Thoracic surface temperature rhythms as circadian biomarkers for cancer chronotherapy

The disruption of the temperature circadian rhythm has been associated with cancer progression, while its amplification resulted in cancer inhibition in experimental tumor models. The current study investigated the relevance of skin surface temperature rhythms as biomarkers of the Circadian Timing System (CTS) in order to optimize chronotherapy timing in individual cancer patients. Baseline skin surface temperature at four sites and wrist accelerations were measured every minute for 4?days in 16 patients with metastatic gastro-intestinal cancer before chronotherapy administration. Temperature and rest-activity were recorded, respectively, with wireless skin surface temperature patches (Respironics, Phillips) and an actigraph (Ambulatory Monitoring). Both variables were further monitored in 10 of these patients during and after a 4-day course of a fixed chronotherapy protocol. Collected at baseline, during and after therapy longitudinal data sets were processed using Fast Fourier Transform Cosinor and Linear Discriminant Analyses methods. A circadian rhythm was statistically validated with a period of 24?h (p?<?0.05) for 49/61 temperature time series (80.3%), and 15/16 rest-activity patterns (93.7%) at baseline. However, individual circadian amplitudes varied from 0.04?°C to 2.86?°C for skin surface temperature (median, 0.72?°C), and from 16.6 to 146.1?acc/min for rest-activity (median, 88.9?acc/min). Thirty-nine pairs of baseline temperature and rest-activity time series (75%) were correlated (r?>?|0.7|; p?<?0.05). Individual circadian acrophases at baseline were scattered from 15:18 to 6:05 for skin surface temperature, and from 12:19 to 15:18 for rest-activity, with respective median values of 01:10 (25–75% quartiles, 22:35–3:07) and 14:12 (13:14–14:31). The circadian patterns in skin surface temperature and rest-activity persisted or were amplified during and after fixed chronotherapy delivery for 5/10 patients. In contrast, transient or sustained disruption of these biomarkers was found for the five other patients, as indicated by the lack of any statistically significant dominant period in the circadian range. No consistent correlation (r?<?|0.7|, p?≥?0.05) was found between paired rest-activity and temperature time series during fixed chronotherapy delivery. In conclusion, large inter-patient differences in circadian amplitudes and acrophases of skin surface temperature were demonstrated for the first time in cancer patients, despite rather similar rest-activity acrophases. The patient-dependent coupling between both CTS biomarkers, and its possible alteration on a fixed chronotherapy protocol, support the concept of personalized cancer chronotherapy.     

Aspects of chronopharmacology and chronotherapy in children

Pediatric studies involving chronopharmacology until now have been limited mainly to investigation of circadian patterns in children of 6 to 15 years. This means that: a. data on newborns and even on infants of one year or younger are not available, and b. other bioperiodicities, such as those of one year (infradian rhythms), have not yet been explored in older children. Biological time-related changes have been documented for phenytoin and theophylline with regard to their pharmacokinetics and for orciprenaline, ipratropium bromide, corticosteroids and anticancerous agents with regard to their effectiveness. Despite the small number of investigations performed to date, results indicate that: a. more comprehensive and precise characterization of pharmacokinetic and pharmacodynamic phenomena can be achieved by a chronopharmacological approach than the conventional one and, b. better therapeutics can be achieved using chronopharmacological facts since an appropriate timing of medicines with regard to biological rhythms is likely to enhance desired and/or reduce undesired effects.     

Calculating activation energies for temperature compensation in circadian rhythms

Many biological species possess a circadian clock, which helps them anticipate daily variations in the environment. In the absence of external stimuli, the rhythm persists autonomously with a period of approximately 24 h. However, single pulses of light, nutrients, chemicals or temperature can shift the clock phase. In the case of light- and temperature-cycles, this allows entrainment of the clock to cycles of exactly 24 h. Circadian clocks have the remarkable property of temperature compensation, that is, the period of the circadian rhythm remains relatively constant within a physiological range of temperatures. For several organisms, temperature-regulated processes within the circadian clock have been identified in recent years. However, how these processes contribute to temperature compensation is not fully understood. Here, we theoretically investigate temperature compensation in general oscillatory systems. It is known that every oscillator can be locally temperature compensated around a reference temperature, if reactions are appropriately balanced. A balancing is always possible if the control coefficient with respect to the oscillation period of at least one reaction in the oscillator network is positive. However, for global temperature compensation, the whole physiological temperature range is relevant. Here, we use an approach which leads to an optimization problem subject to the local balancing principle. We use this approach to analyse different circadian clock models proposed in the literature and calculate activation energies that lead to temperature compensation.     

Entrainment of Drosophila circadian rhythms by temperature cycles

Sleep and Biological Rhythms - The fruit fly, Drosophila melanogaster, has been a good organism for elucidating the molecular and cellular bases of circadian behavioral rhythms. The fly shows a...     

Relationships between the circadian rhythms of finger temperature, core temperature, sleep latency, and subjective sleepiness

Skin temperature circadian rhythms have been explored relatively recently. It has been suggested that distal and proximal skin temperature changes play a role in the regulation of the core temperature circadian rhythm and sleepiness. The authors investigated the circadian finger and core temperature rhythms in conjunction with the circadian rhythms of subjective and objective sleepiness. Fourteen healthy, young, good sleepers participated in a modified constant-routine procedure in which palmar finger temperature, rectal temperature, subjective sleepiness, and objective sleep latency were measured half-hourly across a 48-h period of enforced wakeful bed rest. Individual curves were adjusted to the group mean temperature minimum time of 0500 h and averaged to create the 4 mean curves. The 5 possible cross-correlation curves between these 4 measures were calculated for half-hourly phase lags from 12 h before to 12 h after the group mean core temperature minimum time. Maximum cross-correlations for each curve suggested that finger temperature preceded core temperature by 3 h (r = -0.22), and subjective sleepiness followed core temperature by 0.5 h (r = -0.33) and objective sleepiness by 2 h (r = 0.29). Although these data are correlational, they are consistent with the notion that finger temperature changes drive core temperature changes, which determine changes of subjective and objective sleepiness.     

Hibernation and circadian rhythms of body temperature in free-living Arctic ground squirrels

In mammals, the circadian master clock generates daily rhythms of body temperature (T(b)) that act to entrain rhythms in peripheral circadian oscillators. The persistence and function of circadian rhythms during mammalian hibernation is contentious, and the factors that contribute to the reestablishment of rhythms after hibernation are unclear. We collected regular measures of core T(b) (every 34 min) and ambient light conditions (every 30 s) before, during, and following hibernation in free-living male arctic ground squirrels. Free-running circadian T(b) rhythms at euthermic levels of T(b) persisted for up to 10 d in constant darkness after animals became sequestered in their hibernacula in fall. During steady state torpor, T(b) was constant and arrhythmic for up to 13 d (within the 0.19°C resolution of loggers). In spring, males ended heterothermy but remained in their burrows at euthermic levels of T(b) for 22-26 d; patterns of T(b) were arrhythmic for the first 10 d of euthermia. One of four squirrels exhibited a significant free-running T(b) rhythm (τ = 22.1 h) before emergence; this squirrel had been briefly exposed to low-amplitude light before emergence. In all animals, diurnal T(b) rhythms were immediately reestablished coincident with emergence to the surface and the resumption of surface activity. Our results support the hypothesis that clock function is inhibited during hibernation and reactivated by exposure to light, although resumption of extended surface activity does not appear to be necessary to reinitiate T(b) cycles.     

Relationships between behavioral rhythms, plasma corticosterone and hypothalamic circadian rhythms

Circadian rhythms in physiological processes and behaviors were compared with hypothalamic circadian rhythms in norepinephrine (NE) metabolites, adrenergic transmitter receptors, cAMP, cGMP and suprachiasmatic nucleus (SCN) arginine vasopressin (AVP) in a single population of rats under D:D conditions. Eating, drinking and locomotor activity were high during the subjective night (the time when lights were out in L:D) and low during the subjective day (the time when lights were on in L:D). Plasma corticosterone concentration rose at subjective dusk and remained high until subjective dawn. Binding to hypothalamic alpha 1- and beta-adrenergic receptors also peaked during the subjective night. Cyclic cGMP concentration was elevated throughout the 24-hr period except for a trough at dusk, whereas DHPG concentration peaked at dawn. Arginine vasopressin levels in the suprachiasmatic nucleus peaked in the middle of the day. No rhythm was found either in binding to the alpha 2-adrenergic receptor, or in MHPG or cAMP concentration. Behavioral and corticosterone rhythms, therefore, are parallel to rhythms in hypothalamic alpha 1- and beta-receptor binding and NE-release. Cyclic GMP falls only at dusk, suggesting the possibility that cGMP inhibits activity much of the day and that at dusk the inhibition of nocturnal activity is removed. SCN AVP, on the other hand, peaking at 1400 hr, may play a role in the pacemaking function of the SCN that drives these other rhythms.     

Desynchronization of oral temperature, pulse and performance circadian rhythms in shift working Indian nurses.

Circadian time structure in shift working Indian nurses was studied. In shift workers desynchronization between circadian rhythms in different physiological variables was observed. Circadian amplitudes of oral temperature, pulse and random add speed rhythms decreased significantly in shift workers as compared to control subjects. Circadian mesors of performance rhythms increased significantly in shift workers indicating that the time taken by them was more for performing the tasks. It can be concluded that the subjects studied herein are intolerant to shift work and amplitude decrement may be considered as a chronobiologic index to determine the tolerance of individual workers to shift work.     

Phase shifting the circadian rhythms of nocturnal insects by temperature changes

The behavioural rhythms of three species of nocturnal insects were studied: locomotion in a cockroach, luminescence in a firefly and luminescence in a glow-worm. The behaviour was released at the change from light to dark in all cases. In continuous dim light, a circadian rhythm was apparent with a period of from 22.5 to 27 h in the cockroach, and from 19 to 23.5 h in the glow-worm. In constant dim light, the cockroach shifted the phase of its rhythm when subjected to a change of temperature. A temperature step down some time prior to the expected onset of locomotion generated a phase advance, whereas a temperature step up generated a phase delay; the greater the step up, the greater the phase delay. By advancing the change from light to dark, it was found that glow-worms could synchronize immediately to advances of up to about 6 h only. At greater advances an increasing phase angle difference between onsets of darkness and activity occurred. However, if a temperature step down was applied at the light change, immediate synchronization occurred up to 9–12 h before the normal onset. A theory is propounded which assumes that the onset of rhythmic behaviour is determined by the interaction of a circadian process of sensitization and a threshold for release of the behaviour. The threshold is high at high temperatures and light intensities, and low at low values of these. A temperature step up raises the threshold and delays the activity while a step down lowers the threshold and advances the activity.     

Pharmacological effects of vinorelbine on body temperature and locomotor activity circadian rhythms in mice

The effects of vinorelbine (VRL) on the circadian rhythms in body temperature and locomotor activity were investigated in unrestrained B6D2F₁ mice implanted with radio-telemetry transmitters. A single intravenous VRL dose (24 or 12 mg/kg) was given at 7 h after light onset (HALO), a time of high VRL toxicity, and resulted in transient suppression of temperature and activity circadian rhythms in mice kept in light-dark (LD) 12h:12h. Such suppression was dose-dependent. It occurred within 1-5 d after VRL dosing. Recovery of both rhythms was partially complete within 5 d following the high dose and within 2 or 3 d after the low dose and was not influenced by suppression of photoperiodic synchronization by housing in continuous darkness. Moreover, VRL induced a dose-dependent relative decrease in amplitude and phase shift of the temperature circadian rhythm. The mesor and amplitude of the activity rhythm were markedly reduced following the VRL administration. The relevance of VRL dosing time was studied in mice housed in LD 12h:12h. Vinorelbine was injected weekly (20 mg/kg/injection) for 3 wk at 6 or 18 HALO. Vinorelbine treatment ablated the rest-activity and temperature rhythms 3-6 d after each dose, with fewer alterations after VRL dosing at 18 HALO compared to 6 HALO, especially for the body temperature rhythm. There was at least partial recovery 1 wk after dosing, suggesting the weekly schedule of drug treatment is acceptable for therapeutic purposes. Our findings demonstrate that VRL can transiently, yet profoundly, alter circadian clock function. Vinorelbine-induced circadian dysfunction may contribute to the toxicokinetics of this and possibly other anticancer drugs.     

A systematic review of circadian function,chronotype and chronotherapy in attention deficit hyperactivity disorder

Reports of sleep disturbances in attention deficit hyperactivity disorder (ADHD) are common in both children and adults; however, the aetiology of such disturbances is poorly understood. One potentially important mechanism which may be implicated in disrupted sleep in ADHD is the circadian clock, a known key regulator of the sleep/wake cycle. In this systematic review, we analyse the evidence for circadian rhythm changes associated with ADHD, as well as assessing evidence for therapeutic approaches involving the circadian clock in ADHD. We identify 62 relevant studies involving a total of 4462 ADHD patients. We find consistent evidence indicating that ADHD is associated with more eveningness/later chronotype and with phase delay of circadian phase markers such as dim light melatonin onset and delayed sleep onset. We find that there is evidence that melatonin treatment may be efficacious in addressing ADHD-related sleep problems, although there are few studies to date addressing other chronotherapeutic approaches in ADHD. There are only a small number of genetic association studies which report linkages between polymorphisms in circadian clock genes and ADHD symptoms. In conclusion, we find that there is consistent evidence for circadian rhythm disruption in ADHD and that such disruption may present a therapeutic target that future ADHD research might concentrate explicitly on.     

A neural theory of circadian rhythms: split rhythms, after-effects and motivational interactions

A neural theory of the circadian pacemaker within the hypothalamic suprachiasmatic nuclei (SCN) is used to explain parametric data about mammalian operant behavior. The intensity, duration, and patterning of ultradian activity-rest cycles and the duration of circadian periods due to parametric (LL) and nonparametric (LD) lighting regimes are simulated. Paradoxical data about split rhythms and after-effects are explained using homeostatic and nonhomeostatic neural mechanisms that modulate pacemaker activity. These modulatory mechanisms enable the pacemaker to adjust to pervasive changes in its lighting regime, as during the passage of seasons, and to ultradian changes in internal metabolic conditions. The model circadian mechanisms are homologous to mechanisms that model hypothalamically mediated appetitive behaviors, such as eating. The theory thus suggests that both circadian and appetitive hypothalamic circuits are constructed from similar neural components. Mechanisms of transmitter habituation, opponent feedback interactions between on-cells and off-cells, homeostatic negative feedback, and conditioning are used in both the circadian and the appetitive circuits. Output from the SCN circadian pacemaker is assumed to modulate the sensitivity of the appetitive circuits to external and internal signals by controlling their level of arousal. Both underarousal and overarousal can cause abnormal behavioral syndromes whose properties have been found in clinical data. A model pacemaker can also be realized as an intracellular system.     

Comparative study on circadian rhythms of body temperature, heart rate, and locomotor activity in three species hamsters.

Circadian rhythms of body temperature, heart rate, and locomotor activity were observed in the unanesthetized and unrestrained Syrian hamsters, Djungarian hamsters and Chinese hamsters, and the differences in these biological characters among the three species of hamster were investigated. In each species, body temperature, heart rate, and locomotor activity in the dark period were higher than those in the light period. Heart rate of Chinese hamsters was higher than that of the others in both the light and dark periods. In addition, it was found that the body temperature of Djungarian hamsters decreased rapidly one time a day. These results show species differences in body temperature, heart rate and locomotor activity of Syrian, Djungarian and Chinese hamsters.     

Suprachiasmatic nuclear lesions eliminate circadian rhythms of drinking and activity, but not of body temperature, in male rats

Male Long-Evans rats were maintained in light proof cabinets while drinking, activity, and telemetered body temperature (Tb) data were collected. After suprachiasmatic nuclear (SCN) lesions, the rats were exposed to a 12:12 light-dark cycle, a 6-hr delay in the lighting cycle, and constant dark. Lesions that abolished the drinking and activity rhythms did not eliminate the Tb rhythm. However, the amplitude, phase, and free-running period of the Tb rhythm were altered. Lesions that only partially damaged the SCN had similar, though lesser effects. In some cases, Tb rhythms remained normal, activity rhythms were only temporarily disrupted, and drinking rhythms were eliminated in the same animals. These results support the conclusion that Tb can remain rhythmic after lesions that permanently or temporarily disrupt other circadian rhythms. Of the three rhythms, it appears that drinking rhythms are most easily and Tb rhythms least easily disrupted by SCN lesions.