Erhard Haus

Biological Clocks and Shift Work: Circadian Dysregulation and Potential Long-term Effects

Long-term epidemiologic studies on large numbers of night and rotating shift workers have suggested an increase in the incidence of breast and colon cancer in these populations. These studies suffer from poor definition and quantification of the work schedules of the exposed subjects. Against this background, the pathophysiology of phase shift and phase adaptation is reviewed. A phase shift as experienced in night and rotating shift work involves desynchronization at the molecular level in the circadian oscillators in the central nervous tissue and in most peripheral tissues of the body. There is a change in the coordination between oscillators with transient loss of control by the master-oscillator (the Suprachiasmatic Nucleus, SCN) in the hypothalamus. The implications of the pathophysiology of phase shift are discussed for long-term health effects and for the design of ergonomic work schedules minimizing the adverse health effects upon the worker.

Biologic rhythms in clinical and laboratory medicine

This volume demonstrates how important natural time cycles can be for diagnosis and treatment in todays clinical and laboratory medicine. The editors have gathered a group of specialists to review the role of biological rhythms in the normal and abnormal function of different organ systems. The 20 sections of the book, consisting of 46 chapters, cover everything from basic background information on concepts and methodology to biological rhythms in cells and organs. Important questions addressing practical issues are raised: how do people adapt their normal rhythms to shift work or night work?; how can travellers combat jet lag?; how do physical rhythms work with, or against, drug treatment?; and how can chemotherapy be timed to best combat a tumour?

Biologic rhythms in the immune system.

In all of its components, the immune system shows regularly recurring, rhythmic variations in numerous frequencies; the circadian (about 24 h) rhythms are the best explored. The circadian variations in immunocompetent cells circulating in the peripheral blood are of a magnitude to require attention in medical diagnostics. Both the humoral arm and the delayed (cellular) arm of the immune system function in a rhythmic manner. The response of the immune system to introduction of an antigen and to challenge of the sensitized organism varies in extent in the circadian frequency range and also in lower frequencies, for example, of about a week (circaseptan) or seasonally (circannual). The medical application of the biologic rhythms of the immune system extends to diagnostic measures, as well as treatment.

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 subjects 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 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 todays 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.

ALTERATIONS WITH AGING OF THE ENDOCRINE AND NEUROENDOCRINE CIRCADIAN SYSTEM IN HUMANS

The various rhythms composing the human time structure are found at all levels of organization, from subcellular organelles to the whole organism. They are superimposed on trends like aging, which is often claimed to be related to a loss of the time structure with a decrease of the adaptation capability of various functions of the organism. Rhythm alterations presumably are involved in the processes of cell and organ damage, leading to death of the organism. Whether these rhythm alterations are a cause or a consequence of the aging process in humans is still debated. Evidence for a causative role has been found in plants and in insects. For instance, it has been shown in Drosophila (Pittendrigh and Minis 1972) that transplantation of young adults raised in a 24h light-dark cycle into an environment with a shorter (e.g., 21h) or longer (e.g., 27h) periodicity significantly shortens their life span. The importance of the problem of aging results from the increasing number of subjects reaching the age of 65 or older thanks to medical progress, rather than from the lengthening of life expectancy. The chronobiologic approach to aging aims to study the plasticity of the organism in relation to daily and seasonal environmental changes in an attempt to improve the conditions and quality of life of elderly subjects. This chronobiologic approach has to be extremely broad and has to consider biochemical, cell, and organ systems, as well as the organism as a whole. It cannot be limited to one frequency, but has to consider the entire human time structure, with a wide range of frequencies extending from milliseconds and minutes to many years, in individuals and in populations (for reviews, see Haus et al. 1989; Brock 1991; Haus and Touitou 1994a, 1994b; Touitou and Haus 1994). Changes in the human time structure observed during aging can involve all parameters of biologic rhythms and are found in most frequencies studied. In the circadian range, the most prominent changes in the aging organism are seen in the amplitude and, in some instances, in the timing of rhythms. The latter may lead to changes in the time

Toward a chronotherapy of neoplasia: Tolerance of treatment depends upon host rhythms

C h r o n o b i o l o g y L a b o r a t o r i e s , U n i v e r s i t y of M i n n e s o t a , 380 L y o n L a b o r a t o r i e s , M i n n e a p o l i s ( M i n n e s o t a 55455, U S A ) D e p a r t m e n t of A n a t o m i c a n d Cl in ica l P a t h o l o g y , St . P a u l R a m s e y H o s p i t a l , St . P a u l , M i n n e s o t a ; D e p a r t m e n t of P h a r m a c o l o g y , U n i v e r s i t y of T e n n e s s e e , M e m p h i s , T e n n e s s e e ; D e p a r t m e n t of A n a t o m y , U n i v e r s i t y of A r k a n s a s , L i t t l e R o c k , A r k a n s a s ; D e p a r t m e n t of P h y s i o l o g y a n d H e a l t h Sc ience , B a l l S t a t e U n i v e r s i t y , M u n c i e , I n d i a n a ; L o s A l a m o s Sc i en t i f i c L a b o r a t o r y of t h e U n i v e r s i t y of Ca l i fo rn ia , L o s A l a m o s , N e w M e x i c o ; a n d S l o a n K e t t e r i n g I n s t i t u t e for C a n c e r R e s e a r c h , N e w Y o r k ( N e w Y o r k , U S A ) .

Circadian Variation in Stroke Onset: Identical Temporal Pattern in Ischemic and Hemorrhagic Events

Stroke is the culmination of a heterogeneous group of cerebrovascular diseases that is manifested as ischemia or hemorrhage of one or more blood vessels of the brain. The occurrence of many acute cardiovascular events—such as myocardial infarction, sudden cardiac death, pulmonary embolism, critical limb ischemia, and aortic aneurysm rupture—exhibits prominent 24 h patterning, with a major morning peak and secondary early evening peak. The incidence of stroke exhibits the same 24 h pattern. Although ischemic and hemorrhagic strokes are different entities and are characterized by different pathophysiological mechanisms, they share an identical double‐peak 24 h pattern. A constellation of endogenous circadian rhythms and exogenous cyclic factors are involved. The staging of the circadian rhythms in vascular tone, coagulative balance, and blood pressure plus temporal patterns in posture, physical activity, emotional stress, and medication effects play central and/or triggering roles. Features of the circadian rhythm of blood pressure, in terms of their chronic and acute effects on cerebral vessels, and of coagulation are especially important. Clinical medicine has been most concerned with the prevention of stroke in the morning, when population‐based studies show it is of greatest risk during the 24 h; however, improved protection of at‐risk patients against stroke in the early evening, the second most vulnerable time of cerebrovascular accidents, has received relatively little attention thus far.

Increased Tolerance of Leukemic Mice to Arabinosyl Cytosine with Schedule Adjusted to Circadian System

Mice (BDF1) inoculated with L1210 leukemia survive for a statistically significantly longer span when four courses of arabinosyl cytosine are administered at 4-day intervals-not in courses consisting of eight equal doses at 3-hour intervals, but in sinusoidally increasing and decreasing 24-hour courses, the largest amount being given at previously mapped circadian and circannual times of peak host resistance to the drug. This finding relates to the many therapeutic situations involving rhythmic, and thus predictable, cycles in the hosts tolerance of undesired effects from the agent used.

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

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 of 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. (Author Correspondence: rhermida@uvigo.es or prf@unife.it).