Case-control study of candidate gene methylation and adenomatous polyp formation.

PURPOSE: Colorectal cancer (CRC) is one of the most common and preventable forms of cancer but remains the second leading cause of cancer-related death. Colorectal adenomas are precursor lesions that develop in 70-90 % of CRC cases. Identification of peripheral biomarkers for adenomas would help to enhance screening efforts. This exploratory study examined the methylation status of 20 candidate markers in peripheral blood leukocytes and their association with adenoma formation. METHODS: Patients recruited from a local endoscopy clinic provided informed consent and completed an interview to ascertain demographic, lifestyle, and adenoma risk factors. Cases were individuals with a histopathologically confirmed adenoma, and controls included patients with a normal colonoscopy or those with histopathological findings not requiring heightened surveillance (normal biopsy, hyperplastic polyp). Methylation-specific polymerase chain reaction was used to characterize candidate gene promoter methylation. Odds ratios (ORs) and 95 % confidence intervals (95% CIs) were calculated using unconditional multivariable logistic regression to test the hypothesis that candidate gene methylation differed between cases and controls, after adjustment for confounders. RESULTS: Complete data were available for 107 participants; 36 % had adenomas (men 40 %, women 31 %). Hypomethylation of the MINT1 locus (OR 5.3, 95% CI 1.0-28.2) and the PER1 (OR 2.9, 95% CI 1.1-7.7) and PER3 (OR 11.6, 95% CI 1.6-78.5) clock gene promoters was more common among adenoma cases. While specificity was moderate to high for the three markers (71-97 %), sensitivity was relatively low (18-45 %). CONCLUSION: Follow-up of these epigenetic markers is suggested to further evaluate their utility for adenoma screening or surveillance.

Circadian phase in adults of contrasting ages.

There is evidence that aging may impair phase-shifting responses to light synchronizers, which could lead to disturbed or malsynchronized circadian rhythms. To explore this hypothesis, 62 elder participants (age, 58 to 84 years) and 25 young adults (age, 19 to 40 years) were studied, first with baseline 1-wk wrist actigraphy at home and then by 72 h in-laboratory study using an ultra-short sleep-wake cycle. Subjects were awake for 60 minutes in 50 lux followed by 30 minutes of darkness for sleep. Saliva samples were collected for melatonin, and urine samples were collected for aMT6s (a urinary metabolite of melatonin) and free cortisol every 90 minutes. Oral temperatures were also measured every 90 minutes. The timing of the circadian rhythms was not significantly more variable among the elders. The times of lights-out and wake-up at home and urinary free cortisol occurred earlier among elders, but the acrophases (cosinor analysis-derived peak time) of the circadian rhythm of salivary melatonin, urinary aMT6s, and oral temperature were not significantly phase-advanced among elders. The estimated duration of melatonin secretion was 9.9 h among elders and 8.4 h among young adults (p < 0.025), though the estimated half-life of blood melatonin was shorter among elders (p < 0.025), and young adults had higher saliva melatonin and urinary aMT6s levels. In summary, there was no evidence for circadian desynchronization associated with aging, but there was evidence of some rearrangement of the internal phase-angles among the studied circadian rhythms.

Circadian abnormalities in older adults.

This study examined the circadian phase adjustment of symptomatic elders ages 60-79 years in comparison with that of young, healthy adults ages 20-40 years. Seventy-two elders with complaints of insomnia or depression, and 30 young, healthy adults were assessed for 5-7 days at home. Sleep and illumination were recorded with Actillume wrist monitors and sleep diaries. Urine was collected over two 24-hr periods and assayed for 6-sulphatoxymelatonin (6-smt). The volunteers were then observed continuously for 5 nights and 4 days in the laboratory. In the laboratory, sleep periods were fixed at 8 hr with polysomnographic assessment of sleep, apnea-hypopnea, and nocturnal myoclonus. Circadian dispersion, defined as the mean variation of 6-smt acrophase from the median age-specific acrophase, was significantly greater in the older vs. young adults. Likewise, circadian malsynchronization, defined as the absolute number of hours (advance or delay) between the 6-smt acrophase and the middle of the sleep period, was significantly greater in the older vs. young volunteers. For the older volunteers, multiple regressions were calculated associating sleep with potential correlates of sleep disturbance. Nocturnal myoclonus and circadian malsynchronization were more strongly associated with sleep impairment than other factors (e.g., sleep apnea, depression). These observations suggest that circadian malsynchronization might be a common and significant cause of disturbed sleep among adults over age 60.

Sleep estimation from wrist movement quantified by different actigraphic modalities.

Progress in transducer design and empirical characterization of wrist movement has led to diverse wrist activity monitors, each with its unique features and modality of operation. This study compared sleep--wake estimates from nocturnal wrist activity quantified by different motion-quantifying algorithms. Healthy young adults wore an Actillume and a Mini Motionlogger on the same wrist while nocturnal polysomnography data were recorded simultaneously in the laboratory. Activity data were analyzed with ACTION3 using scoring algorithms independently calibrated for each measurement modality. Overall, each modality yielded accurate and reliable sleep estimates relative to polysomnographic estimates (agreement rates: 91.4--96.5%, correlations for sleep duration: 0.79--0.94). Estimates derived from Actillume modalities were comparable to those of Mini Motionloggers, suggesting that the transducers of these two devices performed comparably for monitoring sleep and wakefulness. Wrist movement quantified by the Mini Motionlogger proportional-integrating mode yielded the best accuracy for detection of sleep--wake states.

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.

The diagnosis of primary insomnia and treatment alternatives.

This review provides information about the diagnosis and treatment of primary insomnia. Several treatment strategies are reviewed including the use of hypnotics, naturopathic remedies and behavioral interventions. We suggest that nonpharmacologic interventions are likely to be the most safe and effective.

The influence of acute exercise on sleep following high caffeine intake.

The purpose of this study was to examine the influence of vigorous acute exercise on nocturnal sleep that had been disrupted by high doses (1200 mg) of caffeine throughout the daytime. Eight moderately fit, young males with a history of moderate caffeine use completed four conditions in a within-subjects, counterbalanced design: 60 min of (i) cycling at 60% VO(2peak) or (ii) quiet rest following placebo consumption, (iii) cycling, or (iv) quiet rest following the consumption of a high dose of caffeine. Each condition was performed twice from 1615-1715 h and followed by all-night polysomnographic recording. Subjects consumed two blinded 200-mg capsules of either lactose placebo or caffeine upon awakening, at 1600 h, and 2 h before bedtime. State anxiety was assessed at bedtime. Criterion scores consisted of the mean data across the two days in each condition. Sleep data were analyzed using a condition (exercise versus quiet rest) by drug (caffeine versus placebo) repeated-measures ANOVA. Caffeine-elicited sleep disturbance that was less than previously reported. Exercise attenuated selected sleep disturbances to a small degree. In general, the effects of exercise on sleep were not greater following caffeine compared to placebo. Indeed, increases in slow-wave sleep after exercise were approximately 1/3 smaller following caffeine treatment compared to placebo.

The influence of air travel on athletic performance.

Rapid transmeridian flight is a common reality for modern athletes and it has often been assumed that air travel has detrimental effects on athletic performance. The plausibility of this assumption is supported by established deteriorations in sleep and mood following transmeridian flight. However, the scientific evidence supporting the assumption is neither consistent nor compelling. Studies that have assessed athletic performance following transmeridian flight have produced mixed results and are characterised by major methodological flaws. Recent retrospective assessments of athletic team performance based on distance travelled have generally failed to indicate performance impairments following transmeridian flight. The plausibility of transmeridian air travel impairing athletic performance would be indicated by demonstration of an internally-driven circadian rhythm of athletic performance, or of deleterious performance consequences following sleep deprivation or desynchronisation between the circadian system and the environment. More rigorous research is needed to establish whether athletic performance is influenced by air travel.

Is sleep disturbed by vigorous late-night exercise?

PURPOSE: This experiment examined the influence of prolonged, vigorous late-night exercise on sleep. METHODS: Sixteen highly fit male cyclists completed each of two 60-h laboratory treatments involving a baseline night, an experimental treatment night, and a recovery night. In counterbalanced order, subjects 1) cycled for 3 h at 65-75% of heart rate reserve combined with bright light exposure (3000 lux) light, and 2) were exposed to a 3 h pulse of bright light (3000 lux) alone. RESULTS: On the baseline and recovery nights, subjects maintained their usual sleep-wake schedules. On the treatment night, exercise + bright light or bright light alone were centered at 6 h before their usual wake times, followed by bedtimes 30 min after the treatments. Illumination was 3000 lux during the experimental treatments, 0 lux during the sleep periods, and 50 lux at other times. Sleep was assessed with an Actillume (Ambulatory Monitoring, Inc., Ardsley, NY) wrist monitor to define sleep onset latency (SOL), wakefulness after sleep onset (WASO), and total sleep time. Subjective assessments of SOL, WASO, and insomnia were also gathered each morning. No significant differences in objective or subjective sleep variables were found between treatments. CONCLUSIONS: These data are inconsistent with the general opinion that vigorous exercise shortly before bedtime disturbs sleep.

Periodic leg movements during sleep and sleep disturbances in elders.

BACKGROUND: Periodic limb movements in sleep (PLMS) are an increasingly pervasive disturbance for aging adults. The aims of this experiment were: (a) to describe the index of periodic limb movements in sleep (myoclonus index [MI] in elderly subjects with complaints of poor sleep or depression (N = 22; 68 +/- 5.5 SD years); and (b) to correlate MI with sleep history, depression scores, and objective and subjective indices of sleep. METHOD: Sleep and leg movements were assessed for 5 consecutive nights. Between-subjects, nonparametric correlations were examined between mean MI and sleep history, depression scores, and objective and subjective sleep characteristics. Associations among within-subject night-to-night variabilities of MI, objective, and subjective variables were examined with repeated measures ANCOVA, entering MI as a covariate. RESULTS: A remarkably high level of MI was found (median 25.8 events per hour; 86% of subjects > 5). Nevertheless, no associations were found between MI and sleep disturbance measures. CONCLUSION: These results extend previous reports that PLMS are remarkably persuasive in elderly volunteers and support other reports questioning whether there is a distinct PLMS syndrome.

Exercise-induced increase in core temperature does not disrupt a behavioral measure of sleep.

On separate nights 90 to 30 min before typical bedtime, eight physically active men completed three conditions: seated rest, low-intensity and moderate-intensity cycle exercise. Low-and moderate-intensity exercise had no significant effect on sleep onset latency, the number of awakenings, total sleep time or sleep efficiency as measured by the Sleep Assessment Device. Mean core body temperature was higher during sleep after moderate intensity (36.80+/-0.02 degrees C) exercise compared to both the low-intensity exercise (36.67+/-0.02 degrees C) and rest (36.51+/-0.02 degrees C) conditions. It is concluded that a 1-h bout of moderate-intensity exercise performed shortly before bed elevates core body temperature before and during sleep; however, this elevated temperature does not disrupt behavioral measures of sleep obtained in the home environment in physically active male college students who were somewhat sleep deprived.

Activity wheel running blunts increased plasma adrenocorticotrophin (ACTH) after footshock and cage-switch stress.

We examined whether chronic circadian physical activity attenuates hypothalamic-pituitary-adrenal hormone responses after footshock with or without cage-switch stress. Young (45 g) male Fischer 344 rats were randomly assigned to individual suspended home cages (HC) or cages with activity wheels (AW) (12 h:12 h light-dark photoperiod). After 6 weeks, each animal from a pair matched on mass (HC and AW) and average weekly running distance (AW) was randomly assigned to controllable or uncontrollable footshock on 2 days separated by 24 h. Half the animals were returned to the HC after the first day of shock, and half were switched to a new shoebox cage. One animal of each pair could end the shock for both rats by performing an FR-2 lever press. The yoked animal could not control the shock. After shock on Day 2, trunk blood was collected after decapitation. Plasma adrenocorticotrophin (ACTH), corticosterone, and prolactin were determined by radioimmunoassay. ANOVA for a 2 Group (AW vs. sedentary) x 2 Test (controllable vs. uncontrollable shock) x 2 Condition (HC vs. cage-switch) design indicated a Group x Test x Condition effect [F(1, 48) = 5.07, p = 0.03] and a Test main effect [F(1, 47) = 6.93, p = 0.01] for ACTH. ACTH was higher for sedentary animals after uncontrollable footshock under cage-switch conditions and higher after uncontrollable versus controllable footshock when averaged across groups and cage conditions. No effects were found for corticosterone or prolactin. Our results extend to activity wheel running prior findings of a cross-stressor attenuation in plasma [ACTH] in response to cage-switch after treadmill exercise training, though the cross-stressor effect was additive with footshock. Consistent with our prior reports, the cross-stressor effect of wheel running was not apparent after footshock administered under home-cage conditions.

Acute exercise reduces caffeine-induced anxiogenesis.

PURPOSE: This experiment examined the influence of acute exercise on anxiety following caffeine-induced elevations in self-rated anxiety. METHODS: Eleven physically active, moderately fit males aged 25.1 +/- 3.8 yr completed four conditions in a within-subject, counterbalanced design involving 60 min of (1) cycling at 60% VO2peak or (2) quiet rest following placebo consumption (800 mg of lactose), as well as (3) cycling at 60% VO2peak and (4) quiet rest following 800 mg of caffeine. State anxiety and blood pressure were assessed 10 min before and 10 and 20 min after the conditions. RESULTS: A main effect for drug (caffeine vs placebo) determined by repeated measures ANOVA, (F(1,8) = 9.77; P = 0.01), indicated that state anxiety was elevated by caffeine. Drug effects were not obtained for blood pressure. Experimental hypotheses were tested by drug-by-condition (exercise vs quiet rest)-by-time (10 and 20 min postcondition) repeated measures ANOVA of change scores from the precondition baseline. A main effect for drug (F(1,8) = 5.81; P = 0.043) indicated that reductions in state anxiety were larger after caffeine ingestion. A condition-by-time effect (F(1,8) = 5.02; P = 0.055) indicated greater reductions in state anxiety 20 min after exercise compared with quiet rest. A condition effect for systolic blood pressure (F(1,10) = 4.56; P = 0.058) and condition-by-time interactions for diastolic (F(1,10) = 8.87; P = 0.014) and mean arterial blood pressures (F(1,10) = 8.46; P = 0.016) indicated reductions after exercise but not after quiet rest following both caffeine and placebo. CONCLUSIONS: We conclude that exercise can reduce anxiety elevated by a high dose of caffeine.

Melatonin: marvel or marker?

Melatonin blanches the skin of frogs, whitens the fur of hamsters, and sometimes makes the gonads atrophy. It is remarkable that such a hormone would be put forward as a defense against ageing. We have been examining excretion of the urinary metabolite of melatonin, 6-sulphatoxymelatonin (6-SMT), in 150 postmenopausal women, in 72 volunteers over the age of 60 years who complained of insomnia or depression, and in 20 healthy younger adult controls, aged 18-40 years. The acrophase or fitted peak of 6-SMT excretion was computed as a marker of the timing of the circadian system. Total daily excretion of 6-SMT was not significantly related to total sleep time, wake-within-sleep or sleep complaints. Nevertheless, whereas the 20 controls displayed a normal range of 6-SMT acrophases from 01.32 to 05.44 h, 42% of the postmenopausal women and 48% of the symptomatic elders had acrophases outside this normal range. Those volunteers with more deviant acrophases displayed more disturbed sleep and more sleep complaints. These data suggest that melatonin is a useful marker of circadian rhythm phase disorders, but suggest a need for more caution in melatonin administration.

Melatonin excretion is not related to sleep in the elderly.

We examined the association between 6-sulphatoxymelatonin (6-SMT) excretion and sleep in 68 volunteers 60-79 years of age who complained of insomnia or depression. An Actillume wrist monitor was worn for 5-7 consecutive days and nights in home-living conditions. Activity was used to estimate total sleep time (TST) and wake after sleep onset (WASO). Throughout two 24 hr periods, urine was collected approximately every 2 hr during the day and after any voidings during the sleep period. During the next week, subjects spent 5 nights and 4 days in the laboratory. Sleep was measured and scored with standard polysomnographic techniques. Urine was collected, as for home recording, on days 1 and 4. Urinary concentrations of 6-SMT were assayed. Cosine-fitting of urine data across both days at home and both laboratory collections established the mesors and amplitudes of 24 hr 6-SMT excretion rhythms, but neither was significantly correlated with sleep. Mean and peak 6-SMT excretion during the sleep period was also determined. Significant correlations were found between mean 6-SMT during the laboratory sleep period and TST and WASO. However, these associations were not independent of circadian timing: sleep was better when sleep occurred near the circadian acrophase of 6-SMT excretion. These data indicate that low melatonin production may not be an important factor in insomnia among the elderly.

The effects of acute exercise on sleep: a quantitative synthesis.

We used meta-analytic methods to examine the influence of acute exercise on sleep. Thirty-eight studies were reviewed yielding 211 effects on 401 subjects. Mean effect sizes were calculated for sleep onset latency (SOL), stage 2, slow-wave sleep (SWS), rapid eye movement (REM) sleep, REM latency (REM-L), total sleep time (TST), and wakefulness after sleep onset (WASO). Moderating influences of subject fitness, heat load, exercise duration, time of day, associated light environment (i.e. indoor or outdoor), sleep schedule, and the scientific quality of the studies were examined. Effect sizes for SWS, REM, REM-L, and TST were moderate [0.18-0.52 standard deviation (SD)] and their associated 95% confidence intervals did not include zero. Exercise duration and time of day were the most consistent moderator variables. In contrast with previous hypotheses, heat load had little influence on sleep. The results of our quantitative synthesis of the literature are inconsistent with previous narrative reviews (1,2) which suggested that exercise elicits larger changes in sleep than those quantified in this meta-analysis. A major delimitation of published studies on the effects of acute exercise has been an exclusive focus on good sleepers. Hence, the effects we report herein may be underestimates of the efficacy of exercise for enhancing sleep among people with sleep disturbances.

Activity wheel running reduces escape latency and alters brain monoamine levels after footshock.

We examined the effects of chronic activity wheel running on brain monoamines and latency to escape foot shock after prior exposure to uncontrollable, inescapable foot shock. Individually housed young (approximately 50 day) female Sprague-Dawley rats were randomly assigned to standard cages (sedentary) or cages with activity wheels. After 9-12 weeks, animals were matched in pairs on body mass. Activity wheel animals were also matched on running distance. An animal from each matched pair was randomly assigned to controllable or uncontrollable inescapable foot shock followed the next day by a foot shock escape test in a shuttle box. Brain concentrations of norepinephrine (NE), dopamine (DA), dihydroxyphenylacetic acid (DOPAC), 5-hydroxytryptamine (5-HT), and 5-hydroxyindole acetic acid (5-HIAA) were assayed in the locus coeruleus (LC), dorsal raphe (DR), central amygdala (AC), hippocampus (CA1), arcuate nucleus, paraventricular nucleus (PVN), and midbrain central gray. After prior exposure to uncontrollable foot shock, escape latency was reduced by 34% for wheel runners compared with sedentary controls. The shortened escape latency for wheel runners was associated with 61% higher NE concentrations in LC and 44% higher NE concentrations in DR compared with sedentary controls. Sedentary controls, compared with wheel runners, had 31% higher 5-HIAA concentrations in CA1 and 30% higher 5-HIAA concentrations in AC after uncontrollable foot shock and had 28% higher 5-HT and 33% higher 5-HIAA concentrations in AC averaged across both foot shock conditions. There were no group differences in monoamines in the central gray or in plasma prolactin or ACTH concentrations, despite 52% higher DA concentrations in the arcuate nucleus after uncontrollable foot shock and 50% higher DOPAC/DA and 17% higher 5-HIAA/5-HT concentrations in the PVN averaged across both foot shock conditions for sedentary compared with activity wheel animals. The present results extend understanding of the escape-deficit by indicating an attenuating role for circadian physical activity. The altered monoamine levels suggest brain regions for more direct probes of neural activity after wheel running and foot shock.

Does exercise truly enhance sleep?

Two recent studies support the commonsense view that exercise improves sleep in individuals with insomnia, but questions still abound. Do patients have to be fit to reap the benefits of exercise? Does exposure to bright light during exercise enhance sleep? Is shorter, more intense exercise more helpful than longer, more moderate activities? Does exercising too close to bedtime inhibit sleep? In considering recent research on sleep and exercise, this article addresses such questions and also looks at the relationship of exercise and sleep to anxiety, depression, circadian rhythms, and age-associated problems, such as sleep apnea.

Increased open field locomotion and decreased striatal GABAA binding after activity wheel running.

Open-field behavior has been used to model reductions in anxiety-related behaviors in the rat after chronic physical activity. Plausible mechanisms for the increased open field locomotion observed after physical activity have not been studied. Open field locomotion is decreased by gamma-aminobutyric acid (GABA) and its agonists, and increased by GABA antagonists, in the ventral striatum. Hence, we tested the hypothesis that increased open field locomotion following chronic physical activity would be accompanied by a decrease in the number of GABAA receptors in the corpus striatum. Young (approximately 55 days) male Sprague-Dawley rats (N = 24) were randomly assigned to three conditions: 24-h access to an activity wheel (AW), running for 1 h without shock 6 days/week on a motorized treadmill (TM), or sedentary control (C). Open field locomotion (total and center squares traversed), defecation, and urination were assessed on each of 3 consecutive days prior to and again after 8 weeks of physical activity. Open field locomotion (total and center squares) increased after activity wheel running, decreased after treadmill training, and did not change for control animals. GABAA receptor density indicated by [3H] bicuculline binding (fmol/mg) was lower for activity wheel animals compared with treadmill animals and controls. GABA concentration (mumol/g) was not different between activity wheel and treadmill groups but was higher for both groups contrasted with controls. Our findings of decreased GABAA density in the corpus striatum concomitant with an increase in open field locomotion are consistent with an anxiolytic effect of chronic activity wheel running.