The association between circadian syndrome and chronic kidney disease in an aging population: a 4-year follow-up study.

Introduction: Circadian syndrome (CircS) is proposed as a novel risk cluster based on reduced sleep duration, abdominal obesity, depression, hypertension, dyslipidemia and hyperglycemia. However, the association between CircS and chronic kidney disease (CKD) remains unclear. To investigate the cross-sectional and longitudinal association between CircS and CKD, this study was performed. Methods: A national prospective cohort (China Health and Retirement Longitudinal Study, CHARLS) was used in this study. To define CKD, the estimated glomerular filtration rate (eGFR) was calculated based on the 2012 CKD-EPI creatinine-cystatin C equation. Participants with eGFR <60 mL.min-1/1.73/m2 were diagnosed with CKD. Multivariate binary logistic regression was used to assess the cross-sectional association between CircS and CKD. Subgroup and interactive analyses were performed to determine the interactive effects of covariates. In the sensitivity analysis, the obese population was excluded and another method for calculating the eGFR was used to verify the robustness of previous findings. In addition, participants without CKD at baseline were followed up for four years to investigate the longitudinal relationship between CircS and CKD. Results: A total of 6355 participants were included in this study. In the full model, CircS was positively associated with CKD (OR = 1.28, 95% CI = 1.04-1.59, P < 0.05). As per one increase of CircS components, there was a 1.11-fold (95% CI = 1.04-1.18, P < 0.05) risk of prevalent CKD in the full model. A significant interactive effect of hyperuricemia in the CircS-CKD association (P for interaction < 0.01) was observed. Sensitivity analyses excluding the obese population and using the 2009 CKD-EPI creatinine equation to diagnose CKD supported the positive correlation between CircS and CKD. In the 2011-2015 follow-up cohort, the CircS group had a 2.18-fold risk of incident CKD (95% CI = 1.33-3.58, P < 0.01) in the full model. The OR was 1.29 (95% CI = 1.10-1.51, P < 0.001) with per one increase of CircS components. Conclusion: CircS is a risk factor for CKD and may serve as a predictor of CKD for early identification and intervention.

Chronic circadian disruption modulates breast cancer stemness and immune microenvironment to drive metastasis in mice.

Breast cancer is the most common type of cancer worldwide and one of the major causes of cancer death in women. Epidemiological studies have established a link between night-shift work and increased cancer risk, suggesting that circadian disruption may play a role in carcinogenesis. Here, we aim to shed light on the effect of chronic jetlag (JL) on mammary tumour development. To do this, we use a mouse model of spontaneous mammary tumourigenesis and subject it to chronic circadian disruption. We observe that circadian disruption significantly increases cancer-cell dissemination and lung metastasis. It also enhances the stemness and tumour-initiating potential of tumour cells and creates an immunosuppressive shift in the tumour microenvironment. Finally, our results suggest that the use of a CXCR2 inhibitor could correct the effect of JL on cancer-cell dissemination and metastasis. Altogether, our data provide a conceptual framework to better understand and manage the effects of chronic circadian disruption on breast cancer progression.

Hypothesis: ubiquitous circadian disruption can cause cancer.

Circadian disruption (CD) was implicated in chains of cancer causation when the International Agency for Research on Cancer classified shift-work involving circadian disruption as probably carcinogenic in 2007. In the following decade, epidemiological studies into causal concepts associated with circadian disruption were inconclusive. Unappreciated complexity with an exclusive focus on shift-work, light-at-night, sleep, and melatonin in regard to circadian disruption may be accountable. With compelling non-epidemiological evidence, we posit that ubiquitous circadian disruption causes cancer and, moreover, that this is unexplored epidemiologically. This hypothesis offers a novel explanation why numerous studies in shift-workers evince inconsistent results: If circadian disruption is a ubiquitous causal phenomenon, confining assessments to the workplace, ignoring circadian disruption at play, and potential misclassification of 'who' is 'when' and 'how much' exposed to circadian disruption may disallow detecting the existence and magnitude of cancer risks. The rationale herein provides plausible explanations for previous observations and makes falsifiable predictions.

Circadian Dysregulation: The Next Frontier in Obstructive Sleep Apnea Research.

OBJECTIVE: To review the effects of the circadian clock on homeostasis, the functional interaction between the circadian clock and hypoxia-inducible factors, and the role of circadian dysregulation in the progression of cardiopulmonary disease in obstructive sleep apnea (OSA). DATA SOURCES: The MEDLINE database was accessed through PubMed. REVIEW METHODS: A general review is presented on molecular pathways disrupted in OSA, circadian rhythms and the role of the circadian clock, hypoxia signaling, crosstalk between the circadian and hypoxia systems, the role of the circadian clock in cardiovascular disease, and implications for practice. Studies included in this State of the Art Review demonstrate the potential contribution of the circadian clock and hypoxia in animal models or human disease. CONCLUSIONS: Molecular crosstalk between the circadian clock and hypoxia-inducible factors has not been evaluated in disease models of OSA. IMPLICATIONS FOR PRACTICE: Pediatric OSA is highly prevalent and, if left untreated, may lead to cardiopulmonary sequelae. Changes in inflammatory markers that normally demonstrate circadian rhythmicity are also seen among patients with OSA. Hypoxia-inducible transcription factors interact with core circadian clock transcription factors; however, the interplay between these pathways has not been elucidated in the cardiopulmonary system. This gap in knowledge hinders our ability to identify potential biomarkers of OSA and develop alternative therapeutic strategies. A deeper understanding of the mechanisms by which OSA impinges on clock function and the impact of clock dysregulation on the cardiopulmonary system may lead to future advancements for the care of patients with OSA. The aim of this review is to shed light on this important clinical topic.

Circadian rhythm abnormalities and autonomic dysfunction in patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis.

Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) patients frequently show autonomic symptoms which may be associated with a hypothalamic dysfunction. This study aimed to explore circadian rhythm patterns in rest and activity and distal skin temperature (DST) and their association with self-reported outcome measures, in CFS/ME patients and healthy controls at two different times of year. Ten women who met both the 1994 CDC/Fukuda definition and 2003 Canadian criteria for CFS/ME were included in the study, along with ten healthy controls matched for age, sex and body mass index. Self-reported measures were used to assess fatigue, sleep quality, anxiety and depression, autonomic function and health-related quality of life. The ActTrust actigraph was used to record activity, DST and light intensity, with data intervals of one minute over seven consecutive days. Sleep variables were obtained through actigraphic analysis and from subjective sleep diary. The circadian variables and the spectral analysis of the rhythms were calculated. Linear regression analysis was used to evaluate the relationship between the rhythmic variables and clinical features. Recordings were taken in the same subjects in winter and summer. Results showed no differences in rhythm stability, sleep latency or number of awakenings between groups as measured with the actigraph. However, daily activity, the relative amplitude and the stability of the activity rhythm were lower in CFS/ME patients than in controls. DST was sensitive to environmental temperature and showed lower nocturnal values in CFS/ME patients than controls only in winter. A spectral analysis showed no differences in phase or amplitude of the 24h rhythm, but the power of the second harmonic (12h), revealed differences between groups (controls showed a post-lunch dip in activity and peak in DST, while CFS/ME patients did not) and correlated with clinical features. These findings suggest that circadian regulation and skin vasodilator responses may play a role in CFS/ME.

Western lifestyle and immunopathology of multiple sclerosis.

There is increasing evidence for a sudden and unprecedented rise in the incidence of multiple sclerosis (MS) in Westernized countries over the past decades, emphasizing the role of environmental factors. Among many candidates, rapid changes in dietary habits seem to play a role in the pathogenesis of MS. Here, we summarize and discuss the available evidence for the role of dietary nutrients, such as table salt, fatty acids, and flavonoids, in the development and pathogenesis of MS. We also discuss new and emerging risk factors accompanying Western lifestyle, such as shift work, sleep, and circadian disruption.

Food in synchrony with melatonin and corticosterone relieves constant light disturbed metabolism.

Circadian disruption is associated with metabolic disturbances such as hepatic steatosis (HS), obesity and type 2 diabetes. We hypothesized that HS, resulting from constant light (LL) exposure is due to an inconsistency between signals related to food intake and endocrine-driven suprachiasmatic nucleus (SCN) outputs. Indeed, exposing rats to LL induced locomotor, food intake and hormone arrhythmicity together with the development of HS. We investigated whether providing temporal signals such as 12-h food availability or driving a corticosterone plus melatonin rhythm could restore rhythmicity and prevent the metabolic disturbances under LL conditions in male rats. Discrete metabolic improvements under these separate treatments stimulated us to investigate whether the combination of hormone treatment together with mealtime restriction (12-h food during four weeks) could prevent the metabolic alterations. LL exposed arrhythmic rats, received daily administration of corticosterone (2.5 µg/kg) and melatonin (2.5 mg/kg) in synchrony or out of synchrony with their 12-h meal. HS and other metabolic alterations were importantly ameliorated in LL-exposed rats receiving hormonal treatment in synchrony with 12-h restricted mealtime, while treatment out of phase with meal time did not. Interestingly, liver bile acids, a major indication for HS, were only normalized when animals received hormones in synchrony with food indicating that disrupted bile acid metabolism might be an important mechanism for the HS induction under LL conditions. We conclude that food-elicited signals, as well as hormonal signals, are necessary for liver synchronization and that HS arises when there is conflict between food intake and the normal pattern of melatonin and corticosterone.

Circadian Disruption and Prostate Cancer Risk: An Updated Review of Epidemiological Evidences.

Since the publication of the International Agency for Research on Cancer Monograph in 2007 classifying night shift work leading to a disruption of circadian rhythm as probably carcinogenic to humans, there is an increasingly growing interest in understanding how circadian disruption may play a role in cancer development.This systematic review provides a comprehensive update on epidemiologic evidences on circadian disruption and prostate cancer since the last review published in 2012. We identified 12 new studies evaluating the effects of several circadian disruptors such as night shift work, sleep patterns, and circadian genes in prostate cancer risk. In contrast, no new studies have focused on exposure to light at night.Several convincing and biologically plausible hypotheses have been proposed to understand how circadian disruption may be related to cancer. However, the current difficulty of concluding on the role of circadian disruption on prostate cancer risk requires further studies including a better characterization of the different night shift systems, data on sleep patterns and chronotype, measurement of biomarkers, and investigations of polymorphisms in the genes regulating the biological clock. Cancer Epidemiol Biomarkers Prev; 26(7); 985-91. ©2017 AACR.

The Pathophysiologic Role of Disrupted Circadian and Neuroendocrine Rhythms in Breast Carcinogenesis.

Most physiological processes in the brain and body exhibit daily (circadian) rhythms coordinated by an endogenous master clock located in the suprachiasmatic nucleus of the hypothalamus that are essential for normal health and functioning. Exposure to sunlight during the day and darkness at night optimally entrains biological rhythms to promote homeostasis and human health. Unfortunately, a major consequence of the modern lifestyle is increased exposure to sun-free environments during the day and artificial lighting at night. Additionally, behavioral disruptions to circadian rhythms (ie, repeated transmeridian flights, night or rotating shift work, or sleep disturbances) have a profound influence on health and have been linked to a number of pathological conditions, including endocrine-dependent cancers. Specifically, night shift work has been identified as a significant risk factor for breast cancer in industrialized countries. Several mechanisms have been proposed by which shift work-induced circadian disruptions promote cancer. In this review, we examine the importance of the brain-body link through which circadian disruptions contribute to endocrine-dependent diseases, including breast carcinogenesis, by negatively impacting neuroendocrine and neuroimmune cells, and we consider preventive measures directed at maximizing circadian health.

Impact of night-shift work on the prevalence of erosive esophagitis in shipyard male workers.

PURPOSE: Whether night-shift work is a risk factor for gastroesophageal reflux disease is controversial. The aim of this study was to investigate the association between night-shift work and other factors, and erosive esophagitis. METHODS: A cross-sectional study with 6040 male shipyard workers was performed. Esophagogastroduodenoscopic examination and a survey about night-shift work status, lifestyle, medical history, educational status, and marital status were conducted in all workers. The odds ratios of erosive esophagitis according to night-shift work status were calculated by using the logistic regression model. RESULTS: The prevalence of erosive esophagitis increased in the night-shift workers [odds ratio, 95 % confidence interval: 1.41 (1.03-1.94)]. According to multiple logistic regression models, night-shift work, obesity, smoking, and alcohol consumption of ≥140 g/week were significant risk factors for erosive esophagitis. By contrast, Helicobacter pylori infection was negatively associated with erosive esophagitis. CONCLUSION: Night-shift work is suggested to be a risk factor for erosive esophagitis. Avoidance of night-shift work and lifestyle modification should be considered for prevention and management of gastroesophageal reflux disease.

[Reproductive health disorders in night shift workers (review of literature)].

The review considers problems of reproductive health disorders in night shift workers. In materials of national and foreign authors, ambiguous opinions are presented on the influence, such as on reproductive sphere malignancies development in shift workers. Data of experimental and clnical laboratory studies are presented, that support reproductive pathologies connected with night shift work. The authors tackle a problem on role of epiphysis and circadian rhythms, that influence physiologic biologic rhythms.

Breast cancer incidence in a cohort of U.S. flight attendants.

BACKGROUND: Flight attendants may have elevated breast cancer incidence (BCI). We evaluated BCI's association with cosmic radiation dose and circadian rhythm disruption among 6,093 female former U.S. flight attendants. METHODS: We collected questionnaire data on BCI and risk factors for breast cancer from 2002-2005. We conducted analyses to evaluate (i) BCI in the cohort compared to the U.S. population; and (ii) exposure-response relations. We applied an indirect adjustment to estimate whether parity and age at first birth (AFB) differences between the cohort and U.S. population could explain BCI that differed from expectation. RESULTS: BCI was elevated but may be explained by lower parity and older AFB in the cohort than among U.S. women. BCI was not associated with exposure metrics in the cohort overall. Significant positive associations with both were observed only among women with parity of three or more. CONCLUSIONS: Future cohort analyses may be informative on the role of these occupational exposures and non-occupational risk factors.

[Have female flight attendants an over-risk of breast cancer?]. / Les hôtesses de l'air sont-elles à risque accru de cancer du sein ?

OBJECTIVE: The aim of this revue was to estimate the level of breast cancer risk among female flight attendants. MATERIAL AND METHODS: The selected articles were taken from the PUBMED database, between January 1st 1995 and December 31st 2013 by the means of the following keywords: "breast cancer", "flight attendants", "airline cabin crew" and "flight personnel". Seventeen articles were finally selected. RESULTS: The incidence of breast cancer is significantly higher among female flights attendants [standardized incidence ratio (SIR) 1.04-5.24, 95% CI 1.00-17.38]. However, no studies have demonstrated a significant increase of mortality by breast cancer [standardized mortality ratio (SMR) 1.0-1.28, 95% CI 0.54-3.7]. The circadian rhythm disruption through night work and time zones leading to disorder of melatonin secretion just as exposure to cosmic radiation could account for this increase of risk. DISCUSSION AND CONCLUSION: A medical supervision concerning breast cancer for flight attendants is recommended. Additional studies seem to be necessary in order to estimate the additional role of other risk factors, in particular hormonal factor.

Circadian misalignment and health.

Circadian rhythms are near 24-h patterns of physiology and behaviour that are present independent of external cues including hormones, body temperature, mood, and sleep propensity. The term 'circadian misalignment' describes a variety of circumstances, such as inappropriately timed sleep and wake, misalignment of sleep/wake with feeding rhythms, or misaligned central and peripheral rhythms. The predominance of early research focused on misalignment of sleep to the biological night. However, discovery of clock genes and the presence of peripheral circadian oscillators have expanded the definitions of misalignment. Experimental studies conducted in animal models and humans have provided evidence of potential mechanisms that link misalignment to negative outcomes. These include dysregulation of feeding behaviours, changes in appetite stimulating hormones, glucose metabolism and mood. This review has two foci: (1) to describe how circadian misalignment has been defined and evaluated in laboratory and field experiments, and (2) to describe evidence linking different types of circadian misalignment to increased risk for physical (cardiovascular disease, diabetes, obesity, cancer) and psychiatric (depression, bipolar, schizophrenia, attention deficit) disorders. This review will describe the role of circadian misalignment as a risk factor for disease in the general population and in clinical populations, including circadian rhythm sleep disorders and psychiatric disorders.

Metabolic syndrome, insulin resistance, circadian disruption, antioxidants and pancreatic carcinoma: an overview.

The incidence and number of deaths caused by pancreatic tumours have been gradually rising, while the incidence and mortality of other common cancers have been declining. Risk factors for this malignant disease include cigarette smoking, family history of chronic pancreatitis, advancing age, male sex, diabetes mellitus, obesity, non-0 blood group, a high-fat diet, alcohol consumption and possibly Helicobacter pylori and hepatitis B virus infections. Metabolic diseases have become the leading cause of death in many countries. Our paper serves as a focused and updated discussion about the development of novel preventive strategies for this deadly disease.

[Shift work and risk of cancer and coronary heart diseases]. / Skifteholdsarbejde og risiko for kræftog hjerte-kar-sygdom.

Shift and night work are among the most frequent occupational exposures. Such work schedules involve exposure to light-at-night, which may reduce normal nocturnal melatonin production, create circadian rhythm disruption, sleep deprivation and unhealthy lifestyle. There is strong experimental evidence that light-at-night and circadian disruption may increase the risk of cancer and coronary heart diseases. There is emerging, but limited epidemiologic evidence that night shift work may increase breast cancer and certain cardiovascular diseases.

Chronodisruption increases cardiovascular risk in zebrafish via reduced clearance of senescent erythrocytes.

The circadian clock and the hypoxic signaling pathway play critical roles in physiological homeostasis as well as in pathogenesis. The bi-directionality of the interaction between both pathways has been shown on physiological and only recently also on molecular level. But the consequences of a disturbed circadian rhythm for the hypoxic response and the cardiovascular system have never been addressed in any organism. Here we show that the hypoxic response of animals subjected to chronodisruption is reduced by approximately 30%, as reflected by decreased expression levels of hypoxia inducible factor 1 and its down-stream target genes erythropoietin, responsible for the generation of red blood cells (RBC) and vascular endothelial growth factor, which is essential for proper vascularization. Beside malformations of their vascular beds, chronodisrupted animals surprisingly revealed elevated numbers of senescent erythrocytes under normoxic conditions, due to a reduced clearance rate via apoptosis. Over-aged erythrocytes in turn are characterized by decreased oxygen transport capacities and an increased tendency for aggregation, explaining the higher mortality of chronodisrupted animals observed in our study. The present study shows for the first time that chronodisruption strongly interferes with the hypoxic signalling cascade, increasing the cardiovascular risk in zebrafish due to elevated proportions of senescent erythrocytes. The results might shed new light on the etiology of the increased cardiovascular risk observed among shiftworkers.

Association of sleep and fatigue with decision regret among critical care nurses.

BACKGROUND: The effects of inadequate sleep on clinical decisions may be important for patients in critical care units, who are often more vulnerable than patients in other units. Fatigued nurses are more likely than well-rested nurses to make faulty decisions that lead to decision regret, a negative cognitive emotion that occurs when the actual outcome differs from the desired or expected outcome. OBJECTIVES: To examine the association between selected sleep variables, impairment due to fatigue, and clinical-decision self-efficacy and regret among critical care nurses. Decision regret was the primary outcome variable. Methods A nonexperimental, descriptive design and extant measures were used to obtain data from a random sample of full-time nurses. Binary logistic regression models were used to examine the association between sleep variables, fatigue, and clinical-decision self-efficacy and regret. The discrimination of the models was compared with the C statistic, the area under the receiver operating characteristic curve. RESULTS: A total of 605 nurses returned the questionnaires (17% response rate). Among these, decision regret was reported by 157 of 546 (29%). Nurses with decision regret reported more fatigue, more daytime sleepiness, less intershift recovery, and worse sleep quality than did nurses without decision regret. Being male, working a 12-hour shift, and clinical-decision satisfaction were significantly associated with decision regret (C statistic, 0.719; SE, 0.024). CONCLUSION: Nurses who experience impairments due to fatigue, loss of sleep, and inability to recover between shifts are more likely than unimpaired nurses to report decision regret.

The trouble with circadian clock dysfunction: multiple deleterious effects on the brain and body.

This review consolidates research employing human correlational and experimental work across brain and body with experimental animal models to provide a more complete representation of how circadian rhythms influence almost all aspects of life. In doing so, we will cover the morphological and biochemical pathways responsible for rhythm generation as well as interactions between these systems and others (e.g., stress, feeding, reproduction). The effects of circadian disruption on the health of humans, including time of day effects, cognitive sequelae, dementia, Alzheimer's disease, diet, obesity, food preferences, mood disorders, and cancer will also be discussed. Subsequently, experimental support for these largely correlational human studies conducted in non-human animal models will be described.

Absence of central circadian pacemaker abnormalities in humans with loss of function mutation in prokineticin 2.

CONTEXT: Loss of prokineticin 2 (PROK2) signaling in mice disrupts circadian rhythms, but the role of PROK2 signaling in the regulation of circadian rhythms in humans is undetermined. OBJECTIVE: The aim of the study was to examine the circadian rhythms of humans with a complete loss-of-function PROK2 mutation using an inpatient constant routine (CR) protocol. DESIGN AND SETTING: We conducted a case study in an academic medical center. SUBJECTS AND METHODS: Two siblings (one male and one female, ages 67 and 62 y, respectively) with isolated GnRH deficiency (IGD) due to a biallelic loss-of-function PROK2 mutation were studied using an inpatient CR protocol. Historical data from inpatient CR protocols conducted in healthy controls (ages 65-81 y) were used for comparison. MAIN OUTCOME MEASURES: We measured circadian phase markers (melatonin, cortisol, and core body temperature) and neurobehavioral performance (psychomotor vigilance task [PVT] and subjective alertness scale). RESULTS: Circadian waveforms of melatonin and cortisol did not differ between the IGD participants with PROK2 mutation and controls. In both IGD participants, neurobehavioral testing with PVT showed disproportionate worsening of PVT lapses and median reaction time in the second half of the CR. CONCLUSIONS: Humans with loss of PROK2 signaling lack abnormalities in circadian phase markers, indicating intact central circadian pacemaker activity in these patients. These results suggest that PROK2 signaling in humans is not required for central circadian pacemaker function. However, impaired PVT in the PROK2-null participants despite preserved endocrine rhythms suggests that PROK2 may transmit circadian timing information to some neurobehavioral neural networks.