Circadian Rhythm In Patients Research Articles

Effects of Total Intravenous Anesthesia on Circadian Rhythms in Patients Undergoing Cardiac Transcatheter Closure

Objective To evaluate the effects of total intravenous anesthesia on the circadian rhythms in the patients undergoing cardiac transcatheter closure. Methods Thirty patients undergoing cardiac transcatheter closure under elective intravenous anesthesia were included in this study.Paired t-tests were performed to compare the mRNA levels of the genes encoding circadian locomotor output cycles kaput(CLOCK),brain and muscle ARNT-1 like protein-1(BMAL1),cryptochrome 1(CRY1),and period circadian clock 2(PER2),the Munich Chronotype Questionnaire(MCTQ)score,and the Pittsburgh Sleep Quality Index(PSQI)score before and after anesthesia.Multiple stepwise regression analysis was performed to screen the factors influencing sleep chronotype and PSQI total score one week after surgery. Results The postoperative mRNA level of CLOCK was higher [1.38±1.23 vs.1.90±1.47;MD(95%CI):0.52(0.20-0.84),t=3.327,P=0.002] and the postoperative mRNA levels of CRY1 [1.56±1.50 vs.1.13±0.98;MD(95%CI):-0.43(-0.81--0.05),t=-2.319,P=0.028] and PER2 [0.82±0.63 vs.0.50±0.31;MD(95%CI):-0.33(-0.53--0.12),t=-3.202,P=0.003] were lower than the preoperative levels.One week after surgery,the patients presented advanced sleep chronotype [3:03±0:59 vs.2:42±0:37;MD(95%CI):-21(-40--1),t=-2.172,P=0.038],shortened sleep latency [(67±64)min vs.(37±21)min;MD(95%CI):-30.33(-55.28--5.39),t=-2.487,P=0.019],lengthened sleep duration [(436±83)min vs.(499±83)min;MD(95%CI):62.80(26.93-98.67),t=3.581,P=0.001],increased sleep efficiency [(87.59±10.35)% vs.(92.98±4.27)%;MD(95%CI):5.39(1.21-9.58),t=2.636,P=0.013],decreased sleep quality score [1.13±0.78 vs.0.80±0.71;MD(95%CI):-0.33(-0.62--0.05),t=-2.408,P=0.023],and declined PSQI total score [6.60±3.17 vs.4.03±2.58;MD(95%CI):-2.57(-3.87--1.27),t=-4.039,P<0.001].Body mass index(BMI)(B=-227.460,SE=95.475,t=-2.382,P=0.025),anesthesia duration(B=-47.079,SE=18.506,t=-2.544,P=0.017),and mRNA level of PER2(B=2815.804,SE=1080.183,t=2.607,P=0.015)collectively influenced the sleep chronotype,and the amount of anesthesia medicine(B=0.067,SE=0.028,t=2.385,P=0.024)independently influenced the PSQI one week after surgery. Conclusion Total intravenous anesthesia can improve sleep habits by advancing sleep chronotype.BMI,anesthesia duration,and mRNA level of PER2 collectively influence sleep chronotype one week after surgery.The amount of anesthesia medicine independently influences the PSQI total score one week after surgery.

Variability in sleep architecture and alterations in circadian rhythms in patients with acute cerebral infarction accompanied by sleep-disordered breathing.

To continuously and dynamically monitor the sleep status of patients in the acute phase of cerebral infarction, and to investigate the characteristics of acute cerebral infarction(ACI)associated with sleep-disordered breathing (SDB), variations in sleep structure, and changes in sleep circadian rhythms. Patients with ACI within 48h of onset who were admitted to the Department of Neurology at Kailuan General Hospital from November 2020 to December 2022 were selected. Detailed baseline information such as age, gender, smoking history, drinking history, were recorded for the selected participants. From the beginning of their hospitalization, the selected participants were monitored for their sleep status continuously for 5 days using the Intelligent Mattress-based Sleep Monitoring Platform System(IMSMPS). Based on the heart rate data obtained from the monitoring, the interdaily stability (IS) and intradaily variability (IV) of the sleep circadian rhythm were calculated. 1,367 patients with ACI were selected. Monitoring results over 5 days indicated 147 cases (10.75%) without SDB, and 1,220 cases (89.25%) with SDB. Among the group with SDB, there were 248 cases (18.14%) with continuous mild SDB, 395 cases (28.90%) with moderate SDB, 295 cases (21.58%) with severe SDB, and 282 cases (20.63%) that fluctuated between different severity levels. Within this fluctuating group, 152 cases (53.90%) fluctuated between two severity levels, 120 cases (42.55%) between three levels, and 10 cases (3.55%) among all four levels. There were statistically significant differences (P < 0.05) in the sleep latency, sleep efficiency, non-rapid eye movement stages 1-2, rapid eye movement, proportion of non-rapid eye movement, proportion of rapid eye movement, wake after sleep onset, time out of bed, number of awakenings, respiratory variability index, and heart rate variability index among patients with ACI monitored from day 1 to 5. However, other monitored sleep structure parameters did not show statistically significant differences (P > 0.05). The coefficient of variation for all sleep monitoring parameters ranged between 14.54 and 36.57%. The IV in the SDB group was higher than in the group without SDB (P < 0.05), and the IS was lower than in the group without SDB (P < 0.05). Patients in the acute phase of cerebral infarction have a high probability of accompanying SDB. The sleep structure of these patients shows significant variability based on the onset time of the stroke, and some patients experience fluctuations among different severity levels of SDB. ACI accompanied by SDB can further reduce the IS of a patient's sleep circadian rhythm and increase its IV.

Seasonal Stability of the Circadian Rhythm in Patients with Type I Myocardial Infarction.

A circadian rhythm of myocardial infarction has been described but there is little data on its relation with seasons and months. From June 2013 to June 2018, we analyzed the alerts for acute ST-segment elevation myocardial infarction (STEMI) in a Spanish region with 6.64 million inhabitants, universal health coverage, and an organized STEMI reperfusion network. We selected those patients which an identifiable culprit plaque. We recruited 6765 cases of STEMI due to type I acute myocardial infarction (type-I AMI), with mean age of 63.2 years (range 17-101, standard deviation [SD] 13.7), 5238 were males (77.4%) and 2801 (41.9%) were 65 years or older. The hourly distribution followed a fixed pattern in all months, with most of the events occurring between 6:00 AM and 4:00 PM, a peak at approximately 01:00 PM and a valley between 10:00 PM and 06:00 AM. No significant difference was found when comparing the mean time to first medical contact between July (the month with more daylight hours) and December (the month with shortest days). No significant differences were found between male and female patients, or between patients aged 65 years or older and younger patients. There was a close correlation between the number of events per month and the number of events occurring during the day (6 AM to 6 PM, r = 0.988, p = 0.001) and during the night (6 PM to 6 AM, r = 0.944, p 0.001), with different slopes of the regression lines (t-test, p 0.001), so that the difference between day-night occurrences increased with the total incidence. There is a circadian pattern in the presentation of STEMI that is not influenced by sex and age. The different incidence of STEMI at different times of the year does not affect the circadian pattern in terms of the shape of the curve or the mean time of presentation, although diurnal events increase more than nocturnal events, suggesting that triggers are most likely to act during vulnerable periods as determined by a circadian-based rhythm.

PHARMACOLOGICAL EFFECTS OF MELATONIN AND ITS POTENTIAL APPLICATION IN THERAPY OF GOUT AND ASSOCIATED DISEASES

Introduction. The disturbance in biosynthetic activity of pinealocytes of the pineal gland and subsequent melatonin deficiency in the body are linked to the progression of certain chronic diseases. This has prompted research into correcting chrono-biological dysfunctions, particularly in conditions such as gout and its comorbidities. This study aims to analyze the potential use of melatonin in correcting metabolic disorders in gout and to justify its use as a pharmacotherapeutic agent for treating metabolic and cardiovascular diseases. Materials and methods. We conducted a comprehensive analysis of modern scientific literature from specialized domestic and foreign sources. Emphasis was placed on studies exploring the pharmacological and pharmacotherapeutic aspects of melatonin use in both experimental and clinical settings, particularly those conducted in the last 5-6 years. Results. The research data revealed three main aspects of the problem that must be addressed to understand the experimental, biological, pharmacological, and pharmacotherapeutic foundations for the long-term use of melatonin in clinical practice. The first part of the review highlighted the significant impact of melatonin homeostasis disruption on the pathogenesis of gout and its progression in comorbidity with other conditions such as hypertension, obesity, insulin resistance, metabolic syndrome, and type 2 diabetes. The role of chronobiological disorders and desynchronosis in the progression of these diseases was also established. Pharmacological studies demonstrated the pivotal role of melatonin, as an important factor in neuroendocrine regulation, in organizing the circadian rhythm of the body's vital functions under normal and pathological conditions. Melatonin was found to normalize the pathological processes underlying gout development and comorbid diseases, providing a scientific basis for its use in the treatment of gout, cardiovascular diseases, disturbed metabolic processes, and normalization of circadian rhythms in patients with these conditions. Conclusions. This paper presents data on the causes of gout development and progression, as well as some comorbid diseases, from the perspective of chronobiological disruptions in the body's functions. The review sections delve into the pharmacological and pharmacotherapeutic aspects of melatonin's therapeutic action. The findings confirm the importance of melatonin in effectively treating gout and other comorbid diseases and metabolic disorders.

Comparative study of sleep and circadian rhythms in patients presenting unipolar or bipolar major depressive episodes

Currently, there is a major challenge in distinguishing between unipolar and bipolar major depressive episode. A significant body of research has been dedicated to identifying biomarkers that can aid in this differentiation due to its crucial implications, particularly for therapeutic and prognostic purposes. Among the biomarkers of interest, markers related to sleep and circadian rhythms show promise and could potentially aid in making this distinction. Nevertheless, no study has simultaneously examined sleep-wake disorders, circadian rhythms, and seasonal patterns using both subjective and objective measures. This study aims to characterize and compare the sleep-wake and rhythm disorders including patients with unipolar major depressive episode (n = 72) and with bipolar major depressive episode (n = 43) using both subjective markers (using self-report questionnaires and sleep complaints) and objective markers (using actigraphy). Patients with unipolar major depressive episode seem to experience significantly poorer quality of sleep, more symptoms of insomnia and lower sleep efficiency compared to patients with bipolar major depressive episode. On the other hand, patients with bipolar major depressive episode exhibit significantly more symptoms of motor retardation and hypersomnia compared to patients with unipolar disorder. These results hold significant implications for identifying individuals with unipolar major depressive episode or bipolar major depressive episode using sleep and circadian markers, and for developing recommended and personalized therapeutic strategies.

Insomnia and circadian rhythms in patients who attempted suicide: potential correlations with inflammatory markers and suicidal lethality

Insomnia and circadian rhythms in patients who attempted suicide: potential correlations with inflammatory markers and suicidal lethality

PROGNOSTIC VALUES OF CIRCADIAN RHYTHM AND SLEEP PARAMETERS IN ASSESSMENT OF STATE ANXIETY IN PARKINSON’S DISEASE WITH REGARD TO MOTOR SUBTYPE

Introduction. Parkinson’s disease is characterized by motor and non-motor symptoms, the connection between which has recently attracted much attention from researchers. Sleep disturbances and anxiety can be non-motor signs of Parkinson’s disease. The specificity of non-motor symptoms in different motor subtypes is being actively studied, with the PIGD (postural instability and gait difficulty) subtype being associated with more severe non-motor symptoms. Methods. We conducted a clinical monocentric cross-sectional study that included 64 patients with Parkinson’s disease. Patients were assessed according to the Unified Parkinson’s Disease Rating Scale, and their motor subtype was determined by calculations using the method of Jankovich and Stebbins. We assessed circadian rhythm using the Ukrainian version of the Munich Chronotype Questionnaire, sleep quality – using the Pittsburgh Sleep Quality Index, excessive daytime sleepiness – using the Epworth Sleepiness Scale, and state anxiety – using the first block of the State-Trait Anxiety Inventory. Results. Our sample consisted of approximately equal numbers of men and women with a mean age of 63.80 ± 9.30 years. All patients were approximately equally distributed by motor subtype and sleep quality. At the same time, our sample was dominated by patients with a high level of state anxiety, morning chronotype, and the absence of excessive daytime sleepiness. State anxiety demonstrated a moderate direct correlation with sleep latency, mid-sleep, subjective sleep quality, subjective sleep latency, sleep disturbance, and total score of Pittsburgh Sleep Quality Index and a moderate indirect association with average weekly light exposure. It was found that an increased mid-sleep time, a decreased average weekly light exposure during the day, poor sleep quality, and PIGD subtype elevated the odds of more severe situational anxiety. Conclusions. Our study demonstrates the relationship between the level of situational anxiety and parameters of sleep and circadian rhythm in patients with Parkinson’s disease, considering their motor subtype. It was found that a later mid-sleep, lower average weekly light exposure, poor sleep quality, and PIGD subtype of Parkinson’s disease had a prognostic role regarding the increase in state anxiety

Are circadian rhythms in disarray in patients with chronic critical illness?

The aim of our study is to assess circadian rhythms in patients with chronic critical illness due to severe brain injury in intensive care unit by establishing the relation between melatonin and cortisol secretion, considering astronomical time and the sleep-wake cycle in chronic critical illness. The study included 54 adult patients with chronic critical illness who resided in the intensive care unit for at least 30 days. The level of consciousness was determined using the CRS-R scale. We did the continuous electroencephalographic (EEG) monitoring with polygraphic leads for 24h. Also, we determined the serum levels of cortisol and melatonin using the tandem mass spectrometry method with ultra-performance liquid chromatography. 90.74% of patients had one acrophase in melatonin secretion curve, which suggests the preservation of the rhythmic secretion of melatonin. These acrophases of the melatonin rhythm occurred during the night time in 91.8% of patients. Most of the patients (69.3%) slept during the period from 2:00 to 4:00 a.m. The evening levels of cortisol and melatonin had an inverse relation (rs=0.61, p<0.05), i.e., a decrease in the level of cortisol secretion accompanies an increase in melatonin. We concluded from our study that the rhythmic secretion of melatonin and cortisol is preserved in patients with chronic critical illness that resulted from severe brain injury. No statistically significant discrepancy between melatonin and cortisol secretion, day-and-night time and the sleep-wake cycle are found. We may focus our future work on finding more reliable methods to stabilize the preservation of circadian rhythms to protect vital organ functions.

Examining Human-Smartphone Interaction as a Proxy for Circadian Rhythm in Patients With Insomnia: Cross-Sectional Study.

The sleep and circadian rhythm patterns associated with smartphone use, which are influenced by mental activities, might be closely linked to sleep quality and depressive symptoms, similar to the conventional actigraphy-based assessments of physical activity. The primary objective of this study was to develop app-defined circadian rhythm and sleep indicators and compare them with actigraphy-derived measures. Additionally, we aimed to explore the clinical correlations of these indicators in individuals with insomnia and healthy controls. The mobile app "Rhythm" was developed to record smartphone use time stamps and calculate circadian rhythms in 33 patients with insomnia and 33 age- and gender-matched healthy controls, totaling 2097 person-days. Simultaneously, we used standard actigraphy to quantify participants' sleep-wake cycles. Sleep indicators included sleep onset, wake time (WT), wake after sleep onset (WASO), and the number of awakenings (NAWK). Circadian rhythm metrics quantified the relative amplitude, interdaily stability, and intradaily variability based on either smartphone use or physical activity data. Comparisons between app-defined and actigraphy-defined sleep onsets, WTs, total sleep times, and NAWK did not reveal any significant differences (all P>.05). Both app-defined and actigraphy-defined sleep indicators successfully captured clinical features of insomnia, indicating prolonged WASO, increased NAWK, and delayed sleep onset and WT in patients with insomnia compared with healthy controls. The Pittsburgh Sleep Quality Index scores were positively correlated with WASO and NAWK, regardless of whether they were measured by the app or actigraphy. Depressive symptom scores were positively correlated with app-defined intradaily variability (β=9.786, SD 3.756; P=.01) and negatively correlated with actigraphy-based relative amplitude (β=-21.693, SD 8.214; P=.01), indicating disrupted circadian rhythmicity in individuals with depression. However, depressive symptom scores were negatively correlated with actigraphy-based intradaily variability (β=-7.877, SD 3.110; P=.01) and not significantly correlated with app-defined relative amplitude (β=-3.859, SD 12.352; P=.76). This study highlights the potential of smartphone-derived sleep and circadian rhythms as digital biomarkers, complementing standard actigraphy indicators. Although significant correlations with clinical manifestations of insomnia were observed, limitations in the evidence and the need for further research on predictive utility should be considered. Nonetheless, smartphone data hold promise for enhancing sleep monitoring and mental health assessments in digital health research.

Hypoxia Induces Alterations in the Circadian Rhythm in Patients with Chronic Respiratory Diseases.

The function of the circadian cycle is to determine the natural 24 h biological rhythm, which includes physiological, metabolic, and hormonal changes that occur daily in the body. This cycle is controlled by an internal biological clock that is present in the body's tissues and helps regulate various processes such as sleeping, eating, and others. Interestingly, animal models have provided enough evidence to assume that the alteration in the circadian system leads to the appearance of numerous diseases. Alterations in breathing patterns in lung diseases can modify oxygenation and the circadian cycles; however, the response mechanisms to hypoxia and their relationship with the clock genes are not fully understood. Hypoxia is a condition in which the lack of adequate oxygenation promotes adaptation mechanisms and is related to several genes that regulate the circadian cycles, the latter because hypoxia alters the production of melatonin and brain physiology. Additionally, the lack of oxygen alters the expression of clock genes, leading to an alteration in the regularity and precision of the circadian cycle. In this sense, hypoxia is a hallmark of a wide variety of lung diseases. In the present work, we intended to review the functional repercussions of hypoxia in the presence of asthma, chronic obstructive sleep apnea, lung cancer, idiopathic pulmonary fibrosis, obstructive sleep apnea, influenza, and COVID-19 and its repercussions on the circadian cycles.

Mediation and Dose-Response Relationship Among Physical Activity, Daylight Exposure, and Rest-Activity Circadian Rhythm in Patients With Esophageal and Gastric Cancer.

Physical activity and daylight exposure predict rest-activity circadian rhythm (RACR) in patients with cancer. However, whether daylight exposure mediates the relationship between physical activity and RACR and the optimal amounts of physical activity and daylight that benefit RACR remain unclear. This study investigated the mediating role of daylight exposure and determined the dose-response relationship among daylight exposure, physical activity, and RACR in patients with cancer. This cross-sectional exploratory study recruited 319 patients with esophageal and gastric cancer from 2 surgery outpatient departments in Taiwan. Daylight exposure (>500 lux), physical activity (up activity mean), and RACR (midline estimating statistic of rhythm) were measured through actigraphy. Regression was performed, and the receiver operating characteristic curve was plotted. Daylight exposure (>500 lux) partially mediated the relationship between physical activity (up activity mean) and RACR (midline estimating statistic of rhythm). The optimal cutoffs for discriminating between satisfactory and poor RACR were 187.43 counts/min for physical activity (sensitivity, 90.3%; specificity, 84.4%) and 35.71 min/d for daylight exposure (sensitivity, 55.9%; specificity, 78.2%). Participants who engaged in physical activity were more likely to receive daylight exposure and experience improved RACR. The optimal level of daylight exposure and frequency of physical activity that can improve RACR in patients with esophageal and gastric cancer are 36 min/d and 187 counts/min, respectively. Healthcare professionals should encourage patients to engage in exercise or physical activity during the daytime to improve their circadian rhythm.

The Impact of Immunotherapy on Sleep and Circadian Rhythms in Patients with Cancer.

Immunotherapy has revolutionized treatments for both early and advanced cancers, and as their role evolves, their impact on sleep and circadian rhythms continues to unfold. The recognition, evaluation, and treatment of sleep and circadian rhythm disturbance leads to improved symptom management, quality of life and treatment outcomes. An intricate complex relationship exists in the microenvironment with immunity, sleep and the tumor, and these may further vary based on the cancer, addition of standard chemotherapy, and pre-existing patient factors. Sleep and circadian rhythms may offer tools to better utilize immunotherapy in the care of cancer patients, leading to better treatment outcome, reduced symptom burden, and increased quality of life.

FRI140 Impact Of Circadian Rhythm Of Aldosterone And Cortisol Levels Upon Adrenal Vein Sampling In Primary Aldosteronism

Abstract Disclosure: M. Kometani: None. M. Yoneda: None. K. Aiga: None. D. Aono: None. S. Karashima: None. Y. Takeda: None. T. Yoneda: None. Purpose: Adrenal venous sampling (AVS) is the gold standard technique for subtype differentiation of primary aldosteronism (PA). AVS is an invasive and challenging test; however, because of the high frequency of PA, it is currently performed at many institutions in Japan. Considering the effects of diurnal variations in the levels of aldosterone and cortisol, the guidelines recommends that AVS without ACTH loading should be performed in the morning. However, owing to staffing issues and general limitations, AVS is performed in the afternoon in many facilities. In this study, we examined the effects of AVS timing (AM/PM) on AVS results. Methods: This multicenter, retrospective, observational study included a total of 753 patients diagnosed with PA at four specialized institutions. The patients were divided into two groups according to the timing of the AVS procedure. The group classification of patients according to the time of the day when AVS was performed was not prospectively designed but rather determined based on feasible conditions at each facility. Among them, 504 and 249 patients underwent AVS in the morning (AM-AVS) and in the afternoon (PM-AVS), respectively. Results: The success rate of basal AVS in the AM-AVS group was 81% and that of ACTH-stimulated AVS was 92%. The success rate of basal AVS in the PM-AVS group was 74% and that of ACTH-stimulated AVS was 88%. There was no significant difference in the AVS success rate between the AM-AVS and PM-AVS groups. There was no significant difference between the AM-AVS and PM-AVS groups concerning the rate of unilateral diagnosis by AVS before ACTH stimulation, the rate of unilateral PA diagnosis by AVS after ACTH stimulation, and the percentage of cases with discrepancies between the two AVSs. Regarding patients with unilateral PA, aldosterone concentrations in adrenal venous blood did not differ between the two groups on the dominant or non-dominant side. Conversely, regarding patients with bilateral PA, aldosterone concentrations in adrenal venous blood were significantly higher in the AM-AVS than in the PM-AVS group. Conclusions: This study evaluated the effect of AVS timing. Although this was a multicenter study, there were no differences in the success rate of AVS, diagnostic rate of subtype, or frequency of deviation in the subtypes between the AM-AVS and PM-AVS groups. These results are relevant for facilities that can perform AVS only in the afternoon. Concerning aldosterone levels, no differences were observed between patients with unilateral lesions in the AM-AVS and PM-AVS groups, whereas its levels were different between patients with bilateral lesions in the AM-AVS and PM-AVS groups, suggesting the involvement of different mechanisms that regulate aldosterone secretion according to the circadian rhythm in patients with unilateral or bilateral lesions. Presentation: Friday, June 16, 2023

Features of short-term variability of arterial pressure with different types of circadian rhythm in patients with hypertension disease who have suffered myocardial infarction

Abstract. Blood pressure variability is an important prognostic parameter and is an independent predictor of cardiovascular disease and mortality. Aim. To assess short-term blood pressure variability with regard to the type of diurnal blood pressure profile in hypertensive patients with myocardial infarction. Materials and methods. 78 hypertensive men who had a myocardial infarction were examined. The average age was 58.0 (54.0; 67.0) years, the experience of hypertension was 9.0 (5.0; 18.0) years, the period after the myocardial infarction was 24.5 (12.0; 84,0) months. All patients underwent daily monitoring of blood pressure with the study of average day and night pressure levels, the degree of nocturnal decrease in blood pressure, blood pressure variability with STD calculation, pure and new variability indices. The results. Increased BP variability during the day and at night was registered with all types of circadian systolic BP rhythm. The highest values of systolic BP variability (STD) during the day and at night were in patients with a night-picker circadian profile. Achieving the target level of systolic BP as a whole in the group was observed in 34.6 % of patients during the day and 42.3 % at night. Patients with an over-dipper circadian blood pressure profile, despite having the highest percentage of target blood pressure achievement, had the highest values of variability characteristics calculated by STD, pure and new indices per day (p &lt; 0.05). Conclusions. Increased blood pressure variability and pressure level at night are important criteria for assessing the prognosis of hypertensive patients after myocardial infarction. Daily monitoring of blood pressure provides a unique opportunity to objectify these prognostic parameters at different times of the day, which, together with the assessment of reaching the target level of blood pressure, is necessary to control the effectiveness of treatment.

Disruption of the Clock Component Bmal1 in Mice Promotes Cancer Metastasis through the PAI-1-TGF-β-myoCAF-Dependent Mechanism.

The circadian clock in animals and humans plays crucial roles in multiple physiological processes. Disruption of circadian homeostasis causes detrimental effects. Here, it is demonstrated that the disruption of the circadian rhythm by genetic deletion of mouse brain and muscle ARNT-like 1 (Bmal1) gene, coding for the key clock transcription factor, augments an exacerbated fibrotic phenotype in various tumors. Accretion of cancer-associated fibroblasts (CAFs), especially the alpha smooth muscle actin positive myoCAFs, accelerates tumor growth rates and metastatic potentials. Mechanistically, deletion of Bmal1 abrogates expression of its transcriptionally targeted plasminogen activator inhibitor-1 (PAI-1). Consequently, decreased levels of PAI-1 in the tumor microenvironment instigate plasmin activation through upregulation of tissue plasminogen activator and urokinase plasminogen activator. The activated plasmin converts latent TGF-β into its activated form, which potently induces tumor fibrosis and the transition of CAFs into myoCAFs, the latter promoting cancer metastasis. Pharmacological inhibition of the TGF-β signaling largely ablates the metastatic potentials of colorectal cancer, pancreatic ductal adenocarcinoma, and hepatocellular carcinoma. Together, these data provide novel mechanistic insights into disruption of the circadian clock in tumor growth and metastasis. It is reasonably speculated that normalization of the circadian rhythm in patients provides a novel paradigm for cancer therapy.

Agomelatine: A Potential Multitarget Compound for Neurodevelopmental Disorders.

Agomelatine (AGM) is one of the latest atypical antidepressants, prescribed exclusively for the treatment of depression in adults. AGM belongs to the pharmaceutical class of melatonin agonist and selective serotonin antagonist ("MASS"), as it acts both as a selective agonist of melatonin receptors MT1 and MT2, and as a selective antagonist of 5-HT2C/5-HT2B receptors. AGM is involved in the resynchronization of interrupted circadian rhythms, with beneficial effects on sleep patterns, while antagonism on serotonin receptors increases the availability of norepinephrine and dopamine in the prefrontal cortex, with an antidepressant and nootropic effect. The use of AGM in the pediatric population is limited by the scarcity of data. In addition, few studies and case reports have been published on the use of AGM in patients with attention deficit and hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Considering this evidence, the purpose of this review is to report the potential role of AGM in neurological developmental disorders. AGM would increase the expression of the cytoskeleton-associated protein (ARC) in the prefrontal cortex, with optimization of learning, long-term memory consolidation, and improved survival of neurons. Another important feature of AGM is the ability to modulate glutamatergic neurotransmission in regions associated with mood and cognition. With its synergistic activity a melatoninergic agonist and an antagonist of 5-HT2C, AGM acts as an antidepressant, psychostimulant, and promoter of neuronal plasticity, regulating cognitive symptoms, resynchronizing circadian rhythms in patients with autism, ADHD, anxiety, and depression. Given its good tolerability and good compliance, it could potentially be administered to adolescents and children.

Microwave Radiothermometry in Evaluating Brain Temperature Changes (Review)

Aim. This review aims to inform physicians of different specialties (anesthesiologists, intensivists, neurologists, neurosurgeons, oncologists) about the diagnostic capabilities of microwave radiothermometry, which enables to identify and analyze features of alterations of cerebral temperature in brain damage.The review displays a critical analysis of 80 recent Russian and foreign open access publications found by keywords.The review presents major clinical features and pathophysiological mechanisms of cerebral thermal balance disruptions in brain lesions. Slow responsiveness and vulnerability of cerebral thermal homeostasis regulation mechanisms that underlie development of different temperature heterogeneity levels in the cerebral cortex in healthy brain and brain lesions are highlighted. The authors postulate their concept about the critical role of hyperthermia in the pathogenesis of brain damage and disruption of interconnections in the global central regulation system. A body of evidence explaining direct association between the depth of consciousness impairment and degree of cerebral cortex temperature heterogeneity manifestation is presented. It is emphasized that a significant increase in temperature heterogeneity with areas of focal hyperthermia accompanies an acute period of ischemic stroke, while in post-comatose state usually associated with prolonged impairment of consciousness, the temperature heterogeneity significantly subsides. It has been suggested that lowering of an increased and rising of the reduced temperature heterogeneity, for example by using temperature exposure, can improve altered level of consciousness in patients with brain damage. The diagnostic capabilities of various technologies used for cerebral temperature measurement, including microwave radiothermometry (MWR), are evaluated. Data on high accuracy of MWR in measurement of the cerebral cortex temperature in comparison with invasive methods are presented.Conclusion. In healthy individuals MWR revealed a distinct daily rhythmic changes of the cerebral cortex temperature, and badly violated circadian rhythms in patients with brain lesions. Since MWR is an easy-toperform, non-invasive and objective diagnostic tool, it is feasible to use this technology to detect latent cerebral hyperthermia and assess the level of temperature heterogeneity disruption, as well as to study the circadian rhythm of temperature changes.

Changes of adrenocorticotropic hormone rhythm and cortisol circadian rhythm in patients with depression complicated with anxiety and their effects on the psychological state of patients.

Objective: This work was to explore the rhythm of adrenocorticotropic hormone (ACTH) and cortisol in patients with depression and anxiety and their effects on mental state. In this work, with depression complicated with anxiety patients as the A-MDD group (n = 21), and depression without anxiety symptoms as the NA-MDD group (n = 21). Firstly, data features were extracted according to the electroencephalo-graph (EEG) data of different patients, and a DR model was constructed for diagnosis. The Hamilton Depression Scale 24 (HAMD-24) was employed to evaluate the severity, and the ACTH and cortisol levels were detected and compared for patients in the A-MDD group and NA-MDD group. In addition, the psychological status of the patients was assessed using the Toronto Alexithymia Scale (TAS). As a result, the AI-based DR model showed a high recognition accuracy for depression. The HAMD-24 score in the A-MDD group (31.81 ± 5.39 points) was statistically higher than the score in the NA-MDD group (25.25 ± 5.02 points) (P < 0.05). No visible difference was found in ACTH levels of patients in different groups (P > 0.05). The incidence of cortisol rhythm disorder (CRD) in the A-MDD group was much higher (P < 0.05). The differences in TAS scores between the two groups were significantly statistically significant (P < 0.01). In conclusion, the AI-based DR Model achieves a more accurate identification of depression; depression with or without anxiety has different effects on the mental state of patients. CRD may be one of the biological markers of depression combined with anxiety.

Relationships Among Physical Activity, Daylight Exposure, and Rest-Activity Circadian Rhythm in Patients With Esophageal and Gastric Cancer: An Exploratory Study.

Although rest-activity circadian rhythm (RACR) disruption is associated with mortality in patients with cancer, few studies have examined the effect of RACR on patients with esophageal and gastric cancer. The aim of this study was to identify the predictors of RACR. This cross-sectional, single-site study included 276 patients with esophageal and gastric cancer recruited from chest-surgery and general-surgery outpatient departments. Actigraphy was used to assess objective physical activity (PA), daylight exposure, and RACR, and 3-day PA was used to indicate the subjective amount of PA. The parameter of objective PA was the up activity mean; the parameter of daylight exposure was >500 lx, and the parameters of RACR were the 24-hour correlation coefficient, in-bed less than out-of-bed dichotomy index, midline estimating statistic of rhythm, and amplitude. The subjective amount of PA was calculated as the sum of mild, moderate, and vigorous PA. The up activity mean predicted 24-hour correlation coefficient. The PA amount and up activity mean predicted in-bed less than out-of-bed dichotomy index. The up activity mean and >500-lx daylight exposure predicted midline estimating statistic of rhythm. Finally, the PA amount and up activity mean predicted the amplitude. Increased PA and daylight exposure may improve RACR. Patients with esophageal and gastric cancer should be encouraged to engage in outdoor PA during the daytime as part of their regular lifestyle to maintain a robust circadian rhythm.

Morning blue light treatment improves sleep complaints, symptom severity, and retention of fear extinction memory in post-traumatic stress disorder.

Disrupted sleep is a major feature in numerous clinical disorders and is related to decrements in affective memory processing. The prevalence of sleep disruption in post-traumatic stress disorder (PTSD) is suggested to be a key feature that exacerbates the impaired ability to recall extinction memories during experimental fear conditioning. We hypothesized that an intervention employing blue-wavelength light therapy (BLT) to regulate sleep and stabilize circadian rhythms in patients with PTSD (i.e., via regulated morning exposure) would be associated with PTSD symptom improvement, decreased sleep-related complaints, as well as improved consolidation and retention of extinction memories relative to a fear conditioning/extinction paradigm. Eighty-two individuals with PTSD underwent a well-validated fear conditioning/extinction protocol with subsequent assignment to receive morning BLUE (BLT) or placebo AMBER (ALT) light therapy daily for 30-min over 6-weeks. Participants returned after the intervention for post-treatment extinction recall, comprised of exposure to the previously conditioned stimuli, with the difference in skin conductance response between the “extinguished” and the “never-extinguished” stimuli at follow-up. Participants also viewed previously conditioned stimuli in a novel context during a functional magnetic resonance imaging (fMRI) scan. BLUE light therapy was associated with improvements relative to correlated decreases between PTSD symptoms and sleep-related complaints. Participants receiving BLT also sustained retention of the extinction memory, while those in the placebo amber light treatment group showed impairment, characterized by the restoration of the extinguished fear response after 6-weeks. Participants in the ALT also demonstrated greater reactivity in the left insula when viewing the previously extinguished fear-conditioned stimuli in a novel context. Daily BLUE-wavelength morning light exposure was associated with greater retention of extinction learning in patients with PTSD when compared to ALT, as supported by both autonomic and neurobiological reactivity. We speculate that improved sleep facilitated by a stabilized circadian rhythm, after fear-learning, led to greater consolidation of the fear extinction memory, decreased PTSD symptom presentation, and associated decreases in sleep-related complaints. Prominent exposure treatments for PTSD incorporate principles of fear extinction, and our findings suggest that blue light treatment may facilitate treatment gains by promoting the consolidation of extinction memories via improved sleep.