by Franz Halberg, Germaine CornÈlissen, Naoto Burioka, George
Katinas, Mary Sampson & Othild Schwartzkopff
1999, the Chronobiology Laboratories at the University of Minnesota
continued their activities, with renewed focus on the Stroke
Prevention and BIOCOS (BIOsphere and the COSmos) projects. For
chronobiology, a new status and a new home The Chronobiology
Laboratories this year became a formal Chronobiology Center,
thanks to a committee of peers headed by Dana Johnson, Professor
of Pediatrics and Head of the Division of Neonatology at the
University of Minnesota, advocating, beyond its continuance,
the penetration of this discipline into everyday teaching and
practice of health care as well as biology, a goal shared with
Earl E. Bakken, builder of the first implantable cardiac pacemakers
for long-term use. By this feat and others (see below), Earl
is the chronocardiologist par excellence. As ìMr. High Tech,î
Earl is engaged in joining instrumented health care to ìhigh-touchî
concern for the individualís needs by establishing projects
in leading institutions around the country. Activities in chronobiology
centers around the world, coordinated in Minnesota, reported
herein, are contributions regularly reviewed with him. Our findings,
reflected in the titles of publications following this report,
were in part reported orally in Brno, Czech Republic, at a special
symposium organized by Dr. Jarmila Siegelova (Professor of Rehabilitative
Medicine, Masaryk University, Brno), opened by one of us, in
celebration of the 80th anniversary of the founding of Masaryk
University in Brno. Important findings were reported by others
on the occasion of a symposium in July 1999, in celebration
of the eightieth birthday of one of us, which coincided with
the fiftieth anniversary of chronobiology at the University
of Minnesota. A summary can be found at our website, http://revilla.mac.cie.uva.
es/chrono. Our thanks are addressed to all those who wrote to
reminisce; their thoughts have been posted on our website.
this celebration, among many other fine presentations, data
on four kinds of cancer cells grown in vitro, exhibited nearly
sinusoidal, extremely regular, about-7-day rhythms. New experience
was gained, old friendships renewed, and new ones established.
We extend our appreciation to Frank Cerra, Senior Vice-President,
Academic Health Center; Leo Furcht, Professor and Head, Department
of Laboratory Medicine and Chronobiology; Susan Dunlop, Development
Officer, Minnesota Medical Foundation; Charles Moldow, Associate
Dean, School of Medicine; Neal Gault, Professor of Medicine
emeritus; and in particular Cherie Perlmutter, Associate Vice-President,
Health Sciences Administration, for their support of chronobiology
expressed at the symposium. Our thanks also go to Minnesota
Governor Jesse Ventura, who presented Franz with a certificate
in recognition of 50 years of Minnesota chronobiology, and to
Dan Wall, Mayor of Roseville, Minnesota, who described his experience
in blood pressure monitoring as a father, concern as a citizen
and opportunity as a public servant, to make such monitoring
available to the community as a whole, inspiring him to initiate
the Roseville citywide blood pressure project.
thanks are here expressed to those who travelled from Japan,
Europe and other parts of the U.S. to attend the Minnesota symposium.
We learned from lectures by Franklin Barnwell, Christopher Bingham,
Brian Brockway, Erhard Haus, Dana Johnson and Philip Regal,
longtime associates of our laboratory. Renewed contact with
Gabriel Fernandes of San Antonio, Texas; Dora K. Hayes and William
Hambley of Fairfax, Virginia; William Hrushesky and Patricia
Wood of Albany, New York; Marilyn Kosmala, originally from Chicago
but now residing in the Twin Cities area; and Edmond Yunis of
Boston were greatly enjoyed and led to projects for new joint
endeavors. We particularly appreciated seeing ìold family membersî:
Leopoldo Garcia Alonso, now Associate Professor of Pediatrics
at t he University of Santiago de Compostela and Chief of Pediatric
Gastroenterology and Nutrition at the Hospital Materno-Infantil
ìTeresa Herreraî in La CoruÒa, Spain; Miguel Revilla of the
Department of Applied Mathematics and Computer Science at the
University of Valladolid, Spain, who deserves the credit for
our website (http://revilla.mac.cie.uva.es/chrono), and for
making software for chronobiological analysis available on the
web; Salvador S·nchez de la PeÒa, now director of the Seccion
de Cronomedicina de la Unidad de Investigacion Medica de Enfermedades
Metabolicas del Hospital de Especialidades del Centro Medico
Nacional Siglo XXI del Instituto Mexicano del Seguro Social
in Mexico City; Kohji Tamura, Professor and Head of Medicine
and Cardiology in the 2nd Department of Medicine at Yamanashi
Medical University in Yamanashi, Japan, with whom we enjoyed
vivid discussions on ìdipping and swingingî; Waldemar Ulmer,
now with Varian International in Zug, Switzerland, who has undertaken
the task of modeling feedsidewards from the viewpoint of theoretical
physics, and whose outstanding experiments on cancer cells grown
in vitro demonstrating prominent circaseptans were a highlight
of the symposium; and Douglas Wilson of ADAS Cardiff in Cardiff,
it was a real pleasure to have not only the professional, but
also the personal family together at the venue in Minneapolis.
Francine and her husband Terry Kessler were able to stay for
a week, a time used to its fullest to enjoy quiet family gatherings,
parties with friends and colleagues, and other occasions for
exciting discussions about diverse chronobiological topics.
symposium coincided in time with our move from Lyon Laboratories,
chronobiologyís Minnesota home for nearly half a century, to
a new center on the seventh floor of the Mayo Building (the
former University of Minnesota Hospital), while the now-empty
Lyon Labs lot will eventually house a Molecular Science building.
In the negotiations leading to the creation of the center, Susan
Dunlop of the Minnesota Medical Foundation played a critical
role with much tact. Sally Palm of the Department of Laboratory
Medicine and Pathology at the University of Minnesota, in innumerable
ways, great and small, has helped to ease the move into our
new quarters. We take this opportunity to express our indebtedness
to both of them.
the past fifty years, our focus has been on circa-rhythms, emphasizing
the genetics of built-in cycles. We started with a study of
inbred mice, reinterpreting as endogenous, with periodogram
analyses, the free-running of mice1 and then of humans, for
the cases of about 24-hour and then of about-weekly and about-yearly
rhythms. Lessons from the monitoring of twins reared apart about
the role of genetics are now explored by many others at the
molecular level. During this same past half-century, the spectrum
of many organismsí rhythms was aligned with corresponding frequencies
in the environment, that may account for how rhythms got into
the genome in the first place.
finding of a free-running about 7-day rhythm had prompted the
search for an about 7-day component in geophysics, now confirmed
by physicists, in addition to an anthropogenic, precise 7-day
component in magnetic disturbance. The half-yearly component
noted by geophysicists, notably Armin Grafe of Niemegk, Germany,
led to the recognition that in human status epilepticus, there
was no yearly component, but a strong half-yearly feature in
the distribution of more than 50,000 cases prompting a call
for an ambulance.
basic findings this past year revolved around numerical near-equivalents
of the 10.5- and 21-year cycles in a variety of physiological
and pathological as well as morphological variables. A hormonal
change in the excretion of urinary 17-ketosteroids showed this
circadecennian cycle, as did heart rate variability and mortality
from myocardial infarctions in Minnesota, peaking shortly after
the time of maximal solar activity. A cascade of these and related
findings makes physiological sense insofar as the trough of
heart rate variability preceded the circadecennian peak in mortality
from myocardial infarctions, and in the same cluster of circadecennians
were turning points of probable genetic changes in bacteria
that may also contribute to the etiology of heart attacks.
findings were reported by one of us in posters at the 22nd General
Assembly of the International Union of Geodesy and Geophysics
(Birmingham, UK, July 19-30) and at the 1999 conference of the
American Geophysical Union (San Francisco, December 15). They
were also presented in part in invited lectures at the 4th Congress
of the International Society of Neuroimmunomodulation (Lugano,
Switzerland, September 29-October 2), and at the Serono USA
International Symposium on the Endocrinology of Aging (Tempe,
Arizona, October 27-30). By contrast to a symposium in Washington
DC in 1964 on ìStress in the Military Climate,î where chronobiology
was the opening theme, as it was in Tempe, any temporal considerations
may have appeared as curiosities in Lugano. A notable exception
was the contribution by Georges Maestroni, one of the organizers.
Immunomodulation is precisely the field where timing can make
the difference between speeding up a cancerous growth and inhibiting
it, with the total dose/week being the same.
meeting in Lugano was a welcome occasion to personally meet
new friends, Peter G. Fedor-Freybergh, familiarly known as Gaudi,
editor-in-chief, of both Neuroendocrinology Letters and the
International Journal of Prenatal and Perinatal Psychology and
Medicine and his partner Lili Maas, art director of the Neuroendocrinonogy
Letters. A staunch friendship had already developed with Gaudi
and Lili, fostered by numerous e-mail exchanges, following the
submission of a manuscript by the late Brunetto Tarquini, presented
last year in Blaubeuren, Germany, at a meeting organized by
Christian and Hella Bartsch.
chronome concept was recognized at the Serono Symposium, where
the links between rhythms, chaos and age and other trends were
emphasized as chronomes. Pertinent to the concept, insofar as
it suggests a link between developmental changes and the circadian
system, is work carried out independently by Dr. Ann Rougvie
of this University and her graduate students on the roundworm
Caenorhabditis elegans. It will be important to explore their
basic contribution in clinical terms.
chronome of heart rate was broadened earlier by inclusion of
focus upon the correlation dimension and complexity in Kuniaki
Otsukaís originally Asian, and now International Chronome Ecologic
Study of Heart Rate Variability, that has been extended from
where he started it in Japan, to China, India, Italy, Norway
(Alta, above the Arctic Circle), Ukraine, and Michigan as well
as Minnesota, USA.
three-pronged human chronome approach, focusing on chaos, rhythms
and trends, depends very heavily on long-term monitoring, which
in turn allows resolution in heart rate and other variability
of changes also along the scale of years. Along the latter scale,
many sources of error are eliminated while new perspectives
are gained by the discovery of circadecennians. As to error,
several years of daily data on human 17-ketosteroid excretion
are compatible with the assumption of a declining androgenic
function, whereas subsequent years show an increase rather than
a continued decrease, both opposite effects now being predictable
parts of a circadecennian cycle. Unobtrusive automatic monitoring
is the key of a new chronomedicine within the physiological
range, which can then separate any trend with age from those
with disease risk elevation.
Roseville blood pressure project
ancient times, people who needed a letter written but were not
able to read or write themselves went to a professional scribe.
When the Puritans of seventeenth- and eighteenth-century England
began promoting universal literacy in the hope that it would
make the Scriptures accessible to the masses, the aristocracy
feared that widespread literacy would render the poor less willing
to earn their keep through heavy and unpleasant labor. Today,
universal education is the norm in most countries that pay at
least lip service to the ideals of democracy and in most technologically
today, many in medicine feel that monitoring of vital signs
such as blood pressure is best performed, and the data so gathered
best interpreted, by trained health care professionals. But
just as it takes time to learn to read and write, so also can
the population at large learn to monitor their blood pressure
with available automatic devices, so that on the basis of the
data thus collected, informed decisions can be made. Personal
blood pressure monitors are becoming as readily available today
as were pens, pencils, typewriters and personal computers in
disease risk syndromes, major focus was placed in 1999 on the
fact that affordable devices have become reasonably generally
available. A major effort was placed on the study of blood pressure
overswinging, which can all occur within the physiological range
of variation, just as heart rate underswinging, or circulating
melatonin overswinging, can also occur with no deviation in
mean value. The stroke prevention endeavor was welcomed by Earl
Bakken, by far our centerís staunchest supporter, and implemented
by Dan Wall, the mayor of Roseville (a St. Paul suburb with
a population of about 34,000), by his offer to each resident
of Roseville of the opportunity to automatically measure his/her
blood pressure and heart rate around the clock for seven days
with an ambulatory monitor. For many, this length of monitoring
seems overly long. In fact monitoring before the patient is
seen by the physician was recommended by T.C. Janeway as far
back as 1904, a lesson long forgotten. For others, including
outstanding opinion-leading physicians, a week is not enough:
they measured to the end of their lives, and some of our contemporary
colleagues intend to do the same. For those who find 7 days
too long for screening, we offer the following examples:
For six days Mayor Wallís blood pressure record was perfectly
acceptable, but he experienced one day of blood pressure overswinging
(circadian hyper-amplitude-tension, or CHAT) while he kept score
on a computer in a youth ice hockey game in which his son was
playing. He had difficulty keeping track of penalty minutes,
and some of the players, who were strong and contentious, did
not hesitate to let him know that they were unhappy with his
officiating outside his primary fields of law and government.
A former head of cardiology at the Mayo Clinicóour mentor of
long standing and the former editor of an important cardiology
journalóhad two initial days of blood pressure recording that
were abnormally high, but thereafter his pressure was acceptable
by chronobiologic criteria, that is in relation to the data
from healthy age-matched peers of the same gender and ethnicity.
A woman in Roseville had five consecutive days of deviant blood
pressure, and thereafter an acceptable record for several months.
Of 12 patients who were recalled after 7 years and who had originally
monitored their blood pressure around the clock for a total
of 9 days, only those two who had consistent abnormality had
an event like myocardial infarction or had been found to need
coronary artery bypass surgery.
conclusion from these anecdotal cases and from studies on their
trends are that for the given person, 7 days is a modest start
and longer monitoring may be needed to avoid stroke, myocardial
infarction, kidney disease and certain kinds of blindness.
City of Roseville is working with the Chronobiology Center to
offer monitoring to all citizens, from adolescents to old age.
In some people, high blood pressures occur at night rather than
during the day, spontaneously or presumably because of long-acting
blood pressure-lowering medications that cease acting earlier
than anticipated. These high blood pressures will not be recognized
in measurements taken only during the day. It will also be possible
to detect other deviant patterns that are indicative of an elevated
cardiovascular disease risk, like a larger-than-usual change
in blood pressure, called CHAT (short for circadian hyper-amplitude-tension),
which usually precedes an overall elevation in blood pressure.
had the pleasure of hosting many visitors in 1999. Many of these
individuals had come to participate in the Minnesota octogenarian
symposium, while others chose to come at quieter times.
November, Hugh Simpson of the University of Glasgow visited
for two weeks, during which time we had many discussions concerning
a chronobiologic brassiere for early detection of breast cancer
risk, as yet available only for clinical use and as a prototype.
Hughís visit enabled the chrono-meta-analysis of findings Hugh
had made and published earlier. The possible use of a bra studded
with thermometric sensors for the long-term monitoring of breast
surface temperature may serve for detecting changes that mammography
cannot detect. Moreover, the thermometric bra may become applicable
at ages when mammography is contraindicated. In the course of
these reanalyses, Germaine made the incidental finding that
the greater the number of live births a woman has, the greater
is the circatrigintan thermal amplitude of her breast surface
temperature, as if pregnancies reverse a trend in breast cancer
risk. This finding suggests the possible use of a thermometric
bra in scrutinies of the etiopathogenesis of breast cancer.
Uezono of the Institute of Health Science at Kyushu University
in Fukuoka, Japan, visited during the summer. New lessons were
learned from her data collected on volunteers who followed different
sleep schedules. Her visit coincided with that of Yoshihiko
Watanabe, a cardiologist from Tokyo Womenís Medical University,
Daini Hospital, Tokyo, Japan. After spending a 6-month sabbatical
with us several years ago, Yoshihiko returns to Minnesota each
summer to summarize data accumulated during the year. The results
obtained during their short visit led to several abstracts listed
in the bibliography below.
Herold, of the Universit”tsklinik f¸r Innere Medizin in Innsbruck,
Austria, visited only briefly after participating in the Serono
USA International Symposium on the Endocrinology of Aging (Tempe,
Arizona, October 27-30), where he gave a presentation on ìAbout-daily
(circadian) and about-weekly (circaseptan) patterns of human
salivary melatonin.î The data he brought us from his laboratory
shed new light on the 8-hourly (rather than circadian periodic)
changes in endothelin-1.
November 1, we have had a new addition to our team: Naoto Burioka,
Lecturer and Associate Professor in the Third Department of
Internal Medicine, Faculty of Medicine, at Tottori University,
Yonago, Japan. Naotoís interests are the chronobiology of asthma
and the chaotic behavior of respiratory movement, the EEG and
the ECG. He will be with us for 10 months on a foreign visiting
scientist fellowship from the Japanese Ministry of Education
we have developed increasingly close relations with two professors.
With Mark Engebretson, Professor of Physics and Director of
the Center for Atmospheric and Space Sciences, Augsburg College,
Minneapolis, we are learning about Pc pulsations and how these
contribute to geomagnetic disturbances. With him, we hope to
gain a better understanding of mechanisms underlying the effects
of space weather on humans and other organisms. With Daniel
Kaplan, Professor of Mathematics, Macalester College, St. Paul,
we are learning about chaos analysis of chronobiological data.
At the University, Dr. Keith Lurie with Dr. David Benditt are
introducing the chronobiologic 7-day blood pressure monitoring
project at the Rasmussen Heart Clinic.
1999, we sadly bade farewell to a noted colleague: Prof. Gunther
Hildebrandt, emeritus head of the Division for Work Physiology
and Rehabilitation Research of Philipps-Universit”t in Marburg,
Germany, died on March 6, 1999, at 75. As a young scientist,
Hildebrandt recognized the basic importance of biological rhythms.
He participated from the outset in the building of chronobiology
after World War II. In his theoretical contributions, he insisted
on the systematization of variations in the normal range, formulating
the spectrum of biological rhythms in different physiological
functions. These rhythms play a central role in Hildebrandtís
physiology of adaptations and in its applications, notably in
the field of physiotherapy and spa medicine. Apart from chronomedical
applications, another focus of his practically oriented interests
was in the field of chronohygiene. Starting in the early 1960s,
he worked on problems of night- and shift-work. There is nowadays
a trend to make shift-work schedules more and more flexible,
which is of growing importance. To contribute to biologically
beneficial shift-work systems and in order to clarify individual
differences in the tolerance of shift-work, Gunther Hildebrandt
was concerned with the internal physiological temporal order
and in how this is modified by unusual external schedules such
as night-work. His most recent achievement was his book with
Michael Moser and Michael Lehofer, ìChronobiologie und Chronomedizin:
Biologische Rhythmen/Medizinische Konsequenzenî (Hippokrates,
Stuttgart, 1998). In addition to this comprehensive treatise,
he is the author of another book on the biological week, perhaps
his biggest contribution. He amassed a very great deal of evidence
for the built-in nature of the week, tracing its origins to
also lost two good friends in John Raidel (January 25, 1919-September
30, 1999), a Gymnasium classmate of Franz Halberg, and his wife
Charlotte (June 29, 1921-August 13, 1999). John Raidel was an
officer, pilot and instructor for the Hungarian Air Force during
World War II.
a happier note, we mark the 62nd birthday of Masayuki Shinoda,
president and chief executive officer of Colin Electronics,
Komaki, Japan. Masayuki started a firm that has made its major
worldwide concern the transition from the measurement of the
blood pressure to the topic of this paper, the chronobiologic
interpretation of blood pressure series. His generous gift of
scores of monitors played a critical role in the development
of a reference data base for blood pressure, from newborns to
centenarians, in Asia and elsewhere. His portable, then ambulatory
instruments were used in everyday life or in isolation from
society for up to 267 days, or while lying in bed for days,
or to assess effects from playing tennis. Pioneering studies
in the field were possible with hand-held tools, but it took
automation to recognize and document disease risk syndromes,
as outlined in two interpretive reviews this year (see bibliography
below), setting the stage for preventive measures, for pre-habilitation.
The ambulatory monitors are also useful in the context of rehabilitation,
but may eventually obviate most of the need for treatment after
a catastrophic illness, with early detection of an elevated
risk in the otherwise asymptomatic patient. Masayuki Shinodaís
monitors played a very great role in leading not only to the
detection, but also to the treatment, of disease risk syndromes.
year also saw the eightieth birthday (on October 29, 1999) of
Theodor Hellbr¸gge, the leading pediatrician in the German-speaking
world; the founder of social pediatrics; the author of the basic
elements of social pediatric developmental rehabilitation; and
above all the pioneer in the chronobiology of the human fetus,
of the newborn, and of the developing child. To many, his social
pediatrics is the cornerstone of mushrooming institutes after
the model of his endeavor realized in bricks and mortar in Munich.
To a few of us, his name is associated with his first scientific
love affair, chronopediatrics, and, we hope, ìon revient toujours
a ses anciens amours.î Theo Hellbr¸gge introduced behavioral
science into pediatrics, and in so doing provided ethological
measures for diagnosis and treatment, for what he conceives
of as developmental rehabilitation. Literally as well as figuratively,
Theoís most spectacular contribution is the Kinderzentrum in
Munich, a model of an interdisciplinary institute for early
diagnosis, early treatment and social integration of children
with disabilities. Against the resistance of all authorities,
he founded the first kindergarten in the world in which children
with and without handicaps learn and interact jointly, in a
continuation of the physiological pedagogy of the French physician
Eduard Seguin and of the Italian educator Maria Montessori.
More than 30 years ago, Theo Hellbr¸gge founded ìAktion Sonnenscheinî
(ìthe Sunshine Projectî) in Munich to benefit children with
reported earlier, endothelin-1 (ET-1), a very potent vasoconstrictor,
undergoes an 8-hour rhythm in the absence of a detectable circadian
variation in a study involving 7 clinically healthy subjects
providing blood samples at hourly intervals for 24 hours. In
another earlier study, circulating ET-1 was also found to be
characterized by a 3.5-day component, which differed between
clinically healthy subjects and patients at an elevated cardiovascular
disease risk. Additional new data from the experimental laboratory
provide further support to these earlier findings. Specifically,
an about 8-hour component was detected for the population density
of endotheliocytes in the capillaries of the connective tissue
of the ear pinnae of mice. Moreover, an about half-weekly component
was also prominent in the absence of a demonstrable circadian
concentration determined in cord blood by Dr. Federico Perfetto
and Dr. Roberto Tarquini of Florence, Italy, was found to be
elevated in the presence of a family history of obesity on the
paternal side, but not on the maternal side. This finding, published
in Pediatrics, was selected for inclusion in the 2000 Yearbook
of Obstetrics and Gynecology, to be published by Mosby, Inc.
Cord blood leptin concentrations were also found to be higher
in spring and summer than in fall and higher in infants born
before vs. after noon. The results point to synchronizing environmental
as well as genetic influences.
on blood pressure and heart rate variability (HRV) focused on
effects from the environment (near and far), notably of helio-
and geomagnetic disturbances. New results led to the formulation
of a new branch of astrobiology, namely chronoastrobiology.
The international project on the chronome mapping of heart rate
variability continued. The long-term goals of the study are
to investigate ecological influences on blood pressure, blood
pressure variability and different endpoints of HRV, such as
the standard deviation, the power in different spectral regions,
the 1/f-like spectral behavior, the correlation dimension and
complexity. The risk associated with a reduced 24-hour standard
deviation of heart rate was confirmed and the relation to risk
was found to be nonlinear. Some of the endpoints of HRV have
been mapped as a function of gender, age and health status.
patient with coronary artery disease was studied before and
after coronary artery bypass grafting (CABG), collecting 7-day
ECG records before and after CABG, from which different endpoints
of heart rate variability were derived. Before CABG, but not
thereafter, a 24-hour synchronized circadian rhythm characterized
all variables examined. After CABG, the circadian amplitude
of most variables was decreased. For some of the variables examined,
the circadian component was no longer detectable with statistical
significance at a trial period of 24 hours, notably in the case
of the 5-min coefficient of variation in heart rate. Instead,
an increase in the circaseptan amplitude of heart rate after
CABG is statistically significant. Additional profiles obtained
in the interim indicate that such a variance transposition was
transient. A drastic decrease in heart rate variability after
CABG is in keeping with results reported by others.
vascular disease risk associated with an elevated circadian
amplitude of blood pressure was further confirmed in a study
of over 2,000 subjects by C.H. Chen, using the left ventricular
mass index as a surrogate outcome measure. As in earlier studies,
the results show that ìoverswingingî carries a higher risk of
morbid events than ìnon-dipping.î Earlier studies by others
first and then by ourselves indicated that while the mean value
of blood pressure was linearly related to both the incidence
of adverse vascular events and to the left ventricular mass
index, the relation of risk with the circadian blood pressure
amplitude was nonlinear. The nonlinearity of the relation between
the circadian amplitude of blood pressure and risk (whether
it is gauged by the actual number of morbid events or by the
left ventricular mass index) was observed consistently in all
subjects investigated. Too low a 24-hour standard deviation
of heart rate has also been shown to be a predictor of risk,
mostly for coronary artery disease and cerebral ischemic events.
The relation between the 24-hour standard deviation of heart
rate and the incidence of adverse vascular events that occurred
within 6 years of the 48-hour profile obtained from each of
the 297 patients was also shown to be nonlinear. For a wide
range of standard deviations, there was no elevation in cardiovascular
disease risk, but once a threshold value was exceeded, the risk
increased drastically and with statistical significance.
heart rate and the standard deviation of heart rate have been
shown to change with an about 10.5-year cycle similar to that
of Wolfís number, used as a gauge of solar activity. The biological
decade has become a component of the spectral element of chronomes
and an important piece of control information. Just as the stages
of the biological year, month, week and day can be confounders
when they are not assessed, the solar cycle stage should also
be recorded. Such a periodicity in human heart rate has been
documented on the basis of two unique data series. One stems
from 31 years of self-measurements carried out 5 to 6 times
a day on most days by Dr. Robert Sothern. The other series consists
of around-the-clock data at 15- to 30-minute intervals for 11
years obtained with an ambulatory monitor by Dr. Yoshihiko Watanabe.
An about 10.5-year variation has also been documented for mortality
from myocardial infarction recorded in Minnesota from 1968 to
1996; it accounts for an excess mortality of 220 cases per year
(an about 5% increase) at times of maximal solar activity in
comparison with times of minimal solar activity.
task ahead is to define the source and the mechanism of the
risk of adverse vascular events, including, beyond myocardial
infarctions and strokes, relations among physiological variables
assessed longitudinally. Among mechanisms of heart rate variability,
the autonomic nervous system comes to mind. Not only have signs
of reduced vagal activity been associated with an enhanced risk
of sudden cardiac death, but impaired heart rate variability
has also been shown to serve as a predictor of mortality in
patients with a variety of other vascular diseases.
heart rate variability on days of high magnetic activity vs.
quiet days has now been documented in the longitudinal ECG record
of Dr. Kuniaki Otsuka, a clinically healthy man. The decrease
in heart rate variability is validated statistically in both
the time and the frequency domains, on the basis of the coefficient
of variation of R-R intervals (analyzed in consecutive 14.4-min
intervals over a 7-day span) and of the total spectral power,
respectively. Moreover, the decrease in spectral power was found
to be primarily contributed by a decrease in power in the ìvery
low frequencyî range (with periods in the range of 6.5 to 333
sec). The decrease in heart rate variability is much less pronounced
in two other spectral regions centered around 10.5 sec (ìlow
frequencyî) and around 3.6 sec (ìhigh frequencyî). If confirmed
on additional cases, this result may point to some underlying
physiological mechanism responsible for the physiological response
to changes in magnetic activity other than the parasympathetic,
usually identified with spectral power in the 3.6 sec region.
December 24, Othild and Franz returned from Antarctica, where
they monitored heart rate and blood pressure on themselves,
to look for a combination of jet and equatorial lag, or possible
transmeridian and trans-parallel lag. Their data show the anticipated
jet lag, the rules of which we documented decades ago. For picking
up any effects of latitudinal crossing, the study of many more
cases and additional variables, notably of salivary melatonin
and cortisol, will be needed to look at the ramifications of
impressions gained from this and earlier monitoring and other
investigations. A latitudinal effect reported by us earlier
for the chronome of melatonin was most recently complemented
by Lennart Wetterbergís finding of a weak latitudinal effect
upon nightly melatonin. It seems possible that the extension
from night to day of the latitudinal study would be informative,
as is a meta-analysis of data published by others concerning
a lack of an age effect upon nocturnal melatonin. When data
taken off published graphs are log-transformed, the age effect
upon amplitude stands out clearly, a reminder that in dealing
with cycles, there is no reason to discard data because they
are too low at certain times; the main information may be at
those particular times. There is a precedent of liver glycogen
rhythmicity, which persists after starvation, as shown originally
in the Biochemical Journal by ‰gren, Wilander and Jorpes ,
and then quantified by Erhard Haus .
the past year, the circumstance that on an unacceptable schedule
the periods found are very close to 24 hours, which we had reported
with Hugh Simpson in Arctic Anthropology , was confirmed;
but today, a broader chronome view is indicated in the light
of the following bibliography.
a follow-up of the visit of Dr. Yuji Kumagai (Lecturer, Department
of Clinical Pharmacology, Kitasato University East Hospital,
Sagamihara, Kanagawa, Japan) and Ken Yasaka (General Manager,
R&D Division, A&D, Tokyo, Japan), the A&D company has offered
us a very great reduction in price of instrumentation for conducting
the research on stroke prevention worldwide. Several collaborators
have already availed themselves of this very generous offer.
In addition to the city of Roseville, these include groups led
by Dr. David Benditt, Dr. Keith Lurie and the Rasmussen Heart
Clinic at the University of Minnesota; Dr. Katarina Borer at
the University of Michigan in Ann Arbor; Dr. Federico Perfetto
and Dr. Roberto Tarquini of the University of Florence, Italy;
Dr. Salvador S·nchez de la PeÒa in Mexico City, Mexico; Dr.
Jarmila Siegelova in Brno, Czech Republic; and Dr. Ziyan Zhao
in Jinan, Peopleís Republic of China. The data thus collected
will be flowing in for chronobiologic analysis.
thank the many friends and co-investigators who have made our
lives rich and exciting. To all, we wish the best of health
and productivity in the new millennium, and the completion of
the numerous endeavors many of us have jointly begun.
‰gren G, Wilander O, Jorpes E. Cyclic changes in the glycogen
content of the liver and the muscles of rats and mice: their
bearing upon the sensitivity of the animals to insulin and their
infuence on the urinary output of nitrogen. Biochem J 1931;
2 Haus E, Halberg F. Persisting circadian rhythm in hepatic
glycogen of mice during inanition and dehydration. Experientia
(Basel) 1966; 22:113-114.
3 Simpson HW, Lobban MC, Halberg F. Urinary near-24-hour rhythms
in subjects living on a 21-hour routine in the arctic. Arctic
Anthropology 1970; 7:144-164.
M., Denisova O., Cornélissen G., Halberg F. Enhanced
circasemiseptan (about 3.5-day) variation in the heart rate
of cancer patients? Anticancer Research 19:853_866, 1999.
C.H., Cornélissen G., Siegelova J., Halberg F. Does overswinging
provide an early warning of cardiovascular disease risk when
non-dipping may fail? A meta-analysis of 2039 cases. Abstract
11, MEFA, Brno, Czech Rep., Nov. 3_6, 1999.
G., Chen C.H., Siegelova J., Halberg F. Vascular disease risk
syndromes affecting both MESOR-normotensives and MESOR-hypertensives:
a meta-analysis of 2039 cases. Abstract 12, MEFA, Brno, Czech
Rep., Nov. 3_6, 1999.
G., Gubin D., Halberg Francine, Milano G., Halberg Franz. Chronomedical
aspects of oncology and geriatrics (review). in vivo 13:77_82,
G., Halberg F. [Book review of Hildebrandt G., Moser M., Lehofer
M. Chronobiologie und Chronomedizin: Biologische Rhythmen/Medizinische
Konsequenzen.] Chronobiology International 16:223, 1999.
G., Halberg F., Schwartzkopff O. [Chronobiologie und Chronomedizin:
Biologische Rhythmen, Medizinische Konsequenzen, von Gunther
Hildebrandt, Maximilian Moser u. Michael Lehofer.] Human Physiology
25 (4):140_141 [Russian v.] or 498 [English v.], 1999.
G., Halberg F., Schwartzkopff O., Delmore P., Katinas G., Hunter
D., Tarquini B., Tarquini R., Perfetto F., Watanabe Y., Otsuka
K. Chronomes, time structures, for chronobioengineering for
"a full life". Biomedical Instrumentation & Technology
G., Perfetto F., Tarquini R., Halberg F. Is cholesterol metabolism
involved in the genetic aspect of leptin as it relates to obesity?
Poster abstract 12, Serono Int. Symp. Endocrinology of Aging,
Tempe, Arizona, Oct. 27_30, 1999, p. 32.
G., Zaslavskaya R.M., Siegelova J., Halberg F. Circadian cardiovascular
changes in conventionally acceptable and elevated blood pressure.
Proc. Symp. Chronobiology and Non-Invasive Methods in Cardiology,
80th Anniversary Masaryk University Foundation, Brno, Czech
Republic, May 26, 1999, pp. 18_21.
A., Gorgo Yu., Cornélissen G., Halberg F. The biometeorological
analysis of 50-day human ECG. In: Proceedings, 15th International
Congress of Biometeorology and International Conference of Urban
Climatology, Sydney, Australia, 8_12 Nov 1999, de Dear R.J.,
Potter J.C. (eds.), ICB25.2: 6 pp. [CD-ROM].
M., Denisova O., Cornélissen G., Halberg F. Toward a
heart rate and axillary temperature chronome in schizophrenia:
gauge of disease severity. Functional Neurology 14:13_20,
P., Cornélissen G., Katinas G.S., Halberg F., Siegelova
J. Astrophysical influences on sectoring in colonies of microorganisms.
Abstract 17, MEFA, Brno, Czech Rep., Nov. 3_6, 1999.
D.G., Gubin G.D., Halberg F., Cornélissen G. Index of
extra-circadian variability (IUSV) of systolic blood pressure
(SBP) in human aging: results from 168-hour ambulatory blood
pressure monitoring (ABPM). Chronobiology Int. 16 (Suppl.
F. Uvod/Introduction/Einleitung. [In Czech, English & German.]
Catalogue, MEFA 7th International Fair of Medical Technology
and Pharmacy, Brno, Czech Rep., Nov. 3_6, 1999, pp. 10_13.
F., Cornélissen F., Schwartzkopff O. What chronoastrobiology
could do on earth and in space. Proc. Symp. Chronobiology and
Non-Invasive Methods in Cardiology, 80th Anniversary Masaryk
University Foundation, Brno, Czech Republic, May 26, 1999, pp.
F., Cornélissen G. Commentary: Chronomes: Time structures
within the physiological range identify early disease risk aiming
at primary prevention. J. Gerontol. Medical Sciences 54A: M309-M311,
1999. [Commentary on Cugini P., Gori M.C., Petrangeli C.M.,
Tisei P., Giubilei F. Maintained blood pressure and heart rate
circadian rhythm in early stage Alzheimer's disease. J. Gerontol.
Med. Sci. 54A: M304-M308, 1999.]
F., Cornélissen G., Engebretson M., Siegelova J., Schwartzkopff
O. Transdisciplinary biological-heliogeophysical relations at
weekly, half-yearly and Schwabe- and Hale-cycle frequencies.
Abstract 10, MEFA, Brno, Czech Rep., Nov. 3_6, 1999.
F., Cornélissen G., Katinas G.S., Herold M., Klotz W.,
Kreze A., Kreze E., Perfetto F., Tarquini R., Maggioni C., Chen
C.H., Schwartzkopff O. Chronomes: time structures as markers
of endocrine rhythms separating age trends from disease risk
syndromes. Speaker presentation abstract, Serono Int. Symp.
Endocrinology of Aging, Tempe, Arizona, Oct. 27_30, 1999, p.
F., Cornélissen G., Portela A., Mikulecky M. Jr, Komornik
J, Mikulecky M. Sr. Circadian and circa(semi)septan rhythm in
blood pressure: man in his terrestrial and cosmic environment.
XXI Seminar, Upice, Czech Republic, May 18_20, 1999, pp. 12_13.
F., Cornélissen G., Sampson M., Katinas G., Schwartzkopff
O. Season's Appreciations 1998. Neuroendocrinology Letters 20:31_43,
F., Cornélissen G., Schwartzkopff O., Cagnoni M., Perfetto
F., Tarquini R. Chronome/chrone. Neuroendocrinology Letters
F., Cornélissen G., Schwartzkopff O., Cagnoni M., Perfetto
F., Tarquini R. Chronorisk/circadian-circannual (Macey, 1994).
Neuroendocrinology Letters 20:102_104, 1999.
F., Cornélissen G., Schwartzkopff O., Cagnoni M., Perfetto
F., Tarquini R. Pineal mythology and chronorisk: the swan song
of Brunetto Tarquini (*February 8, 1938 - December 10,
1998). Neuroendocrinology Letters 20:91_100, 1999.
F., Cornélissen G., Schwartzkopff O., Syutkina E.V.,
Grigoriev A.E., Mitish M.D., Yatsyk G.V., Studenikin M.Y., Gubin
D., Gubin G., Siegelova J., Fiser B., Dusek J., Homolka P.,
Watanabe Y., Otsuka K., Perfetto F., Tarquini R., Delmore P.
Spin-offs from blood pressure and heart rate studies for health
care and space research (review). in vivo 13:67_76, 1999.
F., Cornélissen G., Schwartzkopff O., Watanabe Y., Otsuka
K. Feedsidewards: intermodulation (strictly) among time structures,
chronomes, in and around us, and vasculo-neuroimmunity. Abstract
A24, 4th Int. Cong. International Society for Neuroimmunomodulation,
Lugano, Switzerland, September 29_October 2, 1999. Neuroimmunomodulation
F., Schwartzkopff O., Cornélissen G. Rudolf Engels Zeitstrukturen,
Chronome, erwarten Werner Düchtings Modellieren zu einem
chronobiomimetischen Ingenieurwesen. Festschrift zur Würdigung
der 27-jährigen wissenschaftlichen Arbeit v. Univ.-Prof.
Dr.-Ing. Werner Düchting am Institut für Regelungs-
und Steuerungstechnik der Universität-GH Siegen. aus Anlaß
seiner Emeritierung zum 28.02.1999, pp. 165_186.
F., Sothern R.B., Cornélissen G., Haus E. The chronobiology
of prostate-speci?c antigen (PSA): case report and chrono-metaanalysis.
Anticancer Research 19:857_862, 1999.
M., Cornélissen G., Loeckinger A., Klotz W., Rawson M.J.,
Katinas G., Alinder C., Bratteli C., Cohn J., Halberg F. About-daily
(circadian) and about-weekly (circaseptan) patterns of human
salivary melatonin. Poster abstract 11, Serono Int. Symp. Endocrinology
of Aging, Tempe, Arizona, Oct. 27_30, 1999, p. 32.
T., Halberg F., Otsuka K., Cornélissen G., Halberg F.
Dentist: are you and your patients at undue risk of a stroke
or heart attack? EuroRehab 9:41_48, 1999.
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 Letters 20:55_68, 1999.
K., Cornélissen G., Kubo Y., Shinagawa M., Ohkawa S.,
Halberg F. Information entropy index of heart rate variability
(HRV) detects onset of non-sustained ventricular tachycardia
(NSVT). Therapeutic Research 20 (2):461_466, 1999. [In
Japanese with English summary.]
K., Cornélissen G., Shinagawa M., Halberg F. Blood pressure
variability assessed by semiautomatic and ambulatorily functional
devices for home use. Clin. Exp. Hypertension 21:729_740,
K., Cornélissen G., Shinagawa M., Kubo Y., Yamanaka T.,
Omori K., Ohkawa S-i, Zhao Z.Y., Delyukov A., Gorgo Y., Wang
Z.R., Shankaraiah K., Tarquini B., Weydahl A., Halberg F. Weekly
variation of time domain measures of heart rate variability
and geomagnetics in Asian Chronome Ecological Study of Heart
Rate Variability (ACEHRV). Presentation 15, 15th Meeting, Japanese
Chrono-Cardiology Society. Therapeutic Research 20:388_395,
K., Ohkawa S-i., Cornélissen G., Halberg F. Chronome
and chronoecology. Therapeutic Research 20:113_125, 1999.
[In Japanese with English figure legends.]
K., Yamanaka T., Cornélissen G., Halberg F. Circadian
cardiovascular changes in conventionally acceptable and elevated
blood pressure. Proc. Symp. Chronobiology and Non-Invasive Methods
in Cardiology, 80th Anniversary Masaryk University Foundation,
Brno, Czech Republic, May 26, 1999, pp. 14_17.
R., Galluzzi F., Bindi G., Perfetto F., Tarquini R., Halberg
F., Cornélissen G. Ultradian structure of circulating
melatonin by night in children. Poster abstract 13, Serono Int.
Symp. Endocrinology of Aging, Tempe, Arizona, Oct. 27_30, 1999,
A., Cissé F., Halberg F., Cornélissen G., Martineaud
J.P. The circadian rhythm in central temperature in fasting
subjects in hot climate (Senegal). Proc. Symp. Chronobiology
and Non-Invasive Methods in Cardiology, 80th Anniversary Masaryk
University Foundation, Brno, Czech Republic, May 26, 1999, pp.
R.B., Niaz M.A., Cornélissen G., Otsuka K., Siegelova
J., Fiser B., Halberg F. Circadian rhythmicity of circulating
vitamin concentrations. Abstract 14, MEFA, Brno, Czech Rep.,
Nov. 3_6, 1999.
R., Singh R.K., Mahdi A.A., Saxena S.P., Cornélissen
G., Halberg F. Circadian periodicity of urinary volume, creatinine
and 5-hydroxyindole acetic acid excretion in healthy Indians.
Life Sciences 66:209_214, 1999.
A.G., Penev P.D., Peneva A.V., Cornélissen G., Halberg
F., Ikonomov O.C. Blood pressure and heart rate rhythmicity:
differential effects of late pregnancy. Physiology and Behavior
B., Cornélissen G., Tarquini R., Perfetto F., Halberg
F. General and unspecific damping by malignancy of the circadian
amplitude of circulating human melatonin? Neuroendocrinology
Letters 20:25_28, 1999.
B., Tarquini R., Perfetto F., Cornélissen G., Halberg
F. Genetic and environmental influences on human cord blood
leptin concentration. Pediatrics 103:998_1006, 1999.
K., Halberg F., Corn élissen G., Watanabe Y., SiegelovaJ.,
Schwartzkopff O. Natural near-weeks of biology and geophysics
differ from the man-made week: transdisciplinary meta-analytic
hints. Abstract 15, MEFA, Brno, Czech Rep., Nov. 3_6, 1999.
W., Cornélissen G., Revilla M., Siegelova J., Dusek J.,
Halberg F. Circadian and circaseptan dependence of the beta-ATP
peak of four different cancer cell cultures: implications for
chronoradiotherapy. Abstract 13, MEFA, Brno, Czech Rep., Nov.
A., Cornélissen G., Bryskin Y., Gunas I., Halberg F.
Gender and age differences with similar weekly pattern of myocardial
infarction. Reports of Morphology 1:91_92, 1999.
Y., Cornélissen G., Otsuka K., Ohkawa S., Siegelova J.,
Halberg F. Effect of alcohol intake and treatment with calcium
antagonist on blood pressure and heart rate assessed by ambulatory
monitoring. Abstract 16, MEFA, Brno, Czech Rep., Nov. 3_6, 1999.
F., Cornélissen G., Conti C., Maestroni G., Maggioni
C., Perfetto F., Salti R., Tarquini R., Katinas G.S., Schwartzkopff
O. Pineal and chronobiologic history: mind and spirit as feedsidewards
in time structures, chronomes, for prehabilitation. Proc. Pineal
Gland and Cancer, in press.
G., Halberg F., Perfetto F., Tarquini R., Maggioni C., Wetterberg
L. Melatonin involvement in cancer: methodological considerations.
Proc. Pineal Gland and Cancer, in press.
F., Cornélissen G., Halberg J., Schwartzkopff O., Del
Proc. Pineal Gland and Cancer, in press. more P., Schaffer E.,
Rhodus N., Wu J.Y., Tarquini R., Perfetto F., Masalov A., Syutkin
V., Syutkina E.V., Zhao Ziyan, Zhao Ziying, Weydahl A., Delyukov
A., Gorgo Y., Xue Z.N., Wang Z.R., Halberg Francine, Carandente
F., Watanabe Y., Otsuka K. Case report on rehabilitation with
evidence prompting pre-habilitation. Neuroendocrinol. Lett.,
F., Cornélissen G., Otsuka K., Syutkina E.V., Masalov
A., Breus T., Viduetsky A., Grafe A., Schwartzkopff O. Chronoastrobiology:
neonatal numerical counterparts to Schwabe's 10.5 and Hale's
21-year sunspot cycles. In memoriam Boris A. Nikityuk (Sept.
10, 1933_Sept. 30, 1998). Int. J. Prenat. Perinat. Psychol.
Med., in press.
E.V., Kirdyashkina M.A., Cornelissen G., Abramian A.S., Grigoriev
A.E., Yatsyk G.V., Golovkina I.D., Maslova O.I., Halberg F.
Near-infrared spectrophotometry (NIRS)-monitored circadian variation
of preterm infants' cerebral blood volume and neurological outcome.
Int. J. Prenat. Perinat. Psychol. Med., in press.
G., Rigatuso J., Syutkina E.V., Schwartzkopff O., Johnson D.E.,
Halberg F., International Womb-to-Tomb Chronome Group: Case
report of an acceptable average but overswinging blood pressure
in Circadian Hyper-Amplitude-Tension, CHAT. Int. J. Prenat.
Perinat. Psychol. Med., in press.
F., Cornélissen G., Schwartzkopff O., International Womb-to-Tomb
Chronome Group: The costs of ignoring a long-overdue chronomedicine:
the chronome initiative emerging from the catacombs. Int. J.
Prenat. Perinat. Psychol. Med., in press.
A., Ruffieux C., Cornélissen G., Syutkina E.V., Johnson
D., Halberg F. Circadian and circaseptan patterns of natality
and perinatal mortality of infants with different birth weights.
Int. J. Prenat. Perinat. Psychol. Med., in press.
F., Cornélissen G., Watanabe Y. From time-unspecified
measurements to chronobiological specialties such as chronomedicine
and chronoastrobiology: challenges for manufacturing. Scripta
medica, in press.
G., Otsuka K., Chen C-H., Kumagai Y., Watanabe Y., Halberg F.
Nonlinear relation of the circadian blood pressure amplitude
to cardiovascular disease risk. Scripta medica, in press.
Alonso L., Garcia Penalta X., Cornélissen G., Halberg
F. About-yearly and about-monthly variation in neonatal height
and weight. Scripta medica, in press.
O.C., Stoynev A.G., Penev P.D., Peneva A.V., Cornélissen
G., Samayoa W., Halberg F. Circadian rhythm of blood pressure
and heart rate in uncomplicated healthy human pregnancy. Scripta
medica, in press.
P., Lee R., Cornélissen G., Schwartzkopff O., Halberg
F. Chronomes of oxygen saturation and heart rate in health and
after coronary artery bypass grafting. Scripta medica, in press.
G.S., Cornélissen G., Homans D., Schaffer E., Rhodus
N., Siegelova J., Machat R., Halberg F. Individualized combination
chronotherapy of coexisting CHAT and MESOR-hypertension including
diltiazem HCl. Scripta medica, in press.
K., Yamanaka T., Cornélissen G., Breus T., Chibisov S.M.,
Baevsky R., Halberg F. Altered chronome of heart rate variability
during span of high magnetic activity. Scripta medica, in press.
M.J., Cornélissen G., Holte J., Katinas G., Eckert E.,
Halberg F. Circadian and circaseptan components of blood pressure
and heart rate during depression. Scripta medica, in press.
Y., Cornélissen G., Halberg F., Otsuka K., Ohkawa S-i.,
Kikuchi T. Need for chronobiologic reference values (chronodesms)
smoothed over age: a problem awaiting a BIOCOS solution. Scripta
medica, in press.
R.M., Cornélissen G., Siegelova J., Halberg F. Circadian
cardiovascular changes in conventionally acceptable and elevated
blood pressure. Scripta medica, in press.
F. Chronodiagnosis-based chronotherapy: Is blood pressure monitoring
for weeks too costly to prevent long-term care for years? Geronto-Geriatrics,
F., Cornélissen G., Schwartzkopff O., Schroeder W., Engebretson
M. Chronoastrobiology- and chronobioastronautics-agenda involving
monitoring the Biosphere and Cosmos: the BIOCOS project. Abstract,
22nd General Assembly, International Union of Geodesy and Geophysics,
Birmingham, England, July 19_30, 1999, in press.
G., Sothern R.B., Gheonjian L., Paatashvili T., Watanabe Y.,
Otsuka K., Breus T., Halberg F., Schroeder W., Engebretson M.
Within- and among-solar-cycle (s) variations and human morphology,
physiology and pathology. Abstract, 22nd General Assembly, International
Union of Geodesy and Geophysics, Birmingham, England, July 19_30,
1999, in press.
G.S., Cornélissen G., Irizarry R., Schaffer E., Homans
D., Rhodus N., Schwartzkopff O., Siegelova J., Palat M., Halberg
F. Case report of coexisting elderly MESOR-hypertension and
circadian hyper-amplitude-tension (CHAT). Geronto-Geriatrics,