Journal of Circadian Rhythms - Most accessed articles

Transdisciplinary unifying implications of circadian findings in the 1950s

Franz Halberg — 2003-10-29T00:00:00Z

A few puzzles relating to a small fraction of my endeavors in the 1950s are summarized herein, with answers to a few questions of the Editor-in-Chief, to suggest that the rules of variability in time complement the rules of genetics as a biological variability in space. I advocate to replace truisms such as a relative constancy or homeostasis, that have served bioscience very well for very long. They were never intended, however, to lower a curtain of ignorance over everyday physiology. In raising these curtains, we unveil a range of dynamics, resolvable in the data collection and as-one-goes analysis by computers built into smaller and smaller devices, for a continued self-surveillance of the normal and for an individualized detection of the abnormal. The current medical art based on spotchecks interpreted by reference to a time-unqualified normal range can become a science of time series with tests relating to the individual in inferential statistical terms. This is already doable for the case of blood pressure, but eventually should become possible for many other variables interpreted today only based on the quicksand of clinical trials on groups. These ignore individual differences and hence the individual's needs. Chronomics (mapping time structures) with the major aim of quantifying normalcy by dynamic reference values for detecting earliest risk elevation, also yields the dividend of allowing molecular biology to focus on the normal as well as on the grossly abnormal.

Circadian rhythm and its role in malignancy

Sobia Rana — 2010-03-31T00:00:00Z

Circadian rhythms are daily oscillations of multiple biological processes directed by endogenous clocks. The circadian timing system comprises peripheral oscillators located in most tissues of the body and a central pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Circadian genes and the proteins produced by these genes constitute the molecular components of the circadian oscillator which form positive/negative feedback loops and generate circadian rhythms. The circadian regulation extends beyond clock genes to involve various clock-controlled genes (CCGs) including various cell cycle genes. Aberrant expression of circadian clock genes could have important consequences on the transactivation of downstream targets that control the cell cycle and on the ability of cells to undergo apoptosis. This may lead to genomic instability and accelerated cellular proliferation potentially promoting carcinogenesis. Different lines of evidence in mice and humans suggest that cancer may be a circadian-related disorder. The genetic or functional disruption of the molecular circadian clock has been found in various cancers including breast, ovarian, endometrial, prostate and hematological cancers. The acquisition of current data in circadian clock mechanism may help chronotherapy, which takes into consideration the biological time to improve treatments by devising new therapeutic approaches for treating circadian-related disorders, especially cancer.

Time for sex: nycthemeral distribution of human sexual behavior

Roberto Refinetti — 2005-03-24T00:00:00Z

Background: Nycthemeral (daily) oscillation has been documented in a variety of physiological and behavioral processes. The present study was carried out to evaluate the existence of a nycthemeral rhythm of human sexual behavior and to identify environmental factors responsible for the rhythmic pattern. Methods: Non-traditional university students (ages 18 to 51 years) recorded the times of day when they went to sleep, when they woke up, and when they had sex for 3 consecutive weeks. They also answered a questionnaire designed to identify the causes of their selection of time for sex. Results: The majority of sexual encounters took place at bedtime (11 pm to 1 am). The most common explanations for this temporal pattern were the rigidity of the professional work schedule and family obligations and the availability of the partner, which reduced the opportunity for sexual encounters at other times of the day. Conclusion: Most sexual encounters take place around bedtime. Although the presence of an endogenous component responsible for this temporal pattern cannot be excluded, the evidence indicates strong environmental forcing, particularly from the work/family schedule of the individuals and from partner availability.

The effect of high correlated colour temperature office lighting on employee wellbeing and work performance

Peter Mills — 2007-01-11T00:00:00Z

Background: The effects of lighting on the human circadian system are well-established. The recent discovery of 'non-visual' retinal receptors has confirmed an anatomical basis for the non-image forming, biological effects of light and has stimulated interest in the use of light to enhance wellbeing in the corporate setting. Methods: A prospective controlled intervention study was conducted within a shift-working call centre to investigate the effect of newly developed fluorescent light sources with a high correlated colour temperature (17000 K) upon the wellbeing, functioning and work performance of employees. Five items of the SF-36 questionnaire and a modification of the Columbia Jet Lag scale, were used to evaluate employees on two different floors of the call centre between February and May 2005. Questionnaire completion occurred at baseline and after a three month intervention period, during which time one floor was exposed to new high correlated colour temperature lighting and the other remained exposed to usual office lighting. Two sided t-tests with Bonferroni correction for type I errors were used to compare the characteristics of the two groups at baseline and to evaluate changes in the intervention and control groups over the period of the study. Results: Individuals in the intervention arm of the study showed a significant improvement in self-reported ability to concentrate at study end as compared to those within the control arm (p < 0.05). The mean individual score on a 5 point Likert scale improved by 36.8% in the intervention group, compared with only 1.7% in the control group. The majority of this improvement occurred within the first 7 weeks of the 14 week study. Substantial within group improvements were observed in the intervention group in the areas of fatigue (26.9%), alertness (28.2%), daytime sleepiness (31%) and work performance (19.4%), as assessed by the modified Columbia Scale, and in the areas of vitality (28.4%) and mental health (13.9%), as assessed by the SF-36 over the study period. Conclusion: High correlated colour temperature fluorescent lights could provide a useful intervention to improve wellbeing and productivity in the corporate setting, although further work is necessary in quantifying the magnitude of likely benefits.

Neurotransmitters of the suprachiasmatic nuclei

Vallath Reghunandanan — 2006-02-16T00:00:00Z

There has been extensive research in the recent past looking into the molecular basis and mechanisms of the biological clock, situated in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus. Neurotransmitters are a very important component of SCN function. Thorough knowledge of neurotransmitters is not only essential for the understanding of the clock but also for the successful manipulation of the clock with experimental chemicals and therapeutical drugs. This article reviews the current knowledge about neurotransmitters in the SCN, including neurotransmitters that have been identified only recently. An attempt was made to describe the neurotransmitters and hormonal/diffusible signals of the SCN efference, which are necessary for the master clock to exert its overt function. The expression of robust circadian rhythms depends on the integrity of the biological clock and on the integration of thousands of individual cellular clocks found in the clock. Neurotransmitters are required at all levels, at the input, in the clock itself, and in its efferent output for the normal function of the clock. The relationship between neurotransmitter function and gene expression is also discussed because clock gene transcription forms the molecular basis of the clock and its working.

CLOCK is suggested to associate with comorbid alcohol use and depressive disorders

Louise Sjoholm — 2010-01-21T00:00:00Z

Background: Depression and alcohol abuse or dependence (AUD) co-occur in the general population more frequently than expected by chance. Alcohol use influences the circadian rhythms generated by the central pacemaker in the suprachiasmatic nucleus, and circadian rhythm alterations in turn are common in depressive disorders as well as among persons addicted to alcohol. Methods: 32 SNPs in 19 circadian clockwork related genes were analyzed using DNA from 76 individuals with comorbid depression and AUD, 446 individuals with AUD and 517 healthy controls with no psychiatric diagnosis. The individuals participated in a nationwide health examination study, representative of the general population aged 30 and over in Finland. Results: The CLOCK haplotype TTGC formed by SNPs rs3805151, rs2412648, rs11240 and rs2412646, was associated with increased risk for comorbidity (OR = 1.65, 95% CI = 1.14-2.28, P = 0.0077). The SNPs of importance for this suggestive association were rs2412646 and rs11240 indicating location of the functional variation in the block downstream rs2412648. There was no indication for association between CLOCK and AUD. Conclusion: Our findings suggest an association between the CLOCK gene and the comorbid condition of alcohol use and depressive disorders. Together with previous reports it indicates that the CLOCK variations we found here may be a vulnerability factor to depression given the exposure to alcohol in individuals having AUD.

Magel2, a Prader-Willi Syndrome candidate gene, modulates the activities of circadian rhythm proteins in cultured cells.

Julia Devos — 2011-12-30T00:00:00Z

Background: The Magel2 gene is most highly expressed in the suprachiasmatic nucleus of the hypothalamus, where its expression cycles in a circadian pattern comparable to that of clock-controlled genes. Mice lacking the Magel2 gene have hypothalamic dysfunction, including circadian defects that include reduced and fragmented total activity, excessive activity during the subjective day, but they have a normal circadian period. Magel2 is a member of the MAGE family of proteins that have various roles in cellular function, but the specific function of Magel2 is unknown. Methods: We used a variety of cell-based assays to determine whether Magel2 modifies the properties of core circadian rhythm proteins. Results: Magel2 represses the activity of the Clock:Bmal1 heterodimer in a Per2-luciferase assay. Magel2 interacts with Bmal1 and with Per2 as measured by co-immunoprecipitation in co-transfected cells, and exhibits a subcellular distribution consistent with these interactions when visualized by immunofluorescence. As well, Magel2 induces the redistribution of the subcellular localization of Clock towards the cytoplasm, in contrast to the nucleus-directed effect of Bmal1 on Clock subcellular localization. Conclusion: Consistent with the blunted circadian rhythm observed in Magel2-null mice, these data suggest that Magel2 normally promotes negative feedback regulation of the cellular circadian cycle, through interactions with key core circadian rhythm proteins.

A new approach to understanding the impact of circadian disruption on human health

Mark Rea — 2008-05-29T00:00:00Z

Background: Light and dark patterns are the major synchronizer of circadian rhythms to the 24-hour solar day. Disruption of circadian rhythms has been associated with a variety of maladies. Ecological studies of human exposures to light are virtually nonexistent, however, making it difficult to determine if, in fact, light-induced circadian disruption directly affects human health. Methods: A newly developed field measurement device recorded circadian light exposures and activity from day-shift and rotating-shift nurses. Circadian disruption defined in terms of behavioral entrainment was quantified for these two groups using phasor analyses of the circular cross-correlations between light exposure and activity. Circadian disruption also was determined for rats subjected to a consistent 12-hour light/12-hour dark pattern (12L:12D) and ones subjected to a "jet-lagged" schedule. Results: Day-shift nurses and rats exposed to the consistent light-dark pattern exhibited pronounced similarities in their circular cross-correlation functions and 24-hour phasor representations except for an approximate 12-hour phase difference between species. The phase difference reflects the diurnal versus nocturnal behavior of humans versus rodents. Phase differences within species likely reflect chronotype differences among individuals. Rotating-shift nurses and rats subjected to the "jet-lagged" schedule exhibited significant reductions in phasor magnitudes compared to the day-shift nurses and the 12L:12D rats. The reductions in the 24-hour phasor magnitudes indicate a loss of behavioral entrainment compared to the nurses and the rats with regular light-dark exposure patterns. Conclusion: This paper provides a quantitative foundation for systematically studying the impact of light-induced circadian disruption in humans and in animal models. Ecological light and activity data are needed to develop the essential insights into circadian entrainment/disruption actually experienced by modern people. These data can now be obtained and analyzed to reveal the interrelationship between actual light exposures and markers of circadian rhythm such as rest-activity patterns, core body temperature, and melatonin synthesis. Moreover, it should now be possible to bridge ecological studies of circadian disruption in humans to parametric studies of the relationships between circadian disruption and health outcomes using animal models.

A dynamic model of circadian rhythms in rodent tail skin temperature for comparison of drug effects

Dorothee Girbig — 2012-01-05T00:00:00Z

Menopause-associated thermoregulatory dysfunction can lead to symptoms such as hot fushes severely im-pairing quality of life of affected women. Treatment effects are often assessed by the ovariectomized rat modelproviding time series of tail skin temperature measurements in which circadian rhythms are a fundamental ingre-dient. In this work, a new statistical strategy is presented for analyzing such stochastic-dynamic data with theaim of detecting successful drugs in hot flush treatment. The circadian component is represented by a nonlinear dynamical system which is defined by the van der Pol equation and provides well-interpretable model parameters.Results regarding the statistical evaluation of these parameters are presented.

Circadian light

Mark Rea — 2010-02-13T00:00:00Z

The present paper reflects a work in progress toward a definition of circadian light, one that should be informed by the thoughtful, century-old evolution of our present definition of light as a stimulus for the human visual system. This work in progress is based upon the functional relationship between optical radiation and its effects on nocturnal melatonin suppression, in large part because the basic data are available in the literature. Discussed here are the fundamental differences between responses by the visual and circadian systems to optical radiation. Brief reviews of photometry, colorimetry, and brightness perception are presented as a foundation for the discussion of circadian light. Finally, circadian light (CLA) and circadian stimulus (CS) calculation procedures based on a published mathematical model of human circadian phototransduction are presented with an example.