Effects of different light intensities in the morning on dim light melatonin onset

The present study evaluated the effects of exposure to light intensity in the morning on dim light melatonin onset (DLMO). The tested light intensities were 750 lux, 150 lux, 3000 lux, 6000 lux and 12,000 lux (horizontal illuminance at cornea), using commercial 5000 K fluorescent lamps. Eleven healthy males aged 21-31 participated in 2-day experiments for each light condition. On the first experimental day (day 1), subjects were exposed to dim light (<30 lux) for 3 h in the morning (09:00-12:00). On the same day, saliva samples were taken in dim light (<30 lux) every 30 min from 21:00 to 01:00 to determine the DLMO phase. The subjects were allowed to sleep from 01:00 to 08:00. On the second experimental day (day 2), the subjects were exposed to experimental light conditions for 3 h in the morning. The experimental schedule after light exposure was the same as on day 1. On comparing day 2 with day 1, significant phase advances of DLMO were obtained at 3000 lux, 6000 lux and 12,000 lux. These findings indicate that exposure to a necessary intensity from an ordinary light source, such as a fluorescent lamp, in the morning within one day affects melatonin secretion.     

The dim light melatonin onset, melatonin assays and biological rhythm research in humans

The most useful marker for human circadian phase position is the dim light melatonin onset (DLMO). This is optimally obtained by sampling blood or saliva in the evening at intervals of 30 min or less. Ambient light intensity should not exceed 30-50 lx. For many years, the DLMO was determined mainly with the 'gold standard' GCMS technique for measuring melatonin in human plasma. However, new and improved RIAs now provide the requisite sensitivity and accuracy (specificity) for detecting the time that low daytime levels begin to increase in the evening: the lower the operational threshold for the DLMO, the more reliable it is as a phase marker.     

Relationship between dim light melatonin onset and the timing of sleep in sleep onset insomniacs

Sleep and Biological Rhythms - Dim light melatonin onset (DLMO), a phase marker of the circadian system can be estimated from sleep diaries of good sleepers. Previous studies have shown a strong...     

Calculating the dim light melatonin onset: the impact of threshold and sampling rate

The dim light melatonin onset (DLMO) is the most reliable circadian phase marker in humans, but the cost of assaying samples is relatively high. Therefore, the authors examined differences between DLMOs calculated from hourly versus half-hourly sampling and differences between DLMOs calculated with two recommended thresholds (a fixed threshold of 3 pg/mL and a variable "3k" threshold equal to the mean plus two standard deviations of the first three low daytime points). The authors calculated these DLMOs from salivary dim light melatonin profiles collected from 122 individuals (64 women) at baseline. DLMOs derived from hourly sampling occurred on average only 6-8?min earlier than the DLMOs derived from half-hourly saliva sampling, and they were highly correlated with each other (r?≥?0.89, p?30?min from the DLMO derived from half-hourly sampling. The 3 pg/mL threshold produced significantly less variable DLMOs than the 3k threshold. However, the 3k threshold was significantly lower than the 3 pg/mL threshold (p?相似文献   

Sleep logs of young adults with self-selected sleep times predict the dim light melatonin onset

The purpose of this study was to determine whether a sleep log parameter could be used to estimate the circadian phase of normal, healthy, young adults who sleep at their normal times, and thus naturally have day-to-day variability in their times of sleep. Thus, we did not impose any restrictions on the sleep schedules of our subjects (n = 26). For 14 d, they completed daily sleep logs that were verified with wrist activity monitors. On day 14, salivary melatonin was sampled every 30 min in dim light from 19:00 to 07:30 h to determine the dim light melatonin onset (DLMO). Daily sleep parameters (onset, midpoint, and wake) were taken from sleep logs and averaged over the last 5, 7, and 14 d before determination of the DLMO. The mean DLMO was 22:48 +/- 01:30 h. Sleep onset and wake time averaged over the last 5 d were 01:44 +/- 01:41 and 08:44 +/- 01:26 h, respectively. The DLMO was significantly correlated with sleep onset, midpoint, and wake time, but was most strongly correlated with the mean midpoint of sleep from the last 5 d (r = 0.89). The DLMO predicted using the mean midpoint of sleep from the last 5 d was within 1 h of the DLMO determined from salivary melatonin for 92% of the subjects; in no case did the difference exceed 1.5 h. The correlation between the DLMO and the score on the morningness-eveningness questionnaire was significant but comparatively weak (r = -0.48). We conclude that the circadian phase of normal, healthy day-active young adults can be accurately predicted using sleep times recorded on sleep logs (and verified by actigraphy), even when the sleep schedules are irregular.     

Daily exercise facilitates phase delays of circadian melatonin rhythm in very dim light

Shift workers and transmeridian travelers are exposed to abnormal work-rest cycles, inducing a change in the phase relationship between the sleep-wake cycle and the endogenous circadian timing system. Misalignment of circadian phase is associated with sleep disruption and deterioration of alertness and cognitive performance. Exercise has been investigated as a behavioral countermeasure to facilitate circadian adaptation. In contrast to previous studies where results might have been confounded by ambient light exposure, this investigation was conducted under strictly controlled very dim light (standing approximately 0.65 lux; angle of gaze) conditions to minimize the phase-resetting effects of light. Eighteen young, fit males completed a 15-day randomized clinical trial in which circadian phase was measured in a constant routine before and after exposure to a week of nightly bouts of exercise or a nonexercise control condition after a 9-h delay in the sleep-wake schedule. Plasma samples collected every 30-60 min were analyzed for melatonin to determine circadian phase. Subjects who completed three 45-min bouts of cycle ergometry each night showed a significantly greater shift in the dim light melatonin onset (DLMO(25%)), dim light melatonin offset, and midpoint of the melatonin profile compared with nonexercising controls (Student t-test; P < 0.05). The magnitude of phase delay induced by the exercise intervention was significantly dependent on the relative timing of the exercise after the preintervention DLMO(25%) (r = -0.73, P < 0.05) such that the closer to the DLMO(25%), the greater the phase shift. These data suggest that exercise may help to facilitate circadian adaptation to schedules requiring a delay in the sleep-wake cycle.     

The hockey-stick method to estimate evening dim light melatonin onset (DLMO) in humans

The onset of melatonin secretion in the evening is the most reliable and most widely used index of circadian timing in humans. Saliva (or plasma) is usually sampled every 0.5–1 hours under dim-light conditions in the evening 5–6 hours before usual bedtime to assess the dim-light melatonin onset (DLMO). For many years, attempts have been made to find a reliable objective determination of melatonin onset time either by fixed or dynamic threshold approaches. The here-developed hockey-stick algorithm, used as an interactive computer-based approach, fits the evening melatonin profile by a piecewise linear-parabolic function represented as a straight line switching to the branch of a parabola. The switch point is considered to reliably estimate melatonin rise time. We applied the hockey-stick method to 109 half-hourly melatonin profiles to assess the DLMOs and compared these estimates to visual ratings from three experts in the field. The DLMOs of 103 profiles were considered to be clearly quantifiable. The hockey-stick DLMO estimates were on average 4 minutes earlier than the experts' estimates, with a range of ?27 to +13 minutes; in 47% of the cases the difference fell within ±5 minutes, in 98% within ?20 to +13 minutes. The raters' and hockey-stick estimates showed poor accordance with DLMOs defined by threshold methods. Thus, the hockey-stick algorithm is a reliable objective method to estimate melatonin rise time, which does not depend on a threshold value and is free from errors arising from differences in subjective circadian phase estimates. The method is available as a computerized program that can be easily used in research settings and clinical practice either for salivary or plasma melatonin values.     

Extraocular light exposure does not phase shift saliva melatonin rhythms in sleeping subjects

Preliminary work in humans suggests that extraocular light can shift circadian phase. If confirmed, extraocular light may be of therapeutic benefit in the treatment of circadian-related sleep disorders with the advantage over ocular exposure that it can be administered while subjects are asleep. In sleeping subjects, however, the effect of extraocular light exposure on circadian phase has yet to be fully tested. Likewise, there is limited data on the acute effects of extraocular light on sleep and body temperature that may influence its clinical utility Thirteen subjects [3F, 10M; mean (SD) age = 22.1 (3.0)y] participated in a protocol that totaled 7 nights in the laboratory consisting of a screening phase measurement night followed 1 week later by two counterbalanced experimental sessions each of 3 consecutive nights (habituation, treatment, and posttreatment phase measurement night) separated by 4 days. Saliva was collected for melatonin measurement every half hour from 1800 to 0300 h on the screening night and both the posttreatment phase measurement nights. On the treatment nights, continuous measures of rectal temperature and polysomnographic sleep were collected and overnight urine for measurement of total nocturnal urinary 6-sulphatoxymelatonin excretion. To test for the phase-delaying effects of extraocular light, subjects received either placebo or extraocular light (11,000 lux) behind the right knee from 0100 to 0400 h. Treatment had no significant effect on the onset of saliva melatonin secretion, phase of nocturnal core body temperature, or urinary 6-sulfatoxymelatonin excretion, but a small increase was observed in wakefulness over the light administration period. In summary, extraocular light was not shown to delay circadian phase but was shown to increase wakefulness. The authors suggest that the present protocol has limited application as a treatment for circadian-related sleep disorders.     

Acute phase proteins, body temperature and urinary melatonin under the influence of bright and dim light intensities during the daytime

Concentrations of five acute phase proteins: C-reactive protein (CRP), alpha 1-antichymotrypsin (ACT), transferin (Tf), alpha 2-macroglobulin (alpha 2-M) and haptoglobin (Hp) as well as glycosylation profiles of alpha 1-antichymotrypsin (ACT) were studied in sera samples with 7 healthy volunteers under the influence of two different light intensities during the daytime dim (100 lx) and bright (3000 lx) light. Concentration of transferin (negative proteins) under the influence of bright light during the daytime decreased significantly. Other proteins have the tendency to increase (positive proteins) under the influence of daytime bright light. The microheterogeneity of ACT did not change under the influence of different light intensities. Melatonin and rectal temperature were also measured simultaneously. Rectal temperature decreased to be lower during the first half of the night and urinary melatonin secretion rate increased to be higher during the night when the subjects spent time under the bright light during the day. Thus, it is concluded that the diurnal bright light exposure may activate some parameters of acute phase proteins, increase nocturnal melatonin secretion and accelerate a fall of rectal temperature during first half period of night sleep.     

Chronobiotic effect of melatonin following phase shift of light/dark cycles in the field mouseMus booduga

The objective of this study was to assess whether melatonin accelerates the re-entrainment of locomotor activity after 6 h of advance and delay phase shifts following exposure to LD 12:12 cycle (simulating jet-lag/shift work). An experimental group of adult male field mice Mus booduga were subjected to melatonin (1 mg/kg) through i.p. and the control group were treated with 50 % DMSO. The injections were administered on three consecutive days following 6h of phase advance and delay, at the expected time of “lights off”. The results show that melatonin accelerates the re-entrainment after phase advance (29%) when compared with control mice. In the 6 h phase delay study, the experimental mice (melatonin administered) take more cycles for re-entrainment (51%) than the control. Further, the results suggest that though melatonin may be useful for the treatment of jet-lag caused by eastward flight (phase advance) it may not be useful for westward flight (phase delay) jet-lag     

Suppression of nocturnal plasma melatonin and 6-sulphatoxymelatonin by bright and dim light in man

Previous studies have shown that bright light (2500 lux) suppresses nocturnal secretion of melatonin, while dim light (500 lux) has little or no effect. We have studied the effect of varying intensities of light on 5 normal male volunteers (age 18-28). The experiment was divided into 3 parts which took place at weekly intervals. Subjects remained under artificial light (fluorescent strip 150-250 lux) between 2000 h-2300 h, they then retired to bed in darkness. On each occasion, between 0030 h and 0100 h, the subjects were required to get up and were treated with light of different intensities; (a) less than 1 lux, (b) 300 lux and (c) 2500 lux respectively. Subjects returned to bed in darkness until 0700 h. Blood was sampled hourly from 2000 h-1000 h with additional samples at 2330 h, 0015 h, 0030 h, 0045 h, 0115 h and 0130 h. Plasma melatonin and 6-sulphatoxymelatonin (aMT6s), the major melatonin metabolite, were measured by radioimmunoassay. Dim (300 lux) and bright (2500 lux) light, both significantly suppressed melatonin levels compared to less than 1 lux (P less than 0.05 and P less than 0.01 respectively) at the following time points 0100 h, 0115 h and 0130 h. One subject did not show suppression with 300 lux. There was also a significant suppression of aMT6s levels, compared to less than 1 lux, after both 300 lux and 2500 lux at 0115 h (P less than 0.05, P less than 0.01), 0130 h (P less than 0.01, P less than 0.01) and 0200 h (P less than 0.01, P less than 0.001) respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Entrainment of rhythmic melatonin secretion in man to a 12-hour phase shift in the light/dark cycle

Daily rhythms in melatonin secretion were monitored in four healthy adult males by measuring the melatonin contents of sequential 4-hour urine specimens and of plasma samples collected at 12-hour intervals, or, in one subject, continuously for 24 hours. All subjects exhibited similar diurnal rhythms, with peak urinary melatonin excretion rates and blood melatonin levels occurring during the daily period of darkness and sleep. When the daily light/dark regimen was phase-shifted by 180°, the plasma and urinary melatonin rhythms required 5–7 days (depending on the subject) to re-entrain to the new schedule. Simultaneous measurements of plasma melatonin levels and melatonin excretion rates indicate that urinary melatonin reflects, with remarkable fidelity, circulating melatonin levels.     

Folding of Aquaporin 1: Multiple evidence that helix 3 can shift out of the membrane core

The folding of most integral membrane proteins follows a two‐step process: initially, individual transmembrane helices are inserted into the membrane by the Sec translocon. Thereafter, these helices fold to shape the final conformation of the protein. However, for some proteins, including Aquaporin 1 (AQP1), the folding appears to follow a more complicated path. AQP1 has been reported to first insert as a four‐helical intermediate, where helix 2 and 4 are not inserted into the membrane. In a second step, this intermediate is folded into a six‐helical topology. During this process, the orientation of the third helix is inverted. Here, we propose a mechanism for how this reorientation could be initiated: first, helix 3 slides out from the membrane core resulting in that the preceding loop enters the membrane. The final conformation could then be formed as helix 2, 3, and 4 are inserted into the membrane and the reentrant regions come together. We find support for the first step in this process by showing that the loop preceding helix 3 can insert into the membrane. Further, hydrophobicity curves, experimentally measured insertion efficiencies and MD‐simulations suggest that the barrier between these two hydrophobic regions is relatively low, supporting the idea that helix 3 can slide out of the membrane core, initiating the rearrangement process.     

Dim light melatonin onset in alcohol-dependent men and women compared with healthy controls

Sleep disturbances in alcohol-dependent (AD) individuals may persist despite abstinence from alcohol and can influence the course of the disorder. Although the mechanisms of sleep disturbances of AD are not well understood and some evidence suggests dysregulation of circadian rhythms, dim light melatonin onset (DLMO) has not previously been assessed in AD versus healthy control (HC) individuals in a sample that varied by sex and race. The authors assessed 52 AD participants (mean?±?SD age: 36.0?±?11.0 yrs of age, 10 women) who were 3-12 wks since their last drink (abstinence: 57.9?±?19.3 d) and 19 age- and sex-matched HCs (34.4?±?10.6 yrs, 5 women). Following a 23:00-06:00?h at-home sleep schedule for at least 5 d and screening/baseline nights in the sleep laboratory, participants underwent a 3-h extension of wakefulness (02:00?h bedtime) during which salivary melatonin samples were collected every 30?min beginning at 19:30?h. The time of DLMO was the primary measure of circadian physiology and was assessed with two commonly used methodologies. There was a slower rate of rise and lower maximal amplitude of the melatonin rhythm in the AD group. DLMO varied by the method used to derive it. Using 3 pg/mL as threshold, no significant differences were found between the AD and HC groups. Using 2 standard deviations above the mean of the first three samples, the DLMO in AD occurred significantly later, 21:02?±?00:41?h, than in HC, 20:44?±?00:21?h (t?=?-2.4, p?=?.02). Although melatonin in the AD group appears to have a slower rate of rise, using well-established criteria to assess the salivary DLMO did not reveal differences between AD and HC participants. Only when capturing melatonin when it is already rising was DLMO found to be significantly delayed by a mean 18?min in AD participants. Future circadian analyses on alcoholics should account for these methodological caveats.     

Characterization of a voltage-gated K+ channel that accelerates the rod response to dim light

In this study a K+ current, IKx, in isolated salamander rod photoreceptors was characterized and its role in shaping small photovoltages was examined. IKx is a standing outward current of about 40 pA at -30 mV that deactivates slowly when the cell is hyperpolarized (tau max = 0.25 s). The voltage and time dependence of IKx are similar to that of M-current, but IKx can be distinguished from M-current because it is not suppressed by acetylcholine and is "blocked" by external Ba2+ in a surprising manner: the activation range of IKx is shifted strongly in the positive direction. Using current-clamp recordings and a computer simulation of the photo-response, we show that IKx figures prominently in setting the dark resting potential and accelerates the voltage response to small photocurrents.     

Daytime naps in darkness phase shift the human circadian rhythms of melatonin and thyrotropin secretion

To systematically determine the effects of daytime exposure to sleep in darkness on human circadian phase, four groups of subjects participated in 4-day studies involving either no nap (control), a morning nap (0900-1500), an afternoon nap (1400-2000), or an evening nap (1900-0100) in darkness. Except during the scheduled sleep/dark periods, subjects remained awake under constant conditions, i.e., constant dim light exposure (36 lx), recumbence, and caloric intake. Blood samples were collected at 20-min intervals for 64 h to determine the onsets of nocturnal melatonin and thyrotropin secretion as markers of circadian phase before and after stimulus exposure. Sleep was polygraphically recorded. Exposure to sleep and darkness in the morning resulted in phase delays, whereas exposure in the evening resulted in phase advances relative to controls. Afternoon naps did not change circadian phase. These findings indicate that human circadian phase is dependent on the timing of darkness and/or sleep exposure and that strategies to treat circadian misalignment should consider not only the timing and intensity of light, but also the timing of darkness and/or sleep.     

Exercise elicits phase shifts and acute alterations of melatonin that vary with circadian phase

To examine the immediate phase-shifting effects of high-intensity exercise of a practical duration (1 h) on human circadian phase, five groups of healthy men 20-30 yr of age participated in studies involving no exercise or exposure to morning, afternoon, evening, or nocturnal exercise. Except during scheduled sleep/dark and exercise periods, subjects remained under modified constant routine conditions allowing a sleep period and including constant posture, knowledge of clock time, and exposure to dim light intensities averaging (+/-SD) 42 +/- 19 lx. The nocturnal onset of plasma melatonin secretion was used as a marker of circadian phase. A phase response curve was used to summarize the phase-shifting effects of exercise as a function of the timing of exercise. A significant effect of time of day on circadian phase shifts was observed (P < 0.004). Over the interval from the melatonin onset before exercise to the first onset after exercise, circadian phase was significantly advanced in the evening exercise group by 30 +/- 15 min (SE) compared with the phase delays observed in the no-exercise group (-25 +/- 14 min, P < 0.05). Phase shifts in response to evening exercise exposure were attenuated on the second day after exercise exposure and no longer significantly different from phase shifts observed in the absence of exercise. Unanticipated transient elevations of melatonin levels were observed in response to nocturnal exercise and in some evening exercise subjects. Taken together with the results from previous studies in humans and diurnal rodents, the current results suggest that 1) a longer duration of exercise exposure and/or repeated daily exposure to exercise may be necessary for reliable phase-shifting of the human circadian system and that 2) early evening exercise of high intensity may induce phase advances relevant for nonphotic entrainment of the human circadian system.     

Circadian rhythm of acute phase proteins under the influence of bright/dim light during the daytime

We investigated the influence of two different light intensities, dim (100 lx) and bright (5000 lx), during the daytime on the circadian rhythms of selected acute phase proteins of C-reactive protein (CRP), alpha1-acid glycoprotein (AGP), alpha1-antichymotrypsin (ACT), transfferin (TF), alpha2-macroglobulin (alpha2-m), haptoglobin (HP), and ceruloplasmin (CP). Serum samples were collected from 7 healthy volunteers at 4 h intervals during two separate single 24 h spans during which they were exposed to the respective light intensity conditions. A circadian rhythm was detected only in ACT concentration in the bright light condition. The concentration of ACT, a positive acute phase protein (APP), increased (significantly significant differences in the ACT concentration were detected at 14:00 and 22:00 h) and AGP showed a tendency to be higher under the daytime bright compared to dim light conditions. There were no significant differences between the time point means under daytime dim and bright light conditions for alpha2-M, AGP, Tf, Cp, or Hp. The findings suggest that some, but not all, APP may be influenced by the environmental light intensity.     

Intrinsic period and light intensity determine the phase relationship between melatonin and sleep in humans

The internal circadian clock and sleep-wake homeostasis regulate the timing of human brain function, physiology, and behavior so that wakefulness and its associated functions are optimal during the solar day and that sleep and its related functions are optimal at night. The maintenance of a normal phase relationship between the internal circadian clock, sleep-wake homeostasis, and the light-dark cycle is crucial for optimal neurobehavioral and physiological function. Here, the authors show that the phase relationship between these factors-the phase angle of entrainment (psi)-is strongly determined by the intrinsic period (tau) of the master circadian clock and the strength of the circadian synchronizer. Melatonin was used as a marker of internal biological time, and circadian period was estimated during a forced desynchrony protocol. The authors observed relationships between the phase angle of entrainment and intrinsic period after exposure to scheduled habitual wakefulness-sleep light-dark cycle conditions inside and outside of the laboratory. Individuals with shorter circadian periods initiated sleep and awakened at a later biological time than did individuals with longer circadian periods. The authors also observed that light exposure history influenced the phase angle of entrainment such that phase angle was shorter following exposure to a moderate bright light (approximately 450 lux)-dark/wakefulness-sleep schedule for 5 days than exposure to the equivalent of an indoor daytime light (approximately 150 lux)-dark/wakefulness-sleep schedule for 2 days. These findings demonstrate that neurobiological and environmental factors interact to regulate the phase angle of entrainment in humans. This finding has important implications for understanding physiological organization by the brain's master circadian clock and may have implications for understanding mechanisms underlying circadian sleep disorders.