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Disruption to sleep and circadian rhythms can impact on metabolism. The study aimed to investigate the effect of acute sleep deprivation on plasma melatonin, cortisol and metabolites, to increase understanding of the metabolic pathways involved in sleep/wake regulation processes. Twelve healthy young female participants remained in controlled laboratory conditions for ~92 hr with respect to posture, meals and environmental light (18:00–23:00 hr and 07:00‐09:00 hr, Young females were kept in controlled laboratory conditions comprising baseline sleep, sleep deprivation and recovery sleep and 1–2 hr blood sampling for 70 hr. Night‐time melatonin increased during sleep deprivation, returning to baseline levels during recovery sleep, whilst no significant changes were observed in cortisol. Of 130 plasma metabolites quantified by targeted metabolomics, 41 were altered across the nights (00:00–06:00 hr) and 58 maintained their rhythmicity across the three study days.

The effects of orexinergic peptides are diverse and are mediated by orexin-1 and orexin-2 receptors. Antagonists that target both receptors have been shown to promote sleep initiation and maintenance. Here, we investigated the role of the orexin-2 receptor in sleep regulation in a randomised, double-blind, placebo-controlled, three-period crossover clinical trial using two doses (20 and 50 mg) of a highly selective orexin-2 receptor antagonist (2-SORA) (JNJ-48816274). We used a phase advance model of sleep disruption where sleep initiation is scheduled in the circadian wake maintenance zone. We assessed objective and subjective sleep parameters, pharmacokinetic profiles and residual effects on cognitive performance in 18 healthy male participants without sleep disorders. The phase advance model alone (placebo condition) resulted in disruption of sleep at the beginning of the sleep period compared to baseline sleep (scheduled at habitual time). Compared to placebo, both doses of JNJ-48816274 significantly increased total sleep time, REM sleep duration and sleep efficiency, and reduced latency to persistent sleep, sleep onset latency, and REM latency. All night EEG spectral power density for both NREM and REM sleep were unaffected by either dose. Participants reported significantly better quality of sleep and feeling more refreshed upon awakening following JNJ-48816274 compared to placebo. No significant residual effects on objective performance measures were observed and the compound was well tolerated. In conclusion, the selective orexin-2 receptor antagonist JNJ-48816274 rapidly induced sleep when sleep was scheduled earlier in the circadian cycle and improved self-reported sleep quality without impact on waking performance.

Common cold sufferers frequently report sleep disruption during the symptomatic period of infections. We examined the effects of treatment with a topical aromatic pharmaceutical ointment (Vicks VapoRub®), on associated sleep disturbances. The effects of Vicks VapoRub® versus placebo (petrolatum ointment) on subjective and objective measured sleep parameters were assessed in an exploratory study of 100 common cold patients, in a randomized, single blind, controlled, two-arm, parallel design study. The primary efficacy variable was subjective sleep quality measured with the SQSQ (Subjective Quality of Sleep Questionnaire). Additional measures included, ease of falling asleep and depth of sleep (measured with a post-sleep Visual Analog Scale), total sleep time, sleep onset latency, activity score, percentage of sleep, sleep efficiency (measured with actigraphy and SQSQ) and sleep quality index measured with a modified Karolinska Sleep Diary (KSD). The primary endpoint, “How was the quality of your sleep last night?” showed a statistically significant difference in change from baseline in favour of VapoRub treatment (p = 0.0392) versus placebo. Positive effects of VapoRub versus placebo were also observed for “How refreshed did you feel upon waking up?” (p = 0.0122) (SQSQ), “Did you get enough sleep?” (p = 0.0036) (KSD), “How was it to get up?” (p = 0.0120) (KSD) and “Do you feel well-rested?” (p = 0.0125) (KSD). No statistically significant changes from baseline versus placebo were detected in the Actiwatch endpoints. Vicks VapoRub® when applied before retiring to bed can reduce subjective sleep disturbances during a common cold. The results of this exploratory study support the belief among patients that the use of VapoRub improves subjective sleep quality during common cold which was associated with more refreshing sleep.

The pupillary light reflex (PLR) is a neurological reflex driven by rods, cones, and melanopsin-containing retinal ganglion cells. Our aim was to achieve a more precise picture of the effects of 5-min duration monochromatic light stimuli, alone or in combination, on the human PLR, to determine its spectral sensitivity and to assess the importance of photon flux. Using pupillometry, the PLR was assessed in 13 participants (6 women) aged 27.2 ± 5.41 years (mean ± SD) during 5-min light stimuli of purple (437 nm), blue (479 nm), red (627 nm), and combinations of red+purple or red+blue light. In addition, nine 5-min, photon-matched light stimuli, ranging in 10 nm increments peaking between 420 and 500 nm were tested in 15 participants (8 women) aged 25.7 ± 8.90 years. Maximum pupil constriction, time to achieve this, constriction velocity, area under the curve (AUC) at short (0–60 s), and longer duration (240–300 s) light exposures, and 6-s post-illumination pupillary response (6-s PIPR) were assessed. Photoreceptor activation was estimated by mathematical modeling. The velocity of constriction was significantly faster with blue monochromatic light than with red or purple light. Within the blue light spectrum (between 420 and 500 nm), the velocity of constriction was significantly faster with the 480 nm light stimulus, while the slowest pupil constriction was observed with 430 nm light. Maximum pupil constriction was achieved with 470 nm light, and the greatest AUC0−60 and AUC240−300 was observed with 490 and 460 nm light, respectively. The 6-s PIPR was maximum after 490 nm light stimulus. Both the transient (AUC0−60) and sustained (AUC240−300) response was significantly correlated with melanopic activation. Higher photon fluxes for both purple and blue light produced greater amplitude sustained pupillary constriction. The findings confirm human PLR dependence on wavelength, monochromatic or bichromatic light and photon flux under 5-min duration light stimuli. Since the most rapid and high amplitude PLR occurred within the 460–490 nm light range (alone or combined), our results suggest that color discrimination should be studied under total or partial substitution of this blue light range (460–490 nm) by shorter wavelengths (~440 nm). Thus for nocturnal lighting, replacement of blue light with purple light might be a plausible solution to preserve color discrimination while minimizing melanopic activation.

Since there is less movement during sleep than during wake, the recording of body movements by actigraphy has been used to indirectly evaluate the sleep-wake cycle. In general, most actigraphic devices are placed on the wrist and their measures are based on acceleration detection. Here, we propose an alternative way of measuring actigraphy at the level of the arm for joint evaluation of activity and body position. This method analyzes the tilt of three axes, scoring activity as the cumulative change of degrees per minute with respect to the previous sampling, and measuring arm tilt for the body position inference. In this study, subjects (N = 13) went about their daily routine for 7 days, kept daily sleep logs, wore three ambulatory monitoring devices and collected sequential saliva samples during evenings for the measurement of dim light melatonin onset (DLMO). These devices measured motor activity (arm activity, AA) and body position (P) using the tilt sensing of the arm, with acceleration (wrist acceleration, WA) and skin temperature at wrist level (WT). Cosinor, Fourier and non-parametric rhythmic analyses were performed for the different variables, and the results were compared by the ANOVA test. Linear correlations were also performed between actimetry methods (AA and WA) and WT. The AA and WA suitability for circadian phase prediction and for evaluating the sleep-wake cycle was assessed by comparison with the DLMO and sleep logs, respectively. All correlations between rhythmic parameters obtained from AA and WA were highly significant. Only parameters related to activity levels, such as mesor, RA (relative amplitude), VL5 and VM10 (value for the 5 and 10 consecutive hours of minimum and maximum activity, respectively) showed significant differences between AA and WA records. However, when a correlation analysis was performed on the phase markers acrophase, mid-time for the 10 consecutive hours of highest (M10) and mid-time for the five consecutive hours of lowest activity (L5) with DLMO, all of them showed a significant correlation for AA (R = 0.607, p = 0.028; R = 0.582, p = 0.037; R = 0.620, p = 0.031, respectively), while for WA, only acrophase did (R = 0.621, p = 0.031). Regarding sleep detection, WA showed higher specificity than AA (0.95 ± 0.01 versus 0.86 ± 0.02), while the agreement rate and sensitivity were higher for AA (0.76 ± 0.02 versus 0.66 ± 0.02 and 0.71 ± 0.03 versus 0.53 ± 0.03, respectively). Cohen's kappa coefficient also presented the highest values for AA (0.49 ± 0.04) and AP (0.64 ± 0.04), followed by WT (0.45 ± 0.06) and WA (0.37 ± 0.04). The findings demonstrate that this alternative actigraphy method (AA), based on tilt sensing of the arm, can be used to reliably evaluate the activity and sleep-wake rhythm, since it presents a higher agreement rate and sensitivity for detecting sleep, at the same time allows the detection of body position and improves circadian phase assessment compared to the classical actigraphic method based on wrist acceleration.

Sea-level rise, potential changes in the intensity and frequency of storms, and consequent shoreline erosion and flooding will have increasing impacts on the economy and culture of coastal regions. A growing body of evidence suggests that coastal ecosystemsdnatural infrastructuredcan play an important role in reducing the vulnerability of people and property to these impacts. To effectively inform climate adaptation planning, experts often struggle to develop relevant local and regional information at a scale that is appropriate for decision-making. In addition, institutional capacity and resource constraints often limit planners’ ability to incorporate innovative, scientifically based approaches into planning. In this paper, we detail our collaborative process in two coastal California counties to account for the role of natural infrastructure in climate adaptation planning. We used an interdisciplinary team of scientists, economists, engineers, and law and policy experts and planners, and an iterative engagement process to (1) identify natural infrastructure that is geographically relevant to local jurisdictional planning units, (2) refine data and models to reflect regional processes, and (3) develop metrics likely to resonate within the local decision contexts. Using an open source decisionsupport tool, we demonstrated that protecting existing natural infrastructuredincluding coastal dunes and wetlandsdcould reduce the vulnerability of water resource-related structures, coastal populations, and farmland most exposed to coastal flooding and erosion. This information formed part of the rationale for priority climate adaptation projects the county governments are now pursuing. Our collaborative and iterative approach, as well as replicable use of an open source decision-support tool, facilitated inclusion of relevant natural infrastructure information into regional climate adaptation planning processes and products. This approach can be applied in diverse coastal climate adaptation planning contexts to locate and characterize the degree to which specific natural habitats can reduce vulnerability to sea-level rise and storms.

The increased prevalence of circadian disruptions due to abnormal coupling between internal and external time makes the detection of circadian phase in humans by ambulatory recordings a compelling need. Here, we propose an accurate practical procedure to estimate circadian phase with the least possible burden for the subject, that is, without the restraints of a constant routine protocol or laboratory techniques such as melatonin quantification, both of which are standard procedures. In this validation study, subjects (N = 13) wore ambulatory monitoring devices, kept daily sleep diaries and went about their daily routine for 10 days. The devices measured skin temperature at wrist level (WT), motor activity and body position on the arm, and light exposure by means of a sensor placed on the chest. Dim light melatonin onset (DLMO) was used to compare and evaluate the accuracy of the ambulatory variables in assessing circadian phase. An evening increase in WT: WTOnset (WTOn) and "WT increase onset" (WTiO) was found to anticipate the evening increase in melatonin, while decreases in motor activity (Activity Offset or AcOff), body position (Position Offset (POff)), integrative TAP (a combination of WT, activity and body position) (TAPOffset or TAPOff) and an increase in declared sleep propensity were phase delayed with respect to DLMO. The phase markers obtained from subjective sleep (R = 0.811), WT (R = 0.756) and the composite variable TAP (R = 0.720) were highly and significantly correlated with DLMO. The findings strongly support a new method to calculate circadian phase based on WT (WTiO) that accurately predicts and shows a temporal association with DLMO. WTiO is especially recommended due to its simplicity and applicability to clinical use under conditions where knowing endogenous circadian phase is important, such as in cancer chronotherapy and light therapy.

This study investigated the impact of sleep deprivation on the human circadian system. Plasma melatonin and cortisol levels and leukocyte expression levels of 12 genes were examined over 48 h (sleep vs. no-sleep nights) in 12 young males (mean ± SD: 23 ± 5 yrs). During one night of total sleep deprivation, BMAL1 expression was suppressed, the heat shock gene HSPA1B expression was induced, and the amplitude of the melatonin rhythm increased, whereas other high-amplitude clock gene rhythms (e.g., PER1-3, REV-ERBα) remained unaffected. These data suggest that the core clock mechanism in peripheral oscillators is compromised during acute sleep deprivation.

Light shifts the timing of the circadian clock according to a phase response curve (PRC). To date, all human light PRCs have been to long durations of bright white light. However, melanopsin, the primary photopigment for the circadian system, is most sensitive to short wavelength blue light. Therefore, to optimise light treatment it is important to generate a blue light PRC.We used a small, commercially available blue LED light box, screen size 11.2 × 6.6 cm at ∼50 cm, ∼200 μW cm(−2), ∼185 lux. Subjects participated in two 5 day laboratory sessions 1 week apart. Each session consisted of circadian phase assessments to obtain melatonin profiles before and after 3 days of free-running through an ultradian light–dark cycle (2.5 h wake in dim light, 1.5 h sleep in the dark), forced desynchrony protocol. During one session subjects received intermittent blue light (three 30 min pulses over 2 h) once a day for the 3 days of free-running, and in the other session (control) they remained in dim room light, counterbalanced. The time of blue light was varied among subjects to cover the entire 24 h day. For each individual, the phase shift to blue light was corrected for the free-run determined during the control session. The blue light PRC had a broad advance region starting in the morning and extending through the afternoon. The delay region started a few hours before bedtime and extended through the night. This is the first PRC to be constructed to blue light and to a stimulus that could be used in the real world.

Photoreception in the mammalian retina is not restricted to rods and cones but extends to a small number of intrinsically photosensitive retinal ganglion cells expressing the photopigment melanopsin. These mRGCs are especially important contributors to circadian entrainment, the pupil light reflex, and other so-called nonimage-forming (NIF) responses. The spectral sensitivity of melanopsin phototransduction has been addressed in several species by comparing responses to a range of monochromatic stimuli. The resultant action spectra match the predicted profile of an opsin:vitamin A–based photopigment (nomogram) with a peak sensitivity (λmax) around 480 nm. It would be most useful to be able to use this spectral sensitivity function to predict melanopsin’s sensitivity to broad-spectrum, including “white,” lights. However, evidence that melanopsin is a bistable pigment with an intrinsic light-dependent bleach recovery mechanism raises the possibility of a more complex relationship between spectral quality and photoreceptor response. Here, we set out to empirically determine whether simply weighting optical power at each wavelength according to the 480-nm nomogram and integrating across the spectrum could predict melanopsin sensitivity to a variety of polychromatic stimuli. We show that pupillomotor and circadian responses of mice relying solely on melanopsin for their photosensitivity ( rd/rd cl) can indeed be accurately predicted using this methodology. Our data therefore suggest that the 480-nm nomogram may be employed as the basis for a new photometric measure of light intensity (which we term “melanopic”) relevant for melanopsin photoreception. They further show that measuring light in these terms predicts the melanopsin response to light of divergent spectral composition much more reliably than other methods for quantifying irradiance or illuminance currently in widespread use.

Exogenous melatonin is increasingly used for its phase shifting and soporific effects. We generated a three pulse phase response curve (PRC) to exogenous melatonin (3 mg) by administering it to free-running subjects. Young healthy subjects (n = 27) participated in two 5 day laboratory sessions, each preceded by at least a week of habitual, but fixed sleep. Each 5 day laboratory session started and ended with a phase assessment to measure the circadian rhythm of endogenous melatonin in dim light using 30 min saliva samples. In between were three days in an ultradian dim light (< 150 lux)‐dark cycle (LD 2.5 : 1.5) during which each subject took one pill per day at the same clock time (3 mg melatonin or placebo, double blind, counterbalanced). Each individual’s phase shift to exogenous melatonin was corrected by subtracting their phase shift to placebo (a free-run). The resulting PRC has a phase advance portion peaking about 5 h before the dim light melatonin onset, in the afternoon. The phase delay portion peaks about 11 h after the dim light melatonin onset, shortly after the usual time of morning awakening. A dead zone of minimal phase shifts occurred around the first half of habitual sleep. The fitted maximum advance and delay shifts were 1.8 h and 1.3 h, respectively. This new PRC will aid in determining the optimal time to administer exogenous melatonin to achieve desired phase shifts and demonstrates that using exogenous melatonin as a sleep aid at night has minimal phase shifting effects.

Colonoscopy in children is frequently performed using intravenous sedation. Traditionally, there have been few advocates of general anaesthesia and some have regarded colonoscopy conducted in this way as potentially more hazardous. The aim of this study was to undertake a prospective audit of paediatric colonoscopy carried out under general anaesthesia. The details of all children referred for colonoscopy during a 3.5-y period were collected prospectively and the safety and efficacy of performing colonoscopy under general anaesthesia were analysed. A total of 250 colonoscopies was performed in 215 children of median age 10.7 y (range 5 months to 16y) and ileoscopy was carried out in 164 of these cases. An increasing proportion of patients was investigated as day-cases, including most of the 56 who had additional procedures carried out under the same anaesthetic. There were no complications from the colonoscopy (including the 18 patients who underwent polypectomy). Only one procedure-related complication occurred and this was avoidable. These results confirm the safety of paediatric colonoscopy under general anaesthesia and demonstrate the advantages and feasibility of such an approach.

In humans a range of non-image-forming (NIF) light responses (melatonin suppression, phase shifting and alertness) are short wavelength sensitive (440-480 nm). The aim of the current study was to assess the acute effect of three different short wavelength light pulses (420, 440 and 470 nm) and 600 nm light on subjective alertness. Healthy male subjects (n = 12, aged 27 +/- 4 years, mean +/- S.D.) were studied in 39, 4-day laboratory study sessions. The subjects were maintained in dim light (8 lx) and on day 3 they were exposed to a single 4-h light pulse (07:15-11:15 h). Four monochromatic wavelengths were administered at two photon densities: 420 and 440 nm at 2.3 x 10(13)photons/cm(2)/s and 440, 470 and 600 nm at 6.2 x 10(13)photons/cm(2)/s. Subjective mood and alertness were assessed at 30 min intervals during the light exposure, using four 9-point VAS scales. Mixed model regression analysis was used to compare alertness and mood ratings during the 470 nm light to those recorded with the other four light conditions. There was a significant effect of duration of light exposure (p0.001) on alertness but no significant effect of subject. Compared to 470 nm light, alertness levels were significantly higher in 420 nm light and significantly lower in the 600 nm light (p0.05). These data (420 nm470 nm600 nm) suggest that subjective alertness may be maximally sensitive to very short wavelength light.

Both light and melatonin can be used to phase shift the human circadian clock, but the phase-advancing effect of the combination has not been extensively investigated.The objective of the study was to determine whether phase advances induced by morning intermittent bright light and a gradually advancing sleep schedule could be increased with afternoon melatonin.Healthy adults (25 males, 19 females, between the ages of 19 and 45 yr) participated in the study.There were 3 d of a gradually advancing sleep/dark period (wake time 1 h earlier each morning), bright light on awakening [four 30-min bright-light pulses (approximately 5000 lux) alternating with 30 min room light60 lux] and afternoon melatonin, either 0.5 or 3.0 mg melatonin timed to induce maximal phase advances, or matching placebo. The dim light melatonin onset was measured before and after the treatment to determine the phase advance.There were significantly larger phase advances with 0.5 mg (2.5 h, n = 16) and 3.0 mg melatonin (2.6 h, n = 13), compared with placebo (1.7 h, n = 15), but there was no difference between the two melatonin doses. Subjects did not experience jet lag-type symptoms during the 3-d treatmentAfternoon melatonin, morning intermittent bright light, and a gradually advancing sleep schedule advanced circadian rhythms almost 1 h/d and thus produced very little circadian misalignment. This treatment could be used in any situation in which people need to phase advance their circadian clock, such as before eastward jet travel or for delayed sleep phase syndrome.

Night shift work and rapid transmeridian travel result in a misalignment between circadian rhythms and the new times for sleep, wake, and work, which has health and safety implications for both the individual involved and the general public. Entrainment to the new sleep/wake schedule requires circadian rhythms to be phase-shifted, but this is often slow or impeded. The authors show superimposed light and melatonin PRCs to explain how to appropriately time these zeitgebers to promote circadian adaptation. They review studies in which bright light and melatonin were administered to try to counteract jet lag or to produce circadian adaptation to night work. They demonstrate how jet lag could be prevented entirely if rhythms are shifted before the flight using their preflight plan and discuss the combination of interventions that they now recommend for night shift workers.

The aim of this study was to determine whether circadian phase from salivary melatonin profiles is the same when measured in phase assessments 1 wk apart. Eleven healthy young men and women maintained a fixed, home sleep-wake schedule, in bed, in the dark 23:00-07:00 hr on weekdays. On Friday and Saturday nights they were permitted to wake up and go to bed up to 1 hr later, and on Saturdays and Sundays they could nap between 13:30 and 16:30 hr. The study was run in the summer. Subjects wore sunglasses when outside during the day, and went outside for at least 15 min between 08:00 and 09:00 hr each morning. They maintained this schedule for 15 days before the first assessment and the 6 days in between the two assessments. During the assessments subjects remained awake overnight in

The Acts of Paul: A New Translation with Introduction and Commentary. By Richard I. Pervo. Eugene, Ore.: Cascade Books, 2014. xvii + 376 pp. $45.00 (paper).With his characteristic erudition, Richard Pervo's fresh translation and commentary on the pseudoepigraphic Acts of Paul offers an engaging and well-examined treatment of this apocryphal text. His project is accessible not only to seasoned students of the Apocryphal Acts of the Apostles (ApocActs), but also to those who are novices. Within this collection, the Acts of Paul is one of five surviving narratives that traces the ministry and martyrdom of the apostolic missionaries.The project begins with a complete translation-some surviving segments are quite fragmentary!-of the Acts. The text dates to the latter part of the second century. Paul's Acts, on account of its doctrinal outlook, was more widely accepted in early catholic circles than other texts from the ApocActs.Following the translation, Pervo provides an illuminating survey of the Acts' usage in Christian histoiy. He indexes its secondary attestations and reception in a variety of ancient sources. While some, like Tertullian, condemned the Acts, others, such as Eusebius, maintained a higher estimation of this non-canonical account. A list of reconstructive sources, a discussion of genre, and a survey of editorial theories is also provided. Of particular interest is Pervo s discussion of the book's theology. Here, he highlights both its non-Nicene tenor and its polemical interface with Gnosticism. Further to this, he stresses the text's value as a window into "ordinary Christianity in Asia" (p. 71) during the closing decades of the second century. Major themes of Christianity surface time and again, but not in a systematic manner.The ensuing commentary amply substantiates all of these broad observations. As Pervo strolls through the text, a series of insights on its history, canonical echoes, and cultural influences are published. Consider two representative examples.Chapters 3 and 4 introduce the Thecla narrative. Drawing on a freestanding account, the author incorporates this vignette into Paul's Acts so as to link this beloved female saint with the apostle. Amid this rendition, Pervo discerns a parallel with the popular Greek "romantic novels" (p. 94) extant at this moment in history. These stories relished love at first sight. In like manner, from the moment she hears his voice, Thecla is transfixed with Paul. Her devotion is not romantic, but it is rapt. …

The sleep/wake cycle is accompanied by changes in circulating numbers of immune cells. The goal of this study was to provide an in-depth characterization of diurnal rhythms in different blood cell populations and to investigate the effect of acute sleep deprivation on the immune system, as an indicator of the body's acute stress response.Observational within-subject design.Home environment and Clinical Research Centre.15 healthy male participants aged 23.7 ± 5.4 (standard deviation) yr.Total sleep deprivation.Diurnal rhythms of several blood cell populations were assessed under a normal sleep/wake cycle followed by 29 hr of extended wakefulness. The effect of condition (sleep versus sleep deprivation) on peak time and amplitude was investigated. Interindividual variation of, and the level of correlation between, the different cell populations was assessed. Comprehensive nonlinear curve fitting showed significant diurnal rhythms for all blood cell types investigated, with CD4 (naïve) cells exhibiting the most robust rhythms independent of condition. For those participants exhibiting significant diurnal rhythms in blood cell populations, only the amplitude of the granulocyte rhythm was significantly reduced by sleep deprivation. Granulocytes were the most diverse population, being most strongly affected by condition, and showed the lowest correlations with any other given cell type while exhibiting the largest interindividual variation in abundance.Granulocyte levels and diurnal rhythmicity are directly affected by acute sleep deprivation; these changes mirror the body's immediate immune response upon exposure to stress.

Context: Phase response curves (PRCs) to melatonin exist, but none compare different doses of melatonin using the same protocol. Objective: The aim was to generate a PRC to 0.5 mg of oral melatonin and compare it to our previously published 3.0 mg PRC generated using the same protocol. Design and Setting: The study included two 5-d sessions in the laboratory, each preceded by 7–9 d of fixed sleep times. Each session started and ended with a phase assessment to measure the dim light melatonin onset (DLMO). In between were 3 d in an ultradian dim light (

Reduced sensitivity to short-wavelength (blue) light with age has been shown for light-induced melatonin suppression. The current research aimed to determine if a similar age-related reduction occurs in subjective alertness, mood, and circadian phase-advancing responses. Young ( n = 11, 23.0 ± 2.9 years) and older ( n = 15, 65.8 ± 5.0 years) healthy males participated in laboratory sessions that included a 2-h intermittent monochromatic light exposure, individually timed to begin 8.5 h after their dim light melatonin onset (DLMO) determined in a prior visit. In separate sessions, pupil-dilated subjects were exposed to short-wavelength blue (λ max 456 nm) and medium-wavelength green (λmax 548 nm) light matched for photon density (6 × 1013 photons/cm2/sec). Subjective alertness, sleepiness, and mood were verbally assessed every 15 to 30 min before, during, and up to 5 h after the light exposure. The magnitude of phase advance was assessed as the difference in plasma melatonin rhythm phase markers before and after light exposure. Following blue light exposure, responses in older men were significantly diminished compared with young men for subjective alertness ( p < 0.0001), sleepiness ( p < 0.0001), and mood ( p < 0.05) during and after light exposure. There was no significant effect of age on these parameters following green light exposure. The phase advances to both blue and green light were larger in the young than older subjects, but did not reach statistical significance. In general, phase advances to blue light were slightly larger than to green light in both young and old, but did not reach statistical significance. The current results add to previous findings demonstrating reduced responsiveness to the acute effects of blue light in older people (melatonin suppression, alertness). However, under the study paradigm, the phase-advancing response to light does not appear to be significantly impaired with age.

Background Previous studies have shown that the human circadian system is maximally sensitive to short-wavelength (blue) light. Whether this sensitivity can be utilized to increase the size of phase shifts using light boxes and protocols designed for practical settings is not known. We assessed whether bright polychromatic lamps enriched in the short-wavelength portion of the visible light spectrum could produce larger phase advances than standard bright white lamps. Methods Twenty-two healthy young adults received either a bright white or bright blue-enriched 2-h phase advancing light pulse upon awakening on each of four treatment days. On the first treatment day the light pulse began 8h after the dim light melatonin onset (DLMO), on average about 2h before baseline wake time. On each subsequent day, light treatment began 1h earlier than the previous day, and the sleep schedule was also advanced. Results Phase advances of the DLMO for the blue-enriched (92±78min, n =12) and white groups (76±45min, n =10) were not significantly different. Conclusion Bright blue-enriched polychromatic light is no more effective than standard bright light therapy for phase advancing circadian rhythms at commonly used therapeutic light levels.

Melatonin synthesis from the pineal gland is regulated by the circadian pacemaker located in the suprachiasmatic nuclei and by ocular light exposure. Melatonin has a circadian rhythm that peaks during the night in normally entrained individuals. In the absence of light and other synchronizing signals, the rhythm of melatonin production persists with an elevation that occurs during the subjective, as opposed to the actual, night. There is a relatively direct anatomic pathway between the suprachiasmatic nuclei and the pineal gland, and comparatively few exogenous factors are known to affect melatonin concentrations (see Table 1 from Arendt, 2005, for a summary of these factors).1 As a result, the rhythm of melatonin production has been shown to reflect both the phase and, if collected over more than 1 cycle, the period of the endogenous circadian oscillator, thus providing a reliable means to estimate the timing of the internal circadian clock located in the suprachiasmatic nuclei. The circadian melatonin rhythm is currently the most commonly used circadian phase marker in humans.2–4 A variety of methods for sampling and analyzing melatonin have been described, but there are no established guidelines on when and how these various methods should be used. The multitude of assessment methods described can be confusing to those seeking to assess circadian rhythms in their own patients. Furthermore, the variety of melatonin phase markers reported in the literature increases the difficulty of comparing results from different studies, and the lack of comparable normative values impedes evaluation of results from clinical populations. This workgroup was formed following an Associated Professional Sleep Societies workshop on the use of melatonin as a circadian phase marker. Our goal was to achieve consensus for collecting and analyzing melatonin, thereby assisting clinicians and researchers in determining which method of measuring melatonin is most appropriate for their particular needs, as well as facilitating the comparison of data among researchers and clinicians. We present here a consensus statement on the preferred uses of urine, saliva, and blood samples and discuss the advantages and disadvantages of each approach. Also discussed are factors that may affect the measurement of melatonin and the different circadian phase markers that might be derived from these methods.

Introduction Since there is less movement during sleep than during wake, actigraphy permits to indirectly evaluate the sleep-wake cycle. In general, actigraphs are placed on the wrist and based on acceleration. In this validation study, we propose an alternative way of actigraphy at the level of the arm and expressed as change of degrees per minute. Its accuracy for phase prediction and for evaluating the sleep-wake cycle is assessed by comparing with the DLMO and sleep logs, respectively. Materials and methods In this study, subjects (N = 13) went about their daily routine for 7 days, kept daily sleep logs and wore ambulatory monitoring devices. These devices measured skin temperature at wrist level (WT), motor activity (Arm Activity, AA) and body position (P) on the arm and acceleration at wrist level (Wrist Acceleration, WA). Cosinor, non parametric and Fourier analysis were performed using AA and WA methods, and the results were compared by ANOVA test. Linear correlations were also performed between both methods and WT. DLMO was used to compare and correlate with estimated phase markers. Results Only mesor, RA (relative amplitude), VL5 and VM10 (value for the five and ten consecutive hours of lower and maximum activity, respectively) showed significant differences when estimated by both methods. The remaining parameters were not significantly different between both methods and all correlations between AA and WA were high. However, when phase markers were correlated with DLMO, acrophase, M10 and L5 (timing for the ten and five consecutive hours of highest and lowest activity, respectively) for AA showed a high correlation, while for WA, only acrophase did. Regarding sleep detection, WA showed higher specificity than AA, while the agreement rate and sensitivity were higher for AA. Conclusion An alternative actigraphy method (AA) can be used to evaluate more accurately sleep-wake and motor activity-rest rhythm than conventional actigraphy, since this alternative is more sensitive and presents higher agreement rate for detecting sleep. Besides, it estimates better the phase according to its correlation with the “gold standard” for phase detection: DLMO. Acknowledgements Study supported by Instituto de Salud Carlos III, RETICEF (RD12/0043/0011), MINECO (BFU 2010-21945-C02-01 and IPT-2011-0833-900000) with FEDER cofunding to JAM, and a research fellowship to MABC (FPU2009-1051). We thank Stockgrand Ltd. for melatonin assay reagents. DJ Skene is a Royal Society Wolfson Research Merit Award holder.

Introduction It is important to develop a system able to detect the endogenous circadian phase easily, since current techniques imply either expensive hormonal quantification or uncomfortable monitorization of central temperature by rectal probes. Materials and methods In this work, a new ambulatory circadian monitoring system (ACM) was validated. To this, activity and position, wrist temperature rhythm as well as light exposure pattern were recorded for 10 days in 13 healthy subjects, thanks to an actimeter on the arm, a temperature sensor on the ventral side of the wrist and a pendant luxometer. DLMO was determined in saliva, and it was used as “the gold standard” to evaluate the accuracy of ACM to assess the circadian phase. Besides, subjects completed a sleep log and Horne-Ostberg morningness–eveningness, Pittsburgh Sleep Quality Index and Epworth Sleepiness Scale questionnaires to evaluate diurnal preference and its influence in sleep quality. Results The peripheral wrist temperature increase in the evening (and its new indexes WTOnset or WTOn and WT increase onset or WTiO) anticipated that of melatonin; while the decrease in motor activity, position and the composite variable TAP (including wrist temperature, activity and position), and the increase in sleep probability occurred after the increase in melatonin levels. The score of morningness–eveningness and sleep quality questionnaires showed high correlations with DLMO, confirming that the later the DLMO occurs higher eveningness and worse sleep quality are reported. Conclusion This ambulatory method allows accurately detecting the circadian phase while subjects maintain their normal life style. The proposed new phase markers based on wrist temperature rhythm (named WTOn and WTiO) would be appropriate in Clinics when it is important to know the subject circadian phase, like in cancer chronotherapy or light therapy. Acknowledgements Study supported by Instituto de Salud Carlos III, RETICEF (RD12/0043/0011), MINECO (BFU 2010-21945-C02-01and IPT-2011-0833-900000) with FEDER cofounding to JAM, and a research fellowship to MA Bonmati-Carrion (FPU2009-1051). We also thank Stockgrand Ltd. (UK) for the melatonin assay reagents. DJ Skene is a Royal Society Wolfson Research Merit Award holder.