Superposed epoch analysis of physiological fluctuations: possible space weather connections.

There is a strong connection between space weather and fluctuations in technological systems. Some studies also suggest a statistical connection between space weather and subsequent fluctuations in the physiology of living creatures. This connection, however, has remained controversial and difficult to demonstrate. Here we present support for a response of human physiology to forcing from the explosive onset of the largest of space weather events-space storms. We consider a case study with over 16 years of high temporal resolution measurements of human blood pressure (systolic, diastolic) and heart rate variability to search for associations with space weather. We find no statistically significant change in human blood pressure but a statistically significant drop in heart rate during the main phase of space storms. Our empirical findings shed light on how human physiology may respond to exogenous space weather forcing.

Diagnosing vascular variability anomalies, not only MESOR-hypertension.

Chronobiology is the study of biological rhythms. Chronomics investigates interactions with environmental cycles in a genetically coded autoresonance of the biosphere with wrangling space and terrestrial weather. Analytical global and local methods applied to human blood pressure records of around-the-clock measurements covering decades detect physiological-physical interactions, a small yet measurable response to solar and terrestrial magnetism. The chronobiological and chronomic interpretation of ambulatory blood pressure monitoring (C-ABPM) records in the light of time-specified reference values derived from healthy peers matched by sex and age identify vascular variability anomalies (VVAs) for an assessment of cardio-, cerebro-, and renovascular disease risk. Even within the conventionally accepted normal range, VVAs have been associated with a statistically significant increase in risk. Long-term C-ABPM records help to "know ourselves," serving for relief of psychological and other strain once transient VVAs are linked to the source of a load, prompting adjustment of one's lifestyle for strain reduction. Persistent circadian VVAs can be treated, sometimes by no more than a change in timing of the daily administration of antihypertensive medication. Circadian VVA assessment is an emergency worldwide, prompted in the United States by 1,000 deaths per day every day from problems related to blood pressure. While some heads of state met under United Nation and World Health Organization sponsorship to declare that noncommunicable diseases are a slow-motion disaster, a resolution has been drafted to propose C-ABPM as an added tool complementing purely physical environmental monitoring to contribute also to the understanding of social and natural as well as personal cataclysms.

Toward a personalized chronotherapy of high blood pressure and a circadian overswing.

Timing can greatly affect the response to a stimulus, including antihypertensive medications. Herein, we assess the response of 30 patients to losartan/hydrochlorothiazide (L/H), administered for at least 1 month at a given circadian stage to each patient, this stage being changed during consecutive spans to cover six treatment times from awakening to bedtime at approximately 3-hour intervals. At the end of each stage, each patient underwent a 7-day around-the-clock ambulatory blood pressure (BP) profile, analyzed chronobiologically. A larger reduction of the midline estimating statistic of rhythm (MESOR; a rhythm-adjusted mean) of diastolic BP was achieved by L/H administration in the early morning for more patients (P < .05), while treatment upon awakening was the best choice for most patients to reduce the circadian amplitude of BP the most (P < .01). The optimal treatment time varied considerably among patients, however. Special attention should be given to the effect on the circadian amplitude since treatment can increase it above a threshold, beyond which there is a marked increase in cardiovascular disease risk. The results indicate the desirability to individualize the optimization of the antihypertensive effect of L/H by timing along the circadian scale.

Rhythmic changes in colonic motility are regulated by period genes.

Human bowel movements usually occur during the day and seldom during the night, suggesting a role for a biological clock in the regulation of colonic motility. Research has unveiled molecular and physiological mechanisms for biological clock function in the brain; less is known about peripheral rhythmicity. This study aimed to determine whether clock genes such as period 1 (per1) and period2 (per2) modulate rhythmic changes in colonic motility. Organ bath studies, intracolonic pressure measurements, and stool studies were used to examine measures of colonic motility in wild-type and per1per2 double-knockout mice. To further examine the mechanism underlying rhythmic changes in circular muscle contractility, additional studies were completed in neuronal nitric oxide synthase (nNOS) knockout mice. Intracolonic pressure changes and stool output in vivo, and colonic circular muscle contractility ex vivo, are rhythmic with greatest activity at the start of night in nocturnal wild-type mice. In contrast, rhythmicity in these measures was absent in per1per2 double-knockout mice. Rhythmicity was also abolished in colonic circular muscle contractility of wild-type mice in the presence of N(omega)-nitro-L-arginine methyl ester and in nNOS knockout mice. These findings suggest that rhythms in colonic motility are regulated by both clock genes and a nNOS-mediated inhibitory process and suggest a connection between these two mechanisms.

Abnormalities in circadian blood pressure variability and endothelial function: pragmatic markers for adverse cardiometabolic profiles in asymptomatic obese adults.

BACKGROUND: Cardiovascular disease (CVD) risk, although perceived to be high, is often difficult to demonstrate in disease free (healthy) obese adults. HYPOTHESIS: Changes in circadian blood pressure variability (CBPV) and endothelial function (EF) may be early correlates of cardiometabolic disorders. METHODS: Asymptomatic men and women in 3 groups: normal weight (n = 10), overweight (n = 10) and obese (n = 15) were evaluated. Blood pressure and heart rate were recorded over 7 days: every 30 minutes during the day and every 60 minutes during the night, by automatic ambulatory monitoring. Resting EF was assessed in a fasting state between 8-10 AM by brachial ultrasound. Anthropometric and cardiometabolic indicators were measured and correlations with CBPV and EF were investigated. RESULTS: The 3 groups had (Mean(SD)) BMI: 22.6(1.6), 27(3) and 34(5) kg/m2, respectively, weight: 64(16), 79(14), 95(16) kg and waist circumference: 79(9), 93(10), 107(13) cm. None in normal-weight or overweight groups had abnormal CBPV, while 8 of 15 obese adults had one or more CBPV abnormities (p < 0.05). Obese adults with CBPV abnormalities had elevated hs-CRP (15.3(9.3) mg/L), fibrinogen (593(97) mg/dl), fasting serum glucose (102(16) mg/dL), and cardiac risk ratios (Total-C/HDL-C: 5.2(1.9), LDL-C/HDL-C: 3.1(1.4)). Adults in the 3 respective groups who did not have CBPV abnormalities had flow-mediated brachial artery dilatation (FMD) of 0.22(0.06); 0.20(0.04), 0.23(0.02) mm over resting diameter. Obese participants with CBPV abnormalities (Mesor-hypotension, circadian hyper amplitude tension, elevated pulse pressure), had attenuated FMD at 78, 52, and 56% of resting reference diameter (means 0.18(0.07), 0.12(0.08), and 0.13(0.05) mm; p < 0.05), respectively. CONCLUSIONS: Asymptomatic obese adults with abnormal CBPV and EF exhibit unfavorable cardiometabolic profiles.

Effects of acute and chronic STZ-induced diabetes on clock gene expression and feeding in the gastrointestinal tract.

Diabetes may shift clock gene expression within peripheral organs. However, little is known about the effect of diabetes on the gastrointestinal molecular clock. We therefore investigated the effect of diabetes on gastrointestinal clock gene expression. As peripheral clock gene expression is strongly driven by food intake, we also determined the effect of STZ-induced diabetes on patterns of food intake. The effects of acute (1 week) and chronic (12 weeks) STZ-induced diabetes on period (per) genes in the stomach body, proximal and distal colon, liver, kidney, and lung of C57BL/6J mice were assessed using real-time polymerase chain reaction. Food intake studies were completed using automated feeding equipment. Rhythmicity in expression of per2 and per3 persisted in all organs. However, per2 and per3 expression of STZ-injected mice was generally phase delayed within the gastrointestinal tract but not within the kidney or lung as compared with vehicle-injected mice. The phase delay was most pronounced for per2 in the proximal colon at 12 weeks. Food intake was rhythmic with larger circadian amplitude for diabetic mice than for control mice. Thus, STZ-induced diabetes differentially alters peripheral per expression. STZ-induced diabetes does not alter the circadian phase of food intake. Alterations in clock gene expression in a mouse model of diabetes are most pronounced in those organs that are intimately associated with food processing and metabolism.

Neonatal and maternal concentrations of hydroxil radical and total antioxidant system: protective role of placenta against fetal oxidative stress.

BACKGROUND: Reactive oxygen species (ROS) may cause peroxydation of lipids, proteins and deoxyribonucleic acids with subsequent cell damage. The hydroxyl radical (OH*) represents a measure of global oxidative stress. Hydroxyl radicals are short-lived; they form an important part of radical chemistry nonetheless. The measure of total antioxidant system (TAS) can give useful information about the extent of defence capable of counteracting the oxidative damage. Pregnancy is an important condition that favors oxidative stress in the fetus. Clinical studies indicate a protective mechanism against O2 toxicity in the human feto-placental unit. AIM: This study reports the OH* and TAS concentrations in mother and fetus at birth to evaluate the role of the placenta against fetal oxidative stress. METHODS: Blood samples were collected at delivery from 45 healthy women at term and from their newborns. The maternal and neonatal OH* and TAS concentrations were compared by paired Student t-test. RESULTS: OH* was higher in maternal blood than in cord blood (573.75+/- 170.0 UCarr/l vs 40.08+/-33.37 UCarr/l) (p<0.01); TAS concentrations did not differ between the two groups (1.11+/-0.09 mmol/l vs 1.17+/-0.12 mmol/l). Multiple regression analyses: maternal and neonatal OH* decreases with maternal age; only maternal TAS and OH* are related to gestational age in a nonlinear fashion. Female infants showed higher values of maternal and neonatal TAS as compared to male infants. CONCLUSION: TA protective role of the placenta against oxidative damage is in keeping with a large enough gradient of ROS (between mother and fetus) and the passage of TAS from mother to fetus.

Transcriptional profiling of mRNA expression in the mouse distal colon.

BACKGROUND & AIMS: Intestinal epithelial cells and the myenteric plexus of the mouse gastrointestinal tract contain a circadian clock-based intrinsic time-keeping system. Because disruption of the biological clock has been associated with increased susceptibility to colon cancer and gastrointestinal symptoms, we aimed to identify rhythmically expressed genes in the mouse distal colon. METHODS: Microarray analysis was used to identify genes that were rhythmically expressed over a 24-hour light/dark cycle. The transcripts were then classified according to expression pattern, function, and association with physiologic and pathophysiologic processes of the colon. RESULTS: A circadian gene expression pattern was detected in approximately 3.7% of distal colonic genes. A large percentage of these genes were involved in cell signaling, differentiation, and proliferation and cell death. Of all the rhythmically expressed genes in the mouse colon, approximately 7% (64/906) have been associated with colorectal cancer formation (eg, B-cell leukemia/lymphoma-2 [Bcl2]) and 1.8% (18/906) with various colonic functions such as motility and secretion (eg, vasoactive intestinal polypeptide, cystic fibrosis transmembrane conductance regulator). CONCLUSIONS: A subset of genes in the murine colon follows a rhythmic expression pattern. These findings may have significant implications for colonic physiology and pathophysiology.

Chronobiology and chronomics: detecting and applying the cycles of nature.

We monitor our streets to prevent assault and rodents to develop drugs, but not those for whom the drugs are intended. It took over half a century to begin to monitor blood sugar values in patients with insulin-dependent diabetes. Monitoring blood pressure is equally timely and technically feasible for individual home- and website-based personalised care. It also serves basic science and someday perhaps the management of societal illnesses.

Schedule shifts, cancer and longevity: good, bad or indifferent?

Prompted by a recent report of the possible carcinogenic effect of shiftwork focusing on the disruption of circadian rhythms, we review studies involving shifts in schedule implemented at varying intervals in unicells, insects and mammals, including humans. Results indicate the desirability to account for a broader-than-circadian view. They also suggest the possibility of optimizing schedule shifts by selecting intervals between consecutive shifts associated with potential side-effects such as an increase in cancer risk. Toward this goal, marker rhythmometry is most desirable. The monitoring of blood pressure and heart rate present the added benefit of assessing cardiovascular disease risks resulting not only from an elevated blood pressure but also from abnormal variability in blood pressure and/or heart rate of normotensive as well as hypertensive subjects.

Procedures for numerical analysis of circadian rhythms.

This article reviews various procedures used in the analysis of circadian rhythms at the populational, organismal, cellular and molecular levels. The procedures range from visual inspection of time plots and actograms to several mathematical methods of time series analysis. Computational steps are described in some detail, and additional bibliographic resources and computer programs are listed.

Cancer chronomics I. Origins of timed cancer treatment: early marker rhythm-guided individualized chronochemotherapy.

A 21-year old patient who presented in 1973 with a rare and highly malignant ovarian endodermal sinus tumor with spillage into the peritoneal cavity is alive and well today after receiving chronochemotherapy. During the first four courses of treatment, medications were given at different circadian stages. Complete blood counts and marker variables such as mood, vigor, nausea, and temperature were monitored around the clock and analyzed by cosinor to seek times of highest tolerance. Remaining treatment courses were administered at a time corresponding to the patient's best drug tolerance, rather than extrapolating the timing of optimal cyclophosphamide administration from also-implemented parallel laboratory studies on mice. Notwithstanding remaining hurdles in bringing chronochemotherapy to the clinic for routine care, merits of marker rhythm-guided chronotherapy documented in this and other case reports have led to the doubling of the two-year disease-free survival of patients with large perioral tumors in a clinical trial.

Cancer chronomics III. Chronomics for cancer, aging, melatonin and experimental therapeutics researchers.

This position paper documents the merit of including for basic and clinical investigations the mapping of circadian and other rhythms and yet broader chronomes, time structures in and around us. Chronobiometry used herein relies on inferential statistical methods and on materials documented earlier. The circadian amplitude of melatonin is shown to relate both to cancer risk and to the presence of overt cancer, when no differences are found in the 24-hour average of melatonin. Optimization of treatment by timing, thoroughly documented along the circadian scale earlier, could be broadened to include optimization along the scale of the week, and eventually beyond. In both cases, reliance on marker rhythmometry is advocated. More generally, the limits of knowledge are expanded by considering already mapped spectral components and their characteristics that can be influenced by the dynamics of heliogeomagnetic signals heretofore unassessed.

Cancer chronomics II. Origins of timing cancer treatment.

This paper is a memorial to Mikhail Victorovich Berezkin (MVB) (10 April 1940 - 16 January 2005), an enthusiastic advocate of chrono-oncology. It illustrates his early dose- and circadian time-response curves, limited as yet by a 4-timepoint approach, provides a list of his publications, and offers a succinct overview of individualized marker rhythm-guided oncotherapy.

Age-dependent association of exposure to television screen with children's urinary melatonin excretion?

OBJECTIVES: Changes in magnetic field are associated with a decrease in nocturnal urinary melatonin excretion. Television screens emit low and very low frequency electromagnetic waves (radiofrequencies and light) and exposure to them may be associated with a decrease in 24-hour melatonin in children's urine. Design and setting. An observational study in schools of Cavriglia, Italy, determined melatonin in 24-hour urines from 42 boys and 32 girls 6 to 13 years of age after one week of watching TV and after another week of abstaining from watching TV. RESULTS AND MAIN FINDINGS: In a gender- and age-dependent fashion, exposure to a television screen was associated with lower urinary melatonin concentrations, affecting particularly younger children at a pubertal stage when important changes in melatonin's time structure occur. CONCLUSION: Additional work should test further relations to growth, maturation and development, focusing on any adverse effect from exposure to a television screen also on obesity from a neuro-hormonal viewpoint, quite apart from any decreased activity and/or other lifestyle alterations associated with watching TV.

Opportunity of detecting pre-hypertension: worldwide data on blood pressure overswinging.

Overswinging or CHAT (brief for Circadian Hyper-Amplitude-Tension), that is an excessive circadian variation in blood pressure (BP), has been associated with a large increase in cardiovascular disease risk, present even in the absence of an elevated BP itself. This usually asymptomatic condition is usually overlooked by current practice based on spot-checks, because to be diagnosed, measurements need to be taken around-the-clock, preferably for 7 days at the outset. Once diagnosed, however, a usual circadian BP pattern can be restored by means of certain non-pharmacologic or pharmacologic interventions timed appropriately. Thereby, it is possible to reduce the risk of cardiovascular morbidity and mortality, cerebral ischemic events and nephropathy in particular. For the preparation of guidelines regarding the diagnosis of BP disorders and for the institution of primary as well as secondary preventive measures, it is important to know what the incidence of CHAT is on a global basis. We found 191 cases of CHAT among 1602 mostly 7-day/24-h BP profiles, obtained from several centers in different countries participating in an ongoing project on the BIOsphere and the COSmos (BIOCOS). CHAT incidence is about the same between men and women, but it is diagnosed more often among patients with borderline hypertension or with glucose intolerance. It is also more common among MESOR-hypertensive than among MESOR-normotensive individuals. Priority should be given to the development of an unobtrusive and affordable device to automatically monitor BP and to analyze the data as-one-goes, so that cardiovascular disease risk can be prevented.

Theodor Hellbrugge: 85 years of age - Ad multos transannos, sanos, fortunatos et beatos.

We honor Theo Hellbrugge's acclaimed endeavors in the rehabilitation, or rather the prehabilitation of handicapped children. So far, he has focused on obvious handicaps, and we trust that he will include concern for everybody's silent handicaps in the future by screening for abnormal variability inside the physiological range. Therein, we introduce cis- and trans-years, components of transdisciplinary spectra that are novel for biology and also in part for physics. These components have periods, respectively, shorter and longer than the calendar year, with a counterpart in magnetoperiodism. Transyears characterize indices of geomagnetic activity and the solar wind's speed and proton density. They are detected, alone or together with circannuals, in physiology as well as in pathology, as illustrated for sudden cardiac death and myocardial infarction, a finding calling for similar studies in sudden infant death syndrome (SIDS). As transyears can beat with circannuals, and depend on local factors, their systematic mapping in space and time by transdisciplinary chronomics may serve a better understanding of their putative influence upon the circadian system. Longitudinal monitoring of blood pressure and heart rate detects chronome alterations underlying cardiovascular disease risk, such as that of myocardial infarction and sudden cardiac death. The challenge is to intervene in a timely fashion, preferably at birth, an opportunity for pediatricians in Theo Hellbrugge's footsteps.

Approximate entropy of human respiratory movement during eye-closed waking and different sleep stages.

STUDY OBJECTIVE: The breath-to-breath variability of respiratory parameters changes with sleep stage. This study investigates any alteration in the approximate entropy (ApEn) of respiratory movement as a gauge of complexity in respiration, by stage of consciousness, in the light of putative brain interactions. PARTICIPANTS: Eight healthy men, who were between the ages of 23 and 29 years, were investigated. MEASUREMENTS AND RESULTS: The signals of chest wall movement and EEG were recorded from 10:30 PM to 6:00 AM. After analog-to-digital conversion, the ApEn of respiratory movement (3 min) and EEG (20 s) were computed. Surrogate data were tested for nonlinearity in the original time series. The most impressive reduction in the ApEn of respiratory movement was associated with stage IV sleep, when the ApEn of the EEG was also statistically significantly decreased. A statistically significant linear relation is found between the ApEn of both variables. Surrogate data indicated that respiratory movement had nonlinear properties during all stages of consciousness that were investigated. CONCLUSION: Respiratory movement and EEG signals are more regular during stage IV sleep than during other stages of consciousness. The change in complexity described by the ApEn of respiration depends in part on the ApEn of the EEG, suggesting the involvement of nonlinear dynamic processes in the coordination between brain and lungs.