S, Schwartzman D, et al. Circadian variation of ventricular arrhythmia recurrences after cardioverter-defibrillator implantation in patients with healed myocardial infarcts. Am J Cardiol. 1995;75(16):1140–1144. [PubMed]
14. Fries R, Heisel A, Huwer H, et al. Incidence and clinical significance of short-term recurrent ventricular tachyarrhythmias in patients with implantable cardioverter-defibrillator. Int J Cardiol. 1997;59(3):281–284. [PubMed]
15. Tofler GH, Gebara OC, Mittleman MA, et al. Morning peak in ventricular tachyarrhythmias detected by time of implantable cardioverter/defibrillator therapy. The CPI Investigators. Circulation. 1995;92(5):1203–1208. [PubMed]
16. Nanthakumar K, Newman D, Paquette M, Greene M, Rakovich G, Dorian P. Circadian variation of sustained ventricular tachycardia in patients subject to standard adrenergic blockade. Am Heart J. 1997;134(4):752–757. [PubMed]
17. Venditti FJ, Jr., John RM, Hull M, Tofler GH, Shahian DM, Martin DT. Circadian variation in defibrillation energy requirements. Circulation. 1996;94(7):1607–1612. [PubMed]
18. Staessen JA, Thijs L, Fagard R, et al. Predicting cardiovascular risk using conventional vs ambulatory blood pressure in older patients with systolic hypertension. Systolic Hypertension in Europe Trial Investigators. JAMA. 1999;282(6):539–546. [PubMed]
19. Uzu T, Fujii T, Nishimura M, et al. Determinants of circadian blood pressure rhythm in essential hypertension. Am J Hypertens. 1999;12(1 Pt 1):35–39. [PubMed]
20. Uzu T, Ishikawa K, Fujii T, Nakamura S, Inenaga T, Kimura G. Sodium restriction shifts circadian rhythm of blood pressure from nondipper to dipper in essential hypertension. Circulation. 1997;96:1859–1862. [PubMed]
21. Kimura G, Uzu T, Nakamura S, Inenaga T, Fujii T. High sodium sensitivity and glomerular hypertension/hyperfiltration in primary aldosteronism. J Hypertens. 1996;14(12):1463–1468. [PubMed]
22. Kario K, Motai K, Mitsuhashi T, et al. Autonomic nervous system dysfunction in elderly hypertensive patients with abnormal diurnal blood pressure variation - Relation to silent cerebrovascular disease. Hypertension. 1997;30(6):1504–1510. [PubMed]
23. Millar-Craig MW, Bishop CN, Raftery EB. Circadian variation of blood-pressure. Lancet. 1978;1(8068):795–797. [PubMed]
24. Floras JS, Jones JV, Johnston JA, Brooks DE, Hassan MO, Sleight P. Arousal and the circadian rhythm of blood pressure. Clin Sci Mol Med Suppl. 1978;4:395s–397s. [PubMed]
25. Mancia G, Ferrari A, Gregorini L, et al. Blood pressure and heart rate variabilities in normotensive and hypertensive human beings. Circ Res. 1983;53(1):96–104. [PubMed]
26. Somers VK, Phil D, Dyken ME, Mark AL, Abboud FM. Sympathetic-nerve activity during sleep in normal subjects. N. Eng. J. Med. 1993;328:303–307. [PubMed]
27. Kirby DA, Verrier RL. Differential effects of sleep stage on coronary hemodynamic function during stenosis. Physiol Behav. 1989;45(5):1017–1020. [PubMed]
28. Turton MB, Deegan T. Circadian variations of plasma catecholamine, cortisol and immunoreactive insulin concentrations in supine subjects. Clin Chim Acta. 1974;55(3):389–397. [PubMed]
29. Deedwania PC, Nelson JR. Pathophysiology of silent myocardial ischemia during daily life. Hemodynamic evaluation by simultaneous electrocardiographic and blood pressure monitoring. Circulation. 1990;82(4):1296–1304. [PubMed]
30. Andrews TC, Fenton T, Toyosaki N, et al. Subsets of ambulatory myocardial ischemia based on heart rate activity. Circadian distribution and response to anti-ischemic medication. The Angina and Silent Ischemia Study Group (ASIS) Circulation. 1993;88(1):92–100. [PubMed]
31. Undar L, Turkay C, Korkmaz L. Circadian variation in circulating platelet aggregates. Ann Med. 1989;21(6):429–433. [PubMed]
32. Undar L, Ertugrul C, Altunbas H, Akca S. Circadian variations in natural coagulation inhibitors protein C, protein S and antithrombin in healthy men: a possible association with interleukin-6. Thromb Haemost. 1999;81(4):571–575. [PubMed]
33. Haus E, Cusulos M, Sackett-Lundeen L, Swoyer J. Circadian variations in blood coagulation parameters, alpha-antitrypsin antigen and platelet aggregation and retention in clinically healthy subjects. Chronobiol Int. 1990;7(3):203–216. [PubMed]
34. Jovicic A, Ivanisevic V, Nikolajevic R. Circadian variations of platelet aggregability and fibrinolytic activity in patients with ischemic stroke. Thromb Res. 1991;64(4):487–491. [PubMed]
35. Tofler GH, Stone PH, Maclure M, et al. Analysis of possible triggers of acute myocardial infarction (the MILIS study) Am J Cardiol. 1990;66(1):22–27. [PubMed]
36. Andrews NP, Goldstein DS, Quyyumi AA. Effect of systemic alpha-2 adrenergic blockade on the morning increase in platelet aggregation in normal subjects. Am J Cardiol. 1999;84(3):316–320. [PubMed]
37. Willich SN, Tofler GH, Brezinski DA, et al. Platelet alpha 2 adrenoceptor characteristics during the morning increase in platelet aggregability. Eur Heart J. 1992;13(4):550–555. [PubMed]
38. Del Zar MM, Martinuzzo M, Falcon C, Cardinali DP, Carreras LO, Vacas MI. Inhibition of human platelet aggregation and thromboxane-B2 production by melatonin: evidence for a diurnal variation. J Clin Endocrinol Metab. 1990;70(1):246–251. [PubMed]
39. Krauchi K, Wirz-Justice A. Circadian rhythm of heat production, heart rate, and skin and core temperature under unmasking conditions in men. Am J Physiol. 1994;267(3 Pt 2):R819–829. [PubMed]
40. Burgess HJ, Trinder J, Kim Y, Luke D. Sleep and circadian influences on cardiac autonomic nervous system activity. Am. J. Physiol. 1997;273(4 Pt 2):H1761–1768. [PubMed]
41. Kerkhof GA, Dongen HPAv, Bobbert AC. Absence of endogenous circadian rhythmicity in blood pressure? Am. J. Hypertens. 1998;11(3):373–377. [PubMed]
42. Hu K, Ivanov P, Hilton MF, et al. Endogenous circadian rhythm in an index of cardiac vulnerability independent of changes in behavior. Proc Natl Acad Sci U S A. 2004;101(52):18223–18227. [PubMed]
43. Scheer FAJL, Ter Horst GJ, Van der Vliet J, Buijs RM. Physiological and anatomic evidence for regulation of the heart by suprachiasmatic nucleus in rats. Am. J. Physiol. 2001;280(3):H1391–H1399. [PubMed]
44. Hu K, Scheer FA, Buijs RM, Shea SA. The endogenous circadian pacemaker imparts a scale-invariant pattern of heart rate fluctuations across time scales spanning minutes to 24 hours. J Biol Rhythms. 2008;23(3):265–273. [PMC free article] [PubMed]
45. Scheer FA, Kun Hu, Evoniuk Heather, Kelly Erin E, Malhotra Atul, Doamekpor Lauren A, Laker Michael D, Patel Jignasha, Smales Carolina, Shea Steven A. Additive Influences of the Endogenous Circadian System and Mental Stress on Cardiovascular Risk Factors. Sleep. 2008;31(suppl):S51.
46. Scheer FA, Kun Hu, Evoniuk Heather, Kelly Erin E, Malhotra Atul, Doamekpor Lauren A, Laker Michael D, Patel Jignasha, Smales Carolina, Shea Steven A. Influence of endogenous circadian system, physical excercise and their interaction on cardiovascular risk factors. Sleep. 2008;31(suppl):S46.
47. Cutler NR, Anders RJ, Jhee SS, et al. Placebo-controlled evaluation of three doses of a controlled-onset, extended-release formulation of verapamil in the treatment of stable angina pectoris. Am J Cardiol. 1995;75(16):1102–1106. [PubMed]
48. Frishman WH, Glasser S, Stone P, Deedwania PC, Johnson M, Fakouhi TD. Comparison of controlled-onset, extended-release verapamil with amlodipine and amlodipine plus atenolol on exercise performance and ambulatory ischemia in patients with chronic stable angina pectoris. Am J Cardiol. 1999;83(4):507–514. [PubMed]
49. Prisant LM, Devane JG, Butler J. A steady-state evaluation of the bioavailability of chronotherapeutic oral drug absorption system verapamil PM after nighttime dosing versus immediate-acting verapamil dosed every eight hours. Am J Ther. 2000;7(6):345–351. [PubMed]
50. Smith DH, Neutel JM, Weber MA. A new chronotherapeutic oral drug absorption system for verapamil optimizes blood pressure control in the morning. Am J Hypertens. 2001;14(1):14–19. [PubMed]
51. Prisant LMWH, Black Role of circadian rhtyhm in cardiovascular function-efficacy of a chronotherapeutic approach to controlling hypertensionwith Verelan PM (verapamil HCL) Todays Ther. Trends. 2003;21:201–213.
52. Glasser SP, Neutel JM, Gana TJ, Albert KS. Efficacy and safety of a once daily graded-release diltiazem formulation in essential hypertension. Am J Hypertens. 2003;16(1):51–58. [PubMed]
53. Glasser SP, Gana TJ, Pascual LG, Albert KS. Efficacy and safety of a once-daily graded-release diltiazem formulation dosed at bedtime compared to placebo and to morning dosing in chronic stable angina pectoris. Am Heart J. 2005;149(2):e1–9. [PubMed]
54. Spengler CM, Czeisler CA, Shea SA. An endogenous circadian rhythm of respiratory control in humans. J Physiol. 2000;526(3):683–694. [PubMed]
55. Muller JE, Stone PH, Turi ZG, et al. Circadian variation in the frequency of onset of acute myocardial infarction. N Engl J Med. 1985;313(21):1315–1322. [PubMed]
56. Cohn PF, Lawson WE. Effects of long-acting propranolol on A.M. and P.M. peaks in silent myocardial ischemia. Am J Cardiol. 1989;63(12):872–873. [PubMed]
57. Sica D, Frishman WH, Manowitz N. Pharmacokinetics of propranolol after single and multiple dosing with sustained release propranolol or propranolol CR (innopran XL), a new chronotherapeutic formulation. Heart Dis. 2003;5(3):176–181. [PubMed]
58. Scheer FAJL, Cajochen C, Turek FW, Czeisler CA. Melatonin in the regulation of sleep and circadian rhythms. In: Kryger MH, Roth T, Dement WC, editors. Principles and Practice of Sleep Medicine. 4th ed. W. B. Saunders; Philadelphia, PA: 2005. pp. 395–404.
59. Yasue H, Omote S, Takizawa A, Nagao M, Miwa K, Tanaka S. Circadian variation of exercise capacity in patients with Prinzmetal's variant angina: role of exercise-induced coronary arterial spasm. Circulation. 1979;59(5):938–948. [PubMed]
60. Wortman AB. Chronotherapy in coronary heart disease: comparison of two nitrate treatments. Chronobiol Intl. 1991;8:399–408. [PubMed]
61. Ridker PM, Manson JE, Buring JE, Muller JE, Hennekens CH. Circadian variation of acute myocardial infarction and the effect of low-dose aspirin in a randomized trial of physicians. Circulation. 1990;82(3):897–902. [PubMed]
62. Ridker PM, Cook NR, Lee IM, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med. 2005;352(13):1293–1304. [PubMed]
63. Cornelissen G, Halberg F, Prikryl P, Dankova E, Siegelova J, Dusek J. Prophylactic aspirin treatment: the merits of timing. International Womb-to-Tomb Chronome Study Group. JAMA. 1991;266(22):3128–3129. [PubMed]
64. Reinberg A, Zagula-Mally ZW, Ghata J, Halberg F. Circadian rhythm in duration of salicylate excretion referred to phase of excretory rhythms and routine. Proc Soc Exp Biol Med. 1967;124(3):826–832. [PubMed]
65. Markiewicz A, Semenowicz K. Time dependent changes in the pharmacokinetics of aspirin. Int J Clin Pharmacol Biopharm. 1979;17(10):409–411. [PubMed]
66. Shibasaki T, Obara T, Ohkubo T, et al. Time-dependent effects of imidapril administration in patients with morning hypertension measured as home blood pressure. Clin Exp Hypertens. 2008;30(3):243–254. [PubMed]
67. Kohno I, Ijiri H, Takusagawa M, et al. Effect of imidapril in dipper and nondipper hypertensive patients: comparison between morning and evening administration. Chronobiol Int. 2000;17(2):209–219. [PubMed]
68. Dagenais GR, Pogue J, Teo KK, Lonn EM, Yusuf S. Impact of ramipril on the circadian periodicity of acute myocardial infarction. Am J Cardiol. 2006;98(6):758–760. [PubMed]
69. Hermida RC, Calvo C, Ayala DE, Mojon A, Lopez JE. Relationship between physical activity and blood pressure in dipper and non-dipper hypertensive patients. J Hypertens. 2002;20(6):1097–1104. [PubMed]
70. Ohkubo T, Imai Y, Tsuji I, et al. Relation between nocturnal decline in blood pressure and mortality. The Ohasama Study. Am J Hypertens. 1997;10(11):1201–1207. [PubMed]
71. Jonas M, Garfinkel D, Zisapel N, Laudon M, Grossman E. Impaired nocturnal melatonin secretion in non-dipper hypertensive patients. Blood Press. 2003;12(1):19–24. [PubMed]
72. Scheer FAJL, van Montfrans GA, Van Someren EJW, Mairuhu G, Buijs RM. Daily nighttime melatonin reduces blood pressure in male patients with essential hypertension. Hypertension. 2004;43(2):192–197. [PubMed]
73. Cagnacci A, Cannoletta M, Renzi A, Baldassari F, Arangino S, Volpe A. Prolonged melatonin administration decreases nocturnal blood pressure in women. Am J Hypertens. 2005 [PubMed]
74. Bohadana AB, Hannhart B, Teculescu DB. Nocturnal worsening of asthma and sleep-disordered breathing. J Asthma. 2002;39(2):85–100. [PubMed]
75. Global Initiative for asthma (GINA) NHLBI/WHO Workshop report. Lung and Blood Institute; Bethesda MNH: 1995. Global strategy for asthma management and prevention. Updated March, 2002.
76. Hetzel MR, Clark TJ, Branthwaite MA. Asthma: analysis of sudden deaths and ventilatory arrests in hospital. Br Med J. 1977;1(6064):808–811. [PMC free article] [PubMed]
77. Masoli M, Fabian D, Holt S, Beasley R. The global burden of asthma: executive summary of the GINA Dissemination Committee report. Allergy. 2004;59(5):469–478. [PubMed]
78. Martin RJ, Cicutto LC, Smith HR, Ballard RD, Szefler SJ. Airways inflammation in nocturnal asthma. Am Rev Respir Dis. 1991;143(2):351–357. [PubMed]
79. Kraft M, Djukanovic R, Wilson S, Holgate ST, Martin RJ. Alveolar tissue inflammation in asthma. Am J Respir Crit Care Med. 1996;154(5):1505–1510. [PubMed]
80. Smolensky MH, Barnes PJ, Reinberg A, McGovern JP. Chronobiology and asthma. I. Day-night differences in bronchial patency and dyspnea and circadian rhythm dependencies. J Asthma. 1986;23(6):321–343. [PubMed]
81. Hetzel MR, Clark TJ. Comparison of normal and asthmatic circadian rhythms in peak expiratory flow rate. Thorax. 1980;35(10):732–738. [PMC free article] [PubMed]
82. Bonnet R, Jorres R, Heitmann U, Magnussen H. Circadian rhythm in airway responsiveness and airway tone in patients with mild asthma. J Appl Physiol. 1991;71(4):1598–1605. [PubMed]
83. Gervais P, Reinberg A, Gervais C, Smolensky M, DeFrance O. Twenty-four-hour rhythm in the bronchial hyperreactivity to house dust in asthmatics. J Allergy Clin Immunol. 1977;59(3):207–213. [PubMed]
84. Jarjour NN. Circadian variation in allergen and nonspecific bronchial responsiveness in asthma. Chronobiol Int. 1999;16(5):631–639. [PubMed]
85. Morrison JF, Pearson SB, Dean HG. Parasympathetic nervous system in nocturnal asthma. Br Med J (Clin Res Ed) 1988;296(6634):1427–1429. [PMC free article] [PubMed]
86. Barnes P, FitzGerald G, Brown M, Dollery C. Nocturnal asthma and changes in circulating epinephrine, histamine, and cortisol. N Engl J Med. 1980;303(5):263–267. [PubMed]
87. Khatri IM, Freis ED. Hemodynamic changes during sleep. J Appl Physiol. 1967;22(5):867–873. [PubMed]
88. Hornyak M, Cejnar M, Elam M, Matousek M, Wallin BG. Sympathetic muscle nerve activity during sleep in man. Brain. 1991;114(3):1281–1295. [PubMed]
89. Somers VK, Dyken ME, Mark AL, Abboud FM. Sympathetic-nerve activity during sleep in normal subjects. N Engl J Med. 1993;328(5):303–307. [PubMed]
90. Soutar CA, Costello J, Ijaduola O, Turner-Warwick M. Nocturnal and morning asthma. Relationship to plasma corticosteroids and response to cortisol infusion. Thorax. 1975;30(4):436–440. [PMC free article] [PubMed]
91. Kraft M, Martin RJ, Wilson S, Djukanovic R, Holgate ST. Lymphocyte and eosinophil influx into alveolar tissue in nocturnal asthma. Am J Respir Crit Care Med. 1999;159(1):228–234. [PubMed]
92. Kraft M, Vianna E, Martin RJ, Leung DY. Nocturnal asthma is associated with reduced glucocorticoid receptor binding affinity and decreased steroid responsiveness at night. J Allergy Clin Immunol. 1999;103(1 Pt 1):66–71. [PubMed]
93. Kraft M, Hamid Q, Chrousos GP, Martin RJ, Leung DY. Decreased steroid responsiveness at night in nocturnal asthma. Is the macrophage responsible? Am J Respir Crit Care Med. 2001;163(5):1219–1225. [PubMed]
94. Spengler CM, Shea SA. Endogenous circadian rhythm of pulmonary function in healthy humans. Am J Respir Crit Care Med. 2000;162(3 Pt 1):1038–1046. [PubMed]
95. Shea SA, Scheer FA, Hilton MF. Predicting the daily pattern of asthma severity based on relative contributions of the circadian timing system, the sleep-wake cycle and the environment. Sleep. 2007;30(suppl):S65.
96. Shea SAHM, Scheer FAJL, Ayers RT, Evoniuk HL, Sheils SA, Sugarbreaker RJ, Malhotra A, Massaro AF. An endogenous circadian rhythm in bronchodilators rescue medication use in asthma. Sleep. 2004;27(suppl):S81.
97. National Asthma Education and Prevention Program (NAEPP) Guidelines for the diagnosis and management of asthma: expert panel report 2. Lung, and Blood Institute; Bethesda MNH: 1997.
98. Darow PSV. Therapeutic advantage of unequal dosing of theophylline in patients with nocturnal asthma. Chronobiol Int. 1987;4:349–357. [PubMed]
99. Smolensky MH, Scott PH, Harrist RB, et al. Administration-time-dependency of the pharmacokinetic behavior and therapeutic effect of a once-a-day theophylline in asthmatic children. Chronobiol Int. 1987;4(3):435–447. [PubMed]
100. D'Alonzo GE, Smolensky MH, Feldman S, et al. Twenty-four hour lung function in adult patients with asthma. Chronoptimized theophylline therapy once-daily dosing in the evening versus conventional twice-daily dosing. Am Rev Respir Dis. 1990;142(1):84–90. [PubMed]
101. Neuenkirchen H, Wilkens JH, Oellerich M, Sybrecht GW. Nocturnal asthma: effect of a once per evening dose of sustained release theophylline. Eur J Respir Dis. 1985;66(3):196–204. [PubMed]
102. Reinberg A, Pauchet F, Ruff F, et al. Comparison of once-daily evening versus morning sustained-release theophylline dosing for nocturnal asthma. Chronobiol Int. 1987;4(3):409–419. [PubMed]
103. Kraft M, Torvik JA, Trudeau JB, Wenzel SE, Martin RJ. Theophylline: potential antiinflammatory effects in nocturnal asthma. J Allergy Clin Immunol. 1996;97(6):1242–1246. [PubMed]
104. Reinberg A, Guillet P, Gervais P, Ghata J, Vignaud D, Abulker C. One month chronocorticotherapy (Dutimelan 8 15 mite). Control of the asthmatic condition without adrenal suppression and circadian rhythm alteration. Chronobiologia. 1977;4(4):295–312. [PubMed]
105. Beam WR, Weiner DE, Martin RJ. Timing of prednisone and alterations of airways inflammation in nocturnal asthma. Am Rev Respir Dis. 1992;146(6):1524–1530. [PubMed]
106. Reinberg A, Gervais P, Chaussade M, Fraboulet G, Duburque B. Circadian changes in effectiveness of corticosteroids in eight patients with allergic asthma. J Allergy Clin Immunol. 1983;71(4):425–433. [PubMed]
107. Ceresa F, Angeli A, Boccuzzi G, Molino G. Once-a-day neurally stimulated and basal ACTH secretion phases in man and their response to corticoid inhibition. J Clin Endocrinol Metab. 1969;29(8):1074–1082. [PubMed]
108. Toogood JH, Baskerville JC, Jennings B, Lefcoe NM, Johansson SA. Influence of dosing frequency and schedule on the response of chronic asthmatics to the aerosol steroid, budesonide. J Allergy Clin Immunol. 1982;70(4):288–298. [PubMed]
109. Pincus DJ, Humeston TR, Martin RJ. Further studies on the chronotherapy of asthma with inhaled steroids: the effect of dosage timing on drug efficacy. J Allergy Clin Immunol. 1997;100(6):771–774. [PubMed]
110. Kemp JP, Berkowitz RB, Miller SD, Murray JJ, Nolop K, Harrison JE. Mometasone furoate administered once daily is as effective as twice-daily administration for treatment of mild-to-moderate persistent asthma. J Allergy Clin Immunol. 2000;106(3):485–492. [PubMed]
111. Gaultier C, Reinberg A, Motohashi Y. Circadian rhythm in total pulmonary resistance of asthmatic children. Effects of a beta-agonist agent. Chronobiol Int. 1988;5(3):285–290. [PubMed]
112. D'Alonzo GE, Smolensky MH, Feldman S, Gnosspelius Y, Karlsson K. Bambuterol in the treatment of asthma. A placebo-controlled comparison of once-daily morning vs evening administration. Chest. 1995;107(2):406–412. [PubMed]
113. Faurschou P, Engel AM, Haanaes OC. Salmeterol in two different doses in the treatment of nocturnal bronchial asthma poorly controlled by other therapies. Allergy. 1994;49(10):827–832. [PubMed]
114. Noonan MJ, Chervinsky P, Brandon M, et al. Montelukast, a potent leukotriene receptor antagonist, causes dose-related improvements in chronic asthma. Montelukast Asthma Study Group. Eur Respir J. 1998;11(6):1232–1239. [PubMed]
115. Altman LC, Munk Z, Seltzer J, et al. A placebo-controlled, dose-ranging study of montelukast, a cysteinyl leukotriene-receptor antagonist. Montelukast Asthma Study Group. J Allergy Clin Immunol. 1998;102(1):50–56. [PubMed]
116. Iravani JM. Theophylline and mucocilliary function. Chest. 1987;92(supplement):38–43.
117. Murciano D, Aubier M, Lecocguic Y, Pariente R. Effects of theophylline on diaphragmatic strength and fatigue in patients with chronic obstructive pulmonary disease. N Engl J Med. 1984;311(6):349–353. [PubMed]
118. Rafnsson V, Tulinius H, Jonasson JG, Hrafnkelsson J. Risk of breast cancer in female flight attendants: a population-based study (Iceland) Cancer Causes Control. 2001;12(2):95–101. [PubMed]
119. Mormont MC, Waterhouse J, Bleuzen P, et al. Marked 24-h rest/activity rhythms are associated with better quality of life, better response, and longer survival in patients with metastatic colorectal cancer and good performance status. Clin Cancer Res. 2000;6(8):3038–3045. [PubMed]
120. Nakamura KD, Duffy PH, Lu MH, Turturro A, Hart RW. The effect of dietary restriction on myc protooncogene expression in mice: a preliminary study. Mech Ageing Dev. 1989;48(2):199–205. [PubMed]
121. Fu L, Pelicano H, Liu J, Huang P, Lee C. The circadian gene Period2 plays an important role in tumor suppression and DNA damage response in vivo. Cell. 2002;111(1):41–50. [PubMed]
122. Miller BH, McDearmon EL, Panda S, et al. Circadian and CLOCK-controlled regulation of the mouse transcriptome and cell proliferation. Proc Natl Acad Sci U S A. 2007;104(9):3342–3347. [PubMed]
123. Gery S, Gombart AF, Yi WS, Koeffler C, Hofmann WK, Koeffler HP. Transcription profiling of C/EBP targets identifies Per2 as a gene implicated in myeloid leukemia. Blood. 2005;106(8):2827–2836. [PubMed]
124. Gery S, Komatsu N, Baldjyan L, Yu A, Koo D, Koeffler HP. The circadian gene per1 plays an important role in cell growth and DNA damage control in human cancer cells. Mol Cell. 2006;22(3):375–382. [PubMed]
125. Hua H, Wang Y, Wan C, et al. Circadian gene mPer2 overexpression induces cancer cell apoptosis. Cancer Sci. 2006;97(7):589–596. [PMC free article] [PubMed]
126. Johansen LM, Iwama A, Lodie TA, et al. c-Myc is a critical target for c/EBPalpha in granulopoiesis. Mol Cell Biol. 2001;21(11):3789–3806. [PMC free article] [PubMed]
127. Matsuo T, Yamaguchi S, Mitsui S, Emi A, Shimoda F, Okamura H. Control mechanism of the circadian clock for timing of cell division in vivo. Science. 2003;302(5643):255–259. [PubMed]
128. Wang HMS, Grachtchouk V, Zhuang D, Soengas MS, Gudkov AV, Prochownik EV, Nikiforov MA. c-myc depletion inhibits proliferation of human cells at various stages of the cell cycle. Oncogene. 2008;27:1905–1915. [PMC free article] [PubMed]
129. Prathapam T, Tegen S, Oskarsson T, Trumpp A, Martin GS. Activated Src abrogates the Myc requirement for the G0/G1 transition but not for the G1/S transition. Proc Natl Acad Sci U S A. 2006;103(8):2695–2700. [PubMed]
130. Levi F, Focan C, Karaboue A, et al. Implications of circadian clocks for the rhythmic delivery of cancer therapeutics. Adv Drug Deliv Rev. 2007;59(910):1015–1035. [PubMed]
131. Dang CV, Gerson SL, Litwak M, Padarathsingh M. Gene therapy and translational cancer research. Clin Cancer Res. 1999;5(2):471–474. [PubMed]
132. Lissoni P, Brivio F, Fumagalli L, et al. Neuroimmunomodulation in medical oncology: application of psychoneuroimmunology with subcutaneous low-dose IL-2 and the pineal hormone melatonin in patients with untreatable metastatic solid tumors. Anticancer Res. 2008;28(2B):1377–1381. [PubMed]
133. Lissoni P, Chilelli M, Villa S, Cerizza L, Tancini G. Five years survival in metastatic non-small cell lung cancer patients treated with chemotherapy alone or chemotherapy and melatonin: a randomized trial. J Pineal Res. 2003;35(1):12–15. [PubMed]
134. Blask DE, Brainard GC, Dauchy RT, et al. Melatonin-depleted blood from premenopausal women exposed to light at night stimulates growth of human breast cancer xenografts in nude rats. Cancer Res. 2005;65(23):11174–11184. [PubMed]
135. Pavlova MK, Shea SA, Bromfield EB. Day/night patterns of focal seizures. Epilepsy Behav. 2004;5(1):44–49. [PubMed]
136. Durazzo TS, Spencer SS, Duckrow RB, Novotny EJ, Spencer DD, Zaveri HP. Temporal distributions of seizure occurrence from various epileptogenic regions. Neurology. 2008;70(15):1265–1271. [PubMed]
137. Pavlova MKBE, Evoniuk H, Shea SA. Endogenous Circadian Variation of epileptiform abnormalities in idiopathic Generalized Epilepsy. Sleep. 2005;28(suppl):S71.
138. Herman ST, Walczak TS, Bazil CW. Distribution of partial seizures during the sleep--wake cycle: differences by seizure onset site. Neurology. 2001;56(11):1453–1459. [PubMed]
139. Yegnanarayan R, Mahesh SD, Sangle S. Chronotherapeutic dose schedule of phenytoin and carbamazepine in epileptic patients. Chronobiol Int. 2006;23(5):1035–1046. [PubMed]
140. Orr WC, Allen ML, Robinson M. The pattern of nocturnal and diurnal esophageal acid exposure in the pathogenesis of erosive mucosal damage. Am J Gastroenterol. 1994;89(4):509–512. [PubMed]
141. Lear CS, Flanagan JB, Jr., Moorrees CF. The Frequency of Deglutition in Man. Arch Oral Biol. 1965;10:83–100. [PubMed]
142. Schneyer LH, Pigman W, Hanahan L, Gilmore RW. Rate of flow of human parotid, sublingual, and submaxillary secretions during sleep. J Dent Res. 1956;35(1):109–114. [PubMed]
143. Elsenbruch S, Orr WC, Harnish MJ, Chen JD. Disruption of normal gastric myoelectric functioning by sleep. Sleep. 1999;22(4):453–458. [PubMed]
144. Orr WC, Johnson LF, Robinson MG. Effect of sleep on swallowing, esophageal peristalsis, and acid clearance. Gastroenterology. 1984;86(5):814–819. [PubMed]
145. Satlin A, Volicer L, Stopa EG, Harper D. Circadian locomotor activity and core-body temperature rhythms in Alzheimer's disease. Neurobiol Aging. 1995;16(5):765–771. [PubMed]
146. Hu K, van Someren EJ, Shea SA, Scheer FA. Reduction of scale-invariance of activity fluctuations with aging and Alzheimer's disease: involvement of the circadian pacemaker. Proc Natl Acad Sci U S A. in press. [PubMed]
147. Cohen-Mansfield J, Garfinkel D, Lipson S. Melatonin for treatment of sundowning in elderly persons with dementia - a preliminary study. Arch Gerontol Geriatr. 2000;31(1):65–76. [PubMed]
148. McDuff T, Sumi SM. Subcortical degeneration in Alzheimer's disease. Neurology. 1985;35(1):123–126. [PubMed]
149. Swaab DF, Fliers E, Partiman TS. The suprachiasmatic nucleus of the human brain in relation to sex, age and senile dementia. Brain Res. 1985;342(1):37–44. [PubMed]
150. Selkoe DJ. Cell biology of protein misfolding: the examples of Alzheimer's and Parkinson's diseases. Nat Cell Biol. 2004;6(11):1054–1061. [PubMed]
151. HMaSD Zhou J-N. VIP neurons in the human SCN in relation to sex, age and Alzheimer Disease. Neurology of Aging. 1995;16(4):571–576. [PubMed]
152. Liu RY, Zhou JN, Hoogendijk WJ, et al. Decreased vasopressin gene expression in the biological clock of Alzheimer disease patients with and without depression. J Neuropathol Exp Neurol. 2000;59(4):314–322. [PubMed]
153. Maywood ES, Reddy AB, Wong GK, et al. Synchronization and maintenance of timekeeping in suprachiasmatic circadian clock cells by neuropeptidergic signaling. Curr Biol. 2006;16(6):599–605. [PubMed]
154. Sheward WJ, Maywood ES, French KL, et al. Entrainment to feeding but not to light: circadian phenotype of VPAC2 receptor-null mice. J Neurosci. 2007;27(16):4351–4358. [PubMed]
155. Wu YH, Feenstra MG, Zhou JN, et al. Molecular changes underlying reduced pineal melatonin levels in Alzheimer disease: alterations in preclinical and clinical stages. J Clin Endocrinol Metab. 2003;88(12):5898–5906. [PubMed]
156. Wu YH, Fischer DF, Kalsbeek A, et al. Pineal clock gene oscillation is disturbed in Alzheimer's disease, due to functional disconnection from the “master clock” Faseb J. 2006;20(11):1874–1876. [PubMed]
157. Wang JZ, Wang ZF. Role of melatonin in Alzheimer-like neurodegeneration. Acta Pharmacol Sin. 2006;27(1):41–49. [PubMed]
158. Lahiri DK. Melatonin affects the metabolism of the beta-amyloid precursor protein in different cell types. J Pineal Res. 1999;26(3):137–146. [PubMed]
159. Song W, Lahiri DK. Melatonin alters the metabolism of the beta-amyloid precursor protein in the neuroendocrine cell line PC12. J Mol Neurosci. 1997;9(2):75–92. [PubMed]
160. Zhang YC, Wang ZF, Wang Q, Wang YP, Wang JZ. Melatonin attenuates beta-amyloid-induced inhibition of neurofilament expression. Acta Pharmacol Sin. 2004;25(4):447–451. [PubMed]
161. Arendt J. Melatonin and the mamallian pineal gland. 1st ed. Chapman and Hall; London, UK: 1995.
162. Cardinali DP, Brusco LI, Liberczuk C, Furio AM. The use of melatonin in Alzheimer's disease. Neuro Endocrinol Lett. 2002;23(Suppl 1):20–23. [PubMed]
163. Cardinali DP, Brusco LI, Lloret SP, Furio AM. Melatonin in sleep disorders and jet-lag. NeuroEndocrinol Lett. 2002;23(Suppl 1):9–13. [PubMed]
164. Sasaki M, Jordan P, Joh T, et al. Melatonin reduces TNF-a induced expression of MAdCAM-1 via inhibition of NF-kappaB. BMC Gastroenterol. 2002;2:9. [PMC free article] [PubMed]
165. Pei Z, Cheung RT. Pretreatment with melatonin exerts anti-inflammatory effects against ischemia/reperfusion injury in a rat middle cerebral artery occlusion stroke model. J Pineal Res. 2004;37(2):85–91. [PubMed]
166. Feng Z, Chang Y, Cheng Y, et al. Melatonin alleviates behavioral deficits associated with apoptosis and cholinergic system dysfunction in the APP 695 transgenic mouse model of Alzheimer's disease. J Pineal Res. 2004;37(2):129–136. [PubMed]
167. Feng Z, Cheng Y, Zhang JT. Long-term effects of melatonin or 17 beta-estradiol on improving spatial memory performance in cognitively impaired, ovariectomized adult rats. J Pineal Res. 2004;37(3):198–206. [PubMed]
168. Riemersma-van der Lek RF, Swaab DF, Twisk J, Hol EM, Hoogendijk WJ, Van Someren EJ. Effect of bright light and melatonin on cognitive and noncognitive function in elderly residents of group care facilities: a randomized controlled trial. Jama. 2008;299(22):2642–2655. [PubMed]
169. Ayas NT, White DP, Manson JE, et al. A prospective study of sleep duration and coronary heart disease in women. Arch Intern Med. 2003;163(2):205–209. [PubMed]
170. Harrison Y, Horne JA. The impact of sleep deprivation on decision making: a review. J Exp PsycholAppl. 2000;6(3):236–249. [PubMed]
171. Knutson KL, Van Cauter E. Associations between sleep loss and increased risk of obesity and diabetes. Ann N Y Acad Sci. 2008;1129:287–304. [PubMed]
172. Monk TH. Shift Work: Basic Principles. In: Kryger MRT, Dement WC, editors. Principles and Practice of Sleep Medicine. 4th ed. WB Sounders Co; Philadelphia, PA: 2005. pp. 673–680.
173. Gander PH, Gregory KB, Miller DL, Graeber RC, Connell LJ, Rosekind MR. Flight crew fatigue V: long-haul air transport operations. Aviat Space Environ Med. 1998;69(suppl 9):B37–48. [PubMed]
174. Mitler MM, Miller, Lipsitz JJ, Walsh JK, Wylie CD. The sleep of long-haul truck drivers. N EnglJ Med. 1997;337(11):755–761. [PMC free article] [PubMed]
175. Kawachi I, Colditz GA, Stamfer MJ, et al. Prospective study of shift work and risk of coronary heart disease in women. Circulation. 1996;92:3178–3182. [PubMed]
176. Karlsson B, Alfredsson L, Knutsson A, Andersson E, Toren K. Total mortality and cause-specific mortality of Swedish shift- and dayworkers in the pulp and paper industry in 1952-2001. Scand J Work Environ Health. 2005;31(1):30–35. [PubMed]
177. Boggild H, Suadicani P, Hein HO, Gyntelberg F. Shift work, social class, and ischaemic heart disease in middle aged and elderly men; a 22 year follow up in the Copenhagen Male Study. Occup EnvironMed. 1999;56(9):640–645. [PMC free article] [PubMed]
178. Oishi M, Suwazono Y, Sakata K, et al. A longitudinal study on the relationship between shift work and the progression of hypertension in male Japanese workers. J Hypertens. 2005;23(12):2173–2178. [PubMed]
179. Inoue MMH, Inagaki J, Harada N. Influence of differences in their jobs on cardiovascular risk factors in male blue-collar shift workers in their fifties. Int J Occup Environ Health. 2004;10(3):313–318. [PubMed]
180. Knutsson A, Akerstedt T, Jonsson BG, Orth-Gomer K. Increased risk of ischaemic heart disease in shift workers. Lancet. 1986;328(8498):89–92. [PubMed]
181. Tuchsen F, Hannerz H, Burr H. A 12 year prospective study of circulatory disease among Danish shift workers. Occup Environ Med. 2006;63(7):451–455. [PMC free article] [PubMed]
182. Sgoifo A, Buwalda B, Roos M, Costoli T, Merati G, Meerlo P. Effects of sleep deprivation on cardiac autonomic and pituitary-adrenocortical stress reactivity in rats. Psychoneuroendocrinology. 2006;31(2):197–208. [PubMed]
183. Yamasaki F, Schwartz JE, Gerber LM, Warren K, Pickering TG. Impact of shift work and race/ethnicity on the diurnal rhythm of blood pressure and catecholamines. Hypertension. 1998;32(3):417–423. [PubMed]
184. Kitamura T, Onishi K, Dohi K, et al. Circadian rhythm of blood pressure is transformed from a dipper to a non-dipper pattern in shift workers with hypertension. J Hum Hypertens. 2002;16(3):193–197. [PubMed]
185. Ishizaki MYM, Nakagawa H, Honda R, Kawakami N, Haratani T, Kobayashi F, Araki S, Yamada Y. The influence of work characteristics on Body Mass Index and Waist to Hip Ratio in Japanese Employees. Ind. Health. 2004;42:41–49. [PubMed]
186. Niedhammer I, Lert F, Marne MJ. Prevalence of overweight and weight gain in relation to night work in a nurses' cohort. Int J Obes Relat Metab Disord. 1996;20(7):625–633. [PubMed]
187. Karlsson B, Knutsson A, Lindahl B. Is there an association between shift work and having a metabolic syndrome? Results from a population based study of 27,485 people. Occup Environ Med. 2001;58(11):747–752. [PMC free article] [PubMed]
188. Nagaya T, Yoshida H, Takahashi H, Kawai M. Markers of insulin resistance in day and shift workers aged 30-59 years. Int Arch Occup Environ Health. 2002;75(8):562–568. [PubMed]
189. Mikuni E, Ohoshi T, Hayashi K, Miyamura K. Glucose intolerance in an employed population. Tohoku J Exp Med. 1983;141(suppl):251–256. [PubMed]
190. Kroenke CH, Spiegelman D, Manson J, Schernhammer ES, Colditz GA, Kawachi I. Work characteristics and incidence of type 2 diabetes in women. Am J Epidemiol. 2007;165(2):175–183. [PubMed]
191. Buxton OMSK, Van Cauter E. Modulation of endocrine function and metabolism by sleep and sleep loss. In: Lee-Chiong M, Carskadon M, Sateia M, editors. Sleep Medicine. Hanley&Belfus, Inc.; Phyladelphia: 2002. pp. 59–69.
192. Chaput JP, Despres JP, Bouchard C, Tremblay A. Short sleep duration is associated with reduced leptin levels and increased adiposity: Results from the Quebec family study. Obesity (Silver Spring) 2007;15(1):253–261. [PubMed]
193. Spiegel K, Tasali E, Penev P, Van Cauter E. Brief communication: Sleep curtailment in healthy young men is associated with decreased leptin levels, elevated ghrelin levels, and increased hunger and appetite. Ann Intern Med. 2004;141(11):846–850. [PubMed]
194. Mullington JM, Chan JL, Van Dongen HP, et al. Sleep loss reduces diurnal rhythm amplitude of leptin in healthy men. J Neuroendocrinol. 2003;15(9):851–854. [PubMed]
195. Spiegel K, Leproult R, L'Hermite-Baleriaux M, Copinschi G, Penev PD, Van Cauter E. Leptin levels are dependent on sleep duration: relationships with sympathovagal balance, carbohydrate regulation, cortisol, and thyrotropin. J Clin Endocrinol Metab. 2004;89(11):5762–5771. [PubMed]
196. Muoio DM, Lynis Dohm G. Peripheral metabolic actions of leptin. Best Pract Res Clin Endocrinol Metab. 2002;16(4):653–666. [PubMed]
197. Lichnovska R, Gwozdziewiczova S, Hrebicek J. Gender differences in factors influencing insulin resistance in elderly hyperlipemic non-diabetic subjects. Cardiovasc Diabetol. 2002;1:4. [PMC free article] [PubMed]
198. Saad MF, Khan A, Sharma A, et al. Physiological insulinemia acutely modulates plasma leptin. Diabetes. 1998;47(4):544–549. [PubMed]
199. Shea SA, Hilton MF, Orlova C, Ayers RT, Mantzoros CS. Independent circadian and sleep/wake regulation of adipokines and glucose in humans. J Clin Endocrinol Metab. 2005;90(5):2537–2544. [PMC free article] [PubMed]
200. Gavrila A, Peng CK, Chan JL, Mietus JE, Goldberger AL, Mantzoros CS. Diurnal and ultradian dynamics of serum adiponectin in healthy men: comparison with leptin, circulating soluble leptin receptor, and cortisol patterns. J Clin Endocrinol Metab. 2003;88(6):2838–2843. [PubMed]
201. Oliver P, Ribot J, Rodriguez AM, Sanchez J, Pico C, Palou A. Resistin as a putative modulator of insulin action in the daily feeding/fasting rhythm. Pflugers Arch. 2006;452(3):260–267. [PubMed]
202. Ariyasu H, Takaya K, Tagami T, et al. Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans. J Clin Endocrinol Metab. 2001;86(10):4753–4758. [PubMed]
203. Tritos NA, Mun E, Bertkau A, Grayson R, Maratos-Flier E, Goldfine A. Serum ghrelin levels in response to glucose load in obese subjects post-gastric bypass surgery. Obes Res. 2003;11(8):919–924. [PubMed]
204. Yannielli PC, Molyneux PC, Harrington ME, Golombek DA. Ghrelin effects on the circadian system of mice. J Neurosci. 2007;27(11):2890–2895. [PubMed]
205. Taheri S, Lin L, Austin D, Young T, Mignot E. Short sleep duration is associated with reduced leptin, elevated ghrelin, and increased body mass index. PLoS Med. 2004;1(3):e62. [PMC free article] [PubMed]
206. Scheer FAHM, Mantzoros CS, Shea SA. Metabolic and Cardiovascular Consequences of Circadian Misalignment. Proc Natl Acad Sci U S A. in press. [PubMed]
207. Taylor PJ, Pocock SJ. Mortality of shift and day workers 1956-68. Br J Ind Med. 1972;29(2):201–207. [PMC free article] [PubMed]
208. Schernhammer ES, Laden F, Speizer FE, et al. Rotating night shifts and risk of breast cancer in women participating in the nurses' health study. J Natl Cancer Inst. 2001;93(20):1563–1568. [PubMed]
209. Tynes T, Hannevik M, Andersen A, Vistnes AI, Haldorsen T. Incidence of breast cancer in Norwegian female radio and telegraph operators. Cancer Causes Control. 1996;7(2):197–204. [PubMed]
210. Hansen J. Increased breast cancer risk among women who work predominantly at night. Epidemiology. 2001;12(1):74–77. [PubMed]
211. Schernhammer ES, Laden F, Speizer FE, et al. Night-shift work and risk of colorectal cancer in the nurses' health study. J Natl Cancer Inst. 2003;95(11):825–828. [PubMed]
212. Krstev S, Baris D, Stewart PA, Hayes RB, Blair A, Dosemeci M. Risk for prostate cancer by occupation and industry: a 24-state death certificate study. Am J Ind Med. 1998;34(5):413–420. [PubMed]
213. Demers PA, Checkoway H, Vaughan TL, Weiss NS, Heyer NJ, Rosenstock L. Cancer incidence among firefighters in Seattle and Tacoma, Washington (United States) Cancer Causes Control. 1994;5(2):129–135. [PubMed]
214. Hill SM, Blask DE. Effects of the pineal hormone melatonin on the proliferation and morphological characteristics of human breast cancer cells (MCF-7) in culture. Cancer Res. 1988;48(21):6121–6126. [PubMed]
215. Cos S, Fernandez R, Guezmes A, Sanchez-Barcelo EJ. Influence of melatonin on invasive and metastatic properties of MCF-7 human breast cancer cells. Cancer Res. 1998;58(19):4383–4390. [PubMed]
216. Cos SMM, Fernandez R, et al. Does melatonin induce apoptosis in MCF-7 human breast cancer cells in vitro? J Pineal Res. 2002;32:90–96. [PubMed]
217. Mediavilla MD, Cos S, Sanchez-Barcelo EJ. Melatonin increases p53 and p21WAF1 expression in MCF-7 human breast cancer cells in vitro. Life Sci. 1999;65(4):415–420. [PubMed]
218. Tamarkin L, Cohen M, Roselle D, Reichert C, Lippman M, Chabner B. Melatonin inhibition and pinealectomy enhancement of 7,12-dimethylbenz(a)anthracene-induced mammary tumors in the rat. Cancer Res. 1981;41(11):4432–4436. [PubMed]
219. Zhu Y, Brown HN, Zhang Y, Stevens RG, Zheng T. Period3 structural variation: a circadian biomarker associated with breast cancer in young women. Cancer Epidemiol Biomarkers Prev. 2005;14(1):268–270. [PubMed]
220. Challet E, Poirel VJ, Malan A, Pevet P. Light exposure during daytime modulates expression of Per1 and Per2 clock genes in the suprachiasmatic nuclei of mice. J Neurosci Res. 2003;72(5):629–637. [PubMed]
221. Caldelas I, Poirel VJ, Sicard B, Pevet P, Challet E. Circadian profile and photic regulation of clock genes in the suprachiasmatic nucleus of a diurnal mammal Arvicanthis ansorgei. Neuroscience. 2003;116(2):583–591. [PubMed]
222. Segawa K, Nakazawa S, Tsukamoto Y, et al. Peptic ulcer is prevalent among shift workers. Dig Dis Sci. 1987;32(5):449–453. [PubMed]
223. Rubin NH, Singh P, Alinder G, et al. Circadian rhythms in gastrin receptors in rat fundic stomach. Dig Dis Sci. 1988;33(8):931–937. [PubMed]
224. Larsen KR, Dayton MT, Moore JG. Circadian rhythm in gastric mucosal blood flow in fasting rat stomach. J Surg Res. 1991;51(4):275–280. [PubMed]
225. Larsen KR, Moore JG, Dayton MT. Circadian rhythms of gastric mucus efflux and residual mucus gel in the fasting rat stomach. Dig Dis Sci. 1991;36(11):1550–1555. [PubMed]
226. Moore JG, Mitchell MD, Larsen KR, Dayton MT. Circadian rhythm in prostacyclin activity in gastric tissue of the fasting rat. Am J Surg. 1992;163(1):19–22. [PubMed]
227. Moore JG, Goo RH. Day and night aspirin-induced gastric mucosal damage and protection by ranitidine in man. Chronobiol Int. 1987;4(1):111–116. [PubMed]
228. Larsen KR, Moore JG, Dayton MT, Yu Z. Circadian rhythm in aspirin (ASA)-induced injury to the stomach of the fasted rat. Dig Dis Sci. 1993;38(8):1435–1440. [PubMed]
229. Goo RH, Moore JG, Greenberg E, Alazraki NP. Circadian variation in gastric emptying of meals in humans. Gastroenterology. 1987;93(3):515–518. [PubMed]
230. Kumar D, Wingate D, Ruckebusch Y. Circadian variation in the propagation velocity of the migrating motor complex. Gastroenterology. 1986;91(4):926–930. [PubMed]
231. Moore JG, Halberg F. Circadian rhythm of gastric acid secretion in men with active duodenal ulcer. Dig Dis Sci. 1986;31(11):1185–1191. [PubMed]
232. Larsen KR, Moore JG, Dayton MT. Circadian rhythms of acid and bicarbonate efflux in fasting rat stomach. Am J Physiol. 1991;260(4 Pt 1):G610–614. [PubMed]
233. Axelsson G, Rylander R, Molin I. Outcome of pregnancy in relation to irregular and inconvenient work schedules. Br J Ind Med. 1989;46(6):393–398. [PMC free article] [PubMed]
234. Mamelle N, Laumon B, Lazar P. Prematurity and occupational activity during pregnancy. Am J Epidemiol. 1984;119(3):309–322. [PubMed]
235. Morgenthaler TI, Lee-Chiong T, Alessi C, et al. Practice parameters for the clinical evaluation and treatment of circadian rhythm sleep disorders. An American Academy of Sleep Medicine report. Sleep. 2007;30(11):1445–1459. [PubMed]
236. Lockley SW, Evans EE, Scheer FA, Brainard GC, Czeisler CA, Aeschbach D. Short-wavelength sensitivity for the direct effects of light on alertness, vigilance, and the waking electroencephalogram in humans. Sleep. 2006;29(2):161–168. [PubMed]
237. Khalsa SB, Jewett ME, Cajochen C, Czeisler CA. A phase response curve to single bright light pulses in human subjects. J Physiol. 2003;549(3):945–952. [PubMed]
238. Yoon IY, Jeong DU, Kwon KB, Kang SB, Song BG. Bright light exposure at night and light attenuation in the morning improve adaptation of night shift workers. Sleep. 2002;25(3):351–356. [PubMed]
239. Crowley SJ, Lee C, Tseng CY, Fogg LF, Eastman CI. Complete or partial circadian re-entrainment improves performance, alertness, and mood during night-shift work. Sleep. 2004;27(6):1077–1087. [PubMed]
240. Boivin DB, James FO. Circadian adaptation to night-shift work by judicious light and darkness exposure. J Biol Rhythms. 2002;17(6):556–567. [PubMed]
241. Sharkey KM, Eastman CI. Melatonin phase shifts human circadian rhythms in a placebo-controlled simulated night-work study. Am. J. Physiol. 2002;282(2):R454–463. [PMC free article] [PubMed]
242. Sharkey KM, Fogg LF, Eastman CI. Effects of melatonin administration on daytime sleep after simulated night shift work. J Sleep Res. 2001;10(3):181–192. [PMC free article] [PubMed]
243. Jorgensen KM, Witting MD. Does exogenous melatonin improve day sleep or night alertness in emergency physicians working night shifts? Ann Emerg Med. 1998;31(6):699–704. [PubMed]
244. Walsh JK, Schweitzer PK, Anch AM, Muehlbach MJ, Jenkins NA, Dickins QS. Sleepiness/alertness on a simulated night shift following sleep at home with triazolam. Sleep. 1991;14(2):140–146. [PubMed]
245. Monchesky TC, Billings BJ, Phillips R, Bourgouin J. Zopiclone in insomniac shiftworkers. Evaluation of its hypnotic properties and its effects on mood and work performance. Int Arch Occup Environ Health. 1989;61(4):255–259. [PubMed]
246. Sallinen M, Harma M, Akerstedt T, Rosa R, Lillqvist O. Promoting alertness with a short nap during a night shift. J Sleep Res. 1998;7(4):240–247. [PubMed]
247. Scheer FA, Shea TJ, Hilton MF, Shea SA. An endogenous circadian rhythm in sleep inertia results in greatest cognitive impairment upon awakening during the biological night. J Biol Rhythms. 2008;23(4):353–361. [PMC free article] [PubMed]
248. Czeisler CA, Walsh JK, Roth T, et al. Modafinil for excessive sleepiness associated with shift-work sleep disorder. N Engl J Med. 2005;353(5):476–486. [PubMed]
249. Schweitzer PKRC, Stone K, Erman M, Walsh KJ. Laboratory and Field Studies of Naps and Caffeine as Practical Countermeasures For Sleep-Wake Problems Associated with Night Work. Sleep. 2006;29(1):39–50. [PubMed]
250. Muller JE. Circadian variation and triggering of acute coronary events. Am Heart J. 1999;137(4 Pt 2):S1–S8. [PubMed]
251. Dethlefsen URR. Ein neues therapieprinzip bei nachtlichen asthma. Clin Med. 1985;80:44.