Professor Skene is Section Lead of Chronobiology. She has over 25 years of research experience studying the human circadian timing system and has authored over 190 refereed research publications. Her recent research has been funded by the EU FP6, FP7 and H2020 programmes, UK Cross Research Council New Dynamics of Ageing (NDA) Programme, BBSRC (UK), MRC Newton, NIH and Vanda Pharmaceuticals. She is a Royal Society Wolfson Research Merit Award Holder.
Professor Skene is past President of the European Biological Rhythms Society (EBRS) (2012-2019) (Secretary-Treasurer2002-2009; Vice-President 2012-2015) and is a past Vice-President (Basic) of the European Sleep Research Society (ESRS) (2010-2014). In 2009 Prof Skene established the Joint ESRS-EBRS Symposia that take place each year at the biennial ESRS and EBRS Congresses. She is a past Chair of a Gordon Research Conference (Pineal Cell Biology, 2012), currently an Associate Editor of the Journal of Sleep Research and on the Editorial Board of Chronobiology International; Sleep and Biological Rhythms and Clocks & Sleep. She is a past Co-Director of Stockgrand Ltd and Surrey Assays Ltd, University-based companies specialising in the measurement of melatonin and other circadian rhythm markers.
Professor Skene and her team's research is directed towards characterisation and treatment of circadian rhythm sleep disorders as experienced by blind people, shift workers and older people. Her team's findings have led to the optimisation of melatonin (dose, time of administration) and light (wavelength, time of administration) to affect the human circadian clock. Prof Skene has pioneered studies on the spectral sensitivity of the human circadian axis, being one of the first to show the importance of short wavelength blue light. These results have important implications for the design and use of lighting in situations such as the treatment of circadian rhythm sleep disorders, adaptation to shift work as well as in work and living environments.
Currently Professor Skene's research team is studying the links between human circadian clocks, sleep and metabolism in health, circadian disorders and metabolic diseases (shift workers, Type 2 diabetes, liver disease). Investigating the effect of time of day, circadian clock, sleep and food influences on the human metabolome using targeted LC-MS metabolomics is currently a major focus.
Areas of specialism
University roles and responsibilities
- Section Leader of Chronobiology
- Academic Lead of Metabolomics Core Facility
- Module Organiser, BMS3066 Biological Rhythms
Business, industry and community links
04 MAR 2021
ENLIGHTENme - Innovative new study to investigate the impact of urban lighting on health and wellbeing
03 APR 2020
Does the immune system’s ability to fight viruses change with the seasons? New study investigates
22 FEB 2017
New discovery is a step towards developing Huntington’s disease treatments before symptoms appear
- Circadian rhythms in the blind, effect of visual loss and visual pathologies
- Characterisation and treatment of circadian rhythm disorders as experienced by blind people, shift workers, transmeridian air travellers and older people
- Role of endogenous and exogenous melatonin in circadian rhythm sleep disorders
- Investigation of circadian entrainment (optimum characteristics of light and melatonin) in humans
- Non visual light responses and characteristics of the circadian photoreception pathway in humans; age-related changes in the circadian timing system; effect of light on sleep, activity and clock timing
- Human circadian rhythms, sleep and metabolism in health, circadian disorders and metabolic diseases (shift workers, Type 2 diabetes, liver disease) using metabolomics technology.
Indicators of esteem
Royal Society Wolfson Research Merit Award, Linking light, circadian rhythms, sleep and metabolism in health and disease2011 - 2016
Chair, Gordon Research Conference on Pineal Cell Biology: Links to clocks, sleep and metabolism, Hotel Galvez, Galveston, Texas, USA, 29th January -3rd February, 2012.
- EU FP6 (Marie Curie Research Training Networks), The biomedical and sociological effects of sleep restriction, 2005-2009, Surrey PI, £1,009,228.
- EU FP6 (Integrated Project) EUCLOCK, Entrainment of the circadian clock, 2006-2011, Surrey PI, 455,898 euros.
- Cross-Council New Dynamics of Ageing (NDA) Initiative, a multidisciplinary research programme supported by AHRC, BBSRC, EPSRC, ESRC and MRC, SomnIA, Optimising quality of sleep among older people in the community and care homes: An integrated approach, 2006-2011, Co-I, £1,892,973.
- BBSRC, Food entrainment of the human circadian timing system, 2011 - 2014, Co-I, £1,203,397 (fEC).
- BBSRC, Effect of the circadian clock time of day and sleep on the human metabolome:identification of metabolite rhythms, 2011-2014, PI, £948,715 (fEC).
- EU FP7-HEALTH-2011, EuRhythDia, Impact of lifestyle interventions on diabetogenic and atherogenic effects of changes in diurnal rhythm, 2011 - 2016, Surrey PI, 332,637 euros.
- MRC Newton001, RCUK-CONFAP Research Partnerships, Sleep deprivation in Parkinson's disease: Brazil and United Kingdom research network, 2015-2016, PI £49,857 to UK; and £50,000 to Brazil.
- Vanda Pharmaceuticals, Confidential - VP-VEC-162-0101, 2015 - 2017, PI, £363,755.
- Vanda Pharmaceuticals, Confidential - VP-VEC-162-2102, 2016 - 2017, PI, £182,313.
- NIH Early Independence Award to M.E. Martinez-Bakker (PI) (RM-15-006), Columbia University, US, Hacking epidemics: unlocking the drivers of transmission seasonality to battle vaccine-preventable diseases, 2016 - 2021, Co-I, £333,360.
- BBSRC, Anticipation of meal time in humans, 2019 - 2022, Co-I, £1,012,559 (fEC).
- UKRI Open Call COVID-19 BBSRC grant, Molecular mapping of SARS-Cov2 and the host response with multiomics mass spectrometry to stratify disease outcomes for preventative, therapeutic and diagnostic intervention, 2020 - 2022, COVID-19 MS Coalition, Co-I, £1.8M (£489,000 to Surrey).
- EU H2020-SC1-2020-Two-Stage-RTD, ENLIGHTENme, Innovative policies for improving citizens’ health and wellbeing addressing indoor and outdoor lighting, 2020 - 2025, (S. Tondelli (PI), 22 Partners, 4,999,909 euros), Surrey PI, 277,084 euros.
Objectives: Night shift work is associated with high rates of hypertension and cardiometabolic disease, which are linked to disrupted circadian rhythms. We hypothesized that timed light therapy might improve disrupted circadian rhythms and stabilize diurnal control of blood pressure and glucose in night shift workers. Mthods: We randomized 24 rotating night shift workers (mean age, 36 ± 13 years, 7 men) who had spent a median of 6 years on rotating night shifts (median, six night shifts per month) to 12 weeks of light therapy or no intervention and compared them with 12 daytime workers (37 ± 11 years, 6 men). We measured oral glucose tolerance (OGTT), 24-h blood pressure and arterial stiffness, and the circadian profiles of melatonin, cortisol, metanephrine and nor-metanephrine at baseline, after 12 weeks of intervention, and 12 weeks after the end of intervention. Results: At baseline, fewer night shift workers showed dipper status as compared with daytime workers (29 vs. 58%; P
Study Objectives: To screen the PER3 promoter for polymorphisms and investigate the phenotypic associations of these polymorphisms with diurnal preference, delayed sleep phase disorder/syndrome (DSPD/DSPS), and their effects on reporter gene expression. Design: Interspecific comparison was used to define the approximate extent of the PER3 promoter as the region between the transcriptional start site and nucleotide position −874. This region was screened in DNA pools using PCR and direct sequencing, which was also used to screen DNA from individual participants. The different promoter alleles were cloned into a luciferase expression vector and a deletion library created. Promoter activation was measured by chemiluminescence. Setting: N/A Patients or Participants: DNA samples were obtained from volunteers with defined diurnal preference (3 x 80, selected from a pool of 1,590), and DSPD patients (n = 23). Interventions: N/A Measurements and Results: We verified three single nucleotide polymorphisms (G −320T, C −319A, G −294A), and found a novel variable number tandem repeat (VNTR) polymorphism (−318 1/2 VNTR). The −320T and −319A alleles occurred more frequently in DSPD compared to morning (P = 0.042 for each) or evening types (P = 0.006 and 0.033). The allele combination TA2G was more prevalent in DSPD compared to morning (P = 0.033) or evening types (P = 0.002). Luciferase expression driven by the TA2G combination was greater than for the more common GC2A (P < 0.05) and the rarer TA1G (P < 0.001) combinations. Deletion reporter constructs identified two enhancer regions (−703 to −605, and −283 to −80). Conclusions: Polymorphisms in the PER3 promoter could affect its expression, leading to potential differences in the observed functions of PER3.
We aimed to examine the effects of night work on salivary melatonin concentration during and subsequent to night work and the mediating role of light. We included 254 day workers and 87 night workers who were followed during 322 work days and 301 days off work. Each day was defined as the 24 hour period starting from the beginning of a night shift or from waking in the mornings with day work and days off. Light levels were recorded and synchronized with diary information (start and end of sleep and work). On average, participants provided four saliva samples per day, and these were analyzed for melatonin concentration by liquid chromatography tandem mass spectrometry (LC-MS/MS). Differences between day and night workers on work days and days off were assessed with multilevel regression models with melatonin concentration as the primary outcome. All models were stratified or adjusted by time of day. For light exposure, we estimated the total, direct and indirect effects of night work on melatonin concentrations obtaining 95% confidence intervals through bootstrapping. On work days, night workers showed 15% lower salivary melatonin concentrations compared with day workers (−15.0%; 95% CI: −31.4%; 5.2%). During the night, light exposure mediated a melatonin suppression of approximately 6% (−5.9%, 95% CI: −10.2%; −1.5%). No mediating effect of light was seen during the day time. On days off, we observed no difference in melatonin concentrations between day and night workers. These findings are in accordance with a transient and partly light-mediated effect of night work on melatonin production.
Humans have largely supplanted natural light cycles with a variety of artificial light sources and schedules misaligned with day-night cycles. Circadian disruption has been linked to a number of disease processes, but the extent of circadian disruption among the population is unknown. We measured light exposure and wrist temperature among residents of an urban area for a full week during each of the four seasons, as well as light illuminance in nearby outdoor locations. Daily light exposure was significantly lower for individuals, compared to outdoor light sensors, for all four seasons. There was also little seasonal variation in the realized photoperiod experienced by individuals, with the only significant difference between winter and summer. We tested the hypothesis that differential light exposure impacts circadian phase timing, detected via the wrist temperature rhythm. To determine the influence of light exposure on circadian rhythms, we modeled the impact of morning, afternoon, and nighttime light exposure on the timing of the midline-estimating statistic of rhythm (MESOR). We found that morning light exposure and nighttime light exposure had a significant but opposing impact on MESOR timing. Our results demonstrate that nighttime light can shift/alter circadian rhythms to delay the morning transition from nighttime to daytime physiology, while morning light can lead to earlier onset. Our results demonstrate that circadian shifts and disruptions may be a more regular occurrence in the general population than is currently recognized. Significance Statement: Disruption of circadian rhythms has been linked to various diseases, but the prevalence of circadian disruption among the general population is unknown. Light plays a pivotal role in entraining circadian rhythms to the 24-hour day. Humans have largely supplanted natural light cycles with electrical lighting and through time spent indoors. We have shown that individuals experience a disconnect from natural light cycles, with low daytime light exposure, high levels of light-at-night, and minimal seasonal variation in light exposure. We identified measurable changes in the timing of wrist temperature rhythms as a function of differential light exposure during the morning and nighttime hours. Our findings suggest that circadian shifts, and potentially disruption, may be common in the general population.
Light influences diverse aspects of human physiology and behaviour including neuroendocrine function, the circadian system and sleep. A role for melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) in driving such effects is well-established. However, rod and/or cone signals routed through ipRGCs could also influence 'non-visual' spectral sensitivity. In humans, this has been most extensively studied for acute, light-dependent, suppression of nocturnal melatonin production. Of the published action spectra for melatonin suppression, one demonstrates a spectral sensitivity consistent with that expected for melanopsin while our own (using briefer 30 min light exposures) displays very high sensitivity to short wavelength light, suggesting a contribution of S-cones. To clarify that possibility, six healthy young male participants were each exposed to 30 min of five irradiances of 415 nm monochromatic light (1 - 40 µW/cm ) across different nights. These data were then combined with the original action spectrum. The aggregated data are incompatible with the involvement of any single opsin and multi-opsin models based on the original action spectrum (including Circadian Stimulus) fail to predict the responses to 415 nm stimuli. Instead, the extended action spectrum can be most simply approximated by an ~2:1 combination of melanopsin and S-cone signals. Such a model also better describes the magnitude of melatonin suppression observed in other studies using an equivalent 30 min mono- or polychromatic light paradigm but not those using longer (90 min) light exposures. In sum, these data provide evidence for an initial S-cone contribution to melatonin suppression that rapidly decays under extended light exposure.
Today's modern society is exposed to artificial electric lighting in addition to the natural light-dark cycle. Studies assessing the impact of electric light exposure on sleep and its relation to work hours are rare due to the ubiquitous presence of electricity. Here we report a unique study conducted in two phases in a homogenous group of rubber tappers living and working in a remote area of the Amazon forest, comparing those living without electric light (n = 243 in first phase; n = 25 in second phase) to those with electric light at home (n = 97 in first phase; n = 17 in second phase). Questionnaire data (Phase 1) revealed that rubber tappers with availability of electric light had significantly shorter sleep on work days (30 min/day less) than those without electric light. Analysis of the data from the Phase 2 sample showed a significant delay in the timing of melatonin onset in workers with electric light compared to those without electric light (p
Shift workers experience chronic circadian misalignment, which can manifest itself in reduced melatonin production, and has been associated with metabolic disorders. In addition, chronotype modulates the effect of night shift work, with early types presenting greater circadian misalignment when working night shift as compared to late types. Melatonin supplementation has shown positive results reducing weight gain in animal models, but the effect of exogenous melatonin in humans on body weight in the context of shift work remains inconsistent. The aim of this study was thus to evaluate the effects of exogenous melatonin on circadian misalignment and body weight among overweight night shift workers, according to chronotype, under real life conditions. We conducted a double-blind, randomized, placebo-controlled, crossover trial where melatonin (3 mg) or placebo was administered on non-night shift nights for 12 weeks in 27 female nurses (37.1 yo, ±5.9 yo; BMI 29.9 kg/m2, ±3.3 kg/m2). Melatonin (or placebo) was only taken on nights when the participants did not work night shifts, that is, on nights when they slept (between night shifts and on days-off). Composite Phase Deviations (CPD) of actigraphy-based midsleep timing were calculated to measure circadian misalignment. The analyses were performed for the whole group and by chronotype. We found approximately 20% reduction of circadian misalignment after exogenous melatonin administration considering all chronotypes. Moreover, melatonin supplementation in those who presented high circadian misalignment, as observed in early chronotypes, reduced body weight, BMI, waist circumference, and hip circumference, without any change in the participants’ calorie intake or physical activity levels.
The aim of this pilot study was to explore the risk of metabolic abnormalities in steel workers employed in different shift-work rotations. Male workers in a steel factory [16 employed in a fast clockwise rotation (CW), 18 in slow counterclockwise rotation (CC), 9 day workers (DW); mean age 43.3 ± SD 6.8 years] with at least 5 years experience in their current work schedule participated. All workers provided fasting blood samples between 06:00 and 08:00 h for plasma glucose, insulin, apo-lipoproteins A and B (ApoA, ApoB), high- and low-density lipoproteins (HDL and LDL), total cholesterol (tCH), triglycerides (TG), minimally oxidized (mox) LDL, C-reactive protein (CRP), interleukin-8 (IL-8) and serum 25-hydroxyvitamin D (25(OH)D). HOMA index (homeostatic model assessment) was calculated to evaluate insulin resistance, beta cell function and risk of diabetes. Information on demographics, health, stimulants, sleep, social and work life, chronotype (phase of entrainment) and social jetlag (difference between mid-sleep on workdays and free days) as a surrogate for circadian disruption was collected by questionnaire. Neither chronotype nor social jetlag was associated with any of the metabolic risk blood markers. There were no significant differences in 25(OH)D, ApoA, ApoB, CRP, HDL, IL-8, insulin, LDL, mox-LDL, mox-LDL/ApoB ratio, tCH and TG levels between the three work groups. Although we did observe absolute differences in some of these markers, the small sample size of our study population might prevent these differences being statistically significant. Fasting glucose and HOMA index were significantly lower in CW compared to DW and CC, indicating lower metabolic risk. Reasons for the lower fasting glucose and HOMA index in CW workers remains to be clarified. Future studies of workers in different shift rotations are warranted to understand better the differential effects of shift-work on individual workers and their health indices.
The purpose of this study was to assess whether there is a difference in bone resorption by degree of seasonal change in 25(OH)D and whether this varies by ethnicity. In the recent D-FINES study, (Vitamin D, Food Intake, Nutrition and Exposure to Sunlight in Southern England, 2006-2007), a subset of n=65 from the 293 participants (South Asian (n 30) and Caucasian (n 35)) had blood taken in four seasons for determination of 25(OH)D and serum c-telopeptide (sCTX). sCTX was measured using an electrochemiluminescent immunoassay (Roche cobas e411). Seasonal fluctuation of 25(OH)D was assessed by calculating differences between the winter (nadir) and summer (peak) 25(OH)D. For ease of interpretation these changes were expressed as positive values. This enabled investigation of the absolute change in 25(OH)D but not its direction. This variable was then split into quartiles within ethnicity. The dependent variables were absolute concentration of sCTX in each season as well as summer to winter change in sCTX. ANCOVA was run with absolute summer and winter 25(OH)D status, age, BMI, socioeconomic status, physical activity, and dietary calcium as covariates. In the Asian group there was no clear trend between degree of seasonal fluctuation and absolute sCTX. Indeed, only the autumn data was statistically significant (F=5.93; p= 0.01) and with no consistent pattern among the quartiles. No data were significant for change in summer to winter sCTX in Asians or Caucasians despite a trend in both ethnic groups for lower sCTX in the middle quartiles relative to the highest and lowest. Last, in Caucasians, there was a non-statistically significant (p.0.05) inverse trend between cycling of 25(OH)D and absolute serum C-telopeptide levels. These data suggest lower bone resorption in all seasons in Caucasians with increased cycling, and a reduction in sCTX between summer and winter in both ethnic groups in the middle quartile relative to the other quartiles. As the values were covariate adjusted, these findings are not likely to be due to other variables. However, it must be borne in mind that these results are only trends, which is likely due to the small numbers of subjects. Further research is required to analyse banked urine samples from the D-FINES study (n 293) which would enable us to see if these results are statistically significant with increased statistical power. The D-FINES study was funded by the UK Food Standards Agency. All views are those of the authors alone
This analysis assessed whether seasonal change in 25-hydroxyvitamin D concentration was associated with bone resorption, as evidenced by serum parathyroid hormone and C-terminal telopeptide concentrations. The main finding was that increased seasonal fluctuation in 25-hydroxyvitamin D was associated with increased levels of parathyroid hormone and C-terminal telopeptide. Introduction: It is established that adequate 25-hydroxyvitamin D (25(OH)D, vitamin D) concentration is required for healthy bone mineralisation. It is unknown whether seasonal fluctuations in 25(OH)D also impact on bone health. If large seasonal fluctuations in 25(OH)D were associated with increased bone resorption, this would suggest a detriment to bone health. Therefore, this analysis assessed whether there is an association between seasonal variation in 25(OH)D and bone resorption. Methods: The participants were (n = 279) Caucasian and (n = 88) South Asian women (mean (±SD); age 48.2 years (14.4)) who participated in the longitudinal Diet, Food Intake, Nutrition and Exposure to the Sun in Southern England study (2006-2007). The main outcomes were serum 25(OH)D, serum parathyroid hormone (sPTH) and serum C-terminal telopeptide of collagen (sCTX), sampled once per season for each participant. Results: Non-linear mixed modelling showed the (amplitude/mesor) ratio for seasonal change in log 25(OH)D to be predictive of log sPTH (estimate = 0.057, 95 % CI (0.051, 0.063), p < 0.0001). Therefore, individuals with a higher seasonal change in log 25(OH)D, adjusted for overall log 25(OH)D concentration, showed increased levels of log sPTH. There was a corresponding significant ability to predict the range of seasonal change in log 25(OH)D through the level of sCTX. Here, the corresponding parameter statistics were estimate = 0.528, 95 % CI (0.418, 0.638) and p ≤ 0.0001. Conclusions: These findings suggest a possible detriment to bone health via increased levels of sPTH and sCTX in individuals with a larger seasonal change in 25(OH)D concentration. Further larger cohort studies are required to further investigate these preliminary findings. © 2013 International Osteoporosis Foundation and National Osteoporosis Foundation.
Introduction: It has been hypothesised that the U shaped association between 25(OH)D and some health outcomes may be due to large seasonal fluctuations of 25(OH)D1. It is unknown whether such fluctuation of 25(OH)D (‘cycling’) influences bone health. Methods: In the D-FINES study, n=373 women (South Asian/Caucasian) had repeated measurements in four seasons for serum 25(OH)D and PTH. A random sample (n=66) were measured for serum C-telopeptide (CTX). Seasonal cycling of 25(OH)D was assessed as the absolute difference between winter (nadir) and summer (peak) 25(OH)D and was split into quartiles within ethnicity. Summer to winter change in CTX and PTH were calculated. Results and Discussion: ANCOVA showed no statistically significant association between quartile of cycling of 25(OH)D and CTX or PTH. However, in Asians, there was a trend for increased cycling to be associated with reduced PTH but not CTX, and for an increase in PTH from summer to winter. In Caucasians, there was a trend for increased cycling in all seasons to be associated with reduced CTX. However, increased cycling was associated with increased PTH in summer and spring, but lower PTH in other seasons, as well as a reduction in PTH from summer to winter (p=0.06). Therefore increased cycling in Caucasians was associated with lower bone resorption and was differentially associated with PTH depending on season. Further analysis of banked samples for urine CTX (n=1500) will enable these novel results to be explored further.
There is a lack of research into 25-hydroxyvitamin D (25(OH)D) status, light exposure and sleep patterns in South Asian populations. In addition, results of research studies are conflicting as to whether there is an association between 25(OH)D status and sleep quality. We investigated 25(OH)D status, self-reported and actigraphic sleep quality in n = 35 UK dwelling postmenopausal women (n = 13 South Asians, n = 22 Caucasians), who kept daily sleep diaries and wore wrist-worn actiwatch (AWL-L) devices for 14 days. A subset of n = 27 women (n = 11 South Asian and n = 16 Caucasian) also wore a neck-worn AWL-L device to measure their light exposure. For 25(OH)D concentration, South Asians had a median ± IQR of 43.8 ± 28.2 nmol/L, which was significantly lower than Caucasians (68.7 ± 37.4 nmol/L)(P = 0.001). Similarly, there was a higher sleep fragmentation in the South Asians (mean ± SD 36.9 ± 8.9) compared with the Caucasians (24.7 ± 7.1)(P = 0.002). Non-parametric circadian rhythm analysis of rest/activity patterns showed a higher night-time activity (L5) (22.6 ± 14.0 vs. 10.5 ± 4.4; P = 0.0008) and lower relative amplitude (0.85 ± 0.07 vs. 0.94 ± 0.02; P ˂ 0.0001) in the South Asian compared with the Caucasian women. More South Asians (50%) met the criteria for sleep disorders (PSQI score ˃5) than did Caucasians (27%) (P = 0.001, Fishers Exact Test). However, there was no association between 25(OH)D concentration and any sleep parameter measured (P ˃ 0.05) in either ethnic group. South Asians spent significantly less time in illuminance levels over 200 lx (P = 0.009) than did Caucasians. Overall, our results show that postmenopausal South Asian women have lower 25(OH)D concentration than Caucasian women. They also have higher sleep fragmentation, as well as a lower light exposure across the day. This may have detrimental implications for their general health and further research into sleep quality and light exposure in the South Asian ethnic group is warranted.
It has been hypothesised that the U shaped association between 25(OH)D and some health outcomes may be due to large seasonal fluctuations of 25(OH)D1. It is unknown whether such fluctuation of 25(OH)D (‘cycling’) influences bone health. This is an important issue, because if ‘cycling’ is detrimental for bone, then winter only rather than year round vitamin D supplementation may be useful for bone health to ‘blunt’ the rhythm. In the D-FINES study, n = 373 women (South Asian/Caucasian) had repeated measurements in four seasons for serum 25(OH)D and PTH, as well as a DXA scan in autumn and spring. Serum C-telopeptide (sCTX) was also measured in a random subset (n = 66). Cosinor regression analysis was used to identify individuals showing a significant rhythm (p < 0.10) (‘cyclers’) and those not showing a significant seasonal rhythm (‘non-cyclers’). Potential differences in bone indices between the two groups were assessed within ethnicity. Dependent variables analysed were absolute values for autumn femoral neck and lumbar spine BMD, BMC and bone area, and absolute sCTX and sPTH in each season. Also, change in sCTX and sPTH from summer to winter and change in DXA bone indices from autumn to spring were analysed. ANCOVA was run, adjusting for summer and winter 25(OH)D status, age, socioeconomic status, physical activity, and dietary calcium. BMI was also controlled for in the analysis due to its negative correlation with seasonal change in 25(OH)D. There was no statistically significant difference (p>0.05) between ‘cyclers’ and ‘non-cyclers’ for any of the bone indices in either ethnic group. However, there were trends for a higher CTX and PTH in ‘cyclers’ versus ‘non-cyclers’ in both ethnic groups in every season, but no differences for BMD or BMC (Figs. 1–4). This suggests tentatively that ‘cycling’ could be associated with changes in bone metabolism but may not translate into structural changes. In summary, there is no clear evidence here to suggest that ‘cycling’ is detrimental to bone health, although there are trends in PTH and CTX that warrant further investigation with a larger sample.
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Genome biology approaches have made enormous contributions to our understanding of biological rhythms, particularly in identifying outputs of the clock, including RNAs, proteins, and metabolites, whose abundance oscillates throughout the day. These methods hold significant promise for future discovery, particularly when combined with computational modeling. However, genome-scale experiments are costly and laborious, yielding “big data” that are conceptually and statistically difficult to analyze. There is no obvious consensus regarding design or analysis. Here we discuss the relevant technical considerations to generate reproducible, statistically sound, and broadly useful genome-scale data. Rather than suggest a set of rigid rules, we aim to codify principles by which investigators, reviewers, and readers of the primary literature can evaluate the suitability of different experimental designs for measuring different aspects of biological rhythms. We introduce CircaInSilico, a web-based application for generating synthetic genome biology data to benchmark statistical methods for studying biological rhythms. Finally, we discuss several unmet analytical needs, including applications to clinical medicine, and suggest productive avenues to address them.
Many aspects of human physiology and behavior are dominated by 24-hour circadian rhythms that have a major impact on our health and well-being, including the sleep-wake cycle, alertness and performance patterns, and many daily hormone profiles. These rhythms are spontaneously generated by an internal "pacemaker" in the hypothalamus, and daily light exposure to the eyes is required to keep these circadian rhythms synchronized both internally and with the external environment. Sighted individuals take this daily synchronization process for granted, although they experience some of the consequences of circadian desynchrony when "jetlagged" or working night shifts. Most blind people with no perception of light, however, experience continual circadian desynchrony through a failure of light information to reach the hypothalamic circadian clock, resulting in cyclical episodes of poor sleep and daytime dysfunction. Daily melatonin administration, which provides a replacement synchronizing daily "time cue, " is a promising therapeutic strategy, although optimal treatment dose and timing remain to be determined.
Circadian rhythms, metabolism and nutrition are intimately linked [1, 2], although effects of meal timing on the human circadian system are poorly understood. We investigated the effect of a 5-hour delay in meals on markers of the human master clock and multiple peripheral circadian rhythms. Ten healthy young men undertook a 13-day laboratory protocol. Three meals (breakfast, lunch, dinner) were given at 5-hour intervals, beginning either 0.5 (early) or 5.5 (late) hours after wake. Participants were acclimated to early meals and then switched to late meals for 6 days. After each meal schedule, participants' circadian rhythms were measured in a 37-hour constant routine that removes sleep and environmental rhythms while replacing meals with hourly isocaloric snacks. Meal timing did not alter actigraphic sleep parameters before circadian rhythm measurement. In constant routines, meal timing did not affect rhythms of subjective hunger and sleepiness, master clock markers (plasma melatonin and cortisol), plasma triglycerides, or clock gene expression in whole blood. Following late meals, however, plasma glucose rhythms were delayed by 5.69 ± 1.29 hours (p < 0.001) and average glucose concentration decreased by 0.27 ± 0.05 mM (p < 0.001). In adipose tissue, PER2 mRNA rhythms were delayed by 0.97 ± 0.29 hours (p < 0.01), indicating that human molecular clocks may be regulated by feeding time and could underpin plasma glucose changes. Timed meals therefore play a role in synchronising peripheral circadian rhythms in humans, and may have particular relevance for patients with circadian rhythm disorders, shift workers, and transmeridian travellers.
Electrical activity in the heart exhibits 24-hour rhythmicity, and potentially fatal arrhythmias are more likely to occur at specific times of day. Here, we demonstrate that circadian clocks within the brain and heart set daily rhythms in sinoatrial (SA) and atrioventricular (AV) node activity, and impose a time-of–day dependent susceptibility to ventricular arrhythmia. Critically, the balance of circadian inputs from the autonomic nervous system and cardiomyocyte clock to the SA and AV nodes differ, and this renders the cardiac conduction system sensitive to decoupling during abrupt shifts in behavioural routine and sleep-wake timing. Our findings reveal a functional segregation of circadian control across the heart’s conduction system and inherent susceptibility to arrhythmia.
Studying communities with different levels of urbanization may further the understanding of risk factors underlying metabolic diseases. The present study is unique by comprising detailed assessment of sleep and activity, biological rhythms, and metabolic factors of men from the same geographical location and place of birth that reside in different, rural vs. town, stages of urbanization. Sleep patterns, activity, and metabolic indicators in two groups (rural, n = 22 and town/urban, n = 20) of men residing in an Amazonian community (Xapuri, Acre, Brazil) were compared. Sociodemographic, anthropometric, and metabolic variables – fasting glucose, insulin resistance, triglycerides, total HDL cholesterol, LDL cholesterol, and VLDL cholesterol – were assessed. Sleep patterns, light exposure, and physical activity levels were additionally assessed by actigraphy, plus daily activities were recorded in diaries for 10 days. Town/urban dwellers were found to have significantly higher body weight, fasting glucose, insulin levels, and insulin resistance than rural dwellers, whereas triglycerides levels were similar. Town/Urban dwellers had shorter sleep duration (p < .01) and later sleep onset and offset times (p = .01). Our findings show an association between stage of urbanization and presence of risk factors for metabolic disorders, such as overweight, insulin resistance, increased glucose levels, short sleep duration, and less natural light exposure during work times.
Misalignment between internal circadian rhythmicity and externally imposed behavioral schedules, such as occurs in shift workers, has been implicated in elevated risk of metabolic disorders. To determine underlying mechanisms, it is esse ntial to assess whether and how peripheral clocks are disturbed during shift work and to what extent this is linked to the central suprachiasmatic nuclei (SCN) pacemaker and/or misaligned behavioral time cues. Investigating rhythms in circulating metabolites as biomarkers of peripheral clock distur- bances may offer new insight s. We evaluated the impact of misaligned sleep/wake and feeding/fasting cycles on circulating metabolites using a targeted metabolomics approach. Sequential plasma samples obtained during a 24-h constant routine that followed a 3-d simulated night-s hift schedule, compared with a simulated day-shift schedule, we re analyzed for 132 circulating metabolites. Nearly half of these metabolites showed a 24-h rhyth- micity under constant routine following either or both simulated shift schedules. However, while tradition al markers of the circadian clock in the SCN — melatonin, cortisol, and PER3 expression — maintained a stable phase alignment after both schedules, only a few metabo- lites did the same. Many showed reversed rhythms, lost their rhythms, or showed rhythmicity only under constant routine fol- lowing the night-shift schedule. Here, 95% of the metabolites with a 24-h rhythmicity showed rhythms that were driven by behavior- al time cues externally imposed during the preceding simulated shift schedule rather than being driven by the central SCN circa- dian clock. Characterization of these metabolite rhythms will pro- vide insight into the underlying mechanisms linking shift work and metabolic disorders
Although daily rhythms regulate multiple aspects of human physiology, rhythmic control of the metabolome remains poorly understood. The primary objective of this proof-of-concept study was identification of metabolites in human plasma that exhibit significant 24-h variation. This was assessed via an untargeted metabolomic approach using liquid chromatography-mass spectrometry (LC-MS). Eight lean, healthy, and unmedicated men, mean age 53.6 (SD ± 6.0) yrs, maintained a fixed sleep/wake schedule and dietary regime for 1 wk at home prior to an adaptation night and followed by a 25-h experimental session in the laboratory where the light/dark cycle, sleep/wake, posture, and calorific intake were strictly controlled. Plasma samples from each individual at selected time points were prepared using liquid-phase extraction followed by reverse-phase LC coupled to quadrupole time-of-flight MS analysis in positive ionization mode. Time-of-day variation in the metabolites was screened for using orthogonal partial least square discrimination between selected time points of 10:00 vs. 22:00 h, 16:00 vs. 04:00 h, and 07:00 (d 1) vs. 16:00 h, as well as repeated-measures analysis of variance with time as an independent variable. Subsequently, cosinor analysis was performed on all the sampled time points across the 24-h day to assess for significant daily variation. In this study, analytical variability, assessed using known internal standards, was low with coefficients of variation
Isolation from external time cues allows endogenous circadian rhythmicity to be demonstrated. In this study, also filmed as a television documentary, we assessed rhythmic changes in a healthy man time isolated in a bunker for 9 days/nights. During this period the lighting conditions were varied between: (1) self-selected light/dark cycle, (2) constant dim light, and (3) light/dark cycle with early wake up. A range of variables was assessed and related to the sleep-wake cycle, psychomotor and physical performance and clock-time estimation. This case study using modern non-invasive monitoring techniques emphasizes how different physiological circadian rhythms persist in temporal isolation under constant dim light conditions with different waveforms, free-running with a period (t) between 24 and 25 h. In addition, a significant correlation between time estimation and mid-sleep time, a proxy for circadian phase, was demonstrated.
The response to a zeitgeber, particularly the light/dark cycle, may vary phenotypically. Phenotypic plasticity can be defined as the ability of one genome to express different phenotypes in response to environmental variation. In this opinion paper, we present some evidence that one of the most prominent effects of the introduction of electric light to the everyday life of humans is a significant increase in phenotypic plasticity and differences in interindividual phases of entrainment. We propose that the healthy limits of phenotypic plasticity have been surpassed in contemporary society.
Architectural lighting has potent biological effects but applied lighting practices that capitalize on this potential have been limited. In this review, we endeavor to consolidate and synthesize key references that will be useful for lighting professionals, with the goal of supporting knowledge translation into pragmatic lighting strategies. Specifically, we explain relevant terminology, outline basic concepts, identify key references, provide a balanced overview of the current state of knowledge, and highlight important remaining questions. We summarize the physiological effects of light on human health and well-being, including a description of the processes underlying the photic regulation of circadian, neuroendocrine, and neurobehavioral functions. We review seminal work elucidating the elements mediating the potency of light for these physiological responses, with specific attention to factors critical for interpreting those findings. In parallel, we explain and endorse melanopic Equivalent Daylight Illuminance ( ) as the 𝐸 𝐷65 𝑣, 𝑚𝑒𝑙 preferred measure to quantify the biological potency of light. Ultimately, while future studies are necessary to further facilitate the translation of laboratory knowledge to domestic and workplace settings, the immediate potential for applied lighting to better support human health is clear. Aiming for integrative lighting solutions that have biologically high potency light during the day and low potency during the night is perhaps the most immediate improvement to be made in order to better support applications for humans.
Local and national governments around the world are currently considering the elimination of the annual switch to and from Daylight Saving Time (DST). As an international organization of scientists dedicated to studying circadian and other biological rhythms, the Society for Research on Biological Rhythms (SRBR) engaged experts in the field to write a Position Paper on the consequences of choosing to live on DST or Standard Time (ST). The authors take the position that, based on comparisons of large populations living in DST or ST or on western versus eastern edges of time zones, the advantages of permanent ST outweigh switching to DST annually or permanently. Four peer reviewers provided expert critiques of the initial submission, and the SRBR Executive Board approved the revised manuscript as a Position Paper to help educate the public in their evaluation of current legislative actions to end DST.
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.
Functional connectivity (FC) of the motor network (MN) is often used to investigate how intrinsic properties of the brain are associated with motor abilities and performance. In addition, the MN is a key feature in clinical work to map the recovery after stroke and aid the understanding of neurodegenerative disorders. Time of day variation and individual differences in circadian timing, however, have not yet been considered collectively when looking at FC. A total of 33 healthy, right handed individuals (13 male, 23.1 ± 4.2 years) took part in the study. Actigraphy, sleep diaries and circadian phase markers (dim light melatonin onset and cortisol awakening response) were used to determine early (ECP, n =13) and late (LCP, n = 20) circadian phenotype groups. Resting state functional MRI testing sessions were conducted at 14:00 h, 20:00 h and 08:00 h and preceded by a maximum voluntary contraction test for isometric grip strength to measure motor performance. Significant differences in FC of the MN between ECPs and LCPs were found, as well as significant variations between different times of day. A higher amplitude in diurnal variation of FC and performance was observed in LCPs compared to ECPs, with the morning being most significantly affected. Overall, lower FC was significantly associated with poorer motor performance. Our findings uncover intrinsic differences between times of day and circadian phenotype groups. This suggests that central mechanisms contribute to diurnal variation in motor performance and the functional integrity of the MN at rest influences the ability to perform in a motor task.
Light can be used to facilitate alertness, task performance and circadian adaptation during night work. Novel strategies for illumination of workplaces, using ceiling mounted LED-luminaires, allow the use of a range of different light conditions, altering intensity and spectral composition. This study (ClinicalTrials.gov Identifier NCT03203538) investigated the effects of short-wavelength narrow-bandwidth light (λmax = 455 nm) compared to long-wavelength narrow-bandwidth light (λmax = 625 nm), with similar photon density (~2.8 × 1014 photons/cm2/s) across light conditions, during a simulated night shift (23:00–06:45 h) when conducting cognitive performance tasks. Light conditions were administered by ceiling mounted LED-luminaires. Using a within-subjects repeated measurements study design, a total of 34 healthy young adults (27 females and 7 males; mean age = 21.6 years, SD = 2.0 years) participated. The results revealed significantly reduced sleepiness and improved task performance during the night shift with short-wavelength light compared to long-wavelength light. There was also a larger shift of the melatonin rhythm (phase delay) after working a night shift in short-wavelength light compared to long-wavelength light. Participants’ visual comfort was rated as better in the short-wavelength light than the long-wavelength light. Ceiling mounted LED-luminaires may be feasible to use in real workplaces, as these have the potential to provide light conditions that are favorable for alertness and performance among night workers.
Circadian (∼24-hour) timing systems pervade all kingdoms of life and temporally optimize behavior and physiology in humans. Relatively recent changes to our environments, such as the introduction of artificial lighting, can disorganize the circadian system, from the level of the molecular clocks that regulate the timing of cellular activities to the level of synchronization between our daily cycles of behavior and the solar day. Sleep/wake cycles are intertwined with the circadian system, and global trends indicate that these, too, are increasingly subject to disruption. A large proportion of the world's population is at increased risk of environmentally driven circadian rhythm and sleep disruption, and a minority of individuals are also genetically predisposed to circadian misalignment and sleep disorders. The consequences of disruption to the circadian system and sleep are profound and include myriad metabolic ramifications, some of which may be compounded by adverse effects on dietary choices. If not addressed, the deleterious effects of such disruption will continue to cause widespread health problems; therefore, implementation of the numerous behavioral and pharmaceutical interventions that can help restore circadian system alignment and enhance sleep will be important.
Daylight is ubiquitous and is crucial for mammalian vision as well as for non-visual input to the brain via the intrinsically photosensitive retinal ganglion cells (ipRGCs) that express the photopigment melanopsin. The ipRGCs project to the circadian clock in the suprachiasmatic nuclei and thereby ensure entrainment to the 24-hour day-night cycle, and changes in daylength trigger the appropriate seasonal behaviours. The ipRGCs also project to the perihabenular nucleus and surrounding brain regions that modulate mood, stress and learning in animals and humans. Given that light has strong direct effects on mood, cognition, alertness, performance, and sleep, light can be considered a “drug” to treat many clinical conditions. Light therapy is already well established for winter and other depressions and circadian sleep disorders. Beyond visual and non-visual effects via the retina, daylight contributes to prevent myopia in the young by its impact on eye development, and is important for Vitamin D synthesis and bone health via the skin. The sun is the most powerful light source and, dependent on dose, its ultraviolet radiance is toxic for living organisms and can be used as a disinfectant. Most research involves laboratory-based electric light, without the dynamic and spectral changes that daylight undergoes moment by moment. There is a gap between the importance of daylight for human beings and the amount of research being done on this subject. Daylight is taken for granted as an environmental factor, to be enjoyed or avoided, according to conditions. More daylight awareness in architecture and urban design beyond aesthetic values and visual comfort may lead to higher quality work and living environments. Although we do not yet have a factual basis for the assumption that natural daylight is overall “better” than electric light, the environmental debate mandates serious consideration of sunlight not just for solar power but also as biologically necessary for sustainable and healthy living.
A recent proof-of-concept pilot study proposed using microRNA (miRNA) markers for time of death determination. The markers – miRNA-142-5p and miRNA-541, were reported to show considerable expression differences in vitreous humor between individuals who died during the day or night. Here, we investigated whether these miRNA markers show the same diurnal expression pattern in blood, which would make them useful for estimating bloodstain deposition time to allow molecular alibi testing for forensic casework. We analyzed venous blood samples collected from 12 healthy individuals every 4 h during the 24 h day/night period under controlled sleep-laboratory conditions. MiRNA-142-5p normalized against miRNA-222 showed no statistically significant expression differences between blood samples collected during daytime and nighttime (one-way ANOVA p = 0.81), and also no statistically significant rhythmicity during the 24 h day/night period (cosine fit for all individuals p > 0.05, averaged data p = 0.932). MicroRNA-541 amplification in blood was above the 34-cycle threshold applied in the study, indicating too low quantities for obtaining reliable data. Overall, we conclude that the two miRNA markers previously suggested for time of death determination in vitreous humor are not suitable for estimating the deposition time of forensic bloodstains. Future studies may find out if miRNA markers with significant diurnal expression patterns can be identified and how useful they would be for forensic trace deposition timing.
OBJECTIVES: This study aimed to investigate the relationship between individual natural light exposure, sleep need, and depression at two latitudes, one extreme with a few hours of light per day during winter, and the other with equal hours of light and darkness throughout the year. METHODS: This cross-sectional study included a sample of Brazilian workers (Equatorial, n = 488 workers) and a Swedish sample (Arctic, n = 1,273). RESULTS: The reported mean total natural light exposure per 4-week cycle differed significantly between the Equatorial and Arctic regions. However, shiftworkers from both sites reported similar hours of natural light exposure. Short light exposure was a predictor for insufficient sleep. CONCLUSION: Reduced exposure to natural light appears to increase the perception of obtaining insufficient sleep. Arctic workers were more prone to develop depression than Equatorial workers.
Background There is conflict between living according to our endogenous biological rhythms and our external environment, with disruptions resulting in negative consequences to health and performance. This is often documented in shift work and jet lag, but ‘societal norms’ (eg, typical working hours) can create profound issues for ‘night owls’, people whose internal biological timing predisposes them to follow an unusually late sleep-wake cycle. Night owls have also been associated with health issues, mood disturbances, poorer performance and increased mortality rates. Methods This study used a randomized control trial design aimed to shift the late timing of night owls to an earlier time (phase advance), using non-pharmacological, practical interventions in a real-world setting. These interventions targeted light exposure (through earlier wake up/sleep times), fixed meals times, caffeine intake and exercise. Results Overall, participants demonstrated a significant advance of ~2 h in sleep/wake timings as measured by actigraphy and circadian phase markers (dim light melatonin onset and peak time of the cortisol awakening response), whilst having no adverse effect on sleep duration. Notably, the phase advance was accompanied by significant improvements to self-reported depression and stress, as well as improved cognitive (reaction time) and physical (grip strength) performance measures during the typical 'suboptimal morning hours. Conclusions Our findings propose a novel strategy for shifting clock timing towards a pattern that is more aligned to societal demands that could significantly improve elements of performance, mental health and sleep timing in the real world.
Blue light sensitivity of melatonin suppression and subjective mood and alertness responses in humans is recognised as being melanopsin based. Observations that long wavelength (red) light can potentiate responses to subsequent short wavelength (blue) light have been attributed to the bistable nature of melanopsin whereby it forms stable associations with both 11-cis and alltrans isoforms of retinaldehyde and uses light to transition between these states. The current study examined the effect of concurrent administration of blue and red monochromatic light, as would occur in real-world white light, on acute melatonin suppression and subjective mood and alertness responses in humans. Young healthy males (18-35 years; n = 21) were studied in highly controlled laboratory sessions that included an individually timed 30 min light stimulus of blue (λmax 479 nm) or red (λmax 627 nm) monochromatic light at varying intensities (1013 - 1014 photons/cm2/s) presented, either alone or in combination, in a within-subject randomised design. Plasma melatonin levels and subjective mood and alertness were assessed at regular intervals relative to the light stimulus. Subjective alertness levels were elevated after light onset irrespective of light wavelength or irradiance. For melatonin suppression, a significant irradiance response was observed with blue light. Co-administration of red light, at any of the irradiances tested, did not significantly alter the response to blue light alone. Under the current experimental conditions the primary determinant of the melatonin suppression response was the irradiance of blue 479 nm light and this was unaffected by simultaneous red light administration.
Negative impacts of night work on employees are well documented, but little is known about immediate consequences for family members. This study examines how night work within a rotating shift pattern affects the sleep, mood and cortisol levels of female nurses, their husbands and children. Participants included twenty nurses (42.7 ± 6.5 years), their husbands and children (n=34, 8-18 years) who completed sleep diaries, rated their sleep quality, alertness and mood daily, and collected saliva samples each morning and evening for 14 days. Comparisons were made between night work and other shifts (Wilcoxon Signed Ranks test); and between periods preceding, during and following night shifts (repeated measures ANOVA with Tukey posthoc tests). Nurses’ sleep after the final night shift was significantly shorter (3h 58 mins ± 46 mins) and ended significantly earlier (13:28 ± 0:48h) than after the first night shift (sleep duration 5h 17 mins ± 1h 36 mins; wake time 14:58 ± 1:41h) (p
Background: Interest in biological clock pathways in bipolar disorders (BD) continues to grow, but there has yet to be an audit of circadian measurement tools for use in BD research and practice. Procedure: The International Society for Bipolar Disorders Chronobiology Task Force conducted a critical integrative review of circadian methods that have real-world applicability. Consensus discussion led to the selection of three domains to review – melatonin assessment, actigraphy and self-report. Results: Measurement approaches used to quantify circadian function in BD are described in sufficient detail for researchers and clinicians to make pragmatic decisions about their use. A novel integration of the measurement literature is offered in the form of a provisional taxonomy distinguishing between circadian measures (the instruments and methods used to quantify circadian function, such as dim light melatonin onset) and circadian constructs (the biobehavioural processes to be measured, such as circadian phase). Conclusions: Circadian variables are an important target of measurement in clinical practice and biomarker research. To improve reproducibility and clinical application of circadian constructs, an informed systematic approach to measurement is required. We trust that this review will decrease ambiguity in the literature and support theory-based consideration of measurement options.
Background Nurses and midwives make up almost 50% of the global healthcare shift working workforce. Shift work interferes with sleep and causes fatigue with adverse effects for nurses’ and midwives’ health, as well as on patient safety and care. Where other safety-critical sectors have developed Fatigue Risk Management Systems, healthcare is behind the curve; with published literature only focussing on the evaluation of discreet sleep-related/fatigue-management interventions. Little is known, however, about which interventions have been evaluated for nurses and midwives. Our review is a critical first step to building the evidence-base for healthcare organisations seeking to address this important operational issue. Objectives We address two questions: (1) what sleep-related/fatigue-management interventions have been assessed in nurses and midwives and what is their evidence-base? and (2) what measures are used by researchers to assess intervention effectiveness? Design and data sources The following databases were searched in November, 2018 with no limit on publication dates: MEDLINE, PsychINFO and CINAHL. Review methods We included: (1) studies conducted in adult samples of nurses and/or midwives that had evaluated a sleep-related/fatigue-management intervention; and (2) studies that reported intervention effects on fatigue, sleep, or performance at work, and on measures of attention or cognitive performance (as they relate to the impact of shift working on patient safety/care). Results The search identified 798 potentially relevant articles, out of which 32 met our inclusion criteria. There were 8619 participants across the included studies and all were nurses (88.6% female). We did not find any studies conducted in midwives nor any studies conducted in the UK, with most studies conducted in the US, Italy and Taiwan. There was heterogeneity both in terms of the interventions evaluated and the measures used to assess effectiveness. Napping could be beneficial but there was wide variation regarding nap duration and timing, and we need to understand more about barriers to implementation. Longer shifts, shift patterns including nights, and inadequate recovery time between shifts (quick returns) were associated with poorer sleep, increased sleepiness and increased levels of fatigue. Light exposure and/or light attenuation interventions showed promise but the literature was dominated by small, potentially unrepresentative samples. Conclusions The literature related to sleep-related/fatigue-management interventions for nurses and midwives is fragmented and lacks cohesion. Further empirical work is warranted with a view to developing comprehensive Fatigue Risk Management Systems to protect against fatigue in nurses, midwives, and other shift working healthcare staff.
Melatonin rhythms were assessed in 49 registered blind individuals by measurement of the urinary metabolite of melatonin, 6-sulfatoxymelatonin (aMT6s). Subjects had different causes of visual loss and were classified as having light perception or better (LP; n 5 19) or having no perception of light (NPL; n 5 30). Subjects collected four-hourly urine samples (eight-hourly overnight) for 48 h at weekly intervals for 3–5 weeks. The majority of LP subjects (14 of 19) had normally entrained aMT6s rhythms (mean acrophase range, 2.4–6.2 h), 4 were abnormally entrained to 24 h (mean acrophase range, 8.9–1.0 h), and 1 was unclassified. Conversely, mostNPLsubjects had abnormal rhythms (23 of 30), the incidence of which was greater in uni- and bilaterally enucleated subjects. The majority of NPL subjects (17 of 30) had free-running aMT6s rhythms (period range, 24.13– 24.79 h), 5 were abnormally entrained to 24 h (acrophase range, 7.2–20.6 h), and 1 was unclassified. Output (micrograms of aMT6s per 24 h) and amplitude (micrograms per h) of aMT6s production did not vary between LP and NPL subjects (mean 24-h output 6 SD, 12.7 6 7.5 and 9.4 6 6.4 mg aMT6s/24 h, respectively; mean amplitude 6 SD, 0.660.4 and 0.560.3 mg/h, respectively). These results indicate that a higher proportion of NPL subjects have abnormal melatonin rhythms compared to those with LP. (J Clin Endocrinol Metab 82: 3763–3770, 1997)
The current study investigated the accident rates across morning, late, and night shifts in rotating shift-workers employed in two different shift rotations at the same steel work factory. A retrospective analysis has been performed of accident data (N = 578) over a 5-year period (2003 through 2007) of 730 male shift-workers employed in either a clockwise (mean age of the workers 38.1 ± SD 9.8 years) or counterclockwise rotation (mean age 38.0 ± SD 10.1 years) with comparable work conditions. The overall accident rate across the 24-h day was not significantly different between clockwise and counterclockwise shift rotation. In both shift-work rotations, morning shifts as opposed to night shifts exhibited a significantly higher accident rate. There was no significant difference between late shifts and morning or night shifts in either shift rotation. The increased accident rate in the morning shift at this steel factory could be related to the early starting time of the shift and to this shift being more labor intensive in both shift rotations. These findings suggest that work-related factors must be considered in addition to shift-work schedules when investigating accident rates in rotating shift-workers. © 2013 Copyright Taylor and Francis Group, LLC.
Circadian rhythms, near-24 h oscillations that reflect homeostatic control by an internal timing system rather than the influence of external factors, are an important and sometimes underappreciated aspect of human physiology and biochemistry. Over the past few decades, the pineal gland hormone melatonin has been established both as a robust marker of circadian phase in plasma or saliva, and as a chronobiotic drug administered to reset the timing of the circadian oscillator. Recent work by our own and other laboratories has sought to systematically investigate whole categories of molecular components in blood samples in a hypothesis-free fashion by employing metabolomic methodologies to study low-molecular-weight compounds and transcriptomic methodologies to study gene expression in white blood cells, respectively. A number of components have been pinpointed that show a rhythmic circadian variation or are affected by imposed factors such as sleep deprivation. Although melatonin, a robust and reliable circadian phase marker, will be a hard act to follow, these lines of research suggest numerous potential leads for useful new markers of biological timing.
Light is a potent stimulus for regulating circadian, hormonal, and behavioral systems. In addition, light therapy is effective for certain affective disorders, sleep problems, and circadian rhythm disruption. These biological and behavioral effects of light are influenced by a distinct photoreceptor in the eye, melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs), in addition to conventional rods and cones. We summarize the neurophysiology of this newly described sensory pathway and consider implications for the measurement, production, and application of light. A new light-measurement strategy taking account of the complex photoreceptive inputs to these non-visual responses is proposed for use by researchers, and simple suggestions for artificial/architectural lighting are provided for regulatory authorities, lighting manufacturers, designers, and engineers. © 2013 Elsevier Ltd.
Studying circadian rhythms in most human tissues is hampered by difficulty in collecting serial samples. Here we reveal circadian rhythms in the transcriptome and metabolic pathways of human white adipose tissue. Subcutaneous adipose tissue was taken from seven healthy males under highly controlled ‘constant routine’ conditions. Five biopsies per participant were taken at six-hourly intervals for microarray analysis and in silico integrative metabolic modelling. We identified 837 transcripts exhibiting circadian expression profiles (2% of 41619 transcript targeting probes on the array), with clear separation of transcripts peaking in the morning (258 probes) and evening (579 probes). There was only partial overlap of our rhythmic transcripts with published animal adipose and human blood transcriptome data. Morning-peaking transcripts associated with regulation of gene expression, nitrogen compound metabolism, and nucleic acid biology; evening-peaking transcripts associated with organic acid metabolism, cofactor metabolism and redox activity. In silico pathway analysis further indicated circadian regulation of lipid and nucleic acid metabolism; it also predicted circadian variation in key metabolic pathways such as the citric acid cycle and branched chain amino acid degradation. In summary, in vivo circadian rhythms exist in multiple adipose metabolic pathways, including those involved in lipid metabolism, and core aspects of cellular biochemistry.
Use of blue-enriched light has received increasing interest regarding its activating and performance sustaining effects. However, studies assessing effects of such light during night work are few, and novel strategies for lighting using light emitting diode (LED) technology need to be researched. In a counterbalanced crossover design, we investigated the effects of a standard polychromatic blue-enriched white light (7000 K; 200 lx) compared to a warm white light (2500 K), of similar photon density (1.6 1014 photons/cm2/s), during three consecutive simulated night shifts. A total of 30 healthy participants [10 males, mean age 23.3 (SD = 2.9) years] were included in the study. Dependent variables comprised subjective alertness using the Karolinska Sleepiness Scale, a psychomotor vigilance task (PVT) and a digit symbol substitution test (DSST), all administered at five time points throughout each night shift. We also assessed dim-light melatonin onset (DLMO) before and after the night shifts, as well as participants’ opinion of the light conditions. Subjective alertness and performance on the PVT and DSST deteriorated during the night shifts, but 7000 K light was more beneficial for performance, mainly in terms of fewer errors on the PVT, at the end of the first- and second- night shift, compared to 2500 K light. Blue-enriched light only had a minor impact on PVT response times (RTs), as only the fastest 10% of the RTs were significantly improved in 7000 K compared to 2500 K light. In both 7000 and 2500 K light, the DLMO was delayed in those participants with valid assessment of this parameter [n = 20 (69.0%) in 7000 K light, n = 22 (78.6%) in 2500 K light], with a mean of 2:34 (SE = 0:14) and 2:12 (SE = 0:14) hours, respectively, which was not significantly different between the light conditions. Both light conditions were positively rated, although participants found 7000 K to be more suitable for work yet evaluated 2500 K light as more pleasant. The data indicate minor, but beneficial, effects of 7000 K light compared to 2500 K light on performance during night work. Circadian adaptation did not differ significantly between light conditions, though caution should be taken when interpreting these findings due to missing data. Field studies are needed to investigate similar light interventions in real-life settings, to develop recommendations regarding illumination for night workers.
The hormone melatonin is increasingly used for the treatment of certain sleep disorders, particularly those related to disturbed biological rhythms. This article summarises current knowledge of its mechanism of action and identifies situations where there is good evidence for its efficacy. The authors provide advice, based on their own experience and consistent published data, concerning the dose range of melatonin to be used and the critically important question of the timing of treatment. Anecdotal evidence for the use of melatonin needs to be replaced by data from well-controlled, preferably multi-centre, randomised clinical trials
Patients with liver cirrhosis can develop hyperammonemia and hepatic encephalopathy (HE), accompanied by pronounced daytime sleepiness. Previous studies with healthy volunteers show that experimental increase in blood ammonium levels increases sleepiness and slows the waking EEG. As ammonium increases adenosine levels in vitro, and adenosine is a known regulator of sleep/wake homeostasis, we hypothesized that the sleepiness-inducing effect of ammonium is mediated by adenosine. Eight adult male Wistar rats were fed with an ammonium-enriched diet for 4 weeks; eight rats on standard diet served as controls. Each animal was implanted with electroencephalography/electromyography (EEG/EMG) electrodes and a microdialysis probe. Sleep EEG recording and cerebral microdialysis were carried out at baseline and after 6 hours of sleep deprivation. Adenosine and metabolite levels were measured by HPLC and targeted LC/MS metabolomics, respectively. Baseline adenosine and metabolite levels (12 of 16 amino acids, taurine, t4-hydroxy-proline and acetylcarnitine) were lower in hyperammonemic animals, while putrescine was higher. After sleep deprivation, hyperammonemic animals exhibited a larger increase in adenosine levels, and a number of metabolites showed a different time-course in the two groups. In both groups the recovery period was characterized by a significant decrease in wakefulness/increase in NREM and REM sleep. However, while control animals exhibited a gradual compensatory effect, hyperammonemic animals showed a significantly shorter recovery phase. In conclusion, the adenosine/metabolite/EEG response to sleep deprivation was modulated by hyperammonemia, suggesting that ammonia affects homeostatic sleep regulation and its metabolic correlates.
Following abrupt phase shifts (real or simulated time zone changes, night shift work) there is desynchronisation between the internal circadian rhythms (including melatonin) and the external environment with consequent disturbances in sleep, mood and performance. In humans the pineal hormone melatonin has phase-shifting and resynchronising properties with regard to a number of circadian rhythms. Suitably timed melatonin adrninstration hastened adaptation to phase shift and significantly improved self-rated jet lag in large numbers of time zone travellers. Preliminary results in night shift workers showed improved daytime sleep and night-time alertness. In simulated experiments, appropriately timed melatonin improved subjective sleep, alertness and performance and facilitated the readaptation of the melatonin rhythm following a rapid 9 h advance phase shift. Melatonin has also been assessed in circadian rhythm disorders with disturbed sleep (blindness and delayed sleep phase insomnia). Compared with placebo, melatonin significantly improved sleep and synchronised the sleep wake cycle in some blind subjects. Melatonin treatment significantly advanced the sleep onset time in delayed sleep phase insomnia. Taken together these findings suggest that melatonin is of benefit in facilitating adaptation to forced phase shifts and in conditions of circadian rhythm disturbance.
Parkinson’s disease (PD) is a chronic disorder that presents a range of premotor signs, such as sleep disturbances and cognitive decline, which are key non-motor features of the disease. Increasing evidence of a possible association between sleep disruption and the neurodegenerative process suggests that sleep impairment could produce a detectable metabolic signature on the disease. In order to integrate neurocognitive and metabolic parameters, we performed untargeted and targeted metabolic profiling of the rotenone PD model in a chronic sleep restriction (SR) (6 h/day for 21 days) condition. We found that SR combined with PD altered several behavioural (reversal of locomotor activity impairment; cognitive impairment; delay of rest-activity rhythm) and metabolic parameters (branched-chain amino acids, tryptophan pathway, phenylalanine, and lipoproteins, pointing to mitochondrial impairment). If combined, our results bring a plethora of parameters that represents reliable early-phase PD biomarkers which can easily be measured and could be translated to human studies.
Objective: Environmental (little outdoor light; low indoor lighting) and age-related physiological factors (reduced light transmission through the ocular lens, reduced mobility) contribute to a light-deprived environment for older people living in care homes. Methods: This study investigates the effect of increasing indoor light levels with blue-enriched white lighting on objective (rest-activity rhythms, performance) and self-reported (mood, sleep, alertness) measures in older people. Eighty residents (69 female), aged 86 ± 8 yrs (mean ± SD), participated (MMSE 19 ± 6). Overhead fluorescent lighting was installed in communal rooms (n=20) of seven care homes. Four weeks of blue-enriched white lighting (17000 K ≅ 900 lux) were compared with four weeks of control white lighting (4000 K ≅ 200 lux), separated by three weeks wash-out. Participants completed validated mood and sleep questionnaires, psychomotor vigilance task (PVT) and wore activity and light monitors (AWL). Rest-activity rhythms were assessed by cosinor, non-parametric circadian rhythm (NPCRA) and actigraphic sleep analysis. Blue-enriched (17000 K) light increased wake time and activity during sleep decreasing actual sleep time, sleep percentage and sleep efficiency (p < 0.05) (actigraphic sleep). Compared to 4000 K lighting, blue-enriched 17000 K lighting significantly (p < 0.05) advanced the timing of participants’ rest-activity rhythm (cosinor), increased daytime and night-time activity (NPCRA), reduced subjective anxiety (HADA) and sleep quality (PSQI). There was no difference between the two light conditions in daytime alertness and performance (PVT). Conclusion: Blue-enriched lighting produced some positive (increased daytime activity, reduced anxiety) and negative (increased night-time activity, reduced sleep efficiency and quality) effects in older people.
Working around the clock is common for many occupations, as diverse as nurses, truck drivers, physicians, steel workers, and pilots. Each shift-work profession is individual in more aspects than just work hours and individual work scenarios, each posing a different impact on the health of workers. Related health problems in shift workers, therefore, are also diverse and encompass sleep problems, metabolic and cardiovascular system disturbances, as well as cancer. Little is known about how all these individual factors influence a shift worker's health status, partly because many shift-work studies show inconsistent results. In addition, these individual factors create many methodological difficulties for researchers who investigate such work scenarios. This chapter presents examples from our laboratory and field studies of shift workers, which emphasize the importance of taking individual circumstances into account. Both study approaches, laboratory and field based, are needed to fully account for the difficulties that shift-work studies pose on both workers and researchers. Finally, understanding the mechanisms that underpin interindividual differences in response to shift work will advance our understanding of how to design better and healthier shift-work schedules in the future.
Working around the clock is common for many occupations, as diverse as nurses, truck drivers, physicians, steel workers, and pilots. Each shift-work profession is individual in more aspects than just work hours and individual work scenarios, each posing a different impact on the health of workers. Related health problems in shift workers, therefore, are also diverse and encompass sleep problems, metabolic and cardiovascular system disturbances, as well as cancer. Little is known about how all these individual factors influence a shift worker's health status, partly because many shift-work studies show inconsistent results. In addition, these individual factors create many methodological difficulties for researchers who investigate such work scenarios. This chapter presents examples from our laboratory and field studies of shift workers, which emphasize the importance of taking individual circumstances into account. Both study approaches, laboratory and field based, are needed to fully account for the difficulties that shift-work studies pose on both workers and researchers. Finally, understanding the mechanisms that underpin interindividual differences in response to shift work will advance our understanding of how to design better and healthier shift-work schedules in the future.
Successful pregnancy requires adaptation in maternal physiology. During intrauterine life the mother's circadian timing system supports successful birth and postnatal development. Maternal melatonin is important to transmit circadian timing and day length to the fetus. This study aims to describe the third trimester of pregnancy among day (n = 5) and night (n = 3) workers by assessing their melatonin levels in a natural environment. Additionally, we describe the worker's metabolic profiles and compare the health status of the newborns between groups of day and night working mothers. Our results indicate an occurrence of assisted delivery (caesarean and forceps) among night workers. Moreover, the newborns of night workers showed lower Apgar index and breastfeeding difficulty indicating a worse condition to deal with the immediate outside the womb environment.Additionally, there was lower night-time melatonin production among pregnant night workers compared to day workers. These findings may be related to light-induced suppression of melatonin that occurs during night work. We conclude that night work and consequent exposure to light at unconventional times might compromise the success of pregnancy and the health of the newborn. Further studies need to be carried out to monitor pregnancy and newborn health in pregnant night workers.
Nightshift work is associated with adverse health outcomes, which may be related to eating during the biological night, when circadian rhythms and food intake are misaligned. Nurses often undertake nightshift work, and we aimed to investigate patterns of energy distribution and dietary intake across 14 days in 20 UK National Health Service (NHS) nurses working rotational shifts. We hypothesised that the proportion of daily energy consumed during the nightshift would increase over consecutive nights. Primary and secondary outcome measures included intakes of energy and macronutrients. Our results show that nurses consumed the same total daily energy on nightshifts and non-nightshifts, but redistributed energy to the nightshift period in increasing proportions with a significant difference between Night 1 and 2 in the proportion of total daily energy consumed (26.0 ± 15.7% vs. 33.5 ± 20.2%, mean ± SD; p < 0.01). This finding indicates that, rather than increasing total energy intake, nurses redistribute energy consumed during nightshifts as a behavioural response to consecutive nightshifts. This finding informs our understanding of how the intake of energy during the biological night can influence adverse health outcomes of nightshift work.
Nurses and midwives make up almost 50% of the global healthcare shift working workforce. Shift work interferes with sleep and causes fatigue with adverse effects for nurses’ and midwives’ health, as well as on patient safety and care. Where other safety-critical sectors have developed Fatigue Risk Management Systems, healthcare is behind the curve; with published literature only focussing on the evaluation of discreet sleep-related/fatigue-management interventions. Little is known, however, about which interventions have been evaluated for nurses and midwives. Our review is a critical first step to building the evidence-base for healthcare organisations seeking to address this important operational issue.
Subjects working a 12h night shift offshore for 2 weeks normally adapt to the night shift and are out of synchrony when they return home to day life, with consequent problems of poor sleep. The aim of the study was to investigate the effectiveness of timed light treatment to hasten circadian adaptation and improve sleep after the night shift. Ten male shift workers worked 19.00-07.00h (n=4) or 18.00-06.00h (n=6) offshore shift schedules. They were assessed for the last 7 days of a 14 or 21 day night shift offshore and for the following 14 days at home. Either timed light treatment/sunglasses or no light treatment/no sunglasses were scheduled in a crossover design during days 1-5 after the night shift, theoretically timed to advance the circadian system. Subjects wore an Actiwatch-L throughout the study to monitor light and activity and completed daily sleep diaries. Actigraphic sleep efficiency after the light/sunglasses treatment was significantly improved (days 1-5) 86.7 ± 5.8% (light treatment) compared to the no light treatment leg 79.4 ± 10.3% (mean ± SD) P < 0.05. Subjective and objective sleep duration (days 6-14) was significantly improved in the light treatment leg; actigraphic sleep duration was longer after light treatment (6.75 ± 0.50h) compared to 5.76 ± 0.73h, P < 0.05, whilst subjective sleep duration was 8.05 h ± 0.72h compared to 7.32 ± 0.55h, respectively, P < 0.05. If appropriately timed, light and darkness has beneficial effects on sleep efficiency and sleep duration following a night shift.
Urbanization has contributed to extended wakefulness, which may in turn be associated with eating over a longer period. Here, we present a field study conducted in four groups with different work hours and places of living in order to investigate eating behavior (duration, content, and timing). Anthropometric measures were taken from the participants (rural (n = 22); town (n = 19); city-day workers (n = 11); city-night workers (n = 14)). In addition, a sociodemographic questionnaire was self-answered and 24-h food recalls were applied for three days. The 24-h food recalls revealed that fat intake varied according to the groups, with the highest consumption by the city-day workers. By contrast, city-day workers had the lowest intake of carbohydrate, whereas the rural group had the highest. In general, all groups had some degree of inadequacy in food consumption. Eating duration was negatively correlated with total energy intake, fat, and protein consumption in the rural and town groups. There was a positive correlation between body mass index and eating duration in both city groups. The rural group had the earliest start time of eating, and this was associated with a lower body mass index. This study suggested that food content and timing, as well as eating duration, differed according to place of living, which in turn may be linked to lifestyle.
Melatonin and leptin exhibit daily rhythms that may contribute towards changes in metabolic physiology. It remains unclear, however, whether this rhythmicity is altered in obesity or type 2 diabetes (T2DM). We tested the hypothesis that 24-hour profiles of melatonin, leptin and leptin mRNA are altered by metabolic status in laboratory conditions. Men between 45-65 years old were recruited into lean, obese-non-diabetic or obese-T2DM groups. Volunteers followed strict sleep-wake and dietary regimes for 1 week before the laboratory study. They were then maintained in controlled light-dark conditions, semi-recumbent posture and fed hourly iso-energetic drinks during wake periods. Hourly blood samples were collected for hormone analysis. Subcutaneous adipose biopsies were collected 6-hourly for gene expression analysis. Although there was no effect of subject group on the timing of dim light melatonin onset (DLMO), nocturnal plasma melatonin concentration was significantly higher in obese-non-diabetic subjects compared to weight-matched T2DM subjects (p
Summmary: Sleep medicine is evolving globally into a medical subspeciality in its own right, and in parallel, behavioural sleep medicine and sleep technology are expanding rapidly. Educational programmes are being implemented at different levels in many European countries. However, these programmes would benefit from a common, interdisciplinary curriculum. This 'catalogue of knowledge and skills' for sleep medicine is proposed, therefore, as a template for developing more standardized curricula across Europe. The Board and The Sleep Medicine Committee of the European Sleep Research Society (ESRS) have compiled the catalogue based on textbooks, standard of practice publications, systematic reviews and professional experience, validated subsequently by an online survey completed by 110 delegates specialized in sleep medicine from different European countries. The catalogue comprises 10 chapters covering physiology, pathology, diagnostic and treatment procedures to societal and organizational aspects of sleep medicine. Required levels of knowledge and skills are defined, as is a proposed workload of 60 points according to the European Credit Transfer System (ECTS). The catalogue is intended to be a basis for sleep medicine education, for sleep medicine courses and for sleep medicine examinations, serving not only physicians with a medical speciality degree, but also PhD and MSc health professionals such as clinical psychologists and scientists, technologists and nurses, all of whom may be involved professionally in sleep medicine. In the future, the catalogue will be revised in accordance with advances in the field of sleep medicine. Copyright © 2014 European Sleep Research Society 232 April 2014 10.1111/jsr.12095 Catalogue for sleep medicine Catalogue for sleep medicine © 2013 European Sleep Research Society.
Trace deposition timing reflects a novel concept in forensic molecular biology involving the use of rhythmic biomarkers for estimating the time within a 24-h day/night cycle a human biological sample was left at the crime scene, which in principle allows verifying a sample donor’s alibi. Previously, we introduced two circadian hormones for trace deposition timing and recently demonstrated that messenger RNA (mRNA) biomarkers significantly improve time prediction accuracy. Here, we investigate the suitability of metabolites measured using a targeted metabolomics approach, for trace deposition timing. Analysis of 171 plasma metabolites collected around the clock at 2-h intervals for 36 h from 12 male participants under controlled laboratory conditions identified 56 metabolites showing statistically significant oscillations, with peak times falling into three day/night time categories: morning/noon, afternoon/evening and night/early morning. Time prediction modelling identified 10 independently contributing metabolite biomarkers, which together achieved prediction accuracies expressed as AUC of 0.81, 0.86 and 0.90 for these three time categories respectively. Combining metabolites with previously established hormone and mRNA biomarkers in time prediction modelling resulted in an improved prediction accuracy reaching AUCs of 0.85, 0.89 and 0.96 respectively. The additional impact of metabolite biomarkers, however, was rather minor as the previously established model with melatonin, cortisol and three mRNA biomarkers achieved AUC values of 0.88, 0.88 and 0.95 for the same three time categories respectively. Nevertheless, the selected metabolites could become practically useful in scenarios where RNA marker information is unavailable such as due to RNA degradation. This is the first metabolomics study investigating circulating metabolites for trace deposition timing, and more work is needed to fully establish their usefulness for this forensic purpose.
Ageing is associated with increased disturbances in the timing, duration, and quality of sleep. These disruptions may reflect changes in the circadian timing system and/or the sleep homeostat which are both necessary to produce consolidated sleep at an appropriate time. In addition, it is possible that age-related alterations in the detection and transmission of the photic signal responsible for synchronizing the circadian clock may play a role. Ageing is accompanied by many changes within the eye including alterations in pupil size, lens transmission, and number of photoreceptors. The observed increase in ocular lens density with age will diminish the transmission of short wavelength blue light to which the circadian system has been shown to be most sensitive, and may contribute, in part, to the observed increase in sleep disturbances in older people. We were the first group to test the hypothesis that non-visual responses to blue light would be impaired in older individuals. Our research has demonstrated that whilst acute non-visual effects of blue light are impaired with age, the light resetting effect appears unaltered. Future research should work towards optimizing the light environment for older people to promote good quality sleep and daytime functioning.
Summary: The present paper describes standardized procedures within clinical sleep medicine. As such, it is a continuation of the previously published European guidelines for the accreditation of sleep medicine centres and European guidelines for the certification of professionals in sleep medicine, aimed at creating standards of practice in European sleep medicine. It is also part of a broader action plan of the European Sleep Research Society, including the process of accreditation of sleep medicine centres and certification of sleep medicine experts, as well as publishing the Catalogue of Knowledge and Skills for sleep medicine experts (physicians, non-medical health care providers, nurses and technologists), which will be a basis for the development of relevant educational curricula. In the current paper, the standard operational procedures sleep medicine centres regarding the diagnostic and therapeutic management of patients evaluated at sleep medicine centres, accredited according to the European Guidelines, are based primarily on prevailing evidence-based medicine principles. In addition, parts of the standard operational procedures are based on a formalized consensus procedure applied by a group of Sleep Medicine Experts from the European National Sleep Societies. The final recommendations for standard operational procedures are categorized either as 'standard practice', 'procedure that could be useful', 'procedure that is not useful' or 'procedure with insufficient information available'. Standard operational procedures described here include both subjective and objective testing, as well as recommendations for follow-up visits and for ensuring patients' safety in sleep medicine. The overall goal of the actual standard operational procedures is to further develop excellence in the practice and quality assurance of sleep medicine in Europe. © 2011 European Sleep Research Society.
A considerable proportion of patients with cirrhosis exhibit insomnia, delayed sleep habits, and excessive daytime sleepiness. These have been variously attributed to hepatic encephalopathy and impaired hepatic melatonin metabolism, but the understanding of their pathophysiology remains limited and their treatment problematic. Sleep is regulated by the interaction of a homeostatic and a circadian process. The homeostatic process determines sleep propensity in relation to sleep-wake history, thus the need to sleep increases with the duration of the waking period. The circadian process, which is marked by the 24-hour rhythm of the hormone melatonin, is responsible for the alternation of high/low sleep propensity in relation to dark/light cues. Circadian sleep regulation has been studied in some depth in patients with cirrhosis, who show delays in the 24-hour melatonin rhythm, most likely in relation to reduced sensitivity to light cues. However, while melatonin abnormalities are associated with delayed sleep habits, they do not seem to offer a comprehensive explanation to the insomnia exhibited by these patients. Fewer data are available on homeostatic sleep control: it has been recently hypothesized that patients with cirrhosis and hepatic encephalopathy might be unable, due to excessive daytime sleepiness, to accumulate the need/ability to produce restorative sleep. This review will describe in some detail the features of sleep-wake disturbances in patients with cirrhosis, their mutual relationships, and those, if any, with hepatic failure/hepatic encephalopathy. A separate section will cover the available information on their pathophysiology. Finally, etiological treatment will be briefly discussed. © 2013 by the American Association for the Study of Liver Diseases.
The identification and investigation of novel clock-controlled genes (CCGs) has been conducted thus far mainly in model organisms such as nocturnal rodents, with limited information in humans. Here, we aimed to characterize daily and circadian expression rhythms of CCGs in human peripheral blood during a sleep/sleep deprivation (S/SD) study and a constant routine (CR) study. Blood expression levels of 9 candidate CCGs (SREBF1, TRIB1, USF1, THRA1, SIRT1, STAT3, CAPRIN1, MKNK2, and ROCK2), were measured across 48 h in 12 participants in the S/SD study and across 33 h in 12 participants in the CR study. Statistically significant rhythms in expression were observed for STAT3, SREBF1, TRIB1, and THRA1 in samples from both the S/SD and the CR studies, indicating that their rhythmicity is driven by the endogenous clock. The MKNK2 gene was significantly rhythmic in the S/SD but not the CR study, which implies its exogenously driven rhythmic expression. In addition, we confirmed the circadian expression of PER1, PER3, and REV-ERBα in the CR study samples, while BMAL1 and HSPA1B were not significantly rhythmic in the CR samples; all 5 genes previously showed significant expression in the S/SD study samples. Overall, our results demonstrate that rhythmic expression patterns of clock and selected clock-controlled genes in human blood cells are in part determined by exogenous factors (sleep and fasting state) and in part by the endogenous circadian timing system. Knowledge of the exogenous and endogenous regulation of gene expression rhythms is needed prior to the selection of potential candidate marker genes for future applications in medical and forensic settings.
MAPK pathway activation is frequently observed in human malignancies, including melanoma, and is associated with sensitivity to MEK inhibition and changes in cellular metabolism. Using quantitative mass spectrometry-based metabolomics, we identified in preclinical models 21 plasma metabolites including amino acids, propionylcarnitine, phosphatidylcholines and sphingomyelins that were significantly altered in two B-RAF mutant melanoma xenografts and that were reversed following a single dose of the potent and selective MEK inhibitor RO4987655. Treatment of non-tumour bearing animals and mice bearing the PTEN null U87MG human glioblastoma xenograft elicited plasma changes only in amino acids and propionylcarnitine. In patients with advanced melanoma treated with RO4987655, on-treatment changes of amino acids were observed in patients with disease progression and not in responders. In contrast, changes in phosphatidylcholines and sphingomyelins were observed in responders. Furthermore, pre-treatment levels of 7 lipids identified in the preclinical screen were statistically significantly able to predict objective responses to RO4987655. The RO4987655 treatment-related changes were greater than baseline physiological variability in non-treated individuals. This study provides evidence of a translational exo-metabolomic plasma readout predictive of clinical efficacy together with pharmacodynamic utility following treatment with a signal transduction inhibitor.
Determining the time a biological trace was left at a scene of crime reflects a crucial aspect of forensic investigations as – if possible – it would permit testing the sample donor’s alibi directly from the trace evidence, helping to link (or not) the DNA-identified sample donor with the crime event. However, reliable and robust methodology is lacking thus far. In this study, we assessed the suitability of mRNA for the purpose of estimating blood deposition time, and its added value relative to melatonin and cortisol, two circadian hormones we previously introduced for this purpose. By analysing 21 candidate mRNA markers in blood samples from 12 individuals collected around the clock at 2 h intervals for 36 h under real-life, controlled conditions, we identified 11 mRNAs with statistically significant expression rhythms. We then used these 11 significantly rhythmic mRNA markers, with and without melatonin and cortisol also analysed in these samples, to establish statistical models for predicting day/night time categories. We found that although in general mRNA-based estimation of time categories was less accurate than hormone-based estimation, the use of three mRNA markers HSPA1B, MKNK2 and PER3 together with melatonin and cortisol generally enhanced the time prediction accuracy relative to the use of the two hormones alone. Our data best support a model that by using these five molecular biomarkers estimates three time categories, i.e. night/early morning, morning/noon, and afternoon/evening with prediction accuracies expressed as AUC values of 0.88, 0.88, and 0.95, respectively. For the first time, we demonstrate the value of mRNA for blood deposition timing and introduce a statistical model for estimating day/night time categories based on molecular biomarkers, which shall be further validated with additional samples in the future. Moreover, our work provides new leads for molecular approaches on time of death estimation using the significantly rhythmic mRNA markers established here.
OBJECTIVE Previous animal studies suggest a functional relationship between metabolism, type 2 diabetes, and the amplitude of daily rhythms in white adipose tissue (WAT). However, data interpretation is confounded by differences in genetic background and diet or limited sampling points. We have taken the novel approach of analyzing serial human WAT biopsies across a 24-h cycle in controlled laboratory conditions.RESEARCH DESIGN AND METHODS Lean (n = 8), overweight/obese (n = 11), or overweight/obese type 2 diabetic (n = 8) volunteers followed a strict sleep-wake and dietary regimen for 1 week prior to the laboratory study. They were then maintained in controlled light-dark conditions in a semirecumbent posture and fed hourly during wake periods. Subcutaneous WAT biopsies were collected every 6 h over 24 h, and gene expression was measured by quantitative PCR.RESULTS Lean individuals exhibited significant (P < 0.05) temporal changes of core clock (PERI, PER2, PER3, CRY2, BMAL1, and DBP) and metabolic (REVERB alpha,RIP140, and PGC1 alpha) genes. The BMAL1 rhythm was in approximate antiphase with the other clock genes. It is noteworthy that there was no significant effect (P > 0.05) of increased body weight or type 2 diabetes on rhythmic gene expression.CONCLUSIONS The robust nature of these rhythms and their relative phasing indicate that WAT now can be considered as a peripheral tissue suitable for the study of in vivo human rhythms. Comparison of data between subject groups clearly indicates that obesity and type 2 diabetes are not related to the amplitude of rhythmic WAT gene expression in humans maintained under controlled conditions. Diabetes 60:1577-1581, 2011
1. Non-image forming, irradiance-dependent responses mediated by the human eye include synchronisation of the circadian axis and suppression of pineal melatonin production. The retinal photopigment(s) transducing these light responses in humans have not been characterised. 2. Using the ability of light to suppress nocturnal melatonin production, we aimed to investigate its spectral sensitivity and produce an action spectrum. Melatonin suppression was quantified in 22 volunteers in 215 light exposure trials using monochromatic light (30 min pulse administered at circadian time (CT) 16–18) of different wavelengths (gmax 424, 456, 472, 496, 520 and 548 nm) and irradiances (0.7–65.0 μW cm_2). 3. At each wavelength, suppression of plasma melatonin increased with increasing irradiance. Irradiance–response curves (IRCs) were fitted and the generated half-maximal responses (IR50) were corrected for lens filtering and used to construct an action spectrum. 4. The resulting action spectrum showed unique short-wavelength sensitivity very different from the classical scotopic and photopic visual systems. The lack of fit (r2 < 0.1) of our action spectrum with the published rod and cone absorption spectra precluded these photoreceptors from having a major role. Cryptochromes 1 and 2 also had a poor fit to the data. Fitting a series of Dartnall nomograms generated for rhodopsin-based photopigments over the gmax range 420–480 nm showed that rhodopsin templates between gmax 457 and 462 nm fitted the data well (r2 ≥ 0.73). Of these, the best fit was to the rhodopsin template with gmax 459 nm (r2 = 0.74). 5. Our data strongly support a primary role for a novel short-wavelength photopigment in lightinduced melatonin suppression and provide the first direct evidence of a non-rod, non-cone photoreceptive system in humans.
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.
OBJECTIVES: Plasma melatonin profile abnormalities have been described in patients with cirrhosis and generally attributed to impaired hepatic melatonin metabolism. The possibility that they might reflect circadian clock dysfunction has not been explored. In addition, the relationship between plasma melatonin profiles and the sleep disturbances observed in these patients remains unclear. The aims of this study were: (i) to evaluate circadian clock function and hepatic melatonin metabolism in cirrhotic patients, and (ii) to study the relationship between plasma melatonin profiles and sleep-wake behavior. METHODS: The study population comprised 20 patients with cirrhosis (mean (range) age, 59 (39-77) years) and 9 healthy volunteers (60 (38-84) years). Plasma melatonin/cortisol concentrations were measured hourly, for 24 h, in light/posture-controlled conditions. Urinary 6-sulfatoxymelatonin, the main melatonin metabolite, was measured simultaneously to determine clearance. The ability of light to suppress nocturnal melatonin synthesis was assessed. Habitual sleep quality/timing was evaluated using a questionnaire, actigraphy, and sleep diaries. RESULTS: There was evidence of central circadian disruption in patients compared with healthy controls: peak plasma melatonin/cortisol times were delayed (04:48+/-02:36 vs. 02:48+/-00:54, P=0.01; 10:18+/-02:54 vs. 08:54+/-01:24, P=0.06) and the plasma melatonin response to light was reduced (12%+/-19% vs. 24%+/-15%, P=0.09). However, the mean 24 h plasma melatonin clearance did not differ significantly between patients and healthy volunteers (0.22+/-0.10 vs. 0.28+/-0.17 l/kg per h, P=0.36). Finally, although patients showed a degree of misalignment between sleep and circadian timings, there was no association between circadian abnormalities and impaired sleep quality. CONCLUSIONS: Plasma melatonin profile abnormalities, predominantly central in origin, are observed in patients with mild to moderately decompensated cirrhosis. However, they are substantially unrelated to the sleep disturbances prevalent in this population.
Patients with Primary Biliary Cholangitis (PBC) exhibit delayed sleep-wake habits, disturbed night sleep and daytime sleepiness/fatigue. Such combination of symptoms is reminiscent of delayed sleep-wake phase disorder (DSPD), which benefits from morning light treatment. The aim of the present pilot study was to test the effect of morning light treatment in a group of 13 well-characterized patients with PBC [all females; (mean ± SD) 53 ± 10 years]. Six healthy individuals (4 females, 57 ± 14 years) and 7 patients with cirrhosis (1 female, 57 ± 12 years) served as controls and diseased controls, respectively. At baseline, all participants underwent an assessment of quality of life, diurnal preference, sleep quality/timing (subjective plus actigraphy), daytime sleepiness, and urinary 6-sulphatoxymelatonin (aMT6s) rhythmicity. Then they underwent a 15-day course of morning bright light treatment, immediately after getting up (light box, 10,000 lux, 45 min) whilst monitoring sleep-wake patterns and aMT6s rhythmicity. At baseline, both patients with PBC and patients with cirrhosis had significantly worse subjective sleep quality compared to controls. In patients with PBC, light treatment resulted in an improvement in subjective sleep quality and a reduction in daytime sleepiness. In addition, both their sleep onset and get-up time were significantly advanced. Finally, the robustness of aMT6s rhythmicity (i.e., strength of the cosinor fit) increased after light administration but post-hoc comparisons were not significant in any of the groups. In conclusion, a brief course of morning bright light treatment had positive effects on subjective sleep quality, daytime sleepiness, and sleep timing in patients with PBC. This unobtrusive, side-effect free, non-pharmacological treatment is worthy of further study.
Light affects the circadian axis in at least two ways. It can cause the acute suppression of pineal melatonin synthesis, and/or a phase-shift of the circadian oscillator. As recent evidence has suggested that extraocular light exposure may cause phase-shifts of the circadian clock, we have investigated whether suppression of melatonin can be induced by the same type of light exposure. In the first study subjects’ eyes were exposed to white light (2250 lux for 30 min) via a fibre optic cable. As expected, suppression of nighttime plasma melatonin levels (61 ± 6%) was observed. In the second study, light of the same quality but higher intensity (14,000 or 67,500 lux for 180 mins) was delivered in the same manner to the popliteal region behind the subjects’ knees, whilst shielding their eyes. No suppression of plasma melatonin levels (4 ± 7%) was detected in any of the subjects. Thus, extraocular photoreception, if it exists in mammals, does not affect the suprachiasmatic nuclei-pineal pathway.
While we do not yet understand all the functions of sleep, its critical role for normal physiology and behaviour is evident. Its amount and temporal pattern depend on species and condition. Humans sleep about a third of the day with the longest, consolidated episode during the night. The change in lifestyle from hunter-gatherers via agricultural communities to densely populated industrialized centres has certainly affected sleep, and a major concern in the medical community is the impact of insufficient sleep on health [1,2]. One of the causal mechanisms leading to insufficient sleep is altered exposure to the natural light-dark cycle. This includes the wide availability of electric light, attenuated exposure to daylight within buildings, and evening use of light-emitting devices, all of which decrease the strength of natural light-dark signals that entrain circadian systems .
One of the possible causes of disturbed circadian rhythms and sleep in the elderly may be impaired photic input to the circadian clock. Age-related changes in lens density are known to reduce the transmission of short wavelength light, which has been shown to be most effective in suppressing nocturnal melatonin. The aim of the study therefore was to investigate age-related changes in melatonin suppression in response to short and medium wavelength light. Young premenopausal (n=13) and postmenopausal (n=21) women were exposed to 30 min of monochromatic light at two different wavelengths and irradiances (λmax 456 nm: 3.8 and 9.8 μW/cm2; λmax 548 nm: 28 and 62 μW/cm2). Melatonin suppression was compared across light treatments and between age groups. Significantly reduced melatonin suppression was noted in the elderly subjects following exposure to short wavelength (456 nm) light compared to the young subjects. These results are likely to reflect age-related changes in lens density.
Diurnal behavior in humans is governed by the period length of a circadian clock in the suprachiasmatic nuclei of the brain hypothalamus. Nevertheless, the cell-intrinsic mechanism of this clock is present in most cells of the body. We have shown previously that for individuals of extreme chronotype ("larks" and "owls"), clock properties measured in human fibroblasts correlated with extreme diurnal behavior.
Intrinsically photosensitive retinal ganglion cells (ipRGCs), whose photopigment melanopsin has a peak of sensitivity in the short wavelength range of the spectrum, constitute a common light input pathway to the olivary pretectal nucleus (OPN), the pupillary light reflex (PLR) regulatory centre, and to the suprachiasmatic nuclei (SCN), the major pacemaker of the circadian system. Thus, evaluating PLR under short wavelength light (λmax 500 nm) and creating an integrated PLR parameter, as a possible tool to indirectly assess the status of the circadian system, becomes of interest. Nine monochromatic, photon-matched light stimuli (300 s), in 10 nm increments from λmax 420 to 500 nm were administered to 15 healthy young participants (8 females), analyzing: i) the PLR; ii) wrist temperature (WT) and motor activity rhythms (WA), iii) light exposure (L) pattern and iv) diurnal preference (Horne- Östberg), sleep quality (Pittsburgh) and daytime sleepiness (Epworth). Linear correlations between the different PLR parameters and circadian status index obtained from WT, WA and L recordings and scores from questionnaires were calculated. In summary, we found markers of robust circadian rhythms, namely high stability, reduced fragmentation, high amplitude, phase advance and low internal desynchronization, were correlated with a reduced PLR to 460–490 nm wavelengths. Integrated circadian (CSI) and PLR (cp-PLR) parameters are proposed, that also showed an inverse correlation. These results demonstrate, for the first time, the existence of a close relationship between the circadian system robustness and the pupillary reflex response, two non-visual functions primarily under melanopsin-ipRGC input.
The pronounced cachexia (unexplained wasting) seen in Huntington’s disease (HD) patients suggests that metabolic dysregulation plays a role in HD pathogenesis, although evidence of metabolic abnormalities in HD patients is inconsistent. We performed metabolic profiling of plasma from presymptomatic HD transgenic and control sheep. Metabolites were quantified in sequential plasma samples taken over a 25h period using a targeted LC/MS metabolomics approach. Significant changes with respect to genotype were observed in 89/130 identified metabolites, including sphingolipids, biogenic amines, amino acids and urea. Citrulline and arginine increased significantly in HD compared to control sheep. Ten other amino acids decreased in presymptomatic HD sheep, including branched chain amino acids (isoleucine, leucine and valine) that have been identified previously as potential biomarkers of HD. Significant increases in urea, arginine, citrulline, asymmetric and symmetric dimethylarginine, alongside decreases in sphingolipids, indicate that both the urea cycle and nitric oxide pathways are dysregulated at early stages in HD. Logistic prediction modelling identified a set of 8 biomarkers that can identify 80% of the presymptomatic HD sheep as transgenic, with 90% confidence. This level of sensitivity, using minimally invasive methods, offers novel opportunities for monitoring disease progression in HD patients.
OBJECTIVE: In an effort to enhance the efficiency, brightness, and contrast of light-emitting (LE) devices during the day, displays often generate substantial short-wavelength (blue-enriched) light emissions that can adversely affect sleep. We set out to verify the extent of such short-wavelength emissions, produced by a tablet (iPad Air), e-reader (Kindle Paperwhite 1st generation), and smartphone (iPhone 5s) and to determine the impact of strategies designed to reduce these light emissions. SETTING: University of Surrey dedicated chronobiology facility. METHODS: First, the spectral power of all the LE devices was assessed when displaying identical text. Second, we compared the text output with that of "Angry Birds" - a popular top 100 "App Store" game. Finally, we measured the impact of two strategies that attempt to reduce the output of short-wavelength light emissions. The first strategy employed an inexpensive commercially available pair of orange-tinted "blue-blocking" glasses. The second strategy tested an app designed to be "sleep-aware" whose designers deliberately attempted to reduce short-wavelength light emissions. RESULTS: All the LE devices shared very similar enhanced short-wavelength peaks when displaying text. This included the output from the backlit Kindle Paperwhite device. The spectra when comparing text to the Angry Birds game were also very similar, although the text emissions were higher intensity. Both the orange-tinted glasses and the "sleep-aware" app significantly reduced short-wavelength emissions. CONCLUSION: The LE devices tested were all bright and characterized by short-wavelength enriched emissions. Since this type of light is likely to cause the most disruption to sleep as it most effectively suppresses melatonin and increases alertness, there needs to be the recognition that at night-time "brighter and bluer" is not synonymous with "better." Ideally future software design could be better optimized when night-time use is anticipated, and hardware should allow an automatic "bedtime mode" that shifts blue and green light emissions to yellow and red as well as reduce backlight/light intensity.
Background: Multiple lines of evidence suggest that the onset and course of bipolar disorder is influenced by environmental light conditions. Increased suppression of melatonin by light (supersensitivity) in patients with bipolar disorder has been postulated as an endophenotype by several studies. However, due to methodological shortcomings, the results of these studies remain inconclusive. This study investigated melatonin suppression in euthymic patients with bipolar I disorder using evening blue light specifically targeting the melanopsin system. Methods: Melatonin suppression was assessed in euthymic patients with bipolar I disorder and healthy controls by exposure to monochromatic blue light (λmax = 475 nm; photon density = 1.6 × 10¹³ photons/cm²/s) for 30 minutes at 2300 h, administered via a ganzfeld dome for highly uniform light exposure. Serum melatonin concentrations were determined from serial blood sampling via radioimmunoassay. All participants received mydriatic eye drops and were genotyped for the PER3 VNTR polymorphism to avoid or adjust for potential confounding. As secondary outcomes, serum melatonin concentrations during dark conditions and after monochromatic red light exposure (λmax = 624 nm; photon density = 1.6 × 10¹³ photons/cm²/s) were also investigated. Changes in subjective alertness were investigated for all 3 lighting conditions. Results: A total of 90 participants (57 controls, 33 bipolar I disorder) completed the study. Melatonin suppression by monochromatic blue light did not differ between groups (F1,80 = 0.56; p = 0.46). Moreover, there were no differences in melatonin suppression by monochromatic red light (F1,82 = 1.80; p = 0.18) or differences in melatonin concentrations during dark conditions (F1,74 = 1.16; p = 0.29). Healthy controls displayed a stronger increase in subjective alertness during exposure to blue light than patients with bipolar I disorder (t85 = 2.28; p = 0.027). Limitations: Large interindividual differences in melatonin kinetics may have masked a true difference. Conclusion: Despite using a large cohort and highly controlled laboratory conditions, we found no differences in melatonin suppression between euthymic patients with bipolar I disorder and healthy controls. These findings do not support the notion that supersensitivity is a valid endophenotype in bipolar I disorder.
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.
Physical activity has been recommended as a strategy for improving sleep. Nevertheless, physical effort at work might not be not the ideal type of activity to promote sleep quality. The aim of this study was to evaluate the effects of type of job (low vs. high physical effort) and life-style on sleep of workers from an Amazonian Extractivist Reserve, Brazil. A cross-sectional study of 148 low physical activity (factory workers) and 340 high physical activity (rubber tappers) was conducted between September and November 2011. The workers filled out questionnaires collecting data on demographics (sex, age, occupation, marital status and children), health (reported morbidities, sleep disturbances, musculoskeletal pain and body mass index) and life-style (smoking, alcohol use and practice of leisure-time physical activity). Logistic regression models were applied with the presence of sleep disturbances as the primary outcome variable. The prevalence of sleep disturbances among factory workers and rubber tappers was 15.5% and 27.9%, respectively. The following independent variables of the analysis were selected based on a univariate model (p40 years), and having musculoskeletal pain (≥5 symptoms). Rubber tapper work, owing to greater physical effort, pain and musculoskeletal fatigue, was associated with sleep disturbances. Being female and older than 40 years were also predictors of poor sleep. In short, these findings suggest that demanding physical exertion at work may not improve sleep quality.
Melatonin is a pleiotrophic hormone, synthesised primarily by the pineal gland under the control of the suprachiasmatic nuclei (SCN). It not only provides a hormonal signal of darkness but also has neuroprotective properties. Huntington's disease (HD) is a progressive neurodegenerative disorder characterised by abnormal motor, cognitive and psychiatric symptoms. There is growing evidence, particularly from animal models, that circadian rhythms may also be disturbed in HD. We measured two circadian‐regulated hormones, melatonin and cortisol, in plasma samples collected around‐the‐clock from normal and presymptomatic transgenic HD sheep (Ovis aries) at 5 and 7 years of age, to assess SCN‐driven rhythms and the effect of genotype, sex and age. Melatonin‐related precursors and metabolites (tryptophan, serotonin, kynurenine) were also measured by liquid chromatography (LC)‐mass spectrometry (MS). At 5 years of age in both rams and ewes, plasma melatonin levels were significantly elevated in HD sheep. In ewes measured 2 years later, there was still a significant elevation of nocturnal melatonin. Furthermore, the daytime baseline levels of melatonin were significantly higher in HD sheep. Since increased melatonin could have global beneficial effects on brain function, we suggest that the increased melatonin measured in presymptomatic HD sheep is part of an autoprotective response to mutant huntingtin toxicity that may account, at least in part, for the late onset of disease that characterises HD.
INTRODUCTION Functional connectivity (FC) of the human brain’s intrinsically connected networks underpins cognitive functioning and disruptions of FC are associated with sleep and neurological disorders. However, there is limited research on the impact of circadian phenotype and time of day on FC. STUDY OBJECTIVES The aim of this study was to investigate resting state FC of the default mode network (DMN) in Early and Late circadian phenotypes over a socially constrained day. METHODS 38 healthy individuals (14 male, 22.7 ± 4.2 years) categorised as Early (n =16) or Late (n = 22) using the Munich ChronoType Questionnaire took part. Following a two week baseline of actigraphy coupled with saliva samples for melatonin and cortisol rhythms, participants underwent testing at 14.00 h, 20.00 h and 08.00 h the following morning. Testing consisted of resting state functional MRI, a structural T1 scan, attentional cognitive performance tasks and self-reported daytime sleepiness. Seed based FC analysis from the medial prefrontal and posterior cingulate cortices of the DMN was performed, compared between groups and linked with behavioural data. RESULTS Fundamental differences in the DMN were observed between Early and Late circadian phenotypes. Resting state FC of the DMN predicted individual differences in attention and subjective ratings of sleepiness. CONCLUSION Differences in FC of the DMN may underlie the compromised attentional performance and increased sleepiness commonly associated with Late types when they conform to a societally constrained day that does not match their intrinsic circadian phenotype.
Melatonin has chronobiotic properties in humans. It is able to phase shift strongly endogenous rhythms, such as core temperature and its own endogenous rhythm, together with the sleep-wake cycle. Its ability to synchronize free-running rhythms has not been fully investigated in humans. There is evidence for synchronization of the sleep-wake cycle, but the available data suggest that it is less effective with regard to endogenous melatonin and core temperature rhythms. When suitably timed, most studies indicate that fast release preparations are able to hasten adaptation to phase shift in both field and simulation studies of jet lag and shift work. Both subjective and objective measures support this statement. However, not all studies have been successful. Careful evaluation of the effects on work-related performance is required. When used to alleviate the non-24-h sleep-wake disorder in blind subjects, again most studies report a successful outcome using behavioral measures, albeit in a small number of individuals. The pres suggest, however, that although leep-wake can be stabilized to 24 h, entrainment of other rhythms is exceptionally rare.
OBJECTIVE: The aim of this study was to identify atherosclerotic risk using pulse wave velocity (PWV) in steel workers employed in different shift-work rotations, and to elucidate its relationship to social jetlag and shift schedule details. PARTICIPANTS: Male workers in a steel factory (n=77, 32 fast clockwise (CW), 30 slow counterclockwise (CC), 15 day workers (DW); mean age 42 ± SD 7.6 yrs) with at least 5 years of experience in their current work schedule participated. METHODS: All workers completed questionnaires on demographics, health, psychotropic agents, sleep, social and work life, social jetlag (difference between mid-sleep time on workdays and days off used as a marker of circadian disruption) and chronotype (mid-sleep time on free days corrected for sleep deficit on workdays). In 63 workers we measured PWV, blood pressure (BP), heart rate (HR) between 08:00 and 12:30 h in controlled posture conditions (no caffeine/smoking/exercise). RESULTS: There was no significant difference in PWV (covariates: age, BP) between the different shift-rotations (CW, CC and DW). In all workers combined, HR and social jetlag were significantly positively correlated. Demographic variables did not differ between shift-workers and day workers; shift-workers (CW, CC) reported significantly more stomach upsets, digestion problems, weight fluctuations, and social jetlag. The CW and CC workers did not differ in ratings of how shift-work affected sleep, social and work life. CONCLUSIONS: PWV was not different between the two shift-rotations. This pilot study shows first evidence that HR is related to social jetlag, and therefore warrants more studies in different shift schedules.
Metabolic profiling of individuals with type 2 diabetes mellitus (T2DM) has previously been limited to single-time-point samples, ignoring time-of-day variation. Here, we tested our hypothesis that body mass and T2DM affect daily rhythmicity and concentrations of circulating metabolites across a 24-h day in 3 age-matched, male groups—lean, overweight/obese (OW/OB), and OW/OB with T2DM—in controlled laboratory conditions, which were not confounded by large meals. By using targeted liquid chromatography/mass spectrometry metabolomics, we quantified 130 plasma metabolites every 2 h over 24 h, and we show that average metabolite concentrations were significantly altered by increased body mass (90 of 130) and T2DM (56 of 130). Thirty-eight percent of metabolites exhibited daily rhythms in at least 1 study group, and where a metabolite was rhythmic in >1 group, its peak time was comparable. The optimal time of day was assessed to provide discriminating biomarkers. This differed between metabolite classes and study groups—for example, phospholipids showed maximal difference at 5:00 AM (lean vs. OW/OB) and at 5:00 PM (OW/OB vs. T2DM). Metabolites that were identified with both robust 24-h rhythms and significant concentration differences between study groups emphasize the importance of controlling the time of day for diagnosis and biomarker discovery, offering a significant improvement over current single sampling.—Isherwood, C. M., Van der Veen, D. R., Johnston, J. D., Skene, D. J. Twenty-four-hour rhythmicity of circulating metabolites: effect of body mass and type 2 diabetes. It is widely accepted that obesity is the main risk factor for type 2 diabetes mellitus (T2DM) (1). The progression from obesity to T2DM is largely a result of comorbidities, such as systemic inflammation and insulin resistance. Metabolic profiling by using targeted metabolomics, which enables the quantification of more than 100 low-MW intermediates of metabolism, is increasingly used to characterize (pre)diabetic phenotypes and has identified differences in metabolite profiles between those individuals who are obese and those with T2DM (2–5). Recent work by our group and others has shown a 24-h variation in the human metabolome in healthy individuals, analyzed by using a range of analytical platforms (6–12), which has demonstrated that an estimated 15–20% of the metabolome is rhythmic in blood (6, 7). Transgenic mice that carry targeted genetic manipulation of circadian clock genes also exhibit a phenotype that involves defective metabolism, and associations between the circadian timing system and metabolic responses have been reported in humans (13). Reviews of these studies, including the higher incidence of obesity, T2DM, and related disorders in shift workers, have recently been published (14, 15). Existing metabolomics studies in T2DM have been restricted to the analysis of single-time-point, mostly fasting, samples, which cannot characterize the effect of increased body mass and T2DM on rhythmic metabolites. Characterizing 24-h metabolite rhythms in T2DM compared with age- and body mass–matched controls may therefore provide novel insights into the etiology and progression of T2DM. Identification of the optimal time of day for blood sampling—when metabolite levels show the biggest difference between T2DM and controls—would also provide more discriminating diagnostic biomarkers, rather than taking a single morning fasting sample. We thus assessed the effect of increased body mass [overweight/obese (OW/OB)] and T2DM on 24-h rhythms of circulating metabolites in men by using a quantitative targeted liquid chromatography/mass spectrometry (LC/MS) metabolomics approach. As T2DM is often accompanied by obesity, we set out to distinguish the effects of T2DM from those of increased body mass by incorporating both a lean and an OW/OB control group into the current study design.
Melatonin is a physiological hormone involved in sleep timing and is currently used exogenously in the treatment of primary and secondary sleep disorders with empirical evidence of efficacy, but very little evidence from randomised, controlled studies. The aim of this meta-analysis was to assess the evidence base for the therapeutic effects of exogenous melatonin in treating primary sleep disorders. An electronic literature review search of MEDLINE (1950-present) EMBASE (1980- present), PsycINFO (1987- present), and SCOPUS (1990- present), along with a hand-searching of key journals was performed in July 2013 and then again in May 2015. This identified all studies that compared the effect of exogenous melatonin and placebo in patients with primary insomnia, delayed sleep phase syndrome, Non 24- hour sleep wake syndrome in people who are blind, and REM-Behaviour Disorder. Meta-analyses were performed to determine the effect of magnitude in studies of melatonin in improving sleep. A total of 5030 studies were identified; of these citations, 13 were included for review based on the inclusion criteria of being: double or single-blind, randomised and controlled. Results from the meta-analyses showed the most convincing evidence for exogenous melatonin use was in reducing sleep onset latency in primary insomnia (p=0.002), delayed sleep phase syndrome (p
BACKGROUND: Night shift work has been associated with an increased risk for breast and prostate cancer. The effect of circadian disruption on sex steroid production is a possible underlying mechanism, underinvestigated in humans. We have assessed daily rhythms of sex hormones and melatonin in night and day shift workers of both sexes. METHODS: We recruited 75 night and 42 day workers, ages 22 to 64 years, in different working settings. Participants collected urine samples from all voids over 24 hours on a working day. Urinary concentrations of 16 sex steroid hormones and metabolites (estrogens, progestagens, and androgens) and 6-sulfatoxymelatonin were measured in all samples. Mean levels and peak time of total and individual metabolite production were compared between night and day workers. RESULTS: Night workers had higher levels of total progestagens [geometric mean ratio (GMR) 1.65; 95% confidence intervals (CI), 1.17-2.32] and androgens (GMR: 1.44; 95% CI, 1.03-2.00), compared with day workers, after adjusting for potential confounders. The increased sex hormone levels among night shift workers were not related to the observed suppression of 6-sulfatoxymelatonin. Peak time of androgens was significantly later among night workers, compared with day workers (testosterone: 12:14 hours; 10:06-14:48 vs. 08:35 hours; 06:52-10:46). CONCLUSIONS: We found increased levels of progestagens and androgens as well as delayed peak androgen production in night shift workers compared with day workers. IMPACT: The increase and mistiming of sex hormone production may explain part of the increased risk for hormone-related cancers observed in night shift workers.
Although studies have reported the effects of the menstrual cycle on melatonin rhythmicity, none has investigated the effects of menopause on the melatonin rhythm. The circadian rhythm in melatonin and its relationship to subjective alertness was investigated in pre- and postmenopausal women under constant routine conditions (controlled posture, dim lighting, calorie intake, temperature, and prolonged wakefulness). Eleven healthy pre-menopausal (42+/-4 yr) and 10 postmenopausal women (55+/-2 yr) participated in the study. Salivary melatonin samples and subjective measures of alertness and sleepiness were assessed hourly during the 22 h constant routine protocol. Postmenopausal women had a significantly earlier melatonin acrophase (1.1+/-0.5 h clock time in decimal h; mean+/-SEM, p
This study aimed to analyze individual cortisol levels in relation to work conditions, sleep, and health parameters among truck drivers working day shifts (n?=?21) compared to those working irregular shifts (n?=?21). A total of 42 male truck drivers (39.8???6.2 yrs) completed questionnaires about sociodemographics, job content, work environment, health, and lifestyle. Rest-activity profiles were measured using actigraphy, and cardiovascular blood parameters were collected. Salivary cortisol samples were obtained: (i) at waking time, (ii) 30?min after waking, and (iii) at bedtime, during both one workday and one day off from work. Irregular-shift workers, compared to day-shift workers, showed significantly higher waist-hip ratio, very-low-density lipoprotein (VLDL) cholesterol, tiredness after work, years working as a driver, truck vibration, and less job demand (p?
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 subjects remained in controlled laboratory conditions for ~92 h with respect to posture, meals and environment light (18:00‐23:00 h and 07:00‐09:00 h
OBJECTIVES: Endothelial dysfunction and alterations in heart rate variability (HRV) as well as sleep deprivation and shift work have been associated with cardiovascular disease. The aim of this study was to compare HRV and endothelial function among shift and matched non-shift workers in response to total sleep deprivation and recovery sleep under identical laboratory settings. METHODS: Eleven experienced male shift workers (shift work ≥5 years) and 14 non-shift workers were matched for age, body mass index, and cholesterol. HRV parameters [eg, HR variance and low frequency/high frequency (LF/HF) ratio] were derived from 5-minute electrocardiogram bins at 0.25, 4.25, 11.5, 12.5, and 13.5 hours after habitual wake-up time and endothelial function was assessed by flow-mediated dilatation (FMD) using ultrasound at 0.75 and 10.75 hours after habitual wake-up time, following baseline sleep, total sleep deprivation, and recovery sleep (posture- and food-controlled throughout). Circadian phase was assessed before baseline sleep by salivary dim light melatonin onset. RESULTS: There was no difference in circadian phase between shift and non-shift workers. HR variance was highest at 0.25 hours following total sleep deprivation and lowest after recovery sleep. A significantly higher LF/HF ratio, significantly lower HR variance, and a trend for a lower %FMD (P=0.08) were observed among shift compared to non-shift workers. CONCLUSION: Despite similar demographics, circadian phase, posture and food intake, differences in endothelial function and HRV were observed in the two groups, which may reflect higher sympathetic and/or lower parasympathetic activity, contributing to increased cardiovascular risk among the shift workers.
Several novel animal studies have shown that intrauterine metabolic programming can be modified in the event of reduced melatonin synthesis during pregnancy, leading to glucose intolerance and insulin resistance in the offspring. It is therefore postulated that female night workers when pregnant may expose the offspring to unwanted health threats. This may be explained by the fact that melatonin is essential for regulating energy metabolism and can influence reproductive activity. Moreover, the circadian misalignment caused by shift work affects fertility and the fetus, increasing the risk of miscarriage, premature birth and low birth weight, phenomena observed in night workers. Thus, we hypothesize that light-induced melatonin suppression as a result of night work may alter intrauterine metabolic programming in pregnant women, potentially leading to metabolic disorders in their offspring.
Daylight stems solely from direct, scattered and reflected sunlight, and undergoes dynamic changes in irradiance and spectral power composition due to latitude, time of day, time of year and the nature of the physical environment (reflections, buildings and vegetation). Humans and their ancestors evolved under these natural day/night cycles over millions of years. Electric light, a relatively recent invention, interacts and competes with the natural light–dark cycle to impact human biology. What are the consequences of living in industrialised urban areas with much less daylight and more use of electric light, throughout the day (and at night), on general health and quality of life? In this workshop report, we have classified key gaps of knowledge in daylight research into three main groups: (I) uncertainty as to daylight quantity and quality needed for “optimal” physiological and psychological functioning, (II) lack of consensus on practical measurement and assessment methods and tools for monitoring real (day) light exposure across multiple time scales, and (III) insufficient integration and exchange of daylight knowledge bases from different disciplines. Crucial short and long-term objectives to fill these gaps are proposed.
Conflicting evidence exists as to whether there are differences between males and females in circadian timing. The aim of the current study was to assess whether sex differences are present in the circadian regulation of melatonin and cortisol in plasma and urine matrices during a constant routine protocol. Thirty-two healthy individuals (16 females taking the oral contraceptive pill (OCP)), aged 23.8 ± 3.7 (mean ± SD) years, participated. Blood (hourly) and urine (4-hourly) samples were collected for measurement of plasma melatonin and cortisol, and urinary 6-sulfatoxymelatonin (aMT6s) and cortisol, respectively. Data from 28 individuals (14 females) showed no significant differences in the timing of plasma and urinary circadian phase markers between sexes. Females, however, exhibited significantly greater levels of plasma melatonin and cortisol than males (AUC melatonin: 937 ± 104 (mean ± SEM) vs. 642 ± 47 pg/ml.h; AUC cortisol: 13581 ± 1313 vs. 7340 ± 368 mmol/L.h). Females also exhibited a significantly higher amplitude rhythm in both hormones (melatonin: 43.8 ± 5.8 vs. 29.9 ± 2.3 pg/ml; cortisol: 241.7 ± 23.1 vs. 161.8 ± 15.9 mmol/L). Males excreted significantly more urinary cortisol than females during the CR (519.5 ± 63.8 vs. 349.2 ± 39.3 mol) but aMT6s levels did not differ between sexes. It was not possible to distinguish whether the elevated plasma melatonin and cortisol levels observed in females resulted from innate sex differences or the OCP affecting the synthetic and metabolic pathways of these hormones. The fact that the sex differences observed in total plasma concentrations for melatonin and cortisol were not reproduced in the urinary markers challenges their use as a proxy for plasma levels in circadian research, especially in OCP users.
In our continuously developing 'around the clock' society, there is a need to increase our understanding of how changes in biology, physiology and psychology influence our health and performance. Embedded within this challenge, is the increasing need to account for individual differences in sleep and circadian rhythms, as well as to explore the impact of time of day on performance in the real world. There are a number of ways to measure sleep and circadian rhythms from subjective questionnaire-based methods to objective sleep/wake monitoring, actigraphy and analysis of biological samples. This paper proposes a protocol that combines multiple techniques to categorize individuals into Early, Intermediate or Late circadian phenotype groups (ECPs/ICPs/LCPs) and recommends how to conduct diurnal performance testing in the field. Representative results show large differences in rest-activity patterns derived from actigraphy, circadian phase (dim light melatonin onset and peak time of cortisol awakening response) between circadian phenotypes. In addition, significant differences in diurnal performance rhythms between ECPs and LCPs emphasizes the need to account for circadian phenotype. In summary, despite the difficulties in controlling influencing factors, this protocol allows a real-world assessment of the impact of circadian phenotype on performance. This paper presents a simple method to assess circadian phenotype in the field and supports the need to consider time of day when designing performance studies.
Sleep disturbances are common in patients with cirrhosis but their origins are unknown. The aim of this study was to investigate possible involvement of the circadian system. Sleep was monitored for two weeks, in the home environment, using sleep diaries and actigraphy, in 35 patients with cirrhosis (21 men; mean age [+/- 1SD] 58 +/- 10 yr) and 12 matched healthy controls (eight men; mean age 56 +/- 15 yr); urinary 6-sulphatoxymelatonin (aMT6s), the major metabolite of melatonin, was measured over 56 h, to assess circadian rhythmicity. The patients woke up and got up significantly later than the healthy volunteers and their sleep was significantly more fragmented. Mean 24-hour urinary aMT6s outputs were comparable in the patients and controls (15.5 +/- 13.1 vs. 20.3 +/- 13.8 mu g/24 h) but were significantly lower in the decompensated patients (9.8 +/- 11.3 vs. 17.0 +/- 13.3 mu g/24 h; p=0.03). Significant 24-hour urinary aMT6s rhythms were observed in 26 (79%) of the 33 patients with complete urine collections; 20 patients had a normally timed (midnight-06:00) urinary aMT6s peak, while it was delayed (>= 06:00) in the remainder. Significant correlations were observed between abnormalities in the urinary aMT6s profile (delays and/or lack of a 24-hour rhythm) and indices of sleep timing; parallel delays were observed in sleep habits and urinary aMT6s peaks. The association between delayed circadian rhythms and delayed sleep habits observed in approximately one-third of the patients with cirrhosis is reminiscent of 'delayed sleep phase syndrome'; this condition is managed by attempting to resynchronise the circadian clock by exposure to bright light shortly after morning awakening.
PER3 gene polymorphisms have been associated with differences in human sleep-wake phenotypes, and sensitivity to light. The aims of this study were to assess: i) the frequency of allelic variants at two PER3 polymorphic sites (rs57875989 length polymorphism: PER34, PER35; rs228697 SNP: PER3C, PER3G) in relation to sleep-wake timing; ii) the effect of morning light on behavioural/circadian variables in PER34/PER34 and PER35/PER35 homozygotes. 786 Caucasian subjects living in Northern Italy donated buccal DNA and completed diurnal preference, sleep quality/timing and sleepiness/ mood questionnaires. 19 PER34/PER34 and 11 PER35/PER35 homozygotes underwent morning light administration, whilst monitoring sleep-wake patterns and the urinary 6-sulphatoxymelatonin (aMT6s) rhythm. No significant relationship was observed between the length polymorphism and diurnal preference. By contrast, a significant association was observed between the PER3G variant and morningness (OR = 2.10), and between the PER3G-PER34 haplotype and morningness (OR = 2.19), for which a mechanistic hypothesis is suggested. No significant differences were observed in sleep timing/ aMT6s rhythms between PER35/PER35 and PER34/PER34 subjects at baseline. After light administration, PER34/PER34 subjects advanced their aMT6s acrophase (p < 0.05), and showed a trend of advanced sleep-wake timing. In conclusion, significant associations were observed between PER3 polymorphic variants/their combinations and both diurnal preference and the response to light.
Introduction: Metabolomics is an emerging approach providing new insights into the 7 metabolic changes and underlying mechanisms involved in the pathogenesis of 8 neurological disorders. 9 Areas covered: Here, we present an overview of the current knowledge of metabolic 10 profiling (metabolomics) to provide critical insight on the role of biochemical markers and metabolic alterations in neurological diseases. Expert opinion: Elucidation of characteristic metabolic alterations in neurological disorders is crucial for a better understanding of their pathogenesis, and for identifying potential biomarkers and drug targets. Nevertheless, discrepancies in diagnostic criteria, sample handling protocols, and analytical methods still affect the generalizability of current study results.
Sleep is essential for optimal brain functioning and health, but the biological substrates through which sleep delivers these beneficial effects remain largely unknown. We used a systems genetics approach in the BXD genetic reference population (GRP) of mice and assembled a comprehensive experimental knowledge base comprising a deep "sleep-wake" phenome, central and peripheral transcriptomes, and plasma metabolome data, collected under undisturbed baseline conditions and after sleep deprivation (SD). We present analytical tools to interactively interrogate the database, visualize the molecular networks altered by sleep loss, and prioritize candidate genes. We found that a one-time, short disruption of sleep already extensively reshaped the systems genetics landscape by altering 60%–78% of the transcriptomes and the metabolome, with numerous genetic loci affecting the magnitude and direction of change. Systems genetics integrative analyses drawing on all levels of organization imply α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor trafficking and fatty acid turnover as substrates of the negative effects of insufficient sleep. Our analyses demonstrate that genetic heterogeneity and the effects of insufficient sleep itself on the transcriptome and metabolome are far more widespread than previously reported.
Circadian rhythmicity and non-visual sensitivity to light can be assessed, in healthy subjects, by measuring the rhythm of the urinary melatonin metabolite 6-sulphatoxymelatonin (aMT6s) and by determining the response of plasma melatonin to nocturnal retinal light exposure, respectively. However, the validity of these techniques has not been assessed in disease states in which disruption of the circadian rhythm is known or suspected to occur. Thus, the aims of this study were as follows: (i) to assess the reliability of circadian aMT6s profile estimates derived from 36 h versus 56 h urine collections and (ii) to test different models for calculating melatonin suppression in response to light in healthy volunteers and patients with cirrhosis. Twenty patients with biopsy-proven cirrhosis and 10 matched healthy volunteers undertook: (i) separate 36 - and 56-h urine collections, under controlled conditions, for cosinor analysis of the urinary aMT6s profile; (ii) a melatonin suppression test, comprising of a baseline night, during which subjects were woken and asked to sit in front of a switched off light sphere, and an experimental night, identically executed, except that the light sphere was switched on and the subjects were exposed to white light (4.1 × 10(14) photons/cm(2)/s) for 30 min. Alternative approaches to the calculation of melatonin suppression were taken, with/without inclusion of the baseline night. Eighteen patients and eight healthy volunteers had matched analysable 36 - and 56-h urinary samples. Cosinor analysis showed a significant fit in 88% of the remaining 56 h collections, and 48% of the remaining 36-h collections. Thus, eight patients and five healthy volunteers had matched analysable samples for cosinor analysis. In the healthy volunteers, aMT6s profile indices obtained using the 36 - and the 56-h collections did not differ significantly. In contrast, considerably more variability was observed in patients [i.e. the difference in the aMT6s peak time was 0.5 ± 1.7 h (limits of agreement: -3.9; +2.9 h)]. No difficulties were encountered in obtaining suppression estimates by use of the experimental night only. In contrast, suppression estimates obtained by use of both nights were considered inaccurate in one (11%) healthy volunteer and in 5 (28%) patients, primarily because: (i) melatonin concentrations at the beginning of light administration were significantly different on baseline and experimental night; (ii) the rise in melatonin was inconsistent on baseline night; and (iii) the shape of the rising phase of melatonin was different on baseline and experimental night. In conclusion, shorter urine collections lead to a higher number of profiles with no significant cosinor fit, and differences in cosinor indices obtained from the 36 - and 56-h collections were considerable, especially in patients. Thus, 56-h collections are probably advisable. Use of both baseline and experimental nights to calculate melatonin suppression often resulted in increased variation and confounding, due to point oscillations in melatonin concentration and lack of repeatability of the melatonin profiles on the two nights. Thus, use of the experimental night only is probably advisable.
Epidemiological studies have shown that shift workers are at a greater risk of developing cardiovascular disease which may, in part, be related to metabolic and hormonal changes. Partial sleep deprivation, a common consequence of rotating shift work, has been shown to affect glucose tolerance and insulin sensitivity. The current study investigated the effects of one night of total sleep deprivation, as a proxy for the first night shift, on postprandial glucose, insulin and lipid (triacylglycerols (TAGs) and non-esterified fatty acids (NEFAs)) responses under controlled laboratory conditions in shift workers and non-shift workers. Eleven experienced shift workers (35.7±7.2 years, mean±s.d.) who had worked in shifts for 8.7±5.25 years were matched with 13 non-shift workers who had worked for 32.8±6.4 years. After an adaptation night and a baseline sleep night, volunteers were kept awake for 30.5 h, followed by a nap (4 h) and recovery sleep. Blood samples were taken prior to and after a standard breakfast following baseline sleep, total sleep deprivation and recovery sleep. Basal TAG levels prior to the standard breakfast were significantly lower after sleep deprivation, indicating higher energy expenditure. Basal NEFA levels were significantly lower after recovery sleep. Postprandial insulin and TAG responses were significantly increased, and the NEFA response was decreased after recovery sleep, suggestive of insulin insensitivity. Although there were no overall significant differences between non-shift workers and shift workers, non-shift workers showed significantly higher basal insulin levels, lower basal NEFA levels, and an increased postprandial insulin and a decreased NEFA response after recovery sleep. In future, the reasons for these inter-group differences are to be investigated.
Understanding how metabolite levels change over the 24 hour day is of crucial importance for clinical and epidemiological studies. Additionally, the association between sleep deprivation and metabolic disorders such as diabetes and obesity requires investigation into the links between sleep and metabolism. Here, we characterise time-of-day variation and the effects of sleep deprivation on urinary metabolite profiles. Healthy male participants (n = 15) completed an in-laboratory study comprising one 24 h sleep/wake cycle prior to 24 h of continual wakefulness under highly controlled environmental conditions. Urine samples were collected over set 2-8 h intervals and analysed by (1)H NMR spectroscopy. Significant changes were observed with respect to both time of day and sleep deprivation. Of 32 identified metabolites, 7 (22%) exhibited cosine rhythmicity over at least one 24 h period; 5 exhibiting a cosine rhythm on both days. Eight metabolites significantly increased during sleep deprivation compared with sleep (taurine, formate, citrate, 3-indoxyl sulfate, carnitine, 3-hydroxyisobutyrate, TMAO and acetate) and 8 significantly decreased (dimethylamine, 4-DTA, creatinine, ascorbate, 2-hydroxyisobutyrate, allantoin, 4-DEA, 4-hydroxyphenylacetate). These data indicate that sampling time, the presence or absence of sleep and the response to sleep deprivation are highly relevant when identifying biomarkers in urinary metabolic profiling studies.