Melatonin rhythms in night shift workers.

For some time, it has remained uncertain whether the circadian rhythms of permanent night shift workers are adapted to their night-active schedule. Previous studies of this question have often been limited by "masking" (evoked) effects of sleep and activity on body temperature and cortisol, used as marker rhythms. In this study, the problem of masking was minimized by measuring the timing of melatonin production under dim light conditions. Nine permanent night shift workers were admitted to the Clinical Research Center (CRC) directly from their last work shift of the week and remained in dim light while blood samples were obtained hourly for 24 hours. Melatonin concentrations were measured in these samples using a gas-chromatographic mass-spectrometric method. Sleep diaries were completed for two weeks prior to the admission to the CRC. Overall, the onset of the melatonin rhythm was about 7.2 hours earlier (or 16.8 hours later) in the night workers compared to day-active controls. It was not possible to know whether the phase of the melatonin rhythm was the result of advances or delays. In night shift workers, sleep was initiated (on average) about three hours prior to the onset of melatonin production. In contrast, day-active subjects initiated sleep (on average) about three hours after their melatonin onset. Thus, the sleep times selected by night shift workers may not be well-synchronized to their melatonin rhythm, assumed to mark the phase of their underlying circadian pacemaker.     

Suppression of sleepiness and melatonin by bright light exposure during breaks in night work

Night work is non-optimal for performance and recuperation because of a lack of circadian influence that fully promote a night orientation. Our study assessed, in an industrial setting, the effects of bright light exposure (BL) on sleepiness, sleep and melatonin, during night work and during the following readaptation to day work. In a crossover design, 18 workers at a truck production plant were exposed to either BL (2500 lx) during breaks or normal light during four consecutive weeks. Twenty minute breaks were initiated by 67% of the workers between 03:00 and 04:00 hours. Sleep/wake patterns were assessed through actigraphs and ratings were given in a sleep/wake diary. Saliva melatonin was measured at 2-h intervals before, during and after night shift weeks. A significant interaction demonstrated a reduction of sleepiness in the BL condition particularly on the first two nights at 04:00 and 06:00 hours. Day sleep in the BL condition was significantly lengthened. Bright light administration significantly suppressed melatonin levels during night work and most strongly at 02:00 hours. Daytime melatonin during the readaptation after night work remained unaffected. The present findings demonstrate the feasibility and benefits of photic stimulation in industrial settings to increase adaptation to night work.     

Nocturnal sustained attention during sleep deprivation can be predicted by specific periods of subjective daytime alertness in normal young humans

In our 24-h society, nocturnal sleep-related accidents are common. Because all individuals are not equal in their responses to sleep loss, it is very important to identify predictors of vulnerability to sleep deprivation in normal subjects. We investigated the performance of a cognitive test of sustained attention, electroencephalogram theta/alpha power, subjective sleepiness, and two circadian markers (core temperature and melatonin) in 18 healthy men (nine morning types and nine evening types, 21.4 +/- 1.9 years) during a 36-h sleep deprivation in a constant routine protocol. Sleep need (self-reported) and baseline sleep structure were also investigated. Nighttime performance impairment was defined as the difference between the mean nocturnal number of lapses (00:00-07:30 [corrected] hours) and the mean diurnal number of lapses (07:30-20:30 hours) expressed as a percentage. Feeling fully alert in the morning just after awakening and/or sleepy in early afternoon were the only two factors (Multiple R > 0.80, > 60% of explained variance) which better predicted the decrease in performances of nocturnal operational tasks requiring sustained attention.     

Effects of partial circadian adjustments on sleep and vigilance quality during simulated night work

In most situations, complete circadian adjustment is not recommended for night workers. With complete adjustment, workers experience circadian misalignment when returning on a day-active schedule, causing repeated circadian phase shifts and internal desynchrony. For this reason, partial circadian realignment was proposed as a good compromise to stabilize internal circadian rhythms in night shift workers. However, the extent of partial circadian adjustment necessary to improve sleep and vigilance quality is still a matter of debate. In this study, the effects of small but statistically significant partial circadian adjustments on sleep and vigilance quality were assessed in a laboratory simulation of night work to determine whether they were also of clinical significance. Partial adjustments obtained by phase delay or by phase advance were quantified not only by the phase shift of dim light salivary melatonin onset, but also by the overlap of the episode of melatonin production with the sleep-wake cycle adopted during simulated night work. The effects on daytime sleep and night-time vigilance quality were modest. However, they suggest that even small adjustments by phase delay may decrease the accumulation of sleep debt, whereas the advance strategy improves subjective alertness and mood during night work. Furthermore, absolute phase shifts, by advance or by delay, were associated with improved subjective alertness and mood during the night shift. These strategies need to be tested in the field, to determine whether they can be adapted to real-life situations and provide effective support to night workers.     

Association between melatonin secretion and daytime sleep complaints in night nurses

STUDY OBJECTIVES: To test the hypothesis that nightworkers' diurnal sleep complaints are associated with the timing of melatonin secretion. DESIGN: After a minimum of three consecutive night shifts, the subjects were admitted to the laboratory for 24 hours during which they were allowed to eat and sleep ad lib. Urine was collected every two hours under dim illumination (<25 lux). Concentration of urinary 6-sulphatoxymelatonin (UaMT6s) was determined by radioimmunoassay. Sleep quality was assessed by questionnaires. SETTING: NA PARTICIPANTS: Two groups of 15 night nurses with mild and severe daytime sleep complaints. INTERVENTIONS: NA RESULTS: The proportion of the episode of UaMT6s excretion happening during the day (between 08:00 and 00:00 hours) was smaller in the group of nightworkers with severe daytime sleep complaints, and was negatively correlated with the severity of the complaints over the 30 subjects. A longer duration of melatonin secretion was associated with a lower severity of daytime sleep complaints. However, in most of the subjects with good daytime sleep quality, melatonin secretion remained essentially nocturnal, and the overlap with the time of their sleep episode was small or even absent. CONCLUSIONS: Timing and duration of melatonin secretion were associated with better daytime sleep quality when the subjects had an increased proportion of melatonin secreted during the day. When there was an indication of circadian phase shift, the direction of the shift was not of primary importance for daytime sleep quality. A longer duration of melatonin secretion may increase the tolerance to an abnormal circadian phase.     

Effects of the short-acting benzodiazepine triazolam, taken at bedtime, on circadian and sleep-related hormonal profiles in normal men

Studies in rodents have shown that triazolam, a commonly used hypnotic, may shift circadian rhythms, with the direction and magnitude of the phase-shifts being dependent on the time of drug administration. To determine whether benzodiazepine, taken at standard bedtime, modifies the amount and/or temporal organization of hormonal secretion, six normal men were studied during basal conditions and on the first and third days of treatment with 0.5 mg triazolam. In each study, sleep was polygraphically monitored and plasma cortisol, growth hormone (GH), melatonin, and prolactin (PRL) (i.e., hormones influenced by circadian rhythmicity and/or sleep) were measured at 20-min intervals for 24 h. The sleep latency and the number and duration of awakenings were reduced during triazolam treatment as compared to baseline conditions. The only alteration of sleep architecture was a partial suppression of stages III + IV (SW) in late sleep. Triazolam did not affect the mean cortisol and melatonin levels or the total amount of GH secreted over the 24-h span. The circadian timings of the onsets of cortisol and melatonin secretions were essentially unaltered. The nocturnal rise of melatonin was prolonged by 45 to 60 minutes. Sleep-associated GH release was not modified by triazolam. Sleep-associated PRL secretion persisted, but in half of the nights studied was enhanced almost threefold. This effect of the drug on nocturnal PRL secretion was not specific to either the first or the third night of treatment, nor was it specific to certain subjects. Irrespective of the magnitude of the nocturnal elevation, morning PRL levels were slightly but consistently higher after triazolam treatment than under basal conditions. Normal PRL levels resumed around noon. In conclusion, administration of 0.5 mg triazolam at normal bedtime (2230) for three consecutive days may induce a transient hyperprolactinemia, but does not abolish sleep-related hormone secretion and does not affect the timing of endocrine events controlled by the circadian clock. These findings are consistent with studies in hamsters where treatment with triazolam in the early subjective night was also without effect on the rodent circadian clock.     

Complete or partial circadian re-entrainment improves performance, alertness, and mood during night-shift work

STUDY OBJECTIVES: To assess performance, alertness, and mood during the night shift and subsequent daytime sleep in relation to the degree of re-alignment (re-entrainment) of circadian rhythms with a night-work, day-sleep schedule. DESIGN: Subjects spent 5 consecutive night shifts (11:00 pm-7:00 am) in the lab and slept at home in darkened bedrooms (8:30 am-3:30 pm). Subjects were categorized by the degree of re-entrainment attained after the 5 night shifts. Completely re-entrained: temperature minimum in the second half of daytime sleep; partially re-entrained: temperature minimum in the first half of daytime sleep; not re-entrained: temperature minimum did not delay enough to reach daytime sleep. SETTING: See above. PARTICIPANTS: Young healthy adults (n = 67) who were not shift workers. INTERVENTIONS: Included bright light during the night shifts, sunglasses worn outside, a fixed dark daytime sleep episode, and melatonin. The effects of various combinations of these interventions on circadian re-entrainment were previously reported. Here we report how the degree of re-entrainment affected daytime sleep and measures collected during the night shift. MEASUREMENTS AND RESULTS: Salivary melatonin was collected every 30 minutes in dim light (<20 lux) before and after the night shifts to determine the dim light melatonin onset, and the temperature minimum was estimated by adding a constant (7 hours) to the dim light melatonin onset. Subjects kept sleep logs, which were verified by actigraphy. The Neurobehavioral Assessment Battery was completed several times during each night shift. Baseline sleep schedules and circadian phase differed among the 3 re-entrainment groups, with later times resulting in more re-entrainment. The Neurobehavioral Assessment Battery showed that performance, sleepiness, and mood were better in the groups that re-entrained compared to the group that did not re-entrain, but there were no significant differences between the partial and complete re-entrainment groups. Subjects slept almost all of the allotted 7 hours during the day, and duration did not significantly differ among the re-entrainment groups. CONCLUSIONS: In young people, complete re-entrainment to the night-shift day-sleep schedule is not necessary to produce substantial benefits in neurobehavioral measures; partial re-entrainment (delaying the temperature minimum into the beginning of daytime sleep) is sufficient. The group that did not re-entrain shows that a reasonable amount of daytime sleep is not enough to produce good neurobehavioral performance during the night shift. Therefore, some re-alignment of circadian rhythms is recommended.     

Melatonin in older people with age-related sleep maintenance problems: a comparison with age matched normal sleepers

STUDY OBJECTIVES: To determine whether older people with age-related sleep maintenance problems have significantly lower melatonin levels than comparable normal sleepers. DESIGN: Case-control study. SETTING: A largely urban population, Auckland, New Zealand. PARTICIPANTS: People over the age of 65 years, who either slept normally, or had age-related sleep maintenance problems. Participants were recruited through media advertising, and local interest groups. Initial screening was by mail (Pittsburgh Sleep Quality Index), followed by interviews at a hospital day clinic. Exclusions included those with depression, cognitive impairment, medical and/or environmental problems which might impair sleep. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: A metabolite of plasma melatonin, 6-sulphatoxymelatonin (aMT6s) was measured in the urine of 57 normal sleepers, and 53 people with age-related problems over 24 hours in three aliquots: 12:00-19:00h, 19:00-07:00h, 07:00-12:00h. There were clear differences in self reported quality of sleep but no difference in mean aMT6s 24 hour or total night excretory levels, or night/day ratios. CONCLUSIONS: Older people with age-related sleep maintenance problems do not have lower melatonin levels than older people reporting normal sleep.     

Effects of melatonin administration on daytime sleep after simulated night shift work

Disturbed sleep and on-the-job sleepiness are widespread problems among night shift workers. The pineal hormone melatonin may prove to be a useful treatment because it has both sleep-promoting and circadian phase-shifting effects. This study was designed to isolate melatonin's sleep-promoting effects, and to determine whether melatonin could improve daytime sleep and thus improve night time alertness and performance during the night shift. The study utilized a placebo-controlled, double-blind, cross-over design. Subjects (n=21, mean age=27.0 +/- 5.0 years) participated in two 6-day laboratory sessions. Each session included one adaptation night, two baseline nights, two consecutive 8-h night shifts followed by 8-h daytime sleep episodes and one recovery night. Subjects took 1.8 mg sustained-release melatonin 0.5 h before the two daytime sleep episodes during one session, and placebo before the daytime sleep episodes during the other session. Sleep was recorded using polysomnography. Sleepiness, performance, and mood during the night shifts were evaluated using the multiple sleep latency test (MSLT) and a computerized neurobehavioral testing battery. Melatonin prevented the decrease in sleep time during daytime sleep relative to baseline, but only on the first day of melatonin administration. Melatonin increased sleep time more in subjects who demonstrated difficulty in sleeping during the day. Melatonin had no effect on alertness on the MSLT, or performance and mood during the night shift. There were no hangover effects from melatonin administration. These findings suggest that although melatonin can help night workers obtain more sleep during the day, they are still likely to face difficulties working at night because of circadian rhythm misalignment. The possibility of tolerance to the sleep-promoting effects of melatonin across more than 1 day needs further investigation.     

A benzodiazepine hypnotic facilitates adaptation of circadian rhythms and sleep-wake homeostasis to an eight hour delay shift simulating westward jet lag

STUDY OBJECTIVES: To determine whether appropriately timed administration of a short-acting benzodiazepine hypnotic, which has proven effective in an animal model of jet lag, also facilitates adaptation of circadian rhythmicity and sleep-wake homeostasis in a human model of jet lag. DESIGN: Subjects participated in two double-blind, placebo-controlled studies of adaptation to an 8-hr delay shift of sleep-wake and dark-light cycles simulating westward travel. Each 9-day laboratory study began with a 3-day habituation period followed by a 24-hr study to obtain basal hormonal and sleep profiles (23:00-07:00). Subjects were then kept awake until 07:00 the next day and slept in darkness 07:00-15:00 for the next five 24-hr spans post-shift. SETTING: N/A. PARTICIPANTS: 6 normal, healthy men 24-31 years of age. INTERVENTIONS: Oral Triazolam (0.5 mg) or placebo given at 04:00 before the first shifted sleep/dark period (3 hours before bedtime) and at 07:00 (at bedtime) on days 2-5 post-shift. MEASUREMENTS AND RESULTS: Sleep recordings and 24-hr cortisol and growth hormone profiles were obtained at baseline and on the first, third, and fifth days post-shift. Global measures of treatment efficacy were calculated for multiple endpoints representing circadian rhythmicity and sleep-wake homeostasis. With placebo, the shift induced disturbances of sleep and hormonal secretion, and a gradual re-entrainment of circadian rhythmicity. Triazolam significantly facilitated adaptation by accelerating re-entrainment of circadian rhythms (chronobiotic effect) and normalizing markers of sleep/wake homeostasis (hypnotic effect). CONCLUSIONS: Appropriately timed administration of a benzodiazepine hypnotic appears to facilitate the adaptation of both circadian rhythmicity and sleep-wake homeostasis to a shifted dark/sleep cycle. Compounds with combined chronobiotic/hypnotic properties may be useful in conditions of jet lag or night work.     

Total sleep deprivation induces an acute and transient increase in NK cell activity in healthy young volunteers.

STUDY OBJECTIVES: To investigate the effects of one night's total sleep deprivation (TSD) on NK cell activity, with rigorous control of circadian phase of sampling points as well as physical exercise level in association with sleep deprivation. DESIGN: The mean sleep onset time of each subject before starting the study was defined as his 0000 h. This study was composed of a Sleep-Sleep session (sleep times, 00:00 h - 08:00 h and 24:00 h - 32:00 h) and a Sleep-Wake session (sleep time, 00:00 h - 08:00 h) with TSD (24:00 h - 32:00 h) placed in a cross-over design with 2-week interval between each session. In each session, the subjects were rested in the supine position under dim light from - 06:00 h to 36:00 h (for 42 hours). SETTING: University-based sleep and chronobiology laboratory PARTICIPANTS: 10 healthy adult men (mean age, 20.9 y; age range, 19-23 y) INTERVENTIONS: NA. MEASUREMENTS AND RESULTS: NK cell activity was measured every 4 hours from 12:00 h. NK cell activity during TSD (at 28:00 h) has been revealed to significantly increase (p=0.01) compared with the corresponding value in the Sleep-Sleep session. This effect was weaker at their usual waking time 32:00 h (p=0.07), and disappeared until 36:00 h (4 hours after awakening). The circadian rhythm phases (dim light melatonin onset time) were coincident between the 2 sessions. CONCLUSIONS: The present findings suggest that one night TSD induces an acute and transient increase in NK cell activity that is not influenced by the effects of circadian rhythm or the amount of physical exercise undertaken during TSD.     

Differential endocrine response in rams to intracerebroventricular infusion of genistein

The intracerebroventricular infusions of genistein (total 40 mug) were made in male sheep (November) to test its influence on melatonin, growth hormone (GH) and luteinizing hormone (LH) secretion. The analysis of the results encompassed 3 similar periods: before the infusion (afternoon hours) the first (evening hours) and the second (night hours) halves of the treatment. The night plasma concentration of melatonin in genistein-infused rams was significantly lower than that noted during the respective period in vehicle-infused rams. Plasma GH concentration increased significantly in both vehicle- and genistein-infused rams during the night hours, as compared with the concentrations noted during the afternoon and evening, however, genistein significantly stimulated the amplitude of GH pulses in these latter. The LH concentration was significantly lower during the second part of genistein treatment, than in vehicle-infused rams. The frequency and amplitude of LH pulses clearly tended to decrease following genistein infusion. In conclusion, genistein, acting at the central nervous system level in sexually active rams is able to reduce the secretion of melatonin and LH and has also a slight stimulatory effect on the amplitude of GH pulses.     

Sleep inertia,sleep homeostatic and circadian influences on higher‐order cognitive functions

Sleep inertia, sleep homeostatic and circadian processes modulate cognition, including reaction time, memory, mood and alertness. How these processes influence higher‐order cognitive functions is not well known. Six participants completed a 73‐day‐long study that included two 14‐day‐long 28‐h forced desynchrony protocols to examine separate and interacting influences of sleep inertia, sleep homeostasis and circadian phase on higher‐order cognitive functions of inhibitory control and selective visual attention. Cognitive performance for most measures was impaired immediately after scheduled awakening and improved during the first ~2–4 h of wakefulness (decreasing sleep inertia); worsened thereafter until scheduled bedtime (increasing sleep homeostasis); and was worst at ~60° and best at ~240° (circadian modulation, with worst and best phases corresponding to ~09:00 and ~21:00 hours, respectively, in individuals with a habitual wake time of 07:00 hours). The relative influences of sleep inertia, sleep homeostasis and circadian phase depended on the specific higher‐order cognitive function task examined. Inhibitory control appeared to be modulated most strongly by circadian phase, whereas selective visual attention for a spatial‐configuration search task was modulated most strongly by sleep inertia. These findings demonstrate that some higher‐order cognitive processes are differentially sensitive to different sleep–wake regulatory processes. Differential modulation of cognitive functions by different sleep–wake regulatory processes has important implications for understanding mechanisms contributing to performance impairments during adverse circadian phases, sleep deprivation and/or upon awakening from sleep.     

Shaping the light/dark pattern for circadian adaptation to night shift work

This is the second in a series of simulated night shift studies designed to achieve and subsequently maintain a compromise circadian phase position between complete entrainment to the daytime sleep period and no phase shift at all. We predict that this compromise will yield improved night shift alertness and daytime sleep, while still permitting adequate late night sleep and daytime wakefulness on days off. Our goal is to delay the dim light melatonin onset (DLMO) from its baseline phase of ∼ 21:00 to our target of ∼ 3:00. Healthy young subjects (n = 31) underwent three night shifts followed by two days off. Two experimental groups received intermittent bright light pulses during night shifts (total durations of 75 and 120 min per night shift), wore dark sunglasses when outside, slept in dark bedrooms at scheduled times after night shifts and on days off, and received outdoor light exposure upon awakening from sleep. A control group remained in dim room light during night shifts, wore lighter sunglasses, and had unrestricted sleep and outdoor light exposure. After the days off, the DLMO of the experimental groups was ∼ 00:00-1:00, not quite at the target of 3:00, but in a good position to reach the target after subsequent night shifts with bright light. The DLMO of the control group changed little from baseline. Experimental subjects performed better than control subjects during night shifts on a reaction time task. Subsequent studies will reveal whether the target phase is achieved and maintained through more alternations of night shifts and days off.     

Hypoxia‐induced changes in recovery sleep,core body temperature,urinary 6‐sulphatoxymelatonin and free cortisol after a simulated long‐duration flight

Fatigue and sleep disorders often occur after long‐haul flights, even when no time zones are crossed. In this controlled study, we assessed the effects of two levels of hypoxia (at 8000 ft and 12 000 ft) on recovery sleep. Core body temperature (CBT), a circadian marker, urinary 6‐sulphatoxymelatonin and free cortisol were studied in 20 young healthy male volunteers exposed for 8 h (08:00–16:00 hours) in a hypobaric chamber to a simulated cabin altitude of 8000 ft and, 4 weeks later, 12 000 ft. Each subject served as his own control. Sleep was recorded by polysomnography for three consecutive nights for each exposure. CBT was monitored by telemetry during the three 24‐h cycles (control, hypoxic exposure and recovery). Free urinary cortisol and 6‐sulphatoxymelatonin levels were assayed twice daily between 08:00 and 20:00 hours (day) and between 20:00 and 08:00 hours (night). We showed significant changes in circadian patterns of CBT at both altitudes, suggesting a phase delay, and changes in recovery sleep but only at 12 000 ft. We observed an increase in sleep onset latency which correlated positively with the increase in CBT levels during the first recovery night and a decrease in the duration of stage N₂ (formerly S₂), which correlated negatively with the mid‐range crossing time, a reliable phase marker of CBT rhythm. This study shows clearly the impact of hypobaric hypoxia on circadian time structure during air flights leading to a phase delay of CBT, independent of jet lag and consequences on sleep during recovery.     

Reestablishment of individual sleep structure during a single 14‐h recovery sleep episode after 58 h of wakefulness

Sleep structure is highly stable within individuals but different between individuals. The present study investigated robustness of the individual sleep structure to extended total sleep deprivation. Seventeen healthy men spent a baseline night (23:00–07:00 hours), 58 h of sleep deprivation and a 14‐h recovery night (17:00–07:00 hours) in the laboratory. Intraclass correlation coefficients showed that the agreement between baseline and recovery with respect to the proportion of the different sleep stages increased as a function of recovery sleep duration. High values were reached for most of the sleep stages at the end of 14 h of recovery sleep (intraclass correlation coefficients between 0.38 and 0.76). If sleep duration of the recovery night is extended to 14 h, sleep stage distribution resembles that of a baseline night underlining the robustness of the individual sleep structure.     

Effect of modafinil on plasma melatonin, cortisol and growth hormone rhythms, rectal temperature and performance in healthy subjects during a 36 h sleep deprivation

Modafinil is an alerting substance which has been used successfully to treat narcolepsy. Nothing is known about its effect on hormone secretions. For this purpose, eight healthy young men were enrolled in a double blind trial to test the effects of modafinil on daily plasma melatonin, cortisol and growth hormone (GH) rhythms. Blood was sampled for hormone assays, every hour during the daytime and every 30 min during the nighttime. In addition, rectal temperature and mental performances were determined during the study which comprised 3 sessions, two weeks apart: a 24 h control session including a night with sleep (S1) and two 48 h sessions S2 and S3 with a sleep-deprived night (N1) followed by a recovery night (N2). Modafinil (300 mg2) or placebo were randomly attributed during N1 at 22 h and 8 h.
As expected, performance was improved after modafinil administration and body temperature was maintained or increased. Plasma melatonin and cortisol profiles were similar after modafinil and placebo administration. The levels observed during the recovery and the control nights (N2) displayed no difference. For GH, during both sleep deprived nights, secretion was dramatically reduced compared with the control one, although the number of secretory episodes was unchanged.
These data show that the alerting property of modafinil is not related to an alteration of hormone profiles and suggest that the acute modafinil administration is devoid of short-term side-effects.     

Robust circadian rhythm in heart rate and its variability: influence of exogenous melatonin and photoperiod

Heart rate (HR) and heart rate variability (HRV) undergo marked fluctuations over the 24-h day. Although controversial, this 24-h rhythm is thought to be driven by the sleep-wake/rest-activity cycle as well as by endogenous circadian rhythmicity. We quantified the endogenous circadian rhythm of HR and HRV and investigated whether this rhythm can be shifted by repeated melatonin administration while exposed to an altered photoperiod. Eight healthy males (age 24.4 +/- 4.4 years) participated in a double-blind cross-over design study. In both conditions, volunteers were scheduled to 16 h-8 h rest : wake and dark : light cycles for nine consecutive days preceded and followed by 29-h constant routines (CR) for assessment of endogenous circadian rhythmicity. Melatonin (1.5 mg) or placebo was administered at the beginning of the extended sleep opportunities. For all polysomnographically verified wakefulness periods of the CR, we calculated the high- (HF) and low- (LF) frequency bands of the power spectrum of the R-R interval, the standard deviation of the normal-to-normal (NN) intervals (SDNN) and the square root of the mean-squared difference of successive NN intervals (rMSSD). HR and HRV variables revealed robust endogenous circadian rhythms with fitted maxima, respectively, in the afternoon (16:36 hours) and in the early morning (between 05:00 and 06:59 hours). Melatonin treatment phase-advanced HR, HF, SDNN and rMSSD, and these shifts were significantly greater than after placebo treatment. We conclude that endogenous circadian rhythmicity influences autonomic control of HR and that the timing of these endogenous rhythms can be altered by extended sleep/rest episodes and associated changes in photoperiod as well as by melatonin treatment.     

Length polymorphism in the Period 3 gene is associated with sleepiness and maladaptive circadian phase in night‐shift workers

The objective of the current study was to determine if night‐shift workers carrying the five‐repeat variant of the Period 3 gene show elevated levels of nocturnal sleepiness and earlier circadian phase compared with homozygotes for the four‐repeat allele. Twenty‐four permanent night‐shift workers were randomly selected from a larger study. Participants took part in an observational laboratory protocol including an overnight multiple sleep latency test and half‐hourly saliva collection for calculation of dim‐light melatonin onset. Period 3^–/5 shift workers had significantly lower multiple sleep latency test during overnight work hours compared with Period 3^4/4 workers (3.52 ± 23.44 min versus 10.39 ± 6.41 min, P = 0.003). We observed no significant difference in sleepiness during early morning hours following acute sleep deprivation. Long‐allele carriers indicated significantly higher sleepiness on the Epworth Sleepiness Scale administered at 17:00 hours (12.08 ± 2.55 versus 8.00 ± 1.94, P < 0.001). We observed a significantly earlier melatonin onset in Period 3^–/5 individuals compared with Period 3^4/4 shift workers (20:44 ± 6:37 versus 02:46 ± 4:58, P = 0.021). Regression analysis suggests that Period 3 genotype independently predicts sleepiness even after controlling for variations in circadian phase, but we were unable to link Period 3 to circadian phase when controlling for sleepiness. Period 3^–/5 shift workers showed both subjective and objective sleepiness in the pathological range, while their Period 3^4/4 counterparts showed sleepiness within normal limits. Period 3^–/5 night workers also show a mean circadian phase 6 h earlier (i.e. less adapted) than Period 3^4/4 workers. Because Period 3^–/5 workers have maladaptive circadian phase as well as pathological levels of sleepiness, they may be at greater risk for occupational and automotive accidents. We interpret these findings as a call for future research on the role of Period 3 in sleepiness and circadian phase, especially as they relate to night work.     

Inflammatory changes associated with circadian variation in pulmonary function in subjects with mild asthma

BACKGROUND: Nocturnal enhancement of airway inflammation has been demonstrated in patients with asthma who have a significant drop in pulmonary function at night. OBJECTIVE: To investigate the circadian changes in airway inflammation and their relationship with variations in pulmonary function in subjects with mild atopic asthma. METHODS: Twelve asthma subjects were admitted to the hospital for two separate 24-h visits. Bronchoalveolar lavage (BAL) was performed at 04:00 hours during one visit, and at 16:00 hours during another visit. BAL cells were analysed for lymphocyte phenotype and the capacity to secrete cytokines following ex vivo stimulation with phytohaemagglutinin (PHA). RESULTS: The numbers of BAL lymphocytes and the percentage of CD4+ T cells were higher at 04:00 hours compared with 16:00 hours. At 04:00 hours, the forced expiratory volume in 1 s (FEV1) was inversely correlated with BAL lymphocytes and CD4+ cells. PHA-induced generation of IL-5 by BAL cells correlated with BAL eosinophils and CD4+ cells. Moreover, there was a linear relationship between the relative change (16:00-04:00 hours) in IL-5 and circadian variation in FEV1. CONCLUSIONS: These data suggest that the circadian variation in lung function in asthma is associated with increased airway CD4+ lymphocyte numbers and their capacity to generate IL-5. Furthermore, in mild asthma, these circadian changes appear to fall into a continuous range, suggesting that day/night variations in airway inflammation and lung function occur on a continuum, rather than as an all-or-none phenomenon.