1998

We thank all of those who have supported the continuance of chronobiology at the University of Minnesota, Earl E. Bakken in particular. There may again be a center in our tradition that need not rely mainly on designing and analyzing work done elsewhere. As yet uncertain is experimentation on laboratory animals (1), the very approach that led Erna and Julia to the documentation of a disease risk syndrome (2).

Too much variability in blood pressure (1, 2) and too little in heart rate (3-6) underlie a new type of asymptomatic clinical conditions of high disease risk. One of these risk syndromes is circadian blood pressure overswinging or CHAT, short for circadian hyperamplitudetension. Another syndrome, in health (!), is an excessively low variability in heart rate, called CAHRV, for chronome alterations of heart rate variability. The switch from a focus on rehabilitation (after the fact of catastrophic disease) to the lowering of an elevated disease risk in the superficially healthy person=8Bpre-habilitation=8Bbecame our major concern in 1998, notably for stroke prevention. Locally and in a worldwide cooperation first and foremost, we monitored blood pressures, heart rates and electrocardiograms for spans of not less than 7 days whenever possible. Whenever indicated and for research, we monitored for much longer durations.

We had the very great pleasure of cooperating along several lines with Kuniaki Otsuka, who published a book on a chronocardiology sui generis (3). One of his 7-day monitorings on himself sufficed to detect a lowering of variability in his R-R intervals during a magnetic storm: a statistically significant overall effect was not significant at the 3.6-second power (P>0.50), but was statistically highly significant overall and at frequencies associated perhaps with other aspects of the autonomic nervous system. While this is one case, the overall reduction in heart rate variability was exactly what had earlier characterized the ECGs of eight cosmonauts during a magnetic storm in space vs. the ECGs of 41 cosmonauts in space during magnetically quiet conditions (7), as well as in people at high vascular disease risk (4, 6).

Conceivably because we did not act for pre-habilitation in the absence of a need for rehabilitation, we lost a number of outstanding chronobiologists. This past summer, Juergen Aschoff did not accept our cordial invitation to Minnesota, where we could have monitored him, even if this may not have prevented the series of strokes that claimed his life. Along with Colin Pittendrigh, another prominent late scholar of clocks, he had championed with a good intuition and scholarship what with much sweat and statistical validation we had dubbed with Earl nearly half a century ago as free-running. Now, we recognize, with the built-in biological week, month and year, further components in a rhythm spectrum. We must test the extent to which the half-week, the half-year, the decade and the double decade are probably built into our internal integrative (8) as well as (Darwinian) adaptive time structure. We find evidence suggesting that we still resonate with these spectral components of an invisible yet tangible helio- and geomagnetic master switch (9, 10), complementing light and heat.

Also in 1998, we bade farewell to Werner Menzel in his 90th year. He did all the right things many decades ago: he wrote an invaluable book (11) which remains a source of much useful information, notably in a historical context; he introduced a pump for drug delivery; and he sought quantification by fitting sinusoids to his data.

We also lost a staunch friend, Boris A. Nikityuk, whom we met from a distance on June 30, 1997 (12). Boris was Professor and Head of the Department of Anatomy and Anthropology at the Russian Academy of Physical Education in Moscow, a Member-Correspondent of the Russian Academy of Medical Sciences, and President-Founder of the International Academy of Integrative Anthropology (13). At the June 30, 1997 meeting of the Russian Academy of Medical Sciences on the BIOsphere and the COSmos (BIOCOS), he presented data covering 112 years on the human newborn's height, weight, and head, chest and abdominal circumference, in order to document the effect of non- photic solar activity upon us. Based on these data, Germaine detected the signature in neonatal morphology of solar activity (9).

Sunspots had been recognized by Galileo, Scheinert, Fabricius and Harriot at the beginning of the seventeenth century. These and other luminaries in physics, however, ignored cycles, until the pharmacist Samuel Heinrich Schwabe in 1843 recognized the importance of periodicity in the numbers of sunspots (14). Boris Nikityuk shared our interest in the 10.5-year Schwabe cycle as the "first floor" of politics and economics as well as of biology. A wonderful friendship culminated in our getting acquainted in Vinnitsa, Ukraine, in May 1998 at the II International Congress of his International Academy of Integrative Anthropology. On September 29, 1998, he retired to bed, suffered a massive stroke, and died the following morning without regaining consciousness.

We honored both Boris and Werner by dedicating to them the proceedings of the 3rd International Symposium on Chronobiology and Chronomedicine in Kunming, China, on October 7, 1998 (9). Those in attendance stood in silence for one minute to pay tribute to their contributions. We also dedicated to their memory abstracts at the 6th Conference of the Italian Society for Chronobiology in Chianciano Terme (November 27-28) (15, 16).

Old and new ties in China and Italy led to the coining of pre- habilitation and to laying the seeds for implementing it. In strategic positions in this context are Jarmila Siegelova, the new chair of pathophysiology in Brno, Czech Republic, with her colleagues Bohumil Fiser, the new head of physiology, and Jiri Dusek. So are Jinyi Wu and Zhengrong Wang in Chengdu, Ziyan Zhao and Ziying Zhao in Jinan, and Franca Carandente in Milan. Involved in a key position was Brunetto Tarquini, Professor and Head of Internal Medicine at the University of Florence, the clinical leader in chronomedicine. Sadly, with this season's appreciations, we also bid farewell to Brunetto, the dearest of friends, who passed away on December 10, 1998. Brunetto was on the frontiers of endocrinology, documenting the chronobiology of leptin (17), dehydroepiandrosterone sulfate (18), endothelin-1 (19, 20) and melatonin (21). When many investigators chase putative circadian clocks, he discovered an 8- hour ET-1 rhythm. It is to Manfred Herold's great credit to have shown that a circaoctohoran can coexist with a 24-hourly cortisol pattern in clinical health (22) and that for ET-1 it can be prominent in the absence of a circadian component.

In memory of Brunetto, let us endeavor further to replace a single-sample medical art by the science of time series, in order to pave ways for pre-habilitation, for maintaining what Earl Bakken calls the health-related quality of life by monitoring for risk assessment as a feature of the health sciences (23).

This is what our publications are mostly about. The task on hand is challenging, greater than that of Oliver Wendell Holmes, Joseph Lister and Ignaz Semmelweis. The Bostonian surgeons of Holmes' day, the Britons and Scots of Lister's and the Viennese of Semmelweis' continued to mock the notion that they must scrub before operating, and used their scalpels while wearing their street clothes (24). Are we any less odd by recommending an initial 7-day blood pressure and heart rate profile, and a much longer surveillance of blood pressure when necessary, as is often the case for a lifetime, as long as we have no real cure for a deviant pressure=A0?

Our task is enormous: to realize its scope, we cite the following facts from our Minnesota backyard:

+ One of the best internists in our area, a former student who spent evenings and weekends as a volunteer in our laboratory, scrutinizing the evidence on CHAT=8Ba co-author of a report on that topic=8Bdid not encourage self-measurements by a friend, his patient, because he "could do nothing" about spikes in pressure, evidence to the contrary notwithstanding (25-27).

+ Another co-author, also of a paper on blood pressure monitoring=8B who as a top administrator had defended our science vigorously and wholeheartedly=8Bcould not suppress softly, and perhaps reluctantly saying "hyperbole" when we equated a 24-hour profile of blood pressure in some cases to flipping a coin; yet this same figure was endorsed by an international resolution as well as by data (27).

+ Other scholars who lecture on chronobiology around the world interpret some of their results as deviations from a time- unqualified normal range while maps of circadian, circaseptan and circannual characteristics, their great contribution to research, as yet await integration with chronomes in and around us.

Honi soit qui mal y pense: All these outstanding individuals are invaluable to a budding chronobiology. Nonetheless, chronomedicine will remain a "complementary" medicine unless we recognize that it is the foundation of a scientific approach to health care. For this discipline to enter the mainstream, it must be more than a complement, used mainly for research. Instead, chronobiology is the scientific alternative to the art of health care of our day. There is no other justifiable alternative to lower cost while improving quality (28), but there are several indispensable complementary approaches. The best approach, empirically validated by everybody who practices health care as a profession rather than an occupation, is a good, invaluable "bedside manner" and empathy: what Earl Bakken calls "high touch". Some other complementary health care practices as yet need to be tested. In many cases we confront subtle effects, including the effects of placebos (29-36), occurring mostly within the normal range. Chronobiology is the most sensitive way to gauge any benefit.

Chronobiology may be labelled as "too time-consuming", "too complicated" and/or "too expensive". Learning to read and write is also time-consuming, complicated and expensive. The concept of universal literacy originally met with opposition from those who felt that if everyone could read, no one would be willing to do menial tasks for little (or no) pay. To paraphrase the observation of Joel Chandler Harris' character Uncle Remus, if you put a spelling book in a slave's hands, right then and there you lose a plowhand (37).

In a recent report in the St. Paul Pioneer Press (38), a cardiologist teaming with us in a blood pressure study claims that "... Halberg minimizes the difficulty of wearing an automatic monitor for seven days because 'he has very devoted subjects.'" (One of those subjects, the mayor of the suburb where some of us live, wrote to us and denied he was that devoted=A0!) The population at large, led by its political leaders such as this mayor, must be convinced that just as a literate person no longer needs to rely on scribes to write letters, so is there no longer a need to take "the" blood pressure at the clinic. There is no need for a 24-hour profile, notably when it is not interpreted chronobiologically, and can cost $200. Once a system is developed, as we are attempting to do in Minnesota, the initial 7-day monitoring can become routine. Interested persons should contact us at this time (Germaine Cornelissen: e-mail corne001@maroon.tc.umn.edu=A0; phone [612] 624-6976; fax [612] 624-9989). Until further notice, available user- friendly portable blood pressure monitors make it possible for anyone at this time to do monitoring for 7 days or for longer spans when needed. The indispensable wherewithal for the analysis of the data is available in our laboratory as a start. Our reference values are in the form of 7-day series of hourly or denser around-the-clock data for a minimum of a week, for both genders, from womb to tomb, for "whites" and "Asians".

Paraphrasing an academic engineer (39), breakthroughs in health care depend upon 1. the vision of a leader, 2. the creativity of staff, 3. a friendly work environment, 4. an appropriate technology, 5. an auspicious start time and 6. the adherence to a time line. Indeed, we may not deal with the sum of these ingredients, but with their product.

+ Regarding Item 5, to bring chronobiology into the mainstream, any time is not only auspicious, but overdue, notably if we are sidetracked by unexpected findings prompting our excursions into the cosmos (9, 10).

+ About Item 3, the work environment may not be ideal, and the University's funding is $0.00, as it has been all along. This need not distract us; it will likely stimulate us to derive more fun from our findings (40).

+ Regarding Item 4, the appropriate technology for closing the loop between available diagnostic and therapeutic devices is essential (10).

+ With respect to Item 2, our creativity must be judged by the reader of our bibliographies.

+ Item 6 is a problem. We are general practitioners of chronomedicine, tackling whatever problem comes our way, and are not good in adhering to timelines, except for being at it 7 days a week for many hours each day.

+ For Item 1, we are fortunate to have Earl E. Bakken as the mentor of a future center. He has already made the implantable pacemaker into a reality. This invaluable device in health care is a sine qua non for the rehabilitation of the sick. Earl also had an early encounter with what developed into chronobiology and may now help this established discipline to spawn chronomedicine. His vision, implementable by chronomedicine, is action to improve the health- related quality of life (23). Earl advocates the use of multiple modalities ranging, as he puts it, from high touch to high tech, from bedside manner and placebo effects of use to the patient in their own right to the action of externally provided molecules and devices. Every treatment has some ingredients from high touch and high tech, some treatments more from one than from the other. High touch effects can gain greatly from the monitoring and other methods of chronomedicine, which provide entry into the otherwise-ignored normal range, and thus seek to pick up subtle effects. Earl has a vision, which we share, of making integrated health care into a chronomedical reality. Our name for the road to the realization of this vision is pre-habilitation. The Minnesota center in chronomedicine has as its goal to assure that the entry of benefit from splitting the normal range of variation will not take another hundred years=A0! The center's focus is directed at a scenario eloquently described elsewhere in a different context (41):

You're a vibrant 52-year-old executive, avid tennis player, loving husband and father. Then, in an instant, a stroke irrevocably tears apart the entire fabric of your life. You now can't walk without assistance. Your left arm is crippled and your speech is slurred. When your friends and business associates come to visit you, they can hardly believe it's you. You are a shadow of your former self, unable to work, walk without great difficulty or even carry on a conversation. You must drag yourself up stairs. And you face what seems like an eternity of gruelling therapy to merely regain a fraction of your lost function. Now let me ask you a question "IF YOU COULD AVOID THIS BY TAKING A FEW SIMPLE PRECAUTIONS, WOULDN'T YOU DO IT"? ... [Stroke] strikes half a million Americans every year, killing 150,000 people, 20% within the first month. Depressingly, only 10% of people who have a stroke ever resume completely normal function.

The chronobiologist asks: If you could avoid stroke, which in the worst massive case may even leave you unable to clean, feed, dress or otherwise care for yourself, by investing into a week of somewhat obtrusive monitoring, along with other simple precautions, wouldn't it be worth it=A0? The chronomedical initiative is to motivate the public to focus on the concept of pre-habilitation, not only with respect to stroke and to other vascular conditions, but with attention paid to all possible risks, so that the person saved from a stroke does not end up with another crippling or painful disease. The chronobiology center will accordingly focus on disease risk syndromes and thereby will strive to achieve the change in health care from after-the-fact endeavors to the detection of elevated disease risk and its lowering by treatment, pre-habilitation.

The reduction of too much variability in blood pressure and the augmentation of too little heart rate variability will be the major immediate goals. We will focus on circadian blood pressure overswinging or CHAT, short for circadian hyperamplitudetension, and upon an excessively low standard deviation of heart rate, a CAHRV, a chronome alteration of heart rate variability. For the purpose of diagnosing these conditions, the availability of reference values from peers of both genders, all ages and different ethnic groups, eventually with outcomes, will be critical. For this purpose first and foremost, the data store accumulated over the past 50 years must be organized while at the same time invaluable records of much broader scope are to be catalogued and archived. Equally important is the continuance of the collection of time-specified reference values around the world from womb-to-tomb. This is under way in the context of the ongoing projects on the Biosphere and the Cosmos (BIOCOS). This endeavor gained momentum from Dr. Kuniaki Otsuka's now-international, originally Asian Chronome Ecologic Study of Heart Rate Variability (ACEHRV).

These ongoing projects provide invaluable reference standards for blood pressure, heart rate and other ECG indices, some derived from beat-to-beat 7-day or, when need be, longer ECG records. Invaluable data may continue to accumulate cost-free due to our function as a design and data analysis center. By such planning and analytical endeavors, the center is likely to have further opportunities to bring chronobiology into the mainstream of health care. Its goals include the collection and organization of data on the variability of indices of risks competing with vascular disease risk, such as endocrine gauges of cancer and emotional disease risk. In the course of these endeavors, major focus will also be placed, whenever possible opportunistically, on the underlying mechanisms that may lead to new treatment modalities, involving physical approaches, such as the manipulation of electricity and magnetism.

We will be available to test new technology in order to close the loop between available and yet-to-be-developed diagnostic and treatment devices with a view of their use where they are most needed such as in missions in space where neglect of the limits to acceptable blood pressure and heart rate variability may have consequences such as those of the neglect of limits of O-rings to acceptable temperatures, leading to the Challenger disaster. Focus upon this feature of an applied chronoastrobiology could provide both a model for health care on earth and also basic data on the origins of life, an intellectual dividend for center staff to be pursued mainly outside regular hours.

The bottom line of our endeavors, the detection and treatment of disease risk syndromes, notably stroke prevention, is to be implemented locally as well as by as many as possible in a network of about 100 co-investigators worldwide. The first line of treatment for stroke prevention will be timed relaxation methodology (25, 26) to be applied before drug treatment. For this purpose and more broadly, chronobiologic self-help in health care, including family- and self-monitoring of vital signs, notably for the population of the Twin Cities will be taught and implemented as far as possible. This educational endeavor of the local public in different age groups will also constitute a major goal of the new center.

With Salvador Sanchez de la Pena, the associate editor, we thank the editor-in-chief, the cardiologist Mircea Dumitru of Geronto- Geriatrics, for a Chronome-Geriatrics, and look forward to meeting Mircea in person. We thank Dana Johnson and his committee, Dave Hunter and Phil Regal in particular, for batting for a chronobiology center at the University of Minnesota. We appreciate the guidance to pertinent literature offered by Howard Burchell and again by Earl Bakken.

We conclude these season's appreciations with the following note by Dr. Michael Fossel (2), editor-in-chief of the Journal of Anti- Aging Medicine, whom we look forward to meeting in person, and whose enthusiasm, for which we are grateful, exceeds ours:

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Talking about "blood pressure" as a single figure is similar to knowing the average height of a mountain range: an interesting statistic, but completely useless to a pilot trying to make it through a mountain pass alive. Realistically, we need to consider not merely the mean stress on an aging vascular endothelial cell, but the "peaks" that it has to "fly over" as well. Aging vessels are (to an extent) the end result of such stresses. Halberg et al. suggest that many patients may be apparently normotensive, yet (because of circadian peaks in blood pressure) have the catastrophic risks of any other severely hypertensive patient. They recommend that we avoid "flying blind" and begin to measure peak pressures more accurately if we are to avoid disaster.
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For all of our teachers (= editors = co-authors = referees) who help others and us to avoid flying blind, may every day in 1999 and in the new millennium be a chronobiologically crowned holiday.

Franz Halberg
Germaine Cornelissen
Mary Sampson
George Katinas
Othild Schwartzkopff

PS: Thanks originally to Doug Wilson (doug_wilson@adas.co.uk), and now to Dan Holley (dcholley@aol.com) and Charles Winget (cwinget@mail.arc.nasa.gov), next year may see steps toward a chrono-astrobiology with spin-offs for health care on earth. It all depends on our womb-to-tomb physiological monitoring for: + inquiring into the (earth-surface vs. ocean-floor) sites of life's origins by trends in, e.g., circadian vs. about-weekly amplitudes of time structure during ontogeny and phylogeny, and + for reference values to quantify normalcy, e.g., health, in order to identify hazards from within (e.g., too much blood pressure and too little heart rate variability), critical for astronaut screening before and during space travel, and hazards from without, such as those posed by magnetic storms on earth and in space.


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