The evaluation of melatonin as a possible antidepressive

Melatonin, a hormone of the pineal gland, was evaluated in a variety of animal models of depression. Measurements of the frog righting reflex and rat locomotor activity showed that low doses of melatonin have a serotonin-like potentiating effect following monoamine oxidase inhibition. High doses of melatonin caused a reduction in the duration of rat immobility in the Porsolt model of depression and exerted a chlorpromazine-like effect on conditioned avoidance behaviour. In view of the indoleamine hypothesis of depressive disorders, the possibility of melatonin being a potential antidepressive is discussed and it is concluded that melatonin might be useful in the treatment of "agitated" depression

Visual impairment and circadiam rhythm disorders

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

Resetting the late timing of ‘night owls’ has a positive impact on mental health and performance

Background There is conflict between living according to our endogenous biological rhythms and our external environment, with disruptions resulting in negative consequences to health and performance. This is often documented in shift work and jet lag, but ‘societal norms’ (eg, typical working hours) can create profound issues for ‘night owls’, people whose internal biological timing predisposes them to follow an unusually late sleep-wake cycle. Night owls have also been associated with health issues, mood disturbances, poorer performance and increased mortality rates. Methods This study used a randomized control trial design aimed to shift the late timing of night owls to an earlier time (phase advance), using non-pharmacological, practical interventions in a real-world setting. These interventions targeted light exposure (through earlier wake up/sleep times), fixed meals times, caffeine intake and exercise. Results Overall, participants demonstrated a significant advance of ~2 h in sleep/wake timings as measured by actigraphy and circadian phase markers (dim light melatonin onset and peak time of the cortisol awakening response), whilst having no adverse effect on sleep duration. Notably, the phase advance was accompanied by significant improvements to self-reported depression and stress, as well as improved cognitive (reaction time) and physical (grip strength) performance measures during the typical 'suboptimal morning hours. Conclusions Our findings propose a novel strategy for shifting clock timing towards a pattern that is more aligned to societal demands that could significantly improve elements of performance, mental health and sleep timing in the real world.</p

Human Circadian Phenotyping and Diurnal Performance Testing in the Real World

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

Changes in the 24-h plasma cortisol rhythm in patients with cirrhosis

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Blue-enriched Lighting for Older People Living in Care Homes: Effect on Activity, Actigraphic Sleep, Mood and Alertness

Objective: Environmental (little outdoor light; low indoor lighting) and age-related physiological factors (reduced light transmission through the ocular lens, reduced mobility) contribute to a light-deprived environment for older people living in care homes. Methods: This study investigates the effect of increasing indoor light levels with blue-enriched white lighting on objective (rest-activity rhythms, performance) and self-reported (mood, sleep, alertness) measures in older people. Eighty residents (69 female), aged 86 ± 8 yrs (mean ± SD), participated (MMSE 19 ± 6). Overhead fluorescent lighting was installed in communal rooms (n=20) of seven care homes. Four weeks of blue-enriched white lighting (17000 K ≅ 900 lux) were compared with four weeks of control white lighting (4000 K ≅ 200 lux), separated by three weeks wash-out. Participants completed validated mood and sleep questionnaires, psychomotor vigilance task (PVT) and wore activity and light monitors (AWL). Rest-activity rhythms were assessed by cosinor, non-parametric circadian rhythm (NPCRA) and actigraphic sleep analysis. Blue-enriched (17000 K) light increased wake time and activity during sleep decreasing actual sleep time, sleep percentage and sleep efficiency (p < 0.05) (actigraphic sleep). Compared to 4000 K lighting, blue-enriched 17000 K lighting significantly (p < 0.05) advanced the timing of participants’ rest-activity rhythm (cosinor), increased daytime and night-time activity (NPCRA), reduced subjective anxiety (HADA) and sleep quality (PSQI). There was no difference between the two light conditions in daytime alertness and performance (PVT). Conclusion: Blue-enriched lighting produced some positive (increased daytime activity, reduced anxiety) and negative (increased night-time activity, reduced sleep efficiency and quality) effects in older people

Machine learning estimation of human body time using metabolomic profiling

This work was supported in part by the Netherlands Forensic Institute, Netherlands Genomics Initiative/Netherlands Organization for Scientific Research within the framework of the Forensic Genomics Consortium Netherlands, the 6th Framework project EUCLOCK (018741), and UK Biotechnology and Biological Sciences Research Council Grant BB/I019405/1. Additional funding was received from the Cancer Research UK Cancer Therapeutics Unit award (Ref: C2739/A22897) and a Cancer Therapeutics Centre award (Ref: C309/A25144 to FR), the NWO-STW Perspective Program grant ‘OnTime’ (project 12185 to TW and RAH).Circadian rhythms influence physiology, metabolism, and molecular processes in the human body. Estimation of individual body time (circadian phase) is therefore highly relevant for individual optimization of behavior (sleep, meals, sports), diagnostic sampling, medical treatment, and for treatment of circadian rhythm disorders. Here, we provide a partial least squares regression (PLSR) machine learning approach that uses plasma-derived metabolomics data in one or more samples to estimate dim light melatonin onset (DLMO) as a proxy for circadian phase of the human body. For this purpose, our protocol was aimed to stay close to real-life conditions. We found that a metabolomics approach optimized for either women or men under entrained conditions performed equally well or better than existing approaches using more labor-intensive RNA sequencing-based methods. Although estimation of circadian body time using blood-targeted metabolomics requires further validation in shift work and other real-world conditions, it currently may offer a robust, feasible technique with relatively high accuracy to aid personalized optimization of behavior and clinical treatment after appropriate validation in patient populations.Publisher PDFPeer reviewe

Meal Timing Regulates the Human Circadian System

Circadian rhythms, metabolism and nutrition are intimately linked [1, 2], although effects of meal timing on the human circadian system are poorly understood. We investigated the effect of a 5-hour delay in meals on markers of the human master clock and multiple peripheral circadian rhythms. Ten healthy young men undertook a 13-day laboratory protocol. Three meals (breakfast, lunch, dinner) were given at 5-hour intervals, beginning either 0.5 (early) or 5.5 (late) hours after wake. Participants were acclimated to early meals and then switched to late meals for 6 days. After each meal schedule, participants' circadian rhythms were measured in a 37-hour constant routine that removes sleep and environmental rhythms while replacing meals with hourly isocaloric snacks. Meal timing did not alter actigraphic sleep parameters before circadian rhythm measurement. In constant routines, meal timing did not affect rhythms of subjective hunger and sleepiness, master clock markers (plasma melatonin and cortisol), plasma triglycerides, or clock gene expression in whole blood. Following late meals, however, plasma glucose rhythms were delayed by 5.69 ± 1.29 hours (p < 0.001) and average glucose concentration decreased by 0.27 ± 0.05 mM (p < 0.001). In adipose tissue, PER2 mRNA rhythms were delayed by 0.97 ± 0.29 hours (p < 0.01), indicating that human molecular clocks may be regulated by feeding time and could underpin plasma glucose changes. Timed meals therefore play a role in synchronising peripheral circadian rhythms in humans, and may have particular relevance for patients with circadian rhythm disorders, shift workers, and transmeridian travellers

Evaluation of mRNA markers for estimating blood deposition time : towards alibi testing from human forensic stains with rhythmic biomarkers

This study was supported by grant 27.011.001 by the Netherlands Organization for Scientific Research (NWO) Forensic Science Program, Erasmus MC University Medical Center Rotterdam, by the EU 6th Framework project EUCLOCK (018741), UK Biotechnology and Biological Sciences Research Council (BBSRC) Grant BB/I019405/1, and by a previous grant from the Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) within the framework of the Forensic Genomics Consortium Netherlands (FGCN). D.J.S. is a Royal Society Wolfson Research Merit Award holder.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.PostprintPeer reviewe

Improving fatigue risk management in healthcare: A systematic scoping review of sleep-related/fatigue-management interventions for nurses and midwives.

Background. Nurses and midwives make up almost 50% of the global healthcare shift working workforce. Shift work interferes with sleep and causes fatigue with adverse effects for nurses’ and midwives’ health, as well as on patient safety and care. Where other safety-critical sectors have developed Fatigue Risk Management Systems, healthcare is behind the curve; with published literature only focussing on the evaluation of discreet sleep-related/fatigue-management interventions. Little is known, however, about which interventions have been evaluated for nurses and midwives. Our review is a critical first step to building the evidence-base for healthcare organisations seeking to address this important operational issue. Objectives. We address two questions: 1) What sleep-related/fatigue-management interventions have been assessed in nurses and midwives and what is their evidence-base? and 2) What measures are used by researchers to assess intervention effectiveness? Design & data sources. The following databases were searched in November, 2018 with no limit on publication dates: MEDLINE, PsychINFO and CINAHL. Review methods. We included: 1. studies conducted in adult samples of nurses and/or midwives that had evaluated a sleep-related/fatigue-management intervention; and 2. studies that reported intervention effects on fatigue, sleep, or performance at work, and on measures of attention or cognitive performance (as they relate to the impact of shift working on patient safety/care). Results. The search identified 798 potentially relevant articles, out of which 32 met our inclusion criteria. There were 8619 participants across the included studies and all were nurses (88.6% female). We did not find any studies conducted in midwives nor any studies conducted in the UK, with most studies conducted in the US, Italy and Taiwan. There was heterogeneity both in terms of the interventions evaluated and the measures used to assess effectiveness. Napping could be beneficial but there was wide variation regarding nap duration and timing, and we need to understand more about barriers to implementation. Longer shifts, shift patterns including nights, and inadequate recovery time between shifts (quick returns) were associated with poorer sleep, increased sleepiness and increased levels of fatigue. Light exposure and/or light attenuation interventions showed promise but the literature was dominated by small, potentially unrepresentative samples. Conclusions. The literature related to sleep-related/fatigue-management interventions for nurses and midwives is fragmented and lacks cohesion. Further empirical work is warranted with a view to developing comprehensive Fatigue Risk Management Systems to protect against fatigue in nurses, midwives, and other shift working healthcare staff