2001


 

Franz Halberg*, Germaine Cornélissen*, Christopher Bingham*, Mary Sampson*, George Katinas*, Pavel Prikryl Sr.•, Pavel Prikryl Jr.•, Salvador Sanchez de la Peña‡,
Clicerio Gonzalez‡, Franklin Barnwell*, Cristina Maggioni§, Othild Schwartzkopff*

 

*University of Minnesota, Minneapolis, Minnesota, USA

•Brno, Czech Republic

‡Instituto Politecnico Nacional, Mexico City, Mexico

§Universita degli Studi di Milano, Milan, Italy

 

Address correspondence to:

Franz Halberg, MD

Director, Halberg Chronobiology Center

University of Minnesota

715 Mayo Building · MMC 8609

420 Delaware St. S.E.

Minneapolis, MN 55455, USA

Tel 612.624.6976 · Fax 612.624.9989

E-mail halbe001@umn.edu

 

Support: U.S. Public Health Service (GM-13981); Dr. h.c. Dr. h.c. Earl Bakken Fund; University of Minnesota Supercomputing Institute

 

 

         In the third year of the center, its bibliography (Appendix I: citations from it are prefixed with I) shows the continuing activities of the BIOCOS (The BIOsphere in the COSmos) project. More and more time structures, chronomes, in and around us, were mapped, less and less incompletely. The cartography could be based on longer and sometimes denser time series than earlier. Most important, the kinds of cycles explored, untouchables for classical physiology, broadened in scope. From the prevention of diseases of individuals, we set out on a dangerous journey. We trust that it may perhaps lead us to manageable, since physically and mathematically analyzable, physiologic mechanisms that contribute fundamentally to the ills of society. For this purpose, we further pursued the cartography of some of the internal-external interactions in aligned demographical, physiological and physical time series, including variables pertinent in fighting crime and war, Figure 1. By exclusive reliance on data, we hope to show that by the mapping of variability inside the physiological range, the concepts of chronobiology and chronomics are as important as, if not more important than the concepts of the constancy of the internal environment championed by Claude Bernard at the end of his life (1) and of homeostatic hunting and righting introduced by Walter Bradford Cannon (2). Our aim is to resolve what the young Bernard recognized as his major discovery: the "extreme variability of the internal environment" (3) and to render it useful in everyday life. In this context, by far, the greatest news, a pleasure to report, second to none, is the continuance of Healthwatch, the monitoring of the entire town of Urausu, Japan, under the guidance of two honorary members of our center, clinician Kuniaki Otsuka [photo 1], and epidemiologist Shoki Yano [photo 2].

         We thank the 108 co-authors worldwide who contributed this year to 69 published titles as of December 31, 2001. Franz appreciates his election to the Leibniz Society (the former Prussian academy of science), which he addressed in December 2000 and where he is to introduce chronomics in January 2002. We were pleased to accept an invitation extended to all of us by the geophysicist and historian Wilfried Schröder to address the Joint Scientific Assembly of the International Association of Geomagnetism and Aeronomy/International Association of Seismology and Physics of the Earth's Interior (IAGA/IASPEI), in Hanoi from August 19-25, 2001. We prepared and presented both new data and historical chrono-meta-analyses (I: 11-15) and met interested investigators, some who are now collaborating with us.

Farewells

         Germaine completed a concluding chapter on chronomics for a book, which is now in press, on "Biology of the intestine in growing animals" (4). This paper is dedicated to the memory of Lawrence E. Scheving [photo 3], Rebsamen Professor emeritus of Anatomical Science at the University of Arkansas for Medical Sciences in Little Rock, Arkansas, who died on April 16, 2000, at his home in Wisconsin. Larry's close associate in research on humans, Eugene L. Kanabrocki [photo 4] joined us again in this endeavor. We summarized what Larry painstakingly built first by studies on laboratory animals. Larry mapped DNA labelling throughout the digestive tract and elsewhere. He thereafter turned to investigating human cell division on the back of his own skin and of cooperating test pilots. The demonstration of the persistence of a telemetered core temperature rhythm after the bilateral ablation of the suprachiasmatic nuclei was carried out with him. The demonstration of the persistence also of a host of cellular rhythms after the histologically validated removal of both suprachiasmatic nuclei is his indelible contribution. Gene, with Larry, had done also human chronomics before the name of this endeavor was coined, by monitoring themselves and their comrades on the staff of a World War II field hospital at 10-year or shorter intervals for much of their adult lifetimes. They sampled around the clock, with blood pressure and heart rate, changes in most of the variables determined in routine clinical chemistry and in research, as new laboratory methods were introduced. Larry Scheving had done further critical work in most areas of chronobiology, much of it in gastroenterology and chrono-oncology.

         Marie-Anne Reinberg died on January 16, 2001, at Neuilly-sur-Seine, France, age 79 years. Her surviving husband, Dr. Alain Reinberg, is the pioneer in very many aspects of French clinical chronobiology, notably chronopharmacology. What also should be emphasized, he did the first classical systematic mapping of endocrine aspects of blood pressure chronobiology. With Michael Smolensky, Alain contributed a classical book of the quantitative field as a whole. Marie-Anne was a dentist with chronobiologic interests of her own, and an unforgettable hostess. In her memory, in a paper dedicated to her with Erwin Schaffer, dean emeritus of the University of Minnesota dental school and a chronobiologist for half a century, we summarized a 7-year follow-up of 23 presumably normotensive patients, who were monitored at 15-minute intervals for a total of 9 days in 3 consecutive sessions of 4, 2 and 3 days, respectively, separated by a few weeks (I:7). Twelve patients were reached by phone 7 years after the prior chronobiologically interpreted monitoring. Only two of these patients had abnormalities in all three sessions, and only these two patients reported having experienced an adverse vascular event (one a myocardial infarction, the other coronary artery bypass graft surgery). The difference in outcome between the patients with chronobiological abnormalities in all three sessions vs. the pool of those with abnormalities in only two, one or none of the sessions is statistically significant. Even a 5-day and sometimes a longer profile, while greatly preferred to single measurements, may not suffice for a definite diagnosis of certain patients. Chronobiologically interpreted blood pressure and heart rate monitoring for a week or longer, as a start, detects high-risk states that may be missed by conventional casual measurements and even by the false gold standard of not yet routinely used 24-hour profiles. From the viewpoint of studying circadian and about 7-day (circaseptan) variability, with a 7-day profile, there is no replication of the circaseptan rhythm characteristics, but the 7 replications of the circadian endpoints add reliability. With the more conventional 24-hour profiles, such reliability is lacking in data covering but a single cycle, which is comparable to studying the heartbeat for one second.

         In a tribute to the late Gunther Hildebrandt, a major investigator of human chronomics, his data on visual reaction time and flicker fusion frequency in three groups of patients who started balneotherapy on different weekdays were reanalyzed (5). Inter-individual differences in the operating average were removed by expressing the data as a percentage of each patient's series mean. The reproducible pattern for patients starting balneotherapy during different weekdays (Figure 2) suggests that the circaseptan pattern of the 43 patients examined was synchronized by the start of treatment, irrespective of the weekday when the treatment was begun. Circaseptan and/or circasemiseptan components are usually found to be prominent and to be amplified after the application of a stimulus such as the start of balneotherapy, as documented in earlier reports and/or by the onset of an illness, as known to Hippocrates, Galen and Avicenna (5, 6).

         As this report is being completed, we also learned of the death of Sam O. Ogunade, Professor of Geophysics at Obafemi Awolowo University in Ile-Ife, Nigeria, who had just joined BIOCOS at the IAGA/IASPEI meeting in August in Hanoi and had planned to start ECG monitoring in the long term on himself. We express our deep sympathy to the families of all the deceased.

The built-in biological week

         Every contribution in the appendices carries the signature derived by exquisite analyses of the center's director, Germaine Cornélissen [photo 5]. Many papers constitute entirely her endeavor insofar as designs and analyses are concerned. Hence, it misrepresents and diminishes her Herculean achievement to single out any special publications. With this qualifying restriction, Germaine's many major contributions this year include, first, with Dana Johnson [photo 6], professor of pediatrics and head of neonatology at the University of Minnesota, a long-anticipated heritability of the circaseptan period in diastolic blood pressure, heart rate and body weight of Minnesotan newborn twins (I: 38), Figure 3. Previously, an endogenous aspect of the biological week had been documented by the demonstration of circaseptan desynchronization in newborns and adults, in the latter in one case under 7-day synchronized conditions, in others in isolation from society. The evidence on newborn twins removes any doubt for the case of humans, just as the case of Acetabularia's "week" showed that circaseptans in continuous light characterize the electrical potential of a unicellular giant alga that was presumably present on the surface of the earth 500 million years ago (7; cf. 8).

Global magnetic pollution may perhaps be gauged in Antarctica?

         In 1979, Fraser-Smith (9) reported that fluctuations in geomagnetic activity are characterized by a precise weekly pattern, as a weekend phenomenon. About a decade later, in analyzing the planetary geomagnetic index Kp for the span from 1932-1990, however, we found a spectral peak at a period of 6.74 days, Figure 4 (10), but none at precisely 7 days. This component was found where earlier apparently nobody else had looked. We in turn scrutinized the region because we anticipated finding a near-matching physical environmental counterpart of the biological week.

         Our finding of a near- but not exactly 7-day global geomagnetic disturbance component was then extended by Vladimirskii et al. to the antipodal geomagnetic index aa (11), that goes back to 1868. This year, in data provided by Mark Engebretson [photo 7], professor and head of space physics at Augsburg College, Minneapolis, Minnesota, collected by his stand-alone magnetometer in the relatively less polluted Antarctic, 600 km from the nearest human habitation, Germaine published not only that there is a main (not exactly but) near-7-day component in local geomagnetic pulsations (with a period of ~6.74 days), but also that in the Antarctic the amplitude of the local natural component is still larger than of a second anthropogenic precise 7-day component, which latter is now also present, Figure 5 (I: 38).

Chronomics gauge environmental pollution in antipodal magnetic index aa

         Dewayne Hillman [photo 8] and Germaine showed further the time course of the antipodal geomagnetic index, aa. Germaine confirmed a very qualified "pseudo-weekend phenomenon" reported earlier (9), only when she used exactly the same span as Fraser-Smith had used earlier. She found that Fraser-Smith happened to analyze the accumulating series at a (for the time being) "transient moment" in time, when there happened to be a weekend peak (9). When the series as a whole available to us was analyzed in sections of 6 spans of 22 years (except for the last section of 21 years), some sections showed a weekday and others a workday phenomenon, Figure 6, as would be expected if the overall peak in nature for the longest available span at the time of analysis — up to 1990 for aa (11) and for Kp (10) were different from precisely 7 days, which it was.

         It seemed possible, however, that as a function of time, more and more anthropogenic pollution may have been contributing. If so, the difference between the originally larger natural physical environmental 6.75-day (rounded) spectral geomagnetic component and the presumably anthropogenic, exactly 7-day component should undergo a change, as in their relative prominence. To check this possibility, Dewayne computed the difference between spectral amplitudes at 6.75 and those at 7.0 days for consecutive sections of the aa series. The time course of this difference, as anticipated, underwent a statistically significant change from positive to negative, Figure 7 (I: 53). In the region of 1 cycle/week, the natural circaseptan has predominated in the aa spectrum for the initial spans of 110 (11) or more (I: 53) years, as it also did in the Kp spectrum for the first over half-century of recording, Figure 4 (10), but perhaps no longer. Because there is a solar cycle modulation, which should be taken into account, even though its effect may be reduced by using the difference between 6.75- and.7-day amplitudes, more monitoring of the difference is advocated, notably in Antarctica, as done by Mark Engebretson.

ECG monitoring in the International Chronome Ecologic Study of Heart Rate Variability (ICEHRV) and BIOCOS

         ICEHRV is led by Kuniaki Otsuka of the Division of Neurocardiology at Tokyo Women's Medical University, Daini Hospital, Tokyo, Japan, with data collection thus far in Japan by himself, in China with Ziyan Zhao (Research Professor, Shandong Anti-Senility Research Center, Shandong Academy of Medical Sciences, Jinan, Shandong) and Zhengrong Wang (Vice-Dean, School of Basic Medical Sciences, Professor of Biomedical Engineering, Cardiology and Cardiovascular Pharmacology, Sichuan Medical University, Chengdu, Sichuan), in Ukraine with Anatoly Delyukov and Yuri Gorgo (Institute of Physics, National Academy of Sciences, Kiev), in Norway with Andi Weydahl (Associate Professor, Department of Sports, Leisure and Culture, Division of Arctic Chronobiology, Finnmark College, Alta) and in Minnesota. The activities of this endeavor culminated in the inaugural November 11, 2000, Workshop on Chronoastrobiology and Chronotherapy. The proceedings of this meeting, described last year, have now appeared as Supplement 1 in the Elsevier journal Biomedicine and Pharmacotherapy (I: 36-46). Kuniaki also granted us the opportunity to summarize different topics of ongoing world-wide cooperation for his 2nd International Symposium: Workshop on Chronoastrobiology and Chronotherapy, held at Tokyo Kasei University in Tokyo on November 17, 2001 (I: 47-67).

Geomagnetic influences on heart rate variability in the subarctic

         Heart rate variability in the ECG was studied in clinically healthy students in Alta, Norway, in a subarctic area where geomagnetic disturbances are felt more strongly. Seven-day records by ambulatorily recorded ECG were obtained from now well over 8 clinically healthy subjects. Frequency and time domain measures of heart rate variability were compared between 24-hour spans of high geomagnetic disturbance versus quiet conditions (I: 39, I: 40, I: 48). A 5.9% increase in the 24-hour average of heart rate (P=0.020) and a 25.2% decrease in heart rate variability (P=0.002) were documented on days of high geomagnetic disturbance on the first 8 students and fully corroborated as additional profiles were collected. The decrease in spectral power was found primarily at frequencies lower than 0.04 Hz and was not statistically significant around 3.6 s. The physiological mechanism involved may be other than the parasympathetic, usually identified with spectral power centered around 3.6 s, a spectral region wherein no statistically significant differences were found either in an earlier study. Two longitudinal data sets, spanning decades, also showed, clearly and with high statistical significance, the damping of overall heart rate variability during high magnetic activity (I: 42; 12). The decrease in heart rate variability associated with geomagnetic disturbances in two subjects is illustrated in Figures 8 and 9, by reliance upon the ECG or upon the mostly half-hourly ambulatory monitoring of the heart rate (and the blood pressure) over 11 years, respectively.

Deterministic chaos in geomagnetic pulsations in the Antarctic

         As a measure of complexity, the approximate entropy (ApEn) of the horizontal component of the changes in magnetic field recorded in Antarctica was computed over 30-minute intervals, spread over 3 days (from April 29 to May 1, 1998). Thirty intervals were considered. For each 30-minute series, the ApEn of the original data and 10 surrogate time series was computed. On the average, the ApEn value of surrogates was larger than the ApEn value of the original data (t=3.979; P<0.001 by paired t-test), suggesting the presence of nonlinear features in geomagnetic pulsations. The computation of Theiler's sigma, separately for each 30-minute series of dBx/dt considered, indicates that nonlinear properties may only be present at some but not necessarily at all times. Figure 10 shows that ApEn also follows a 24-hour pattern, findings deserving extended study (I: 38).

Brain-lung associations

         Naoto Burioka (Associate Professor, 3rd Department of Internal Medicine, Tottori University, Yonago, Japan) participated in the foregoing studies and others, including some on data he brought along on signals from the electroencephalogram (EEG) and those from respiratory movement which he investigated using the correlation dimension (D2) (I: 9). During a sabbatical in our laboratory, he observed a statistically significant positive correlation between D2 of the EEG and D2 of respiratory movement for the original data, but not for surrogate data. A reduced D2 of the EEG may be associated with an increased regularity of breathing in deep sleep (stage IV). Likewise, the increased D2 of respiratory movement during rapid eye movement may be associated with increased complexity of the signals. Whether there is a direct coordination between brain and lungs or whether brainstem systems, including that of the cholinergic, affect both respiration and cortex requires further investigation (I: 9).

Both-way searches for physical-environmental vs. biological near-matches in period

         Figure 11 shows that there is a very prominent half-yearly component in planetary geomagnetic disturbance gauged by the Kp index (13). This prominence, notably in the phase-weighted cosinor spectrum of Kp, led us back to our postulate that any old or newly observed periodicity in the physico-chemical environment should prompt the search for a near-match in biology as a putative synchronizer or influencer and/or, what seems at least equally likely, as a feature built into organisms and vice versa (13). We find counterparts not only for the biological week in the near-week of geomagnetics (10, 11) and rainfall (14), but biological circasemiannuals are near-matches of those in geomagnetics. By the same token, ~10.5­‑, ~21.0- and ~50.0-year spectral components of physiological or demographic variables in the biosphere are near-matches of periodicities in non-photic solar activity, Figure 12.

Circasemiannuals

         Phenomena such as the birth rate at high latitudes (15), body weight and height at birth (12, 16-18) or the gain in weight and height during the first 15 months of life (19) show about half-yearly patterns. As noted earlier, the circasemiannual can reflect the non-sinusoidality in the waveform of the circannual component, but in some series the half-yearly component is the sole statistically significant feature. Circasemiannuals further characterize the vasopressin-containing nuclei of the human hypothalamus (20), the incidence of hallucinations (21), of hormone-related cancers (22), and most prominently the incidence of status epilepticus during a 3-year span of intensive magnetic activity (10).

Intrauterine growth retardation

         As reported earlier, there is further a half-yearly component in the circulating melatonin of human pregnancies with intrauterine growth retardation (23) (but not in clinically healthy pregnancies). In the past year, Cristina Maggioni [photo 9] also found a half-yearly aspect of estriol, E3, by comparing 14 healthy uncomplicated pregnancies with 11 IUGR-complicated pregnancies. By population-mean cosinor, a circadian rhythm is found to characterize women with IUGR (P=0.040) but not healthy women (P=0.131). The half-yearly component in E3 for women with IUGR, but not in healthy women, is in keeping with a circasemiannual component prominently characterizing body weight and length at birth of children with birth characteristics below usual norms. Conceivably, these variations may reflect influences from geomagnetic disturbances that are also characterized by a prominent half-yearly pattern, Figure 11, to which the pineal has been shown to be sensitive (I: 61). This is also the interpretation of half-yearly components characterizing both circulating melatonin and estriol of the women with IUGR and not in the healthy women (I: 61; 23).

Circasemiannuals may depend on latitude and/or solar cycle stage

         At middle latitudes, in years of a solar activity minimum, human circulating melatonin exhibits a circasemiannual component by night and a circannual during the daylight hours (24), whereas at high latitudes circulating melatonin shows a circasemiannual component at noon (24; cf. 25). These results, found at solar minimum in a large sample of subjects, were not reproduced in the ascending stage of solar activity on another large sample (unpublished). The differences as a function of interacting circadian and circaseptan patterns came to mind (6). It seems likely that rhythms with several frequencies interact and some intermodulations may be expressed by differences as a function of the stage of longer and longer cycles (26). There is no substitute to mapping these cycles to fill in holes. Results of longitudinal surveillance ar to be fitted into an ever broader picture puzzle of a spectrum of multifrequency biological rhythms once there are novel chronome maps.

Life expectancy

         The Gavrilovs unexpectedly found and published that month of birth was a predictor of life expectancy of adult women of 30 years or older, in a database representing cohorts from 1800 to 1880 (27). Germaine's analyses show a statistically significant half-yearly component in these invaluable uncensored data and in the data on the geomagnetic index aa, analyzed insofar as 13 years of aa were available from the much longer span covered by the Gavrilovs' data base. The cross-correlation function of these two variables, one characterizing longevity of a presumably magnetolabile, possibly frail since probably inbred population, peaks at lag 2, Figure 13, indicating perhaps, among other possibilities, that maximal human longevity follows maximal geomagnetics by 2 months. Should there be a causal positive relation, the effect could take place 2 or so months before birth, or if it is a negative association, it could occur 5 months before birth (2 months and one half of a 6-month cycle). The degree of generality of this finding is pursued with data from California, in cooperation with Natalia Udaltsova (I: 50) [photo 10] and in data from Ukraine of Alexander Vaiserman (I: 51).

Broadening non-photic spectrum: decadal and multidecadal rhythms

         The circaseptan and circasemiannual environmental signatures of geomagnetic disturbance and perhaps rainfall (14) in the biosphere complement other ~10.5-, ~21.0- (Figure 12) and even ~50.0-year, Figure 1, biological near-matches of solar non-photic activity, the circadecadal, circadidecadal and circaquindecadal biological cycles, that still await validation as rhythms. Sometimes these biological components, of presumably non-photic origin, can be more prominent in amplitude than the photic signatures of the physical day, in the case of circaseptans vs. circadians of blood pressure and heart rate in the first week of life (I: 58). Also in other non-photic signatures, circadecadal (non-photic) biological signatures can have a larger amplitude than that of the yearly change, as shown in Table 1. Studies on twins (that have already shown the heritability of both a circadian amplitude of human adult heart rate, Figure 14 [28] and the circaseptan period of human neonatal heart rate, diastolic blood pressure and body weight, Figure 3) would be a way to behaviorally document the presumed heritability of about 10.5­‑, 21.0- and 50.0-year spectral components in humans, that is at frequencies that characterize important variables in the biosphere, such as time series of international battles, Figure 1 (I: 59). It seems possible that during the, perhaps, billion years of evolution, genetic coding was the fate not only of the consistently recurring (like photic daily and yearly) but also of wobbly (non-photic) cycles. This possibility is rendered plausible by the now-documented heritability of the wobbliest of all major environmental components (except during the first week of the newborn human baby's and the first 6 months of a crayfish's life), the near-week, Figure 3.

Cartographic methodology

         During the past year, as in the previous two years, George S. Katinas, Emeritus Professor and Head of Morphology at the Medical Institute of St. Petersburg (who had been with us for 6 months in 1971 as an exchange scientist during a U.S.-Soviet thaw), continued to perform an essential role in the center. With Sylvain Nintcheu-Fata (I: 27) [photo 11], a young colleague in engineering, he guided the development of software for maps of moving amplitudes, probabilities and percentage rhythms (the latter showing relative prominences), as described in Figures 15a-e (I: 24, I: 27, I: 54, I: 55), also used in cooperation with us by Hans W. Wendt, Emeritus Professor of Psychology, Macalester College, St. Paul, Minnesota [photo 12]. Moving spectral displays of various characteristics complement chronobiological serial sections that are restricted to a frequency of interest, allowing us to scrutinize the time course of probabilities, Figure 15b, or relative prominence, Figure 15c, as well as of amplitudes, Figure 15a, at all frequencies in a given spectral region of interest. By thus examining the more detailed course of solar activity, one can guard against wrong impressions, such as a cessation of cyclic solar activity during the Maunder minimum (1540-1710), Figure 15a (I: 55). Figure 15b shows the continuance of a circaundecennian (or succinctly circadecadal) cycle of a high statistical significance and Figure 15c shows a greater prominence of this cycle during the late 17th as compared to the late 18th century (cf. also 29, 30). Cooperation with Christine Mazaudier [photo 13], who had found persistence of cyclic solar activity by local periodograms before us (30), started at the Hanoi meeting last summer.

Remove and replace

         The procedures visualized in Figure 15, among others, can be used for comparisons of the behavior of biological time series during spans when a given environmental component is more vs. less prominent or ideally when, in the light of all methods used for its detection, the component is present vs. spans when the component is absent (remove) and then is again present (replace) (31). This "remove-and-replace" approach is somewhat comparable to that of removing a gland, finding the changes associated with the loss and then correcting the change by the replacement of the hormone or a transplant. Best would be the identification of the physical agent involved, e.g., in a desirable effect. The administration of this agent, as perhaps in the case of spirituality-related rhythms, could act, as does endocrine substitution therapy, by the administration of the gland's hormone. Extending the analogy to a harmful effect, another challenge yet to be met is the blocking of, or shielding from or compensating for the undesirable response, e.g., in the case of crime.

         At the present stage of our ignorance, the sun or earth do both the removal and the replacement of magnetic storms, of galactic and/or other cosmic rays displaced by these storms and/or of other mediating factors (31). Figure 12 also shows the physical environmental counterparts (on top) that match the period of some of the important biological spectral components (below). Table 2 shows that the principal geophysical components nearest to 50 years are quite different from the period of the biological components in the span for which they are available, while Wolf's relative sunspot numbers are on the average closest. The wobbliness of this component of solar activity is seen in Figures 15d and 15e. Remove-replace approaches remain to be implemented further when one of the two near-matches loses or gains in amplitude, to see what the other does, in order not to rely solely upon the hint (no more) of periodicities with similar cycle lengths. When environmental and biospherical near-matches have non-overlapping 95% confidence intervals, the possibility of environmental cycle stage-dependent responses has to be kept in mind (18), if environmental factors contribute to chronomes, in part through genomes.

Biospherical cycles in search of near-matches: Ultradian and infradian changes in cells producing endothelin

         In studies carried out by the late Brunetto Tarquini, we had earlier found about 8- and about 84-hour spectral components for circulating endothelin in the blood of healthy humans and of patients with altered characteristics in conditions of an elevated disease risk. Separately, George Katinas had studied the population density changes of a variety of cells in mouse ear pinna for over a week before and after a trauma, including population-density changes in ET-1-producing endotheliocytes. In the data before the trauma, least-squares spectra overall and moved through the series detected in population densities of endotheliocytes pronounced circasemiseptan (and 8-hour) oscillations, as shown in a surface chart, Figure 16. These results correspond to components of the endothelin-1 chronome in human blood plasma, reported earlier. Circadians were more pronounced in population densities of capillaries. After trauma, circasemiseptan oscillations appeared also in population densities of capillaries (32).

Associations between positive and negative affect and blood pressure?

         To assess any circadian and/or infradian components in mood in a battery of cardiovascular variables and to relate their characteristics to examine any association between mood and circulation, Gen Mitsutake [photo 14], a clinically healthy 34-year-old man, filled out the Positive and Negative Affective State questionnaire 5 times a day for 86 days. During the same span, he monitored his blood pressure and heart rate around the clock at 30-minute intervals, and collected saliva samples for the later determination of melatonin and cortisol. A circadian rhythm was demonstrated for all variables, as illustrated for mood assessed separately for positive and negative affect in Figure 17 and for salivary melatonin and cortisol in Figure 18. A correlation matrix indicated a positive association between the circadian amplitude of negative affect and the MESOR of both systolic and diastolic blood pressure, suggesting that blood pressure is raised in the presence of large swings in negative affect.

Toward a chronobra: mapping sequential luteal cycle-associated mammary changes

         Different experts in their field have documented physiological changes in breast tissue during the menstrual cycle, mostly related to the time of the cycle when there is a corpus luteum. Using inferential statistical methods, the relative position of physiological and morphological changes in breast tissue during the luteal phase of the menstrual cycle was estimated (33). The data collected by Hugh W. Simpson, a lifetime member of our center, stemmed from selected publications focusing on breast variables measured in the context of the phase of the menstrual cycle. A 28-day cosine curve was fitted by least squares to all data series available to obtain an estimate of the acrophase. For six of the eight variables considered, the zero amplitude assumption could be rejected at the 5% probability level, and for the remaining two below the 16% probability level. The sequence of acrophases is presented in Figure 19, each acrophase being plotted with its 95% confidence interval. All acrophases are found to occur during the progesterone-promoted luteal phase of the menstrual cycle. The peaks of the variables listed in Figure 19 are led in time by salivary progesterone, an easily measured variable which closely follows plasma concentration. The peak of progesterone is followed a day later by the peak of mitosis in mammary tissue. The next events are all estimated to have a maximum some 2-4 days after the progesterone peak. They include breast volume, mammary epithelial volume, breast surface temperature, breast water content and breast blood flow. After these more or less contemporary events, there is a peak of apoptosis in the mammary tissue just before the menses, that is some five days after the progesterone peak. The lack of overlap among confidence intervals, for instance, of mitotic and apoptotic activity, attests to the statistically significantly different timing of these variables.

Test pilots

         As we have every year for the past 10 years, we had the pleasure of hosting Yoshihiko Watanabe [photo 15], also a cardiologist at Tokyo Women's Medical University, Daini Hospital, who brought data from his patients in an attempt to optimize the antihypertensive drug losartan by timing its administration. Yoshihiko also performed familial chronomics: his automatic blood pressure and heart rate monitoring, mostly at 30-minute intervals, covers nearly a decade and a half. He also brought data at similar intervals from his son's first few months of life (I: 58). His own record enabled the finding of cross-spectral coherence between vascular variables and Wolf's relative sunspot numbers (I: 42), providing a putative basis for the probably cycle stage-dependent associations of solar activity and myocardial infarctions (12, 18). Yoshihiko also found that in lieu of the usually assumed consolidation of ultradians into circadians in sleep/wakefulness, the post-natal course of his son's heart rate examined by moving spectra reveals an independent time course for infradian, circadian and ultradian components. The infradians dominate in these living fossils for the first week of life. That the finding bears on more than one subject was shown earlier for blood pressure and heart rate by the summary of staggered 48-hour profiles obtained in different babies on two different consecutive days of the first week of life (I: 58), Figure 20.

         The record holder in self-monitoring is Robert B. Sothern [photo 16], whose more than three decades of data are summarized elsewhere (34; cf. 18). In his blood pressure and heart rate, there is a cross-spectral coherence coefficient with Kp of 0.74 at 5.9 months away from any spectral peaks, a further limit of associations, direct or indirect, with geomagnetics (Kp). Bob has measured psychophysiological variables about 5 times each day on most days for over 34 years. His endeavor surpasses that of Santorio Santorio and serves as a model further for the kinds of questions that arise when rhythms with periods covering decades are being mapped in 11 variables and results of analyses differ (Table 2 in ref. 18), so that, for this reason as well, all of the variables cannot be used as replications. The relative brevity of a now 34-year record in examining ~10.5­-, 21.0- and eventually 50.0-year cycles prompted historical examinations of reports of cycles based on relatively short series. In a historical perspective, we suggest that as-one-goes analyses could speed up discovery by hypothesis formulation, but they are no substitute for continued prolonged data collection, not only for experimental validation of a given spectral component, but in order to detect such components with lower and lower frequencies.

Missed opportunities of cautious predecessors

         Figure 21a shows our chrono-meta-analyses of data on geomagnetic variability (on daily magnetic declination) collected by Col. Mark Beaufoy starting in April 1813, listed monthly December 1820 (published in 1851 by Lamont; 35). We analyzed these data by the cosinor adaptation (36) of Gauss' least-squares procedure (37), already used in 1801 to locate the lost asteroid Ceres (38) and hence by then in the public eye. We cannot reject the no-rhythm assumption by the fit of an 8.414-year period, which fits the original data best (>0.10), Figure 21a, yet statistical significance is reached once the prominent 1.0- and 0.5-year components are removed, Figure 21b. We thus validate the very period length of about 8 years which we also find in Schwabe's first 12 years of data (39), Table 3, from which, without analysis, Schwabe did not yet dare draw a written inference of a periodicity. To do this, he waited for another six years (40). According to a check by Christopher (Kit) Bingham [photo 17] of the sunspot data of the past 300 years, Figure 22, Schwabe may have been unlucky since he happened to start studying an extremum, i.e., the shortest solar cycle in 300 years, when computed based on 12-year intervals. Actually, to realize without analyses that he dealt with a cycle, he was twice lucky since it was the shortest rather than the longest cycle that could be viewed in 12-year intervals, whereas he would have been indeed unlucky had he started the 12-year analyses on a few other occasions when a period could not be demonstrated by the method used herein. Had Schwabe analyzed Beaufoy's shorter earlier data series and his own series, however, he could even have obtained a hint of some relation between the periods of geomagnetics and sunspots, decades before the era of Lamont (35), Sabine (41) and Wolf (42). In any event, the analyses in Figures 23a and b of Lamont's geomagnetic data should have only served to confirm Beaufoy's rather than vice versa, if one proceeded with data analyses, a step to be recommended in particular to octogenarians (such as the senior author) in dealing with 50-year cycles (who is pulling his own legs).

         The inferential statistical validation is found in Figures 21-23; qualifications by 95% confidence intervals are given in Table 3. The foregoing possible inferences from an immediate sequential analysis of the accumulating original data hold in the light of the subsequent centuries of physical records. Figures 21-23 constitute transdisciplinary historical examples for the merit and the promise of analyzing as-one-goes the decadal biological cycles for hypothesis formulation, irrespective of the relative brevity of time series. The presence of such cycles has to be scrutinized with a combination of inferential statistical, physical, physiological and archival methods. Lessons from this historical approach are the more needed since we are dealing with important societal variables such as wars, the economy and religiosity. It seems important to resolve any physiological mechanisms that underlie the plethora of new about 21- and 10.5-year, Figure 12 (I: 18), if not yet of the 50-year spectral components of Figure 1, even when there is non-sinusoidality of the waveform, as in the Schwabe (and Beaufoy geomagnetic) activity cycle.

Caveat concerning waveforms

         Figure 24, however, shows in an abstract way that a non-sinusoidal waveform can yield aberrant nonsensical periods, when data over a single cycle are fitted by a cosine function. This figure shows that data covering at least 5 consecutive cycles are desirable to approximate the period in such cases. Nonsinusoidal rhythms must be approached with this abstract caveat in mind (cf. Table 3).

Paleochronobiology

         Otto Appenzeller [photo 18] of the NMHEMC Research Foundation in Albuquerque, New Mexico, prompted another visit into paleochronobiology (I: 59), with focus now on infradians (cycles with a period longer than 28 hours). These infradians are prominent early in the ontogeny of humans and some other species, i.e., in "living fossils" (10). With Otto, we assessed infradians in truly dug-up fossils, in ancient teeth from a North Chilean (San Pedro) prehistoric culture (of 1100-1600 years ago). Otto had measured the interval between the long-known brown striae of Retzius in the enamel. In the want of any other time scale, we designated the interval between two consecutive striae as a bioweek, since in contemporaneous teeth, striae of Retzius form once about every 7 days. In comparing patterns in ancient and contemporaneous teeth, Otto had found the intervals to be thicker in the ancient teeth as compared to the modern ones. This bioweek in the enamel also had a different phase-weighted spectrum in ancient vs. contemporaneous teeth (I: 59). Otto had postulated that these different spectra may represent the autonomic nervous system then (1100 or more years ago) vs. now, or at least the behavior of a neuroendocrine chronome under pre-Edisonian conditions. The lack of exposure to artificial light could be one difference between ancient and modern conditions. Whether responses to a geophysical circaseptan were favored by the relative brevity of the daily naturally illuminated span can be considered. In view of the difference between ancient and contemporary spectra, one might have to look for two past and/or present environmental frequencies, rather than one, and one would also have to indicate (if two corresponding infradians were found) why ancient teeth responded to one and contemporary teeth to the other. What seems certain, cast into teeth, there is new information for those who care to scrutinize the infradian domain now vs. then (early vs. later in ontogeny on the living fossil in babies and the aged or in contemporaneous vs. truly fossilized teeth). A study of mechanisms underlying circadians, begun by Hisashi Shinoda's team (43) by focus on the suprachiasmatic nuclei needs an infradian extension against the further background of earlier endeavors with Hans Kaiser, aimed at a chronohologeny (44).

Independent, synergistic vascular disease risks

         CHAT (short for circadian hyper-amplitude-tension), a condition defined by an excessive circadian amplitude of blood pressure, above a threshold approximated by the upper 95% prediction limit of clinically healthy peers matched by gender, age and ethnicity, is associated with a large increase in vascular disease risk, cerebral ischemic events and nephropathy in particular, Figure 25. DHRV (short for decrease in heart rate variability) constitutes another condition associated with an increased risk of developing vascular diseases: a lower 24-hour standard deviation of heart rate is associated with an increased risk not only of coronary artery disease, but also of cerebral ischemic events. In a data base of 297 patients (reported upon earlier), the question whether these two conditions are two aspects of the same syndrome and/or constitute disease risks in their own right was investigated (43, 44). As apparent from Figure 25, of the 297 patients, 39 experienced a morbid event within 6 years. There were 16 cases of coronary artery disease, 14 cerebral ischemic events, 18 cases of nephropathy and 16 cases of retinopathy. Among the 39 patients who experienced a morbid event, 20 had a circadian diastolic blood pressure amplitude and a 24-hour standard deviation of heart rate within acceptable limits; 7 had DBP-CHAT but no DHRV; 8 had DHRV but no DBP-CHAT; and 4 had both DBP-CHAT and DHRV. Of the remaining 258 patients who had no morbid events, 233 had a circadian amplitude of diastolic blood pressure and a 24-hour standard deviation of heart rate within acceptable limits, whereas 13 had DBP-CHAT but no DHRV; 11 had DHRV but no DBP-CHAT; and only 1 had both DBP-CHAT and DHRV. Using the patients with neither DBP-CHAT nor DHRV as reference, the relative risk of DBP-CHAT only, DHRV-only, and combined DBP-CHAT and DHRV was invariably increased. Using the patients who had either DBP-CHAT only or DHRV-only as reference, the relative risk of combined DBP-CHAT and DHRV was estimated to be 2.08 (95% CI: 1.15-3.76; c2=3.117; P=0.078). The relation between the circadian amplitude of diastolic blood pressure and the 24-hour standard deviation of heart rate is not statistically significant (r=0.062; P=0.287), in keeping with the assumption of independent syndromes (12), yielding cumulative risks taken when coexisting, Figure 25. The condition may have been missed since the increase in risk is nonlinear (12).

Circadian cardiovascular rhythms and low-dose aspirin effects upon them

         The resumption this year of active collaboration with Pavel Prikryl Sr. [photo 19] and the beginning of cooperation with Pavel Prikryl Jr. [photo 20], Jiri Neubauer and Zdenek Karpisek was a pleasure. Pavel Sr. initiated our decade-long cooperation with Brno and the original demonstration of the time-dependence of several effects of low-dose aspirin (45, 46). In 2001, Pavel's team demonstrated new circadian cardiovascular rhythms (I: 60), including one in a time index (TI) and one in the ejection fraction (EF) of the left ventricle, Table 4. This group also documented circadians in low-density lipoproteins in cholestin (LDLc), separately in lipoprotein a (LPa) and C-reactive protein (CRP), along with heart rate (HR), also measured by ECG as a reference variable. As compared to the placebo span, treatment with low doses of aspirin was associated with a statistically significant increase in EF (by 2.31 ± 0.52%; paired t = 4.440; P<0.001) and in TI (by 0.33 ± 0.05 l.min-1.m-2; paired t = 6.175; P<0.001), and with a statistically significant reduction in LDLc (by 0.35 ± 0.08 mmol/l; paired t = 4.329; P<0.001), LPa (by 128.9 ± 33.0 mmol/l; paired t = 3.903; P=0.001), CRP (by 117.4 ± 22.4 mg/l; paired t = 5.239; P<0.001) and HR (by 1.9 ± 0.5 beats/min; paired t = 3.708; P=0.001) (I: 60). These effects were observed in clinically healthy unmedicated subjects as well as in cardiac patients (hypertension II, hyperlipidemia, angina pectoris, ischemic heart disease, NYHA I or II) treated with a variety of drugs (beta-blockers, ACE-inhibitors, digitalis, nitroglycerin). Further work on larger groups is needed to determine whether the response to low-dose aspirin may differ between clinically healthy subjects and cardiac patients, in terms of the extent and/or timing of optimal efficacy, an exploration underlying this study aimed at chronotherapy. The present results do not contradict a recommendation for aspirin in the morning, in the light of earlier work on other variables, although aspirin is better tolerated in the evening.

Diabetes

         Salvador Sanchez de la Peña and Clicerio Gonzalez studied the chronomics of blood pressure and heart rate in 26 clinically healthy glycemic controls, 17 with glucose intolerance, and 117 with non-insulin-dependent diabetes mellitus (NIDDM). The circadian amplitude of systolic blood pressure was found to be the largest in patients with glucose intolerance (F=3.938; P=0.021). Monitoring for 7 days, rather than only for 24 hours as done in this study, has been recommended to obtain a reliable estimate of the circadian amplitude or standard deviation of blood pressure and heart rate. The limitations of the 24-hour only monitoring profiles of this study notwithstanding, Salvador and Clicerio found that: 1. at the transition between normal glycemic control and NIDDM, that is in patients with glucose intolerance, the circadian blood pressure amplitude is increased, making it more likely to diagnose, if not "1-week CHAT", then "24-hour [possibly transient] CHAT". The latter was diagnosed in 17.7% of the patients with glucose intolerance, but only in 7.7% of the normoglycemic controls and in 10.3% of the NIDDM patients. An odd timing of the circadian blood pressure acrophase was found to occur in about 40% of the NIDDM patients (I: 62).

Recent increase in stroke deaths

         The resolution of variability inside the physiological range in terms of multifrequency rhythms and other chronome elements yields new endpoints that may be invaluable not only to recognize pre-disease before the onset of overt symptoms, Figure 25, and to avoid the misinterpretation when long-term decadal or multidecadal variations are involved. The ubiquitous about 10.5-year changes, components of lower frequencies of 1 cycle in about 21 and 50 to 60 years are also being mapped (18). Sampling over spans shorter than a full cycle of any one of these decadal solar spectral components may erroneously suggest the presence of an increasing or decreasing trend when records over longer spans readily reveal partly spontaneous cyclic changes, perhaps built into the gene pool of populations, whether or not they are synchronized by contemporaneous cycles in solar activity. Of particular interest is the incidence of stroke deaths. With the qualification that there have been changes in the classification of mortality from stroke, non-monotonic trends over the past 50 years have been documented, both in Minnesota and in the Czech Republic. Can the decline in stroke during the past two decades be accounted for, at least in part, by a natural about 50-year cycle, notably since an upward trend has been observed in most recent years in Minnesota as well as in the Czech Republic, in Slovakia, in Lund, Sweden, and in Arkansas, Table 5. Extreme caution is indicated when one considers an about 50-year periodicity based on data covering only 50 years; but the fact of a recent upward trend remains a concern. Historically, one can argue that changes in the time course of a statistic with less than 2 cycles in hand prompted Samuel Heinrich Schwabe to describe the sunspot cycle validated by hundreds of years and thus pointing out a phenomenon with biological implications, which now continue to accumulate in the 10- and 20-year region of the spectrum. Like Schwabe, we simply face the task of reporting the facts so that they can be pursued for the future, with the possibility that at least some of the "secularity" can be identified as a feature of non-random phenomena, possibly related to non-photic effects from the sun and beyond.

Stroke prevention-oriented 7-day/24-hour blood pressure/heart rate monitoring

         During the past year, Germaine continued to serve in the implementation of this endeavor, also ongoing in several locations worldwide, most extensively in cooperation with Kuniaki Otsuka. With Kuniaki's lead, as noted at the start of this report, the entire city of Urausu, near Sapporo, Japan, is being screened, also with the cooperation of Shoki Yano, who plans to make it a government study and has given the chronome study visibility on national TV. In Europe, Brno's St. Anna Hospital with Pavel Homolka under the auspices of Jarmila Siegelova is the leader of this endeavor. Germaine also provided analyses to practitioners in Brussels, Belgium; to Nubar Aslanyan, who joined BIOCOS from Yerevan, Armenia; and continued a fruitful cooperation with Katarina Borer in Ann Arbor, Michigan, focusing on exercise effects upon blood pressure and heart rate variability, while simultaneously taking care of all comers in Minnesota. Katarina also detected the first case of 7-day CHAT (circadian hyper-amplitude-tension) in an African-American woman.

Indispensability of maps for research and practice

         When rhythms are ignored, as is generally the case, we can confront a host of nonsense results, Figure 26. Alternatively, once mapped, the signatures of solar and/or galactic activity can be further tested by methods for dealing with major aspects of human emotions, the mind and even motivation, if not spirituality. Studies of intentionality by prominent physicists (47, 48) are cases in point. Our approach relies first on the cartography of hard social outcomes, Figures 1 and 12 and Appendix II. Then it seeks physiological mechanisms by monitoring. Cross-spectral coherence away from spectral peaks can help where correlations can mislead. Analyses culminate whenever possible in the already introduced remove-and-replace approach, in its many forms, including superposed cycles and the study of effects specified as a function of phase, examined further by superposed epochs, with control epochs.

         Among the putative non-photic associations of the environment and demography, perhaps the most exciting new finding was that of a latitude-dependent signature on the earth's surface of the Hale cycle in sunspot bipolarity of about 21 years, characterizing religious motivation worldwide, as described in detail in a separate accompanying paper by Starbuck et al. This year, we also started a gallery of chronobiologists described while they are alive so that they may comment on what is written about them (I: 18). Earl Bakken, the first to be selected for this gallery, gave us not only a pacemaker for the heart but also concern, via his Archaeus Project, about the brain. In addition, spectral components in criminality demonstrated earlier (Figure 15 in I: 18) and over 2.5 millennia of data on wars show ~50-year solar signatures, Figure 1. These are, of course, all multifactorial phenomena; nonetheless, they may provide an environmental clue to major ills of society that have to be solved by the "remove and replace" approaches of chronomics when other means seem to have failed.

Findings underlying some of the very many remaining tasks

         My wife Othild, supporting in all ways, offers the experience of a professional life time in health care, to most of the topics in I. The challenge is to start prevention early and her pediatric experience is invaluable as is her presence and help always as needed. Her interest in sensitive stages of pregnancy to certain hormones, like cortisone, leading to physical abnormality such as a cleft palate, was matched by the finding by Elena V. Syutkina [photo 21], head of chrononeonatology at the Institute of Pediatrics of the Russian Academy on Medical Sciences in Moscow, that betamimetics have effects lasting into adolescence. There may be sensitive stages also to physical agents, very early in life. Their effect may be far from trivial if the half-yearly signature of geomagnetics affects life spans as a whole. Elena Syutkina also has the credit, among many other contributions, of having mapped an about 10-year cycle in neonatal blood pressure. Her lead in this case, as in others, such as her demonstration, with K.Yu. Pimenov under the auspices of Tamara Breus, of a correlation between the circaseptan periods of blood pressure and heart rate and the circaseptans of local geomagnetic activity supports recent findings (I: 40, I: 47, I: 48). It can only be hoped that with support from her colleagues Mitrofan Studenikin and Galina Yatsyk, Elena will be enabled to continue this mapping, as Schwabe did, precisely because she has already created a new field. Closely associated with Elena is Anatoly Masalov [photo 22], whose laser model of periodicity and deterministic chaos awaits testing as to its predictive use in dealing with the components of chaos and rhythms in chronomes.

         Gennady [photo 23] and Denis [photo 24] Gubin, father and son, of the Tyumen (Russia) Medical Institute, pursue further the extension of studies on murine circadian ontogeny to the human  ontogeny of blood pressure and heart rate.

         Awaiting detailed publication is the finding of Franklin Barnwell [photo 25], (former head and) professor of human ecology and behavior at the University of Minnesota. By using cosinor methodology a period statistically significantly different from both precisely 12 and precisely 12.4 hours is shown by him in Table 6. A time-macroscopically and time-microscopically validated circasemidian component can be neither a result of a circadian nonsinusoidality nor a direct match of the lunar tidal period; it constitutes another feature of non-photic environmental origin now built into the spectrum of the fiddler crab, i.e., into a feature of the biosphere.

         We are grateful to Giorgio Villoresi, Professor of Physics, "Roma Tre" University, Rome Italy, who guided our work on cosmic rays, putting at our disposal the data he collected in Rome. Ellen Berscheid, Regents Professor of Psychology; Candace Kruttschnitt, Professor and Head of the Department of Sociology; and Leonard V. Kuhi, Professor and Head of the Department of Astronomy, from the University of Minnesota kindly provided advice on problems posed by any associations among the variables in Figures 1 and 12. The initials IMF, often used in the context of the topic discussed herein, stand for Interplanetary Magnetic Field, and must be distinguished from Initial Mass Function, which describes the process of star formation. There remains the need for transdisciplinary cooperation that should lead to generally understood terms and concepts, notably when one deals with spectra of different disciplines. Tables 7 and 8 illustrate references to high vs. low frequency in drastically different spectral regions. We are grateful to Robert P. Sonkowsky, Professor of Classical and Near Eastern Studies at the University of Minnesota, for his always-invaluable help with terminology.

         Lynn Peterson, as in previous years, helped with the instrumentation as was necessary, and thus fulfilled a most important task. We enjoyed this year a visit from Miguel Revilla, Professor of Applied Mathematics and Computer Science, University of Valladolid, Spain [photo 26], who continues to be instrumental in making available materials from the center on our website (http://revilla.mac.cie.uva.es/chrono; http://www.msi.umn.edu/~halberg/). We started cooperation with Robert P. Patterson, Professor of Physical Medicine and Rehabilitation and director of the Bakken Medical Instrumentation and Device Laboratory at the University of Minnesota [photo 27], by analyzing data on his blood pressure. Bob is now in his 16th month of around-the-clock monitoring of his own heart rate variability.

Summary: irreproducible results vs. chronomics

         Genetics spawned the mapping of genes and proteins, genomics and proteomics, in well over a century since the time of Johann Gregor Mendel. This reductionist journey deep into organismic space can be complemented by chronobiology, the study of the mechanisms of temporal organization in ALL cells, coordinated by the adrenal-pituitary-hypothalamic-pineal network, with period, amplitude and phase coordination in the brain's suprachiasmatic nuclei. Within the past half century, chronobiology has now led to chronomics, the mapping of interacting time structures, chronomes, in us and around us. Deterministic and other chaos, an ever broader spectrum of rhythms with longer and longer periods, now measuring decades, soon to be assessed in centuries and perhaps millennia, and trends with age and risk elevation, that in a population may again become rhythms, are all to be mapped by neo- and paleo-chronomics. Illustrative topics of the use of chronomes, maps in time, for basic evolutionary and contemporary science, in medical and social implications, also constitute indispensable control information, with applications today in prevailing vascular diseases of the individual, such as strokes, myocardial infarctions and kidney disease. Tomorrow perhaps, the ills of society, murders and wars, can be targetted by exploring counter-measures built upon the identification of the physical and/or physiological underlying mechanisms.

         Before Harvey recognized that "The movement of blood occurs constantly in a circular manner and is the result of the beating of the heart" there could be no pacemaker. Hence, it was urgent that we follow-up on the signatures of invisible solar activity in the form of transdisciplinary ~10.5­‑, ~21.0- and/or ~50.0-year cycles in, e.g., 2556 years of international battles, half a millennium of economics and 100 years of criminality, and a signature again of the Hale cycle in religious motivation, relating latitude-dependently to the brain. A common thread is the time horizon that the mapping provides for any study on the brain and beyond, of chronomes in us and around us. Information in the form of mapped characteristics of rhythms predicting occurrences over decades is required for the design and interpretation of studies over shorter (such as yearly) system times than the long-term (such as decadal) rhythms, the stage of which may relate to critically different outcomes along the shorter time scales, as Hörz's indispensable time horizon.

         Circadian desynchronization in blinded mice that led us to chronobiology was a confusing fact of reversals in one group but not in another, before it was readily resolved as a period difference between two groups along the 24-hour scale originally but along any scale, as Figure 26 demonstrates. The role of a decadal rhythm as a confounder is illustrated by the example of the excretion of metabolites of steroidal hormones. In this case, over several years, a statistically highly significant decrease with age was demonstrated. Over the ensuing several years, in the same subject there was a statistically highly significant increase, superficially again as a function of age. When all data were used, it was clear that one was dealing with a spontaneous presumably built-in about 10-year cycle. In different stages of this cycle, there were positive, negative and non-significant correlations with age or with any other, e.g., environmental factor examined. Figure 27 thus shows nonsense correlations occurring between steroids and helio- or geomagnetic indices. These spurious results would be expected as confounders for any rhythmic function. But what functions are not rhythmic? Most if not all of them are, but the periods have to be known before any results can be meaningfully interpreted. Maps are needed so that each figurative traveler in science, e.g., in health care knows what he deals with in order to avoid the monophasic or biphasic nonsense of Figure 27.

         On the positive side, based on a summary of over 1,000 individuals monitored by over 100,000 measurements, the utility of chronobiologic gender- and age‑, and whenever possible ethnicity-specified blood pressure and heart rate reference values for the detection of events such as ischemic strokes was demonstrated. The risk is great even when all values are in the "normal range", one reason to advocate a health watch that is now being implemented citywide in Urausu, Hokkaido, Japan, as a model for a national healthwatch campaign. Also on the positive side, purely geophysical chronomics gauge global environmental pollution even in the relatively unpolluted Antarctic. Any science, physical, medical, sociologic or purely demographic can only gain from chronomics. This transdisciplinary endeavor replaces the inferentially statistically and chronome-stage unqualified plethora of simply descriptive cycles that are not systematically monitored and analyzed by remove and replace approaches, as one goes. Among many other fields, chronomics could serve an understanding of economic variables and may be invaluable to insurers. The challenge is to follow the lessons learned from geophysics and even these, as can be shown, could have been much accelerated had the then already available methods been used.

Conclusion

         Human beings have shielded themselves from the unkind features of obvious extremes of weather and climate by building houses and have developed means, e.g., sulfonamides and antibiotics, to deal with at least some of the microbial contagions confronting us, that may be accelerated by solar activity (Figure 3 in I: 18), as stated with foresight and invaluable data by Chizhevsky and others (49-51), one more reason to explore the possibility of feedsidewards underlying phase response curves along genetically anchored built-in cycles from "then" (a billion years of evolution ago) as well as "now". There is a need for a transdisciplinary combined archival, physiological and demographic, always inferential statistical methodology in order to resolve multifactorial interactions underlying "contagions" of the mind, which may also be under the non-photic influence of the sun or the galaxies, at least insofar as their cyclicity is concerned. They may lead to a heightened susceptibility of the masses to demagogues as well as to the demagogues themselves. We face the task of a scientific chronobioethic that should complement chronomics and chronobiology in everybody's service.

         BIOCOS undertakes this kind of dangerous journey, which, however, is no more dangerous than the concept of circadians, labeled "Halberg's paranoia" half a century ago. From the viewpoint of chronobioethics (52, 53), it can only be hoped that the actual benefit already documented by timing the treatment of cancer or by detecting a risk higher than a high blood pressure in disease risk syndromes (12, 18) will be used more broadly in a much needed context (54, 55), so that what is under way in Urausu as Healthwatch may become the law in every country, like clean water, clean air, clean and safe streets, and safe circulation.

 

Acknowledgement

         The authors are greatly indebted to Peter G. Fedor-Freybergh, Editor-in-Chief, and to Lili Maas, Art Director, for publishing during the last few years this yearly update, originally sent to them only as information. To save space in a fine journal, the reader is referred to figures already published in earlier issues primarily of this journal.

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19.        Garcia Alonso L, Hillman D, Cornélissen G, Garcia Penalta X, Wang ZR, Halberg F. Nature, not solely nurture: chronome as well as season governs growth patterns of infants. In: Otsuka K, Cornélissen G, Halberg F, editors. Chronocardiology and Chronomedicine: Humans in Time and Cosmos. Tokyo: Life Science Publishing, 1993: 71-75.

20.        Portela A, Cornélissen G, Halberg Franz, Halberg Francine, Halberg J, Hofman MA, Swaab DF, Ikonomov OC, Stoynev AG. Metachronanalysis of circannual and circasemiannual characteristics of human suprachiasmatic vasopressin-containing neurons. In vivo 1995; 9: 347-358.

21.        Randall W, Randall S. The solar wind and hallucinations—a possible relation due to magnetic disturbances. Bioelectromagnetics 1991; 12: 67-70.

22.        Ronco A, Cornélissen G, Halberg F, Revilla M, De Stefani E. About-half-yearly pattern in the incidence of hormone-related cancers in Uruguay. Abstract #314, 5th Int. Conf. Anticancer Research, October 17-22, 1995, Corfu, Greece. Anticancer Res 1995; 15: 1753.

23.        Maggioni C, Cornélissen G, Antinozzi R, Ferrario M, Grafe A, Halberg F. A half-yearly aspect of circulating melatonin in pregnancies complicated by intrauterine growth retardation. Neuroendocrinology Letters1999; 20: 55-68.

24.        Tarquini B, Cornélissen G, Perfetto F, Tarquini R, Halberg F. Chronome assessment of circulating melatonin in humans. In vivo 1997; 11: 473-484.

25.        Martikainen H, Tapanainen J, Vakkuri O, Leppaluoto J, Huhtaniemi I. Circannual concentrations of melatonin, gonadotrophins, prolactin and gonadal steroids in males in a geographical area with a large annual variation in daylight. Acta endocrinol (Copenhagen) 1985; 109: 446-450.

26.        Halberg F, Cornélissen G, Watanabe Y, Otsuka K, Fiser B, Siegelova J, Mazankova V, Maggioni C, Sothern RB, Katinas GS, Syutkina EV, Burioka N, Schwartzkopff O. Near 10-year and longer periods modulate circadians: intersecting anti-aging and chronoastrobiological research. J Gerontol A Biol Sci Med Sci 2001; 56: M304-M324.

27.        Gavrilov LA, Gavrilova NS. Season of birth and human longevity. J Anti-Aging Med 1999; 2 (4): 365-366.

28.        Kumagai Y, Cornélissen G, Lykken DT, Bouchard TJ Jr, Tuna N, Delmore P, Zaslavskaya R, Teibloom M, Eckert E, Halberg F. In vitro and in vivo evidence for built-in features of the human heart rate chronome. In: Cornélissen G, Halberg E, Bakken E, Delmore P, Halberg F (eds.): Toward phase zero preclinical and clinical trials: chronobiologic designs and illustrative applications. University of Minnesota Medtronic Chronobiology Seminar Series, #6, second extended edition, February 1993, Part I, pp. 47-83.

29.        Schove DJ (ed.). Sunspot Cycles. Benchmark Papers in Geology/68. Stroudsburg, PA: Hutchinson Ross, 1983, 397 pp.

30.        Legrand JP, Le Goff M, Mazaudier C, Schröder W. Solar and auroral activities during the seventeenth century. Acta Geod Geoph Mont Hung 1992; 27 (2-4): 251-282.

31.        Cornélissen G, Halberg F, Wendt HW, Bingham C, Sothern RB, Haus E, Kleitman E, Kleitman N, Revilla MA, Revilla M Jr, Breus TK, Pimenov K, Grigoriev AE, Mitish MD, Yatsyk GV, Syutkina EV. Resonance of about-weekly human heart rate rhythm with solar activity change. Biologia (Bratislava) 1996; 51: 749-756.

32.        Katinas GS, Halberg F, Cornélissen G, Hawkins D, Bueva MV, Korzhevsky DE, Sapozhnikova LR, Rhodus N, Schaffer E. About 8- and ~84-hour rhythms in endotheliocytes as in endothelin‑1 and effect of trauma. Peptides 2001; 22: 647-659.

33.        Simpson HW, Cornélissen G, Katinas GS, Halberg F. Meta-analysis of sequential luteal-cycle-associated changes in human breast tissue. Breast Cancer Research and Treatment 2000; 63: 171-173.

34.        Sothern RB, Cornélissen G, Bingham C, Watanabe Y, Grafe A, Halberg F. Solar cycle stage: an important influence on physiology that must not be ignored. In: Proc. 3rd International Symposium of Chronobiology and Chronomedicine, Kunming, China, October 7-12, 1998. Chinese Society for Chronobiology and Chronomedicine, Chengdu, China, 1998, p. 144.

35.        Lamont J. Über die zehnjährige Period, welche sich in der Grösse der täglichen Bewegung der Magnetnadel darstellt. Annalen der Physik 1851; 84 (Series 2): 572-582.

36.        Halberg F. Chronobiology. Ann Rev Physiol 1969; 31: 675-725.

37.        Gauss CF. Theorematis fundamentalis in doctrine de residuis quadraticis demonstrationes et ampliationes novae. Commentationes societatis regiae scientiarum gottingensis recentiores 1820; 4: cl. math. 3-20.

38.        Schwartzkopff O, Cornélissen G, Bingham C, Homolka P, Katinas G, Sonkowsky RP, Halberg F, International BIOCOS Project Team. Long-term, when-needed lifelong monitoring concerns governments, ethics committees and everybody. Laudatio, Jarmila Siegelova's 60th Birthday, Brno, Czech Republic, January 2002, in press.

39.        Schwabe H. Über die Flecken der Sonne. Astronomische Nachrichten 1838; 15: 244-248 (no. 350).

40.        Schwabe H. Sonnen-Beobachtungen im Jahre 1843. Astronomische Nachrichten 1844; 21: 254-256 (no. 495).

41.        Sabine E. On periodical laws discoverable in the mean effects of the larger magnetic disturbances, No. II. Philosophical Transactions, Royal Society of London, 1852; 103-124.

42.        Wolf JR. Sonnenflecken-Beobachtungen in der ersten Hälfte des Jahres 1852; Entdeckung des Zusammenhanges zwischen den Declinations-variationen der Magnetnadel und des Sonnenflecken. Mittheilungen der Naturforschenden Gesellschaft in Bern 1852; 179-184.

43.        Ohtsuka-Isoya M, Hayashi H, Shinoda H. Effect of suprachiasmatic nucleus lesion on circadian dentin increment in rats. Am J Physiol Regulatory Integrative Comp Physiol 2001; 280: R1364-R1370.

44.        Kaiser H, Cornélissen G, Halberg F. Paleochronobiology: circadian rhythms, gauges of adaptive Darwinian evolution; about 7-day (circaseptan) rhythms, gauges of integrative internal evolution. Progress in Clinical and Biological Research 1990; 341B: 755-762.

45.        Prikryl P, Siegelova J, Cornélissen G, Dusek J, Dankova E, Fiser B, Vacha J, Ferrazzani S, Tocci A, Caruso A, Rao G, Fink H, Halberg F, International Womb-to-Tomb Chronome Initiative Group: Chronotherapeutic pilot on 6 persons may guide tests on thousands: Toward a circadian optimization of prophylactic treatment with daily low-dose aspirin. University of Minnesota/Medtronic Chronobiology Seminar Series, #3, December 1991, 4 pp. text, 4 figures.

46.        Cornélissen G, Halberg F, Prikryl P, Dankova E, Siegelova J, Dusek J, International Womb-to-Tomb Chronome Study Group: Prophylactic aspirin treatment: the merits of timing. JAMA 1991; 266: 3128-3129.

47.        Tiller WA, Dibble WE, Kohane MJ. Conscious Acts of Creation: The Emergence of a New Physics. Walnut Creek, CA: Pavior, 2001, 418 pp.

48.        Jahn RG. Out of this aboriginal sensible muchness: consciousness, information, and human health. J Am Soc Psychical Res 1995; 89: 301-312.

49.        Chizhevsky AL. The Earth in the Universe. V.V. Fedynsky ed. NASA TT F-345 TT 66-51025, 1968, 280 pp.

50.        Sigel F. Vinovato solntse [The Sun is Guilty]. (Dreier W, Lerche D, German translation; Göring H, scientific editor, German edition.) Moscow: Verlag MIR/Leipzig: VEB Fachbuchverlag, 1975.

51.        Ertel S. Influenza pandemics and sunspots—easing the controversy. Naturwissenschaften 1994; 82: 308-310.

52.        Cornélissen G, Bingham C, Siegelová J, Fiser B, Dusek J, Prikryl P, Sonkowsky RP, Halberg F. Cardiovascular disease risk monitoring in the light of chronobioethics. Chronobiologia 1994; 21: 321-325.

53.        Halberg F, Bingham C, Siegelová J, Fiser B, Dusek J, Prikryl P, Sonkowsky RP, Cornélissen G. “Cancer marker chronomes” assessed in the light of chronobioethics. Chronobiologia 1994; 21: 327-330.

54.        Goldstein LB, Adams R, Becker K, Furberg CD, Gorelick PB, Hademenos G, Hill M, Howard G, Howard VJ, Jacobs B, Levine SR, Mosca L, Sacco RL, Sherman DG, Wolf PA, del Zoppo GJ. Primary prevention of ischemic stroke: a statement for  healthcare professionals from the Stroke Council of the American Heart Association. Circulation 2001; 103: 163-182.

55.        Grundy SM, Pasternak R, Greenland P, Smith S Jr, Fuster V. Assessment of cardiovascular risk by use of multiple-risk-factor assessment equations. A statement for healthcare professionals from the American Heart Association and the American College of Cardiology. Circulation 1999; 100: 1481-1492.

 

 

Legends

         Figure 1. Maps of some about 50-year cycles, documented by linear-nonlinear rhythmometry. In each case, the period estimate is shown with its 95% confidence interval. Note close estimates for homicides recorded during 100 years in the USA and for an index of international wars available since 600 BC. © Halberg.

         Figure 2. Circaseptan patterns of visual reaction time (left) and flicker-fusion frequency (right) in three groups of patients who started (arrow) balneotherapy on different workdays. © Halberg.

         Figure 3. Documentation of the heritability of the circaseptan component by intra-class correlation coefficient, comparing the intra- vs. the inter-twin variability in the nonlinearly assessed circaseptan period, for data on diastolic blood pressure (top), heart rate (middle) and body weight (bottom), recorded in the neonatal intensive care unit. For these three variables, the circaseptan period was more similar between the twins in a pair than among twin pairs. © Halberg.

         Figure 4.Least-squares spectrum of the geomagnetic disturbance index Kp. © Halberg.

         Figure 5. From daily analyses of 1-min standard deviations of Pc pulsations, the 24-hour average value was analyzed over a 25-month recording span. There is a slight increase in spectral power in the circaseptan region, which was anticipated and is found to be statistically significant. Apart from a 7-day synchronized component, another component with a period slightly but statistically significantly shorter than 7 days is found to be even more prominent. Both components are resolved by nonlinear least squares. © Halberg.

         Figure 6. Inconsistency of the 7-day synchronized pattern in the geomagnetic antipodal index aa over consecutive spans of 22 (or 21) years. © Halberg.

         Figure 7. Change as a function of time in the relative prominence of the natural ~6.75-day and the 7-day synchronized components in the geomagnetic antipodal index aa. © Halberg.

         Figure 8. During days of high magnetic activity, heart rate variability is reduced to a different extent depending on the spectral region, greatly around 46.5 s and not around 3.6 s. Results obtained from 7-day ECG from a clinically healthy 48-year-old man, comparing days of high magnetic activity vs. days of low magnetic activity. Result confirmed on additional cases (not shown) suggests that the underlying mechanism responsible for the physiological response to changes in magnetic activity is other than the parasympathetic, usually identified with spectral power in the 3.6 s region. © Halberg.

         Figure 9. As shown elsewhere in relation to solar activity (gauged by Wolf numbers), heart rate correlates positively and heart rate variability correlates negatively with the geomagnetic disturbance index Kp. Data are monthly statistics from August 1987 to July 1998. © Halberg.

         Figure 10. Over a 3-day span in 1998 (April 29-May 1), the approximate entropy (ApEn) of Pc pulsations was computed over several 30-min spans for dBx/dt, using the original data sampled at 2 Hz. This index of deterministic chaos undergoes a circadian variation, assuming lower values during the night than during the day. A similar circadian variation characterizes the surrogate data, which on the average assume higher values of ApEn than the original data, suggesting that Pc pulsations may have nonlinear properties. Using the criterion of Theiler's sigma, the presence of nonlinear features in Pc pulsations could be documented for some but not all 30-min spans investigated. © Halberg.

         Figure 11. Least-squares spectrum of Kp shows peak at half a year, notably for the phase-weighted amplitudes. The large 1-year amplitude in the rms spectrum stems from the presence of a 1-year desynchronized component characterizing Kp, which remains large when data are analyzed over consecutive 1-year spans. © Halberg.

         Figure 12. Mapping of about 10.5‑, 21.0- and 50.0-year cycles in biology, aligned with similar cycles in natural environmental variables. © Halberg.

         Figure 13. Longevity peaks 2 months after the maximum in the geomagnetic antipodal index aa, both variables being characterized by a 6-month component. In view of the communality of periods, the results may have several interpretations, assuming there is some causality, raising new hypotheses that are testable in follow-up studies. © Halberg.

         Figure 14. Around-the-clock ECG records from groups of monozygotic and dizygotic twin pairs reared apart document the emergenic heritability of the circadian amplitude of human heart rate. The intra-class correlation coefficient is statistically significant for the 70 monozygotic twins, but not for the 44 dizygotic twins. © Halberg.

         Figure 15. Contour maps of Wolf numbers, gauging solar activity (yearly values 1500-1999) showing varying characteristics of the about 11-year cycles as a function of time, including the Maunder minimum: a: amplitude; b: ordering probability; c: percentage rhythm. Wobbliness of ~50- and ~100-year components is illustrated in d and e. © Halberg.

         Figure 16. Contour map of endotheliocytes from murine ear pinna show about 3.5-day and about 8-hour components reported earlier for human circulating ET‑1. © Halberg.

         Figure 17. Circadian pattern of mood, self-rated by a clinically healthy man, 34 years of age, about 5 times a day between May 3 and July 27, 2000 (N=413). © Halberg.