Othild Schwartzkopff

Transdisciplinary unifying implications of circadian findings in the 1950s

A few puzzles relating to a small fraction of my endeavors in the 1950s are summarized herein, with answers to a few questions of the Editor-in-Chief, to suggest that the rules of variability in time complement the rules of genetics as a biological variability in space. I advocate to replace truisms such as a relative constancy or homeostasis, that have served bioscience very well for very long. They were never intended, however, to lower a curtain of ignorance over everyday physiology. In raising these curtains, we unveil a range of dynamics, resolvable in the data collection and as-one-goes analysis by computers built into smaller and smaller devices, for a continued self-surveillance of the normal and for an individualized detection of the abnormal. The current medical art based on spotchecks interpreted by reference to a time-unqualified normal range can become a science of time series with tests relating to the individual in inferential statistical terms. This is already doable for the case of blood pressure, but eventually should become possible for many other variables interpreted today only based on the quicksand of clinical trials on groups. These ignore individual differences and hence the individuals needs. Chronomics (mapping time structures) with the major aim of quantifying normalcy by dynamic reference values for detecting earliest risk elevation, also yields the dividend of allowing molecular biology to focus on the normal as well as on the grossly abnormal.

Cycles Tipping the Scale between Death and Survival (="Life")

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.

The Pineal Gland and Chronobiologic History: Mind and Spirit as Feedsidewards in Time Structures for Prehabilitation

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.

Feedsidewards: Intermodulation (Strictly) among Time Structures, Chronomes, in and around Us, and Cosmo‐vasculo‐neuroimmunity: About Ten‐yearly Changes: What Galileo Missed and Schwabe Found

Abstract: 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 bodys 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.

Chronomics of circulating plasma lipid peroxides and anti-oxidant enzymes and other related molecules in cirrhosis of liver. In the memory of late Shri Chetan Singh.

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 < 0.01). In addition to anticipated differences in overall mean value (MESOR), patients differed from healthy volunteers also in terms of their circadian pattern. 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.

Chronomics, neuroendocrine feedsidewards and the recording and consulting of nowcasts--forecasts of geomagnetics.

A multi-center four-hourly sampling of many tissues for 7 days (00:00 on April 5-20:00 to April 11, 2004), on rats standardized for 1 month in two rooms on antiphasic lighting regimens happened to start on the day after the second extremum of a moderate double magnetic storm gauged by the planetary geomagnetic Kp index (which at each extremum reached 6.3 international [arbitrary] units) and by an equatorial index Dst falling to -112 and -81 nT, respectively, the latter on the first day of the sampling. Neuroendocrine chronomes (specifically circadian time structures) differed during magnetically affected and quiet days. The circadian melatonin rhythm had a lower MESOR and lower circadian amplitude and tended to advance in acrophase, while the MESOR and amplitude of the hypothalamic circadian melatonin rhythm were higher during the days with the storm. The circadian parameters of circulating corticosterone were more labile during the days including the storm than during the last three quiet days. Feedsidewards within the pineal-hypothalamic-adrenocortical network constitute a mechanism underlying physiological and probably also pathological associations of the brain and heart with magnetic storms. Investigators in many fields can gain from at least recording calendar dates in any publication so that freely available information on geomagnetic, solar and other physical environmental activity can be looked up. In planning studies and before starting, one may gain from consulting forecasts and the highly reliable nowcasts, respectively.

Season's appreciations

To follow the tradition set by the late Franz Halberg, highlights of research performed over the last year from his Minnesota Center are summarized. They illustrate the broad international cooperation enjoyed by his center and the diversity of applications of the discipline he founded. The results briefly summarized herein in the form of an annotated bibliography are a testimony that his legacy continues to live on and constitutes a tribute to his memory.

Circadian time structure of circulating plasma lipid peroxides, antioxidant enzymes and other small molecules in peptic ulcers.

BACKGROUND 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. METHODS 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. RESULTS By population-mean cosinor analysis, a marked circadian variation was demonstrated for all variables in healthy subjects and in ulcer patients (p<0.001). 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. CONCLUSION 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.

Chronobiologically Interpreted Ambulatory Blood Pressure Monitoring in Health and Disease

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 tires 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 bodys 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.

Thirty-five-year climatic cycle in heliogeophysics, psychophysiology, military politics, and economics

Cycles of about 35 years found in the climate by Brückner 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.