Circadian Dysregulation Research Articles

More than sleep and wake disturbances: An actigraphic study showing the sleep-wake pattern dysregulation in epilepsy

ObjectiveThis study aimed to assess the sleep-wake pattern in patients with epilepsy compared to controls. MethodsPatients with epilepsy and controls underwent a 14-day actigraphic recording to evaluate the rest-activity cycle. A sleep medicine interview was performed to exclude conditions interfering with the sleep-wake cycle in both patients and controls. Patients presenting seizures during the actigraphic recording were excluded. Daytime activity, nocturnal sleep, and non-parametric circadian rhythm activity (NPCRA) were analysed. ResultsTwenty-two patients (mean age 49.5 ± 19.84 years; 50% female) and 17 controls were included. Patients showed lower sleep efficiency and longer sleep latency than controls. NPCRA analysis showed lower inter-daily stability and higher intra-daily variability in patients, who also presented lower daytime activity and a longer central phase measure (CPM) than controls. ConclusionsPatients showed a significant alteration of the sleep-wake pattern, featured by lower synchronization and higher fragmentation of the rest-activity rhythm. Moreover, patients showed a delayed CPM compared with controls, corresponding to an evening chronotype tendency. Nocturnal sleep alteration and lower daytime activity were also evident. Therefore, patients with epilepsy present an alteration of the sleep-wake pattern and clinicians should increase their awareness about circadian rhythmicity dysregulation in epilepsy.

A Computational Analysis in a Cohort of Parkinson's Disease Patients and Clock-Modified Colorectal Cancer Cells Reveals Common Expression Alterations in Clock-Regulated Genes.

Simple SummaryCancer and neurodegenerative diseases are two aging-related pathologies with differential developmental characteristics, but they share altered cellular pathways. Interestingly, dysregulations in the biological clock are reported in both diseases, though the extent and potential consequences of such disruption have not been fully elucidated. In this study, we aimed at characterizing global changes on common cellular pathways associated with Parkinson’s disease (PD) and colorectal cancer (CRC). We used gene expression data retrieved from an idiopathic PD (IPD) patient cohort and from CRC cells with unmodified versus genetically altered clocks. Our results highlight common differentially expressed genes between IPD patients and cells with disrupted clocks, suggesting a role for the circadian clock in the regulation of pathways altered in both pathologies. Interestingly, several of these genes are related to cancer hallmarks and may have an impact on the overall survival of colon cancer patients, as suggested by our analysis.Increasing evidence suggests a role for circadian dysregulation in prompting disease-related phenotypes in mammals. Cancer and neurodegenerative disorders are two aging related diseases reported to be associated with circadian disruption. In this study, we investigated a possible effect of circadian disruption in Parkinson’s disease (PD) and colorectal cancer (CRC). We used high-throughput data sets retrieved from whole blood of idiopathic PD (IPD) patients and time course data sets derived from an in vitro model of CRC including the wildtype and three core-clock knockout (KO) cell lines. Several gene expression alterations in IPD patients resembled the expression profiles in the core-clock KO cells. These include expression changes in DBP, GBA, TEF, SNCA, SERPINA1 and TGFB1. Notably, our results pointed to alterations in the core-clock network in IPD patients when compared to healthy controls and revealed variations in the expression profile of PD-associated genes (e.g., HRAS and GBA) upon disruption of the core-clock genes. Our study characterizes changes at the transcriptomic level following circadian clock disruption on common cellular pathways associated with cancer and neurodegeneration (e.g., immune system, energy metabolism and RNA processing), and it points to a significant influence on the overall survival of colon cancer patients for several genes resulting from our analysis (e.g., TUBB6, PAK6, SLC11A1).

Распространенность нарушений сна среди студентов-медиков

Sleep disturbance is a common health problem that can influence the quality of life. There are several types of sleep disorders, such as obstructive sleep apnea, insomnia, narcolepsy, periodic limb movement disorder, and circadian dysregulation. Medical students are probably more prone to sleep disturbances due to their extreme academic stress. In this research, the incidence of sleep disturbance among medical students was examined, and the concomitant risk factors were determined. That was one-time research. A questioning was used to collect social, demographic and sleeping data. 678 1st, 2nd and 3rd year medical students were surveyed. 29% complained of at least one sleep disturbance. The most widely spread sleep disturbance observed among 51.8% medical students included insomnia (initial insomnia and sleep maintenance). 4th year students and those who spend much time on smartphones were more prone to sleep disturbances. Sleep disturbances are common among medical students. They need to be discovered and paid attention to before the situation gets worse.

Sox2 Ablation in the Suprachiasmatic Nucleus Perturbs Anxiety- and Depressive-like Behaviors.

Mood disorders negatively impact the lives of hundreds of millions of individuals worldwide every year, yet the precise molecular mechanisms by which they manifest remain elusive. Circadian dysregulation is one avenue by which mood disorders are thought to arise. SOX2 is a transcription factor that is highly expressed in the murine suprachiasmatic nucleus (SCN), the circadian master clock, and has been recently found to be an important regulator of Per2, a core component of the molecular clock. Genetic ablation of the Sox2 gene in GABAergic neurons selectively impacts SCN neurons, as they are one of very few, if not the only, GABAergic populations that express Sox2. Here, we show that GABAergic-restricted ablation of Sox2 results in anxio-depressive-like phenotypes in mice as observed in the elevated plus maze, forced swim test, tail suspension test, and sucrose preference test. We further observe a reduction in basal and/or forced swim-induced c-Fos expression, a marker of neuronal activation, in the nucleus incertus, arcuate nucleus, and dentate gyrus of Sox2 conditional knockout (cKO) mice. Given the restricted disruption of SOX2 expression in the SCN of Sox2 cKO mice, we propose that their mood-associated phenotypes are the consequence of a dysregulated central clock that is unable to communicate appropriately timed signals to other brain nuclei that regulate affective behaviors.

Circadian Factors Impact Survival From Brain Metastases for Patients Treated With Whole Brain Radiation

There are established links between circadian clock dysregulation, and cancer risk. Numerous reports of increased risk for breast cancer in night shift workers led the World Health Organization to classify circadian disruption as a probable carcinogen. Additionally, the circadian clock has been known to influence the body's response to medications and most recently, a handful of studies demonstrate a link between radiation toxicity and time of day the patient received radiation. Prior studies investigating the temporal association of radiotherapy outcomes have yielded overall conflicting data and contemporary evaluations of this effect are sparse. To determine if chronotherapy should be considered to modulate radiation outcomes, we sought to evaluate if the time of day when radiation treatment was delivered affected outcomes for patients with brain metastases.Retrospective data was collected for all consecutive patients between 2010 and 2020 with a diagnosis of brain metastases who were treated with whole brain radiotherapy. Patients were eligible to be included if ≥80% of their total dose was delivered either before or after 12:00 noon as documented by treatment times in the electronic medical record and if outcome data was available. Data on sex, age, performance status, control of primary disease, extracranial metastases, radiation dose, race, BMI, and zip code were collected. Radiation was delivered as whole-brain radiation to a median dose of 3000 cGY. Analysis of survival was performed using Mantel-Haenszel hazard ratio and log-rank test to compare Kaplan-Meier curves between groups.Complete data were available for 84 patients. The majority of patients had a primary diagnosis of breast or lung cancer (93%) and a small minority had a melanoma, thyroid, or unknown primary. 43 (51%) patients were excluded who did not receive ≥80% of their cumulative radiation either before or after noon, leaving n = 41 patients included for analysis. Demographic data were comparable between groups and overall: 56% female, 44% male; 56% ≥65 years, 44% younger. Distributions for BMI, extracranial metastasis, control of primary disease, and performance status were also similar between groups. Results showed a strong trend toward improved survival in the group that received ≥80% treatment in the afternoon (P = 0.057, HR 0.28-1.02).Treatment time of day impacted survival from brain metastases in our patient population treated with whole brain radiation. Potential explanations for these results include the influence of multiple circadian pathways on tissue and tumor sensitivity through melatonin signaling and other mechanisms, warranting further exploration. Future investigations into entraining circadian rhythms via time of day treatments, light therapy or pharmaceutical interventions to alter radiation outcomes and toxicity should be considered.

Dietary Pterostilbene and Resveratrol Modulate the Gut Microbiota Influenced by Circadian Rhythm Dysregulation.

A causal relationship between circadian misalignment and microbiota dysbiosis has been discussed recently, due to their association to pathogenesis. Herein, the possible impact of pterostilbene (PSB) and resveratrol (RES) on the gut microbiota brought by chronic jet-lag in mice is investigated. Dietary supplement of RES and PSB (0.25%) are given to 16 week-jetlagged mice to examine the effects on microbiota and physiological functions. Jetlag significantly induces weight gained that could be effectively prevented by PSB. Both supplements also retain oscillation patterns that found to be lost in jetlag induced (JLG) group, including serum biochemical parameters and gut microbiota. The results of beta diversity suggest the supplementations efficiently lead to distinct gut microbial composition as compared to JLG group. Besides, the supplementation forestalls some microbial elevation, such as Eubacterium ventriosum and Acetitomaculum. Growth of health beneficial bacteria like Blautia and Lachnospiraceae UCG-001 is facilitated and abundance of these bacteria could be correlated to oscillation of biochemical parameters. Result of KEGG indicates distinct effect brought by microbial re-shaping. The result suggests that supplementation of RES and PSB could potentially dampen some adverse effects of gut microbiota dysbiosis, and at the same time, re-composite and facilitate the growth of health beneficial microbiota.

Advances in Unhealthy Nutrition and Circadian Dysregulation in Pathophysiology of NAFLD.

Unhealthy diets and lifestyle result in various metabolic conditions including metabolic syndrome and non-alcoholic fatty liver disease (NAFLD). Much evidence indicates that disruption of circadian rhythms contributes to the development and progression of excessive hepatic fat deposition and inflammation, as well as liver fibrosis, a key characteristic of non-steatohepatitis (NASH) or the advanced form of NAFLD. In this review, we emphasize the importance of nutrition as a critical factor in the regulation of circadian clock in the liver. We also focus on the roles of the rhythms of nutrient intake and the composition of diets in the regulation of circadian clocks in the context of controlling hepatic glucose and fat metabolism. We then summarize the effects of unhealthy nutrition and circadian dysregulation on the development of hepatic steatosis and inflammation. A better understanding of how the interplay among nutrition, circadian rhythms, and dysregulated metabolism result in hepatic steatosis and inflammation can help develop improved preventive and/or therapeutic strategies for managing NAFLD.

The vascular clock: a new insight into endothelial cells and pericytes crosstalk

Abstract Background/Introduction Circadian rhythms, defined as biological oscillations with a period of circa 24h, regulate many physiological processes in the cardiovascular system, such as vascular function, vascular tone, blood pressure, heart rate and thrombus formation [1]. The vasculature responds to the main pacemaker located in the brain, but it also possesses its own clock. Indeed, a molecular clock has been identified in endothelial cells (EC) and smooth muscle cells (SMC). The disruption of the circadian clock profoundly affects cardiovascular functionality with adverse cardiovascular events such as myocardial infarction or stroke showing a 24h rhythmicity with a peak incidence in the early morning. Among several mechanisms affected by circadian dysregulation, angiogenesis plays a fundamental role in homeostasis and development of new blood vessels. EC and pericytes (PC) are the two main cell populations in the capillaries, and their physical and paracrine interaction drives and regulates the sprouting. However, the presence and the role of circadian rhythms in pericytes and whether the molecular clock affects the endothelial/pericyte interactions remain unexplored. Purpose The aim of this study is to identify a molecular clock in human vascular pericytes and elucidate the impact of the circadian clock on the formation of new blood vessels. Methods Human primary PC were synchronised and the rhythmicity of clock genes measured by luminescence, immunofluorescence, and qPCR. Synchronised PC were co-cultured with Bmal1::LUC human primary EC. The effect of PC synchronisation and circadian clock disruption by shRNA on EC clock genes and angiogenic potential were measured by luminescence and Matrigel assay, respectively. A macroporous polyurethane scaffold was developed for 3D co-cultures. Results PC presented rhythmic expression of the principal circadian genes with a circa 24h period but in our experimental setting, EC did not show circadian rhythmicity. Synchronised PC supported the rhythmic expression of the clock gene Bmal1 in EC in a contact co-culture system, suggesting a secondary form of EC molecular clock regulation. Non-contact co-cultures failed to synchronise EC. Furthermore, when the clock was disrupted in PC, their capacity to support EC's tube-forming capacity on Matrigel was impaired; clock disruption in EC did not affect angiogenesis, supporting the hypothesis that a disrupted clock in perivascular cells affects angiogenesis. In a 3D tissue engineering scaffold seeded with both EC and PC, the synchronisation of the clock led to the development of organised vascular-like structures around the scaffold's pores, as compared to the non-synchronised condition where cells appeared disorganised. Conclusion This study defines for the first time the existence of an endogenous molecular circadian clock in perivascular cells and suggests implications for circadian clock synchronisation in physiological and therapeutic angiogenesis. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): University of Surrey Doctoral CollegeUniversity of Surrey Bioprocess and Biochemical Engineering (BioProChem) Group.

Circadian Rhythm, Energy Metabolism, and the Gut Microbiome: a Review

This review discussed the interrelationship between the circadian rhythm of the host and of the intestinal microbiome and the implications of this new field on energy metabolism, specifically implications relating to obesity. Circadian rhythm, or the 24-hour system that bodies use to expect and to increase receptivity to certain factors in the environment, is present in almost every organ and system. However, the data that this review utilized relates mainly to the intestinal microbiome: a group of bacteria, yeasts, and viruses that inhabit the colon, with this review’s focus placed on bacteria. This interrelationship is mainly discussed through possible effects of circadian disruption and through an analysis of different methods by which the circadian rhythm of the host and the rhythm of the microbiome interact. TRF, or time-restricted feeding, has been identified as one of the potential methods to reduce the negative consequences of circadian dysregulation on metabolic processes, and various related studies were discussed in-depth. Data from four databases were analyzed to produce a variety of both experimental and review papers. All papers that related to the topic under review were thoroughly analyzed and incorporated into the review.

Circadian Rhythm, Clock Genes, and Hypertension: Recent Advances in Hypertension.

Accumulating evidence suggests that the molecular circadian clock is crucial in blood pressure (BP) control. Circadian rhythms are controlled by the central clock, which resides in the suprachiasmatic nucleus of the hypothalamus and peripheral clocks throughout the body. Both light and food cues entrain these clocks but whether these cues are important for the circadian rhythm of BP is a growing area of interest. The peripheral clocks in the smooth muscle, perivascular adipose tissue, liver, adrenal gland, and kidney have been recently implicated in the regulation of BP rhythm. Dysregulation of the circadian rhythm of BP is associated with adverse cardiorenal outcomes and increased risk of cardiovascular mortality. In this review, we summarize the most recent advances in peripheral clocks as BP regulators, highlight the adverse outcomes of disrupted circadian BP rhythm in hypertension, and provide insight into potential future work in areas exploring the circadian clock in BP control and chronotherapy. A better understanding of peripheral clock function in regulating the circadian rhythm of BP will help pave the way for targeted therapeutics in the treatment of circadian BP dysregulation and hypertension.

Endogenous melatonin levels and therapeutic use of exogenous melatonin in tension type headache: A systematic review.

A bidirectional relationship appears to connect tension-type headache (TTH) and circadian dysregulation. The present systematic review examined the published evidence for melatonin (MT) supplementation in the prophylaxis of TTH. Initially, we reviewed case-control studies investigating nocturnal MT or 6-sulphatoxymelatonin (aMT6s, a urine-discarded metabolite) in TTH individuals and healthy controls (HC). Secondly, we reviewed studies appraising the use of MT in the prevention of TTH. The search strategy involved MEDLINE EMBASE, CENTRAL, PsycINFO, trial registries, Google Scholar and OpenGrey. Case-control studies were appraised according to the Newcastle-Ottawa-Scale, whereas randomised controlled trials were assessed based on the risk-of-bias Cochrane tool. Infrequent, as well as frequent, episodic, and chronic TTH patients were evaluated separately in children and adults. Our search strategy yielded two case-control studies. One (high-quality) did not reveal any difference in morning salivary MT concentration between children with frequent episodic TTH and HC. The second (moderate-quality) was indicative of a disturbed nocturnal secretion pattern in adults with chronic TTH. For the second part, five uncontrolled studies were retrieved. In total, 94 adults with chronic TTH were assessed and results were suggestive of a beneficial effect of MT on headache frequency, intensity, induced disability, and induced analgesic consumption. However, the uncontrolled-unblinded designs may have induced an important placebo effect. Non-adult populations and frequent TTH were substantially understudied. There are not enough studies to designate the role of MT in the prevention of TTH. Given the disease's background, additional relevant research is warranted for chronic TTH.

A METHOD FOR OBJECTIVE ASSESSMENT OF REST ACTIVITY PATTERNS AND LIGHT LEVELS IN THE ICU

TOPIC: Critical Care TYPE: Original Investigations PURPOSE: Patients in the intensive care unit (ICU), experience disturbed sleep due to environmental factors, as well as critical illness itself. Insufficient and fragmented sleep is linked to increased morbidity, mortality, and ICU length of stay. Despite these correlations, objectively measured sleep and circadian patterns are not routinely examined in ICU patients, and assessment methods are not standardized. In this study, we devised a method to use wrist actigraphy to examine rest-activity patterns and light in a medical ICU. METHODS: As part of an ongoing randomized placebo-controlled trial testing the effect of a sleep medication in preventing ICU delirium, we enrolled patients admitted to the medical ICU at Rhode Island Hospital. Patients were monitored with continuous actigraphy while they were in the ICU. We estimated sleep and wake durations using algorithms validated with polysomnography as well as maximum and average light levels. We summarized data for 2 defined periods across 24-hours based on timing of the investigational sleep aid and ICU routines in our hospital. “Subjective night” was defined from the time of study drug administration to 5:59 AM, and “subjective day” was defined from 6:00 AM to the next study drug treatment time. We used Wilcoxon Signed Ranks Tests to compare sleep and light measured between subjective night and day. RESULTS: Fifty-eight patients are included in these analyses, 45% of which are women. The mean age was 61 years, and the mean APACHE II score was 21. The mean actigraphy-recording days was 4.3. Median duration of subjective night was 513 minutes (IQR=472-526), and of subjective day was 708 minutes, (IQR=537-793; Z=-5.922, p<.0001). Patients spent a higher percentage of the subjective night asleep compared to subjective day (53.7% (IQR=32.8-72.4) vs. 32.9% (IQR=15.4-50.0), Z=-5.767, p<.0001), but estimated sleep duration did not differ between subjective night and day (median 280 minutes (IQR=175-362) vs. 216 minutes (IQR=82-342), Z=-0.664, p=.519). Mean and maximum illuminance were significantly lower during subjective night than day (median average lux 7.3 (IQR=3.0-14.0) vs. 53.8 (IQR=28.2-87.6), Z=-5.692, p<.0001; median maximum lux 116.8 (IQR=53.5-254.2) vs. 445.0 (311.8-643.4), Z=-4.854, p<.0001). CONCLUSIONS: In our study, estimated sleep percentages were higher during subjective night than day, but patients obtained similar amounts of sleep during the subjective day and night, indicating poor sleep consolidation. While patients experienced low light levels during the night, they also experienced low daytime light levels, potentially contributing to higher risk of circadian dysregulation and nighttime sleep disturbance. CLINICAL IMPLICATIONS: Our results provide evidence of disrupted rest-activity patterns in critically ill patients and of low daytime light levels in the ICU, highlighting the need for continued investigation into interventions to improve sleep quality in the ICU. DISCLOSURES: No relevant relationships by David Baek, source=Web Response No relevant relationships by Debasree Banerjee, source=Web Response No relevant relationships by Shi-Yo Chen, source=Web Response No relevant relationships by Jisoo Lee, source=Web Response No relevant relationships by Mitchell Levy, source=Web Response No relevant relationships by Amy Mathew, source=Web Responseauthor royalties relationship with UpToDate Please note: 2016-present Added 04/29/2021 by Katherine Sharkey, source=Web Response, value=Royalty

Circadian Rhythm Dysregulation and Restoration: The Role of Melatonin.

Sleep is an essential component of overall human health but is so tightly regulated that when disrupted can cause or worsen certain ailments. An important part of this process is the presence of the well-known hormone, melatonin. This compound assists in the governing of sleep and circadian rhythms. Previous studies have postulated that dysregulation of melatonin rhythms is the driving force behind sleep and circadian disorders. A computer-aided search spanning the years of 2015–2020 using the search terms melatonin, circadian rhythm, disorder yielded 52 full text articles that were analyzed. We explored the mechanisms behind melatonin dysregulation and how it affects various disorders. Additionally, we examined associated therapeutic treatments including bright light therapy (BLT) and exogenous forms of melatonin. We found that over the past 5 years, melatonin has not been widely investigated in clinical studies thus there remains large gaps in its potential utilization as a therapy.

In utero Exposure to Valproic-Acid Alters Circadian Organisation and Clock-Gene Expression: Implications for Autism Spectrum Disorders.

Autism Spectrum Disorder (ASD) is a pervasive neurodevelopmental disorder characterised by restrictive patterns of behaviour and alterations in social interaction and communication. Up to 80% of children with ASD exhibit sleep-wake cycle disturbances, emphasising the pressing need for novel approaches in the treatment of ASD-associated comorbidities. While sleep disturbances have been identified in ASD individuals, little has been done to assess the contribution of the circadian system to these findings. The objective of this study is to characterise circadian behaviour and clock-gene expression in a valproic acid (VPA)-induced animal model of autism to highlight perturbations potentially contributing to these disturbances. Male and female VPA-exposed offspring underwent circadian challenges, including baseline light-dark cycles, constant dark/light and light pulse protocols. Baseline analysis showed that VPA-exposed males, but not females, had a greater distribution of wheel-running behaviour across light-dark phases and a later activity offset (p < 0.0001), while controls showed greater activity confinement to the dark phase (p = 0.0256). Constant light analysis indicated an attenuated masking response and an increase in the number of days to reach arrhythmicity (p < 0.0001). A 1-h light pulse (150 lux) at CT 15 after 6 days of constant dark showed that both sexes exposed to VPA exhibited a lesser phase-shift when compared to controls (p = 0.0043). Immunohistochemical and western-blot assays reveal no alterations in retinal organisation or function. However, immunohistochemical assay of the SCN revealed altered expression of BMAL1 expression in VPA-exposed males (p = 0.0016), and in females (p = 0.0053). These findings suggest alterations within the core clockwork of the SCN and reduced photic-entrainment capacity, independent of retinal dysfunction. The results of this study shed light on the nature of circadian dysregulation in VPA-exposed animals and highlights the urgent need for novel perspectives in the treatment of ASD-associated comorbidities.

Women's health and night shift work: Potential targets for future strategies in breast cancer (Review).

Breast cancer is the leading cause of cancer-associated amongst women worldwide. Several studies have shown that individual, environmental and occupational factors can serve an important role in the onset of breast cancer; although the majority of studies have demonstrated this association, and several studies have investigated the biological pathways, it is impossible to describe with certainty the causal relationship that involve circadian rhythm disruption and melatonin dysregulation with the oncogenic processes. Over the years, due to the introduction of more effective screening tools, an increase in the incidence of breast cancer as well as a decrease in the age at diagnosis has been witnessed. Subsequently, an increasing number of individuals have obtained care at a younger age, which has meant that after surgery and chemotherapy, these workers have had to return to work. In light of these paradigmatic changes, the aim of the present review was to identify potential targets for future organisational strategies that should be adopted in the workplace by occupational physicians, both for prevention and for the return-to-work process of working women who have suffered from breast cancer.

Energy Balance and Control of Body Weight: Possible Effects of Meal Timing and Circadian Rhythm Dysregulation.

Conservation of the energy equilibrium can be considered a dynamic process and variations of one component (energy intake or energy expenditure) cause biological and/or behavioral compensatory changes in the other part of the system. The interplay between energy demand and caloric intake appears designed to guarantee an adequate food supply in variable life contexts. The circadian rhythm plays a major role in systemic homeostasis by acting as “timekeeper” of the human body, under the control of central and peripheral clocks that regulate many physiological functions such as sleep, hunger and body temperature. Clock-associated biological processes anticipate the daily demands imposed by the environment, being synchronized under ideal physiologic conditions. Factors that interfere with the expected demand, including daily distribution of macronutrients, physical activity and light exposure, may disrupt the physiologic harmony between predicted and actual behavior. Such a desynchronization may favor the development of a wide range of disease-related processes, including obesity and its comorbidities. Evidence has been provided that the main components of 24-h EE may be affected by disruption of the circadian rhythm. The sleep pattern, meal timing and meal composition could mediate these effects. An increased understanding of the crosstalk between disruption of the circadian rhythm and energy balance may shed light on the pathophysiologic mechanisms underlying weight gain, which may eventually lead to design effective strategies to fight the obesity pandemic.

Reversible dysregulation of renal circadian rhythm in lupus nephritis

BackgroundWe have found disruption of expression of major transcriptional regulators of circadian rhythm in the kidneys of several mouse models of lupus nephritis. Here we define the consequence of this disturbance with respect to circadian gene expression and renal homeostatic function in a mouse model of lupus nephritis.MethodsMolecular profiling of kidneys from 47 young and 41 nephritic female NZB/W F1 mice was performed at 4 hourly intervals over a 24 h period. Disruption of major circadian transcriptional regulators was confirmed by qPCR. Molecular data was normalized and analyzed for rhythmicity using RAIN analysis. Serum aldosterone and glucose and urine sodium and potassium were measured at 4 hourly intervals in pre-nephritic and nephritic mice and blood pressure was measured every 4 h. Analyses were repeated after induction of complete remission of nephritis using combination cyclophosphamide and costimulatory blockade.ResultsWe show a profound alteration of renal circadian rhythms in mice with lupus nephritis affecting multiple renal pathways. Using Cosinor analysis we identified consequent alterations of renal homeostasis and metabolism as well as blood pressure dipper status. This circadian dysregulation was partially reversed by remission induction therapy.ConclusionsOur studies indicate the role of inflammation in causing the circadian disruption and suggest that screening for loss of normal blood pressure dipping should be incorporated into LN management. The data also suggest a potential role for circadian agonists in the treatment of lupus nephritis.

Comment on “COVID-19, the Built Environment, and Health”

Comment on “COVID-19, the Built Environment, and Health”

Every Night and Every Morn: Effect of Variation in CLOCK Gene on Depression Depends on Exposure to Early and Recent Stress.

The role of circadian dysregulation is increasingly acknowledged in the background of depressive symptoms, and is also a promising treatment target. Similarly, stress shows a complex relationship with the circadian system. The CLOCK gene, encoding a key element in circadian regulation has been implicated in previous candidate variant studies in depression with contradictory findings, and only a few such studies considered the interacting effects of stress. We investigated the effect of CLOCK variation with a linkage-disequilibrium-based clumping method, in interaction with childhood adversities and recent negative life events, on two phenotypes of depression, lifetime depression and current depressive symptoms in a general population sample.Methods: Participants in NewMood study completed questionnaires assessing childhood adversities and recent negative life events, the Brief Symptom Inventory to assess current depressive symptoms, provided data on lifetime depression, and were genotyped for 1054 SNPs in the CLOCK gene, 370 of which survived quality control and were entered into linear and logistic regression models with current depressive symptoms and lifetime depression as the outcome variable, and childhood adversities or recent life events as interaction variables followed by a linkage disequilibrium-based clumping process to identify clumps of SNPs with a significant main or interaction effect.Results: No significant clumps with a main effect were found. In interaction with recent life events a significant clump containing 94 SNPs with top SNP rs6825994 for dominant and rs6850524 for additive models on current depression was identified, while in interaction with childhood adversities on current depressive symptoms, two clumps, both containing 9 SNPs were found with top SNPs rs6828454 and rs711533.Conclusion: Our findings suggest that CLOCK contributes to depressive symptoms, but via mediating the effects of early adversities and recent stressors. Given the increasing burden on circadian rhythmicity in the modern lifestyle and our expanding insight into the contribution of circadian disruption in depression especially as a possible mediator of stress, our results may pave the way for identifying those who would be at an increased risk for depressogenic effects of circadian dysregulation in association with stress as well as new molecular targets for intervention in stress-related psychopathologies in mood disorders.

Behaviorally and environmentally induced non-24-hour sleep-wake rhythm disorder in sighted patients.

To determine whether there was evidence of circadian or sleep-regulatory dysfunction in sighted individuals with non-24-hour sleep-wake rhythm disorder. Three sighted individuals with signs and/or symptoms of non-24-hour sleep-wake rhythm disorder were studied. Thirty-five- to 332-day laboratory and home-based assessments of sleep-wake and circadian timing, endogenous circadian period, photic input to the circadian pacemaker, and/or circadian and sleep-wake-dependent regulation of sleep were conducted. No evidence of circadian dysfunction was found in these individuals. Instead, sleep-wake timing appeared to dissociate from the circadian timing system, and/or self-selected sleep-wake and associated light/dark timing shifted the circadian pacemaker later, rather than the circadian pacemaker determining sleep-wake timing. These findings suggest that the etiology of this disorder may be light- and/or behaviorally induced in some sighted people, which has implications for the successful treatment of this disorder. Emens JS, St Hilaire MA, Klerman EB, etal. Behaviorally and environmentally induced non-24-hour sleep-wake rhythm disorder in sighted patients. J Clin Sleep Med. 2022;18(2):453-459.