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The circadian rhythm, as part of a broad time structure (chronome) of lipid peroxides and antioxidant defense mechanisms may relate to prevention, efficacy and management of preventive and curative chronotherapy.Fifty newly diagnosed patients with peptic ulcers, 30-45 years of age, and 60 age-matched clinically healthy volunteers were synchronized for one week with diurnal activity from about 06:00 to about 22:00 and nocturnal rest. Breakfast was served around 08:30, lunch around 13:30 and dinner around 20:30. Drugs known to affect the free-radical systems were not taken. Blood samples were collected at 6-hour intervals for 24h under standardized, presumably 24-hour synchronized conditions. Plasma lipid peroxides, in the form of malondialdehyde (MDA), blood superoxide dismutase (SOD), glutathione peroxide (GPx), glutathione reductase (GR), catalase (CAT) activities, and serum total protein, albumin, ascorbic acid, total serum cholesterol, and HDL-cholesterol concentrations were determined.By population-mean cosinor analysis, a marked circadian variation was demonstrated for all variables in healthy subjects and in ulcer patients (p0.001). As compared to controls, patients had a lower MESOR of MDA, SOD, GPx, GR, ascorbic acid, and HDL-C. They also had smaller circadian amplitude of SOD, CAT, GPx, GR, ascorbic acid, T-C, and HDL-C, but larger circadian amplitude of MDA and albumin. As compared to healthy subjects, the circadian acrophase of ulcer patients occurred later for MDA and GR and earlier for GPx.Mapping circadian rhythms, important chronome components that include trends with age and extra-circadian components characterizing antioxidants and pro-oxidants, is needed for exploring their putative role as markers in the treatment and management of peptic ulcers.

This work aims at studying in children the prevalence of some vascular variability anomalies (VVAs), i.e. indices of an increased risk of heart and vessel diseases revealed by chronobiologic analysis of cardiovascular monitoring data – systolic (SBP) and diastolic (DBP) MESOR-hypertension/hypotension, circadian hyper-amplitude-tension (CHAT), ecphasia and an excessive pulse pressure (EPP). A reference group of 138 healthy Moscow schoolchildren (age 12–17 years) was used for determination of 90% prediction limits for the circadian parameters of SBP and DBP, specified by gender and age (or height). The test group included another 194 children of the same age range with headache and abnormal BP values by casual measurement. BP data series from each child were analyzed by the COSINOR method. VVAs were found in 44.8% of children from the test group. In boys, VVAs occur more often than in girls (51.5% vs. 30.6%). One child may have up to 3 VVAs. The presence of VVAs may be related to an elevated BMI. The most common VVAs in childhood are the abnormalities of PP and systolic CHAT. Cosinor analysis can reveal a large number of children with PP higher than a threshold (60 mmHg) during a relatively long portion of the day (more than 1/3 of the 24 h span).

Dr Franz Halberg, a towering figure in cardiovascular research who founded and developed the new science of modernized chronobiology, passed away a month shy of 94 years of age on June 9, 2013. The chronobiological vocabulary and ambulatory monitoring methods were his original conceptions. Dr Halberg’s international stature and contributions to hypertension research through chronobiological methods were monumental, and we pay our respects to this outstanding scientist, educator, and scientific father and his dedication to the advancement of heart attack and stroke victims, hypertension research through chronobiological methods in individual monitoring, analyses, and interpretation in variations as a function of Time. In the early stages of his professional life, his keen observations of biological variations in living beings enabled him to find periodicities shared between biological systems and their broad environments, influenced by the sun and the cosmos, leading to chronomics (broad time structures beyond circadian rhythms). Biological time structures (clock hours) and chronomes are considered essential parameters in blood pressure monitoring, as well as in neurohormonal rhythms and other organs/systemic variations. The impact Dr Halberg had in science stemmed not only from his original findings but also from his vision of their implications that led beyond a scientific breakthrough to a new way of thinking as a truly great scientist. His lifetime of hard work after his medical education and training seeking optimal configurations of the time structure has contributed to some of the greatest advancements in the modern scientific world and standardized clinical practice, especially in hypertension. His research on timing guided by the circadian clock observed early changes in blood pressure and heart rate variability, especially large fluctuations in amplitudes and shift changes in peak hours among heart attack and stroke victims, and cancer patients. The changed rhythms can be detected during subclinical stages by ambulatory monitoring, …

To honor Douglas Wilson, this paper reviews evidence for studying and quantifying rhythms as the indispen- sable control, whether to assess the effect of a fixed-calorie meal taken as breakfast or dinner, or to understand how human physiology and pathology may be affected by space-terrestrial weather. Since D. Wilson's work has dealt intensively with salivary hormonal determinations, we illustrate what can be learned from longitudinal series obtained in health or from a patient suffering from adynamic depression episodes recurring twice a year and lasting 2-3 months. The socially less unacceptable collection of serial salivary samples should be introduced more broadly into laboratory medicine for a more refined diagnosis and as a means to guide the optimization of any needed treatment by timing.

This tribute to her parents by one co-author (NDP) is the fruit of a more than a decade-long search by the senior author (FH) for the details of the lives of Bernhard and Gertraud (''Traute'') Düll. These pioneers studied how space/terrestrial weather may differentially influence human mortality from various causes, the 27-day mortality pattern being different whether death was from cardiac or respiratory disease, or from suicide. FH is the translator of personal information about her parents provided by NDP in German. Figuratively, he also attempts to ''translate'' the Dülls' contribution in the context of the literature that had appeared before their work and after their deaths. Although the Dülls published in a then leading journal, among others (and FH had re-analyzed some of their work in a medical journal), they were unknown to academies or libraries (where FH had inquired about them). The Dülls thoroughly assembled death certificates to offer the most powerful evidence for an effect of solar activity reflected in human mortality, as did others before them. They went several steps further than their predecessors, however. They were the first to show possibly differential effects of space and/or Earth weather with respect to suicide and other deaths associated with the nervous and sensory systems vs. death from cardiac or respiratory disease as well as overall death by differences in the phase of a common 27-day cycle characterizing these mortality patterns. Furthermore, Bernhard Düll developed tests of human visual and auditory reaction time to study effects of weather and solar activity, publishing a book (his professorial dissertation) on the topic. His unpublished finding of an increased incidence of airplane crashes in association with higher solar activity was validated after his death, among others, by Tatiana Zenchenko and A. M. Merzlyi.

To detect vascular variability anomalies (VVAs), a blood pressure and heart rate profile around the clock for at least 7 days is a start. As a minimum, measurement every 60 or preferably 30 minutes for a week is needed, to be continued if abnormality is found, to assess the about 24-hour (circadian) variability that exists in all individuals. As a first dividend, one then also obtains a glimpse of 2 of the very many longer-than-circadian periodicities, the biological half-week and week. Certainly if we can have sensors and computer chips in our cars that continuously monitor the pressure over a tire's life, we should be able to do the same job for ourselves for diagnostic and therapeutic decisions. Healthcare today emphasizes wellness with recommendations for exercise and a proper diet, yet these evaluations may not be adequate. BP may be measured at a visit to the doctor or before an exercise session, along with measuring body weight and performing a physical exam. The seeds of disease are planted long before they are visible, and what appears to be normal from a conventional point of view may in fact be abnormal. Hidden alterations of physiological function, masked by the body's remarkable adaptive capabilities, may become visible through a new diagnostic and therapeutic realm—-chronobiology—-that reveals hitherto unseen abnormalities. The tools of chronobiology may yield additional dividends, such as the detection of physiological “loads” related to stress and stress relief and the undesirable effects of space weather upon personal events such as sudden cardiac death, societal events like terrorism and war, and natural disasters. Chronobiologically interpreted automatic ambulatory BP and heart rate (HR) monitoring (C-ABPM) may detect the antecedents of these types of events. C-ABPM is of interest in preventive cardiology, since it reveals new diagnoses as vascular variability anomalies (VVAs) and renders previous conventional diagnoses more reliable, such as that of an elevated BP. These VVAs include MESOR (midline-estimating statistic of rhythm)-hypertension, an elevation of the MESOR, which is diagnosed, like all other VVAs, only after 1 or preferably several replications of 7-day around-the-clock BP monitoring with available, affordable, and unobtrusive instrumentation. The recommendation for continuous C-ABPM recognizes several principles that constitute inseparably intertwined contributors to severe cardio-, cerebro- and renovascular diesase. C-ABPM gauges wear and tear of genetics, physical loads, and in particular mental stress placed upon individuals from “womb to tomb” by daily life, including weather in extraterrestrial space as well as that on earth, as a continuous surveillance paradigm preventing us from flying blind to a change from less than 5% to near 100% in the risk of a stroke within 6 years.

Cycles of about 35 years found in the climate by Bruckner and Egeson were aligned with periodic changes in the length of the solar cycle by the Lockyers. The solar-cycle length and climate were subsequently revisited without reference to any cyclicity or those who discovered it. The descriptive statistics of Bruckner and Lockyer were repeatedly questioned and, with notable exceptions, have been forgotten. Bruckner’s data, taken from his summary chart, are shown here for the first time inferentially statistically validated as nonstationary (to the point of intermittency) and, as transdisciplinary, extending from meteorology to 2556 years of international battles; to 2189 years of tree rings; to ∼900 years of northern lights; to 400 years of economics; to 173 years of military affairs; and to ∼40 years of helio-, interplanetary- and geomagnetics matching a longitudinal record by a healthy individual who self-measured his heart rate and mental functions (with a 1-min time estimation), among other variables. Space weather, mirrored in the circulation of human blood, can be tracked biologically as a dividend from self-assessed preventive health care including the automatically and ambulatory-recorded heart rate and blood pressure for detecting and treating heretofore ignored vascular variability disorders. A website providing free analyses for anyone (in exchange for their data) could serve any community with computer-savvy members and could start focusing the attention of the population at large on problems of societal as well as individual health. Space weather was found to affect the human cardiovascular system, and it has been supposed that data on space weather can be inversely assimilated from biological self-monitoring data.

In the late 19th century, Charles Egeson, a map compiler at the Sydney Observatory, carried out some of the earliest research on climatic cycles, linking them to about 33-year cycles in solar activity, and predicted that a devastating drought would strike Australia at the turn of the 20th century. Eduard Brückner and William J. S. Lockyer, who, like Egeson, found similar cycles, with notable exceptions, are also, like the map compiler, mostly forgotten. But the transtridecadal cycles are important in human physiology, economics and other affairs and are particularly pertinent to ongoing discusions of climate change. Egeson's publication of daily weather reports preceded those officially recorded. Their publication led to clashes with his superiors and his personal life was marked by run-ins with the law and, possibly, an implied, but not proven, confinement in an insane asylum and premature death. We here track what little is known of Egeson's life and of his bucking of the conventional scientific wisdom of his time with tragic results.

Systematic chronobiologically interpreted ambulatory blood pressure (BP) and heart rate (HR) monitoring (C-ABPM 7D/24H is now automatically possible; if continued around the clock over a week, this approach detects vascular variability disorders (VVDs) that include, among others, high BP itself and CHAT, short for circadian hyper-amplitude-tension. BP is never a constant “true” (resting) value and can be more reliably diagnosed by CABPM 7d/24h as MESOR-hypertension, MH. CHAT carries a risk of hard events greater than MH and can be treated, among other VVDs, which if they coexist constitute vascular variability syndromes (VVSs). A project on The BIOsphere and the COSmos, BIOCOS (corne001@umn.edu), provides, in exchange for the data, cost-free analyses and the opportunity of obtaining monitors at a cost reduction of 80%. Biospheric monitoring complements the records from purely physical tools for surveilling the variable sun, by validating in the biosphere the reality of intermittent, aeolian environmental spectral components that can be more consistent than their physical counterparts once they are coded in genes. C-ABPM 7D/24H indicates relevant associations of space weather with human health and ecology. Monitoring reveals, around and in living matter, a system of transdisciplinary cycles with common average periods, quantified with point-and-interval estimates of parameters. The cycles in space climate are critical in discussing global warming. The cycles’ periods are described as congruent when their CIs (95% confidence intervals) overlie or overlap and the amplitudes’ CIs’ lower limits are positive. Some congruent cycles in organisms, counterparts of the environmental day and the seasons, relate to electromagnetic radiation in the visible domain; these are the usually environmentally synchronized socio-photo-thermoperiodisms (photics). The biosphere also resonates with or is pulled or driven by nonstationary, environmental nonphotic cycles (nonphotics) — particle emissions from the sun and the wider cosmos, cosmoheliogeomagnetics, ultraviolet flux, gravitation, acoustics and others. Nonphotics, a set of in part transdisciplinarily-novel spectral components, can be intermittent; when present, they coexist and compete with signatures of photic cycles, monitored, e.g., in BP and HR. Nonphotics of, e.g., about (∼) 1 week (circaseptans) and ∼17 months (transyears), characterize mood and performance, modulate and sometimes override society’s (photic) schedules, even in dying suddenly either unintentionally or by one’s own will or at the hand of others. Nonphotics persist, but are damped in physiology or in terrorism, when their environmental counterpart is not detected. Their elucidation provides information on how a set of cycles covering 18 orders of magnitude in the frequency domain of the biosphere bears on the question “What is life?”: a resonance of the biosphere with periods of its environment constitutes life itself.

Chronomic cardiovascular surveillance serves to recognise and treat any risk elevation as well as overt disease, and to ascertain whether treatment is effective and, if so, for how long treatment effects lasts, be it for lowering an increased risk and/or in surveilling the success or failure of treatment. A treatment-associated increase in circadian amplitude of blood pressure (BP) may induce iatrogenic overswinging, also dubbed CHAT ( circadian hyper- amplitude- tension), in some patients, thereby increasing cardiovascular disease risk unknowingly to care provider and receiver.

New components of transdisciplinary spectra or known components in new variables in us, matching those around us, are being mapped. Their hardly trivial interactions associated with the good and bad around us - from religiosity to crime and war - are being rendered measurable, for the eventual development of countermeasures to the diseases of societies and nations. Internal cycles not only underlie life itself and underlie our evolving genetics at all levels of organization; they also constitute the essential control and reference information in all transdisciplinary science. In preparing for travel to Mars and other missions in space that may take more than a year, let us do what is immediately practicable. Transyears may have very small amplitudes yet are associated with sudden cardiac death in some terrestrial locations; if they should play a role in these electrical incidents of the heart, among others like myocardial infarction and stroke, they will jeopardize lengthy missions in extraterrestrial space, away from hospitals.The likelihood of stroke or cardiac death can be immediately reduced by chronobiologically assessing blood pressure and heart rate variability and by optimizing the efficacy of timed treatment rather than relying on an unacceptable and often inaccurate spotcheck and treating by convenience rather than pertinence. Needed are: detection of nocturnal abnormality when medication may no longer be effective (or is too effective) neither seen during office visits by day; detection of circadian hyper-amplitude-tension (CHAT) associated with a risk of stroke and kidney disease greater than other risks (including "hypertension" when all risks are assessed concomitantly); detection of CHAT as high risk among normotensives who may not need anti-hypertensive medication; individualized inferential statistical testing to determine whether a drug or non-drug intervention such as autogenic training (relaxation) is effective and for how long (detecting any initial and later success or failure), some of which conditions otherwise are not found without chronobiology; individualization of treatment timing, since the same dose of the same medication can further lower the subject's blood pressure average and circadian amplitude when the timing of daily administration is optimized, as ascertained by sequential testing and parameter tests.Thus, we save lives by monitoring and assessing, and if need be treating, vascular disease risk through chronobiologically interpreted 24-hour or preferably longer (24-hour/7-day) blood pressure and heart rate variability. Abnormalities in the variability of blood pressure and heart rate, impossible to find during a conventional office visit (the latter aiming at the fiction of a "true" blood pressure), can raise cardiovascular disease risk in the next six years from 4% to 100%.

Looking back on our January 20–27, 2005 visit to India, it was a whirlwind trip, very rewarding, exciting and also strenuous, in particular for Franz and also for myself, though on a somewhat different level, since I was mainly free of responsibilities. We returned 3 days before I started this note, maybe not long enough to be able to attain a more settled impression and judgment. My main purpose is to give a descriptive report about Franz’ effort to bring advances made in mapping chronomes (time structures) into practice in areas with limited resources. In particular, we wish to bring diagnostic and preventive possibilities into the clinical armament by the timely recognition and treatment of otherwise silent yet greatly increased risks of heart and brain attacks.

In Göttingen, Germany, circadian variations in melatonin had been determined time-macroscopically in pineal glands, blood plasma and duodenum of chicken and rats. When these data were meta-analyzed, they agreed with the results from an independent survey on tissues from rats collected in a laboratory in Pécs, Hungary. In the latter study, tissues were analyzed chemically in Bratislava, Slovakia, and numerically in Minneapolis, MN, USA, all by single- and multiple-component cosinor and parameter tests. In rats and chickens, these inferential statistical procedures clearly demonstrated a lead in phase of the 24-h cosine curves best fitting all of the duodenal vs. those best fitting all of the pineal melatonin values in each species in 2 geographic (geomagnetic) locations. The 24-h cosine curve of circulating melatonin was found to be in an intermediate phase position. Mechanisms of the phase differences and the contribution of gastrointestinal melatonin to circulating hormone concentrations are discussed.

Background. The chronome (from chronos , time, and nomos , rule; time structure) of lipid peroxidation and anti-oxidant defense mechanisms may relate to the efficacy and management of preventive and curative chronotherapy. Patients and methods. Thirty patients with liver cirrhosis, 25–45 years of age, and 60 age-matched clinically healthy volunteers were synchronized for 1 week with diurnal activity from about 06:00 to about 22:00 and nocturnal rest. Breakfast was around 08:30, lunch around 13:30 and dinner around 20:30. Drugs known to affect the free-radical system were not taken. Blood samples were collected at 6-h intervals for 24 h under standardized, presumably 24-h synchronized conditions. Determinations included plasma lipid peroxides, in the form of malondialdehyde (MDA), blood superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR) activities, and serum total protein, albumin, ascorbic acid, and uric acid concentrations. Results. A marked circadian variation was demonstrated for each variable in each group by population-mean cosinor ( P Conclusion. Mapping the broader time structure (chronome) with age and multifrequency rhythm characteristics of antioxidants and pro-oxidants is needed for exploring their putative role as markers in the treatment and management of liver cirrhosis.

On Sunday morning June 9, 2013, one of the greatest scientists of the 20th and 21st centuries left us. His close associates also lost a very staunch friend and a mentor who never ceased to inspire....

Longitudinal records of blood pressure (BP) and heart rate (HR) around the clock for days, weeks, months, years, and even decades obtained by manual self-measurements (during waking) and/or automatically by ambulatory monitoring reveal, in addition to well-known large within-day variation, also considerable day-to-day variability in most people, whether normotensive or hypertensive. As a first step, the circadian rhythm is considered along with gender differences and changes as a function of age to derive time-specified reference values (chronodesms), while reference values accumulate to also account for the circaseptan variation. Chronodesms serve for the interpretation of single measurements and of circadian and other rhythm parameters. Refined diagnoses can thus be obtained, namely MESOR-hypertension when the chronome-adjusted mean value (MESOR) of BP is above the upper limit of acceptability, excessive pulse pressure (EPP) when the difference in MESOR between the systolic (S) and diastolic (D) BP is too large, CHAT (circadian hyper-amplitude tension) when the circadian BP amplitude is excessive, DHRV (decreased heart rate variability) when the standard deviation (SD) of HR is below the acceptable range, and/or ecphasia when the overall high values recurring each day occur at an odd time (a condition also contributing to the risk associated with 'non-dipping'). A non-parametric approach consisting of a computer comparison of the subject's profile with the time-varying limits of acceptability further serves as a guide to optimize the efficacy of any needed treatment by timing its administration (chronotherapy) and selecting a treatment schedule best suited to normalize abnormal patterns in BP and/or HR. The merit of the proposed chronobiological approach to BP screening, diagnosis and therapy (chronotheranostics) is assessed in the light of outcome studies. Elevated risk associated with abnormal patterns of BP and/or HR variability, even when most if not all measurements lie within the range of acceptable values, becomes amenable to treatment as a critical step toward prevention (prehabilitation) to reduce the need for rehabilitation (the latter often after costly surgical intervention).

A test of the relative merits of timed melatonin for the treatment of cardiac ischemia as well as hypertension refractory to other drugs is documented against the background of earlier chronobiological studies on blood pressure (BP), disease risks, circadian hyper-amplitude-tension and melatonin effects broadly.

Gliding spectral windows illustrate the changes as a function of time in the relative prominence of signals in a given frequency range, viewed in 3D or as surface charts. As an example, the method is applied to a 2189-year series of averages of ring measurements on 11 sequoia trees published by Douglass. Analyses of the original data and after filtering reveal, among others, components with periods of about 10.5 and 21 years similar to the Schwabe and Hale solar activity cycles. An alignment of gliding spectra with a global spectrum serves to define, by minima, the ranges of variability around the anticipated Schwabe and Hale cycles. This procedure may have more general applicability when dealing with ranges of only transiently synchronized, wobbly, and perhaps sometimes free-running periodicities. Solar activity is known to affect climate and changes in climate are reflected to some extent in tree growth. The spectral structure in tree rings could serve not only to check any relations of climate with sunspots, auroras and more modern measures of solar activity, but also to check any purely mathematical extrapolations from the much shorter available actual data on solar activity. With such extrapolated series and the data analyzed herein, the task remains to align physical and physiological variables to further study the influence of natural environmental factors near and far on biota, including international battles, which cover an even longer span of 2556 years.

We suggest a putative benefit from timing nutriceuticals (substances that are both nutrients and pharmaceuticals) such as antioxidants for preventive or curative health care, based on the proven merits of timing nutrients, drugs, and other treatments, as documented, i.a., in India. The necessity of timing melatonin, a major antioxidant, is noted. A protocol to extend the scope of chronoradiotherapy awaits testing. Imaging in time by mapping rhythms and broader time structures, chronomes, for earliest diagnoses, for example detection of vascular disease risk, is recommended. The study of rhythms and broader chronomes leads to a dynamic functional genomics, guided by imaging in time of free radicals and antioxidants, amongst many other variables.

Seven of the eight authors of this report each performed physiologic self-surveillance, some around the clock for decades. We here document the presence of long cycles (decadals, including circaundecennians) in the time structure of systolic (S) and diastolic (D) blood pressure (BP) and heart rate (HR). Because of the non-stationary nature in time and space of these and other physiologic and environmental periodic components that, like the wind, can appear and disappear in a given or other geographic location at one or another time, they have been called “Aeolian”. The nonlinear estimation of the uncertainties of the periods (τs) of two or more variables being compared has been used to determine whether these components are congruent or not, depending on whether their CIs (95% confidence intervals) overlap or not. Among others, congruence has been found for components with τs clustering around 10 years in us and around us. There is a selective assortment among individuals, variables and cycle characteristics (mean and circadian amplitude and acrophase). Apart from basic interest, like other nonphotic solar signatures such as transyears with periods slightly longer than one year or about 33-year Brückner-Egeson-Lockyer (BEL) cycles, about 10-year and longer cycles present in 7 of 7 self-monitoring individuals are of interest in the diagnosis of Vascular Variability Anomalies (VVAs), including MESOR-hypertension, and others. Some of the other VVAs, such as a circadian overswing, i.e., CHAT (Circadian Hyper-Aplitude-Tension), or an excessive pulse pressure, based on repeated 7-day around-the-clock records, can represent a risk of severe cardiovascular events, greater than that of a high BP. The differential diagnosis of physiologic cycles, infradians (components with a τ longer than 28 hours) as well as circadians awaits the collection of reference values for the infradian parameters of the cycles described herein. Just as in stroke-prone spontaneously hypertensive rats during the weeks after weaning CHAT precedes an elevation of the BP MESOR, a decadal overswing seems to precede the occurrence of high BP in two of the subjects here examined. Only around-the-clock monitoring in health for the collection of reference values will allow on their basis the differential diagnosis of the onsets of a circadian versus a circadecadal overswing in BP and the specification whether, and if so, when to initiate hypotensive non-drug or drug treatment.

Biological cycles with relatively long and some unusual periods in the range of the half-week, the half-year, years, or decades are being discovered. Their prior neglect constituted a confounder in aging and much other research, which then “flew blind” concerning the uncertainties associated with these cycles when they are not assessed. The resolution of more about 10-year and other cycles, some reported herein, replaces the admission of complete unpredictability, implied by using the label “secularity.” Heretofore unaccounted-for variability becomes predictable insofar as it proves to be rhythmic and is mapped systematically to serve as a battery of useful reference values. About 10-year cycles in urinary 17-ketosteroid excretion and in heart rate and its variability, among others, are aligned with cycles of similar length in mortality from myocardial infarction. Associations accumulate between cycles of natural physical time structures, chronomes such as the 10.5-year (circadecennian) Schwabe and the 21-year (circavigintunennian) Hale cycles of solar activity, and chronomes in biota. There are about 50-year (circasemicentennian) cycles in mortality from stroke in Minnesota and in the Czech Republic and also in human morphology at birth, the latter result reducing the likelihood that these cycles are purely human made. Associations among large populations warrant long-term systematic coordinated sampling of natural physical and biological variables of interest for the design of countermeasures against already documented elevated risks of stroke, myocardial infarction, and other catastrophic diseases, notably in elderly adults. New findings will be introduced against the background of the documented value of mapping rhythms in medicine and gerontology. In both these fields, rhythms promise the seeming paradox of better care for less.

New reports corroborate our prior finding that hypotension in infancy is associated with impaired neurodevelopment later in childhood. We had also found that neurological deficit is further associated with a more pronounced circadian variation in transcutaneous pO2 (tcpO2). New evidence in adulthood prompts the recommendation to automatically monitor vital signs for continued surveillance, relying on the methods of chronobiology for data analysis as-one-goes. This applies notably early in extra-uterine life when infants may be particularly sensitive to ischemic cerebral injury secondary to systemic hypotension. Monitoring at this sensitive lifetime stage has also provided a glimpse of unseen effects of the cosmos on the patterns of blood pressure variability, detected by chronomics.

Geomagnetic variations of partly interplanetary origin, with cyclic signatures in human affairs and pathology include the incidence of various diseases, regarding which this study of healthy subjects attempted to determine an underlying mechanism by worldwide archival and physiological monitoring, notably of heart rate variability (HRV). In the past half-century, the possible health and other hazards of natural, solar variability-driven temporal variations in the earth's magnetic field have become a controversial subject in view of the inconsistent results. Some well-documented claims of associations between geomagnetic storms and myocardial infarction or stroke have been rejected by a study based on more comprehensive data analyzed by rigorous methods - covering, however, only part of a solar cycle in only part of a hemisphere. It seems possible that inter-solar cycle and geographic variability, if not geographic differences, may account for discrepancies. Herein, we examine the start of a planetary study on any influence of geomagnetic disturbances that are most pronounced in the auroral oval, on human HRV. The magnetic field variations exhibit complex spectra and include the frequency band between 0.001-10 Hz, which is regarded as ultra-low frequency by physicists. Since the 'ultra-low-frequency' range, like other endpoints used in cardiology, refers to much higher frequencies than the about-yearly changes that are here shown to play a role in environmental-organismic interactions revealed by HRV, the current designations used in cardiology are all placed in quotation marks to indicate the need for possible revision. Whether or not this suggestion has an immediate response, we have pointed to a need for the development of instrumentation and software that renders the assessment of circadian, infradian and even infra-annual (truly low frequency) modulations routinely feasible. HRV was examined on the basis of nearly continuous 7-day records by ECG between December 10, 1998, and November 2, 2000, on 19 clinically healthy subjects, 21 to 54 years of age, in Alta, Norway. A geomagnetic record was obtained from the Auroral Observatory of the University of Tromso. First, frequency-domain measures of HRV were compared for each person in 24-hour spans of high geomagnetic disturbance versus quiet conditions. Second, cross-spectra between geomagnetic activity and HRV measures were quantified via the squared coherence spectrum using 7-day time series. A 7.5% increase in the 24-hour average of heart rate, HR (P = 0.00020) and a decrease in HRV were documented on days of high geomagnetic disturbance. The decrease in HRV was validated statistically for the 'total frequency', 'TF' endpoint (18.6% decrease, P= 0.00009). The decrease in spectral power was found primarily in the 'circaminutan frequency', 'VLF' (21.9% decrease, P< 0.000001) in conjunction with the 'minutes-to-hours' component, ultra-low-frequency, 'ULF' (15.5% decrease, P= 0.00865) and circadecasecundan 'low frequency', 'LF' (14.2% decrease, P = 0.00187) regions of the spectrum. Power-law scaling of the power spectra did not show any statistically significant difference. It is noteworthy that most of the decrease in HRV, except for the circaminutan (VLF) component, was observed only in the season in which sunshine alternated with darkness (D/L), a finding suggesting a mechanism influenced by the alternation of light and darkness. The hypothesis of a light-dark-influenced magnetoreception was also supported by cross-spectral analysis. Group-averaged coherence at frequencies coincident with the geomagnetic Pc 6 pulsations (with periods ranging from 10 minutes to 5 hours) differed with a statistical significance (P < 0.000001) among the three natural lighting conditions, the association being weaker during UL or D/D than during D/L. By contrast, no statistically significant differences were found in terms of the circadian and circasemidian frequencies in relation to the alternation of sunshine with darkness or rather circannual rhythm stage. In conclusion, evidence is provided herein that an alteration of HRV is most apparent in the circaminutan ('VLF') region, which is clinically important, because a reduction in its power is a predictor of morbidity and mortality from cardiovascular disease. The circadecasecundan ('LF') component of HRV also decreased in association with geomagnetic disturbance, which may reflect an episodic alteration of arterial pressure related to changes in geomagnetic activity. Lastly, our study suggests the existence of a light-dark-influenced magnetoreception mechanism in humans involving mainly the Pc 6 band of the magnetic field.

For dealing with everyday physiology, that is, with respect to physiological variation in the normal range, the prevailing position corresponds to that in preatomic physics. The "a-tom" was then the smallest known particle that could not be further split. Breaking the atom opened the door to a new universe of particles governed by new forces and physical laws. Nuclear physics evolved and brought new knowledge, a new energy source and a wealth of practical applications. The analogy applies to the splitting of the normal range into the time structures of everyday physiology. From picking different times of day and seasons for study, a trans-disciplinary science, chronobiology, emerged. Chronobiology objectively maps chronomes (portmanteau'd from chronos = time and nomos = rule), time structures quantifying the relations among cycles and other events. The chronomes of variables in and around us intermodulate with each other; thus, we start exploring organisms as dynamic systems open to their environments nea...

Serial measurements, taken around the clock in the laboratory and clinic, can be analyzed by computer-implemented curve-fitting to assess the approximate 24-hour (circadian) variation, among other rhythmic and chaotic components of the time structure (chronome) of any variable. This approach is particularly important to quantify blood pressure variability, which renders even the most accurate single measurement into a snapshot on a roller coaster. A seemingly acceptable blood pressure can be particularly misleading when accompanied by the recommendation of another check-up in 2 years, which is the official position of the World Health Organization. An overswinging of the blood pressure along the 24-hour scale may then be missed. This excessive circadian amplitude, called "circadian hyper-amplitude-tension" (CHAT), constitutes a new disease risk syndrome, warranting screening, diagnosis, and treatment. With or without the midline-estimating statistic of rhythm (MESOR) (i.e., the [chronome-adjusted] mean va...

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.

An impeccable time series, published in 1930, consisting of hourly observations on colony advance in a fluid culture of E. coli, was analyzed by a periodogram and power spectrum in 1961. While the original senior author had emphasized specifically periodicity with no estimate of period length, he welcomed further analyses. After consulting his technician, he knew of no environmental periodicity related to human schedules other than an hourly photography. A periodogram analysis in 1961 showed a 20.75-h period. It was emphasized that "... the circadian period disclosed is not of exactly 24-h length." Confirmations notwithstanding, a committee ruled out microbial circadian rhythms based on grounds that could have led to a different conclusion, namely first, the inability of some committee members to see (presumably by eyeballing) the rhythms in their own data, and second, what hardly follows, that there were "too many analyses" in the published papers. Our point in dealing with microbes and humans is that analyses are indispensable for quantification and for discovering a biologically novel spectrum of cyclicities, matching physical ones. The scope of circadian organization estimated in 1961 has become broader, including about 7-day, about half-yearly, about-yearly and ex-yearly and decadal periodisms, among others. Microbial circadians have become a field of their own with eyeballing, yet time-microscopy can quantify characteristics with their uncertainties and can assess broad chronomes (time structures) with features beyond circadians. As yet only suggestive differences between eukaryotes and prokaryotes further broaden the perspective and may lead to life's sites of origin and to new temporal aspects of life's development as a chronomic tree by eventual rhythm dating in ontogeny and phylogeny.

We propose to initiate the automatic self-assessment of wear and tear as “stress and strain” by the time structures of blood pressure (BP) and heart rate (HR), in order to arrive eventually at an individualized timely and timed routine of life and to early preventive intervention as soon as needed. The routine may involve physiological scheduling of physical and mental activities and meals, and if need be of non-drug or drug treatment for stress amplification, e.g., by exercise, and/or strain (not stress) relief by relaxation. In so doing, we recognize the circulation as a pillar and marker of preventive and active neuroimmunomodulation (NIM), suggesting that some concerns of a vasculo– and broader NIM can be quantified by transdisciplinary chronobiology using its cartography—chronomics—of time structures, i.e., chronomes, from chronos = time and nomos = rule. Thus, we are introducing the chronomics of BP, HR and of other variables in the historical context of pioneers who were indispensable to experimental medicine. We build upon their contributions, but we must point out when, in the past, by necessity rather than choice, the giants provided rationalizing truisms that are no substitute for systematic serial data collection and appropriate computer analysis. A time-unspecified spotcheck as a baseline is much better than no measurement, but very often it is not enough, and it is always insufficient when an estimate of variability constitutes the information needed. For dynamic cycles, there are only reference cycles as a routine, although when maps are available, single timed spotchecks can be invaluable. With reference to their historical context, here we rely only upon data which necessity, rather than philosophy, compels us to collect.

An initial infradian prominence characterizes the spectral element of the chronome or the time structure of half-hourly heart rates during the first 40 days after birth of a boy born at term. Immediately pertinent infradian prominence, which was previously documented for many premature infants and anticipated from the integration of 2-day segments of half-hourly data from infants born at term, is now displayed longitudinally. Dominating first are an about-weekly (circaseptan) or half-weekly (circasemiseptan) and an about 26-day (circatrigintan) component, with a subsequent change from infradian to circadian prominence.

System time is defined as the duration (T) and sampling density (deltat) of a given study. A time horizon is obtained by combining analytical results on endpoints of time structures (chronomes), usually on control groups, from accumulating diverse studies carried out with drastically different values of T and deltat. These two design considerations depend upon and are limited by resources. The desideratum of a small At e.g., for studies of chaotic endpoints, limits T, e.g., has thus far precluded a continuous mapping of decadal cycles in endpoints such as the approximate entropy or the correlation dimension. Time horizons are being documented for an increasing number of variables that undergo cycles with infra-annual frequencies - with one cycle in about one, two and/or five decades - in the biosphere as in the environment. These infra-annuals, in and around us, modulate ultra-annuals, including circadians, as well as about 7-day (circaseptan) and about half-yearly (circasemiannual) cycles, all prominent, e.g., in geophysical and biospheric specta. Neglect of infra-annual chronomics can lead to blunders. A statistically highly significant decrease in the excretion of steroidal metabolites (or in heart rate variability) may be misinterpreted as premature aging if it lasts for several years, and may be unnecessarily acted upon, e.g., by drugs. The decrease, however, may only be transient, occurring only during a given stage of a circadecadal cycle, and it may be followed for the next several years by an also spurious "rejuvenation", possibly misinterpreted as a drug effect. When recognized as the alternating stages of decadal cycles and assessed with an affordable deltat, infra-annuals of variables involved in major problems of our day, including homicides and wars, may lead us to manipulable internal or external mechanisms, and thus, eventually, possibly to countermeasures to crime and terror as well as to the optimization of aims such as spirituality.

Taking the heart rate (HR) for one cycle, whether to examine behavior in the region of periods of 1 s, 1 day, 1 week, 1.3 or 10.5 years, etc., is hazardous. Replications, when possible are mandatory for examining altered variability, whatever the period(s) involved may be. This replication in the individual, and across individuals when the periods are long, measured in decades, may serve for diagnosis and treatment. This rule applies in particular to a seemingly transient circadian hyper-amplitude-tension (CHAT), an over peer-threshold variability in blood pressure (BP), based on the fit of a 24-h cosine curve to time series of appropriate length, rather than to a mere snapshot covering just a single day or week. Transient CHAT may turn into intermittent CHAT, as determined in two cases presented herein. One case of transient CHAT could be so named after a successful treatment (Rx) change eliminated CHAT as an effect validated by monitoring at 30-min intervals for a 7-day span on a new treatment. CHAT disappeared for over 300 consecutive half-hourly measurements, but thereafter it reappeared. During the ensuing nearly continuously monitored 5 years, CHAT continued to appear and disappear sometimes without a treatment change. In another case, which was responsive to a change in the timing of medication, CHAT also disappeared and thereafter reappeared. In a short-term perspective of weeks or months of monitoring, CHAT seemed to be transient, but further monitoring again revealed it to be intermittent. Cases of intermittent CHAT require follow-up for outcomes by comparison with the population at large. Miniaturized instrumentation for their detection should be a high priority, but it must be realized that the automatic ambulatorily functioning monitors, available at 10% of the regular price through a BIOCOS project (corne001@umn.edu), already signify great progress, as compared to previously used manual measurements made around the clock by hypertensive opinion leaders in medicine from diagnosis to death. On automatically collected time series of BP and HR, gliding pergressive spectral windows as such, or such pergressive windows aligned further with global spectral windows, visualize the changing dynamics involved in health and disease, in the steps of Werner Menzel and Paolo Scarpelli.

Objectives: To review mechanisms of circadian variations in heart rate variability (HRV) and blood pressure variability (BPV) and mortality and morbidity due to cardiovascular diseases (CVD). Methods: Results from 7-day/24-h HRV and BPV are interpreted by gender and age-specified reference values in the context of a Medline search. Results: Abnormal HRV and BPV measured around the clock for 7 days provides information on the risk of subsequent morbid events in subjects without obvious heart disease and without abnormality outside the conventional (in the sense of chronobiologically unquantified) physiological range. Meditation, β-blockers, ACE inhibitors, n-3 fatty acids and estrogens may have a beneficial influence on HRV, but there is no definitive outcome-validated therapy. Low HRV has been associated with a risk of arrhythmias and arrhythmic death, unstable angina, myocardial infarction, progression of heart failure and atherosclerosis. BPV may be characterized by treatable circadian-hyper-amplitude-tension (CHAT), which can be transient ‘24-h CHAT' or ‘7-day-CHAT', MESOR-hypertension and/or an unusually-timed (odd) circadian acrophase (ecphasia), all associated with an increased risk of stroke, stroke death, myocardial infarction, and kidney disease. Conclusions: Precise insight into the patho-physiology in time of HRV and BPV is needed with development of a consensus on best measures of HRV for clinical purposes and to determine when a 7-day record interpreted chronobiologically suffices and when it does not, for detection within as well as outside the conventional normal range, for diagnostic clinical practice and to direct therapy of risk greater than that associated with hypertension, smoking or any other risk factor.

Any influence of the natural variation in the geomagnetic field on human health has become an increasingly pertinent question in view of associations in space with myocardial infarction and stroke in Israel, Mexico, Minneapolis and Russia. HRV is examined on the basis of 7-day records by Holter ECG on 14 clinically healthy subjects (21-54 years) in Alta, Norway. Cross-spectra between geomagnetic activity and HRV measures were quantified via the squared coherence spectrum. Coherence was observed at the circadian frequency in VLF (coherence value: 0.6895), LF (0.6667) and HF (0.7065). Circadian coherence between geomagnetic disturbance and HRV endpoints would prompt the hypothesis that in polar regions human circadian periodicity is coordinated not only by photic factors, but also by non-photic circadian geomagnetic disturbance.

The spectrum of biological rhythms is extended far beyond circadians, circannuals, and ultradians, such as 1.5-hourly melatonin and 8-hourly endothelin-1 (ET-1) rhythms by statistics of natality, growth, morbidity, and mortality, some covering decades or centuries on millions of individuals. These reveal infradian cycles to be aligned with half-weekly rhythms in ET-1, weekly and half-yearly ones in melatonin, and even longer-about 50-, about 20-, and about 10-year cycles found in birth statistics. About daily, weekly, yearly, and ten-yearly patterns are also found in mortality from myocardial infarctions; the 10-yearly ones are also in heart rate and its variability; in steroid excretion, an aspect of resistance, for example, to bacteria; and in the genetic changes of the bacteria themselves. Automatic physiological measurements cover years and, in one case, cover a decade; the latter reveal an about 10-year (circadecennial) cycle. ECGs, covering months beat-to-beat, reveal circaseptans, gaining prominence in response to magnetic storms or after coronary artery bypass grafting. A spectrum including cycles from fractions of 1 Hz to circasemicentennians is just one element in biological time structures, chronomes. Chaos, trends, and any unresolved variability are the second to fourth elements of chronomes. Intermodulations, feedsidewards, account for rhythmically and thus predictably recurring quantitative differences and even for opposite treatment effects of the same total dose(s) of (1) immunomodulators inhibiting or stimulating DNA labeling of bone in health or speeding up versus slowing down a malignant growth and thus shortening or lengthening survival time, or (2) raising or lowering blood pressure or heart rate in the vascular aspect of the body's defense. Latitude-dependent competing photic and nonphotic solar effects upon the pineal are gauged by alternating yearly (by daylight) and half-yearly (by night) signatures of circulating melatonin at middle latitudes and by half-yearly signatures at noon near the pole. These many (including novel near 10-yearly) changes, for example, in 17-ketosteroid excretion, heart rate, heart rate variability, and myocardial infarction in us and those galactic, solar, and geophysical ones around us have their own special signatures and contribute to a cosmo-vasculo-immunity and, if that fails, to a cosmo(immuno?) pathology.

Not only circadian rhythms — recurring patterns with a period of about 24 h (in the range of 20-28 h) — but also ultradian and infradian rhythms (with periods shorter than 20 h and longer than 28 h, respectively), characterize melatonin in humans, whether it is measured in blood, saliva, or urine. Among infradians, the about-yearly (circannual) and half-yearly (circasemiannual) components are noteworthy. At mid-latitude, circannuals may predominate in circulating melatonin during the daytime, whereas circasemiannuals may become more prominent during the nighttime. A stable half-yearly component also prominently characterizes the geomagnetic disturbance index Kp. Support for the hypothesis that Kp may influence human melatonin is provided by the fact that closer to tine pole, at 65 °N in Oulu, Finland, geomagnetic effects are stronger. There, circulating melatonin, measured around noon, exhibits a clear circasemiannual variation. Circaseptans and circasemiseptans, with periods of about a week and half a week, are found ubiquitously in relation to the pineal gland. In the case of melatonin secreted into the superfusion fluid by the pike pineal in vitro, kept at constant temperature in continuous darkness, the circaseptan component has an amplitude larger than that of the circadian rhythm. Circaseptans are also observed in the mouse pineal gland in vivo, wherein the presence of melatonin has been questioned, yet established by three independent groups of investigators who all documented a circadian variation peaking during the dark (rest) span.

Magnetic storms trigger myocardial infarctions with mechanisms relating to heart rate variability. Solar cycle-to-solar cycle differences and solar cycle stage dependence shown herein may resolve prior controversy and serve to advocate coordinated worldwide systematically aligned biological and physical monitoring. * This paper was originally invited by the historian-geophysicist Wilfried SCHRöDER of Bremen, Germany, for his biographical "Encounters," and is to serve as an update on the project on the BIOsphere and the Cosmos (BIOCOS) and its offspring ICEHRV (Dr. Kuniaki Otsuka's International Chronome Ecologic Study of Heart Rate Variability). It is intended for distribution at a NATO conference on space weather hazards, organized by Dr. Ioannis Daglis, June 18-29, 2000.

A joining of chronobiology and endocrinology was achieved in 1974 at a symposium focusing on the critical role of the hypothalamic-pituitary-adrenal network on the basic side and on the first drug to carry timing in its name. The next step is a section on chronobiology in this neuroendocrinology journal. An account of the problems encountered before both asepsis and universal literacy became the law of the profession and of the land serves here as background to endeavors in behalf of chronobiologic literacy. A step toward the latter goal is the use of systematically collected measurements of heart rate and blood pressure evaluated by computer against reference standards from peers of corresponding age, gender and ethnicity. Thereby, an illustrative, clinically relevant aspect of everyday physiology is resolved within the otherwise neglected normal range, and disease risk syndromes are detected so that preventive treatment can be instituted before catastrophic disease occurs. The scope of this chronobiology section of the Neuroendocrinology Letters is to map the time-qualified feedsideward interactions within the neuroendocrines, in the rest of an organism and in the environment. Thereby, we replace time-unqualified feedbacks and feedforwards, along imaginary axes, by neuroendocrine and cellular networks operating predictably insofar as rhythmically within the range of everyday physiology. Subtle effects are thus found that are otherwise covered by the curtain of ignorance drawn over the normal range. More important, feedsidewards account for opposite effects that recur rhythmically, and thus help clarify mechanisms that may underlie the difference between stimulating or inhibiting a malignancy and thus shortening or lengthening the lifespan.

Brunetto Tarquini became professor of medical semeiotics and cardiology in 1981, and chief of an internal medicine department in 1990, a position he held until his untimely death. As director of the Inter-University Center for Clinical Chronobiology and as coordinator of a post-doctoral school in chronobiology, Brunetto influenced many young Italian physicians. He became the leader of a budding specialty of chronomedicine, coordinating an international group. His focus included temporal aspects of vascular diseases from womb-to-tomb as well as oncological risk factors. His research thus ranged from neonatology over neuroendocrinology to geriatrics, by studies on the pineal in particular, documenting the signature of heliogeomagnetic master switches for circulating human melatonin.