The Effects of Circadian Rhythmicity and Time‐Awake on a Simple Motor Task

The aim of the study was to assess if a simple motor task, one that required muscle contractions well below maximum, showed evidence of circadian changes and time‐awake. The task consisted of using a larger counter to flick a number of smaller counters to land as near as possible to the center of a target. The closer a counter landed next to the center of the target, the higher the score obtained. Two distances from the target were used (long and short), and 20 counters were flicked at each distance. The task was performed by 72 diurnally active healthy participants at six test sessions distributed every 4 h throughout the day (08:00 h, 12:00 h, … , 04:00 h), so covering a circadian cycle. When performing the sessions, subjects had been awake for about 1, 4, … , 20 h. Before each test session, sublingual temperature was measured, and estimates of the individual's fatigue and alertness were made. Clear normally phased circadian rhythms (p<0.0001) in oral temperature and alertness with mean peak time (i.e., acrophases of 17.2 h and 15.9 h, respectively) and fatigue (i.e., mean acrophase of 3.4 h) were detected. The total scores for both the long and short distances also showed circadian rhythms that peaked slightly before the temperature rhythm (by 2.31±0.91 h and 1.77±0.77 h, mean±SE, respectively), and the number of occasions that the target was missed altogether showed rhythms that were in anti‐phase (mean acrophases=3.8 h and 4.1 h for the long and short distances, respectively) to that of total scores (mean acrophases=16.0 h and 15.2 h for the long and short distances, respectively). With the long and, particularly, short distances, there were generally significant correlations (r<0.0005) between both the measures of accuracy (total score and number of misses) and body temperature and time‐awake. The accuracy of performance at this task seems to show circadian and time‐awake effects, and so makes it of potential value in protocols where repetitive measurements during the course of a day are required.     

Circadian rhythms and their association with body temperature and time awake when performing a simple task with the dominant and non-dominant hand

The two main aims of the study were to compare the dominant and non-dominant hand with regard to circadian rhythms of accuracy of performance at a task that required eye-hand coordination and sub-maximum muscle contraction, as well as to investigate if there were differences between the dominant and non-dominant hands in the associations between circadian rhythms of performance and core temperature and time awake. The task consisted of using a larger counter to flick a set of 20 smaller counters to land as near as possible to the center of a target. The nearer to the center of the target a counter landed, the higher the score awarded. Three measures of accuracy were calculated: the total score, the number of times the counter missed the target altogether, and the mean score for those counters that hit the target. Seventy-eight healthy participants performed the task at each of six test sessions distributed every 4 h throughout the day (at 08:00, 12:00... . 04:00 h), the participants then having been awake for about 1, 4... . 20 h, respectively. Before each test session, sub-lingual temperature (an estimate of core temperature) was measured, and estimates of the individual's alertness and fatigue were obtained. Temperature, alertness, and fatigue all showed circadian rhythms that were phased conventionally. Measures of accuracy of performance also showed significant circadian rhythms that were phased closer to the rhythms of alertness and fatigue than to that of oral temperature. In addition, and in support of our previous work, there were significant associations between performance and temperature (positive) and time awake (negative) for most measures of accuracy. Even though circadian rhythms of performance accuracy and effects of oral temperature and time awake were generally very similar between the dominant and non-dominant hand, there was a suggestion that time awake affected some aspects of performance of the non-dominant hand to a greater extent. There was little evidence to support the view that the 24-h rhythmicity was less marked in the non-dominant hand, which argues against internal desynchronization, at least for the task used in this study.     

Malate Dehydrogenase Activity of Rat Testis: Circadian Rhythm and its Ontogeny

Malate dehydrogenase activity and soluble protein content in testes from rats exposed to a 14:00 h light:10:00 h dark photoperiod, have been determined every two or four hours over a 24 hour period in 5, 15, 25 and 120 day-old rats. By using the Cosinor method, the ontogeny of an unimodal rhythm was studied for MDH activity and soluble protein content in testis. In 5 and 15 day-old rats, the MDH acrophases were recorded around 19:00 h and 17:00 h, respectively. Rats aged 25 and 110 days showed the MDH acrophases during the dark period. An inversion of the MDH circadian rhythms was detected in 25 day-old compared to those of 5 and 15 day-old rats. An inversion of the protein circadian rhythm was also detected at 15 days compared to that at 5 days. These inversions persist in the adult rats. The amplitude of the MDH and protein rhythms reached the lowest value in adulthood. The mean daily value of testicular MDH increased between day 5 and 15, decreasing at day 35 and remaining unchanged until adulthood. The variation of malate dehydrogenase activity, soluble protein content levels, and the circadian rhythm parameters during the maturation process may be related to gonad development.     

Malate Dehydrogenase Activity of Rat Testis: Circadian Rhythm and its Ontogeny

Malate dehydrogenase activity and soluble protein content in testes from rats exposed to a 14:00 h light:10:00 h dark photoperiod, have been determined every two or four hours over a 24 hour period in 5, 15, 25 and 120 day-old rats. By using the Cosinor method, the ontogeny of an unimodal rhythm was studied for MDH activity and soluble protein content in testis. In 5 and 15 day-old rats, the MDH acrophases were recorded around 19:00 h and 17:00 h, respectively. Rats aged 25 and 110 days showed the MDH acrophases during the dark period. An inversion of the MDH circadian rhythms was detected in 25 day-old compared to those of 5 and 15 day-old rats. An inversion of the protein circadian rhythm was also detected at 15 days compared to that at 5 days. These inversions persist in the adult rats. The amplitude of the MDH and protein rhythms reached the lowest value in adulthood. The mean daily value of testicular MDH increased between day 5 and 15, decreasing at day 35 and remaining unchanged until adulthood. The variation of malate dehydrogenase activity, soluble protein content levels, and the circadian rhythm parameters during the maturation process may be related to gonad development.     

RETINAL CIRCADIAN RHYTHMS IN HUMANS *

Circadian rhythms in the retina may reflect intrinsic rhythms in the eye. Previous reports on circadian variability in electrophysiological human retinal measures have been scanty, and the results have been somewhat inconsistent. We studied the circadian variation of the electrooculography (EOG), electroretinography (ERG), and visual threshold (VTH) in subjects undergoing a 36h testing period. We used an ultrashort sleep-wake cycle to balance effects of sleep and light-dark across circadian cycles. Twelve healthy volunteers (10 males, 2 females; mean age 26.3 years, standard deviation [SD] 8.0 years, range 19-40 years) participated in the study. The retinal functions and oral temperature were measured every 90 min. The EOG was measured in the light, whereas the ERG and the VTH were measured in the dark. Sleep was inferred from activity detected by an Actillume monitor. The EOG peak-to-peak responses followed a circadian rhythm, with the peak occurring late in the morning (acrophase 12:22). The ERG b-wave implicit time peaked in the early morning (acrophase 06:46). No statistically significant circadian rhythms could be demonstrated in the ERG a-wave implicit time or peak-to-peak amplitude. The VTH rhythm peaked in the early morning (acrophases 07:59 for blue and 07:32 for red stimuli). All retinal rhythms showed less-consistent acrophases than the temperature and sleep rhythms. This study demonstrated several different circadian rhythms in retinal electrophysiological and psychophysical measures of healthy subjects. As the retinal rhythms had much poorer signal-to-noise ratios than the temperature rhythm, these measures cannot be recommended as circadian markers. (Chronobiology International, 18(6), 957-971, 2001)     

RETINAL CIRCADIAN RHYTHMS IN HUMANS*

Circadian rhythms in the retina may reflect intrinsic rhythms in the eye. Previous reports on circadian variability in electrophysiological human retinal measures have been scanty, and the results have been somewhat inconsistent. We studied the circadian variation of the electrooculography (EOG), electroretinography (ERG), and visual threshold (VTH) in subjects undergoing a 36h testing period. We used an ultrashort sleep-wake cycle to balance effects of sleep and light-dark across circadian cycles. Twelve healthy volunteers (10 males, 2 females; mean age 26.3 years, standard deviation [SD] 8.0 years, range 19–40 years) participated in the study. The retinal functions and oral temperature were measured every 90 min. The EOG was measured in the light, whereas the ERG and the VTH were measured in the dark. Sleep was inferred from activity detected by an Actillume monitor. The EOG peak-to-peak responses followed a circadian rhythm, with the peak occurring late in the morning (acrophase 12:22). The ERG b-wave implicit time peaked in the early morning (acrophase 06:46). No statistically significant circadian rhythms could be demonstrated in the ERG a-wave implicit time or peak-to-peak amplitude. The VTH rhythm peaked in the early morning (acrophases 07:59 for blue and 07:32 for red stimuli). All retinal rhythms showed less-consistent acrophases than the temperature and sleep rhythms. This study demonstrated several different circadian rhythms in retinal electrophysiological and psychophysical measures of healthy subjects. As the retinal rhythms had much poorer signal-to-noise ratios than the temperature rhythm, these measures cannot be recommended as circadian markers. (Chronobiology International, 18(6), 957–971, 2001)     

Sleep and Circadian Rhythms in Spousally Bereaved Seniors

A laboratory study of sleep and circadian rhythms was undertaken in 28 spousally bereaved seniors (≥60 yrs) at least four months after the loss event. Measures taken included two nights of polysomnography (second night used), ～36 h of continuous core body temperature monitoring, and four assessments of mood and alertness throughout a day. Preceding the laboratory study, two‐week diaries were completed, allowing the assessment of lifestyle regularity using the 17‐item Social Rhythm Metric (SRM) and the timing of sleep using the Pittsburgh Sleep Diary (PghSD). Also completed were questionnaires assessing level of grief (Texas Revised Inventory of Grief [TRIG] and Index of Complicated Grief [ICG]), subjective sleep quality (Pittsburgh Sleep Quality Index [PSQI]), morningness‐eveningness (Composite Scale of Morningness [CSM]), and clinical interview yielding a Hamilton Depression Rating Scale (HDRS) score. Grief was still present, as indicated by an average TRIG score of about 60. On average, the bereaved seniors habitually slept between ～23:00 and ～06:40 h, achieving ～6 h of sleep with a sleep efficiency of ～80%. They took about 30 min to fall asleep, and had their first REM episode after 75 min. About 20% of their sleep was in Stage REM, and about 3% in Stages 3 or 4 (slow wave sleep). Their mean PSQI score was 6.4. Their circadian temperature rhythms showed the usual classic shape with a trough at ～01:00 h, a fairly steep rise through the morning hours, and a more gradual rise to mid‐evening, with an amplitude of ～0.8°C. In terms of lifestyle regularity, the mean regularity (SRM) score was 3.65 (slightly lower than that usually seen in seniors). Mood and alertness showed time‐of‐day variation with peak alertness in the late morning and peak mood in the afternoon. Correlations between outcome sleep/circadian variables and level of grief (TRIG score) were calculated; there was a slight trend for higher grief to be associated with less time spent asleep (p=0.07) and reduced alertness at 20:00 h (p=0.05). Depression score was not correlated with TRIG score (p>0.20). When subjects were divided into groups by the nature of their late spouse's death (expected/after a long‐term chronic illness [n=18] versus unexpected [n=10]), no differences emerged in any of the variables. In conclusion, when studied at least four months after the loss event, there appears to be some sleep disruption in spousally bereaved seniors. However, this disruption does not appear to be due to bereavement‐related disruptions in the circadian system.     

Consistent changes in the circadian rhythms of blood pressure and atrial natriuretic peptide in congestive heart failure.

We demonstrated in previous works that the circadian rhythms of blood pressure (BP) and atrial natriuretic peptide (ANP) are antiphasic in normal subjects and in essential hypertension. The aim of the present study was to assess the circadian rhythms of BP and ANP in 20 patients with stable congestive heart failure (CHF), divided into two groups of 10 according to their New York Heart Association functional class. A matched control group of 10 normal volunteers was also studied. Noninvasive BP monitoring at 15-min intervals was performed for 24 h. Peripheral blood samples were also obtained at 4-h intervals starting from 08:00 h. The mean (+/- SEM) circadian mesors of ANP plasma levels were 13.4 +/- 1.7 pmol/L in the control group, 28.6 +/- 2.4 pmol/L in the group of 10 patients in class II, and 81.5 +/- 12 pmol/L in the group of 10 patients in class III-IV. In normal subjects, plasma ANP concentration was highest at 04:00 h (21.5 +/- 2.7 pmol/L) and lowest at 16:00 h (8.8 +/- 2.4 pmol/L; p less than 0.01). Both groups of patients with CHF showed no significant circadian change in the plasma levels of ANP and also a significantly blunted circadian rhythm of BP. Cosinor analysis confirmed the loss of the circadian rhythms of ANP and BP in CHF patients. Our findings support the existence of a causal relationship between the circadian rhythms of ANP and BP.     

Chronobiotic effects of the melatonin agonist LY 156735 following a simulated 9h time shift: results of a placebo-controlled trial

Introduction: The melatonin agonist LY 156735 (LY) is a new investigational drug under development to treat circadian rhythm disorders. The present study assessed the efficacy of LY to alleviate the symptoms of shift lag and to enhance readaptation of desynchronized circadian rhythms to a new time zone.

Subjects and methods: Eight healthy male volunteers of age 25-35 yr participated in three identical trials of 13d duration in a temporal isolation unit separated by washout intervals. A high dose (HD) of 5 mg and a low dose (LD) of 0.5 mg of LY and placebo (PL) were administered double-blinded in a three-period cross-over design. Each trial consisted of an adaptation period, a pre-shift period for baseline measurements, a simulated 9h phase-advance shift, and a post-shift period for follow-up. The time shift was performed at 23:00h of day 6 by advancing the laboratory time to 08:00h of day 7. Double-blind study medication was administered at 14:30h on day 6, and at 22:30h on days 7-10. Subjective ratings of jet lag, alertness, tenseness, and daytime fatigue were assessed using visual analog scales (VAS) and standardized questionnaires. The objective markers of readaptation included core body temperature, wrist actigraphy, cortisol and electrolyte excretion, and a battery of computerized performance tests.

Results: HD but not LD enhanced the readaptation speed of all physiological rhythms investigated, as demonstrated by a significantly faster movement of acrophases towards the post-shift target time. HD (p=0.05) significantly blunted the post-shift deterioration of performance in those tests that were sensitive to shift lag. Parameters of subjective well-being were not significantly affected by either dose.

Conclusion: This pilot study demonstrates the chronobiotic efficacy of LY when taken at a dose of 5 mg/d.     

Sleep and circadian rhythms in spousally bereaved seniors

A laboratory study of sleep and circadian rhythms was undertaken in 28 spousally bereaved seniors (> or =60 yrs) at least four months after the loss event. Measures taken included two nights of polysomnography (second night used), approximately 36 h of continuous core body temperature monitoring, and four assessments of mood and alertness throughout a day. Preceding the laboratory study, two-week diaries were completed, allowing the assessment of lifestyle regularity using the 17-item Social Rhythm Metric (SRM) and the timing of sleep using the Pittsburgh Sleep Diary (PghSD). Also completed were questionnaires assessing level of grief (Texas Revised Inventory of Grief [TRIG] and Index of Complicated Grief [ICG]), subjective sleep quality (Pittsburgh Sleep Quality Index [PSQI]), morningness-eveningness (Composite Scale of Morningness [CSM]), and clinical interview yielding a Hamilton Depression Rating Scale (HDRS) score. Grief was still present, as indicated by an average TRIG score of about 60. On average, the bereaved seniors habitually slept between approximately 23:00 and approximately 06:40 h, achieving approximately 6 h of sleep with a sleep efficiency of approximately 80%. They took about 30 min to fall asleep, and had their first REM episode after 75 min. About 20% of their sleep was in Stage REM, and about 3% in Stages 3 or 4 (slow wave sleep). Their mean PSQI score was 6.4. Their circadian temperature rhythms showed the usual classic shape with a trough at approximately 01:00 h, a fairly steep rise through the morning hours, and a more gradual rise to mid-evening, with an amplitude of approximately 0.8 degrees C. In terms of lifestyle regularity, the mean regularity (SRM) score was 3.65 (slightly lower than that usually seen in seniors). Mood and alertness showed time-of-day variation with peak alertness in the late morning and peak mood in the afternoon. Correlations between outcome sleep/circadian variables and level of grief (TRIG score) were calculated; there was a slight trend for higher grief to be associated with less time spent asleep (p=0.07) and reduced alertness at 20:00 h (p=0.05). Depression score was not correlated with TRIG score (p>0.20). When subjects were divided into groups by the nature of their late spouse's death (expected/after a long-term chronic illness [n=18] versus unexpected [n=10]), no differences emerged in any of the variables. In conclusion, when studied at least four months after the loss event, there appears to be some sleep disruption in spousally bereaved seniors. However, this disruption does not appear to be due to bereavement-related disruptions in the circadian system.     

Phase-dependent effect of room light exposure in a 5-h advance of the sleep-wake cycle: implications for jet lag

The acute disruption in sleep quality, vigilance levels, and cognitive and athletic performance observed after transmeridian flights is presumed to be the result of a transient misalignment between the endogenous circadian pacemaker and the shifted sleep schedule. Several laboratory and field experiments have demonstrated that exposure to bright artificial light can accelerate circadian entrainment to a shifted sleep-wake schedule. In the present study, the authors investigated whether the schedule of exposure to indoor room light, to which urban dwellers are typically exposed, can substantially affect circadian adaptation to a simulated eastward voyage. We enrolled 15 healthy young men in a laboratory simulation of a Montreal-to-London voyage. Subjects were exposed to 6 h of room light (mean +/- SD: 379+/-10) prior to bedtime (n = 7) or when on a progressively advancing schedule (n = 8) early in the day. The remaining 10 hours of wakefulness were spent in dim light (4+/-1 lux). Circadian assessments, performed via the constant routine procedure, evaluated the phase of the endogenous circadian rhythms of core body temperature and plasma melatonin before and after 1 week on the shifted schedule. At the end of the study, only subjects exposed to room light on the advancing schedule expressed oscillations of the endogenous circadian pacemaker in phase with the new sleep-wake cycle. In this group, a mean advance shift of the nadir of core body temperature of +5:22+/-0:15 h was observed, with parallel shifts in plasma melatonin concentration and subjective alertness. The circadian rhythms of subjects exposed to room light later in the day remained much more adjusted to the departure than to the destination time zone. These results demonstrate that the schedule of exposure to room light can substantially affect circadian adaptation to a shifted sleep-wake schedule.     

Differences in sleep, light, and circadian phase in offshore 18:00-06:00 h and 19:00-07:00 h shift workers

Complaints concerning sleep are high among those who work night shifts; this is in part due to the disturbed relationship between circadian phase and the timing of the sleep-wake cycle. Shift schedule, light exposure, and age are all known to affect adaptation to the night shift. This study investigated circadian phase, sleep, and light exposure in subjects working 18:00-06:00 h and 19:00-07:00 h schedules during summer (May-August). Ten men, aged 46+/-10 yrs (mean+/-SD), worked the 19:00-07:00 h shift schedule for two or three weeks offshore (58 degrees N). Seven men, mean age 41+/-12 yrs, worked the 18:00-06:00 h shift schedule for two weeks offshore (61 degrees N). Circadian phase was assessed by calculating the peak (acrophase) of the 6-sulphatoxymelatonin rhythm measured by radioimmunoassay of sequential urine samples collected for 72 h at the end of the night shift. Objective sleep and light exposure were assessed by actigraphy and subjective sleep diaries. Subjects working 18:00-06:00 h had a 6-sulphatoxymelatonin acrophase of 11.7+/-0.77 h (mean+/-SEM, decimal hours), whereas it was significantly later, 14.6+/-0.55 h (p=0.01), for adapted subjects working 19:00-07:00 h. Two subjects did not adapt to the 19:00-07:00 h night shift (6-sulphatoxymelatonin acrophases being 4.3+/-0.22 and 5.3+/-0.29 h). Actigraphy analysis of sleep duration showed significant differences (p=0.03), with a mean sleep duration for those working 19:00-07:00 h of 5.71+/-0.31 h compared to those working 18:00-06:00 h whose mean sleep duration was 6.64+/-0.33 h. There was a trend to higher morning light exposure (p=0.07) in the 19:00-07:00 h group. Circadian phase was later (delayed on average by 3 h) and objective sleep was shorter with the 19:00-07:00 h than the 18:00-06:00 h shift schedule. In these offshore conditions in summer, the earlier shift start and end time appears to favor daytime sleep.     

Circadian rhythms in healthy aging--effects downstream from the pacemaker

Using both previously published findings and entirely new data, we present evidence in support of the argument that the circadian dysfunction of advancing age in the healthy human is primarily one of failing to transduce the circadian signal from the circadian timing system (CTS) to rhythms “downstream” from the pacemaker rather than one of failing to generate the circadian signal itself. Two downstream rhythms are considered: subjective alertness and objective performance. For subjective alertness, we show that in both normal nychthemeral (24h routine, sleeping at night) and unmasking (36h of constant wakeful bed rest) conditions, advancing age, especially in men, leads to flattening of subjective alertness rhythms, even when circadian temperature rhythms are relatively robust. For objective performance, an unmasking experiment involving manual dexterity, visual search, and visual vigilance tasks was used to demonstrate that the relationship between temperature and performance is strong in the young, but not in older subjects (and especially not in older men). (Chronobiology International, 17(3), 355-368, 2000)     

CIRCADIAN RHYTHMS IN HEALTHY AGING—EFFECTS DOWNSTREAM FROM THE PACEMAKER

Using both previously published findings and entirely new data, we present evidence in support of the argument that the circadian dysfunction of advancing age in the healthy human is primarily one of failing to transduce the circadian signal from the circadian timing system (CTS) to rhythms “downstream” from the pacemaker rather than one of failing to generate the circadian signal itself. Two downstream rhythms are considered: subjective alertness and objective performance. For subjective alertness, we show that in both normal nychthemeral (24h routine, sleeping at night) and unmasking (36h of constant wakeful bed rest) conditions, advancing age, especially in men, leads to flattening of subjective alertness rhythms, even when circadian temperature rhythms are relatively robust. For objective performance, an unmasking experiment involving manual dexterity, visual search, and visual vigilance tasks was used to demonstrate that the relationship between temperature and performance is strong in the young, but not in older subjects (and especially not in older men). (Chronobiology International, 17(3), 355–368, 2000)     

Differences of behavioral rhythms observed by flat cage and running-wheel cage in female rat

The ambulatory, wheel-running, and drinking activities were measured in Wistar-Imamichi strain female rats under 12 L:12 D condition (6:00-18:00), using Gundai type ambulo-drinkometer (for simultaneous measurements of ambulation and drinking) and wheel-drinkometer (for simultaneous measurements of wheel-running and drinking) to compare the rhythmicities of each behavioral activity. These apparatuses are able to measure the behavioral activities over a long period, successively and automatically. The circadian patterns of ambulatory activity had two large peaks at 21 or 24:00 and at 6:00 (acrophase). Contrary to the above results, the wheel-running activity exhibited clear mono-peak at 21:00 (acrophase). Thus, apparent differences of the pattern were observed between the two activities. However, ambulatory and wheel-running activities fluctuated showing 4-days rhythmicity, and both activities increased in estrus and proestrus stages, respectively. The circadian rhythms of drinking activities measured by both apparatuses showed almost same patterns with acrophases at 6:00, and 4-days rhythmicities were also observed and were characterized by remarkable decrease of activity in every proestrus stages. From these results, it is concluded that circadian pattern of ambulatory activity is different from that of wheel-running activity, but circadian patterns of drinking activities are stable regardless of different methods of the measurement. The ambulatory, wheel-running and drinking activities reflect the behavioral changes in sexual cycles.     

Assessment of constancy and plasticity of biological rhythms of physiological processes under comfortable and subextreme (high altitude and desert) conditions

A relative constancy of the acrophases of human circadian rhythms of autonomic functions was studied. Quantitative assessment was performed for interdaily, interindividual, intragroup, intraindividual, and total changes in the acrophases of the circadian rhythms of 22 parameters of hemodynamics, heart rate control, thermal status, and salivary electrolyte levels under comfortable environmental conditions and during early adaptation to high-altitude hypoxic and hot desert conditions. A biological interpretation was given for different criteria of changes in the acrophases. Phase-constant and phase-shifting circadian rhythms were determined.     

Alteration of the circadian rhythm in peak expiratory flow of nocturnal asthma following nighttime transdermal beta2-adrenoceptor agonist tulobuterol chronotherapy

We investigated the efficacy of nighttime transdermal tulobuterol (beta2-adrenoceptor agonist) chronotherapy for nocturnal asthma by assessing changes both in the frequency of symptoms and features of the circadian rhythm in peak expiratory flow (PEF), a measure of airway caliber. Thirteen patients with nocturnal asthma were evaluated before and during tulobuterol patch chronotherapy, applied once daily in the evening for 6 consecutive days. Patients were asked to record their PEF every 4h between 03:00 and 23:00 h for one day. Circadian rhythms in PEF were examined by group-mean cosinor analysis. The group average PEF at 03:00 h, the time during the 24 h when PEF is generally the poorest, before the application of the chronotherapy, when asthma was unstable and nocturnal symptoms frequent, was 276 +/- 45 L/min. Application of the tulobuterol patch at nighttime significantly increased (p < 0.001) the 03:00 h group average PEF to 363 +/- 67 L/min. Significant circadian rhythms in PEF were observed during the span of study when nocturnal symptoms were frequent as well as with the use of the tulobuterol patch. Before the initiation of tulobuterol chronotherapy, the bathyphase (trough time of the circadian rhythm) in PEF narrowed to around 04:00h, and the group circadian amplitude was 28.8 L/min. In contrast, the group circadian amplitude significantly (p < 0.01) decreased to 10.4 L/min, and the 24 h mean PEF increased significantly with tulobuterol patch chronotherapy. These changes indicate that tulobuterol chronotherapy significantly increased both the level and stability of airway function over the 24 h. The circadian rhythm in PEF varied with the severity and frequency of asthmatic symptoms with and without the nighttime application of the tulobuterol patch medication. We conclude that the parameters of the circadian rhythm of PEF proved useful both in determining the need for and effectiveness of tulobuterol chronotherapy for nocturnal asthma.     

The circadian body temperature rhythm in the elderly: effect of single daily melatonin dosing

The present study is part of a more extensive investigation dedicated to the study and treatment of age-dependent changes/disturbances in the circadian system in humans. It was performed in the Tyumen Elderly Veteran House and included 97 subjects of both genders, ranging from 63 to 91 yrs of age. They lived a self-chosen sleep-wake regimen to suit their personal convenience. The experiment lasted 3 wks. After 1 control week, part of the group (n=63) received 1.5 mg melatonin (Melaxen) daily at 22:30 h for 2 wks. The other 34 subjects were given placebo. Axillary temperature was measured using calibrated mercury thermometers at 03:00, 08:00, 11:00, 14:00, 17:00, and 23:00 h each of the first and third week. Specially trained personnel took the measurements, avoiding disturbing the sleep of the subjects. To evaluate age-dependent changes, data obtained under similar conditions on 58 young adults (both genders, 17 to 39 yrs of age) were used. Rhythm characteristics were estimated by means of cosinor analyses, and intra- and inter-individual variability by analysis of variance (ANOVA). In both age groups, the body temperature underwent daily changes. The MESOR (36.38+/-0.19 degrees C vs. 36.17+/-0.21 degrees C) and circadian amplitude (0.33+/-0.01 degrees C vs. 0.26+/-0.01 degrees C) were slightly decreased in the elderly compared to the young adult subjects (p<0.001). The mean circadian acrophase was similar in both age groups (17.19+/-1.66 vs. 16.93+/-3.08 h). However, the inter-individual differences were higher in the older group, with individual values varying between 10:00 and 23:00 h. It was mainly this phase variability that caused a decrease in the inter-daily rhythm stability and lower group amplitude. With melatonin treatment, the MESOR was lower by 0.1 degrees C and the amplitude increased to 0.34+/-0.01 degrees C, a similar value to that found in young adults. This was probably due to the increase of the inter-daily rhythm stability. The mean acrophase did not change (16.93 vs. 16.75 h), although the inter-individual variability decreased considerably. The corresponding standard deviations (SD) of the group acrophases were 3.08 and 1.51 h (p<0.01). A highly significant correlation between the acrophase before treatment and the phase change under melatonin treatment indicates that this is due to a synchronizing effect of melatonin. Apart from the difference in MESOR, the body temperature rhythm in the elderly subjects undergoing melatonin treatment was not significantly different from that of young adults. The data clearly show that age-dependent changes mainly concern rhythm stability and synchronization with the 24 h day. A single daily melatonin dose stabilizes/synchronizes the body temperature rhythm, most probably via hypothermic and sleep-improving effects.     

Circadian rhythm of atrioventricular conduction predicts long-term survival in patients with chronic atrial fibrillation

The R-R interval of the electrocardiogram during atrial fibrillation (AF) appears absolutely irregular. However, the Poincaré plot of the R-R interval reveals a sector shape of distribution that is unique to AF. Furthermore, the height of lower envelope (LE1.0) of the distribution and the degree of scatter above the envelope (scattering index) may reflect the refractoriness and concealment of atrioventricular (AV) conduction, respectively. We previously observed that both the LE1.0 and scattering index show clear circadian rhythms in patients with chronic AF and that the rhythms are blunted in those with congestive heart failure and chronic AF. In the present study, we examined if the blunted circadian rhythm of the AV conduction has prognostic value in patients with chronic AF. We studied a retrospective cohort of 120 patients who underwent 24h Holter monitoring at baseline. During an observation period of 33 +/- 16 mon, there were 25 deaths (21%) including 13 cardiac and 8 stroke deaths. All patients showed significant circadian rhythms in both LE1.0 and scattering index with acrophases occurring at night; however, patients dying subsequently from cardiac causes, but not those from fatal stroke were blunted in the circadian rhythms (the amplitudes were < 55% of those in surviving patients). Furthermore, the reduced circadian amplitude of scattering index was an increased risk for cardiac death even after adjustment of coexisting cardiovascular risks [adjusted relative risk (95% confidence interval) per 1-SD decrement, 4.24 (1.54-11.6)]. When patients were divided by the circadian amplitude of the scattering index of 36.5 msec (mean minus 1-SD), the 5yr cardiac mortality below and above the cutoff was 57 and 6%, respectively (log-rank test, p < 0.001). We conclude that the blunted circadian rhythm of AV conduction is an independent risk for cardiac death in patients with chronic AF.     

Circadian rhythmicity of cortisol and body temperature: morningness-eveningness effects

The purpose of this study was to describe and compare the circadian rhythm of body temperature and cortisol, as well as self-reported clock times of sleep onset and offset on weekdays and weekends in 19 healthy adult "larks" (morning chronotypes) and "owls" (evening chronotypes), defined by the Home and Ostberg questionnaire. Day-active subjects entered the General Clinical Research Center, where blood was sampled every 2 h over 38 h for later analysis for cortisol concentration by enzyme immunoassay. Rectal body temperature was measured continuously. Lights were turned off at 22:30 for sleep and turned on at 06:00, when subjects were awakened. The acrophases (peak times) of the cortisol and temperature rhythms occurred 55 minutes (P < or = .05) and 68 minutes (P < .01), respectively, earlier in the morningness group. The amplitude of the cortisol rhythm was lower in the eveningness than in the morningness group (P = n.s.). Subject groups differed on all indices of habitual and preferred timing of sleep and work weekdays and weekends (P = .05-.001).