Risk of obesity in male shift workers: A chronophysiological approach.

AIMS: Why are some healthy male shift workers (SWers) overweight [body mass index (BMI) >25 and <30] if not obese (BMI >30)? Seven risk factors potentially causing overweight and obesity were evaluated, namely (1) age, (2) physical/sports activity, (3) length of exposure to shift work (SW), (4) speed of shift rotation, (5) tolerance to SW, (6) internal desynchronization of circadian rhythms and (8) night eating (nocturnal nibbling). "New" as well as "old" data, acquired from longitudinal and individual time series of 5-56 days recording span, were reanalyzed. The data were analyzed from a set of field studies of 67 SWers and 53 non-shift workers (non-SWers). To estimate the respective weight of these factors, a multiple regression analysis (MRA) was used among other statistical tools. A similar age-related increase in BMI was validated (with p < 0.001) in both SWers and non-SWers. However, in SWers, desynchronization of rhythms increases the effect of age on BMI. Length of exposure to SW, tolerance to SW and speed of rotation do not seem to play a role as risk factors. Major effects are likely to relate to a sedentary lifestyle (lack of regular physical or sport activities) (MRA with p < 0.01), as well as, presumably, to a nocturnal nibbling of carbohydrates, which mimics the night eating syndrome.

Diurnal and twenty-four hour patterning of human diseases: cardiac, vascular, and respiratory diseases, conditions, and syndromes.

Various medical conditions, disorders, and syndromes exhibit predictable-in-time diurnal and 24 h patterning in the signs, symptoms, and grave nonfatal and fatal events, e.g., respiratory ones of viral and allergic rhinorrhea, reversible (asthma) and non-reversible (bronchitis and emphysema) chronic obstructive pulmonary disease, cystic fibrosis, high altitude pulmonary edema, and decompression sickness; cardiac ones of atrial premature beats and tachycardia, paroxysmal atrial fibrillation, 3rd degree atrial-ventricular block, paroxysmal supraventricular tachycardia, ventricular premature beats, ventricular tachyarrhythmia, symptomatic and non-symptomatic angina pectoris, Prinzmetal vasospastic variant angina, acute (non-fatal and fatal) incidents of myocardial infarction, sudden cardiac arrest, in-bed sudden death syndrome of type-1 diabetes, acute cardiogenic pulmonary edema, and heart failure; vascular and circulatory system ones of hypertension, acute orthostatic postprandial, micturition, and defecation hypotension/syncope, intermittent claudication, venous insufficiency, standing occupation leg edema, arterial and venous branch occlusion of the eye, menopausal hot flash, sickle cell syndrome, abdominal, aortic, and thoracic dissections, pulmonary thromboembolism, and deep venous thrombosis, and cerebrovascular transient ischemic attack and hemorrhagic and ischemic stroke. Knowledge of these temporal patterns not only helps guide patient care but research of their underlying endogenous mechanisms, i.e., circadian and others, and external triggers plus informs the development and application of effective chronopreventive and chronotherapeutic strategies.

Diurnal and twenty-four hour patterning of human diseases: acute and chronic common and uncommon medical conditions.

The symptom intensity and mortality of human diseases, conditions, and syndromes exhibit diurnal or 24 h patterning, e.g., skin: atopic dermatitis, urticaria, psoriasis, and palmar hyperhidrosis; gastrointestinal: esophageal reflux, peptic ulcer (including perforation and hemorrhage), cyclic vomiting syndrome, biliary colic, hepatic variceal hemorrhage, and proctalgia fugax; infection: susceptibility, fever, and mortality; neural: frontal, parietal, temporal, and occipital lobe seizures, Parkinson's and Alzheimer's disease, hereditary progressive dystonia, and pain (cancer, post-surgical, diabetic neuropathic and foot ulcer, tooth caries, burning mouth and temporomandibular syndromes, fibromyalgia, sciatica, intervertebral vacuum phenomenon, multiple sclerosis muscle spasm, and migraine, tension, cluster, hypnic, and paroxysmal hemicranial headache); renal: colic and nocturnal enuresis and polyuria; ocular: bulbar conjunctival redness, keratoconjunctivitis sicca, intraocular pressure and anterior ischemic optic neuropathy, and recurrent corneal erosion syndrome; psychiatric/behavioral: major and seasonal affective depressive disorders, bipolar disorder, parasuicide and suicide, dementia-associated agitation, and addictive alcohol, tobacco, and heroin cravings and withdrawal phenomena; plus autoimmune and musculoskeletal: rheumatoid arthritis, osteoarthritis, axial spondylarthritis, gout, Sjögren's syndrome, and systemic lupus erythematosus. Knowledge of these and other 24 h patterns of human pathophysiology informs research of their underlying circadian and other endogenous mechanisms, external temporal triggers, and more effective patient care entailing clinical chronopreventive and chronotherapeutic strategies.

[2013 Ambulatory blood pressure monitoring recommendations for the diagnosis of adult hypertension, assessment of cardiovascular and other hypertension-associated risk, and attainment of therapeutic goals (summary). Joint recommendations from the International Society for Chronobiology (ISC), American Association of Medical Chronobiology and Chronotherapeutics (AAMCC), Spanish Society of Applied Chronobiology, Chronotherapy, and Vascular Risk (SECAC), Spanish Society of Atherosclerosis (SEA), and Romanian Society of Internal Medicine (RSIM)]. / Recomendaciones 2013 para el uso de la monitorización ambulatoria de la presión arterial para el diagnóstico de hipertensión en adultos, valoración de riesgo cardiovascular y obtención de objetivos terapéuticos (resumen). Recomendaciones conjuntas de la International Society for Chronobiology (ISC), American Association of Medical Chronobiology and Chronotherapeutics (AAMCC), Sociedad Española de Cronobiología Aplicada, Cronoterapia y Riesgo Vascular (SECAC), Sociedad Española de Arteriosclerosis (SEA) y Romanian Society of Internal Medicine (RSIM).

Correlation between systolic (SBP) and diastolic (DBP) blood pressure (BP) level and target organ damage, cardiovascular disease (CVD) risk, and long-term prognosis is much greater for ambulatory BP monitoring (ABPM) than daytime office measurements. The 2013 ABPM guidelines specified herein are based on ABPM patient outcomes studies and constitute a substantial revision of current knowledge. The asleep SBP mean and sleep-time relative SBP decline are the most significant predictors of CVD events, both individually as well as jointly when combined with other ABPM-derived prognostic markers. Thus, they should be preferably used to diagnose hypertension and assess CVD and other associated risks. Progressive decrease by therapeutic intervention in the asleep BP mean is the most significant predictor of CVD event-free interval. The 24 h BP mean is not recommended to diagnose hypertension because it disregards the more valuable clinical information pertaining to the features of the 24 h BP pattern. Persons with the same 24 h BP mean may display radically different 24 h BP patterns, ranging from extreme-dipper to riser types, representative of markedly different risk states. Classification of individuals by comparing office with either the 24 h or awake BP mean as "masked normotensives" (elevated clinic BP but normal ABPM), which should replace the terms of "isolated office" or "white-coat hypertension", and "masked hypertensives" (normal clinic BP but elevated ABPM) is misleading and should be avoided because it disregards the clinical significance of the asleep BP mean. Outcome-based ABPM reference thresholds for men, which in the absence of compelling clinical conditions are 135/85 mmHg for the awake and 120/70 mmHg for the asleep SBP/DBP means, are lower by 10/5 mmHg for SBP/DBP in uncomplicated, low-CVD risk, women and lower by 15/10 mmHg for SBP/DBP in male and female high-risk patients, e.g., with diabetes, chronic kidney disease (CKD), and/or past CVD events. In the adult population, the combined prevalence of masked normotension and masked hypertension is >35%. Moreover, >20% of "normotensive" adults have a non-dipper BP profile and, thus, are at relatively high CVD risk. Clinic BP measurements, even if supplemented with home self-measurements, are unable to quantify 24 h BP patterning and asleep BP level, resulting in potential misclassification of up to 50% of all evaluated adults. ABPM should be viewed as the new gold standard to diagnose true hypertension, accurately assess consequent tissue/organ, maternal/fetal, and CVD risk, and individualize hypertension chronotherapy. ABPM should be a priority for persons likely to have a blunted nighttime BP decline and elevated CVD risk, i.e., those who are elderly and obese, those with secondary or resistant hypertension, and those diagnosed with diabetes, CKD, metabolic syndrome, and sleep disorders.

Recomendaciones 2013 para el uso de la monitorización ambulatoria de la presión arterial para el diagnóstico de hipertensión en adultos, valoración de riesgo cardiovascular y obtención de objetivos terapéuticos (resumen). Recomendaciones conjuntas de la International Society for Chronobiology (ISC), American Association of Medical Chronobiology and Chronotherapeutics (AAMCC), Sociedad Española de Cronobiología Aplicada, Cronoterapia y Riesgo Vascular (SECAC), Sociedad Española de Arteriosclerosis (SEA) y Romanian Society of Internal Medicine (RSIM) / 2013 Ambulatory blood pressure monitoring recommendations for the diagnosis of adult hypertension, assessment of cardiovascular and other hypertension-associated risk, and attainment of therapeutic goals (summary). Joint recommendations from the International Society for Chronobiology (ISC), American Association of Medical Chronobiology and Chronotherapeutics (AAMCC), Spanish Society of Applied Chronobiology, Chronotherapy, and Vascular Risk (SECAC), Spanish Society of Atherosclerosis (SEA), and Romanian Society of Internal Medicine (RSIM)

La correlación entre los niveles de presión arterial (PA) sistólica (PAS) y diastólica (PAD) y el daño en órganos diana, el riesgo cardiovascular ( CV ) y el pronóstico a largo plazo es mucho mayor para la monitorización ambulatoria de la PA (MAPA) que para las medidas clínicas convencionales de PA. Las recomendaciones 2013 de MAPA especificadas en este documento se basan en estudios de morbimortalidad CV de pacientes evaluados con MAPA y constituyen una revisión sustancial del conocimiento actual. La media de descanso y la profundidad de la PAS son los predictores más significativos de episodios CV, tanto de forma individual como conjuntamente cuando se combinan con otros parámetros derivados de la MAPA. Por ello, estos 2 parámetros se deben utilizar de forma preferente para diagnosticar hipertensión y evaluar el riesgo CV. La disminución progresiva de la media de descanso de la PA mediante intervención terapéutica es el predictor más significativo de supervivencia libre de episodios CV. La media de 24 h de la PA es insuficiente y no se recomienda para el diagnóstico de hipertensión, ya que no tiene en cuenta las características de la variación circadiana de la PA, información extremadamente valiosa desde el punto de vista clínico. Personas con la misma media de 24 h de PA pueden tener patrones circadianos radicalmente diferentes, desde el tipo dipper-extremo hasta el riser, lo que conlleva niveles de riesgo CV marcadamente distintos. Son de particular interés los sujetos con «normotensión enmascarada» (PA clínica elevada y MAPA normal) —que debería sustituir a los de «hipertensión aislada en (..) (AU)

Correlation between systolic (SBP) and diastolic (DBP) blood pressure (BP) level and target organ damage, cardiovascular disease (CVD) risk, and long-term prognosis is much greater for ambulatory BP monitoring (ABPM) than daytime office measurements. The 2013 ABPM guidelines specified herein are based on ABPM patient outcomes studies and constitute a substantial revision of current knowledge. The asleep SBP mean and sleep-time relative SBP decline are the most significant predictors of CVD events, both individually as well as jointly when combined with other ABPM-derived prognostic markers. Thus, they should be preferably used to diagnose hypertension and assess CVD and other associated risks. Progressive decrease by therapeutic intervention in the asleep BP mean is the most significant predictor of CVD event-free interval. The 24 h BP mean is not recommended to diagnose hypertension because it disregards the more valuable clinical information pertaining to the features of the 24 h BP pattern. Persons with the same 24 h BP mean may display radically different 24 h BP patterns, ranging from extreme-dipper to riser types, representative of markedly different risk states. Classification of individuals by comparing office with either the 24 h or awake BP mean as “masked normotensives” (elevated clinic BP but normal ABPM), which should replace the terms of “isolated office” or “white-coat hypertension”, and “masked hypertensives” (normal clinic BP but elevated ABPM) is misleading and should be avoided because it disregards the clinical significance of the asleep BP mean. Outcome-based ABPM reference thresholds for men, which in the absence of compelling clinical conditions are 135/85 mmHg for the awake and 120/70 mmHg for the asleep SBP/DBP means, are lower by 10/5 mmHg for SBP/DBP in uncomplicated, low-CVD risk, women and lower by 15/10 mmHg for SBP/DBP in male and female high-risk patients, e.g., with (..) (AU)

Shift work and cancer risk: potential mechanistic roles of circadian disruption, light at night, and sleep deprivation.

Shift work that includes a nighttime rotation has become an unavoidable attribute of today's 24-h society. The related disruption of the human circadian time organization leads in the short-term to an array of jet-lag-like symptoms, and in the long-run it may contribute to weight gain/obesity, metabolic syndrome/type II diabetes, and cardiovascular disease. Epidemiologic studies also suggest increased cancer risk, especially for breast cancer, in night and rotating female shift workers. If confirmed in more controlled and detailed studies, the carcinogenic effect of night and shift work will constitute additional serious medical, economic, and social problems for a substantial proportion of the working population. Here, we examine the possible multiple and interconnected cancer-promoting mechanisms as a consequence of shift work, i.e., repeated disruption of the circadian system, pineal hormone melatonin suppression by exposure to light at night, sleep-deprivation-caused impairment of the immune system, plus metabolic changes favoring obesity and generation of proinflammatory reactive oxygen species.

Expression of melatonin receptors in triple negative breast cancer (TNBC) in African American and Caucasian women: relation to survival.

In the normal rodent breast, the pineal hormone melatonin controls the development of ductal and alveolar tissue. Melatonin counteracts tumor occurrence and tumor cell progression in vivo and in vitro in animal and human breast cancer cell cultures. It acts predominantly through its melatonin MT1 receptor. Our aim was to investigate the presence or absence of the MT1 melatonin receptor in the aggressive triple negative group of human breast carcinoma (TNBC) and its possible relationship to the course of the disease. A total of 167 patients with a ER-, PR-, Her-2/neu- phenotype in which tissue for receptor studies was available were examined. The MT1 receptor immunostain was evaluated semiquantitatively as staining intensity (0, 1, 2, 3), percentage of stained cells and the weighted index (WI) (staining intensity times percentage of stained cells). A score of WI < 60 was regarded as "negative". There was a striking difference in incidence of MT1 positivity and staining intensity between carcinomas in African American (AA) and Caucasian (C) women. The AA showed a higher incidence of MT1 negative tumors (41/84 = 48.8 % in AA, 6/51 = 11.8 % in C) and a lower average WI. MT1 positivity in TNBC was associated with a lower stage and a smaller tumor size at time of diagnosis. In multivariable survival analysis, MT1 negative TNBC in all cases regardless of race showed a significantly higher hazard ratio for disease progression, shorter progression free survival, and disease-related death, and shorter OS. This was especially pronounced in the AA group but did not reach statistical significance in the smaller group of C alone. These results suggest that melatonin or a melatonin receptor agonist may be useful biologic additions in the treatment of some forms of TNBC, especially in AA who generally show a more aggressive course of their disease.

Rheumatoid arthritis: circadian rhythms in disease activity, signs and symptoms, and rationale for chronotherapy with corticosteroids and other medications.

Biological processes and functions at all hierarchical levels are organized in time as biological rhythms of discrete periods. Circadian (24-hour) rhythms, which are of direct importance to clinical medicine, are orchestrated by a set of clock genes of the master brain clock situated in the suprachiasmatic nuclei of the hypothalamus plus numerous subservient peripheral cellular clocks of all tissues and organs. Circadian rhythms are kept in step with the surrounding physical and social milieu by periodic external time cues, the most important one being the 24-hour environmental light-dark cycle. The circadian time structure gives rise to predictable-in-time day-night patterns in morbid and mortal events plus symptom occurrence and severity of common chronic conditions, including rheumatoid arthritis (RA). The circadian pattern of various cytokines and hormones in RA disease activity suggests a new treatment paradigm (i.e., chronotherapy-timing medications to 24-hour rhythms in disease pathophysiology) to improve desired outcomes. Since the 1950s, RA chronotherapy in the United States and Europe has involved several nonsteroid anti-inflammatory drugs (NSAIDs), certain disease modifying antirheumatic drugs (DMARDs), and various synthetic corticosteroid medications.

Decadal Cycles in the Human Cardiovascular System.

Seven of the eight authors of this report each performed physiologic self-surveillance, some around the clock for decades. We here document the presence of long cycles (decadals, including circaundecennians) in the time structure of systolic (S) and diastolic (D) blood pressure (BP) and heart rate (HR). Because of the non-stationary nature in time and space of these and other physiologic and environmental periodic components that, like the wind, can appear and disappear in a given or other geographic location at one or another time, they have been called "Aeolian". The nonlinear estimation of the uncertainties of the periods (τs) of two or more variables being compared has been used to determine whether these components are congruent or not, depending on whether their CIs (95% confidence intervals) overlap or not. Among others, congruence has been found for components with τs clustering around 10 years in us and around us. There is a selective assortment among individuals, variables and cycle characteristics (mean and circadian amplitude and acrophase). Apart from basic interest, like other nonphotic solar signatures such as transyears with periods slightly longer than one year or about 33-year Brückner-Egeson-Lockyer (BEL) cycles, about 10-year and longer cycles present in 7 of 7 self-monitoring individuals are of interest in the diagnosis of Vascular Variability Anomalies (VVAs), including MESOR-hypertension, and others. Some of the other VVAs, such as a circadian overswing, i.e., CHAT (Circadian Hyper-Aplitude-Tension), or an excessive pulse pressure, based on repeated 7-day around-the-clock records, can represent a risk of severe cardiovascular events, greater than that of a high BP. The differential diagnosis of physiologic cycles, infradians (components with a τ longer than 28 hours) as well as circadians awaits the collection of reference values for the infradian parameters of the cycles described herein. Just as in stroke-prone spontaneously hypertensive rats during the weeks after weaning CHAT precedes an elevation of the BP MESOR, a decadal overswing seems to precede the occurrence of high BP in two of the subjects here examined. Only around-the-clock monitoring in health for the collection of reference values will allow on their basis the differential diagnosis of the onsets of a circadian versus a circadecadal overswing in BP and the specification whether, and if so, when to initiate hypotensive non-drug or drug treatment.

Acute exposure to 50-Hz magnetic fields increases interleukin-6 in young healthy men.

Some epidemiologic studies have suggested that extremely low frequency magnetic fields might affect human health and, in particular, that the incidence of certain types of cancer might increase among individuals living or working in environments exposed to such fields. This study is part of a broad study we conducted in humans. The study presented here was designed to look for possible effects of acute exposure to 50-Hz magnetic fields (10 µT) on the interleukin 1 beta (IL-1ß), interleukin 2 (IL-2), interleukin 6 (IL-6), interleukin-1 receptor antagonist (IL-1RA), and the interleukin-2 receptor (IL-2R) production. Thirty-two young men (20-30 years old) were divided into two groups (sham-exposed or control group and exposed group) of 16 subjects each. All subjects participated in two 24-h experiments to evaluate the effects of both continuous and intermittent (1 h "off" and 1 h "on" with the field switched "on" and "off" every 15 s) exposure to linearly polarized magnetic fields. The subjects were exposed to the magnetic field from 2300 to 0800 while recumbent. Blood samples were collected during each session at 11:00, 17:00, 22:00, 01:00, 04:00, 06:00, and 08:00. Results showed that exposure to 50-Hz magnetic fields (10 µT) significantly increases IL-6 when subjects were exposed to an intermittent magnetic field. However, no effect has been observed on interleukin IL-1ß, IL-2, IL-1RA, and IL-2R.

Considerations of circadian impact for defining 'shift work' in cancer studies: IARC Working Group Report.

Based on the idea that electric light at night might account for a portion of the high and rising risk of breast cancer worldwide, it was predicted long ago that women working a non-day shift would be at higher risk compared with day-working women. This hypothesis has been extended more recently to prostate cancer. On the basis of limited human evidence and sufficient evidence in experimental animals, in 2007 the International Agency for Research on Cancer (IARC) classified 'shift work that involves circadian disruption' as a probable human carcinogen, group 2A. A limitation of the epidemiological studies carried out to date is in the definition of 'shift work.' IARC convened a workshop in April 2009 to consider how 'shift work' should be assessed and what domains of occupational history need to be quantified for more valid studies of shift work and cancer in the future. The working group identified several major domains of non-day shifts and shift schedules that should be captured in future studies: (1) shift system (start time of shift, number of hours per day, rotating or permanent, speed and direction of a rotating system, regular or irregular); (2) years on a particular non-day shift schedule (and cumulative exposure to the shift system over the subject's working life); and (3) shift intensity (time off between successive work days on the shift schedule). The group also recognised that for further domains to be identified, more research needs to be conducted on the impact of various shift schedules and routines on physiological and circadian rhythms of workers in real-world environments.

Shift work and cancer - considerations on rationale, mechanisms, and epidemiology.

This paper summarizes the rationale for, possible mechanisms of, and problems related to risk assessment of the association between shift work and cancer. The mechanisms by which circadian disruption may favor the induction and/or promotion of malignant tumors are complex and multifactorial. The multilevel endocrine changes caused by circadian disruption with melatonin suppression through light at night (LAN) lead to the oncogenic targeting of the endocrine-responsive breast in women and possibly the prostate in men. Repeated phase shifting with internal desynchronization may lead to defects in the regulation of the circadian cell cycle, thus favoring uncontrolled growth. Sleep deprivation leads to the suppression of immune surveillance that may permit the establishment and/or growth of malignant clones. The epidemiological studies published so far, although dealing with large cohorts and controlling for several personal confounders, have defined the exposure to shift and/or night work rather loosely and consequently do not allow for the proper assessment of the risk connected with circadian disruption.

Working memory capacity is decreased in sleep-deprived internal medicine residents.

BACKGROUND: Concerns about medical errors due to sleep deprivation during residency training led the Accreditation Council for Graduate Medical Education to mandate reductions in work schedules. Although call rotations with extended shifts continue, effects on resident sleep-wake times and working memory capacity (WMC) have not been investigated. OBJECTIVES: The objective of this study was to measure effects of call rotations on sleep-wake times and WMC in internal medicine residents. METHODS: During 2 months of an internal medicine training program adhering to ACGME work-hour restrictions (between April 2006 and June 2007), residents completed daily WMC tests, wore actigraphy watches, and logged their sleep hours. This observational study was conducted during a call month requiring 30-hour call rotations every fourth night, whereas the noncall month, which allowed sleep/wake cycle freedom, was used as the control. MAIN OUTCOME MEASURES: Sleep hours per night and WMC testing. RESULTS: Thirty-nine residents completing the study had less sleep per night during their call month (6.4 vs 7.3 h per night noncall, p < 0.001) and sleep per night varied from 3.7 to 10.1 hours. Call rotation caused greater self-assessed sleepiness and reduced WMC recall scores (-2.6/test, p < 0.05), and more math errors occurred when on call (+1.07/test, p < 0.04). Full recovery of WMC did not occur until the fourth day after call. On-call rotation on the first month had a confounding detrimental effect on WMC. CONCLUSION: A month of call rotations reduced overall sleep per night; sleep hours per night were variable, and WMC was adversely affected. Decreased WMC could explain impaired judgment during sleep deprivation, although clinical error rates were not evaluated.

Schedule shifts, cancer and longevity: good, bad or indifferent?

Prompted by a recent report of the possible carcinogenic effect of shiftwork focusing on the disruption of circadian rhythms, we review studies involving shifts in schedule implemented at varying intervals in unicells, insects and mammals, including humans. Results indicate the desirability to account for a broader-than-circadian view. They also suggest the possibility of optimizing schedule shifts by selecting intervals between consecutive shifts associated with potential side-effects such as an increase in cancer risk. Toward this goal, marker rhythmometry is most desirable. The monitoring of blood pressure and heart rate present the added benefit of assessing cardiovascular disease risks resulting not only from an elevated blood pressure but also from abnormal variability in blood pressure and/or heart rate of normotensive as well as hypertensive subjects.

Chronobiology in the endocrine system.

Biological signaling occurs in a complex web with participation and interaction of the central nervous system, the autonomous nervous system, the endocrine glands, peripheral endocrine tissues including the intestinal tract and adipose tissue, and the immune system. All of these show an intricate time structure with rhythms and pulsatile variations in multiple frequencies. Circadian (about 24-hour) and circannual (about 1-year) rhythms are kept in step with the cyclic environmental surrounding by the timing and length of the daily light span. Rhythmicity of many endocrine variables is essential for their efficacy and, even in some instances, for the qualitative nature of their effects. Indeed, the continuous administration of certain hormones and their synthetic analogues may show substantially different effects than expected. In the design of drug-delivery systems and treatment schedules involving directly or indirectly the endocrine system, consideration of the human time organization is essential. A large amount of information on the endocrine time structure has accumulated, some of which is discussed in this review.

Chronobiology of hemostasis and inferences for the chronotherapy of coagulation disorders and thrombosis prevention.

The hemostatic system in its multiple components displays an intricate organization in time which is characterized by circadian (approximately 24-hour), circaseptan (approximately 7-day), menstrual (approximately monthly), and circannual (approximately yearly) bioperiodicities. The interaction of the rhythms of the variables participating in hemostasis determine transient risk states of thromboembolic events, including myocardial infarction and stroke, and of hemorrhage and hemorrhagic events, each with a unique timing. The circadian staging of the rhythms in vascular, cellular, and coagulation factors that favors blood coagulation and thrombosis coincides with the daily minimum in fibrinolytic activity; as a result there is elevated risk in the morning of acute myocardial infarction and stroke. Similar hemostatic rhythms may determine the epidemiology of thromboembolic and hemorrhagic events during the week, month and year. This article focuses on the large-amplitude circadian rhythms operative in the hemostatic system. Their implication for preventive and curative pharmacotherapy of hemostatic disorders is presented, with discussion of related problems.