From David to Mario Cagnoni
The surgeon-scientist Harvey Cushing was reportedly surprised when he visited Florence to see Michelangelo's David and other works of Renaissance art and architecture, and found in addition a flourishing medicine. Beyond the quattrocento and cinquecento, Italy is also known for the Galileo of physics, who started himself as a medical student. Florence and greater Italy should further be known for scientists and physicians after Cushing's time, in the second half of the 20th century, who provided the biomedical and broader transdisciplinary background for Giorgio Piccardi, all of whom are here gratefully honored. As a physical chemist, Piccardi studied the "extreme variability of water" from a physicochemical viewpoint, in keeping with Claude Bernard, who recognized the "extreme variability of the internal environment" as one of his major contributions (1). On this point, the senior author wholeheartedly agrees, although for a professional lifetime he fought -- with Mario Cagnoni and Paolo Tomasso Scarpelli, and in particular with the late Brunetto Tarquini, all from the Semeiotica Medica -- the misinterpretation of the elderly Bernard's "relative constancy of the internal environment" (2) and homeostasis (3). These oversimplifications are too often used as an excuse, if not as an outright invitation, to ignore rhythms, the latter actually recognized at least by a brief statement in a book by Cushing (4). The scientific Florence and Italy of Piccardi, who emphasized the merits of periodicity analysis second to none, lead to the mapping and use of time structures, chronomes, with a broad spectrum of rhythms, including cycles of non-photic origin, such as the biological week, half-week, half-year and decade. The Florentine school led to chronomics, a coordinated international mapping of chronomes, one of the aims of Piccardi's focus with his tests of environmental influences upon the physical chemistry of water.
Biography
Giorgio Piccardi was born in Florence on October 13, 1895. He started his academic studies at the local "Istituto superiore" under the direction of Ugo Schiff in 1913, transferring the following year to study mathematics at the "Politecnico" of Turin. In 1915 he enrolled in the Alpine Corps as a cadet until the end of World War I. Returning to Turin he eventually came back to Florence to the Istituto di Studi Superiori and graduated in 1922 in chemistry under the tutelage of Luigi Rolla.
From 1924-26 Piccardi taught a course in the physico-chemical laboratory. From 1926-27 until 1931-32, he gave a course in mathematics at the "Istituto Superiore Agrario Forestale" which was attended by students in the natural sciences, chemistry and pharmacy. In 1926-27 and 1935-36 he also gave a course in chemistry and a special course in mathematics (1932-33 and 1936-37) in connection with a course in "spectroscopy in chemistry and physics". In 1934 he became an assistant in inorganic chemistry until he won the concorso (competition) for the chair of physical chemistry in Genoa in 1938 and in 1944-45 at the Faculty of Science in Florence. He was charged with the teaching of physical chemistry since he could not return to Genoa because of World War II. In 1946 the Florentine faculty offered him the directorship of the new Institute of Physical Chemistry where he had a series of assistants, some of them voluntary, Enzo Ferroni preeminent among them.
His recorded contributions are many: he worked on methods for measuring the ionization potential which allowed him to document a relation of a periodic kind with the atomic number of elements. He also continued studies with Luigi Rolla on the fractionation of "rare earth". But unquestionably, his major contribution relates to bio-climatology.
In 1962, in relation to his tests defined in Table 1, Piccardi wrote:
I would like to point out that in the field of climatology, the periodical analysis ... will be a highly valued means of investigation because in revealing, as it does, true rhythms (not choosing just the harmonic rhythms), it can show which phenomena are in true mutual relationship, even if the raw data do not reveal similar behaviours. [His physico-chemical] Test F and test D, during the diminishing phase of the old solar cycle, revealed what was apparently a highly varying behaviour, but under periodical analysis they revealed the same periods (5).
Piccardi recognized the need for assessing recurring phenomena in physical and biological nature, including the signatures on earth of circadecadal cycles in solar activity. Herein, we resolve some of the pertinent cycles by methods that became more readily applicable in the computer era by focus on time structures, chronomes, by chronomics (see Introduction to Chronobiology at http://www.msi.umn.edu/~halberg/ ).
Chrono-meta-analysis of Piccardi's data
The information in Piccardi's research is time-macroscopic. Estimates of uncertainties are usually missing. Hence, it seemed important to use time-microscopy on the data available to us from his book (5). Actually, our meta-analyses confirm his statements, with the merit of adding information on the uncertainties involved.
The data from Figure 17 on page 95 of Piccardi’s 1962 book were taken off and analyzed by linear-nonlinear rhythmometry (6-8) In his graph, Wolf's relative sunspot numbers gauging solar activity are plotted together with results from Piccardi’s D-test, as yearly values during the span from 1951 to 1959. The short 9-year span notwithstanding, a circadecadal component could be demonstrated in both series with statistical significance, Table 2. The circadecadal component characterizing the D-test results accounts for 76% of the total variance and has a double amplitude of over 40% of the MESOR, the chronome (time structure)-adjusted mean. The Wolf numbers are slightly overfitted. The period estimates obtained nonlinearly (6-8), however, are not very close (7.72 and 9.14 years for the chemical and geophysical series, respectively). Their 95% confidence intervals are quite wide, as anticipated in view of the short observation span of only 9 years.
A similar analysis of daily Wolf numbers downloaded from NOAA's website yields almost identical results, the nonlinear period estimate being of 9.30 years for the particular 9-year span investigated, but with a much narrower 95% confidence interval (Table 2). The acrophases at two different periods in the top two rows of Table 2 are, of course, not comparable. Hence, in order to further examine any association between the D-test results and solar activity, the circadecadal acrophases of both data series were recomputed at two different trial periods: first at 9.3 years, corresponding to the daily values of Wolf numbers for 1951-1959; and second at 8.5 years, corresponding to the average best fitting period of the two series investigated. At both trial periods, the acrophases are very close, differing only by 5 or 7 degrees, respectively (Table 2), a validation and quantification of the interpretation by Piccardi's unaided eye. The chronometaanalyses are in keeping with the assumption of similar periods, but such findings constitute hints, sometimes very useful ones, but no more. To examine the possibility of more than chance associations, fortunately Piccardi also provided data from superposed epochs, a method often used by others as well as by us (9, 10). More specifically, on page 87, in Table XIV, Piccardi also reports on results from superposed epochs for 3 consecutive years (1951, 1952, and 1953). These results examined the effect of solar eruptions on outcomes from his F and D tests. Piccardi provides data on averages of F and D tests for the day of eruption and for four days before and four days after eruption. Whereas no statistically significant effect was apparent for the results of D tests, an increase in F tests coincides with days of solar eruptions. Because the raw data were not available and only results from 3 consecutive years were published, results from each separate year were expressed as percentage of the 9-day series mean value. For each day relative to solar eruptions (-4 to +4), the average relative data from the F tests were computed and tested versus 100% (no effect) by paired t-test. Only on the day of solar eruptions was an effect of borderline statistical significance found (t=3.924, P=0.059). In view of the absence of original data and hence of the very small number of replications available for testing, a one-way analysis of variance was carried out, which tested the equality of means over the following 3 spans: days –4 to –1 (before), day 0 (during), and days 1-4 (after) solar eruptions.
As illustrated in Figure 1, during solar eruptions, results from F tests are statistically significantly larger than either before or after a solar eruption (F=16.736, P<0.001).
Transdisciplinary cycles reflected in life
Physics currently lacks a unified field theory that bridges no more than gravitation and electromagnetism. It is the more important that biology comes to the aid of physics in the footsteps of William Gilbert, who was the first to view the earth as a great magnet. By becoming transdisciplinary, everybody aids science, his/her own as well as that of others. In dealing with the biosphere, we can view it as a set of cyclic radiation generators and detectors. Life, as a microcosm, has acquired many features of its macrocosm, in the variety of its continuous interactions with its environment, near and far. Life has reproducibly recurrent features within broad time structures, chronomes, consisting of the elements of probabilistic chaos, trends and predictable cyclicities. The latter constitute essential dynamics of life and keys to optimization, also in the context of the weather and climate and their effect upon us. In terms of its cycles, the life of an individual or population can be viewed as an electromagnetically recordable entity sui generis, with metric characteristics, which Santorio Santorio, Galileo''s student in Padua, measured assiduously for perhaps 3 decades, an example followed by others. Life can reproduce itself, yielding population cycles, and in so doing evolves, as a system not only open to its environment and adjusting to it, but beyond Darwinian adaptation, life is subject also to an internal evolution (11, 12) for integration both within and beyond spatial organismic boundaries. Last not least, in the course of integration with the environment, homo faber changes the latter, trying to optimize it from an often short-term viewpoint, but unwittingly and helplessly polluting it from another often long-term perspective. The cycles of both the environment and the organism, including humans who build space stations or destroy skyscrapers, await the periodicity analysis advocated by Piccardi on an international scale, i.e., await chronomics. As a beginning, the BIOCOS (The BIOsphere in the COSmos) project (12) pursues clues to solving the mechanisms and developing countermeasures for dealing with major problems of our day. . . Eventually, the realistic goal will be to optimize the weather. This is a Herculean task; in the light of opinion-leading minds of a figurative yesterday, even purely physical short-term weather prediction would never be possible (13). In 1940, Einstein suggested that such prediction is impossible because of the multiplicity of factors involved. But in 2002, at least some, but not all, short-term aspects of the weather can be foreseen, with a specifiable likelihood but not yet (or never?) with certainty. If, however, there should be progress toward narrowing the uncertainties, the cyclicities involved are a putative key. Piccardi recognized the multifactorial situation from the viewpoint of only weather and climate and their effect on earth, on humans par excellence, without including economics and politics, with their chronomes.
He wrote that the status quo must be overcome and deplored that there was "no mutual contact and penetration" (5) among fields with a bearing on weather prediction. Piccardi introduced his 1962 book with the premise that
"Someday it may be possible to speak with precision and depth of the chemical basis of medical climatology ... Since it is a natural science of a general character, there can be no progress in climatology if there is no progress in those branches of knowledge which lie on the boundaries between climatology and other sciences: astrophysics, geophysics, meteorology, physical chemistry, biophysics, biology ..."
[And, we suggest, also medicine and indeed sociology and ecology. Organisms in general and humans in particular may be not only excellent radiation detectors; they proliferate, even clone, and beyond a sheep, a cat or other already-cloned organisms, create cycles of their own making.]
"The traditional climatic factors are almost exclusively meteorological factors: temperature, pressure, humidity, wind, air masses, fronts, precipitations, the state of the weather and the meteorological situation and its evolution. "(5)
Piccardi, however, was interested in much more than these "traditional" climatic factors in themselves; he also speaks of the "chemical basis" of medical climatology, which in fact is a "physico-chemical" basis, as having its roots in the cosmos, endeavoring to prove this point with his test outcomes, one of which, as shown here, revealed a statistically significant circadecadal cycle. Piccardi follows the lead of Chizhevsky (14, 15), Düll and Düll (16-18), Peterson (19, 20), de Rudder (21) and Reiter (22), among others (cited on pp. 16 and 17 of [5]). Piccardi recognized that "Periodicities existed even hundreds of millions of years ago, and thus were the same as today with respect to one of the more important cycles, that of sun spots."
Spectra show that some aspects of the time structure, or chronome, of solar variability such as a circadecadal cycle, Figure 2, rather than "being the same", vary drastically in a characteristic such as cycle length,
Figures 3 and 4 (23-25), but generalizing along the time scale he chose, from the Precambrian to the Oligocene (5), as Piccardi did, he is probably correct in suggesting a degree of "sameness" for the circadecadal element of cyclicities in the solar activity chronome (23). Piccardi properly notes (5):
"Our experiments have not yet covered an entire solar cycle, but the greater part of one has been covered: nine and one-half years out of eleven. What we have seen is already sufficiently clear. There is no doubt that chemical test D will close its cycle together with the sun spots."
[In 1962, or even as far back as 1801, when the lost asteroid Ceres was relocated (23-25), available methods (26) could have allowed predictions based on no more than data covering a large portion of a single cycle. This was demonstrated in chrono-meta-analyses (23) of data by Beaufoy published by Lamont, as in the data of Lamont himself (27),
Figure 5, in the very context of physico-chemical periodicities. These latter were so dear to Piccardi (5, 28) that he mapped them internationally in the footsteps of Humboldt and Sabine, those of Gauss and Weber, and those of Schwabe (29-32; cf. 33-38).]
Chrono-meta-analyses of microbial data
Studies on a nearly daily basis of microbial sectoring as a possible gauge of mutation or other genetic change, published since 1971 (39-46), have more than complemented Piccardi's invaluable data, not only by a greater length as compared to that of the series of Piccardi's tests, but the sectoring data represent more than a match in importance, since they extend to bacteria, and thus to life, what Piccardi demonstrated for physical chemistry. Chronometaanalyses provide a microbial parallel to Piccardi's Figure 18 on p. 96 of his book (5). There, Piccardi discusses an observation presented by him time-macroscopically in a graph. Therein the naked eye cannot detect a yearly change in Wolf number, whereas there are changes along the scale of a year in Piccardi's test. Should his original data be available, it would be interesting to see whether the geophysically prominent half-year may be present in them as well, apart from (or in addition to Piccardi's theory of) a signature of a helicoidal motion of the earth in the galaxy, referred to the neighboring stars, leaving its mark in a physicochemical test.
In this context, Figure 6 shows for time-macroscopic viewing, original data on microbial sectoring extending for over a decade. An unmistakable, albeit irregular, circadecadal pattern emerged and was time-microscopically analyzed elsewhere. But even the unaided eyes can tell that there is more information in the data. This quantifiable result from linear-non-linear analyses is given at the bottom of this figure, first as a period of 9.4 years. In a 2-component model, also shown at the bottom of Figure 6, a 1-year component, in addition to the circadecadal component, is also resolved, the two-component model in the figure fitting reasonably well.
To improve the model, Figure 7 shows, along with the same original data on air bacterial sectoring, a 3-component model. Now, a half-yearly component is also statistically significant, albeit both the yearly and half-yearly components are smaller in amplitude than the circadecadal component. Both the store of microbial data and, if available, Piccardi's data await analyses for further periodicities that can be resolved as a function of the density and length of the available data.
The resolvable characteristics are limited by the sampling times of the original observations. Systematic microbial studies could be planned with a sufficient density to analyze at least circadians and preferably ultradian components and of sufficient length to assess any multidecadals as well: the entire spectrum of infradian changes, that were of interest to Piccardi. To realize this goal, one could start with storing data from sensitivity tests to antibiotics done routinely in hospitals. In such tests, controls are included, but in current instrumentation, the control data are not kept and with some instruments not even displayed. It seems desirable, in view of the data on sectoring and of Piccardi's goals, to develop universally applicable test methods as part of routine testing for sensitivity to antibiotics. Piccardi's physico-chemical monitoring coupled with Faraone's microbiological monitoring could both be carried out under conditions of shielding from (or compensating for) environmental agents such as cosmic rays or geomagnetics at different latitudes and longitudes, to examine, with the classical factors involved in weather and climate, any signatures of other near and distant drummers as well.
Chronomedical Florence in the second half of the 20th century
Piccardi lived in a city of prominent active chronobiologists, represented by Mario Cagnoni, Paolo Tomasso Scarpelli, the late Brunetto Tarquini, Salvatore Romano, Giorgio Mello, Giancarlo Mainardi, Riccardo Livi, Federico Perfetto, Roberto Tarquini and Emanuele Croppi, who cooperated with the Minnesota chronobiology center in a total of well over 100 published titles (e.g., 47-59). The contributions of these Italian, or rather world-class pioneers in a quantitative clinical chronobiology along with those of their Minnesotan and wider international associates, are found in fields as diverse as neonatology, early public primary and secondary education, oncology, cardiology and general, notably preventive health care (e.g., 56-58). These also parallel and complement Piccardi's longitudinal studies with specific tests of changes that the outsider would describe as the study of temporal much aspects along a longer time scale in physical chemistry, with particular focus upon water (5). Piccardi's point, emphasized in a lecture given in Paris, was that water (among other liquids, notably inorganic and organic colloids), is sensitive to solar and terrestrial influences. He asks rhetorically: If water and inorganic colloids respond to the action of the cosmos, one does not deal with a phenomenon relevant to one or the other organism, one or the other phenomenon, or one or the other disease, but relates to the complex state of living matter as a whole (28) (and, we add, this effect, in its many diverse forms, can be recognized as predictable by the periodicities or broader chronomes involved).
Mario Cagnoni, heading the Cattedra di Patologia speciale medica e metodologia clinica (Semeiotica Medica) at the faculty of medicine, made important contributions in many fields, including oncology and cardiology, and set an example with his colleagues in self-monitoring the electrocardiogram for days rather than only for 24 hours. He set the stage for marker rhythmometry in the field of cancer treatment in patients with multiple myeloma. In a broad cooperative context, the excretion of Bence-Jones protein was found to be circadian periodic in the clinic and laboratory (60-63). Marker-guided chronotherapy eventually doubled 2-year survival rate after the timed chronoradiotherapy of very advanced perioral cancers (62). Mario demonstrated chronopathology in the human breast as an alteration of endocrine rhythms. For serum prolactin, he showed circannual chronopathology in fibrocystic mastopathy as compared to health. This important step toward a chronomedicine revealed precancerous pathology, as initiated by Cagnoni (54) and pursued by Tarquini's team (48).
Mario prompted Paolo Tomasso Scarpelli's leadership, who first went into schools to advocate and study chronobiologic self-measurements with special reference to blood pressure. In this context, Paolo Tomasso emphasized prevention, while he also discovered, at first in the adult clinic, the importance of an increased circadian amplitude of blood pressure, even in the absence of an increased rhythm-adjusted mean or MESOR and started the first national Italian chronobiologic 5-city study (56) with only a local parallel in the USA (64, 65) and Germany (23, 65) and a follow-up now in Urausu, Japan (65).
The late Brunetto Tarquini, who took over Cagnoni's chair in Semieotica Medica, further enabled the documentation of ultradians and infradians in the circulating vasoconstrictor endothelin-1 (ET-1) (51, 52). He provided the data for changes along the scale of years in the spectrum of ET-1. Before Tarquini, Artigou et al. (66) had reported a circadian rhythm in ET-1, as illustrated time-macroscopically in
Figure 8. By cosinor analysis, the circadian rhythm was statistically significant (P<0.01).
In keeping with Artigou et al. (66) was a report by Perfetto et al. (59), also reporting a circadian rhythm in ET-1,
Figure 9. In these first 10 ET-1 profiles, an effect of age was suggested, albeit only with borderline statistical significance (P<0.10),
Figure 10. But as data accumulated in Florence, the circadian rhythm in ET-1 was lost, Figures 11 and 12. In a person sampled at 20-minute intervals, ultradians came to the fore in the original data,
Figure 13, and after detrending, Figure 14. Hourly sampling on 7 subjects then sufficed to demonstrate an about 8-hour component in healthy medical students in Innsbruck (67),
Figure 15. Briefly, the usually prominent circadian variation could not be validated and was replaced by an unusually prominent 8-hour component that could be replicated. Circaoctohoran changes had been documented earlier for urinary epinephrine excretion by Hugh Simpson, Fred Bartter and others (68) under the unusual circumstances of an equidistant isocaloric diet in 4 patients with Bartter syndrome and 4 controls. They were statistically highly significant, but the circaoctohorans were not dominant on the usual routine (69). In the study by Herold et al. (67), however, the subjects followed usual conditions of life. The circaoctohoran component of ET-1 was statistically significant, but was it also scientifically and/or clinically important? This question was raised before its relevance was surprisingly further validated by another separate chronometaanalytic study on a different variable carried out in a different geographic and geomagnetic location (70).
But before we turn from Piccardi's Florence to Russia, another clinical point can be made. From a circaseptan perspective, the same Florentine ET-1 data showed that more than a circadian rhythm alteration may serve for risk assessment, for what Tarquini called chronorisk (49, 52). A new finding of the ET-1 study was a chronome alteration involving the about half-weekly rhythmicity in health, as a circasemiseptan chronopathology,
Figure 16 (52). Most interestingly, this involved the parameter phase, i.e., a circasemiseptan ecphasia. In diabetes, we had earlier found a circadian ecphasia, that is an alteration of the timing along the 24-hour scale, for blood pressure (64) confirmed by others time-macroscopically as non-dipping, which can be an unspecific label of several conditions, ranging from a reduced circadian amplitude to a change in phase. Certainly, ET-1 deserves further scrutiny as a putative mechanism, as well as an index, underlying chronopathology.
Apart from clinical aspects, the discovery of circaoctohoran rhythmicity in circulating ET-1 in one species (humans) (51, 67) in two geographic locations (Florence and Innsbruck) could be matched in another geographic location (St. Petersburg, Russia) (70), at least in period length, for another species (mice) for another tissue (ear pinna rather than blood) in the population density of the very cells that produce ET-1 (the endotheliocytes). Thus arose the still-unanswered question of any known environmental counterpart to circaoctohorans, now and/or in the past, that Piccardi and his colleagues could have tried to answer with physico-chemical tests. In any event, Cagnoni, Scarpelli and Tarquini had created a school that made their medical and other colleagues sensitive to non-photic environmental features, in keeping with Piccardi's concerns about periodic signatures, gauging those of weather and climate near and far (5). Conceivably, the environment may be guilty of a change in the ET-1 spectrum, possibly with a circadecadal pattern. This possibility deserves further study, but remains a guess.
Another possible link to the cosmos is due to the neonatologist Giancarlo Mainardi when the Florentine group led by the late Brunetto Tarquini developed a test inspired by the work of Scarpelli in humans (58) and Julia Halberg on stroke-prone rats (71) on the importance of the circadian amplitude of blood pressure. In two-day profiles at 30-minute intervals of blood pressure and heart rate, Mainardi with Tarquini provided data that could separate groups of human newborn babies with a positive family history of high blood pressure and/or of other vascular disease from babies with a negative such history,
Figure 17 (and Figures 16a-e in [24]). On 164 babies accumulated over 2 years, the separation was statistically significant (72; cf. 64, 73-76). The increase in the circadian amplitude of blood pressure with vascular disease risk corresponded to earlier findings made by Scarpelli (56, 57) and others (73) on children, adolescents and adults, again as a function of a positive vs. negative family history. The finding was extended to Doppler flow-meter assessed variables (75) and to the exposure in the uterus to betamimetic drugs (37, 77). The positive family history or the exposure to betamimetics were both associated with a larger circadian amplitude of blood pressure. Data of the 164 babies showed this difference immediately after birth during 1985 and 1986, a minimum of solar activity. During the next few years, however, this separation of newborns as a function of family history immediately after birth could not be found,
Figures 18 and 19 (and Figures 16a-e in [24]). On the average during 1987-1989, as compared to the preceding years, the circadian amplitude of systolic, mean arterial and diastolic blood pressure had increased, as shown in
Figure 18, in babies with a negative family history of high blood pressure but not in babies with a positive such history. This change brought about a corresponding (?) change in the test result between the minimum of solar activity vs. the ascending stage of solaractivity, as visualized in
Figure 19.
The same studies also revealed that, as compared to the circadian component, an about-weekly (circaseptan) component was much more prominent
(Figure 16a-e in [24]). A comparison of the circaseptan amplitude between babies with a positive or negative family history again showed a statistically significant difference, the larger amplitude characterizing babies with a positive family history (74). It is conceivable, but not proven, that the stage of the solar cycle, of great interest to Piccardi (5), was "guilty" for the failure of the circadian test, as shown in
Figure 19, notably since an association between circaseptan characteristics of blood pressure and heart rate was found to correlate with circaseptan aspects of local geomagnetic disturbance (78). A putative test for cardiovascular disease risk as yet remains to be sought based on the circaseptan rather than circadian amplitude, should recordings on healthy babies for 7 days as a minimum become available. The circumstance of associations of cardiovascular rhythms with local geomagnetic activity supports this assumption, among other lines of evidence reviewed elsewhere (12, 36).
It must be kept in mind that there was apparently no known change in the handling of babies in the Florentine neonatal clinic. Hence it seems reasonable to try to account for spontaneous secular changes as a function presumably of solar cycle stage and number,
Figure 19. In so doing, the senior author is reminded of other inter-group differences that were lost and even reversed half a century ago (79-82). In one study, he had then taken tail blood for counts of blood eosinophil cells from two groups of mice with a very large difference in breast cancer incidence. Changes were found with the circadian stage at which the groups were compared. More specifically, at a conveniently fixed time of day, the difference was statistically highly significant in one direction. It was tempting to draw inferences; but when he wanted to reproduce the effect, he got up earlier to study more mice and found no difference. The first two sets of results seemed confusing. To clarify the situation, he got up even earlier to start earlier and thereby to study even more mice, and now found a difference in the opposite direction, as compared to the first investigation,
Figure 20. Actually, in the three surveys, he had studied two circadian rhythms, which were out of phase (for the two groups being compared). But this was only one possibility for getting discrepant results in two groups according to different synchronizers. Indeed, one group was fed ad libitum and was primarily synchronized by the alternation of light and darkness at 12-hour intervals. The other group, being restricted by 50% in dietary calories by having access to food only during part of the day, was differently synchronized (out of phase) as a function of the time of food accessibility, overriding any effect of the lighting regimen (80), a possibility recently confirmed (83, 84).
Another possibility for the disappearance (and eventually a reversal) of an inter-group difference is a slight difference in period. This actually led the senior author to coin "circadian" to describe the behavior of sham-operated and blinded mice (79, 81; cf. 85). In the investigations of
Figure 19, the problem may be yet more complex. We may deal with a response rhythm to solar cycle stage in one group and perhaps not in another, among many possibilities. Without further information we conclude no more than the need to consider a much wider time horizon than the span (read: system time, in
Figure 19) for sampling blood pressure every half-hour for only two days to compare the neonate's risk of developing vascular disease later in life. When we continuously survey supermarkets to prevent theft and parking facilities to prevent violent crimes, we may well invest into monitoring health to avoid major threats of crippling diseases.
The chronome maps of each variable must include the characteristics of Piccardi's circadecadals that may confuse much more research than do circadians, particularly research on aging, which is necessarily confounded by circadecadals. We need to acquire maps of the stages of all rhythms involved, including circadecadals, precisely what Piccardi strove for (5). Whenever we encounter "secular" variation, a word hiding our ignorance, we must resolve the chronomes involved. With respect to neonatal studies on any variable, since circaseptans are much more prominent immediately after birth in the circulation, any short-term diagnostic test of the circulation at birth is best focused upon the 7-day scale, when it involves, e.g., blood pressure or heart rate. Likewise, many if not all variables will also have to be mapped along the scale of decades, since the infant is quite sensitive to the environment. Whether we do physico-chemical and microbiological tests or human monitoring, there is no shortcut by ignoring the need for a decadal time horizon by words such as reference to homeostasis. If we do so, blunders will be unavoidable.
The current authors' and Piccardi's goals met once more in findings made over the years concerning another variable of Florentine patients for which reliance upon 24-hour and 1-year profiles does not suffice: melatonin, a hormone much in the foreground from the viewpoint of decadal rhythms, yet to be mapped (53; 86-89),
Figure 19. Conceivably, in the case of ET-1 and melatonin as well as blood pressure and heart rate, it may be worthwhile to find a better explanation than "secular variation" for changes with time of a circadian rhythm into a circaoctohoran one and someday perhaps vice versa. Qui vivrà, vedrà (Time will tell).
Perspective
Concern for an ~11-year cycle, although he did not yet have data covering 11 years, sets Piccardi apart from his colleagues Galileo or Newton, both of whom had fine telescopes, but missed one of the most prominent solar dynamics. Galileo discovered sunspots, even followed their behavior along the scale of the year, and eventually published his drawings of sunspots. But like Newton, whose name is associated with periodicity in the rings named after him, Galileo apparently was unaware or uninterested in any circadecadal cycle of solar activity discovered by Samuel Heinrich Schwabe, the pharmacist turned botanist and astronomer, a friend of Alexander von Humboldt (31, 32). Periodicity and attitudes toward it have not yet changed from those of the 18th-century investigators cited by Manuel J. Johnson, president of the Royal Astronomical Society, in 1856 when he awarded Schwabe the society's gold medal (90):
Piccardi did his testing against a "mainstream" of such persistent pessimistic attitudes as did Mario Cagnoni and his school. Both Cagnoni's and Piccardi's schools were concerned with longer than short-term changes around us. For weather and climate, Piccardi laid the foundation of any relation by focusing on the periodical processes involved within his specialty physical chemistry. He wrote:
"Thus periodical analysis would be an analytical method to introduce in order to establish once and for all which are the periods comprising the periodicity of the natural phenomena of climatological interest. " (5)
This essay is also an expression of gratitude to most of friends in Florentine medicine and science and for their splendid cooperation with some of us in Minnesota. In this much broader context, and against the background of a memorial of Brunetto Tarquini (47), this essay is both a chrono-meta-analysis and a sincere laudatio of Giorgio Piccardi. We honor Piccardi by the goals he set for himself (and for all of us): 1. to resolve any effect of weather near and far, now and then (in evolutionary history) upon health and disease; 2. by his recognition that this requires long-term systematic measurement, including his very field of physical chemistry as well as requiring 3. the use of periodicity analyses; and 4. for implementing, in the light of the foregoing considerations, a global international transdisciplinary cooperation from the poles to the equator. This endeavor was started in geomagnetics by Alexander von Humboldt and General Sir Edward Sabine (29) as well as by Carl Friedrich Gauss and Wilhelm Weber (30; cf. 33), and its extension, in a transdisciplinary, including biomedical context (34-38), is long overdue.
Conclusion
In honoring Piccardi, we conclude by presumably paraphrasing Galileo. Like Galileo, both Piccardi and Cagnoni were active in Florence, at least for a large part of their professional lives. Cagnoni, Piccardi and Galileo have further in common the principle traditionally attributed, perhaps in the spirit of the time, to Galileo: "Omnia metire quaecumque licet et immensa ad mensuram redige": "Measure what is measurable, and what is not measurable, make so". With Prof. Robert Sonkowsky at the University of Minnesota and the late Agostino Carandente, we have paraphrased the foregoing further "Omnia metire quaecumque licet et immensa ad mensuram tempestive et ergo significative redige": "Measure what is measurable, and what is not measurable, make so, in time and hence meaningfully".
In this sense, Italy, with Leonardo da Vinci and Michelangelo, in the forefront in the past 500 years, should stimulate in the new millennium a new generation of transdisciplinary Renaissance men and women in the tradition of Cagnoni and Piccardi and their as-yet separate schools that must transcend disciplinary boundaries. In this context, we must not forget the first Cattedra di Cronobiologia of Franca Carandente in Milan.
Epilogue
Future work may also check the report made half a century ago from Vienna by Dr. Franz Vering (91). He noted, albeit without estimating the uncertainties involved, that atmospheric bacteria have two daily maxima, at 08:00 and 20:00, and two daily minima, at 02:00 and 14:00. He also plotted the daily growth for seven days of agar cultures in Petri dishes kept at 37°C, exposed daily around 18:00 for 5 minutes under air pressure. He did this mapping during a week of atmospheric quiet and another week under disturbed conditions and reported differences. Much remains to be done along the scale of periodicities of many orders of magnitude; we need to replace the putative "baseline" of today by the mapping of chronomics. There is a need for a concerted effort, as early as possible, for imaging in time to complement molecular biology by gene expression at different temporal as well as spatial levels of integration. Already, Anatoly Delyukov and Yuri Gorgo have attempted to correlate the proximal and distal battery of factors impinging upon a continuous electrocardiographic record covering 50 and 70 days (92, 93).
These are beginnings as compared to less dense monitoring now ongoing for 35 years (12, 94). We need to match Giorgio Piccardi's interest and studies from the poles to the equator, that set the stage for a long-term, if not continuous mapping in the service of bioclimatology and far beyond. There is a need to develop countermeasures for diseases of society as well as of individuals. Conceivably, the best line of evidence of a solar effect is that relating to epidemics. Chizhevsky described a circadecadal incidence of cholera by superposed cycles (14, 15), as did Ertel (95), and indeed an organism's resistance to insults such as an infection stems in part from the protection afforded by physiological doses of the steroids of the adrenal cortex that undergo a circadecadal cyclicity (96). That the microorganisms themselves are affected by remote drummers was the topic of earlier CIFA and other reports. Much has been done, but much more can now be undertaken based on available results.
Figure 21 shows once more the original microbial and solar data on the right and the averages on the left. The clear difference in phase established time-microscopically is here shown for the naked eye time-macroscopically. Recently, Stoupel et al. (97) reported a negative correlation between geomagnetic activity and sudden cardiac death and asked whether high magnetic activity can protect the electrically vulnerable heart (97). An about 5.6% decrease in the incidence of sudden cardiac deaths in Moscow during 1979-1981 was also found to occur two days after a magnetic storm, gauged by a southward turn of the vertical component Bz of the interplanetary magnetic field (P<0.05) (98).
Figure 21 shows only that one aspect of corpuscular solar activity, which also influences geomagnetic activity, is out of phase with microbial sectoring. The cycles involved may be a reflection not only or not necessarily of geomagnetic activity, but also at least in part an effect of the displacement by the latter of galactic if not solar cosmic rays. Whatever the effect may be, it will be most interesting to carry out microbial studies under conditions, shielded, unshielded or compensated for known environmental factors (such as geomagnetics) and, perhaps, also deep underground to reduce the effect of cosmic rays (cf. 99).
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FARAONE’S REMARKS: Errata Corrige of N 10 ( Mater.Methods), are mentioned from the paper / N 43 of References. It’s possible to ask Faraone’s papers or other his techn.news, mailing him to:
piefarao@tin.it
Send correspondence to:
Franz Halberg, MD
Director, Halberg Chronobiology Center
University of Minnesota
715 Mayo · MMC 8609
420 Delaware St. SE
Minneapolis, MN 55455, USA
TEL +1.612.624.6976 · FAX +1.612.624.9989
E-MAIL: halbe001@umn.edu