Independent associations of exposure to evening light and nocturnal urinary melatonin excretion with diabetes in the elderly

Circadian misalignment between internal and environmental rhythms dysregulates glucose homeostasis because of disruption of the biological clock, and increases risk of diabetes. Although exposure to evening light and decreased melatonin secretion are both associated with the circadian misalignment, it remains unclear whether they are associated with diabetes. In this cross-sectional study on 513 elderly individuals (mean age, 72.7 years), we measured ambulatory light intensity during the 4?h prior to bedtime at 1-min intervals during two consecutive days and overnight urinary 6-sulfatoxymelatonin excretion (UME) along with glucose metabolism. The median average intensity of evening light exposure and UME were 25.4?lux (interquartile range 17.5–37.6) and 6.6?μg (interquartile range 3.9–9.7), respectively. Both log-transformed average intensity of evening light exposure and log-transformed UME were significantly associated with diabetes in a multivariate logistic regression model adjusted for covariates, including gender, body mass index, duration in bed, and night-time light exposure [adjusted odds ratio (OR), 1.72; 95% confidence interval (CI), 1.12–2.64; p?=?0.01; and adjusted OR, 0.66; 95% CI, 0.44–0.97; p?=?0.04; respectively]. An increase in evening light exposure from 17.5 to 37.6?lux (25–75th percentiles) was associated with a 51.2% (95% CI, 8.2–111.4%) increase in prevalent diabetes, and an increase in UME from 3.9 to 9.7?μg (25–75th percentiles) was associated with a 32.0% (95% CI, 1.9–52.8%) decrease in prevalent diabetes. In conclusion, this study in elderly individuals demonstrated that evening light exposure in home settings and UME were significantly and independently associated with diabetes.     

Association between light exposure at night and nighttime blood pressure in the elderly independent of nocturnal urinary melatonin excretion

Circadian misalignment between internal and environmental rhythms dysregulates blood pressure (BP) variability because of disruption of the biological clock, resulting in increased nighttime BP. Although exposure to light-at-night is associated with the circadian misalignment, it remains unclear whether exposure to light-at-night in home settings is associated with nighttime BP. In this cross-sectional analysis of 528 elderly individuals (mean age: 72.8 years), we measured bedroom light intensity at 1-min intervals on two consecutive nights along with ambulatory BP, overnight urinary melatonin excretion and actigraphy. With regard to adjusted mean comparisons using analysis of covariance, the light-at-night group (average: ≥5?lux; n?=?109) showed significantly higher nighttime systolic BP (SBP; adjusted mean: 120.8 vs. 116.5?mmHg, p?=?0.01) and diastolic BP (70.1 vs. 67.1?mmHg, p?<?0.01) compared with the Darker group (average: <5?lux; n?=?419) independently of potential confounding factors including overnight urinary melatonin excretion and actigraphic sleep quality. We observed consistent associations between light-at-night and nighttime BP in different cutoff values for light-at-night intensity (i.e. 3 and 10?lux). In conclusion, exposure to light-at-night in home settings is significantly associated with increased nighttime BP in elderly individuals independently of overnight urinary melatonin excretion. A 4.3?mmHg increase in nighttime SBP is associated with a 6.1% increase in total mortality, which corresponds to approximately 10?000 annual excess deaths in Japanese elderly population.     

Association between light exposure at night and insomnia in the general elderly population: The HEIJO-KYO cohort

Chronic circadian misalignment between the internal and environmental rhythms, which is typically related to night-shift work and clock-gene variants, is associated with disruption of suprachiasmatic nucleus function and increased risk of insomnia. Under controlled laboratory conditions, light at night (LAN) suppresses melatonin secretion, delays the internal biological rhythm, and reduces sleepiness. Therefore, LAN exposure may cause circadian misalignment and insomnia, though it remains unclear in real-life situations whether LAN exposure is associated with insomnia. To evaluate an association between LAN exposure and sleep quality in home settings, we conducted a cross-sectional community-based study in 857 elderly individuals (mean age, 72.2 years). We evaluated bedroom light intensity using a light meter and subjectively and objectively measured sleep quality using the Pittsburgh Sleep Quality Index and an actigraph, respectively, along with urinary 6-sulfatoxymelatonin excretion. Compared with the lowest quartile group of LAN intensity, the highest quartile group revealed a significantly higher odds ratio (OR) for subjective insomnia in a multivariate model adjusted for age, gender, body mass index, daytime physical activity, urinary 6-sulfatoxymelatonin excretion, bedtime, rising time, and day length (adjusted OR, 1.61, 95% confidence interval, 1.05–2.45, p?=?0.029). In addition, higher OR for subjective insomnia was significantly associated with the increase in quartiles of LAN intensity (p_trend?=?0.043). Consistently, we observed significant association trends between the increase in quartiles of LAN intensity and poorer actigraphic sleep quality, including decreased sleep efficiency, prolonged sleep-onset latency, increased wake-after-sleep onset, shortened total sleep time, and delayed sleep-mid time in multivariate models adjusted for the covariates mentioned above (all p_trend?<?0.001). In conclusion, we demonstrated that LAN exposure in home settings is significantly associated with both subjectively and objectively measured sleep quality in a community-based elderly population.     

Light exposure at night is associated with subclinical carotid atherosclerosis in the general elderly population: The HEIJO-KYO cohort

Epidemiological and cellular biological studies indicate the influence of impaired circadian biological rhythmicity on atherosclerosis. Increased exposure to light at night (LAN) is common in modern life, and LAN exposure is the most important environmental cue for circadian misalignment. However, the association between LAN exposure and atherosclerosis has never been explored in humans. In this cross-sectional study, we measured nighttime light intensity in the bedroom along with the intima-media thickness (IMT) of the common carotid artery using ultrasonography in 700 elderly individuals (mean age 71.6 years). Averages of mean and maximal carotid IMT were 0.88?±?0.15?mm and 1.09?±?0.32?mm, respectively. Median intensity of LAN exposure was 0.74?lux (interquartile range, 0.08–3.34). Both mean and maximal carotid IMT significantly increased across quartiles of increasing LAN intensity (p for trend?=?0.002 and <0.001, respectively). After adjustment for confounding factors, including age, gender, body mass index, current smoking status, hypertension, diabetes, dyslipidemia, sleep medication, estimated glomerular filtration rate, nocturia, bedtime, duration in bed (scotoperiod), day length (photoperiod), urinary 6-sulfatoxymelatonin excretion and daytime and nighttime physical activity, multivariate linear regression models revealed significant associations of LAN exposure with carotid IMT measurements [mean: β, 0.032 (fourth versus first quartiles); 95% confidence intervals (CI), 0.002–0.061; p?=?0.037; maximal: β, 0.100 (fourth versus first quartiles); 95% CI, 0.034–0.165; p?=?0.003]. In conclusion, these results suggested that LAN exposure in home settings is significantly associated with subclinical carotid atherosclerosis in the general elderly population.     

Melatonin Treatment Effects on Adolescent Students' Sleep Timing and Sleepiness in a Placebo-Controlled Crossover Study

During the last few decades, the incidence of sleep-onset insomnia, due to delay of circadian phase, has increased substantially among adolescents all over the world. We wanted to investigate whether a small dose of melatonin given daily, administered in the afternoon, could advance the sleep timing in teenagers. Twenty-one students, aged 14–19 yrs, with sleep-onset difficulties during school weeks were recruited. The study was a randomized, double blind, placebo (PL)-controlled crossover trial, lasting 5 wks. During the first 6 d in wks 2 and 4, the students received either PL or melatonin (1 mg) capsules between 16:30 and 18:00 h. During the first 6 d of wk 5, all students received melatonin. Wks 1 and 3 were capsule-free. In the last evening of each week and the following morning, the students produced saliva samples at home for later melatonin analysis. The samples were produced the same time each week, as late as possible in the evening and as early as possible in the morning. Both the student and one parent received automatic mobile text messages 15 min before saliva sampling times and capsule intake at agreed times. Diaries with registration of presumed sleep, subjective sleepiness during the day (Karolinska Sleepiness Scale, KSS) and times for capsule intake and saliva samplings were completed each day. Primary analysis over 5 wks gave significant results for melatonin, sleep and KSS. Post hoc analysis showed that reported sleep-onset times were advanced after melatonin school weeks compared with PL school weeks (p < .005) and that sleep length was longer (p < .05). After the last melatonin school week, the students fell asleep 68 min earlier and slept 62 min longer each night compared with the baseline week. Morning melatonin values in saliva diminished compared with PL (p < .001) and evening values increased (p < .001), indicating a possible sleep phase advance. Compared with PL school weeks, the students reported less wake up (p < .05), less school daytime sleepiness (p < .05) and increased evening sleepiness (p < .005) during melatonin weeks. We conclude that a small dose of melatonin given daily, administered in the afternoon, could advance the sleep timing and make the students more alert during school days even if they continued their often irregular sleep habits during weekends. (Author correspondence: arne.lowden@stress.su.se)     

Entrainment of Circadian Programs

Circadian rhythms were recently proposed as a measure of physiological state and prognosis in disorders of consciousness (DOC). So far, melatonin regulation was never assessed in vegetative state (VS). Aim of our research was to investigate the nocturnal melatonin levels and light-induced melatonin suppression in a cohort of VS patients. We assessed six consecutive patients (four men, age 33.3?±?9.3 years) with post-traumatic VS and nine age-matched healthy volunteers (five men, age 34.3?±?8.9 years) on two consecutive nights: one baseline and one light exposure night. During baseline, night subjects were in bed in a dim (<5?lux) room from 10?pm to 8?am. Blood samples were collected hourly 00:30–3:30?am (00:30?=?MLT1; 1:30?=?MLT2; 2:30?=?MLT3; and 3:30?=?MLT4). Identical setting was used for melatonin suppression test night, except for the exposure to monochromatic (470?nm) light from 1:30 to 3:30?am. Plasma melatonin levels were evaluated by radioimmunoassay. Magnitude of melatonin suppression was assessed by melatonin suppression score (caMSS) and suppression rate. We searched for group differences in melatonin levels, differences between repeated samples melatonin concentrations during baseline night and light exposure night, and light-induced suppression of melatonin secretion. During baseline night, controls showed an increase of melatonin (MLT4 vs MLT1, p?=?0.037), while no significant changes were observed in VS melatonin levels (p?=?0.172). Baseline night MLT4 was significantly lower in VS vs controls (p?=?0.036). During light-exposure night, controls displayed a significant suppression of melatonin (MLT3 and MLT4 vs MLT2, p?=?0.016 and 0.002, respectively), while VS patients displayed no significant changes. The magnitude of light-induced suppression of melatonin levels was statistically different between groups considering control adjusted caMSS (p?=?0.000), suppression rate (p?=?0.002) and absolute percentage difference (p?=?0.012). These results demonstrate for the first time that VS patients present an alteration in night melatonin secretion and reduced light-induced melatonin suppression. These findings confirm previous studies demonstrating a disruption of the circadian system in DOC and suggest a possible benefit from melatonin supplementation in VS.     

Older Poor-Sleeping Women Display a Smaller Evening Increase in Melatonin Secretion and Lower Values of Melatonin and Core Body Temperature Than Good Sleepers

Melatonin concentration and core body temperature (CBT) follow endogenous circadian biological rhythms. In the evening, melatonin level increases and CBT decreases. These changes are involved in the regulation of the sleep-wake cycle. Therefore, the authors hypothesized that age-related changes in these rhythms affect sleep quality in older people. In a cross-sectional study design, 11 older poor-sleeping women (aged 62–72 yrs) and 9 older good-sleeping women (60–82 yrs) were compared with 10 younger good-sleeping women (23–28 yrs). The older groups were matched by age and body mass index. Sleep quality was assessed by the Pittsburgh Sleep Quality Index questionnaire. As an indicator of CBT, oral temperature was measured at 1-h intervals from 17:00 to 24:00?h. At the same time points, saliva samples were collected for determining melatonin levels by enzyme-linked immunosorbent assay (ELISA). The dim light melatonin onset (DLMO), characterizing the onset of melatonin production, was calculated. Evening changes in melatonin and CBT levels were tested by the Friedman test. Group comparisons were performed with independent samples tests. Predictors of sleep-onset latency (SOL) were assessed by regression analysis. Results show that the mean CBT decreased in the evening from 17:00 to 24:00?h in both young women (from 36.57°C to 36.25°C, p < .001) and older women (from 36.58°C to 35.88°C, p < .001), being lowest in the older poor sleepers (p < .05). During the same time period, mean melatonin levels increased in young women (from 16.2 to 54.1 pg/mL, p < .001) and older women (from 10.0 to 23.5 pg/mL, p < .001), being lowest among the older poor sleepers (from 20:00 to 24:00?h, p < .05 vs. young women). Older poor sleepers also showed a smaller increase in melatonin level from 17:00 to 24:00?h than older good sleepers (mean?±?SD: 7.0?±?9.63 pg/mL vs. 15.6?±?24.1 pg/mL, p = .013). Accordingly, the DLMO occurred at similar times in young (20:10?h) and older (19:57?h) good-sleeping women, but was delayed ～50?min in older poor-sleeping women (20:47?h). Older poor sleepers showed a shorter phase angle between DLMO and sleep onset, but a longer phase angle between CBT peak and sleep onset than young good sleepers, whereas older good sleepers had intermediate phase angles (insignificant). Regression analysis showed that the DLMO was a significant predictor of SOL in the older women (R²?=?0.64, p < .001), but not in the younger women. This indicates that melatonin production started later in those older women who needed more time to fall asleep. In conclusion, changes in melatonin level and CBT were intact in older poor sleepers in that evening melatonin increased and CBT decreased. However, poor sleepers showed a weaker evening increase in melatonin level, and their DLMO was delayed compared with good sleepers, suggesting that it is not primarily the absolute level of endogenous melatonin, but rather the timing of the circadian rhythm in evening melatonin secretion that might be related to disturbances in the sleep-wake cycle in older people. (Author correspondence: mdittmar@zoologie.uni-kiel.de)     

LIGHT INTENSITY EXPOSURE,SLEEP DURATION,PHYSICAL ACTIVITY,AND BIOMARKERS OF MELATONIN AMONG ROTATING SHIFT NURSES

Long-term, night shiftwork has been identified as a potential carcinogenic risk factor. It is hypothesized that increased light at night exposure during shiftwork reduces melatonin production, which is associated with increased cancer risk. Sleep duration has been hypothesized to influence both melatonin levels and cancer risk, and it has been suggested that sleep duration could be used as a proxy for melatonin production. Finally, physical activity has been shown to reduce cancer risk, and laboratory studies indicate it may influence melatonin levels. A cross-sectional study of light exposure, sleep duration, physical activity, and melatonin levels was conducted among 61 female rotating shift nurses (work schedule: two 12?h days, two 12?h nights, five days off). Light intensity was measured using a light-intensity data logger, and sleep duration and physical activity were self-reported in a study diary and questionnaire. Melatonin concentrations were measured from urine and saliva samples. The characteristics of nurses working day and night shifts were similar. Light intensity was significantly higher during sleep for those working at night (p<?0.0001), while urinary melatonin levels following sleep were significantly higher among those working days (p?=?0.0003). Mean sleep duration for nurses working during the day (8.27?h) was significantly longer than for those working at night (4.78?h, p<?0.0001). An inverse association (p?=?0.002) between light exposure and urinary melatonin levels was observed; however, this was not significant when stratified by shift group. There was no significant correlation between sleep duration and melatonin, and no consistent relationship between physical activity and melatonin. Analysis of salivary melatonin levels indicated that the circadian rhythms of night workers were not altered, meaning peak melatonin production occurred at night. This study indicates that two nights of rotating shift work may not change the timing of melatonin production to the day among those working at night. Additionally, in this study, sleep duration was not correlated with urinary melatonin levels, suggesting it may not be a good proxy for melatonin production. (Author correspondence: anne.grundy@queensu.ca)     

HYPERSENSITIVITY OF MELATONIN SUPPRESSION IN RESPONSE TO LIGHT IN PATIENTS WITH DELAYED SLEEP PHASE SYNDROME*

Patients with delayed sleep phase syndrome (DSPS) experiencea chronic mismatch between the usual daily schedule required by the individual'senvironment and their circadian sleep-wake pattern, resulting in major academic,work, and social problems. Although functional abnormalities of the circadianpacemaker system have been reported in patients with DSPS, the etiology ofDSPS has not been fully elucidated. One hypothesis proposed to explain whypatients with DSPS fail to synchronize their 24h sleep-wake cycle to theirenvironment is that they might have reduced sensitivity to environmental timecues, most notably light-dark cycles. Therefore, we compared the sensitivityof melatonin suppression in response to light in patients with DSPS and normalcontrol subjects. Fifteen patients with DSPS and age- and sex-matched healthycontrols were studied. As the melatonin secretion rhythm in patients withDSPS was expected to be delayed compared to the controls, the time of peakmelatonin secretion was determined in each subject in the first session. Inthe second session, each subject was exposed to light with an intensity of1000 lux for 2h beginning 2h prior to his or her peak melatonin secretion.Melatonin was measured by radioimmunoassay in saliva sampled every 30 minutesduring the period of light exposure. Suppression of the melatonin concentrationin saliva was dependent on duration of light exposure. In addition, the suppressiveeffect of light on the melatonin concentration was significantly greater inpatients with DSPS than in control subjects. The results suggest hypersensitivityto nighttime light exposure in patients with this syndrome. Our findings thereforesuggest that evening light restriction is important for preventing patientswith DSPS from developing a sleep phase delay. (ChronobiologyInternational, 18(2), 263–271, 2001)     

Association of the melatonin circadian rhythms with clock 3111T/C gene polymorphism in Caucasian and Asian menopausal women with insomnia

A comparative analysis of melatonin circadian rhythms in Caucasian (incoming population) and Asian (indigenous population) menopausal women with/without sleep disorders depending on the genotype of Clock 3111T/C gene polymorphism was realized.The melatonin level in the saliva was determined four times a day (6:00–7:00, 12:00–13:00, 18:00–19:00, 23:00–00:00 h). The Caucasian women—carriers of the TT-genotype with insomnia as compared to control group—had a higher morning melatonin level and a lower night melatonin level. The Asian women with TT-genotype and insomnia had a lower levels of melatonin as compared to control at daytime, evening and night. A significantly higher melatonin level in the early morning hours was detected in the Caucasian women—carriers of the TT-genotype with insomnia as compared to group womencarriers of the minor 3111C-allele. There were no statistically significant differences in the circadian rhythms of melatonin in the Asian women depending on the genotype of the Clock 3111T/C polymorphism. An assumption with respect to the protective role of the minor allele 3111C in the development of insomnia associated with the displacement of melatonin circadian rhythms in the representatives of the incoming population was made.     

SUPPLEMENTARY ADMINISTRATION OF ARTIFICIAL BRIGHT LIGHT AND MELATONIN AS POTENT TREATMENT FOR DISORGANIZED CIRCADIAN REST-ACTIVITY AND DYSFUNCTIONAL AUTONOMIC AND NEUROENDOCRINE SYSTEMS IN INSTITUTIONALIZED DEMENTED ELDERLY PERSONS

Increased daytime napping, early morning awakening, frequent nocturnal sleep interruptions, and lowered amplitude and phase advance of the circadian sleep-wake rhythm are characteristic features of sleep-waking and chronobiological changes associated with aging. Especially in elderly patients with dementia, severely fragmented sleep-waking patterns are observed frequently and are associated with disorganized circadian rhythm of various physiological functions. Functional and/or organic deterioration of the suprachiasmatic nucleus (SCN), decreased exposure to time cues such as insufficient social interaction and reduced environmental light, lowered sensitivity of sensory organs to time cues, and reduced ability of peripheral effector organs to express circadian rhythms may cause these chronobiological changes. In many cases of dementia, the usual treatments for insomnia do not work well, and the development of an effective therapy is an important concern for health care practitioner and researchers. Recent therapeutical trials of supplementary administration of artificial bright light and the pineal hormone melatonin, a potent synchronizer for mammalian circadian rhythm, have indicated that these treatments are useful tools for demented elderly insomniacs. Both bright light and melatonin simultaneously ameliorate disorganized thermoregulatory and neuroendocrine systems associated with disrupted sleep-waking times, suggesting a new, potent therapeutic means for insomnia in the demented elderly. Future studies should address the most effective therapeutic design and the most suitable types of symptoms for treatment and investigate the use of these tools in preventive applications in persons in early stages of dementia. (Chronobiology International, 17(3), 419–432, 2000)     

Decreased daytime light intensity at nonwindow hospital beds: Comparisons with light intensity at window hospital beds and light exposure in nonhospitalized elderly individuals

Light is crucial for the synchronization of internal biological rhythms with environmental rhythms. Hospitalization causes a range of unfavorable medical conditions, including delirium, sleep disturbances, depressed mood, and increased fall, especially in elderly people. The hospital room environment contributes significantly to patients’ circadian physiology and behavior; however, few studies have evaluated light intensity in hospital settings. In this study, bedside light intensity during the daytime (6:00–21:00) was measured at 1-min intervals using a light meter on 4869 bed-days at the Inabe General Hospital in Mie, Japan (latitude 35°N), for approximately 1 month in each season. Daytime light exposure in home settings was measured in nonhospitalized elderly individuals (n = 1113) for two consecutive days at 1-min intervals using a wrist light meter. Median daytime light intensities at window and nonwindow hospital beds were 327.9 lux [interquartile range (IQR), 261.5–378.4] and 118.4 lux (IQR, 100.6–142.9), respectively, and daytime light intensity measured in nonhospitalized elderly individuals was 337.3 lux (IQR, 165.5–722.7). Compared with data in nonhospitalized elderly individuals, nonwindow beds were exposed to significantly lower daytime light intensity (p < 0.001), whereas window beds were exposed to similar daytime light intensity to that of home settings (p = 1.00). These results were consistent regardless of seasons (spring, summer, fall, and winter) or room directions (north vs. south facing). The lowest median daytime light intensity was observed at nonwindow beds in north-facing rooms during the winter (84.8 lux; IQR, 76.0–95.8). Further studies evaluating the incidence of in-hospital outcomes between patients hospitalized in window and nonwindow beds are needed.     

Circadian Phase,Sleepiness, and Light Exposure Assessment in Night Workers With and Without Shift Work Disorder

Most night workers are unable to adjust their circadian rhythms to the atypical hours of sleep and wake. Between 10% and 30% of shiftworkers report symptoms of excessive sleepiness and/or insomnia consistent with a diagnosis of shift work disorder (SWD). Difficulties in attaining appropriate shifts in circadian phase, in response to night work, may explain why some individuals develop SWD. In the present study, it was hypothesized that disturbances of sleep and wakefulness in shiftworkers are related to the degree of mismatch between their endogenous circadian rhythms and the night-work schedule of sleep during the day and wake activities at night. Five asymptomatic night workers (ANWs) (3 females; [mean?±?SD] age: 39.2?±?12.5 yrs; mean yrs on shift?=?9.3) and five night workers meeting diagnostic criteria (International Classification of Sleep Disorders [ICSD]-2) for SWD (3 females; age: 35.6?±?8.6 yrs; mean years on shift?=?8.4) participated. All participants were admitted to the sleep center at 16:00?h, where they stayed in a dim light (<10 lux) private room for the study period of 25 consecutive hours. Saliva samples for melatonin assessment were collected at 30-min intervals. Circadian phase was determined from circadian rhythms of salivary melatonin onset (dim light melatonin onset, DLMO) calculated for each individual melatonin profile. Objective sleepiness was assessed using the multiple sleep latency test (MSLT; 13 trials, 2-h intervals starting at 17:00?h). A Mann-Whitney U test was used for evaluation of differences between groups. The DLMO in ANW group was 04:42?±?3.25?h, whereas in the SWD group it was 20:42?±?2.21?h (z = 2.4; p?<?.05). Sleep did not differ between groups, except the SWD group showed an earlier bedtime on off days from work relative to that in ANW group. The MSLT corresponding to night work time (01:00–09:00?h) was significantly shorter (3.6?±?.90?min: [M?±?SEM]) in the SWD group compared with that in ANW group (6.8?±?.93?min). DLMO was significantly correlated with insomnia severity (r = ?.68; p < .03), indicating that the workers with more severe insomnia symptoms had an earlier timing of DLMO. Finally, SWD subjects were exposed to more morning light (between 05:00 and 11:00?h) as than ANW ones (798 vs. 180 lux [M?±?SD], respectively z?=??1.7; p?<?.05). These data provide evidence of an internal physiological delay of the circadian pacemaker in asymptomatic night-shift workers. In contrast, individuals with SWD maintain a circadian phase position similar to day workers, leading to a mismatch/conflict between their endogenous rhythms and their sleep-wake schedule. (Author correspondence: vgumeny1@hfhs.org)     

Lack of exposure to natural light in the workspace is associated with physiological,sleep and depressive symptoms

The diurnal light cycle has a crucial influence on all life on earth. Unfortunately, modern society has modified this life-governing cycle by stressing maximum production and by giving insufficient attention to the ecological balance and homeostasis of the human metabolism. The aim of this study is to evaluate the effects of exposure or lack of exposure to natural light in a rest/activity rhythm on cortisol and melatonin levels, as well as on psychological variables in humans under natural conditions. This is a cross-sectional study. The subjects were allocated split into two groups according to their workspace (10 employees in the “with window” group and 10 in the “without window” group). All participants were women and wore anactigraph (Actiwatch 2, Philips Respironics), which measures activity and ambient light exposure, for seven days. Concentrations of melatonin and cortisol were measured from the saliva samples. Participants were instructed to collect saliva during the last day of use of the actigraph at 08:00 am, 4:00 pm and 10:00 pm. The subjects answered the Self-Reporting Questionnaire-20 (SRQ-20) to measure the presence of minor psychiatric disorders; the Montgomery-Asberg (MA) scale was used to measure depression symptoms, and the Pittsburgh Sleep Quality Index questionnaire (PSQI) was used to evaluate the quality of sleep. The Rayleigh analysis indicates that the two groups, “with window” an d “without window”, exhibited similar activities and light acrophases. In relation to light exposure, the mesor was significantly higher (t?=??2.651, p?=?0.023) in t he “with window” group (191.04?±?133.36) than in the “without window” group (73.8?±?42.05). Additionally, the “with window” group presented the highest amplitude of light exposure (298.07?±?222.97). Cortisol levels were significantly different between the groups at 10:00 pm (t?=?3.009, p?=?0.008; “without window” (4.01?±?0.91) “with window” (3.10?±?0.30)). In terms of the melatonin levels, the groups differed at two different times of day: 08:00 am (t?=?2.593, p?=?0.018) and 10:00 pm (t?=??2.939, p?=?0.009). The “with window” group had a lower melatonin level at 08:00 am (3.54?±?0.60) but a higher level at 10:00 pm (24.74?±?4.22) than the “without window” group. Higher cortisol levels were positively correlated with minor psychiatric disorders and depressive symptoms (MA) at 10:00 pm. Lower melatonin levels at 10:00 pm were correlated with depressive symptoms and poor quality of sleep (PSQI). Our study demonstrated that not only may light pollution affect human physiology but also lack of exposure to natural light is related to high levels of cortisol and lower levels of melatonin at night, and these, in turn, are related to depressive symptoms and poor quality of sleep.     

Systematic review of light exposure impact on human circadian rhythm

Light is necessary for life, and artificial light improves visual performance and safety, but there is an increasing concern of the potential health and environmental impacts of light. Findings from a number of studies suggest that mistimed light exposure disrupts the circadian rhythm in humans, potentially causing further health impacts. However, a variety of methods has been applied in individual experimental studies of light-induced circadian impacts, including definition of light exposure and outcomes. Thus, a systematic review is needed to synthesize the results. In addition, a review of the scientific evidence on the impacts of light on circadian rhythm is needed for developing an evaluation method of light pollution, i.e., the negative impacts of artificial light, in life cycle assessment (LCA). The current LCA practice does not have a method to evaluate the light pollution, neither in terms of human health nor the ecological impacts. The systematic literature survey was conducted by searching for two concepts: light and circadian rhythm. The circadian rhythm was searched with additional terms of melatonin and rapid-eye-movement (REM) sleep. The literature search resulted to 128 articles which were subjected to a data collection and analysis. Melatonin secretion was studied in 122 articles and REM sleep in 13 articles. The reports on melatonin secretion were divided into studies with specific light exposure (101 reports), usually in a controlled laboratory environment, and studies of prevailing light conditions typical at home or work environments (21 studies). Studies were generally conducted on adults in their twenties or thirties, but only very few studies experimented on children and elderly adults. Surprisingly many studies were conducted with a small sample size: 39 out of 128 studies were conducted with 10 or less subjects. The quality criteria of studies for more profound synthesis were a minimum sample size of 20 subjects and providing details of the light exposure (spectrum or wavelength; illuminance, irradiance or photon density). This resulted to 13 qualified studies on melatonin and 2 studies on REM sleep. Further analysis of these 15 reports indicated that a two-hour exposure to blue light (460 nm) in the evening suppresses melatonin, the maximum melatonin-suppressing effect being achieved at the shortest wavelengths (424 nm, violet). The melatonin concentration recovered rather rapidly, within 15 min from cessation of the exposure, suggesting a short-term or simultaneous impact of light exposure on the melatonin secretion. Melatonin secretion and suppression were reduced with age, but the light-induced circadian phase advance was not impaired with age. Light exposure in the evening, at night and in the morning affected the circadian phase of melatonin levels. In addition, even the longest wavelengths (631 nm, red) and intermittent light exposures induced circadian resetting responses, and exposure to low light levels (5–10 lux) at night when sleeping with eyes closed induced a circadian response. The review enables further development of an evaluation method of light pollution in LCA regarding the light-induced impacts on human circadian system.     

Hypersensitivity of melatonin suppression in response to light in patients with delayed sleep phase syndrome

Patients with delayed sleep phase syndrome (DSPS) experience a chronic mismatch between the usual daily schedule required by the individual's environment and their circadian sleep-wake pattern, resulting in major academic, work, and social problems. Although functional abnormalities of the circadian pacemaker system have been reported in patients with DSPS, the etiology of DSPS has not been fully elucidated. One hypothesis proposed to explain why patients with DSPS fail to synchronize their 24h sleep-wake cycle to their environment is that they might have reduced sensitivity to environmental time cues, most notably light-dark cycles. Therefore, we compared the sensitivity of melatonin suppression in response to light in patients with DSPS and normal control subjects. Fifteen patients with DSPS and age- and sex-matched healthy controls were studied. As the melatonin secretion rhythm in patients with DSPS was expected to be delayed compared to the controls, the time of peak melatonin secretion was determined in each subject in the first session. In the second session, each subject was exposed to light with an intensity of 1000 lux for 2h beginning 2h prior to his or her peak melatonin secretion. Melatonin was measured by radioimmunoassay in saliva sampled every 30 minutes during the period of light exposure. Suppression of the melatonin concentration in saliva was dependent on duration of light exposure. In addition, the suppressive effect of light on the melatonin concentration was significantly greater in patients with DSPS than in control subjects. The results suggest hypersensitivity to nighttime light exposure in patients with this syndrome. Our findings therefore suggest that evening light restriction is important for preventing patients with DSPS from developing a sleep phase delay. (Chronobiology International, 18(2), 263-271, 2001)     

Differences in circadian patterns between rural and urban populations: An epidemiological study in countryside

The physiological pattern of the sleep–wake cycle is influenced by external synchronizing agents such as light and social patterns, creating variations in each individual’s preferred active and sleep periods. Because of the demands of a 24-h working society, it may be imperative for many people to adapt their sleep patterns (physiologically) to their daily activities. Therefore, we analyzed the difference in sleep patterns and chronobiological parameters between an essentially rural farming and urban small-town populations. We studied 5942 subjects (women, 67.1%, N?=?3985; mean age, 44.3?±?13.1 years), from which the chronotype, circadian sleep pattern, and period of light exposure were collected using the Munich Chronotype Questionnaire (MCTQ). A structured questionnaire was also made for collection of social and demographic information. Compared with the urban population (N?=?3427, 57.7%), the rural population (N?=?2515, 42.3%) presented a more predominantly early sleep pattern, as determined by the mid-sleep phase (rural: 2.26?±?1.16; urban: 3.15?±?1.55; t-test, p?<?0.001). We also found less social jetlag (rural: 0.32; urban: 0.55; Mann–Whitney U test, p?<?0.001) and higher light-exposure (rural: 9.55?±?2.31; urban: 8.46?±?2.85; t test, p?<?0.001) in the rural population. Additionally, the rural population presented a higher prevalence of psychiatric disorders (rural: 156, 6.20%; urban: 165, 4.80%; Chi-square, p?<?0.05), and a lower prevalence of metabolic diseases (rural: 143, 5.70%; urban: 225, 6.60%; Chi-square, p?<?0.05). The significant difference in sleep parameters, chronotype, and light exposure between groups remained after multivariate regression analysis (r^2?=?0.41, F?=?297.19, p?<?0.001, β?=?1.208). In this study, there was a significant difference between the rural and urban populations in natural light exposure and sleeping patterns. Because of agricultural work schedules, rural populations spend considerable time outside that is an obligation related to work schedules. Our results emphasize the idea that latitude may not be the main factor influencing individual circadian habits. Rather, circadian physiology adapts to differences in exposure to light (natural and artificial) as well as social and work schedules.     

Older poor-sleeping women display a smaller evening increase in melatonin secretion and lower values of melatonin and core body temperature than good sleepers

Melatonin concentration and core body temperature (CBT) follow endogenous circadian biological rhythms. In the evening, melatonin level increases and CBT decreases. These changes are involved in the regulation of the sleep-wake cycle. Therefore, the authors hypothesized that age-related changes in these rhythms affect sleep quality in older people. In a cross-sectional study design, 11 older poor-sleeping women (aged 62-72 yrs) and 9 older good-sleeping women (60-82 yrs) were compared with 10 younger good-sleeping women (23-28 yrs). The older groups were matched by age and body mass index. Sleep quality was assessed by the Pittsburgh Sleep Quality Index questionnaire. As an indicator of CBT, oral temperature was measured at 1-h intervals from 17:00 to 24:00?h. At the same time points, saliva samples were collected for determining melatonin levels by enzyme-linked immunosorbent assay (ELISA). The dim light melatonin onset (DLMO), characterizing the onset of melatonin production, was calculated. Evening changes in melatonin and CBT levels were tested by the Friedman test. Group comparisons were performed with independent samples tests. Predictors of sleep-onset latency (SOL) were assessed by regression analysis. Results show that the mean CBT decreased in the evening from 17:00 to 24:00?h in both young women (from 36.57°C to 36.25°C, p < .001) and older women (from 36.58°C to 35.88°C, p < .001), being lowest in the older poor sleepers (p < .05). During the same time period, mean melatonin levels increased in young women (from 16.2 to 54.1 pg/mL, p < .001) and older women (from 10.0 to 23.5 pg/mL, p < .001), being lowest among the older poor sleepers (from 20:00 to 24:00?h, p < .05 vs. young women). Older poor sleepers also showed a smaller increase in melatonin level from 17:00 to 24:00?h than older good sleepers (mean?±?SD: 7.0?±?9.63 pg/mL vs. 15.6?±?24.1 pg/mL, p = .013). Accordingly, the DLMO occurred at similar times in young (20:10?h) and older (19:57?h) good-sleeping women, but was delayed ～50?min in older poor-sleeping women (20:47?h). Older poor sleepers showed a shorter phase angle between DLMO and sleep onset, but a longer phase angle between CBT peak and sleep onset than young good sleepers, whereas older good sleepers had intermediate phase angles (insignificant). Regression analysis showed that the DLMO was a significant predictor of SOL in the older women (R(2)?=?0.64, p < .001), but not in the younger women. This indicates that melatonin production started later in those older women who needed more time to fall asleep. In conclusion, changes in melatonin level and CBT were intact in older poor sleepers in that evening melatonin increased and CBT decreased. However, poor sleepers showed a weaker evening increase in melatonin level, and their DLMO was delayed compared with good sleepers, suggesting that it is not primarily the absolute level of endogenous melatonin, but rather the timing of the circadian rhythm in evening melatonin secretion that might be related to disturbances in the sleep-wake cycle in older people.     

Circadian Variation in the Response to Experimental Endotoxemia and Modulatory Effects of Exogenous Melatonin

Disturbances in circadian rhythms are commonly observed in the development of several medical conditions and may also be involved in the pathophysiology of sepsis. Melatonin, with its antioxidative and anti-inflammatory effects, is known to modulate the response to endotoxemia. In this paper, we investigated the circadian variation with or without melatonin administration in an experimental endotoxemia model based on lipopolysaccharide (LPS). Sixty male Sprague-Dawley rats were assigned to six groups receiving an intraperitoneal injection of either LPS (5?mg/kg), LPS?+?melatonin (1?mg/kg), or LPS?+?melatonin (10?mg/kg) at either daytime or nighttime. Superoxide dismutase (SOD) was analyzed in liver samples collected after decapitation. Furthermore, inflammatory plasma markers (cytokines interleukin [IL]-6, IL-10) and oxidative plasma markers (ascorbic acid [AA], dehydroascorbic acid [DHA], and malondialdehyde [MDA]) were analyzed before and 5?h after the onset of endotoxemia. There were significant higher levels of SOD (p?<?0.05), IL-6 (p?<?0.01), and IL-10 (p?<?0.05) during nighttime endotoxemia compared with daytime. At daytime, melatonin 1 and 10?mg reduced the levels of MDA and increased SOD, IL-6, IL-10, and DHA (p?<?0.05). At nighttime, melatonin reduced the levels of MDA and increased DHA (p?<?0.05). Additionally, 10?mg melatonin resulted in lower levels of AA during daytime (p?<?0.05). No dose relationship of melatonin was observed. The results showed that the response induced by experimental endotoxemia was dependent on time of day. Melatonin administration modulated the inflammatory and oxidative stress responses induced by endotoxemia and also resulted in higher levels of antioxidants during daytime. The effect of circadian time on the endotoxemia response and possible modulatory effects of melatonin need further investigations in a human endotoxemia model.     

An observational study on disturbed peripheral circadian rhythms in hemodialysis patients

The quality of life of hemodialysis (HD) patients is hampered by reduced nocturnal sleep quality and excessive daytime sleepiness. In addition to the sleep/wake cycle, levels of circadian biomarkers (e.g. melatonin) are disturbed in end-stage renal disease (ESRD). This suggests impaired circadian clock performance in HD patients, but the underlying mechanism is unknown. In this observational study, diurnal rhythms of sleep, serum melatonin and cortisol concentrations and clock gene mRNA expression are compared between HD patients (n?=?9) and healthy control subjects (n?=?9). In addition, the presence of circulating factors that might affect circadian rhythmicity is tested in vitro with cell culture experiments. Reduced sleep quality (median sleep onset latency [interquartile range] of 23.9 [17.3]?min for patients versus 5.0 [10] minutes for controls, p?<?0.01; mean (± SD) sleep efficiency 70.2?±?8.1% versus 82.9?±?10.9%, p?=?0.02 and mean awake minutes after sleep onset 104.8?±?27.9 versus 54.6?±?41.6 minutes, p?= 0.01) and increased daytime sleepiness (mean Epworth Sleepiness Score of 10.0?±?4.8 versus 3.9?±?2.0, p?<?0.01) were confirmed in HD patients. Reduced nocturnal melatonin concentrations (1 AM: 98.1 [122.9] pmol/L versus 12.5 [44.2] pmol/L, p?= 0.019; 5 AM: 114.0 [131.6] pmol/L versus 11.8 [86.8] pmol/L, p?= 0.031) and affected circadian control of cortisol rhythm and circadian expression of the clock gene REV-ERBα were found. HD patient serum had a higher capacity to synchronize cells in vitro, suggesting an accumulated level of clock resetting compounds in HD patients. These compounds were not cleared by hemodialysis treatment or related to frequently used medications. In conclusion, the abovementioned results strongly suggest a disturbance in circadian timekeeping in peripheral tissues of HD patients. Accumulation of clock resetting compounds possibly contributes to this. Future studies are needed for a better mechanistic understanding of the interaction between renal failure and perturbation of the circadian clock.