Twenty-four hour pattern of childhood febrile seizures substantiated by time series meta-analysis: Circadian medicine perspectives.

Major objectives of this work were to: (1) substantiate the 24-hour pattern in the occurrence of childhood febrile seizures (CFSs) by a novel time series meta-analysis of past reported time-of-day data and (2) discuss its potential circadian rhythm-dependencies. Comprehensive search of the published literature retrieved eight articles that met inclusion criteria. Three investigations were conducted in Iran, two in Japan, and one each in Finland, Italy, and South Korea, representing a total of 2461 mostly simple febrile seizures of children who were on average about 2 years of age. Population-mean cosinor analysis validated (p < .001) a 24-hour pattern in the onset of CFSs, with an approximate four-fold difference in the proportion of children expressing seizures at its peak at 18:04 h (95% confidence interval: 16:40-19:07 h) vs trough at 06:00 h, in the absence of meaningful time-of-day differences in mean body temeprarure. The CFS time-of-day pattern likely derives from the actions of multiple circadian rhythms, particularly the cytokines that comprise the pyrogenic inflammatory pathway and melatonin that influences the excitation level of central neurons and helps regulate body temperature. Past laboratory animal and patient investigations document that the vulnerability to a seizure by a provoking trigger of the same intensity is not the same but different in a predictable-in-time manner during the 24 h as a circadian susceptibility/resistance rhythm. Knowledge of the marked disparity in the time-of-day risk of CFSs can be translated into improved prevention, particularly during the late afternoon and early evening when highest, through proper timing of prophylactic interventions.

Does Patient-Applied Testosterone Replacement Therapy Pose Risk for Blood Pressure Elevation? Circadian Medicine Perspectives.

We reviewed medication package inserts, US Food and Drug Administration (FDA) reports, and journal publications concerning the 10 nonbiosimilar patient-applied (PA) testosterone (T) replacement therapies (TRTs) for intraday serum T patterning and blood pressure (BP) effects. Blood T concentration is circadian rhythmic in young adult eugonadal males, being highest around awakening and lowest before bedtime. T level and 24 h variation are blunted in primary and secondary hypogonadism. Utilized as recommended, most PA-TRTs achieve nonphysiologic T 24 h patterning. Only Androderm® , an evening PA transdermal patch, closely replicates the normal T circadian rhythmicity. Accurate determination of risk for BP elevation and hypertension (HTN) by PA-TRTs is difficult due to limitations of office BP measurements (OBPM) and suboptimal methods and endpoints of ambulatory BP monitoring (ABPM). OBPM is subject to "White Coat" pressor effect resulting in unrepresentative BP values plus masked normotension and masked HTN, causing misclassification of approximately 45% of trial participants, both before and during treatment. Change in guideline-recommended diagnostic thresholds over time causes misclassification of an additional approximately 15% of participants. ABPM is improperly incorporated into TRT safety trials. It is done for 24 h rather than preferred 48 h; BP is oversampled during wakefulness, biasing derived 24 h mean values; 24 h mean systolic and diastolic BP (SBP, DBP) are inappropriate primary outcomes, because of not being best predictors of risk for major acute cardiovascular events (MACE); "daytime" and "nighttime" BP means referenced to clock time are reported rather than biologically relevant wake-time and sleep-time BP means; most importantly, asleep SBP mean and dipping, strongest predictors of MACE, are disregarded. © 2022 American Physiological Society. Compr Physiol 12: 1-20, 2022.

Perspectives on the relevance of the circadian time structure to workplace threshold limit values and employee biological monitoring.

The circadian time structure (CTS) and its disruption by rotating and nightshift schedules relative to work performance, accident risk, and health/wellbeing have long been areas of occupational medicine research. Yet, there has been little exploration of the relevance of the CTS to setting short-term, time-weighted, and ceiling threshold limit values (TLVs); conducting employee biological monitoring (BM); and establishing normative reference biological exposure indices (BEIs). Numerous publications during the past six decades document the CTS substantially affects the disposition - absorption, distribution, metabolism, and elimination - and effects of medications. Additionally, laboratory animal and human studies verify the tolerance to chemical, biological (contagious), and physical agents can differ extensively according to the circadian time of exposure. Because of slow and usually incomplete CTS adjustment by rotating and permanent nightshift workers, occupational chemical and other contaminant encounters occur during a different circadian stage than for dayshift workers. Thus, the intended protection of some TLVs when working the nightshift compared to dayshift might be insufficient, especially in high-risk settings. The CTS is germane to employee BM in that large-amplitude predictable-in-time 24h variation can occur in the concentration of urine, blood, and saliva of monitored chemical contaminants and their metabolites plus biomarkers indicative of adverse xenobiotic exposure. The concept of biological time-qualified (for rhythms) reference values, currently of interest to clinical laboratory pathology practice, is seemingly applicable to industrial medicine as circadian time and workshift-specific BEIs to improve surveillance of night workers, in particular. Furthermore, BM as serial assessments performed frequently both during and off work, exemplified by employee self-measurement of lung function using a small portable peak expiratory flow meter, can easily identify intolerance before induction of pathology.

Temporal Patterns of In-Hospital Falls of Elderly Patients.

BACKGROUND: A potentially important factor yet to receive adequate study is the time when hospital falls occur. A prior study conducted before the system-wide introduction of preventive measures revealed a biphasic 24-hour pattern of hospital falls with major peak in the morning. OBJECTIVES: The purpose was to identify the temporal patterning of falls among elderly patients in hospitals with comprehensive fall prevention programs in place. METHODS: A 4-year observational study was conducted by the local health authority in the five nonteaching public hospitals located in the province of Ferrara, Italy. Fall records involving patients of ages ≥65 years hospitalized in the general medical departments were used. Single- and multiple-component cosinor (time series) analyses were used to explore 24-hour, weekly, and annual patterns of falls. RESULTS: A total of 763 falls were experienced by 709 different elderly hospitalized patients. Falls typically took place in the patient's hospital room (72%) and bathroom (23%). Major causes were patient instability (32%) and accident (13%), and most occurred when not wearing footwear (45%) or wearing inappropriate sling-back open-toe shoes (39%). Falls happened while standing (39%), while seated (21%), and while getting into, out of, or laying in bed (32%)-either with the bed rails raised or lowered. Fall outcome usually involved no injury (58%) or slight injury (35%), but some (7%) were disabling. Fall occurrence was higher during the night (46%) compared to either the morning (30%) or afternoon (24%) shift. Patterns across 24 hours were characterized by a single major and one or more minor peaks that seemed to be associated with a variety of scheduled patient, hospital, and nursing activities. Multiple-component cosinor analysis identified significant (p < .05) prominent day-night patterns according to fall location, patient position, cause, injury severity, and type of footwear. Falls were more frequent, but not significantly so, on Fridays, Sundays, and Mondays compared with Tuesdays, and were more frequent in winter and spring (p = .003). DISCUSSION: Documentation by cause and circumstance of these moderate- to high-amplitude temporal patterns in hospital falls of elderly patients advances the knowledge of fall epidemiology by identifying the times of day, week, and year and nursing shifts of elevated risk that is of critical importance to improving hospital patient safety programs.

Risk of obesity in male shift workers: A chronophysiological approach.

AIMS: Why are some healthy male shift workers (SWers) overweight [body mass index (BMI) >25 and <30] if not obese (BMI >30)? Seven risk factors potentially causing overweight and obesity were evaluated, namely (1) age, (2) physical/sports activity, (3) length of exposure to shift work (SW), (4) speed of shift rotation, (5) tolerance to SW, (6) internal desynchronization of circadian rhythms and (8) night eating (nocturnal nibbling). "New" as well as "old" data, acquired from longitudinal and individual time series of 5-56 days recording span, were reanalyzed. The data were analyzed from a set of field studies of 67 SWers and 53 non-shift workers (non-SWers). To estimate the respective weight of these factors, a multiple regression analysis (MRA) was used among other statistical tools. A similar age-related increase in BMI was validated (with p < 0.001) in both SWers and non-SWers. However, in SWers, desynchronization of rhythms increases the effect of age on BMI. Length of exposure to SW, tolerance to SW and speed of rotation do not seem to play a role as risk factors. Major effects are likely to relate to a sedentary lifestyle (lack of regular physical or sport activities) (MRA with p < 0.01), as well as, presumably, to a nocturnal nibbling of carbohydrates, which mimics the night eating syndrome.

Circadian disruption: New clinical perspective of disease pathology and basis for chronotherapeutic intervention.

Biological processes are organized in time as innate rhythms defined by the period (τ), phase (peak [Φ] and trough time), amplitude (A, peak-trough difference) and mean level. The human time structure in its entirety is comprised of ultradian (τ < 20 h), circadian (20 h > τ < 28 h) and infradian (τ > 28 h) bioperiodicities. The circadian time structure (CTS) of human beings, which is more complicated than in lower animals, is orchestrated and staged by a brain central multioscillator system that includes a prominent pacemaker - the suprachiasmatic nuclei of the hypothalamus. Additional pacemaker activities are provided by the pineal hormone melatonin, which circulates during the nighttime, and the left and right cerebral cortices. Under ordinary circumstances this system coordinates the τ and Φ of rhythms driven by subservient peripheral cell, tissue and organ clock networks. Cyclic environmental, feeding and social time cues synchronize the endogenous 24 h clocks and rhythms. Accordingly, processes and functions of the internal environment are integrated in time for maximum biological efficiency, and they are also organized and synchronized in time to the external environment to ensure optimal performance and response to challenge. Artificial light at night (ALAN) exposure can alter the CTS as can night work, which, like rapid transmeridian displacement by air travel, necessitates realignment of the Φ of the multitude of 24 h rhythms. In 2001, Stevens and Rea coined the phrase "circadian disruption" (CD) to label the CTS misalignment induced by ALAN and shift work (SW) as a potential pathologic mechanism of the increased risk for cancer and other medical conditions. Current concerns relating to the effects of ALAN exposure on the CTS motivated us to renew our long-standing interest in the possible role of CD in the etiopathology of common human diseases and patient care. A surprisingly large number of medical conditions involve CD: adrenal insufficiency; nocturia; sleep-time non-dipping and rising blood pressure 24 h patterns (nocturnal hypertension); delayed sleep phase syndrome, non-24 h sleep/wake disorder; recurrent hypersomnia; SW intolerance; delirium; peptic ulcer disease; kidney failure; depression; mania; bipolar disorder; Parkinson's disease; Smith-Magenis syndrome; fatal familial insomnia syndrome; autism spectrum disorder; asthma; byssinosis; cancers; hand, foot and mouth disease; post-operative state; and ICU outcome. Poorly conceived medical interventions, for example nighttime dosing of synthetic corticosteroids and certain ß-antagonists and cyclic nocturnal enteral or parenteral nutrition, plus lifestyle habits, including atypical eating times and chronic alcohol consumption, also can be causal of CD. Just as surprisingly are the many proven chronotherapeutic strategies available today to manage the CD of several of these medical conditions. In clinical medicine, CD seems to be a common, yet mostly unrecognized, pathologic mechanism of human disease as are the many effective chronotherapeutic interventions to remedy it.

Nocturnal light pollution and underexposure to daytime sunlight: Complementary mechanisms of circadian disruption and related diseases.

Routine exposure to artificial light at night (ALAN) in work, home, and community settings is linked with increased risk of breast and prostate cancer (BC, PC) in normally sighted women and men, the hypothesized biological rhythm mechanisms being frequent nocturnal melatonin synthesis suppression, circadian time structure (CTS) desynchronization, and sleep/wake cycle disruption with sleep deprivation. ALAN-induced perturbation of the CTS melatonin synchronizer signal is communicated maternally at the very onset of life and after birth via breast or artificial formula feedings. Nighttime use of personal computers, mobile phones, electronic tablets, televisions, and the like--now epidemic in adolescents and adults and highly prevalent in pre-school and school-aged children--is a new source of ALAN. However, ALAN exposure occurs concomitantly with almost complete absence of daytime sunlight, whose blue-violet (446-484 nm λ) spectrum synchronizes the CTS and whose UV-B (290-315 nm λ) spectrum stimulates vitamin D synthesis. Under natural conditions and clear skies, day/night and annual cycles of UV-B irradiation drive corresponding periodicities in vitamin D synthesis and numerous bioprocesses regulated by active metabolites augment and strengthen the biological time structure. Vitamin D insufficiency and deficiency are widespread in children and adults in developed and developing countries as a consequence of inadequate sunlight exposure. Past epidemiologic studies have focused either on exposure to too little daytime UV-B or too much ALAN, respectively, on vitamin D deficiency/insufficiency or melatonin suppression in relation to risk of cancer and other, e.g., psychiatric, hypertensive, cardiac, and vascular, so-called, diseases of civilization. The observed elevated incidence of medical conditions the two are alleged to influence through many complementary bioprocesses of cells, tissues, and organs led us to examine effects of the totality of the artificial light environment in which humans reside today. Never have chronobiologic or epidemiologic investigations comprehensively researched the potentially deleterious consequences of the combination of suppressed vitamin D plus melatonin synthesis due to life in today's man-made artificial light environment, which in our opinion is long overdue.

Diurnal and twenty-four hour patterning of human diseases: cardiac, vascular, and respiratory diseases, conditions, and syndromes.

Various medical conditions, disorders, and syndromes exhibit predictable-in-time diurnal and 24 h patterning in the signs, symptoms, and grave nonfatal and fatal events, e.g., respiratory ones of viral and allergic rhinorrhea, reversible (asthma) and non-reversible (bronchitis and emphysema) chronic obstructive pulmonary disease, cystic fibrosis, high altitude pulmonary edema, and decompression sickness; cardiac ones of atrial premature beats and tachycardia, paroxysmal atrial fibrillation, 3rd degree atrial-ventricular block, paroxysmal supraventricular tachycardia, ventricular premature beats, ventricular tachyarrhythmia, symptomatic and non-symptomatic angina pectoris, Prinzmetal vasospastic variant angina, acute (non-fatal and fatal) incidents of myocardial infarction, sudden cardiac arrest, in-bed sudden death syndrome of type-1 diabetes, acute cardiogenic pulmonary edema, and heart failure; vascular and circulatory system ones of hypertension, acute orthostatic postprandial, micturition, and defecation hypotension/syncope, intermittent claudication, venous insufficiency, standing occupation leg edema, arterial and venous branch occlusion of the eye, menopausal hot flash, sickle cell syndrome, abdominal, aortic, and thoracic dissections, pulmonary thromboembolism, and deep venous thrombosis, and cerebrovascular transient ischemic attack and hemorrhagic and ischemic stroke. Knowledge of these temporal patterns not only helps guide patient care but research of their underlying endogenous mechanisms, i.e., circadian and others, and external triggers plus informs the development and application of effective chronopreventive and chronotherapeutic strategies.

Diurnal and twenty-four hour patterning of human diseases: acute and chronic common and uncommon medical conditions.

The symptom intensity and mortality of human diseases, conditions, and syndromes exhibit diurnal or 24 h patterning, e.g., skin: atopic dermatitis, urticaria, psoriasis, and palmar hyperhidrosis; gastrointestinal: esophageal reflux, peptic ulcer (including perforation and hemorrhage), cyclic vomiting syndrome, biliary colic, hepatic variceal hemorrhage, and proctalgia fugax; infection: susceptibility, fever, and mortality; neural: frontal, parietal, temporal, and occipital lobe seizures, Parkinson's and Alzheimer's disease, hereditary progressive dystonia, and pain (cancer, post-surgical, diabetic neuropathic and foot ulcer, tooth caries, burning mouth and temporomandibular syndromes, fibromyalgia, sciatica, intervertebral vacuum phenomenon, multiple sclerosis muscle spasm, and migraine, tension, cluster, hypnic, and paroxysmal hemicranial headache); renal: colic and nocturnal enuresis and polyuria; ocular: bulbar conjunctival redness, keratoconjunctivitis sicca, intraocular pressure and anterior ischemic optic neuropathy, and recurrent corneal erosion syndrome; psychiatric/behavioral: major and seasonal affective depressive disorders, bipolar disorder, parasuicide and suicide, dementia-associated agitation, and addictive alcohol, tobacco, and heroin cravings and withdrawal phenomena; plus autoimmune and musculoskeletal: rheumatoid arthritis, osteoarthritis, axial spondylarthritis, gout, Sjögren's syndrome, and systemic lupus erythematosus. Knowledge of these and other 24 h patterns of human pathophysiology informs research of their underlying circadian and other endogenous mechanisms, external temporal triggers, and more effective patient care entailing clinical chronopreventive and chronotherapeutic strategies.

Expression of melatonin receptors in triple negative breast cancer (TNBC) in African American and Caucasian women: relation to survival.

In the normal rodent breast, the pineal hormone melatonin controls the development of ductal and alveolar tissue. Melatonin counteracts tumor occurrence and tumor cell progression in vivo and in vitro in animal and human breast cancer cell cultures. It acts predominantly through its melatonin MT1 receptor. Our aim was to investigate the presence or absence of the MT1 melatonin receptor in the aggressive triple negative group of human breast carcinoma (TNBC) and its possible relationship to the course of the disease. A total of 167 patients with a ER-, PR-, Her-2/neu- phenotype in which tissue for receptor studies was available were examined. The MT1 receptor immunostain was evaluated semiquantitatively as staining intensity (0, 1, 2, 3), percentage of stained cells and the weighted index (WI) (staining intensity times percentage of stained cells). A score of WI < 60 was regarded as "negative". There was a striking difference in incidence of MT1 positivity and staining intensity between carcinomas in African American (AA) and Caucasian (C) women. The AA showed a higher incidence of MT1 negative tumors (41/84 = 48.8 % in AA, 6/51 = 11.8 % in C) and a lower average WI. MT1 positivity in TNBC was associated with a lower stage and a smaller tumor size at time of diagnosis. In multivariable survival analysis, MT1 negative TNBC in all cases regardless of race showed a significantly higher hazard ratio for disease progression, shorter progression free survival, and disease-related death, and shorter OS. This was especially pronounced in the AA group but did not reach statistical significance in the smaller group of C alone. These results suggest that melatonin or a melatonin receptor agonist may be useful biologic additions in the treatment of some forms of TNBC, especially in AA who generally show a more aggressive course of their disease.

Rheumatoid arthritis: circadian rhythms in disease activity, signs and symptoms, and rationale for chronotherapy with corticosteroids and other medications.

Biological processes and functions at all hierarchical levels are organized in time as biological rhythms of discrete periods. Circadian (24-hour) rhythms, which are of direct importance to clinical medicine, are orchestrated by a set of clock genes of the master brain clock situated in the suprachiasmatic nuclei of the hypothalamus plus numerous subservient peripheral cellular clocks of all tissues and organs. Circadian rhythms are kept in step with the surrounding physical and social milieu by periodic external time cues, the most important one being the 24-hour environmental light-dark cycle. The circadian time structure gives rise to predictable-in-time day-night patterns in morbid and mortal events plus symptom occurrence and severity of common chronic conditions, including rheumatoid arthritis (RA). The circadian pattern of various cytokines and hormones in RA disease activity suggests a new treatment paradigm (i.e., chronotherapy-timing medications to 24-hour rhythms in disease pathophysiology) to improve desired outcomes. Since the 1950s, RA chronotherapy in the United States and Europe has involved several nonsteroid anti-inflammatory drugs (NSAIDs), certain disease modifying antirheumatic drugs (DMARDs), and various synthetic corticosteroid medications.

Acute exposure to 50-Hz magnetic fields increases interleukin-6 in young healthy men.

Some epidemiologic studies have suggested that extremely low frequency magnetic fields might affect human health and, in particular, that the incidence of certain types of cancer might increase among individuals living or working in environments exposed to such fields. This study is part of a broad study we conducted in humans. The study presented here was designed to look for possible effects of acute exposure to 50-Hz magnetic fields (10 µT) on the interleukin 1 beta (IL-1ß), interleukin 2 (IL-2), interleukin 6 (IL-6), interleukin-1 receptor antagonist (IL-1RA), and the interleukin-2 receptor (IL-2R) production. Thirty-two young men (20-30 years old) were divided into two groups (sham-exposed or control group and exposed group) of 16 subjects each. All subjects participated in two 24-h experiments to evaluate the effects of both continuous and intermittent (1 h "off" and 1 h "on" with the field switched "on" and "off" every 15 s) exposure to linearly polarized magnetic fields. The subjects were exposed to the magnetic field from 2300 to 0800 while recumbent. Blood samples were collected during each session at 11:00, 17:00, 22:00, 01:00, 04:00, 06:00, and 08:00. Results showed that exposure to 50-Hz magnetic fields (10 µT) significantly increases IL-6 when subjects were exposed to an intermittent magnetic field. However, no effect has been observed on interleukin IL-1ß, IL-2, IL-1RA, and IL-2R.

Working memory capacity is decreased in sleep-deprived internal medicine residents.

BACKGROUND: Concerns about medical errors due to sleep deprivation during residency training led the Accreditation Council for Graduate Medical Education to mandate reductions in work schedules. Although call rotations with extended shifts continue, effects on resident sleep-wake times and working memory capacity (WMC) have not been investigated. OBJECTIVES: The objective of this study was to measure effects of call rotations on sleep-wake times and WMC in internal medicine residents. METHODS: During 2 months of an internal medicine training program adhering to ACGME work-hour restrictions (between April 2006 and June 2007), residents completed daily WMC tests, wore actigraphy watches, and logged their sleep hours. This observational study was conducted during a call month requiring 30-hour call rotations every fourth night, whereas the noncall month, which allowed sleep/wake cycle freedom, was used as the control. MAIN OUTCOME MEASURES: Sleep hours per night and WMC testing. RESULTS: Thirty-nine residents completing the study had less sleep per night during their call month (6.4 vs 7.3 h per night noncall, p < 0.001) and sleep per night varied from 3.7 to 10.1 hours. Call rotation caused greater self-assessed sleepiness and reduced WMC recall scores (-2.6/test, p < 0.05), and more math errors occurred when on call (+1.07/test, p < 0.04). Full recovery of WMC did not occur until the fourth day after call. On-call rotation on the first month had a confounding detrimental effect on WMC. CONCLUSION: A month of call rotations reduced overall sleep per night; sleep hours per night were variable, and WMC was adversely affected. Decreased WMC could explain impaired judgment during sleep deprivation, although clinical error rates were not evaluated.

Circadian and ultradian (12 h) variations of skin blood flow and barrier function in non-irritated and irritated skin-effect of topical corticosteroids.

The skin is the organ that receives the greatest exposure to light and shows a high-amplitude circadian rhythm in epidermal cell proliferation. We have previously demonstrated that the skin barrier function has a significant circadian rhythm. Corticosteroids (CS) are the most commonly used topical treatment in dermatology. Time-dependent differences in their efficacy and side-effects would be of considerable interest. The aims of the current study were to examine time-dependent cycles in the effect of topical CS application in healthy and irritated skin on skin blood flow and its relationship to barrier function. Twenty clinically healthy, diurnally active subjects were examined at eight and nine time points over a 24 or 28 h span respectively, using non-invasive skin bioengineering techniques of laser Doppler imaging, a transepidermal water loss (TEWL) device and a skin thermometer in a 28 h session. The results of this current study demonstrate circadian and ultradian (12 h) variations in skin blood flow. A significant correlation was found between skin temperature and skin blood flow but not with TEWL. Circadian and ultradian rhythms are maintained during treatment with high-potency and mid-potency CS in healthy skin. These rhythms persist during stratum corneum disruption with and without CS application.