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Objective: To explore the association of circadian rhythm disruption with polycystic ovary syndrome (PCOS) and the potential underlying mechanism in ovarian granulosa cells (GCs)., Design: Multicenter questionnaire-based survey, in vivo and ex vivo studies., Setting: Twelve hospitals in China, animal research center, and research laboratory of a women's hospital., Patients/animals: A total of 436 PCOS case subjects and 715 control subjects were recruited for the survey. In vivo and ex vivo studies were conducted in PCOS-model rats and on ovarian GCs collected from women with PCOS and control subjects., Intervention(s): The PCOS rat model was established with the use of testosterone propionate., Main Outcome Measure(s): Assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq), RNA sequencing, rhythmicity analysis, functional enrichment analysis., Result(s): There was a significant correlation between night shift work and PCOS. PCOS-model rats presented distinct differences in the circadian variation of corticotropin-releasing hormone, adrenocorticotropic hormone, prolactin, and a 4-h phase delay in thyrotropic hormone levels. The motif enrichment analysis of ATAC-seq revealed the absence of clock-related transcription factors in specific peaks of PCOS group, and RNA sequencing ex vivo at various time points over 24 hours demonstrated the differential rhythmic expression patterns of women with PCOS. Kyoto Encyclopedia of Genes and Genomes analysis further highlighted metabolic dysfunction, including both carbohydrate and amino acid metabolism and the tricarboxylic acid cycle., Conclusion(s): There is a significant association of night shift work with PCOS, and genome-wide chronodisruption exists in ovarian GCs., (Copyright © 2020 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Studies of breast cancer etiology suggest evidence that night shift working and occupational exposure to ionizing radiation (IR) are defined risk factors for breast cancer development. There are few studies to clarify neuroendocrine and inflammatory status and the possible consequences particularly in occupational exposure., Aim of the Study: Our aim was to associate the redox and inflammatory biomarkers with either nightshift working or occupational radiation exposure, and to compare their levels between the two groups at Alexandria University Hospitals, Alexandria, Egypt., Methods: We included 150 female nurses at Alexandria University Hospitals: 50 nightshift workers, 50 radiation workers, and 50 dayshift workers as a control group (neither work nightly nor radiation workers). In morning serum sample (7 am), we measured the concentrations of serum melatonin, Cortisol, tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) by ELISA; malondialdehyde (MDA) and total antioxidant capacity (TAC) levels colorimetrically, and C-reactive protein (C-RP) levels by turbidimetric method., Results: Nightshift workers had significantly lower levels of melatonin and TAC, and higher levels of serum inflammatory markers and cortisol, than day shift control group of workers. Workers occupationally exposed to IR had significantly higher levels of serum melatonin, MDA and inflammatory markers, lower levels of serum cortisol, and lower TAC than day shift workers., Conclusion: Occupational exposure to IR and working nightly alter circulating redox and inflammatory biomarkers., (Copyright © 2020 IMSS. Published by Elsevier Inc. All rights reserved.)

Background: Sleep deprivation and circadian disruption are associated with decreased insulin sensitivity and hyperglycemia. It is uncertain whether circadian sleep-wake disorder (CRSWD), which relates to both the homeostatic sleep system and the circadian timing system, affects glycemic regulation and insulin secretion. We aimed to examine the associations among sleep duration, sleep architecture or circadian rhythm of the sleep-wake cycle, and glucose metabolism in children, adolescents, and young adults with CRSWD., Methods: This cross-sectional observational study of 124 patients with CRSWD took place at Hyogo Children's Sleep and Development Medical Research Center in Hyogo, Japan. The patients underwent a 3-hour oral glucose tolerance test, anthropometric measurements, sleep-log analyses, and polysomnography. Analysis of covariance models were used to assess the association between sleep architecture or circadian rhythm of sleep-wake cycle and glucose/insulin homeostasis, adjusted for confounding variables such as age, gender, standardized body mass index, and sleep apnea index., Results: Impaired glucose tolerance was detected in 25.8% of all patients with CRSWD. After adjustment for confounding variables, we found a negative association between total sleep time (TST) and the 2-hour plasma glucose level. Stage N1 (%TST) was also a significant predictor of 3-hour glucose level. However, we did not detect an association between circadian rhythm of the sleep-wake cycle and glucose/insulin measures., Conclusions: Decreased sleep duration and increased stage N1 (%TST) were associated with hyperglycemia in patients with CRSWD. Further research should elucidate how circadian misalignment in patients with CRSWD is associated with glucose and insulin homeostasis., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose of Review: In recent years, new studies have investigated the role and influence of sleep on female fertility and early pregnancy outcomes, providing a growing body of knowledge demonstrating how regulation by sleep of hormones are important to reproduction, and how disruptions in sleep, circadian rhythms, and genes regulating circadian rhythmicity can negatively impact fertility and early pregnancy outcomes. This review aims to summarize the most recent research on the relationship among circadian rhythms, fertility, and early pregnancy outcomes in women, and to explore possible fertility interventions., Recent Findings: Recent studies have found altered levels of FSH, LH, and prolactin with sleep disturbance or circadian dysrhythmia. Disruption of circadian rhythms in the form of shift work, jet lag, and daylight savings time changes have been associated with poorer fertility and early pregnancy outcomes. Alterations in the expression of circadian rhythm-regulating circadian locomotor output cycles kaput (CLOCK) genes have been associated with decreased fertility and increased rates of miscarriage., Summary: Overall, undisrupted sleep and circadian rhythmicity appear to optimize fertility and early pregnancy outcomes and may play an important role in the success of fertility treatment.

We describe the time course of bone formation marker (P1NP) decline in men exposed to ~ 3 weeks of sleep restriction with concurrent circadian disruption. P1NP declined within 10 days and remained lower with ongoing exposure. These data suggest even brief exposure to sleep and circadian disruptions may disrupt bone metabolism., Introduction: A serum bone formation marker (procollagen type 1 N-terminal, P1NP) was lower after ~ 3 weeks of sleep restriction combined with circadian disruption. We now describe the time course of decline., Methods: The ~ 3-week protocol included two segments: "baseline," ≥ 10-h sleep opportunity/day × 5 days; "forced desynchrony" (FD), recurring 28 h day (circadian disruption) with sleep restriction (~ 5.6-h sleep per 24 h). Fasted plasma P1NP was measured throughout the protocol in nine men (20-59 years old). We tested the hypothesis that PINP would steadily decline across the FD intervention because the magnitude of sleep loss and circadian misalignment accrued as the protocol progressed. A piecewise linear regression model was used to estimate the slope (β) as ΔP1NP per 24 h with a change point mid-protocol to estimate the initial vs. prolonged effects of FD exposure., Results: Plasma P1NP levels declined significantly within the first 10 days of FD ([Formula: see text] = - 1.33 μg/L per 24 h, p < 0.0001) and remained lower than baseline with prolonged exposure out to 3 weeks ([Formula: see text] = - 0.18 μg/L per 24 h, p = 0.67). As previously reported, levels of a bone resorption marker (C-telopeptide (CTX)) were unchanged., Conclusion: Sleep restriction with concurrent circadian disruption induced a relatively rapid decline in P1NP (despite no change in CTX) and levels remained lower with ongoing exposure. These data suggest (1) even brief sleep restriction and circadian disruption can adversely affect bone metabolism, and (2) there is no P1NP recovery with ongoing exposure that, taken together, could lead to lower bone density over time.

Shift work induces chronic circadian disturbance, which might result in increased health risks, including cardio-metabolic diseases. Previously, we identified sCD36 as a potential non-circadian biomarker of chronic circadian disturbance in mice. The aim of the current study (n = 232 individuals) was to identify whether sCD36 measured in plasma can be used as a non-circadian marker of chronic circadian disturbance in humans, which would allow its use to measure the effects of interventions and monitoring in large-scale studies. We compared levels of plasma sCD36 of day workers with recent (< 2 years) and experienced (> 5 years) night-shift workers within the Klokwerk study. We detected no differences in sCD36 levels between day workers and recent or experienced night-shift workers, measured during a day or afternoon shift. In addition, sCD36 levels measured directly after a night shift were not different from sCD36 levels measured during day or afternoon shifts, indicating no acute effect of night shifts on sCD36 levels in our study. In summary, our study does not show a relation between night-shift work experience (recent or long-term) and plasma levels of sCD36. Since we do not know if and for which time span night-shift work is associated with changes in sCD36 levels, and our study was relatively small and cross-sectional, further evidence for an association between chronic circadian disruption and this candidate biomarker sCD36 should be gathered from large cohort studies., Competing Interests: The authors have declared that no competing interests exist.

Alcohol-induced intestinal hyperpermeability (AIHP) is a known risk factor for alcoholic liver disease (ALD), but only 20-30% of heavy alcoholics develop AIHP and ALD. The hypothesis of this study is that circadian misalignment would promote AIHP. We studied two groups of healthy subjects on a stable work schedule for 3 mo [day workers (DW) and night workers (NW)]. Subjects underwent two circadian phase assessments with sugar challenge to access intestinal permeability between which they drank 0.5 g/kg alcohol daily for 7 days. Sleep architecture by actigraphy did not differ at baseline or after alcohol between either group. After alcohol, the dim light melatonin onset (DLMO) in the DW group did not change significantly, but in the NW group there was a significant 2-h phase delay. Both the NW and DW groups had no change in small bowel permeability with alcohol, but only in the NW group was there an increase in colonic and whole gut permeability. A lower area under the curve of melatonin inversely correlated with increased colonic permeability. Alcohol also altered peripheral clock gene amplitude of peripheral blood mononuclear cells in CLOCK, BMAL, PER1, CRY1, and CRY2 in both groups, and inflammatory markers lipopolysaccharide-binding protein, LPS, and IL-6 had an elevated mesor at baseline in NW vs. DW and became arrhythmic with alcohol consumption. Together, our data suggest that central circadian misalignment is a previously unappreciated risk factor for AIHP and that night workers may be at increased risk for developing liver injury with alcohol consumption., (Copyright © 2016 the American Physiological Society.)

Background: Shift work-related carcinogenesis is hypothesized to be mediated by melatonin; however, few studies have considered the potential effect modification of this underlying pathway by chronotype or specific aspects of shift work such as the number of consecutive nights in a rotation. In this study, we examined melatonin patterns in relation to shift status, stratified by chronotype and number of consecutive night shifts, and cumulative lifetime exposure to shift work., Methods: Melatonin patterns of 261 female personnel (147 fixed-day and 114 on rotations, including nights) at Kingston General Hospital were analyzed using cosinor analysis. Urine samples were collected from all voids over a 48-hour specimen collection period for measurement of 6-sulfatoxymelatonin concentrations using the Buhlmann ELISA Kit. Chronotypes were assessed using mid-sleep time (MSF) derived from the Munich Chronotype Questionnaire (MCTQ). Sociodemographic, health, and occupational information were collected by questionnaire., Results: Rotational shift nurses working nights had a lower mesor and an earlier time of peak melatonin production compared to day-only workers. More pronounced differences in mesor and acrophase were seen among later chronotypes, and shift workers working ≥3 consecutive nights. Among nurses, cumulative shift work was associated with a reduction in mesor., Conclusion: These results suggest that evening-types and/or shift workers working ≥3 consecutive nights are more susceptible to adverse light-at-night effects, whereas long-term shift work may also chronically reduce melatonin levels., Impact: Cumulative and current exposure to shift work, including nights, affects level and timing of melatonin production, which may be related to carcinogenesis and cancer risk. Cancer Epidemiol Biomarkers Prev; 25(5); 830-8. ©2016 AACR., (©2016 American Association for Cancer Research.)

Shift work is a risk factor for hypertension, inflammation, and cardiovascular disease. This increased risk cannot be fully explained by classic risk factors. One of the key features of shift workers is that their behavioral and environmental cycles are typically misaligned relative to their endogenous circadian system. However, there is little information on the impact of acute circadian misalignment on cardiovascular disease risk in humans. Here we show-by using two 8-d laboratory protocols-that short-term circadian misalignment (12-h inverted behavioral and environmental cycles for three days) adversely affects cardiovascular risk factors in healthy adults. Circadian misalignment increased 24-h systolic blood pressure (SBP) and diastolic blood pressure (DBP) by 3.0 mmHg and 1.5 mmHg, respectively. These results were primarily explained by an increase in blood pressure during sleep opportunities (SBP, +5.6 mmHg; DBP, +1.9 mmHg) and, to a lesser extent, by raised blood pressure during wake periods (SBP, +1.6 mmHg; DBP, +1.4 mmHg). Circadian misalignment decreased wake cardiac vagal modulation by 8-15%, as determined by heart rate variability analysis, and decreased 24-h urinary epinephrine excretion rate by 7%, without a significant effect on 24-h urinary norepinephrine excretion rate. Circadian misalignment increased 24-h serum interleukin-6, C-reactive protein, resistin, and tumor necrosis factor-α levels by 3-29%. We demonstrate that circadian misalignment per se increases blood pressure and inflammatory markers. Our findings may help explain why shift work increases hypertension, inflammation, and cardiovascular disease risk.

The interaction of age with shift rotation in relation to sleep-wakefulness and inflammation were studied among male employees (n = 772). Cross-sectional analyses in day, two-shift and three-shift work with different shift rotations, as well as changes in leukocytes and hsCRP among three shift workers who changed their shift system during the 2.5- yr follow-up were completed. Shift work was associated with problems to fall asleep (p < 0.001) and feeling of the current working time being harmful to sleep and wakefulness (p < 0.001). Quickly forward-rotation shift workers considered their working time less harmful compared with slower backward-rotation shift workers. Age did not influence sleep in general, but older workers in the quickly forward-rotating three-shift system had less sleep complaints than their younger colleagues. The age differences in the inflammatory markers partly depended on the shift system. The results give some support that rapidly forward-rotating shift systems are more 'age-friendly' than backward-rotating shift systems.

Objectives: Irregular sleep patterns can adversely affect physiological functions and have been associated with increased physiological and psychological stress. Nocturnal work of physicians during 24-hour on-call shifts (OCS) disrupts the sleep/wake cycle. Chronic exposure to distress has been shown to affect cardiovascular homeostasis and to impair performance in neurocognitive and simulated clinical tasks., Methods: In a prospective cohort study, biochemical and physiological stress parameters were assessed in 11 female and 9 male physicians (median age: 32 years, range 26-42 years) before a normal working day and after a 24-hour OCS in internal medicine. In addition, various tests of attentional performance (TAP) were conducted., Results: The levels of thyroid stimulating hormone (TSH) were significantly higher after a 24- hour OCS, while there were no significant changes in cortisol, epinephrine, and norepinephrine levels. Heart rate variability and skin resistance increased following an OCS, although the differences were not statistically significant. Intrinsic alertness was comparable, while phasic alertness was significantly improved following a 24-hour OCS. Focused attention tended to be better following a night shift. There was no correlation with age or medical working experience; however, men experienced more stress than women., Conclusions: Following a 24-hour OCS, (i) TSH may be an early and sensitive biochemical predictor of stress; (ii) other classical biochemical stress parameters do not depict the psychological stress perceived by physicians; (iii) there may be a mismatch between experienced and objective stress levels; (iv) neurocognitive functions are not impaired, while performance may even be improved; and (v) men might be more sensitive to distress.

Treatment of circadian rhythm sleep disorders (CRSD) may include light therapy, chronotherapy and melatonin. Exogenous melatonin is increasingly being used in patients with insomnia or CRSD. Although pharmacopoeias and the European food safety authority (EFSA) recommend administering melatonin 1-2 h before desired bedtime, several studies have shown that melatonin is not always effective if administered according to that recommendation. Crucial for optimal treatment of CRSD, melatonin and other treatments should be administered at a time related to individual circadian timing (typically assessed using the dim light melatonin onset (DLMO)). If not administered according to the individual patient's circadian timing, melatonin and other treatments may not only be ineffective, they may even result in contrary effects. Endogenous melatonin levels can be measured reliably in saliva collected at the patient's home. A clinically reliably DLMO can be calculated using a fixed threshold. Diary and polysomnographic sleep-onset time do not reliably predict DLMO or circadian timing in patients with CRSD. Knowing the patient's individual circadian timing by assessing DLMO can improve diagnosis and treatment of CRSD with melatonin as well as other therapies such as light or chronotherapy, and optimizing treatment timing will shorten the time required to achieve results., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Muslims go through strict Ramadan fasting from dawn till sunset for one month yearly. These practices are associated with disturbed feeding and sleep patterns. We recently demonstrated that, during Ramadan, circadian cortisol rhythm of Saudis is abolished, exposing these subjects to continuously increased cortisol levels., Hypothesis: Secretory patterns of other hormones and metabolic parameters associated with cortisol, and insulin resistance, might be affected during Ramadan., Protocol: Ramadan practitioners (18 males, 5 females; mean age ±SEM = 23.16±1.2 years) were evaluated before and two weeks into Ramadan. Blood was collected for measurements of endocrine and metabolic parameters at 9 am (±1 hour) and again twelve hours later., Results: In Ramadan, glucose concentration was kept within normal range, with a significant increase in the morning. Mean morning concentration of leptin was significantly higher than pre-Ramadan values (p = 0.001), in contrast to that of adiponectin, which was significantly lower (p<0.001). These changes were associated with increased insulin resistance in morning and evening. Concentrations of hsCRP were lower during Ramadan than those during regular living conditions, however, normal circadian fluctuation was abolished (p = 0.49). Even though means of liver enzymes, total bilirubin, total protein and albumin were all decreased during Ramadan, statistically lower means were only noted for GGT, total protein, and albumin (p = 0.018, 0.002 and 0.001 respectively)., Discussion: Saudi Ramadan practitioners have altered adipokine patterns, typical of insulin resistance. The noted decreases of hsCRP, liver enzymes, total protein, and albumin, are most likely a result of fasting, while loss of circadian rhythmicity of hsCRP is probably due to loss of circadian cortisol rhythm., Conclusions: Modern Ramadan practices in Saudi Arabia, which are associated with evening hypercortisolism, are also characterized by altered adipokines patterns, and an abolished hsCRP circadian rhythm, all likely to increase cardiometabolic risk.

To evaluate the impact of day-and-night rotating shift work (RSW) on liver health, we performed a retrospective analysis of the association between long-term RSW exposure and the normalization of plasma alanine transaminase (ALT) levels over a five-year period. The data from physical examinations, blood tests, abdominal sonographic examinations, personal histories, and occupational records were collected from a cohort of workers in a semiconductor manufacturing company. The sample population was divided into three subgroups for analysis, according to self-reported shift work status over the five-year interval: persistent daytime workers, workers exposed intermittently to RSW (i-RSW), and workers exposed persistently to RSW (p-RSW). Records were analyzed for 1196 male workers with an initial mean age of 32.5 years (SD 6.0 years), of whom 821 (68.7%) were identified as rotating shift workers, including 374 i-RSW (31.3%) and 447 p-RSW workers (37.4%). At the beginning of the follow-up, 275 were found to have elevated ALT (e-ALT): 25.1% daytime workers, 23.0% i-RSW workers, and 21.3% p-RSW workers (p = 0.098). Of those with e-ALT at the beginning, 101 workers showed normalized serum ALT levels at the end of five-year follow-up: 40 (10.7%) of 375 daytime workers, 32 (8.6%) of 374 i-RSW workers, and 29 (6.5%) of 447 p-RSW workers (p = 0.016). Compared with the workers having persistent e-ALT at the end of follow-up, the workers normalized serum ALT levels had significantly lesser exposures to RSW during follow-up. By performing multivariate logistic regression analyses, and comparing with the persistent daytime co-workers, after controlling for confounding variables (age, occupational factors, educational levels, lifestyle factors, metabolic syndrome, hepatovirus infection, and fatty liver), analysis indicated that the workers exposed to p-RSW were 46% less likely (OR, 0.54; 95% CI, 0.30-0.95; p = 0.03) to attain normal ALT levels within a five-year interval. These observations demonstrate that persistent day-and-night RSW pose a vigorous obstacle to the normalization of e-ALT among workers with preexisting abnormal liver function. We suggest that workers and managers approach with caution the consideration of assigning or accepting long-term day-and-night RSW when an employee health screening shows evidence of abnormal liver function.

Background: Lack of sleep and increased consumption of energy-dense foods and sugar-sweetened beverages (SSBs) have all been suggested as factors contributing to the increased prevalence of overweight and obesity., Objective: To evaluate whether objectively measured sleep duration (average and day-to-day variability) as well as parent-reported sleep problems are independently associated with proposed dietary risk factors for overweight and obesity in 8-11-year-old children., Design: In this cross-sectional study, data on sleep duration and day-to-day variability in sleep duration were measured in 676 Danish, apparently healthy children by an objective measure (actigraphy) for 8 nights, and the Children's Sleep Habits Questionnaire (CSHQ) was filled out by the parents. Diet was recorded using a web-based food record for 7 consecutive days. Fasting blood samples were obtained for measurements of plasma leptin and ghrelin levels., Results: Sleep duration (h per night) was negatively associated with energy density (ED) of the diet (β = -0.32 kJ g(-1)), added sugar (β = -1.50 E%) and SSBs (β = -1.07 E%) (all P ≤ 0.003). Furthermore, variability in sleep duration (10-min per night) was positively associated with SSBs (β = 0.20 E%, P = 0.03), independent of sleep duration, and CSHQ score was positively associated with ED (β = 0.16 kJ g(-1), P = 0.04). All of these associations were independent of potential confounders (age, sex, pubertal status, height, weight, screen time, moderate-to-vigorous physical activity and parental education and ethnicity)., Conclusion: Our study suggests that short sleep duration, high sleep duration variability and experiencing sleep problems are all associated with a poor, obesity-promoting diet in children.

Objective: Shift work is associated with circadian rhythm disorder, impaired sleep and behavioural changes, including eating habits, predisposing to obesity and metabolic dysfunctions. It involves a neuro-hormonal dysregulation of appetite towards positive energy balance, including increased ghrelin and decreased leptin, but little is known about other hormones, such as xenin, derived from the upper gut (like ghrelin), and lower gut hormones. Our objective was to compare night workers with day workers in relation to appetite-regulating hormones and other metabolic parameters., Design: Cross-sectional, observational study., Participants: Twenty-four overweight women, divided into night shift workers (n = 12) and day shift workers (n = 12)., Measurements: BMI, waist circumference, fat mass percentage; diet composition; Pittsburgh Sleep Quality Index; lipids; adipokines; meal tolerance test curves of glucose, insulin, ghrelin, PYY3-36, oxyntomodulin, xenin, GLP-1; insulin sensitivity (Stumvoll index)., Results: Night workers, as compared with day workers, had greater body fat mass percentage and tendency to greater waist circumference despite similar BMI; greater energy intake; impaired sleep; lower insulin sensitivity; increased triglycerides and tendency to increased C-reactive protein; similar levels of leptin and other adipokines. Night workers had a blunted post-meal suppression of ghrelin (AUCi(0-60 min) 19·4 ± 139·9 vs -141·9 ± 9·0 ng/ml·60 min, P < 0·01); blunted rise of xenin (AUC(0-180 min) 8690·9 ± 2988·2 vs 28 504·4 ± 20 308·3 pg/ml·180 min, P < 0·01) and similar curves of PYY3-36, oxyntomodulin and GPL-1., Conclusion: Compared with day workers within the same BMI range, night workers presented a disrupted control of ghrelin and xenin, associated with behavioural changes in diet and sleep and increased adiposity and related metabolic alterations., (© 2012 John Wiley & Sons Ltd.)

Shiftwork is common in medical training and is necessary for 24-h hospital coverage. Shiftwork poses difficulties not only because of the loss of actual sleep hours but also because it can affect other factors related to lifestyle, such as food intake, physical activity level, and, therefore, metabolic patterns. However, few studies have investigated the nutritional and metabolic profiles of medical personnel receiving training who are participating in shiftwork. The aim of the present study was to identify the possible negative effects of food intake, anthropometric variables, and metabolic and sleep patterns of resident physicians and establish the differences between genders. The study included 72 resident physicians (52 women and 20 men) who underwent the following assessments: nutritional assessment (3-day dietary recall evaluated by the Adapted Healthy Eating Index), anthropometric variables (height, weight, body mass index, and waist circumference), fasting metabolism (lipids, cortisol, high-sensitivity C-reactive protein [hs-CRP], glucose, and insulin), physical activity level (Baecke questionnaire), sleep quality (Pittsburgh Sleep Quality Index; PSQI), and sleepiness (Epworth Sleepiness Scale; ESS). We observed a high frequency of residents who were overweight or obese (65% for men and 21% for women; p = 0.004). Men displayed significantly greater body mass index (BMI) values (p = 0.002) and self-reported weight gain after the beginning of residency (p = 0.008) than women. Poor diet was observed for both genders, including the low intake of vegetables and fruits and the high intake of sweets, saturated fat, cholesterol, and caffeine. The PSQI global scores indicated significant differences between genders (5.9 vs. 7.5 for women and men, respectively; p = 0.01). Women had significantly higher mean high-density lipoprotein cholesterol (HDL-C; p < 0.005), hs-CRP (p = 0.04), and cortisol (p = 0.009) values than men. The elevated prevalence of hypertriglyceridemia and abnormal values of low-density lipoprotein cholesterol (LDL-C; >100 mg/dL) were observed in most individuals. Higher than recommended hs-CRP levels were observed in 66% of the examined resident physicians. Based on current recommendations, a high prevalence of low sleep quality and excessive daytime sleepiness was identified. These observations indicate the need to monitor health status and develop actions to reassess the workload of medical residency and the need for permission to perform extra night shifts for medical residents to avoid worsening health problems in these individuals.

Background: Circadian rhythm sleep disorder, free-running type (FRT), is an intractable sleep disorder in which sleep and wake times progressively delay each day even in normal living environments. This disorder severely affects the social functioning of patients because of periodic nighttime insomnia, excessive daytime sleepiness, and a high rate of comorbid psychiatric disorders. Although abnormal regulation of the biological clock is suspected, the pathophysiology of FRT has yet to be elucidated. In this study, the endogenous circadian period, τ, of FRT patients with normal vision was compared with that of healthy individuals whose circadian rhythms are entrained to a 24-hour cycle., Methods: Six FRT patients and 17 healthy individuals (9 intermediate chronotypes and 8 evening chronotypes) were subjected to a 7-day, 28-hour sleep-wake schedule according to the forced desynchrony protocol. Phase shifts in melatonin rhythm were measured under constant routine conditions to calculate τ., Results: In FRT patients, τ was significantly longer than in intermediate chronotypes, whereas in evening chronotypes, it ranged widely and was not significantly different from that in FRT patients. Moreover, τ of melatonin rhythm in FRT patients showed no significant correlation with τ of sleep-wake cycles measured before the study., Conclusions: The findings suggest that although a prolongation of τ may be involved in the onset mechanism of FRT, a prolonged τ is not the only factor involved. It appears that several factors including abnormal entrainment of circadian rhythms are involved in the onset of FRT in a multilayered manner., (Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

The non-interventional study VIVALDI was carried out to evaluate the treatment with agomelatine, an innovative antidepressant, in routine practice.665 psychiatrists treated 3 317 patients over 12 weeks with agomelatine and documented antidepressant effects via svMADRS, CGI scale and CircScreen questionnaire. Subgroups with severe depression (svMADRS ≥30) and elderly patients (≥65 years) were also analyzed.In the total population, svMADRS total score decreased from 30.6 at baseline to 12.8 at final visit, in severely depressed patients from 36.7 to 14.7, in elderly patients from 29.0 to 12.2. In total 65.8% of patients could be classified as responders (≥50% decrease in svMADRS total score) and 54.8% as remitters (svMADRS ≤12). Daytime sleepiness was ameliorated in 78.2% of patients. Adverse drug reactions were reported for 10.0%, 8.9% and 10.1% of patients in total population, severely ill and elderly patients, respectively.In this study, the antidepressant effects, improvement of circadian rhythm disorders and good tolerability of agomelatine were observed in unselected depressed patients, including multimorbid elderly and severely depressed patients under routine practice., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Sleep problems are known to be common in Angelman syndrome (AS), a neurodevelopmental disorder which is associated with an abnormality of chromosome 15q11-q13. However, the circadian aspect of sleep disorders in AS and an effective treatment for the disorder have yet to be established., Methods: We elucidated the sleep-wake patterns of AS patients and its relationship to the serum melatonin levels. The serum melatonin levels of 15 AS patients were measured every 4h for one day and the values were compared with those of age-matched controls. We also examined the effectiveness of the oral administration of melatonin on AS patients with circadian rhythm sleep disorders (CRSD)., Results: A total of eight of the 15 AS patients had CRSD (irregular sleep-wake type, n=4; free-running type n=2; delayed sleep phase type, n=2). The nighttime serum melatonin levels of the AS patients were significantly lower than those of the controls at the measured time points during the night. The nocturnal melatonin levels were comparably low both in AS patients with and without CRSD except for the cases with delayed sleep phase type, which showed normal but delayed peak melatonin level. Six out of eight CRSD cases were given a daily dose of 1mg of melatonin between 18:00 and 19:00 regularly for three months. After receiving the treatment, the sleep patterns improved in four cases., Conclusion: This study revealed a high prevalence of CRSD in AS patients, which may be related to abnormal serum melatonin profiles., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Armodafinil, the longer lasting R-isomer of racemic modafinil, improves wakefulness in patients with excessive sleepiness associated with shift work disorder (SWD). Pharmacokinetic studies suggest that armodafinil achieves higher plasma concentrations than modafinil late in a dose interval following equal oral doses. Pooled Multiple Sleep Latency Test (MSLT) data from 2 randomized, double-blind, placebo-controlled trials in 463 patients with SWD, 1 with armodafinil 150 mg/d and 1 with modafinil 200 mg/d (both administered around 2200 h before night shifts), were used to build a pharmacokinetic/pharmacodynamic model. Predicted plasma drug concentrations were obtained by developing and applying a population pharmacokinetic model using nonlinear mixed-effects modeling. Armodafinil 200 mg produced a plasma concentration above the EC(50) (4.6 µg/mL) for 9 hours, whereas modafinil 200 mg did not exceed the EC(50). Consequently, armodafinil produced greater increases in predicted placebo-subtracted MSLT times of 0.5-1 minute (up to 10 hours after dosing) compared with modafinil. On a milligram-to-milligram basis, armodafinil 200 mg consistently increased wakefulness more than modafinil 200 mg, including times late in the 8-hour shift.

Patients with chronic kidney disease including those undergoing haemodialysis have deranged sleep-wake pattern. In large part this is due to an abnormal circadian cycle of melatonin, a hormone secreted by the pineal gland in the evening and induces sleep. Subjects undergoing automated peritoneal dialysis or nocturnal haemodialysis have better sleep profile compared to those on daytime dialysis. Studies have shown that exogenous melatonin improves sleep-wake cycle in daytime haemodialysis patients. However, large randomised controlled trials are needed in order to establish its role in this patient population., (© 2012 European Dialysis and Transplant Nurses Association/European Renal Care Association.)

Epidemiological studies link short sleep duration and circadian disruption with higher risk of metabolic syndrome and diabetes. We tested the hypotheses that prolonged sleep restriction with concurrent circadian disruption, as can occur in people performing shift work, impairs glucose regulation and metabolism. Healthy adults spent >5 weeks under controlled laboratory conditions in which they experienced an initial baseline segment of optimal sleep, 3 weeks of sleep restriction (5.6 hours of sleep per 24 hours) combined with circadian disruption (recurring 28-hour "days"), followed by 9 days of recovery sleep with circadian re-entrainment. Exposure to prolonged sleep restriction with concurrent circadian disruption, with measurements taken at the same circadian phase, decreased the participants' resting metabolic rate and increased plasma glucose concentrations after a meal, an effect resulting from inadequate pancreatic insulin secretion. These parameters normalized during the 9 days of recovery sleep and stable circadian re-entrainment. Thus, in humans, prolonged sleep restriction with concurrent circadian disruption alters metabolism and could increase the risk of obesity and diabetes.

Cardiovascular diseases remain a major public health problem. The involvement of several occupational factors has recently been discussed, notably the organization of work schedules, e.g. shift work. To analyse the progress of knowledge on the relationship between cardiovascular risk factors and shift work. A review of English-language literature dealing with the link between cardiovascular factors and shift workers (published during 2000-2010) was conducted. Studies published in the past 10 years tend to document an impact of shift work on blood pressure, lipid profile (triglyceride levels), metabolic syndrome and, possibly, body mass index. However, the consequences on glucose metabolism are unclear. These results are not yet firmly established, but are supported by strong hypotheses. Some advice could reasonably be proposed to guide the clinical practitioner., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Although low vitamin D status resulting from night work is a suspected cause of various health disorders, few studies have investigated the association between night-shift work and vitamin D status. Here, we examined serum 25-hydroxyvitamin D (25OHD) levels in 19 Japanese indoor workers, including night-shift workers, in blood samples collected at the annual medical checkup (late July) in a metal tool factory. Analyses were finally restricted to 14 male workers (33-59 yr) in 3 groups: fixed daytime work (n=6), and rotating shift work with (n=4) and without (n=4) night shifts. No significant differences in serum 25OHD levels were observed among the three groups (p=0.98, Kruskal-Wallis test). One to two participants in each group had 25OHD levels lower than the 20 ng/ml reference value for vitamin D deficiency even in summer. These results clearly indicate the need for large-scale studies to test the hypothesis that night-shift work is associated with lower 25OHD levels.

Background: In obese adults, sleep apnea is associated with excessive daytime sleepiness (EDS) and cardiometabolic risk factors. In children, on the other hand, sleep-disordered breathing (SDB) is primarily associated with anatomic abnormalities and neurocognitive impairment, whereas studies on potential concurrent metabolic aberrations and EDS have been limited and inconsistent. In this study, we examined the joint effect of SDB and obesity in EDS as well as proinflammatory and metabolic markers., Methods: One hundred fifty children, aged 5-17 yr, were consecutively recruited from our sleep disorders clinic and a subset of the Penn State Children's Cohort. Every child had a thorough history and physical examination, 9-h polysomnographic study, and a single blood draw for the assessment of IL-6, TNFalpha, soluble IL-6 receptor, TNF receptor-1, hypersensitive C-reactive protein, leptin, and adiponectin. In addition, parents completed a subjective questionnaire to assess EDS. Analysis of covariance was performed on four groups that were separated by SDB severity and body mass index., Results: EDS frequency increased progressively and significantly in the four groups. There was a significant linear trend in plasma IL-6, TNF receptor-1, hypersensitive C-reactive protein, and leptin concentrations, with lowest levels observed in lean controls and highest in overweight/obese with moderate SDB. Adiponectin followed the opposite pattern., Conclusions: This study suggests that in a clinical sample of obese children, SDB is associated with EDS, elevation of proinflammatory cytokines, increased leptin, and decreased adiponectin. All these changes point to an inflammatory/insulin resistance state, suggesting that SDB in obese children share many similarities with SDB in obese adults.

Study Objective: To produce a compromise circadian phase position for permanent night shift work in which the sleepiest circadian time is delayed out of the night work period and into the first half of the day sleep period. This is predicted to improve night shift alertness and performance while permitting adequate late night sleep on days off., Design: Between-subjects., Setting: Home and laboratory., Participants: 24 healthy subjects., Interventions: Subjects underwent 3 simulated night shifts, 2 days off, and 4 more night shifts. Experimental subjects received five, 15 minute bright light pulses from light boxes during night shifts, wore dark sunglasses when outside, slept in dark bedrooms at scheduled times after night shifts and on days off, and received outdoor afternoon light exposure (the "light brake"). Control subjects remained in normal room light during night shifts, wore lighter sunglasses, and had unrestricted sleep and outdoor light exposure., Measurements and Results: The final dim light melatonin onset (DLMO) of the experimental group was approximately approximately 04:30, close to our target compromise phase position, and significantly later than the control group at approximately 00:30. Experimental subjects performed better than controls, and slept for nearly all of the allotted time in bed. By the last night shift, they performed almost as well during the night as during daytime baseline. Controls demonstrated pronounced performance impairments late in the night shifts, and exhibited large individual differences in sleep duration., Conclusions: Relatively inexpensive and feasible interventions can produce adaptation to night shift work while still allowing adequate nighttime sleep on days off.

Objective: The purpose of this study was to test the hypothesis that disturbances in levels of plasma melatonin differentiate pregnant and postpartum women with major depression from matched pregnant and postpartum healthy comparison women., Method: Participants were 25 pregnant women (10 with major depression, 15 healthy) and 24 postpartum women (13 with major depression, 11 healthy). Healthy comparison women were matched on the number of weeks pregnant or postpartum. Plasma melatonin levels for each subject were measured every 30 minutes, in dim light (<30 lux), from 6:00 p.m. to 11:00 a.m. The values of plasma melatonin levels were log-transformed, and calculations were determined for the following measures: baseline and synthesis onset and offset times, duration, peak concentration, and area under the curve. Groups were compared by analyses of covariance, with age, number of weeks pregnant or postpartum, breast-feeding status, and body mass index as covariates., Results: Morning melatonin levels from 2:00 a.m. to 11:00 a.m. were significantly lower in pregnant women with major depression relative to healthy pregnant women. However, these levels were significantly higher in postpartum women with major depression across time intervals relative to postpartum healthy women. Pregnant but not postpartum women with a personal or family history of depression, regardless of their current diagnosis, had significantly earlier melatonin synthesis and baseline offset times relative to women without a family history of depression. In pregnant healthy women but not pregnant women with major depression, melatonin levels increased during the course of pregnancy. This association was not found among postpartum women with major depression or postpartum healthy women., Conclusions: Plasma nocturnal melatonin concentrations, particularly during morning hours, were lower in depressed pregnant women but elevated in depressed postpartum women relative to matched healthy comparison women. In addition, melatonin timing measures were advanced in pregnant women with a personal or family history of depression. These findings implicate disturbances in the regulation of the melatonin generating system in pregnancy and postpartum depression.

Nocturnal sleep restriction and compensation with daytime naps is common in today's society. In a between-participants design, we examined the effects of chronic (10 nights) sleep restriction on 24 h plasma melatonin profiles in humans. Following a baseline period with 8.2 h time in bed (TIB) for sleep, participants were randomized to a control (8.2 h TIB) or sleep-restriction condition (4.2 h TIB), with and without diurnal naps. Sleep restriction was achieved via delaying bedtime and advancing wake time by 2 h each relative to the baseline sleep period. Participants were maintained in a controlled, time isolated laboratory environment throughout the protocol, with light levels below 40 lx at all times. Twenty-four hour plasma melatonin profiles were assessed at baseline and at the end of the sleep-restriction period, with subjects maintained in a constant posture protocol. Compared with the baseline assessment and the 8.2 h TIB control group, a significant phase delay in melatonin onset (1.2 +/- 0.9 h) occurred in all sleep-restriction (4.2 h TIB) groups (P < 0.05). There was no evidence of a phase advance or shortening of the period of melatonin secretion associated with the advanced waking time. These results suggest that nocturnal light and dark exposure may be more potent in effecting circadian phase shifts than exposure to morning light, at least in conditions of controlled, dim lighting in the laboratory.

Chromotherapy is based on the effect of colored light with different frequencies on human neurohormonal pathways, precisely on melatonin and serotonin pathways in brain. There is evidence that visible electromagnetic spectrum of light we see as colors can have impact on human health, Cicardian rhythm or biological clock is complex fundamental physiological and biological cycle in human organism. The biological clock in humans is located in the specialized group of brain cells called suprachiasmatic nucleus (SCN) within the anterior hypothalamus. The complex process of neurohormonal regulation of cicardian rhythm in humans is essential for synchronized interaction and coordination of internal body function with the environment. Given these facts it is clear that any shift in cicardian rhythm results in neurohormonal imbalance which consequently could lead to various psychiatric disorders affecting humans. Studies on sleep disorders, depression, seasonal affective disorder (SAD) and post-traumatic stress disorder (PTSD) suggested that symptoms, signs, and biologic markers associated to these psychiatric disorders are due to marked alterations in melatonin and serotonin levels. The main hypothesis of chromotherapy is that specific colors of the visible spectrum are activators or inhibitors of complex physiological, biological and biochemical processes in human brain such as synthesis of various neurohormons. According to all previous findings, our goal is future investigation of the effect and possible application of chromotherapy in the complementary psychiatric treatment in patients with diagnostic criteria which are clearly related to melatonin and serotonin disturbances.

Normal circadian rhythms are synchronized to a regular 24 h environmental light-dark cycle, and the suprachiasmatic nucleus and the hormone melatonin have important roles in this process. Desynchronization of circadian rhythms, as occurs in chronobiological disorders, can produce severe disturbances in sleep patterns. According to the International Classification of Sleep Disorders, circadian rhythm sleep disorders (CRSDs) include delayed sleep phase syndrome, advanced sleep phase syndrome, non-24 h sleep-wake disorder, jet lag and shift-work sleep disorder. Disturbances in the circadian phase position of plasma melatonin levels have been documented in all of these disorders. There is compelling evidence to implicate endogenous melatonin as an important mediator in CRSD pathophysiology, although further research involving large numbers of patients will be required to clarify whether the disruption of melatonin secretion is a causal factor in CRSDs. In this Review, we focus on the use of exogenous melatonin and light therapy to treat the disturbed sleep-wake rhythms seen in CRSDs.

Objectives: A controlled intervention study was conducted to evaluate the effects of two changes in shift characteristics on alertness and cardiovascular risk factors: a change in shift rotation (direction and speed) and a change in the flexibility of the shift system., Methods: Altogether 84 male workers currently working in a backward-rotating shift system volunteered for the study. A total of 40 men changed to a rapidly forward-rotating shift system, 22 changed to a more flexible shift system, and 22 remained with the old shift system. Health effects were studied with the use of clinical measurements, blood tests, and questionnaires before and after the shift changes. Analyses of variance were used with repeated measures to study associations of cardiovascular risk factors and daytime sleepiness according to the change in shift systems., Results: The mean number of days on which the workers reported sleepiness decreased in the group with the forward-rotating shift system when compared with that of the group on the old shift system (from 2.9 to 2.1 days/week, P=0.02). Systolic blood pressure decreased (from 142 to 136 mm Hg, P=0.049), and heart rate showed a declining trend (from 66 to 60 beats/minute, P=0.06) in the flexible shift system when the three groups were compared., Conclusions: The study indicates that a faster speed, together with a change to the forward direction, in shift rotation alleviates daytime sleepiness. Combining individual flexibility with company-based flexibility in a shift system may have favorable effects on shift workers' blood pressure.

The relationship between actigraphy- or diary-based sleep parameters and salivary melatonin-based dim light melatonin onsets (DLMOs) was examined in 21 adolescents with a history of substance abuse and current complaints of sleep difficulties. The adolescents displayed relationships between diary-based sleep times and DLMO that were of comparable strength with those reported for adult insomniacs and healthy adolescents during the school year, but weaker than those observed in healthy adults and healthy adolescents on summer vacation. When the sample was divided into adolescents with late and early DLMOs, the 2 groups had significantly different phase angles between DLMO and sleep variables but no other significant differences in sleep parameters. However, circadian phase and its relationship to sleep may have sleep and behavioral consequences.

The purpose of this pilot study was to examine the differences in temperature rhythms, rest/activity rhythms, melatonin rhythms, sleep percentages, and daytime sleepiness between two cohort-matched older adult groups in a continuing care retirement residence. Ten nursing home residents experienced disrupted rhythms, slept more, and experienced more daytime sleepiness compared with 10 apartment-dwelling residents. Nighttime light exposure was small in both groups but significantly greater in the nursing home. Gerontological nursing practice implications are to improve older residents' sleep by eliminating nighttime light and sleep-disrupting routines in all care settings for older adults.

Study Objectives: Because serotonin (5-HT) is a neurotransmitter associated with circadian rhythm regulation, we explored a possible relation among 5-HT, serotonin metabolite, 5-hydroxyindolacetic acid (5HIAA), and the functional polymorphism of the serotonin transporter gene (SLC6A4) promoter with rotating shift work., Design and Participants: 683 men were included in this study: 437 day workers were compared with 246 rotating shift workers., Results: Platelet 5-HT content differed significantly (P = 0.002) between day workers (41.28+/-1.99 pg/mg) and rotating shift workers (37.91+/-4.16 pg/mg); 5-HIAA content was also significantly (P = 0.00004) higher in day workers (11.40+/-0.82 pg/mg) than in rotating shift workers (9.33+/-1.02 pg/ mg). We looked for further differences in SLC6A4 promoter (5-HTTLPR, 44 bp insertion: long (L)/deletion: short (S) alleles). We found a significant (P = 0.016) difference in genotype distribution between day workers LL: 126 (28.8%), LS: 202 (46.2%), and SS: 109 (24.9%), and rotating shift workers LL: 47 (19.1%), LS: 124 (50.4%), and SS: 75 (30.5%). When we divided the subjects between workers with less and more than 60 month rotating shift-work exposure, the difference in SLC6A4 genotypes frequency was only significant in the group with > or =60 months (P = 0.011). In addition, there was a significantly lower content of platelet 5-HIAA in S allele carriers in comparison with the other genotypes (SS: 9.2+/-1.0 pg/mg vs. SL/LL: 11.0+/-0.8 pg/mg, P <0.02)., Conclusions: Platelet 5-HT and 5-HIAA contents were significantly lower in rotating shift workers than day workers, and there was a significant association between the S variant of SLC6A4 promoter and shift work. These findings may be important for targeting effective therapeutic strategies to ameliorate the associated comorbidities and behavioral problems in rotating shift workers.

A standard sleep questionnaire was given to the parents of 26 infants with protein-energy malnutrition who underwent polysomnographic evaluation. These investigations were repeated approximately 2 months after enrolment in a nutritional rehabilitation programme based on World Health Organization guidelines. Anthropometric values and serum serotonin levels were also measured. After nutritional rehabilitation there was a significantly higher percentage of non-rapid eye movement (REM) sleep; 2nd REM time, and latency times for sleep and REM sleep increased. Percentages of REM sleep and serum serotonin levels decreased significantly. Protein-energy malnutrition seems to affect the sleep-wake cycle; disturbed serotonin levels may be among the factors responsible.

Sleep deprivation has been shown to be associated with an increase in inflammatory makers such as interleukin-6 and C-reactive protein. The purpose of the present study was to investigate the relation between subjective poor sleep and white blood cell (WBC) count, an inflammatory marker. The subjects were 208 male Japanese workers in a synthetic fiber-manufacturing plant, who responded to a cross-sectional survey of a questionnaire on basic attributes, life style, and sleep. All male workers in the plant took an annual health checkup. WBC count was also examined in the checkup. The WBC count was greater in shift workers than in daytime workers. Shift workers complained of poor sleep more frequently, though their sleeping hours were longer. Multiple regression analysis showed that poor sleep as well as smoking habit, BMI and age were independent factors for an increase in WBC count, while sleeping hours and work pattern (shift work) were not significant factors. The present finding that poor sleep was associated with higher WBC count in male workers might suggest the importance of quality of sleep, particularly among shift workers.

Objective: : We studied whether the endogenous melatonin patterns in adult patients with developmental brain disorders have any role in response to exogenous melatonin given as a sleep-promoting medicine., Methods: : Participants included 15 adults (18-60 years, five females) with developmental brain disorders of varying etiologies, motor handicaps, and long-term history of sleep problems. According to the 24-h patterns of serum melatonin, patients were divided into two subgroups: lower and higher secretors. The pretreatment sleep disorder was characterized by a structured interview, 24-h ambulatory polysomnography and 7-day wrist actigraphy. Patients received 1, 3, or 6mg fast-release melatonin tablets, each for 4 weeks in increasing order, at a constant time of 30min before the desired sleep onset. Similarly, placebos with different codes were given during 3x4 weeks. The 7-day actigraphy was repeated at the end of each drug period. Outcome measures were six different parameters of non-parametric circadian rhythm analysis. Drug effects and 40 confounding/modulating factors were evaluated by applying two-level regression analyses with co-variables., Results: : Exogenous melatonin decreased the fragmentation of the rest-activity rhythm, increased the day/night ratio of activity and advanced the onset of rest period. The effects on fragmentation and day/night ratio were more pronounced in the lower than higher secretors of melatonin. Other contributing factors in the drug effects were blindness and some features of the original sleep disorder (disrupted cyclicity of the sleep architecture in polysomnography or reported daytime somnolence)., Conclusions: : Exogenous melatonin consolidated the fragmented rest-activity in about half of the patients. Low endogenous serum melatonin levels at night predicted improvement by the drug. Higher doses were not more effective than the lowest dose.

There is evidence supporting an association between shift work and cardiovascular morbidity, but the underlying mechanisms are unknown. The present paper investigated the levels of cardiovascular biochemical risk factors in shift-workers both with (n=26) and without (n=103) sleep complaints, and in day-workers (n=173) working in the same plant. Blood samples were taken in the morning after an overnight fast and analyzed for homocysteine, C-reactive protein, and lipid profile. Biochemical data were compared among groups after stratifying workers by age (i.e., <40 and > or = 40 yrs). Shift-workers who complained about sleep disturbances and who were > or = 40 years of age had significantly higher levels of homocysteine than did their younger counterparts - shift-workers who did not complain of sleep disturbances and day-workers. There were no other between-group differences in any of the biochemical variables. The results of this investigation demonstrate an association between sleep disturbances in older shift-workers and mild hyperhomocysteinemia. The elevated homocysteine levels may play a role in the increased rates of cardiovascular morbidity in shift-workers, and they may have practical implications regarding the nutrition of shift-workers.

Study Objectives: To assess temporal stability across multiple assessments and predictors of circadian phase in participants with delayed sleep phase syndrome (DSPS), relative to normal-sleeping matched controls., Design: Circadian phase was assessed by salivary dim light melatonin onset (DLMO) during 3 laboratory visits, separated by at least 5 days--2 scheduled at the end of the week (Friday) and 1 scheduled at the end of the weekend (Sunday)., Patients: Eight young volunteers who met International Classification of Sleep Disorders-Revised criteria for DSPS, and 8 age- and sex-matched controls (age range 19-27 years old)., Interventions: N/A., Measurements and Results: As expected, salivary DLMO occurred significantly later in patients with DSPS than in controls (F 10.561, p = .006). However, circadian phase did not change significantly across the 3 DLMO assessments in either group. Estimations of circadian phase were not significantly different in the assessments conducted on weekdays versus weekends. Predictors of circadian phase included time of morning light exposure (R2 = 0.777; p < .001), recent wake time (R2 = 0.701, p < .001), and self-reported chronotype (R2 = 0.320, p = .016). DLMO preceded wake time in both groups by approximately 10.75 hours., Conclusions: Across serial laboratory assessments on an ad lib sleep schedule, patients with DSPS appeared more similar to than different from normal-sleeping control subjects, except for a stable delay in circadian phase.

Study Design: Case-controlled preliminary observational study., Objective: Melatonin is usually secreted only at night and may influence sleep. We previously found that complete cervical spinal cord injury (SCI) interrupts the neural pathway required for melatonin secretion. Thus, we investigated whether the absence of night time melatonin in cervical SCI leads to sleep disturbances., Setting: General Clinical Research Center, Brigham and Women's Hospital, Boston, USA., Methods: In an ancillary analysis of data collected in a prior study, we assessed the sleep patterns of three subjects with cervical SCI plus absence of nocturnal melatonin (SCI levels: C4A, C6A, C6/7A) and two control patients with thoracic SCI plus normal melatonin rhythms (SCI levels: T4A, T5A). We also compared those results to the sleep patterns of 10 healthy control subjects., Results: The subjects with cervical SCI had significantly lower sleep efficiency (median 83%) than the control subjects with thoracic SCI (93%). The sleep efficiency of subjects with thoracic SCI was not different from that of healthy control subjects (94%). There was no difference in the proportion of the different sleep stages, although there was a significantly increased REM-onset latency in subjects with cervical SCI (220 min) as compared to subjects with thoracic SCI (34 min). The diminished sleep in cervical SCI was not associated with sleep apnea or medication use., Conclusion: We found that cervical SCI is associated with decreased sleep quality. A larger study is required to confirm these findings. If confirmed, the absence of night time melatonin in cervical SCI may help explain their sleep disturbances, raising the possibility that melatonin replacement therapy could help normalize sleep in this group.

Study Objectives: To assess the wavelength-dependent sensitivity of the acute effects of ocular light exposure on alertness, performance, waking electroencephalogram (EEG), and cortisol., Design: A between-subjects design was employed to compare the effects of exposure to 460-nm or 555-nm light for 6.5 hours during the biological night., Setting: Intensive Physiological Monitoring Unit, Brigham and Women's Hospital, Boston, MA., Patients and Participants: Sixteen healthy adults (8 women; mean age +/- SD = 23.3 +/- 2.4 years)., Interventions: Subjects were exposed to equal photon densities (2.8 x 10(13) photons x cm(-2) x s(-1)) of either 460-nm (n = 8) or 555-nm (n = 8) monochromatic light for 6.5 hours, 15 minutes after mydriasis., Measurements and Results: Subjects underwent continuous EEG/electrooculogram recordings and completed a performance battery every 30 to 60 minutes. As compared with those exposed to 555-nm light, subjects exposed to 460-nm light had significantly lower subjective sleepiness ratings, decreased auditory reaction time, fewer attentional failures, decreased EEG power density in the delta-theta range (0.5-5.5 Hz), and increased EEG power density in the high-alpha range (9.5-10.5 Hz). Light had no direct effect on cortisol., Conclusions: Short-wavelength sensitivity to the acute alerting effects of light indicates that the visual photopic system is not the primary photoreceptor system mediating these responses to light. The frequency-specific changes in the waking EEG indicate that short-wavelength light is a powerful agent that immediately attenuates the negative effects of both homeostatic sleep pressure and the circadian drive for sleep on alertness, performance, and the ability to sustain attention.

This case study describes a 14-year-old male suffering from significant academic and personal difficulties, who has been diagnosed with depression, schizotypal personality disorder, and learning disabilities. Because of excessive sleepiness, assessment for a potential sleep disorder was performed. An overnight polysomnographic study revealed no primary sleep disorders. Wrist actigraphy revealed a non-24-hour sleep-wake pattern. Delay in temperature rhythm and dissociation with melatonin rhythms were also noted. Treatment with oral melatonin restored normal sleep-wake schedule. In a follow-up psychiatric evaluation, none of the above diagnoses were present. Greater awareness of sleep disorders may prevent psychiatric misdiagnosis of treatable sleep-wake schedule disorders.

A growing body of animal and human research suggests reciprocal associations between sleep and activity of the hypothalamic pituitary adrenocortical (HPA) axis. However, few studies have examined associations between sleep and stress-induced cortisol responses in children and adolescents. This pilot study examined associations among 3 sleep parameters (sleep-wake behavior problems, daytime sleepiness, sleep quantity) and cortisol responses to stress in 31 participants ages 10 to 17 (15 males, 16 females). During a "rest" session in which participants habituated to the laboratory, daytime sleepiness, sleep-wake behavior problems, and sleep quantity were assessed using a modified Sleep Habits Survey. On a separate day, participants completed a laboratory stress session involving 3 performance stressors. Salivary cortisol was collected during baseline, stress, and recovery periods. Significant associations between participant reported sleep-wake behavior problems and cortisol reactivity were found, with greater sleep-wake behavior problems associated with decreased cortisol responses. No associations emerged between sleep quantity and cortisol responses to stress; daytime sleepiness showed a trend toward an effect on cortisol reactivity. Although preliminary, results suggest there may be important influences of sleep quality but not quantity on HPA regulation and responses to daytime stressors in children and adolescents, and further study is warranted.

Recent research provides evidence for an interaction between sleep and the activation of the hypothalamic-pituitary-adrenal (HPA)-axis, but detailed studies in patients are still missing. We investigated hourly evening and nocturnal plasma cortisol secretion and sleep in seven male patients with severe chronic primary insomnia and age- and gender-matched controls. Evening and nocturnal cortisol levels were significantly increased in patients. Evening cortisol correlated with the number of nocturnal awakenings in patients and controls. Additionally, patients showed significant correlations between sleep parameters and the first 4 h of nocturnal cortisol secretion. These results are indicative of changes in the HPA system in insomnia and may reflect a pathophysiological mechanism of chronic insomnia resulting in a vicious cycle of both disturbed HPA functions and chronic insomnia according to the arousal hypothesis of insomnia.

Rapid eye movement (REM) density, a measure of the frequency of rapid eye movements during REM sleep, is known to increase over the course of the sleep episode. However, the circadian modulation of REM density has not been thoroughly evaluated. Data from a forced desynchrony protocol, in which 20 consecutive sleep opportunities were systematically scheduled over the entire circadian cycle, were analysed. The REM density was evaluated from polysomnographically recorded REM sleep episodes, and analyzed as a function of time in the sleep opportunity and as a function of phase in the circadian cycle. The REM density showed a robust increase over the course of the sleep episode. This sleep-dependent increase was observed regardless of circadian phase, because data analyzed from different thirds of the circadian cycle exhibited a similar pattern. The REM density did not show a significant circadian-dependent modulation for data from the entire sleep opportunity. However, analysis of circadian modulation from separate thirds of the sleep opportunity revealed a significant circadian modulation in the last third of the sleep episode. Maximum REM densities were observed when the last third of the sleep episode coincided with the wake-maintenance zone, i.e.;8-10 h before the crest of the circadian rhythm of REM sleep propensity. These results confirm the dominant sleep-dependent modulation of REM density, and indicate that the density of REMs is greatest when sleep pressure is low, such as in the latter part of the sleep episode, at which time the circadian modulation of REM density is also appreciable.

There is increased evidence that the dopaminergic system plays a major role in the pathophysiology of the restless legs syndrome (RLS). Dopamine is the major inhibitory factor of prolactin release and also influences growth hormone (hGH) secretion. The aim of this study was to measure the endocrine activity of RLS patients, to compare it with that of normal subjects and to detect possibly altered patterns of hormonal secretion in RLS patients. Prolactin, hGH and cortisol plasma levels were measured every 20 min for 24 hours in 10 male never-medicated RLS patients (aged 56 +/- 6 years) who have had mild to moderate symptoms for 15 +/- 10 years and in 8 age-matched male controls (aged 57 +/- 5 years). The blood samples taken during the night were paralleled by polysomnographic recordings including the assessment of periodic leg movements (PLM). Plasma levels as well as frequency and amplitude of the pulses of prolactin, hGH and cortisol were not different between RLS patients and controls. Both groups showed the same rhythms during the night- and daytime for all hormones. Cross correlations resulted in high correlation coefficients for each hormone at lag 0 (0.964,0.943 and 0.971 for mean locations of cortisol, hGH and prolactin, respectively). Concerning sleep parameters, there were no significant differences between the two groups apart from a higher PLMS arousal index in RLS patients (25.9 +/- 17.1) compared with the controls (12.0 +/- 9.2; p < 0.05). It is suggested that a possible dysfunction of the dopaminergic system in RLS does not affect the release of prolactin and hGH from the pituitary gland.

Using a 10-min blood sampling procedure, we established 24-h plasma melatonin and cortisol rhythms in 11 night workers and determined whether the extent in the shift of the melatonin onset, highly variable among night workers, was reflected in the shift of the markers of the cortisol rhythm, i.e. the quiescent period of secretion and the acrophase. In all day-active subjects, the melatonin onset occurred during low cortisol secretion, with a time lag between the start of the quiescent period and the melatonin onset of 1 h 28+or-27 min. In night workers, whatever the shift of the melatonin surge, the start of the quiescent period of cortisol secretion remained phase locked to the melatonin onset with a similar time lag (1 h 25+or-27 min). There was a significant correlation between the timing of the melatonin onset and the timing of the start of the quiescent period (r=0.88; P=0.0072). No preserved time lag was found between the melatonin onset and the other cortisol phase markers, either with the end of the quiescent period or with the acrophase. These results settle the start of the quiescent period of cortisol and the melatonin onset as two coordinate markers, and suggest that each of them are reliable to assess circadian phase in humans.

Delayed sleep phase syndrome involves undesirable late bed times and arising times with extreme difficulties in falling asleep and in awakening at a desired clock time. These patients present a delayed circadian system. Chronotherapy and phototherapy are designed to have a training effect on the circadian system. Response to these treatments varies widely and depends on the patient's motivation and associated psychological disorders. Other treatments have been proposed with less evident results. The few studies testing the effect of melatonin in delayed sleep phase syndrome concern a small number of patients and present methodological drawbacks. It can be concluded from these studies however that exogenous melatonin influences endogenous secretion more than other secretion rhythms. The effect on sleep time is significant but clinically moderate. More studies are needed to examine the effect of exogenous melatonin as a treatment strategy in delayed sleep phase syndrome.