Association between circadian rhythm disruption and polycystic ovary syndrome.

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.

Exposure to Radiation During Work Shifts and Working at Night Act as Occupational Stressors Alter Redox and Inflammatory Markers.

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.

Inadequate sleep as a contributor to impaired glucose tolerance: A cross-sectional study in children, adolescents, and young adults with circadian rhythm sleep-wake disorder.

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.

Impact of circadian rhythms on female reproduction and infertility treatment success.

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.

Plasma sCD36 as non-circadian marker of chronic circadian disturbance in shift workers.

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.

Rapid suppression of bone formation marker in response to sleep restriction and circadian disruption in men.

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 (ß) 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.

Night workers with circadian misalignment are susceptible to alcohol-induced intestinal hyperpermeability with social drinking.

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.

Shift Work, Chronotype, and Melatonin Patterns among Female Hospital Employees on Day and Night Shifts.

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.

Circadian misalignment increases cardiovascular disease risk factors in humans.

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.

No stress after 24-hour on-call shifts?

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.

Shift rotation and age - interactions with sleep-wakefulness and inflammation.

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.

Health impact of fasting in Saudi Arabia during Ramadan: association with disturbed circadian rhythm and metabolic and sleeping patterns.

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.

Why the dim light melatonin onset (DLMO) should be measured before treatment of patients with circadian rhythm sleep disorders.

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.

Short sleep duration and large variability in sleep duration are independently associated with dietary risk factors for obesity in Danish school children.

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 (ß = -0.32 kJ g(-1)), added sugar (ß = -1.50 E%) and SSBs (ß = -1.07 E%) (all P ≤ 0.003). Furthermore, variability in sleep duration (10-min per night) was positively associated with SSBs (ß = 0.20 E%, P = 0.03), independent of sleep duration, and CSHQ score was positively associated with ED (ß = 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.

Long-term day-and-night rotating shift work poses a barrier to the normalization of alanine transaminase.

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.

Dietary patterns, metabolic markers and subjective sleep measures in resident physicians.

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.

Intrinsic circadian period of sighted patients with circadian rhythm sleep disorder, free-running type.

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.

Appetite-regulating hormones from the upper gut: disrupted control of xenin and ghrelin in night workers.

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.

Melatonin profile and its relation to circadian rhythm sleep disorders in Angelman syndrome patients.

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.

The antidepressant agomelatine in daily practice: results of the non-interventional study VIVALDI.

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.