Circadian rhythm of the soluble p75 tumor necrosis factor (sTNF-R75) receptor in humans--a possible explanation for the circadian kinetics of TNR-alpha effects

Circadian alterations of several immune functions in vivo are well established, and may have important physiological and clinical implications. In line with this, tumor necrosis factor (TNF)-alpha has been implicated in the circadian regulation of body temperature. As soluble TNF receptors (TNF-R) act as naturally occurring competitive inhibitors of this cytokine, we investigated plasma levels of the soluble sTNF-R55 and sTNF-R75 in comparison with plasma cortisol and body temperature in nine healthy male volunteers during a defined 16 h light/8 h dark cycle. It was found that sTNF-R75, but not sTNF-R55, exhibited a clear-cut circadian rhythm with a significant (P < 0.01) peak at 7:51 a.m. +/- 58 min. The phase of the sTNF-R75 rhythm preceded that of cortisol by approximately 1 h and inversely corresponded to the circadian rhythm of body temperature. Moreover, the individual amplitudes of sTNF-R75 and body temperature exhibited a significant (P < 0.01) positive correlation. These results suggest that (i) the two sTNF-R are regulated independently, (ii) the sTNF-R75 rhythm is not primarily due to the cortisol rhythm and (iii) the fluctuation of the sTNF-R may contribute to the regulation of body temperature by modulating the availability of free TNF.      

Circadian control of thermoregulation in the squirrel monkey, Saimiri sciureus.

The characteristics and control of the circadian rhythms of core body temperature (colonic) and skin temperature (tail) were studied in chair-acclimatized squirrel monkeys (Saimiri sciureus). When animals were entrained to a light-dark cycle (12 h 600 lx; 12 h less than 1 lx) these two temperatures displayed prominent, reproducible, tightly coupled circadian rhythms. In contsant light of 600 lx, where no other effective circadian time cues were present, both temperature rhythms persisted with free-running periods. Within each animal, however, these rhythms were not as tightly coupled to one another as in LD. On occasion colonic and tail temperature rhythms free-ran with different circadian periods and some animals demonstrated "splitting" of the colonic temperature rhythm, with the colonic temperature rhythm displaying a bimodal pattern. These results suggest that the circadian rhythm of body temperature in primates is under the control of more than one potentially independent circadian oscillator.     

Effects of light intensity on the circadian temperature and feeding rhythms in the squirrel monkey

The circadian rhythms of body temperature and feeding appear to be timed by separate pacemakers. Tonic administration of light has been used to investigate the response of the pacemaker timing behavioral rhythms; however, the response of the body temperature rhythm has not been similarly examined. This study investigates the circadian timing of the body temperature rhythm under conditions of different light intensity. We simultaneously recorded the patterns of both feeding and body temperature in squirrel monkeys free-running in an environment free of external time cues. In each lighting condition, the periods of the body temperature and feeding rhythms were identical. In constant bright light the rhythm periods were longer than when the animals were exposed to constant dim light. In addition, the variability of the periods was dependent on light intensity. The feeding rhythm period variance of animals in constant bright light was smaller than when in dim light. Conversely, the period of the free-running body temperature rhythm exhibited more variability in bright light than in dim light. Further, in each condition, there were changes in phase angle relationship between feeding and body temperature which were qualitatively similar to those observed in humans, although quantitatively smaller in magnitude. Thus, in the squirrel monkey, tonic light studies reveal that the mean circadian period of the body temperature and feeding rhythms are similar. However, changes in phase relationship, and differential rhythm period stabilities suggest differences in the period of the underlying, tightly coupled pacemakers.     

Brain temperature as related to gross motor activity in the unanesthetized chicken

Brain temperature was recorded, together with activity, continuously for up to 8 days at various depths of the tissue in awake, but moderately restrained chicken. The animals were kept in a small round arena with a movable floor and exposed to either a light-dark cycle or constant dim illumination. In entrained as well as in free running rhythms, the circadian rise of temperature preceded onset of activity by several hours. Circadian rhythms of brain temperature were clearly expressed in animals showing no activity rhythm. Short bursts of activity were positively correlated with increases in temperature during the time of circadian low temperatures (sleep) but not during high temperatures (wakefulness). It is concluded that brain temperature and gross motor activity are only loosely coupled to each other, and that especially the circadian rhythm of temperature does not depend on a concurrent rhythm of activity.     

Circadian temperature and wake rhythms of rats exposed to prolonged continuous illumination

The purpose of this study was to simultaneously measure temperature and sleep in the rat under continuous illumination in an attempt to reveal properties of the underlying circadian oscillators. At first, the circadian rhythms of temperature and wake free-ran in parallel. Within weeks or months, circadian arrhythmicity developed in most animals. Both circadian rhythms eventually damped out, even at fairly low light intensities. The circadian rhythm of wake was weaker and disintegrated sooner than the circadian rhythm of temperature. Although the data did not rule out control by separate circadian oscillators, one for temperature and one for wake, a single oscillator model was sufficient to explain this phenomenon. Ultradian variations with a period of about 2–5 hr were superimposed upon the circadian rhythms. When the circadian rhythms damped out, the ultradian variations remained. The ultradian bursts of wake preceded the ultradian bursts of temperature, suggesting a causal relationship. On the other hand, the circadian rhythm of temperature could not be dependent on the circadian rhythm of wakefulness, because the temperature rhythm could persist while the wake rhythm was absent.     

The chronobiology of the Natal mole-rat, Cryptomys hottentotus natalensis

The Natal mole-rat, Cryptomys hottentotus natalensis, rarely, if ever, is exposed to external light cues because it occurs in completely sealed tunnel systems. As a result, their classical visual system is regressed, and therefore, their circadian system is expected proportionally to be expanded. Locomotor activity was investigated under a number of different photic regimes. Nine of the 12 mole-rats exhibited endogenous circadian rhythms of locomotor activity under constant darkness, with a mean free run period of 24.13 h (range 23.93-24.13 h), with these animals entrained to a light-dark cycle (12 L:12 D). Because C. hottentotus natalensis are able to entrain their locomotor activity to an external light source, light must reach the suprachiasmatic nucleus (SCN), suggesting a functional circadian clock. A clear day-night rhythm of melatonin secretion in animals housed under a neutral photoperiod (12 L:12 D) was observed, with higher melatonin concentrations in the dark compared with the light phase. The rhythm was maintained after the animals were transferred to either continuous light (LL) or dark (DD), suggesting that the endogenous rhythm was maintained under acute exposure to light and dark. However, under DD, the rhythm appeared to shift slightly, potentially as a result of the rhythm free running. These results show that C. hottentotus natalensis has endogenous rhythms of both locomotor activity and melatonin secretion, which are modulated by light.     

Circadian variation in endothelial function is attenuated in postmenopausal women

OBJECTIVE: The present study was undertaken to investigate the possible existence of an endogenously generated circadian rhythm in endothelial function in women and whether this rhythm is altered after the menopause. METHODS: Healthy non smoking women (11 pre-menopausal and 13 postmenopausal women) were studied during a 22 h period under constant routine conditions; endothelium-dependent (flow-mediated dilation (%FMD)) and -independent (glyceryl-trintrate (GTN)-mediated) function was assessed every 2 and 4 h, respectively, by high-resolution ultrasound of the brachial artery. RESULTS: %FMD and %GTN was significantly higher in pre-menopausal women (9.9+/-1.0%FMD (mean+/-S.E.M.); 18.2+/-1.8%GTN; P<0.01) compared with postmenopausal women (6.5+/-0.5%FMD; 11.5+/-1.6%GTN). A significant day-night variation in %FMD was observed pre-menopausal women (day 9.2+/-0.8%; night 10.4+/-1%; P<0.05) with an attenuated rhythm in postmenopausal women (day 6.8+/-0.6%; night 6.0+/-0.4%). CONCLUSIONS: The findings show a circadian rhythm in %FMD in pre-menopausal women, which disappears after the menopause. The reduction in %FMD and an absence of a day-night variation in %FMD in postmenopausal women may have important implications for the incidence of coronary heart disease in women after the menopause.     

Splitting of the circadian rhythm of body temperature in the golden hamster

The circadian rhythm of hamster locomotor activity “splits” into two distinct circadian components during conditions of constant illumination. To determine if the circadian rhythm of body temperature also splits under these conditions, body temperature and locomotor activity were monitored concurrently in animals housed in constant illumination. Splitting of the body temperature rhythm into two circadian components was observed in animals manifesting split activity rhythms. Concurrent splitting of both rhythms suggests a common mechanism either for the generation or coupling of these rhythms.     

Effect of a short photoperiod on circadian rhythms of body temperature and motor activity in old rats

Circadian rhythms of body temperature and motor activity were documented in young and old rats (four 8-week-old and five 22-month-old male Wistars, implanted with telemetric probes and housed in a chronobiological facility) under two different photoperiod conditions. The animals were maintained in a light:dark (LD) cycle of 12 h each (LD 12:12) for 4 weeks and then exposed to a LD 6:18 cycle for 7 weeks to assess the effect of age on the desynchronization of the temporal structure of the rhythms. In old rats under LD 12:12, the power of the 24-h component and the circadian amplitude of body temperature and motor activity were markedly lower than in the young and both rhythms were phase-advanced. After the shift to LD 6:18, the circadian rhythmicity was maintained for both variables and the same phase delay (+5+/-1 h) was observed in both age groups, as was a gradual expansion of the patterns of both functions with the longer night. The photoperiod reduction (6 weeks under LD 6:18) did not modify the power of the 24-h component of body temperature and motor activity in old rats. In young rats, however, the power and amplitude of the 24-h component of motor activity rhythm fell to the levels of those in old rats, while the power of the 24-h component of body temperature rhythm and the amplitude did not change. Our data show that the circadian rhythm of motor activity, but not of body temperature, responds age dependently to a photoperiod reduction.     

Circadian, sleep and brain temperature rhythms in cats under sustained daily light-dark cycles and constant darkness

In adult cats, sleep-wake states and brain temperatures were determined under experimental LD cycles and prolonged DD. Convincing rhythms had not previously been well-established for this animal. The present results demonstrated daily fluctuation in total sleep time (TST) and in brain temperature (Tb). These comprise predominantly nocturnal wakefulness and high temperatures but include a bi-modal component marking dawn and dusk peaks. In addition there are ultradian variations with a period of 2-4 hour superimposed on the circadian rhythm. The latter continued at the beginning of prolonged DD, but gradually diminished and disappeared after about ten days. The TST circadian rhythm diminished more quickly than the Tb rhythm. This result suggests that the former is coupled more strongly to the circadian oscillator than the latter, and that the brain temperature rhythm could not depend on the circadian rhythm of sleep-wakefulness. These results encourage use of cats in further chronobiological studies of sleep and other physiological rhythms.     

Variations in deep body temperature in the young unrestrained pig over the 24 hour period

1. The temperature near the carotid artery has been measured in the unrestrained pig by means of radiotelemetry. When the animals were housed singly under constant conditions of temperature and lighting the temperature rhythm appeared to be related only to the time of feeding. A similar record was obtained from temperature measurements made in the hypothalamus.2. Over the range of ambient temperatures 10-30 degrees C the mean body temperature was 38.8 degrees C. No consistent variation occurred with ambient temperature, but on initial transfer from 10 to 30 degrees C ambient temperature the body temperature decreased, while on initial transfer from 30 to 10 degrees C it increased.3. When one pig was housed in a hut with a small outside yard a nychthemeral rhythm was sometimes superimposed on that imposed by feeding. When two pigs were kept in a paddock containing a hut the nychthemeral rhythm was more pronounced.4. It is concluded that in the pig there is very little innate circadian temperature rhythm and that the temperature variations seen are related chiefly to feeding and activity.     

The circadian rhythm of core temperature: effects of physical activity and aging

The circadian rhythm of core temperature depends upon several interacting rhythms, of both endogenous and exogenous origin, but an understanding of the process requires these two components to be separated. Constant routines remove the exogenous (masking) component at source, but they are severely limited in their application. By contrast, several purification methods have successfully reduced the masking component of overt circadian rhythms measured in field circumstances. One important, but incidental, outcome from these methods is that they enable a quantitative estimate of masking effects to be obtained. It has been shown that these effects of activity upon the temperature rhythm show circadian rhythmicity, and more detailed investigations of this have aided our understanding of thermoregulation and the genesis of the circadian rhythm of core temperature itself. The observed circadian rhythm of body temperature varies with age; in comparison with adults, it is poorly developed in the neonate and deteriorates in the aged subject. Comparing masked and purified data enables the reasons for these differences--whether due to the body clock, the effector pathways or organs, or irregularities due to the individual's lifestyle--to begin to be understood. Such investigations stress the immaturity of the circadian rhythm in the human neonate and its deterioration in elderly compared with younger subjects, but they also indicate the robustness of the body clock itself into advanced age, at least in mice.     

Uncertainty analysis of absorbed dose calculations from thermoluminescence dosimeters.

Thermoluminescence dosimeters (TLD) are widely used to verify absorbed doses delivered from radiation therapy beams. Specifically, they are used by the Radiological Physics Center for mailed dosimetry for verification of therapy machine output. The effects of the random experimental uncertainties of various factors on dose calculations from TLD signals are examined, including: fading, dose response nonlinearity, and energy response corrections; reproducibility of TL signal measurements and TLD reader calibration. Individual uncertainties are combined to estimate the total uncertainty due to random fluctuations. The Radiological Physics Center's (RPC) mail out TLD system, utilizing throwaway LiF powder to monitor high-energy photon and electron beam outputs, is analyzed in detail. The technique may also be applicable to other TLD systems. It is shown that statements of +/- 2% dose uncertainty and +/- 5% action criterion for TLD dosimetry are reasonable when related to uncertainties in the dose calculations, provided the standard deviation (s.d.) of TL readings is 1.5% or better.     

Role of heat loss and heat production in generation of the circadian temperature rhythm of the squirrel monkey

To study heat production and heat loss in determination of the daily body temperature rhythm, we examined colonic temperature, skin (tail, foot and abdomen) temperatures and oxygen consumption in chair-restrained squirrel monkeys maintained in isolation in an environmental chamber with a 24-hr light-dark cycle (LD 12:12), maintained at a constant thermoneutral temperature (26 degrees C). In all experiments repeated high amplitude (2 degrees C) diurnal rhythms in colonic temperature were observed. Heat loss, estimated from changes in skin temperature, also displayed a circadian rhythm, although there was considerable variation in waveform. On average, a rhythm in heat production, indicated by changes in the rate of oxygen consumption, was also present. However, a large degree of variability was seen in oxygen consumption, and in several cycles from various animals there were no observable 24-hr rhythms. The circadian body temperature rhythm is thus not simply a consequence of daily changes in metabolism, but rather a regulated response that involves both heat production and heat loss.     

Circadian rhythm of histamine release from the hypothalamus of freely moving rats.

Using an in vivo microdialysis technique coupled with HPLC-fluorometry, the release of neuronal histamine from the anterior hypothalamic area was monitored continuously in conscious, freely moving rats under a 12:12 h light:dark cycle. Spontaneous locomotor activity of the rats was measured simultaneously using a locomotor activity counter. Histamine release gradually increased in the second half of the light period (1400-2000) and the average histamine release during the dark period (2000-0800, 0.20 +/- 0.02 pmol/30 min) was significantly higher than that during the light period (0.12 +/- 0.01 pmol/30 min). This clear circadian change in the release suggests that the central histaminergic system is related to the circadian rhythm of rats.     

Circadian and age-related modulation of thermoreception and temperature regulation: mechanisms and functional implications

At older ages, the circadian rhythm of body temperature shows a decreased amplitude, an advanced phase, and decreased stability. The present review evaluates to what extent these changes may result from age-related deficiencies at several levels of the thermoregulatory system, including thermoreception, thermogenesis and conservation, heat loss, and central regulation. Whereas some changes are related to the aging process per se, others appear to be secondary to other factors, for which the risk increases with aging, notably a decreased level of fitness and physical activity. Moreover, functional implications of the body temperature rhythm are discussed. For example, the relation between circadian rhythm and thermoregulation has hardly been investigated, while evidence showed that sleep quality is dependent on both aspects. It is proposed that the circadian rhythm in temperature in homeotherms should not be regarded as a leftover of ectothermy in early evolution, but appears to be of functional significance for physiology from the level of molecules to cognition. A new view on the functional significance of the circadian rhythm in peripheral vasodilation and the consequent out-of-phase rhythms in skin and core temperature is presented. It is unlikely that the strong, daily occurring, peripheral vasodilation primarily represents heat loss in response to a lowering of set point, since behavioral measures are simultaneously taken in order to prevent heat loss. Several indications rather point towards a supportive role in immunological host defense mechanisms. Given the functional significance of the temperature rhythm, research should focus on the feasibility and effectiveness of methods that can in principle be applied in order to enhance the weakened circadian temperature rhythm in the elderly.     

Gravity and thermoregulation: metabolic changes and circadian rhythms

Gravity appears to alter thermoregulation through changes in both the regulated level of body temperature and the rhythmic organization of temperature regulation. Gravity has been hypothesized to have an associated metabolic cost. Increased resting energy expenditure and dietary intake have been observed in animals during centrifuge experiments at hypergravity. Thus far, only animals have shown a corresponding reduction in metabolism in microgravity. Altered heat loss has been proposed as a response to altered gravitational environments, but remains documented only as changes in skin temperature. Changes in circadian timing, including the body temperature rhythm, have been shown in both hypergravity and microgravity, and probably contribute to alterations in sleep and performance. Changes in body temperature regulation may result from circadian disturbance, from the direct or indirect actions of gravity on the regulated temperature, or from changes in thermoregulatory effectors (heat production and heat loss) due to altered gravitational load and convective changes. To date, however, we have little data on the underlying thermoregulatory changes in altered gravity, and thus the precise mechanisms by which gravity alters temperature regulation remain largely unknown.     

A study comparing circadian rhythm and sleep quality of athletes and sedentary subjects engaged in night work.]

The aim of this study was to show the resistance and persistence of the circadian rhythm of temperature (T degree) and the sleep quality of athletic subjects and sedentary subjects engaged in night work, and attempt to explain the mechanisms that influence these differences. The effects of night work on biological rhythms have been studied extensively in the past few years. The contradictory situations for the night workers irrefutably affect their biological systems. Individuals with high amplitudes in their circadian rhythms have been found to be more tolerant to shift work and this results in a greater stability of circadian rhythms. This seems beneficial in coping with frequent rhythm disturbances. The physical training program seems to improve several mechanisms of the human biological system: amplitudes of circadian rhythms were increased and the circadian rhythm period was more resistant to an environment extreme (night work, shift work, sleep deprivation, or jet lag). To test this hypothesis, athletes and sedentary subjects who were engaged in regular night work were selected in the PSA Peugeot Citro?n Automobiles Group in French Normandy country. The circadian rhythm of the T degree for both groups was studied with a specific methodology and with extensive spectral analysis, especially the spectral elliptic inverse method. Study models of the rhythm of the T degree were determined and the characteristic parameters were exposed. A complementary actigraphic study showed the physical training program's effects on the sleep quality. The results revealed a large stability in the rhythm of circadian variation of T degree for the athletes: the amplitude was still large but for the sedentary subjects the amplitude of the T degree decreased and it was difficult to adjust a period on the rhythm of T degree. The stability and persistent quality of the athletes' circadian rhythm was confirmed. We observed that the actigraphic sleep was greater for athletes than for sedentary subjects, and the acrophase time for the athletes was later than for the sedentary subjects during the night shift.     

Social interaction and sex differences influence rat temperature circadian rhythm under LD cycles and constant light

Circadian rhythms produce an efficient organization of animal behaviour over the 24h day. In some species, social cues have been found to have a role as synchronizers of these rhythms. Here, the influence of social interaction on rat circadian behaviour was investigated, addressing the question of whether cohabitation would produce a delay in the appearance of arrhythmicity under constant light conditions. To this end, the circadian rhythms of male and female rat body temperature were studied for 10days under light-dark conditions, followed by 33days under constant bright light. Half of the animals were maintained in individual cages, whilst the others were maintained in larger cages in groups of three rats of the same sex. Results showed that individual circadian rhythms under 24hour light-dark (LD) cycles were more stable and with higher amplitude in grouped than in isolated animals, and higher in males than in females. During the first days under constant light (LL), the stability of the rhythm was also higher in males than in females, but there were no differences according to the group. Moreover, we did not find significant differences in the time of circadian rhythm loss under LL, since high individual variability was found for this variable. On the other hand, female rats living in isolation showed a delayed acrophase in the circadian rhythm under LD conditions compared with those living in groups. These results suggest that cohabitation increases the internal coherence of circadian behaviour, and could be interpreted as indicating that living in isolation may induce a level of stress that disturbs manifestation of the circadian rhythm, especially in females, which are also more reactive than males to external signals.     

Alpha-1 adrenoceptor agonists generate a "fast" NMDA receptor-independent motor rhythm in the neonatal rat spinal cord

Noradrenaline, a potent activator of rhythmogenic networks in adult mammals has not been reported to produce functional rhythmic patterns in isolated spinal cords of newborn rats. We now show that a "fast" (cycle time: 1-4 s) transient rhythm was induced in sacrococcygeal (SC) and rostral-lumbar spinal segments of the neonatal rat by bath-applied noradrenaline. The fast rhythm was blocked by 1 microM of the alpha1-adrenoceptor antagonist prazosin but not by 1-20 microM of the alpha2-adrenoceptor blocker yohimbine, it could be initiated and maintained by alpha1-adrenoceptor agonists, and it was accompanied by a slow nonlocomotor rhythm. Transection at the lumbosacral junction abolished the fast-thoracolumbar (TL) rhythm while the fast-SC and slow-TL rhythms were unaffected. The N-methyl-d-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonopentanoic acid (AP5) abolished the slow- and did not interrupt the fast rhythm. Thus alpha1-adrenoceptor agonists induce an NMDA receptor-independent rhythm in the SC cord and modulate NMDA receptor-dependent rhythmicity in TL segments. Injection of current steps into S(2) and flexor-dominated L(2) motoneurons during the fast rhythm revealed a 20-30% decrease in input-resistance (R(N)), coinciding with contralateral bursting. The R(N) of extensor-dominated L(5) motoneurons did not vary with the fast rhythm. The rhythmic fluctuations of R(N) in L(2) motoneurons were abolished, but the alternating left-right pattern of the fast rhythm was unchanged in midsagittally split TL cords. We suggest that the locomotor generators were not activated during the fast rhythm, that crossed-inhibitory pathways activated by SC projections controlled the rhythmic decrease in R(N) in L(2) motoneurons, and that the alternating pattern of the split TL cord was maintained by excitatory SC projections.