Leone AM, Skene D (1994) Melatonin concentrations in pineal organ culture are suppressed by sera from tumor-bearing mice., J Pineal Res 17 (1) pp. 17-19
The melatonin rhythm is significantly attenuated in a wide range of human and animal tumor types. Since surgical removal of the tumor has been shown to restore this rhythm, we hypothesized that a plasma borne tumor-associated factor (TAMF) could be responsible. A population of mice were injected with tumor cells and sequentially killed and bled over the following 9 days, i.e., to the maximal state of tumor growth. Pooled serum from the different collection days was added to an established pineal organ culture system, and melatonin concentrations measured. A highly significant correlation between melatonin concentrations and the stage of tumor growth was seen with maximal inhibition occurring at day 9 (P
SKENE DJ, VIVIENROELS B, PEVET P (1989) PINEAL 5-METHOXYTRYPTOPHOL RHYTHMS IN THE BOX TURTLE - EFFECT OF PHOTOPERIOD AND ENVIRONMENTAL-TEMPERATURE, NEUROSCIENCE LETTERS 98 (1) pp. 69-73 ELSEVIER SCI IRELAND LTD
Montagnese S, Middleton B, Mani AR, Skene DJ, Morgan MY (2009) HEPATO-ADRENAL SYNDROME: DOES CORTISOL SAMPLE TIME MATTER?, JOURNAL OF HEPATOLOGY 50 pp. S84-S84 ELSEVIER SCIENCE BV
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 (e5 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.
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 e5 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.
Kantermann T, Duboutay F, Haubruge D, Hampton S, Darling AL, Berry JL, Kerkhofs M, Boudjeltia KZ, Skene DJ (2014) The direction of shift-work rotation impacts metabolic risk independent of chronotype and social jetlag--an exploratory pilot study., Chronobiol Int 31 (10) pp. 1139-1145
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.
GAUER F, MASSONPEVET M, SKENE DJ, VIVIENROELS B, PEVET P (1993) DAILY RHYTHMS OF MELATONIN BINDING-SITES IN THE RAT PARS TUBERALIS AND SUPRACHIASMATIC NUCLEI - EVIDENCE FOR A REGULATION OF MELATONIN RECEPTORS BY MELATONIN ITSELF, NEUROENDOCRINOLOGY 57 (1) pp. 120-126 KARGER
Arendt J, Middleton B, Stone B, Skene D (1999) Complex effects of melatonin: Evidence for photoperiodic responses in humans?, SLEEP 22 (5) pp. 625-635 AMER SLEEP DISORDERS ASSOC
Darling AL, Hart KH, Skene DJ, Arber S, Lanham-New SA (2014) Vitamin D status, functional ability and muscle strength in older South Asian and Caucasian women in the UK, PROCEEDINGS OF THE NUTRITION SOCIETY 73 (OCE1) pp. E23-E23 CAMBRIDGE UNIV PRESS
Ackermann K, Revell VL, Lao O, Rombouts EJ, Skene DJ, Kayser M (2012) Diurnal Rhythms in Blood Cell Populations and the Effect of Acute Sleep Deprivation in Healthy Young Men, SLEEP 35 (7) pp. 933-940
Zawilska JB, Skene DJ, Nowak JZ (1998) 5-Methoxytryptophol rhythms in the chick pineal gland: effect of environmental lighting conditions, NEUROSCIENCE LETTERS 251 (1) pp. 33-36 ELSEVIER SCI IRELAND LTD
SKENE DJ, BOJKOWSKI CJ, ARENDT J (1994) COMPARISON OF THE EFFECTS OF ACUTE FLUVOXAMINE AND DESIPRAMINE ADMINISTRATION ON MELATONIN AND CORTISOL PRODUCTION IN HUMANS, BRITISH JOURNAL OF CLINICAL PHARMACOLOGY 37 (2) pp. 181-186 BLACKWELL SCIENCE LTD
Nicholls J, Skene DJ, Hourani SMO (1997) Use of a newly developed technique to isolate rat pinealocytes and study the effects of adenosine agonists on melatonin production, JOURNAL OF PINEAL RESEARCH 23 (3) pp. 164-168 WILEY-BLACKWELL
Montagnese S, Middleton B, Mani AR, Skene DJ, Morgan MY (2006) Evidence of central circadian disruption in patients with cirrhosis, JOURNAL OF HEPATOLOGY 44 pp. S276-S276 ELSEVIER SCIENCE BV
Montagnese S, Middleton B, Mani AR, Skene DJ, Morgan MY (2008) EVIDENCE OF CENTRAL CIRCADIAN DISRUPTION IN PATIENTS WITH CIRRHOSIS, HEPATOLOGY 48 (4) pp. 1063A-1063A JOHN WILEY & SONS INC
Revell VL, Skene DJ (2008) Authors' response, Chronobiology International 25 (4) pp. 655-656
Darling AL, Gossiel F, Hannon R, Skene DJ, Berry JL, Eastell R, Lanham-New SA (2010) ASSOCIATION BETWEEN DEGREE OF SEASONAL FLUCTUATION (?CYCLING?) OF 25(OH)D, PTH AND BONE RESORPTION IN UK SOUTH ASIAN AND CAUCASIAN WOMEN LIVING AT 51ON (SURREY),
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.
Zawilska JB, Berezinska M, Lorenc A, Skene DJ, Nowak JZ (2004) Retinal illumination phase shifts the circadian rhythm of serotonin N-acetyltransferase activity in the chicken pineal gland, NEUROSCIENCE LETTERS 360 (3) pp. 153-156 ELSEVIER SCI IRELAND LTD
Skene DJ, Lockley SW, Tabandeh H, DeFrance R, Bird AC, Arendt J (1997) Visual pathology and human circadian rhythms, pp. 349-353 P J D PUBLICATIONS LTD
Arendt J, Van Someren EJW, Appleton R, Skene DJ, Akerstedt T (2008) Clinical update: melatonin and sleep disorders, CLINICAL MEDICINE 8 (4) pp. 381-383 ROY COLL PHYS LONDON EDITORIAL OFFICE
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
Darling AL, Skene DJ, Lanham-New SA (2011) Preliminary evidence of an association between vitamin D status and self-assessed sleep duration but not overall sleep quality: results from the D-FINES study of South Asian and Caucasian pre- and post-menopausal women living in Southern England, PROCEEDINGS OF THE NUTRITION SOCIETY 70 (OCE3) pp. E88-E88 CAMBRIDGE UNIV PRESS
Gogenur I, Middleton B, Burgdorf S, Rasmussen LS, Skene DJ, Rosenberg J (2007) Impact of sleep and circadian disturbances in urinary 6-sulphatoxymelatonin levels, on cognitive function after major surgery, JOURNAL OF PINEAL RESEARCH 43 (2) pp. 179-184 BLACKWELL PUBLISHING
Tzischinsky O, Skene D, Epstein R, Lavie P (1991) Circadian rhythms in 6-sulphatoxymelatonin and nocturnal sleep in blind children., Chronobiol Int 8 (3) pp. 168-175
This article describes the relationship between melatonin secretion and sleep quality and subjective complaints about sleep in totally blind children. Eleven boarding-school children (mean age 15.2 years) participated. The major urinary melatonin metabolite 6-sulphatoxymelatonin (aMT6s) was measured five times a day for 48 h. Sleep-wake cycles were recorded by continuous actigraphic recordings during the same time period. Results showed that delayed secretory peaks in aMT6s were significantly associated with disturbed nocturnal sleep and with complaints about morning fatigue.
SKENE DJ, MODIPANE A, JOUBERT PH (1984) SERUM DIGOXIN LEVELS - A COST-BENEFIT-ANALYSIS, SOUTH AFRICAN MEDICAL JOURNAL 65 (1) pp. 15-15 MED ASSOC S AFRICA
Mistlberger RE, Skene DJ (2004) Social influences on mammalian circadian rhythms: animal and human studies, BIOLOGICAL REVIEWS 79 (3) pp. 533-556 CAMBRIDGE UNIV PRESS
Skene DJ, Arendt J (2006) Human circadian rhythms: physiological and therapeutic relevance of light and melatonin, ANNALS OF CLINICAL BIOCHEMISTRY 43 pp. 344-353 ROYAL SOC MEDICINE PRESS LTD
Schmoll C, Lascaratos G, Dhillon B, Skene D, Riha RL (2011) The role of retinal regulation of sleep in health and disease, SLEEP MEDICINE REVIEWS 15 (2) pp. 107-113 W B SAUNDERS CO LTD
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?.05). High cortisol levels in irregular-shift workers were correlated with certain stressors, such as short sleep duration and low job satisfaction, and to metabolic parameters, such as total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), VLDL, and triglycerides. Day-shift workers had higher cortisol levels collected 30?min after waking (p?=?.03) and a higher cortisol awakening response (CAR; p?=?.02) during workdays compared to off days. Irregular-shift workers had higher cortisol levels on their off days compared to day-shift workers (p?=?.03). In conclusion, for the day-shift workers, a higher cortisol response was observed on workdays compared to off days. Although no direct comparisons could be made between groups for work days, on off days the irregular-shift workers had higher cortisol levels compared to day-shift workers, suggesting a prolonged stress response in the irregular-shift group. In addition, cortisol levels were correlated with stressors and metabolic parameters. Future studies are warranted to investigate further stress responses in the context of irregular work hours. (Author correspondence: email@example.com ).
Study Objectives: To investigate the link between extreme diurnal preference, delayed sleep phase syndrome, and a length polymorphism in Per3. Design: Subjects were genotyped using polymerase chain reaction. Patients or Participants: Subjects with defined diurnal preference as determined by the Horne-Östberg questionnaire and patients with delayed sleep phase syndrome. Measurements and Results: The Per3 polymorphism correlated significantly with extreme diurnal preference, the longer allele associating with morningness and the shorter allele with eveningness. The shorter allele was strongly associated with the delayed sleep phase syndrome patients, 75% of whom were homozygous. Conclusion: The length of the Per3 repeat region identifies a potential genetic marker for extreme diurnal preference.
Ruberg FL, Skene DJ, Hanifin JP, Rollag MD, English J, Arendt J, Brainard GC (1996) Melatonin regulation in humans with color vision deficiencies, JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM 81 (8) pp. 2980-2985 ENDOCRINE SOC
Zawilska JB, Lorenc A, Berezinska M, Vivien-Roels B, Pevet P, Skene DJ (2006) Daily oscillation in melatonin synthesis in the turkey pineal gland and retina: Diurnal and circadian rhythms, CHRONOBIOLOGY INTERNATIONAL 23 (1-2) pp. 341-350 TAYLOR & FRANCIS INC
Montagnese S, Middleton B, Mani AR, Skene DJ, Morgan MY (2011) Changes in the 24-h plasma cortisol rhythm in patients with cirrhosis, JOURNAL OF HEPATOLOGY 54 (3) pp. 588-590 ELSEVIER SCIENCE BV
Darling AL, Hart KH, Skene DJ, Arber S, Lanham-New SA (2013) Vitamin D, sunlight exposure, sleep disturbances and musculoskeletal health of older South Asian women in the UK: biological and social influences, PROCEEDINGS OF THE NUTRITION SOCIETY 72 (OCE4) pp. E187-E187 CAMBRIDGE UNIV PRESS
SKENE DJ, SMITH I, ARENDT J (1986) RADIOIMMUNOASSAY OF PINEAL 5-METHOXYTRYPTOPHOL IN DIFFERENT SPECIES - COMPARISON WITH PINEAL MELATONIN CONTENT, JOURNAL OF ENDOCRINOLOGY 110 (1) pp. 177-184 J ENDOCRINOLOGY LTD
Davies SK, Ang JE, Revell VL, Holmes B, Mann A, Robertson FP, Cui N, Middleton B, Ackermann K, Kayser M, Thumser AE, Raynaud FI, Skene DJ (2014) Effect of sleep deprivation on the human metabolome, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 111 (29) pp. 10761-10766
NATL ACAD SCIENCES
SKENE DJ, LEONE RM, YOUNG IM, SILMAN RE (1983) THE ASSESSMENT OF A PLASMA MELATONIN ASSAY USING GAS-CHROMATOGRAPHY NEGATIVE-ION CHEMICAL IONIZATION MASS-SPECTROMETRY, BIOMEDICAL MASS SPECTROMETRY 10 (12) pp. 655-659 JOHN WILEY & SONS LTD
Montagnese S, Middleton B, Skene DJ, Morgan MY (2008) Sleep disturbances are not a feature of hepatic encephalopathy, JOURNAL OF HEPATOLOGY 48 pp. S40-S40 ELSEVIER SCIENCE BV
Montagnese S, Middleton B, Mani A, Skene D, Morgan MY (2005) Plasma melatonin abnormalities in patients with cirrhosis reflect both hepatic and cerebral dysfunction, HEPATOLOGY 42 (4) pp. 755A-755A JOHN WILEY & SONS INC
SKENE DJ, MODIPANE A, JOUBERT PH (1985) INVESTIGATION OF POSSIBLE POLYMORPHIC DRUG OXIDATION IN BLACK SOUTH AFRICANS, SOUTH AFRICAN MEDICAL JOURNAL 68 (9) pp. 653-654 MED ASSOC S AFRICA
Gogenur I, Middleton B, Kristiansen VB, Skene DJ, Rosenberg J (2007) Disturbances in melatonin and core body temperature circadian rhythms after minimal invasive surgery, ACTA ANAESTHESIOLOGICA SCANDINAVICA 51 (8) pp. 1099-1106 BLACKWELL PUBLISHING
Zawilska JB, Rosiak J, Vivien-Roels B, Skene DJ, Pevet P, Nowak JZ (2000) Effects of cycloheximide and aminophylline on 5-methoxytryptophol and melatonin contents in the chick pineal gland, GENERAL AND COMPARATIVE ENDOCRINOLOGY 120 (2) pp. 212-219 ACADEMIC PRESS INC
Pagani L, Moriggi E, Revell VR, Hack LM, Izakovic J, Lockley SW, Arendt J, Wirz-Justice A, Cajochen C, Skene DJ, Brown SA, Eckert A (2009) Human molecular circadian rhythms and ageing, PHARMACOPSYCHIATRY 42 (5) pp. 235-235 GEORG THIEME VERLAG KG
Zawilska JB, Rosiak J, Vivien-Roels B, Skene DJ, Pevet P, Nowak JZ (2002) Daily variation in the concentration of 5-methoxytryptophol and melatonin in the duck pineal gland and plasma, JOURNAL OF PINEAL RESEARCH 32 (4) pp. 214-218 BLACKWELL MUNKSGAARD
SKENE DJ, POTGIETER B (1981) INVESTIGATION OF 2 ANIMAL-MODELS OF DEPRESSION, SOUTH AFRICAN JOURNAL OF SCIENCE 77 (4) pp. 180-182 BUREAU SCIENTIFIC PUBL
Revell VL, Skene DJ (2007) Light-induced melatonin suppression in humans with polychromatic and monochromatic light, CHRONOBIOLOGY INTERNATIONAL 24 (6) pp. 1125-1137 TAYLOR & FRANCIS INC
Jones KH, Ellis J, Von Schantz M, Skene DJ, Dijk D, Archer SN (2006) Age-related change in the association between a variable number tandem repeat polymorphism in the (PER3) gene and preferred timing of sleep and waking activities, JOURNAL OF SLEEP RESEARCH 15 pp. 97-98 BLACKWELL PUBLISHING
Skene DJ, Timbers SE, Middleton B, English J, Kopp C, Tobler I, Ioannides C (2006) Mice convert melatonin to 6-sulphatoxymelatonin, GENERAL AND COMPARATIVE ENDOCRINOLOGY 147 (3) pp. 371-376 ACADEMIC PRESS INC ELSEVIER SCIENCE
Montagnese S, Middleton B, Skene DJ, Morgan MY (2009) Night-time sleep disturbance does not correlate with neuropsychiatric impairment in patients with cirrhosis, LIVER INTERNATIONAL 29 (9) pp. 1372-1382 WILEY-BLACKWELL PUBLISHING, INC
Lockley SW, Skene DJ, Tabandeh H, Bird AC, Defrance R, Arendt J (1997) Relationship between napping and melatonin in the blind., J Biol Rhythms 12 (1) pp. 16-25
Daytime sleepiness is a common complaint in blind subjects. Abnormally timed melatonin has been invoked as a possible cause of both daytime sleepiness and nighttime awakening. In free-running blind individuals, there is an opportunity to assess the relationship between endogenous melatonin rhythms and subjective sleepiness and naps. The aim of this study was to characterize melatonin rhythms and simultaneously to evaluate subjective napping. A total of 15 subjects with no conscious light perception (NPL) were studied for 1 month. Prior to the study, sleep disorders were assessed using the Pittsburgh Sleep Quality Index. Cosinor and regression analysis revealed that 9 of the 15 NPL subjects had free-running 6-sulphatoxymelatonin (aMT6s) rhythms (period [tau] range = 24.34 to 24.79 h), 3 were entrained with an abnormal phase, and 3 were normally entrained. Most of the subjects (13 of 15) had daytime naps; the 2 individuals who did not made conscious efforts not to do so. Subjects with abnormal aMT6s rhythms had more naps of a longer duration than did those with normal rhythms. Free-running nap rhythms occurred only in subjects with free-running aMT6s rhythms. The 2 abnormally entrained subjects who napped did so at times that coincided with high levels of aMT6s (mean aMT6s acrophase [phi] +/- SD = 14.30 +/- 1.08 h, 20.30 +/- 0.62 h; mean nap time +/- SD = 14.01 +/- 3.60 h, 18.23 +/- 3.20 h, respectively). Regardless of aMT6s rhythm abnormality, significantly more naps occurred with a 4-h period before and after the estimated aMT6s acrophase. In 4 free-running subjects, aMT6s acrophase (phi) passed through an entire 24-h period. When aMT6s was in a normal phase position (24:00 to 06:00 h), night-sleep duration tended to increase with a significant reduction in the number and duration of naps. Sleep onset and offset times tended to advance and delay as the aMT6s rhythms advanced and delayed. Our results show a striking relationship between the timing of daytime production of melatonin and the timing of daytime naps. This suggests that abnormally timed endogenous melatonin may induce sleepiness in blind subjects.
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:
SKENE DJ, PEVET P, VIVIENROELS B, MASSONPEVET M, ARENDT J (1987) EFFECT OF DIFFERENT PHOTOPERIODS ON CONCENTRATIONS OF 5-METHOXYTRYPTOPHOL AND MELATONIN IN THE PINEAL-GLAND OF THE SYRIAN-HAMSTER, JOURNAL OF ENDOCRINOLOGY 114 (2) pp. 301-309 J ENDOCRINOLOGY LTD
Fischer J, Dogas Z, Bassetti CL, Berg S, Grote L, Jennum P, Levy P, Mihaicuta S, Nobili L, Riemann D, Puertas Cuesta FJ, Skene DJ, Stanley N, Pevernagie D, Raschke F (2012) Standard procedures for adults in accredited sleep medicine centres in Europe, Journal of Sleep Research 21 (4) pp. 357-368
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.
Walters JF, Hampton SM, Deanfield JE, Donald AE, Skene DJ, Ferns GAA (2006) Circadian variation in endothelial function is attenuated in postmenopausal women, MATURITAS 54 (3) pp. 294-303 ELSEVIER IRELAND LTD
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 (»max 479 nm) or red (»max 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
SKENE DJ, VIVIENROELS B, SPARKS DL, HUNSAKER JC, PEVET P, RAVID D, SWAAB DF (1990) DAILY VARIATION IN THE CONCENTRATION OF MELATONIN AND 5-METHOXYTRYPTOPHOL IN THE HUMAN PINEAL-GLAND - EFFECT OF AGE AND ALZHEIMERS-DISEASE, BRAIN RESEARCH 528 (1) pp. 170-174 ELSEVIER SCIENCE BV
Penzel T, Pevernagie D, Dogas Z, Grote L, de Lacy S, Rodenbeck A, Bassetti C, Berg S, Cirignotta F, d'Ortho M-P, Garcia-Borreguero D, Levy P, Nobili L, Paiva T, Peigneux P, Pollmächer T, Riemann D, Skene DJ, Zucconi M, Espie C (2013) Catalogue of knowledge and skills for sleep medicine, Journal of Sleep Research Wiley
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. © 2013 European Sleep Research Society.
Mistlberger RE, Skene DJ (2005) Nonphotic entrainment in humans?, JOURNAL OF BIOLOGICAL RHYTHMS 20 (4) pp. 339-352 SAGE PUBLICATIONS LTD
Herljevic M, Middleton B, Thapan K, Skene DJ (2005) Light-induced melatonin suppression: age-related reduction in response to short wavelength light, EXPERIMENTAL GERONTOLOGY 40 (3) pp. 237-242 PERGAMON-ELSEVIER SCIENCE LTD
Lockley SW, Dijk D-J, Kosti O, Skene DJ, Arendt J (2008) Alertness, mood and performance rhythm disturbances associated with circadian sleep disorders in the blind, JOURNAL OF SLEEP RESEARCH 17 (2) pp. 207-216 WILEY-BLACKWELL
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.
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.
The increased prevalence of circadian disruptions due to abnormal coupling between internal and external time makes the detection of circadian phase in humans by ambulatory recordings a compelling need. Here, we propose an accurate practical procedure to estimate circadian phase with the least possible burden for the subject, that is, without the restraints of a constant routine protocol or laboratory techniques such as melatonin quantification, both of which are standard procedures. In this validation study, subjects (N = 13) wore ambulatory monitoring devices, kept daily sleep diaries and went about their daily routine for 10 days. The devices measured skin temperature at wrist level (WT), motor activity and body position on the arm, and light exposure by means of a sensor placed on the chest. Dim light melatonin onset (DLMO) was used to compare and evaluate the accuracy of the ambulatory variables in assessing circadian phase. An evening increase in WT: WTOnset (WTOn) and "WT increase onset" (WTiO) was found to anticipate the evening increase in melatonin, while decreases in motor activity (Activity Offset or AcOff), body position (Position Offset (POff)), integrative TAP (a combination of WT, activity and body position) (TAPOffset or TAPOff) and an increase in declared sleep propensity were phase delayed with respect to DLMO. The phase markers obtained from subjective sleep (R = 0.811), WT (R = 0.756) and the composite variable TAP (R = 0.720) were highly and significantly correlated with DLMO. The findings strongly support a new method to calculate circadian phase based on WT (WTiO) that accurately predicts and shows a temporal association with DLMO. WTiO is especially recommended due to its simplicity and applicability to clinical use under conditions where knowing endogenous circadian phase is important, such as in cancer chronotherapy and light therapy.
Johnston JD, Skene DJ (2015) 60 YEARS OF NEUROENDOCRINOLOGY: Regulation of mammalian neuroendocrine physiology and rhythms by melatonin., J Endocrinol 226 (2) pp. T187-T198
The isolation of melatonin was first reported in 1958. Since the demonstration that pineal melatonin synthesis reflects both daily and seasonal time, melatonin has become a key element of chronobiology research. In mammals, pineal melatonin is essential for transducing day-length information into seasonal physiological responses. Due to its lipophilic nature, melatonin is able to cross the placenta and is believed to regulate multiple aspects of perinatal physiology. The endogenous daily melatonin rhythm is also likely to play a role in the maintenance of synchrony between circadian clocks throughout the adult body. Pharmacological doses of melatonin are effective in resetting circadian rhythms if taken at an appropriate time of day, and can acutely regulate factors such as body temperature and alertness, especially when taken during the day. Despite the extensive literature on melatonin physiology, some key questions remain unanswered. In particular, the amplitude of melatonin rhythms has been recently associated with diseases such as type 2 diabetes mellitus but understanding of the physiological significance of melatonin rhythm amplitude remains poorly understood.
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.
Zawilska JB, Skene DJ, Arendt J (2009) Physiology and pharmacology of melatonin in relation to biological rhythms, PHARMACOLOGICAL REPORTS 61 (3) pp. 383-410 POLISH ACAD SCIENCES INST PHARMACOLOGY
Bonmati-Carrion MA, Middleton B, Revell VL, Skene DJ, Rol MA, Madrid JA (2015) Validation of an innovative method, based on tilt sensing, for the assessment of activity and body position., Chronobiol Int 32 (5) pp. 701-710
Since there is less movement during sleep than during wake, the recording of body movements by actigraphy has been used to indirectly evaluate the sleep-wake cycle. In general, most actigraphic devices are placed on the wrist and their measures are based on acceleration detection. Here, we propose an alternative way of measuring actigraphy at the level of the arm for joint evaluation of activity and body position. This method analyzes the tilt of three axes, scoring activity as the cumulative change of degrees per minute with respect to the previous sampling, and measuring arm tilt for the body position inference. In this study, subjects (N = 13) went about their daily routine for 7 days, kept daily sleep logs, wore three ambulatory monitoring devices and collected sequential saliva samples during evenings for the measurement of dim light melatonin onset (DLMO). These devices measured motor activity (arm activity, AA) and body position (P) using the tilt sensing of the arm, with acceleration (wrist acceleration, WA) and skin temperature at wrist level (WT). Cosinor, Fourier and non-parametric rhythmic analyses were performed for the different variables, and the results were compared by the ANOVA test. Linear correlations were also performed between actimetry methods (AA and WA) and WT. The AA and WA suitability for circadian phase prediction and for evaluating the sleep-wake cycle was assessed by comparison with the DLMO and sleep logs, respectively. All correlations between rhythmic parameters obtained from AA and WA were highly significant. Only parameters related to activity levels, such as mesor, RA (relative amplitude), VL5 and VM10 (value for the 5 and 10 consecutive hours of minimum and maximum activity, respectively) showed significant differences between AA and WA records. However, when a correlation analysis was performed on the phase markers acrophase, mid-time for the 10 consecutive hours of highest (M10) and mid-time for the five consecutive hours of lowest activity (L5) with DLMO, all of them showed a significant correlation for AA (R = 0.607, p = 0.028; R = 0.582, p = 0.037; R = 0.620, p = 0.031, respectively), while for WA, only acrophase did (R = 0.621, p = 0.031). Regarding sleep detection, WA showed higher specificity than AA (0.95 ± 0.01 versus 0.86 ± 0.02), while the agreement rate and sensitivity were higher for AA (0.76 ± 0.02 versus 0.66 ± 0.02 and 0.71 ± 0.03 versus 0.53 ± 0.03, respectively). Cohen's kappa coefficient also present
Skene DJ, Lockley SW, Arendt J (1999) Melatonin in circadian sleep disorders in the blind, BIOLOGICAL SIGNALS AND RECEPTORS 8 (1-2) pp. 90-95 KARGER
Thorne H, Hampton S, Morgan L, Skene DJ, Arendt J (2008) Differences in sleep, light, and circadian phase in offshore 18.00-06.00 h and 19.00-07.00 h shift workers, CHRONOBIOLOGY INTERNATIONAL 25 (2-3) pp. 225-235 INFORMA HEALTHCARE
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.
Skene DJ (2003) Optimization of light and melatonin to phase-shift human circadian rhythms, 15 pp. 438-441 BLACKWELL PUBLISHING LTD
Potter GDM, Skene DJ, Arendt J, Cade JE, Grant PJ, Hardie LJ (2016) Circadian Rhythm and Sleep Disruption: Causes Metabolic Consequences and Countermeasures, Endocrine Reviews 37 (6) Endocrine Society
Gogenur I, Ocak U, Altunpinar O, Middleton B, Skene DJ, Rosenberg J (2007) Disturbances in melatonin, cortisol and core body temperature rhythms after major surgery, WORLD JOURNAL OF SURGERY 31 (2) pp. 290-298 SPRINGER
Gringras P, Middleton B, Skene DJ, Revell VL (2015) Bigger, Brighter, Bluer-Better? Current Light-Emitting Devices - Adverse Sleep Properties and Preventative Strategies., Frontiers in public health 3 pp. 233-233 Frontiers Media
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.University of Surrey dedicated chronobiology facility.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.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.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.
Zawilska JB, Berezinska M, Rosiak J, Vivien-Roels B, Skene DJ, Pevet P, Nowak JZ (2003) Daily variation in the concentration of melatonin and 5-methoxytryptophol in the goose pineal gland, retina, and plasma, GENERAL AND COMPARATIVE ENDOCRINOLOGY 134 (3) pp. 296-302 ACADEMIC PRESS INC ELSEVIER SCIENCE
Darling AL (2014) Vitamin D, light exposure, sleep and musculoskeletal health in South Asian and Caucasian women: biological and social influences,
There is an urgent need to better understand the problem of vitamin D deficiency, and its health effects, in population groups of different ethnicity. The principal aim of this project was to examine vitamin D status, sunlight exposure, and health outcomes in UK dwelling South Asian and Caucasian women. A cohort of 80 postmenopausal and 32 premenopausal South Asian and Caucasian women were assessed for vitamin D status (serum 25-hydroxyvitamin D; 25(OH)D), musculoskeletal health, light exposure and sleep-wake cycles.
In postmenopausal women, South Asians had a significantly lower vitamin D concentration than Caucasians (p=0.002), with 83% of Asians vs. 24% of Caucasians below 50nmol/l for 25(OH)D. Despite adaptations in tibial bone structure of the South Asians to improve bone strength, their bones were weaker by 38% compared with Caucasians (p
For both premenopausal and postmenopausal women, Caucasians showed a significantly higher actigraphic sleep efficiency (p
The implications of this work are that older South Asian women are in need of intervention to improve vitamin D status. There is also some evidence for poorer musculoskeletal health, lower light exposure and poorer sleep in this group. The qualitative research included in the current study offers future intervention options to improve the health of UK dwelling South Asian women.
SKENE DJ, VIVIENROELS B, PEVET P (1990) 5-METHOXYTRYPTOPHOL INJECTIONS IN THE SYRIAN-HAMSTER - PLASMA AND PINEAL CONCENTRATIONS, NEUROSCIENCE LETTERS 108 (1-2) pp. 138-142 ELSEVIER SCI IRELAND LTD
Darling AL, Hart KH, Gibbs MA, Lanham-New SA, Gossiel F, Eastell R, Kantermann T, Horton K, Johnsen S, Berry JL, Skene DJ, Vieth R (2014) Greater seasonal cycling of 25-hydroxyvitamin D is associated with increased parathyroid hormone and bone resorption, Osteoporosis International 25 (3) pp. 933-941
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
Jones KHS, Ellis J, Von Schantz M, Skene DJ, Dijk D-J, Archer SN (2007) Age-related change in the association between a polymorphism in the PER3 gene and preferred timing of sleep and waking activities, JOURNAL OF SLEEP RESEARCH 16 (1) pp. 12-16 BLACKWELL PUBLISHING
Pagani L, Semenova EA, Moriggi E, Revell VL, Hack LM, Lockley SW, Arendt J, Skene DJ, Meier F, Izakovic J (2010) The physiological period length of the human circadian clock in vivo is directly proportional to period in human fibroblasts., PLoS One 5 (10)
Public Library of Science
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.
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.
Arendt J, Skene DJ, Middleton B, Lockley SW, Deacon S (1997) Efficacy of melatonin treatment in jet lag, shift work, and blindness, JOURNAL OF BIOLOGICAL RHYTHMS 12 (6) pp. 604-617 SAGE PUBLICATIONS INC
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 4h during the 24hday/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 24hday/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.
Robilliard DL, Archer SN, Arendt J, Lockley SW, Hack LM, English J, Leger D, Smits MG, Williams A, Skene DJ, von Schantz M (2002) The 3111 Clock gene polymorphism is not associated with sleep and circadian rhythmicity in phenotypically characterized human subjects, JOURNAL OF SLEEP RESEARCH 11 (4) pp. 305-312 BLACKWELL PUBLISHING LTD
Turco M, Caccin L, Corrias M, Biscontin A, De Pitta C, Middleton B, Skene DJ, Costa R, Montagnese S (2014) Length polymorphism in the human clock gene Period3 and diurnal preference, subjective sleepiness and the response to morning light, JOURNAL OF SLEEP RESEARCH 23 pp. 55-56 WILEY-BLACKWELL
Lockley SW, Skene DJ, Arendt J (1998) Changes in sleep in relation to circadian phase in the blind, 1152 pp. 247-252 ELSEVIER SCIENCE BV
Walters JF, Skene DJ, Hampton SM, Ferns GAA (2003) Biological rhythms, endothelial health and cardiovascular disease, Medical Science Monitor 9 (1)
The activity of several components of the vascular system appears to be diurnally regulated. Endothelial cell activation, leukocyte and platelet interactions and lipoprotein metabolism have all been shown to vary with time of day, but whether these variations are due to the endogenous circadian clock, exogenous factors, such as the light-dark cycle, or an interaction between the two remains to be determined. Endothelium-dependent vasodilation also varies diurnally. This rhythmicity is lost in individuals with established coronary disease has been shown to occur in the early stages of atherosclerosis. The incidence of coronary events appears to be higher in the early hours of the morning, this may be related to heightened activity of the autonomic nervous system at this time. Higher circulating levels of catecholamines in the morning are associated with increased vascular tone, affecting circulating blood volume and blood pressure. Time dependent variations may be of particular significance for individuals with disrupted circadian rhythms, including rotating shift workers, transmeridian travellers and blind individuals with no light perception. Variations in endothelial function are observed during the menstrual cycle, varying with circulating oestrogen levels. Oestrogen deficiency in postmenopausal women may contribute to endothelial dysfunction, together with other modifiable risk factors. The absolute risk of coronary disease is greater for men than for pre-menopausal women. Following the menopause gender differences in coronary risk are thought to diminish, although this remains controversial. This review focuses on the influence of both endogenous biological rhythms and environmental factors on the function and health of the human vascular system.
von Schantz M, Skene DJ (2015) Telling biological time from a blood sample: current capabilities and future potential, pp. 699-701 SAGE PUBLICATIONS INC
Deacon S, Skene D, Arendt J (1996) Use of light and/or melatonin in adaptation to phase shifts, pp. 398-405 WALTER DE GRUYTER
Carpen JD, Archer SN, Skene DJ, Smits M, von Schantz M (2005) A single-nucleotide polymorphism in the 5 '-untranslated region of the hPER2 gene is associated with diurnal preference, JOURNAL OF SLEEP RESEARCH 14 (3) pp. 293-297 BLACKWELL PUBLISHING
Darling AL, Gossiel F, Hannon R, Skene DJ, Berry JL, Eastell R, Lanham-New SA (2010) Evidence for an Association Between Seasonal Fluctuation of 25(OH)D and Serum C-telopeptide (CTx): Preliminary Evidence from the D-FINES study.,
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
Hack LM, Lockley SW, Arendt J, Skene DJ (2003) The effects of low-dose 0.5-mg melatonin on the free-running circadian rhythms of blind subjects, JOURNAL OF BIOLOGICAL RHYTHMS 18 (5) pp. 420-429 SAGE PUBLICATIONS LTD
Montagnese S, Middleton B, Mani AR, Skene DJ, Morgan MY (2009) PLASMA CORTISOL PROFILES IN PATIENTS WITH CIRRHOSIS: BEWARE THE TIME OF SAMPLING, GUT 58 pp. A76-A76 B M J PUBLISHING GROUP
Arendt J, Skene DJ (2005) Melatonin as a chronobiotic, SLEEP MEDICINE REVIEWS 9 (1) pp. 25-39 W B SAUNDERS CO LTD
Montagnese S, Middleton B, Mani AR, Skene DJ, Morgan MY (2009) Sleep and circadian abnormalities in patients with cirrhosis: features of delayed sleep phase syndrome?, METABOLIC BRAIN DISEASE 24 (3) pp. 427-439 SPRINGER/PLENUM PUBLISHERS
Lockley SW, Skene DJ, Thapan K, English J, Ribeiro D, Haimov I, Hampton S, Middleton B, von Schantz M, Arendt J (1998) Extraocular light exposure does not suppress plasma melatonin in humans, J CLIN ENDOCR METAB 83 (9) pp. 3369-3372
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.
Zawilska JB, Lorenc A, Berezinska M, Vivien-Roels B, Pevet P, Skene DJ (2007) Photoperiod-dependent changes in melatonin synthesis in the turkey pineal gland and retina, POULTRY SCIENCE 86 (7) pp. 1397-1405 POULTRY SCIENCE ASSOC INC
Walters JF, Hampton SM, Ferns GAA, Skene DJ (2005) Effect of menopause on melatonin and alertness rhythms investigated in constant routine conditions, CHRONOBIOLOGY INTERNATIONAL 22 (5) pp. 859-872 TAYLOR & FRANCIS INC
Possible interactions of melatonin with concurrently administered drugs were investigated in in vitro studies utilising human hepatic post-mitochondrial preparations; similar studies were conducted with rat preparations to ascertain whether rat is a suitable surrogate for human. Drugs were selected based not only on the knowledge that the 6-hydroxylation of exogenous melatonin, its principal pathway of metabolism, is mainly mediated by hepatic CYP1A2, but also on the likelihood of the drug being concurrently administered with melatonin. Hepatic preparations were incubated with either melatonin or 6-hydroxymelatonin in the presence and absence of a range of concentrations of interacting drug, and the production of 6-sulphatoxymelatonin monitored using a radioimmunoassay procedure. Of the drugs screened, only the potent CYP1A2 inhibitor 5-methoxypsoralen impaired the 6-melatonin hydroxylation at pharmacologically relevant concentrations, and is likely to lead to clinical interactions; diazepam, tamoxifen and acetaminophen (paracetamol) did not impair the metabolic conversion of melatonin to 6-sulphatoxymelatonin at concentrations attained following therapeutic administration. 17-Ethinhyloestradiol appeared not to suppress the 6-hydroxylation of melatonin but inhibited the sulphation of 6-hydroxymelatonin, but this is unlikely to result in an interaction following therapeutic intake of the steroid. Species differences in the inhibition of melatonin metabolism in human and rat hepatic post-mitochondrial preparations were evident implying that the rat may not be an appropriate surrogate of human in such studies.
Darling A, Gossiel F, Hannon R, Skene D, Berry J, Eastell R, Lanham-New S (2010) ASSOCIATION BETWEEN DEGREE OF SEASONAL FLUCTUATION ('CYCLING') OF 25(OH)D, PTH AND BONE RESORPTION IN UK SOUTH ASIAN AND CAUCASIAN WOMEN LIVING AT 51 degrees N (SURREY), OSTEOPOROSIS INTERNATIONAL 21 pp. S516-S517 SPRINGER LONDON LTD
SKENE DJ, RAYNAUD F, PEVET P (1993) MELATONIN AND 5-METHOXYTRYPTOPHOL BINDING-SITES IN THE RETINA, 1017 pp. 87-94 ELSEVIER SCIENCE PUBL B V
Arendt J, Stone B, Skene DJ (2005) Sleep Disruption in Jet Lag and Other Circadian Rhythm-Related Disorders, pp. 659-672
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.
Skene DJ, Lockley SW, Arendt J (1999) Use of melatonin in the treatment of phase shift and sleep disorders, 467 pp. 79-84 KLUWER ACADEMIC/PLENUM PUBL
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 in
HOFMAN MA, SKENE DJ, SWAAB DF (1995) EFFECT OF PHOTOPERIOD ON THE DIURNAL MELATONIN AND 5-METHOXYTRYPTOPHOL RHYTHMS IN THE HUMAN PINEAL-GLAND, BRAIN RESEARCH 671 (2) pp. 254-260 ELSEVIER SCIENCE BV
JOUBERT PH, SEBATA PDB, BAM WJ, SKENE DJ (1984) HOME URINARY GLUCOSE TESTING - ITS IMPACT ON A THIRD-WORLD DIABETIC POPULATION, SOUTH AFRICAN MEDICAL JOURNAL 65 (18) pp. 731-733 MED ASSOC S AFRICA
MENGEAUD V, SKENE D, PEVET P, ORTONNE JP (1994) NO HIGH-AFFINITY MELATONIN BINDING-SITES ARE DETECTED IN MURINE MELANOMA-CELLS AND IN NORMAL HUMAN MELANOCYTES CULTURED IN-VITRO, MELANOMA RESEARCH 4 (2) pp. 87-91 RAPID SCIENCE PUBLISHERS
Abi-Saab WM, Skene DJ, Stiger TR, McRobie C, Middleton B, Kaplan IV, Soares HD, Saltarelli MD (2004) Attenuation of the effects of light on nocturnal melatonin production in humans by the selective NK1 receptor antagonist CP-122,721, BIOLOGICAL PSYCHIATRY 55 pp. 40S-40S ELSEVIER SCIENCE INC
SKENE DJ, CHURCHILL A, RAYNAUD F, PEVET P, ARENDT J (1989) RADIOIMMUNOASSAY OF 5-METHOXYTRYPTOPHOL IN PLASMA, CLINICAL CHEMISTRY 35 (8) pp. 1749-1752 AMER ASSOC CLINICAL CHEMISTRY
Bonmati-Carrion MA, Hild K, Isherwood C, Sweeney SJ, Revell VL, Skene DJ, Rol MA, Madrid JA (2016) Relationship between Human Pupillary Light Reflex and Circadian System Status, PLoS One 11 (9) e0162476 Public Library of Science (PLoS)
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 (»max 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 »max 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
Warman VL, Dijk DJ, Warman GR, Arendt J, Skene DJ (2003) Phase advancing human circadian rhythms with short wavelength light, NEUROSCIENCE LETTERS 342 (1-2) pp. 37-40 ELSEVIER SCI IRELAND LTD
Skene DJ, Davies SK, Ang JE, Revell VL, Holmes B, Mann A, Robertson R, Cui N, Middleton B, Ackermann K, Kayser M, Thumser AE, Raynaud FI (2014) Effect of sleep deprivation on human plasma metabolome rhythms, JOURNAL OF SLEEP RESEARCH 23 pp. 36-37 WILEY-BLACKWELL
Isherwood C, Otway DT, Maentele S, Middleton B, Wright J, Robertson MD, Skene DJ, Gibbs M, Johnston JD (2015) Daily rhythms in hormonal markers of diabetes and obesity: effect of weight and Type 2 diabetes, PROCEEDINGS OF THE NUTRITION SOCIETY 74 (OCE1) pp. E37-E37 CAMBRIDGE UNIV PRESS
LOCKLEY S, TABANDEH H, SKENE D, BUTTERY R, BIRD A, DEFRANCE R, ARENDT J (1995) DAYTIME NAPS AND MELATONIN IN BLIND PEOPLE, LANCET 346 (8988) pp. 1491-1491 LANCET LTD
Zawilska JB, Berezinska M, Stasikowska O, Lorenc A, Skene DJ, Nowak JZ (2005) Posthatching developmental changes in noradrenaline content in the chicken pineal gland, JOURNAL OF PINEAL RESEARCH 38 (2) pp. 123-129 BLACKWELL MUNKSGAARD
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
Papantoniou K, Pozo OJ, Espinosa A, Marcos J, Castaño-Vinyals G, Basagaña X, Ribas FC, Mirabent J, Martín J, Carenys G, Martín CR, Middleton B, Skene DJ, Kogevinas M (2014) Circadian variation of melatonin, light exposure, and diurnal preference in day and night shift workers of both sexes., Cancer Epidemiol Biomarkers Prev 23 (7) pp. 1176-1186
BACKGROUND: Light-at-night has been shown in experimental studies to disrupt melatonin production but this has only partly been confirmed in studies of night shift workers. In this cross-sectional study, we examined the circadian variation of melatonin in relation to shift status, individual levels of light-at-night exposure, and diurnal preference, an attribute reflecting personal preference for activity in the morning or evening. METHODS: One hundred and seventeen workers (75 night and 42 day) of both sexes, ages 22 to 64 years, were recruited from four companies. Participants collected urine samples from all voids over 24 hours and wore a data logger continuously recording their light exposure. Sociodemographic, occupational, lifestyle, and diurnal preference information were collected by interview. Concentrations of urinary 6-sulfatoxymelatonin (aMT6s), the main melatonin metabolite, were measured. RESULTS: Mean aMT6s levels were lower in night [10.9 ng/mg creatinine/hour; 95% confidence interval (CI), 9.5-12.6] compared with day workers (15.4; 95% CI, 12.3-19.3). The lowest aMT6s levels were observed in night workers with morning preference (6.4; 95% CI, 3.0-13.6). Peak time of aMT6s production occurred 3 hours later in night (08:42 hour, 95% CI, 07:48-09:42) compared with day workers (05:36 hour, 95% CI, 05:06-06:12). Phase delay was stronger among subjects with higher light-at-night exposure and number of nights worked. CONCLUSIONS: Night shift workers had lower levels and a delay in peak time of aMT6s production over a 24-hour period. Differences were modified by diurnal preference and intensity of light-at-night exposure. IMPACT: Night shift work affects levels and timing of melatonin production and both parameters may relate to future cancer risk.
Thapan K, Arendt J, Skene DJ (2001) An action spectrum for melatonin suppression: evidence for a novel non-rod, non-cone photoreceptor system in humans, J PHYSIOL-LONDON 535 (1) pp. 261-267 CAMBRIDGE UNIV PRESS
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
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 ¼W 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
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 e 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.
SKENE DJ, MASSONPEVET M, PEVET P (1993) SEASONAL-CHANGES IN MELATONIN BINDING-SITES IN THE PARS TUBERALIS OF MALE EUROPEAN HAMSTERS AND THE EFFECT OF TESTOSTERONE MANIPULATION, ENDOCRINOLOGY 132 (4) pp. 1682-1686 ENDOCRINE SOC
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.
Revell VL, Arendt J, Terman M, Skene DJ (2005) Short-wavelength sensitivity of the human circadian system to phase-advancing light, JOURNAL OF BIOLOGICAL RHYTHMS 20 (3) pp. 270-272 SAGE PUBLICATIONS LTD
Viola AU, Archer SN, James LM, Groeger JA, Lo JCY, Skene DJ, von Schantz M, Dijk D-J (2007) PER3 polymorphism predicts sleep structure and waking performance, CURRENT BIOLOGY 17 (7) pp. 613-618 CELL PRESS
Montagnese S, Middleton B, Mani AR, Skene DJ, Morgan MY (2010) Melatonin Rhythms in Patients With Cirrhosis, AMERICAN JOURNAL OF GASTROENTEROLOGY 105 (1) pp. 220-222 NATURE PUBLISHING GROUP
JAMES K, SKENE DJ, LUCINI V, STANKOV B, ARENDT J (1995) CHARACTERIZATION OF MELATONIN BINDING-SITES IN THE EYE OF THE JAPANESE-QUAIL (COTURNIX JAPONICA), GENERAL AND COMPARATIVE ENDOCRINOLOGY 100 (2) pp. 188-196 ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS
SKENE DJ, DALI P, BAM WJ, JOUBERT PH (1982) DIABETES IN A DEVELOPING COMMUNITY - EPIDEMIOLOGY AND MANAGEMENT PROBLEMS, SOUTH AFRICAN MEDICAL JOURNAL 61 (13) pp. 463-464 MED ASSOC S AFRICA
Lucas RJ, Brown TM, Peirson SN, Berson DM, Cooper HM, Czeisler CA, Lockley SW, Figueiro MG, Gamlin PD, O'Hagan JB, Price LLA, Provencio I, Skene DJ, Brainard GC (2014) Measuring and using light in the melanopsin age, Trends in Neurosciences 37 (1) pp. 1-9
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.
Skene DJ, Swaab DF (2003) Melatonin rhythmicity: effect of age and Alzheimer's disease, EXPERIMENTAL GERONTOLOGY 38 (1-2) PII S0531-5565(02)00198-5 pp. 199-206 PERGAMON-ELSEVIER SCIENCE LTD
Skene DJ (1996) The miracle of melatonin: Fact, fancy and future, CHEMISTRY & INDUSTRY (17) pp. 637-640 SOC CHEMICAL INDUSTRY
Dzaja A, Arber S, Hislop J, Kerkhofs M, Kopp C, Pollmacher T, Polo-Kantola P, Skene DJ, Stenuit P, Tobler I, Porkka-Heiskanen T (2005) Women's sleep in health and disease, JOURNAL OF PSYCHIATRIC RESEARCH 39 (1) pp. 55-76 PERGAMON-ELSEVIER SCIENCE LTD
SKENE DJ (1992) N-ACETYLTRANSFERASE AND MELATONIN IN THE RETINA - REGULATION, FUNCTION AND MODE OF ACTION, 20 pp. 312-315 PORTLAND PRESS
Ang JE, Pandher R, Asad Y, Skene DJ, Workman P, Eccles S, De Bono J, Kaye S, Banerji U, Davies S, Raynaud FI (2014) Plasma metabolomic signature of novel signal transduction inhibitors from preclinical identification to clinical validation, EUROPEAN JOURNAL OF CANCER 50 pp. 148-149 ELSEVIER SCI LTD
Revell VL, Arendt J, Louis FF, Skene DJ (2006) Alerting effects of light are sensitive to very short wavelengths, NEUROSCIENCE LETTERS 399 (1-2) pp. 96-100 ELSEVIER IRELAND LTD
Zawilska JB, Lorenc A, Berezinska M, Vivien-Roels B, Pevet P, Skene DJ (2006) Diurnal and circadian rhythms in melatonin synthesis in the turkey pineal gland and retina, GENERAL AND COMPARATIVE ENDOCRINOLOGY 145 (2) pp. 162-168 ACADEMIC PRESS INC ELSEVIER SCIENCE
Lockley SW, Skene DJ, James K, Thapan K, Wright J, Arendt J (2000) Melatonin administration can entrain the free-running circadian system of blind subjects, JOURNAL OF ENDOCRINOLOGY 164 (1) pp. R1-R6 SOC ENDOCRINOLOGY
Zawilska JB, Vivien-Roels B, Skene DJ, Pevet P, Nowak JZ (2000) Phase-shifting effects of light on the circadian rhythms of 5-methoxytryptophol and melatonin in the chick pineal gland, JOURNAL OF PINEAL RESEARCH 29 (1) pp. 1-7 MUNKSGAARD INT PUBL LTD
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-ERB±) remained unaffected. These data suggest that the core clock mechanism in peripheral oscillators is compromised during acute sleep deprivation.
BOJKOWSKI CJ, ALDHOUS ME, ENGLISH J, FRANEY C, POULTON AL, SKENE DJ, ARENDT J (1987) SUPPRESSION OF NOCTURNAL PLASMA MELATONIN AND 6-SULFATOXYMELATONIN BY BRIGHT AND DIM LIGHT IN MAN, HORMONE AND METABOLIC RESEARCH 19 (9) pp. 437-440 GEORG THIEME VERLAG
Revell VL, Skene DJ (2010) Impact of age on human non-visual responses to light, SLEEP AND BIOLOGICAL RHYTHMS 8 (2) pp. 84-94 WILEY-BLACKWELL
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.
Flynn-Evans EE, Tabandeh H, Skene DJ, Lockley SW (2014) Circadian Rhythm Disorders and Melatonin Production in 127 Blind Women with and without Light Perception., J Biol Rhythms 29 (3) pp. 215-224
Light is the major environmental time cue that synchronizes the endogenous central circadian pacemaker, located in the suprachiasmatic nuclei of the hypothalamus, and is detected exclusively by the eyes primarily via specialized non-rod, non-cone ganglion cell photoreceptors. Consequently, most blind people with no perception of light (NPL) have either nonentrained or abnormally phased circadian rhythms due to this inability to detect light. Conversely, most visually impaired participants with some degree of light perception (LP) exhibit normal entrainment, emphasizing the functional separation of visual and "nonvisual" photoreception. The aims of the study were to identify the prevalence of circadian disorders in blind women, with the further aim of examining how eye disease may relate to the type of circadian disorder. Participants (n = 127, age 50.8 ± 13.4 years) completed an 8-week field study including daily sleep diaries and sequential 4 to 8 hourly urine collections over 48 h on 2 to 3 occasions separated by at least 2 weeks. Circadian type was determined from the timing and time course of the melatonin rhythm measured by cosinor-derived urinary 6-sulfatoxymelatonin rhythm peak. Of the participants with NPL (n = 41), the majority were abnormally phased (24%) or nonentrained (39%), with 37% classified as normally entrained. Of the participants with LP (n = 86), the majority were normally entrained (69%). Eighteen LP participants (21%) were abnormally phased (8 advanced, 10 delayed). Nine LP participants (10%) were nonentrained. The eye conditions most associated with abnormal phase and/or nonentrained circadian rhythms were bilateral enucleation (67%) and retinopathy of prematurity (57%). By contrast, 84% of participants with retinitis pigmentosa and 83% of those with age-related macular degeneration were normally entrained. These findings suggest that the etiology of blindness in addition to LP status is related to an individual's ability to process the circadian light signal.
PEVET P, VIVIENROELS B, MASSONPEVET M, STEINLECHNER S, SKENE D, CANGUILHEM B (1989) MELATONIN, SEROTONIN, 5-HYDROXYINDOLE-3-ACETIC ACID AND N-ACETYLTRANSFERASE IN THE PINEAL OF THE EUROPEAN HAMSTER (CRICETUS-CRICETUS) KEPT UNDER NATURAL ENVIRONMENTAL-CONDITIONS - LACK OF A DAY NIGHT RHYTHM IN MELATONIN FORMATION IN SPRING AND EARLY SUMMER, JOURNAL OF PINEAL RESEARCH 6 (3) pp. 233-242 MUNKSGAARD INT PUBL LTD
Ang JE, Pal A, Asad YJ, Henley AT, Valenti M, Box G, de haven Brandon A, Revell Victoria, Skene Debra, Venturi M, Rueger R, Meresse V, Eccles SA, de Bono JS, Kaye SB, Workman P, Banerji U, Raynaud FI (2017) Modulation of plasma metabolite biomarkers of MAPK pathway with the MEK
inhibitor RO4987655: pharmacodynamic and predictive potential in metastatic
melanoma., Molecular Cancer Therapeutics
American Association for Cancer Research
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.
SKENE DJ, VIVIENROELS B, PEVET P (1991) DAY AND NIGHTTIME CONCENTRATIONS OF 5-METHOXYTRYPTOPHOL AND MELATONIN IN THE RETINA AND PINEAL-GLAND FROM DIFFERENT CLASSES OF VERTEBRATES, GENERAL AND COMPARATIVE ENDOCRINOLOGY 84 (3) pp. 405-411 ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS
Daugaard S, Garde A, Bonde J, Christoffersen J, Hansen A, Markvart J, Schlünssen V, Skene D, Vistisen H, Kolstad H (2017) Night work, light exposure and melatonin on work days and days off, Chronobiology International 34 (7) pp. 942-955
Taylor & Francis
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.
Mäntele S, Otway D, Middleton BA, Bretschneider S, Wright J, Robertson MD, Skene DJ, Johnston JD (2012) Daily Rhythms of Plasma Melatonin, but Not Plasma Leptin or Leptin mRNA, Vary between Lean, Obese and Type 2 Diabetic Men., PLoS One 7 (5)
Public Library of Science
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
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.
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
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.
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
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.
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
de la Iglesia HO, Moreno C, Lowden A, Louzada F, Marqueze E, Levandovski R, Pilz LK, Valeggia C, Fernandez-Duque E, Golombek DA, Czeisler CA, Skene Debra, Duffy JF, Roenneberg T (2016) Ancestral sleep., Current Biology 26 (7) pp. R271-R272
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 (»max 456 nm: 3.8 and 9.8 ¼W/cm2; »max 548 nm: 28 and 62 ¼W/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.
Lucas R, Brown T, Peirson S, Berson D, Cooper H, Czeisler C, Lockley S, Figueiro M, Gamlin P, O'Hagan J, Price L, Provencio I, Skene D, Brainard G (2013) Measuring and using light in the melanopsin age, Trends in Neurosciences 37 (1) pp. 1-9
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.
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
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
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.
Turco M, Biscontin A, Corrias M, Caccin L, Bano M, Chiaromanni F, Salamanca M, Mattei D, Salvoro C, Mazzotta G, De Pittà C, Middleton Benita, Skene Debra, Montagnese S, Costa R (2017) Diurnal preference, mood and the response to morning light in
relation to polymorphisms in the human clock gene PER3, Scientific Reports 7 (6967) pp. 1-10
Nature Publishing Group
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
sleep-wake timing. In conclusion, significant associations were observed between PER3 polymorphic
variants/their combinations and both diurnal preference and the response to light.
Montagnese S, De Rui M, Corrias M, Turco M, Merkel C, Amodio P, Gatta A, De Pittà C, Costa R, Skene Debra (2014) Sleep-wake abnormalities in patients with cirrhosis, Hepatology 59 (2) pp. 705-712
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.
Marini S, Santangeli O, Saarelainen P, Middleton Benita, Chowdhury Namrata Roy, Skene Debra, Costa R, Porkka-Heiskanen T, Montagnese S (2017) Abnormalities in the Polysomnographic, Adenosine and Metabolic Response to Sleep Deprivation in an Animal Model of Hyperammonemia, Frontiers in Physiology 8 636
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.
Hughes M, Abruzzi K, Allada R, Anafi R, Arpat A, Asher G, Baldi P, de Bekker C, Bell-Pedersen D, Blau J, Brown S, Ceriani M, Chen Z, Chiu J, Cox J, Crowell A, DeBruyne J, Dijk D, DiTacchio L, Doyle F, Duffield G, Dunlap J, Eckel-Mahan K, Esser K, FitzGerald G, Forger D, Francey L, Fu Y, Gachon F, Gatfield D, de Goede P, Golden S, Green C, Harer J, Harmer S, Haspel J, Hastings M, Herzel H, Herzog E, Hoffmann C, Hong C, Hughey J, Hurley J, de la Iglesia H, Johnson C, Kay S, Koike N, Kornacker K, Kramer A, Lamia K, Leise T, Lewis S, Li J, Li X, Liu A, Loros J, Martino T, Menet J, Merrow M, Millar A, Mockler T, Naef F, Nagoshi E, Nitabach M, Olmedo M, Nusinow D, Ptá
ek L, Rand D, Reddy A, Robles M, Roenneberg T, Rosbash M, Ruben M, Rund S, Sancar A, Sassone-Corsi P, Sehgal A, Sherrill-Mix S, Skene D, Storch K, Takahashi J, Ueda H, Wang H, Weitz C, Westermark P, Wijnen H, Xu Y, Wu G, Yoo S, Young M, Zhang E, Zielinski T, Hogenesch J (2017) Guidelines for Genome-Scale Analysis of Biological Rhythms, Journal of Biological Rhythms 32 (5) pp. 380-393
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.
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.
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
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
Diessler Shanaz, Jan Maxime, Emmenegger Yann, Guex Nicolas, Middleton Benita, Skene Debra J., Ibberson Mark, Burdet Frederic, Götz Lou, Pagni Marco, Sankar Martial, Liechti Robin, Hor Charlotte N., Xenarios Ioannis, Franken Paul (2018) A systems genetics resource and analysis of sleep regulation in the mouse, PLOS Biology 16 (8) e2005750 pp. 1-39
Public Library of Science
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 ±-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.
Lech Karolina, Liu Fan, Davies Sarah K., Ackermann Katrin, Ang Joo Ern, Middleton Benita, Revell Victoria L., Raynaud Florence I., Hoveijn Igor, Hut Roelof A., Skene Debra J., Kayser Manfred (2017) investigation of metabolites for estimating blood deposition time, International Journal of Legal Medicine 132 (1) pp. 25-32
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.
In the last eighteen years there has been the identification of a novel photopigment, melanopsin, and its subsequent localization to human intrinsically photosensitive retinal ganglion cells (ipRGCs). Since melanopsin?s peak sensitivity is in the short wavelength portion of the visible spectrum (from 447 nm to 484 nm), there has been a steady increase in studies investigating the physiological effects of blue light. This thesis examines polychromatic light mixtures of blue light for circadian, neuroendocrine and neurobehavioral effects in humans.
White blue-enriched fluorescent lamps were tested at equal photon densities for increased efficacy for melatonin suppression, increased alertness, and circadian phase shifting. Results demonstrated that compared to white fluorescent light, blue-enriched fluorescent light was significantly stronger for suppressing melatonin and resulted in significantly reduced subjective sleepiness. Blue-enriched light, however, was not significantly stronger in eliciting circadian phase-delay or increasing objective measures of alertness.
Next, blue-appearing narrowband solid-state light was examined for its ability to acutely suppress nocturnal melatonin as well as enhance cognitive performance and alertness in healthy men and women when compared to dim white lighting. The results demonstrated that narrowband blue solid-state light was significantly stronger for melatonin suppression compared to dim white light. Subjective and objective assessments of alertness, however, were not significantly increased by blue-enriched light exposure.
The final study tested the hypothesis that certain combinations of light wavelengths are additive or opponent to the photoreceptor system that mediates the melatonin suppression. The results demonstrated that the melatonin suppression responses to dual narrow bandwidth light combinations were not significantly different from single wavelength exposures.
Taken together, the results suggest that melanopsin sensitivity is not the sole consideration for predicting the efficacy of white polychromatic lighting. The different effects of blue light on alertness, circadian phase-shifting and melatonin suppression imply a either a context dependent sensitivity and/or differential involvement of the classical photoreceptors in these light responses.
Turco Matteo, Cazzagon Nora, Franceschet Irene, Formentin Chiara, Frighetto Giovanni, Giordani Francesca, Cellini Nicola, Mazzotta Gabriella, Costa Rodolfo, Middleton Benita, Skene Debra, Floreani Annarosa, Montagnese Sara (2018) Morning Bright Light Treatment for Sleep-Wake Disturbances in Primary Biliary Cholangitis: A Pilot Study, Frontiers in Physiology 9 1530
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.
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.
Christou Skevoulla, Wehrens Sophie M T, Isherwood Cheryl, Moller-Levet Carla S, Wu Huihai, Revell Victoria L, Bucca Giselda, Skene Debra J, Laing Emma E, Archer Simon N, Johnston Jonathan D (2019) Circadian regulation in human white adipose tissue revealed by transcriptome and metabolic network analysis, Scientific Reports
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.
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.
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.
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.
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.
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.
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 Â 0.0001) in the South Asian compared with the Caucasian women. More South Asians (50%) met the criteria for sleep disorders (PSQI score Ã5) 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 Ã 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.
Fagotti Juliane, Targa Adriano D. S., Rodrigues Lais S., Noseda Ana Carolina D., Dorieux Flávia W. C., Scarante Franciele F., Ilkiw Jessica L., Louzada Fernando M., Chowdhury Namrata, Van Der Veen Daan, Middleton Benita, Pennings Jeroen L. A., Swann Jonathan R., Skene Debra, Lima Marcelo M. S. (2019) Chronic sleep restriction in the rotenone Parkinson?s disease model in rats reveals peripheral early-phase biomarkers, Scientific Reports 9 (1) 1898
Springer Nature Publishing
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
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
Nehme P.A., Amaral F.G., Middleton B., Lowden A., Marqueze E., França-Junior I., Antunes J.L.F., Cipolla-Neto J., Skene D.J, Moreno C.R.C. (2019) Melatonin profiles during the third trimester of pregnancy and health status in the offspring among day and night workers: A case series, Neurobiology of Sleep and Circadian Rhythms 6 pp. 70-76
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.
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.
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.
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.
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.
Roenneberg Till, Wirz-Justice Anna, Skene Debra J., Ancoli-Israel Sonia, Wright Kenneth P., Dijk Derk-Jan, Zee Phyllis, Gorman Michael R., Winnebeck Eva C., Klerman Elizabeth B. (2019) Why Should We Abolish Daylight Saving Time?, Journal of Biological Rhythms 34 (3) pp. 227-230
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.
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.
Opioid dependency remains a worldwide crisis and treatments aimed at abstinence and recovery are mainly ineffective with high relapse rates. There is mounting evidence that social deficits and emotional co-morbid impairments negatively impact recovery from opioid dependency following detoxification and constitute a motivational trigger to relapse.
This work aimed to identify risk and protective factors for relapse to opioid misuse following the start of treatment. Given the emergence of preclinical and clinical data showing anti-addictive properties of neuropeptide oxytocin, a randomised double-blind placebo-controlled pilot trial was performed to investigate the efficacy of intranasal oxytocin in preventing relapse in post-detoxified opioid-dependent individuals. This work also investigated the efficacy of intranasal oxytocin in reducing opioid craving, anxiety, depression, social anxiety and sleep disturbances while enhancing social cognition and quality of life in these individuals.
The results described in this thesis show that inpatient psychosocial support was a protective factor against relapse, compared to a community centre treatment program. Also, remaining in and completing a treatment program was protective against relapse. The pilot trial did not complete due issues with the supply of oxytocin. Two participants were administered intranasal oxytocin over 2 treatment days, and showed reduced anxiety and social anxiety, improved sociability, improved mood, increased trustworthiness, decreased hostility and decreased subjective withdrawal symptoms with reduced sleep disturbances, compared to baseline. This thesis also provides a reflective analysis on the difficulties in recruiting and working with vulnerable participants as well as the challenges of setting up and running a clinical trial of an investigative medicinal product, within the NHS. The work suggests some changes to be implemented for a successful clinical trial.
Given these results and the evidence for anti-addiction and pro-social properties of oxytocin, future studies would direct attention to oxytocin-based treatment programs, looking to engage addicts in psychosocial treatment programmes.
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.
Ritter Philipp, Wieland Falk, Skene Debra J., Pfennig Andrea, Weiss Maria, Bauer Michael, Severus Emanuel, Güldner Henry, Sauer Cathrin, Soltmann Bettina, Neumann Stefanie (2019) Melatonin suppression by melanopsin-weighted light in patients with bipolar I disorder compared to healthy controls, Journal of Psychiatry and Neuroscience pp. 1-8
Canadian Medical Association
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
Methods: Melatonin suppression was assessed in euthymic patients with bipolar I disorder and healthy controls by
exposure to monochromatic blue light (»max = 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 (»max = 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.
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.
Bonmati-Carrion Maria-Angeles, Revell Victoria, Cook Tom J., Welch Thomas R.E, Rol Maria-Angeles, Skene Debra, Madrid Juan Antonio (2020) Living Without Temporal Cues: A Case Study, Frontiers in Physiology
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,
Munch Mirjam, Wirz-Justice Anna, Brown Steven, Kantermann Thomas, Martiny Klaus, Stefani Oliver, Vetter Celine, Wright Jr. Kenneth P., Wulff Katharina, Skene Debra (2020) The role of daylight for humans: Gaps in current knowledge, Clocks and Sleep 2 (1) pp. 61-85
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.