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.

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.

The biological effects of solar activity.

The synchronization of biological circadian and circannual rhythms is broadly viewed as a result of photic solar effects. Evidence for non-photic solar effects on biota is also slowly being recognized. The ultrastructure of cardiomyocytes from rabbits, the time structure of blood pressure and heart rate of neonates, and the heart rate variability of human adults on earth and in space were examined during magnetically disturbed and quiet days, as were morbidity statistics. Alterations in both the about-daily (circadian) and about-weekly (circaseptan) components are observed during disturbed vs. quite days. The about-weekly period of neonatal blood pressure correlates with that of the local geomagnetic disturbance index K. Circaseptans which are seen early in human life and in various other forms of life, including unicells, may provide information about the possible site(s) of life's origins from an integrative as well as adaptive evolutionary perspective.

Circadian characteristics of urinary epinephrine and norepinephrine from healthy young women in Japan and U.S.A.

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.

Optimization of the chronotherapeutic index in the experimental animal laboratory.

Large animal studies show that the effects of fixed doses of anticancer drugs vary predictably with multi-frequency rhythms' stages--components of a genetically--anchored, habitat synchronized, cosmically influenced time structure--the chronome. Both the tolerance by the host of the toxic drugs and the treatment's efficacy in killing cancer cells contribute to these changes. Chronotherapy, timing treatment according to the chronome, attempts to first maximize treatment efficacy while also minimizing toxicity, so as to optimize the therapeutic ratio. Outcomes have been improved by several hundred per cent by treating rodents at the "right" time with single or multiple agents under controlled laboratory conditions, and by chronoradiotherapy of human perioral tumors, using tumor temperature as a marker rhythm.

From experimental units to unique experiments: chronobiologic pilots complement large trials.

The timing of treatment affects outcome. For mapping multi-frequency rhythm spectra first to optimize chronochemotherapy, 1000 marker determinations on the subject are more informative than a few determinations on each of hundreds of patients. N-of-6 subgroups should follow, with one subject assigned to each of 6 marker rhythm stages, 60 (e.g. 4 hours on a 24-hour scale) apart. Once the time structure has been mapped, minimal sampling requirements determined, and guidelines for treatment established, the information gained from chronobiologic n-of-1 and n-of-6 test pilot designs can be built cost-effectively into randomized controlled trials to benefit large patient populations. Sequential tests combined with marker rhythmometry and cosinor analysis on single test subjects, small groups and eventually on each patient are powerful tools that can extract information otherwise unattainable even at great cost and bring the P-value from publications to the patients.

Cugini's syndrome in statu nascendi. Oratio contra morem prevalentem et pro chronobiologica ratione ad pressione sanguinis curandam. A plea against the prevailing custom and in favor of a chronobiological approach to treating blood pressure.

An increase in the circadian amplitude (A) of blood pressure (BP) had been reported to precede a rise in the circadian BP average (MESOR, M), as pre-hypertension in the stroke-prone Okamoto rat. In humans, children with a positive family history of high BP and/or related cardiovascular disease had, on average, a larger BP-A than children with a negative family history, and an elevated BP-A was associated with intermediate values of the left ventricular mass index (LVMI), whereas an elevation in BP-M was only observed for larger LVMI values. Against this background, with 24-hour ambulatory monitoring (ABPM) interpreted chronobiologically, Pietro Cugini (University La Sapienza of Rome, Italy) has reported an elevation of both the circadian BP-M and BP-A as occurring with a minimal change (hypertensive) retinopathy. He determined by cosinor the extent of predictable BP change within a day as BP-2A, estimated by the least squares fit of a 24-hour cosine curve to the data. As compared to controls without retinopathy, he found a retinal end-organ involvement associated with average systolic (S) / diastolic (D) BP-Ms of 124/76 vs. 112/72 mmHg, with corresponding SBP/DBP-As of 12/10 vs. 8/7 mmHg. We refer to "Cugini's syndrome", suggesting the need for clarification, preferably in longitudinal studies, of any generalizable sequence in end-organ involvement, that may occur in the course of the development of some human Vascular Variability Disorders (VVDs) of unknown etiology, that include an elevation of the circadian BP-A and/or BP-M, concomitantly or separately in a sequence with the BP-A increase preceding that in BP-M, as in models of high BP in the rat or vice versa. Seven-day half-hourly or hourly around-the-clock monitoring of BP and HR variability interpreted chronobiologically, C-ABPM, as a minimum, is recommended for routine medical care to detect VVDs consisting of 1. MESOR-hypertension, MH; 2. Circadian Hyper-Amplitude-Tension, CHAT (BP overswing); 3. odd timing of the circadian rhythm of BP but not that of HR; 4. above-threshold pulse pressure; and/or 5. below-threshold HR variability. All conditions are best determined by 24-hour/7-day or, when abnormality is detected, longer C-ABPM. Eventually, all conditions will need to be assessed in the light of reference values from gender- and age-matched peers, as is now the case for the fi rst three VVDs listed above. When C-ABPM is not practicable, a 7-day series of 3-hourly manual self-measurements during waking (and one measurement about mid-sleep) (C-MBPM) is recommended. When continuous monitoring becomes possible, as it is within the state of the science, detecting Cugini's syndrome will also become possible with the clarification as to whether any change in BP-M and/or BP-A occurs concomitantly or sequentially, with changes in BP-A anticipated to precede changes in BP-M.

[Circadian periodicity and stomach ulcer. An animal experiment model for the detection of rhythm factors in the genesis of civilization diseases]. / Zirkadian-Periodik und Magengeschwür. Ein tierexperimentelles Modell zum Nachweis von rhythmischen Faktoren in der Genese von Zivilisationskrankheiten.

Against the background of clinical experience attesting to the role of the circadian and circannual rhythm stage in gastric ulcerogenesis, animal experiments provide a model where by circadian stage and sex are both revealed as determinants of gastric ulcerogenesis. Experiments on the genetically mesor-hypertensive Okamoto rat demonstrate the critical interaction of multiple loads in ulcerogenesis, in keeping with a report by Glavin and Mikhail. While stimulation by single loads of a certain intensity--immobilization, food deprivation or cooling--did not regularly lead to the production of gastric ulcers, the combination of these same loads did so as a function of circadian state at the beginning of exposure time.

Plexo-serial linear-nonlinear rhythmometry of blood pressure, pulse and motor activity by a couple in their sixties.

A Nippon-Colin (model BP-203X) instrument was used for longitudinal monitoring of systolic and diastolic blood pressure and pulse, at 10-min or other intervals for 26 days and for a shorter span, by a healthy woman, 60 years of age, and her husband, 61 years of age, both following their usual routine in an academic setting and at home. Due to the quasi-portable nature of the instrument, it was possible on most mornings to bring it from the home by car to the laboratory at the University and to return it to the home on most evenings, for about 2 months. The sturdy instrument withstood transportation and functioned flawlessly for the spans investigated. While the lack of true portability is definitely a handicap of the instrument which precludes it from use in sports and during ambulation, the circumstance that measurements during certain excessive activities away from a given site are not feasible can lead to a more standardized assessment of the blood pressure profile in subjects who pursue sedentary occupations. The procedures of linear-nonlinear rhythmometry applied to the data from the woman covering 26-day spans each and her husband covering 3 days, partly at 10-min and 3-min intervals, respectively, reveal the feasibility of quantifying parameters of circadian rhythmicity rather consistently. Spans as short as 48-h, invariably for the case of systolic blood pressure and usually for the case of diastolic blood pressure, though with lesser consistency for heart rate, sufficed to assess the circadian rhythmic component of this couple in their sixties and may constitute an individualized reference standard for blood pressure monitoring by the elderly with a view of assessing blood pressure rhythm alteration before it may become pathogenetic.

Chronobiologic monitoring and analysis for anesthesiologists: another look at a chronoanesthetic index.

A circadian rhythm in anesthetic index is quantified by the single cosinor method in data published earlier. Although the double circadian amplitude, a measure of the extent of predictable change, is only 14%, the assumption of no rhythm (zero amplitude) is rejected at the 1% level of statistical significance. It seems likely that, in the absence of noise, the amplitude of the rhythmic change in the response to the anesthetic will be larger. The broader importance of chronobiology for anesthesiologists is also indicated. Hardware and software for the monitoring of a patient's vital signs before, during, and after surgery provide refined dynamic endpoints from the analysis of data series and lead to time-specified reference values that improve even the interpretation of time-specified single values.

Testing period for single cosinor: extent of human 24-h cardiovascular 'synchronization' on ordinary routine.

A clinically healthy woman monitored her systolic and diastolic blood pressure and pulse for 26 days at approximately 10-min intervals, with interruptions. Data over subspans of varying length were analyzed by single cosinor. A method for testing a period assumed to characterize data analyzed by single cosinor was introduced and programmed to compute a 95% confidence interval for the circadian period. Statistically significant deviations from precisely 24 h were found. The likelihood of their occurrence was found to vary as a function of the length of the interval analyzed. Under ordinary conditions in health, the circadian period may vary around 24 h, indicating that strict frequency-synchronization with the environment need not occur on a short-term basis. Deviations from an average circadian period may be brought about in part by infradian components modulating the circadian rhythm and by day-to-day changes in waveform.

Circadian and circatrigintan rhythms in pulse, oral temperature and blood pressure of a clinically healthy Japanese woman.

The circadian and circatrigintan (menstrual) system of a healthy Japanese woman has been quantified by single cosinor analyses. The results obtained at only 2 frequencies are discussed against the background of prior chronobiologic information. The paper documents different acrophase relations of rhythms with different frequencies in the same variables and includes a sketch of the position of the single cosinor method as a tool in a methodologic armamentarium of broader interest in anthropology, medicine and more generally in biology.

Changes with age characterize circadian rhythm in telemetered core temperature of stroke-prone rats.

In a stroke-prone (SP) strain of laboratory rats, aging is associated with quantifiable changes of the circadian rhythm in body core temperature: (1) its timing becomes less tight, as revealed by a larger standard error of the acrophase (the peak in the 24-hour cosine function best approximating all data) and (2) the acrophase in old SPs occurs earlier than in young ones--quite apart from (3) a decrease in circadian amplitude reported earlier. These results gain particularly in interest in the context of the recent finding that a large (approximately 90 degrees) acrophase-advance is associated with bilateral lesions of the suprachiasmatic nuclei in inbred (non-SP) Fischer rats. These observations may be of interest to those developing models of aging functions in disorders with blood pressure elevation.

Circadian urinary characteristics of adolescents: sensitive dynamic indices complement mean values as new physiologic endpoints.

To introduce the study of physiologic urinary rhythms into secondary education, six girls and 11 boys, 14-18 years of age, collected urine at about 3-hr intervals for 24 hr. The volume and the excretion in urine of creatinine, potassium, and sodium were determined. Blood pressure was measured during the same 24-hr span to teach the students some elements of chronobiologic sampling and analysis in the context of evaluating the risk of developing a high blood pressure later in life. Herein, we examine on urinary excretory rates whether dynamic chronobiologic endpoints such as the amplitude (A) and/or acrophase (phi) may complement the more static mesor (M) in distinguishing groups of adolescents. In a comparison of the two sexes, dynamic characteristics of the urinary excretion of sodium and of the ratio of sodium/potassium do not separate the two groups, while the M does so. The reverse holds true for the excretion of potassium. In the case of urinary creatinine, the circadian A in itself is an index suggesting a "sex" difference; whereas in urinary volume, the M alone, and to a lesser extent the combination of (M, A, phi), yields a P value below the 5% level. The groups are rather small and heterogeneous; a study of ethnicity is beyond our scope. These qualifications notwithstanding, results indicate the need for testing multiple chronobiologic characteristics in comparing groups whether one's interest in the future relates to ethnicity, sex, or other factors. Such studies of urinary rhythms of high-school students serve for instruction and research and to instill responsibility for self-help in preventive health care.

Ultradian rhythmometry by adaptive line enhancer.

Widrow's adaptive line enhancer (ALE) was applied to human rectal temperatures at 12-min intervals for 9 days. Changes along the scale of 9 days in circadian pattern suggested the occurrence of infradian variation, resolved by analyses of the entire series by linear-nonlinear rhythmometry. Once the original signal is filtered to extract the circadian component, ultradian components appear. A wide peak with a period of about 100 min, seen each day, may reflect a consistent ultradian component. Other peaks at lower ultradian frequencies (around a period of approximately 8 hr) are unsteady and may correspond to harmonics of the partially extracted circadian oscillation. Ultradian components with periods of approximately 131 and approximately 68 min were also suggested independently by population-mean cosinor summarizing data collected over a total of 158 days. Results show the ability of ALE to detect and reconstruct periodic components in noise and to track their changes in frequency, notably when other methods are also used to assess separately the components and the corresponding uncertainties involved.

Lighting cycle and social isolation affect development of elevated blood pressure in spontaneously hypertensive rats.

Around-the-clock blood pressure measurements repeated from the 2nd to 6th month of life in spontaneously hypertensive rats (SHR) quantify circadian rhythmicity during the development of an elevated mean blood pressure. The rise in overall pressure is aggravated by social isolation in SHR maintained on a 12-hour white light/12-hour dim red light cycle, but not in SHR kept in continuous dim red light. The demonstration of this interaction is not possible with blood pressure measurements performed only at certain (convenient) times: failure to quantify the circadian rhythm in systolic blood pressure leads to conclusions which can vary with the circadian time at which measurements are made, even in comparisons at the same fixed clock-hour. Thus, in order to model and optimize multiple factors interacting in the genesis of overall mammalian pressure in SHR, rhythmometry is an indispensable tool as it is in other fields.

Chronomodulatory infradian synchronization by placebo or ACTH 1-17 of Musca autumnalis mortality on shifted lighting regimens.

The face fly, Musca autumnalis, exposed to shifts of an LD16:8 lighting schedule at varying intervals, whether previously untreated or given placebo or ACTH 1-17 treatment, before the initiation of shifts, exhibits an infradian frequency response in mortality. At overall 50% mortality, a periodicity of approximately 4.5 days is found for flies exposed to placebo or ACTH 1-17 as a response to the shift interval. As compared to controls, the mortality of flies treated with placebo or ACTH 1-17 is delayed. Not all shift schedules are detrimental; some are actually beneficial.

Circadian and circannual aspects of the complement cascade - new and old results, differing in specificity.

Single cosinor analyses of several elements in the complement cascade suggest the occurrence of circadian rhythms in this immunochemical system. Some earlier results, obtained with less specific methods and reported as properdin, on reanalysis also reveal circadian and circannual rhythms in the aspects of immunology represented. The topic of the complement cascade as a whole is briefly reviewed in the content of modern knowledge.

Chronobiometry with pocket calculators and computer systems.

Selected 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.