Halberg E

Chronobiometry with pocket calculators and computer systems

SummarySelected methods for the study of biologic time series are reviewed and their relative merits are discussed in the light of underlying assumptions. Their potential applications are exemplified in several fields of biology and medicine. The monitoring of environmental integrity, notably of pollution, is investigated. The need for specifying optimal sampling requirements is underlined. An individualized and time-qualified definition of health by the establishment of reference intervals is required for increasingly rational individualized program for the prevention and/or treatment of disease. With these reference intervals and rhythm characteristics available, one can better interpret with single samples or time series an increased risk of a certain disease or the inception of the disease. For all of these aims the monitoring of environmental and/or personal marker rhythms is essential — to obtain large data bases from which information can be more easily derived for monitoring personal health, to recognize risk as well as to diagnose disease early and to optimize treatment by timing according to rhythms.

Chronobiologic blood pressure assessment with a cardiovascular summary, the sphygmochron

Chronobiology deals with rhythmic patters that occur in all forms of life [1–5, 7–33, 35–38, 40–44, 47]. Virtually all organisms exhibit approximately daily (circadian) cycles. In human beings, prominent rhythms are found in blood pressure, circulatory pulse, body core and surface temperature and in chemical variables of blood, urine, and tissues. (Fig. 1). The medical section of this new science explores the relationships of rhythms to prediction, prevention, diagnosis, and treatment of diseases. Several decades of research worldwide have established that medical diagnoses can be subject to a much higher proportion of false positives (e. g., “office hypertension”) and false negatives (e. g., “odd-hour” hypertension) when only single samples are taken at arbitrary times of the day instead of taking rhythms into account. Radiation, chemotherapy, and other treatments have been shown to have markedly different efficacy and safety depending upon the pattern of administration within the day. Without modern engineering tools, chronobiology had to rely on manual measurement series that were cumbersome to collect and required methods of analysis that were not generally available. Modern bioengineering with microcomputers can bring the findings of chronobiology on circadian and other rhythms into the mainstream of medicine. Chronobiology can thus provide new dimensions to an individualized, positive assessment of health complementing the current negative approach relying solely on the absence of unusual values or overt disease.

Circadian variation in urinary melatonin in clinically healthy women in Japan and the United States of America

Urinary melatonin excretion is lower in East-Asian (Japanese) than in North-American (whites of mixed ethnic origin) women. Moreover, a statistically significant circadian rhythm is demonstrated by population-mean cosinor in the data pool from both groups of women. Furthermore, statistical significance characterizes interactions of effects from geographic differences (between ethnic groups) with temporal factors. Such spatio-temporal interactions await further scrutiny with a view inter alia of carcinogenesis as it is influenced by a spectrum of intermodulating rhythms.

Pineal modulation of ACTH 1–17 effect upon murine corticosterone production

In tests of corticosterone production in vitro, aqueous pineal homogenate (APH) modulates the effect of a short-chain ACTH analogue, ACTH 1-17, added to adrenals from different circadian stages. Adrenal and pineal glands from female B6D2F1 mice, standardized on staggered LD 12:12 regimens, were obtained at the same clock-hour from each room, in order to cover 6 different circadian stages. Adrenals from each circadian stage were bisected and incubated with APH from the same circadian stage (isophasic incubation) or from one of the other 5 circadian stages (heterophasic incubation). ACTH 1-17 (0.05 IU) was added to each incubation medium. After 4 hours of incubation at 37 degrees C with 95% O2 and 5% CO2, the media were stored at -20 degrees C until corticosterone RIA were done. APH was found to have a statistically significant modulatory effect upon the stimulation by ACTH 1-17 of adrenal corticosterone production in vitro. This APH effect changed rhythmically as a function of circadian stage from amplification over no effect to attenuation, as a so-called feed-sideward.

Circadian placebo and ACTH effects on urinary cortisol in arthritics

The effect of placebo and ACTH-1-17 (Synchrodyn, Hoechst) upon urinary free cortisol was examined at 5 different circadian stages on 10 men with Steinbrocker Stage II-III rheumatoid arthritis. A mean cosinor analysis of urinary cortisol data from the subjects prior to treatment with either ACTH or placebo revealed a statistically highly-significant rhythm. A circadian variation in a response of urinary free cortisol to a placebo was also seen. Moreover, the response of the midline-estimating statistic of rhythm (rhythm-adjusted circadian average) of urinary free cortisol to ACTH-1-17 by patients with rheumatoid arthritis is circadian rhythmic. This reactivity rhythm is out of phase with the spontaneous rhythm in urinary cortisol acrophases-in the tests limited thus far to midsummer. The further assessment of the circadian component in the context of broader interactions by rhythms with other frequencies in various conditions in health and disease is warranted by the demonstration of rhythms here presented for men with rheumatoid arthritis.

Circadian Characteristics of Urinary Epinephrine and Norepinephrine from Healthy Young Women in Japan and USA

Clinically healthy diurnally active young adult women were studied during the same season (March) at the Universities of Kyushu (Fukuoka City, Japan) and of Minnesota (Minneapolis, U.S.A.), under comparable conditions, except that the habitual diets were not changed. The subjects (20 Japanese and 16 Americans of mixed Caucasian background) were studied over a single 24-hr span. Urine was collected at 4-hr intervals. A circadian rhythm in total urinary norepinephrine excretion showed similar characteristics in Japanese and Americans. In epinephrine excretion, the Japanese women showed a statistically significantly higher amplitude with higher peak values, but no statistically significant difference in the rhythm-adjusted mean. This intergroup difference is strictly time dependent; it does not come to the fore in urine samples covering the nocturnal rest span of the subjects.

Chronobiology, Radiobiology and Steps Toward the Timing of Cancer Radiotherapy

Radiotherapists and most radiobiologists approach the organism and its responsiveness, e.g., its radiosensitivity, as a more or less constant entity. Radiotherapy is hence scheduled during ‘regular’ working hours on weekdays only, as a function of practicality. In the past few decades, however, a quantitative science, chronobiology, has developed. This science shows that the host harboring a malignancy and some malignancies themselves are dynamic entities. Human and other hosts exhibit recurrent changes. These can be assessed by inferential statistical means. Thus, a variety of bioperiodicities is uncovered. Their frequencies range from 1 cycle in less than 20 hours (ultradians), over one in about 24 hours (circadians) to one cycle in more than 28 hours (infradians). Infradians include changes with a frequency of 1 cycle in about a week (circaseptans) or in about a year (circannuals), as well as about 30-day cycles (circatrigintans). These latter cycles are found in menstrually cycling women (but also years before the first and decades after the last menstruation); furthermore, circatrigintans are also found in men (66).

Chronobiologic assessment of human blood pressure variation in health and disease

Once long and dense measurement series are available, biologic rhythm characteristics are readily computed. To assess such characteristics, we present suitable methods for blood pressure data collection and analysis. Since intra- and inter-individual differences are greater for blood pressure than for many other physiologic variables, any rhythm should and can be assessed for the individual subject by an inferential statistical approach. Circadian rhythms are thus mapped in human blood pressure in health and disease, under ordinary conditions and in social isolation, and can be shifted in their timing by changes in work schedule. Under all of the foregoing conditions, these rhythms account for a large part of the variability in blood pressure measurements. Their assessment renders changes in blood pressure predictable to a substantial degree, whereas their neglect can lead to false positive and false negative diagnoses of “hypertension”. Changes in a measure of the extent of reproducible change, such as the circadian amplitude, can lead to amplitude-hypertension occurring before the 24-h mean becomes elevated: mesor-hypertension. When changes in biologic rhythm characteristics precede an elevation of the 24-h mean of systolic blood pressure, they are harbingers of cardiovascular disease. Once automatic and/or self-measurement covers at least 48 hours with proper density, rhythmometry yields stable characteristics. High school students and adults alike can handle inferential statistical tests whereby rhythm characteristics a) are determined in actual or presumed health and b) may be found to be altered, the alteration (indicating, e.g., amplitude and/or mesorhypertension) prompting intervention. Statistical tests also gauge the effect of intervention, motivate compliance and thus contribute toward the success of preventive or curative measures. A system of education and software for rhythm analysis, wedded to hardware for self- and automatic blood pressure measurement, is particularly suitable for screening, diagnosis and the optimization by timing of non-drug and drug treatments to enhance the desired effect and to reduce side effects. Rhythmometry of data from room-restricted automatic monitoring demonstrates the effect of a shift from a betablocker to a placebo within 24 hours and corroborates it within 48 hours.

Inversion of lighting regimen alters acrophase relations of circadian rhythms in body temperature, heart rate and movement of pocket mice.

A biotelemeter capable of simultaneously monitoring body temperature, heart rate, and animal movement was used to determine (1), whether those three parameters could be uncoupled or made to change their circadian phase relationship in response to reversal of the photoperiod (2), if measuring the three parameters could improve our understanding of circadian phenomenon in pocket mice, and (3), whether a cosinor form of time series analysis could be applied meaningfully to pocket mice data which appear as high amplitude square waves. All three questions were answered affirmatively although considerable individual variability was observed between the three mice studied.

The Sphygmochron for Chronobiologic Blood Pressure and Heart Rate Assessment in Cancer Patients

Chronobiometry (11, 15), a subdiscipline of chronobiology*, serves, among other uses, for cardiovascular assessment of a cancer patient. This approach is advocated for everyone, in order to obtain individualized reference standards in health. The assessment of a reliable chronobiologic mean (the midline-estimating statistic of rhythm, briefly the MESOR) is particularly pertinent in the case of heart rate for patients with cancer who are treated with doxorubicin, where it can serve as a gauge of cardiotoxicity. The purpose of this chapter is to introduce the chronobiologie approach to the measurement of blood pressure and heart rate and to distinguish it from any conventional 24-hour ambulatory monitoring. The 24-hour profile (carried out without chronobiologie analyses) is a valuable yet incomplete substitute for the conventional casual spotchecks, currently practiced for convenience rather than at pertinent times.