G. Katinas

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.

Multiple resonances among time structures, chronomes, around and in us. Is an about 1.3-year periodicity in solar wind built into the human cardiovascular chronome?

Aims: Velocity changes in the solar wind recorded by satellite (IMP8 and Wind) are characterized by a solar cycle–dependent ∼1.3-year component. The presence of any ∼1.3-year component in human blood pressure (BP) and heart rate (HR) and in mortality from myocardial infarction (MI) is tested and its relative prominence compared to the 1.0-year variation. Materials and Methods: Around-the-clock manual or automatic BP and HR measurements from four subjects recorded over 5–35 years and a 29-year record of mortality from MI in Minnesota were analyzed by linear–nonlinear rhythmometry. Point and 95% confidence interval (CI) estimates were obtained for the ∼1.3-year period and amplitude. The latter is compared with the 1.0-year amplitude for BP and HR records concurrent to the solar data provided by one of the authors (JDR). Results: An ∼1.3-year component is resolved nonlinearly for MI, with a period of 1.23 (95% CI: 1.21, 1.26) years. This component was invariably validated with statistical significance for BP and HR by linear rhythmometry. Nonlinearly, the 95% CI for the 1.3-year amplitude did not overlap zero in 11 of the 12 BP and HR series. Given the usually strong synchronizing role of light and temperature, it is surprising that 5 of the 12 cardiovascular series had a numerically larger amplitude of the 1.3-year versus the precise 1.0-year component. The beating of the ∼1.3-year and 1.0-year components was shown by gliding spectra on actual and simulated data. Discussion and Conclusion: The shortest 5-year record (1998–2003) revealed an ∼1.3-year component closer to the solar wind speed period characterizing the entire available record (1994–2003) than the value for the concurrent 5-year span. Physiological variables may resonate with nonphotic environmental cycles that may have entered the genetic code during evolution.

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.

Geomagnetics and society interact in weekly and broader multiseptans underlying health and environmental integrity

Evidence for the ubiquity and partial endogenicity of about-weekly (circaseptan) components and multiples and/or submultiples thereof (the multiseptans) accumulates as longer and denser records become available. Often attributed to a mere response to the social schedule, circaseptan components now have been documented to characterize environmental variables related to primarily non-photic solar effects. Plausibly, like circadians, circaseptans are anchored in genomes, from bacteria to humans, via both an internal and external evolution. If so, circaseptans, like circadians, may be found in the absence of a 7-day schedule, whereas the social schedule may play a synchronizing role and be responsible for the detection of prominent weekly variations in population statistics. The wobbliness of multiseptans and other components of some environmental time structures (chronomes) may correspond to the wobbliness of multiseptans found in cardiovascular morbidity statistics. Here, the latter stem primarily, but not exclusively, from an extensive database on the incidence of daily calls for an ambulance in Moscow, Russia from 1979-1981. A modulation of multiseptans and other chronome components of both environmental and biological variables by the about 11-year solar activity cycle (and of other low-frequency signals reviewed elsewhere) may account for prior controversies and scepticism about a variety of non-photic effects on biota. This is notably the case when relatively short series are analyzed without consideration of effects of unassessed long-term variations; this is the task of the new field of chronomics. In the spectral element of the chronomes of geophysical and biospherical variability, there are natural near weeks,apart from any precise 7-day periodicity.

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.

Meta-analysis of sequential luteal-cycle-associated changes in human breast tissue

We chronobiologically estimate the time relations of physiological and morphological changes in breast tissue during the luteal phase of the menstrual cycle, as a cascade led by the progesterone peak. The timing and uncertainties of maxima in epithelial mitotic frequency, breast and epithelial volume, breast surface temperature, water content, blood flow and apoptosis are given as parts of a rhythmic element in a broader time structure or chronome.

About 8- and ∼84-h rhythms in endotheliocytes as in endothelin-1 and effect of trauma

Population densities (PD) of capillaries (C) and endotheliocytes (E) were determined in pinnal dermis of C57BL mice before and after trauma. Moving (and overall) least-squares spectra before trauma detected in EPD (versus CPD) pronounced 3.5-day (circasemiseptan) and 8-h oscillations corresponding to components of the endothelin-1 chronome in human blood plasma reported earlier. Circadians were more pronounced in CPD. After trauma, circasemiseptan oscillations appeared also in CPD; their period gradually shortened and in two weeks split into about 2.5- and about 4.5-day oscillations; and circadian components became very pronounced. The pre-traumatic chronome was not restored within three weeks following trauma.

Circaseptan aspects of self-assessed sleep protocols covering 70 nights on 33 clinically healthy persons.

This study aimed to describe quantitatively some changes in sleep behavior. During 70 consecutive nights, 28 women and 3 men, 30 to 40 years of age and presumably clinically healthy, recorded the time of each awakening. Times of falling asleep were estimated from markings at 10-min. intervals from the times of lying down to sleep as an indication that the subject had not yet fallen asleep. Sleep duration and an index of effective sleep derived there from were analyzed by rhythmometric methods. On a group basis, anticipated components with periods of 1 and 0.5 wk., synchronized with the social schedule, were detected with statistical significance. Until long-term polysomnographic monitoring can readily cover the week automatically rather than only one or a few daily sleep spans, the self-monitoring of sleep behavior, yielding the circaseptan endpoints derived herein, may serve as a cost-effective tool in sleep research. By virtue of their relative simplicity, they could be part of a protocol designed to assess pharmacologic or nonpharmacologic interventions of sleep disturbance aimed at restoring undisturbed sleep.