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A 35-year-old cardiologist monitored himself with an automatic ABPM-630 (Colin Electronics) monitor, mostly at 15-minute intervals around-the-clock for three years with a few interruptions. In this subject with a family history of high blood pressure and stroke, a cross-spectral analysis revealed a statistically significant coherence at 27.7 days between systolic and diastolic blood pressure and heart rate vs. the geomagnetic disturbance index, Kp. A lesser peak in coherence was found for systolic blood pressure with Kp at a trial period of 4.16 days (P = 0.046). These results suggest that changes in geomagnetism may influence the human circulation, at least in the presence of familial cardiovascular disease risk, and they may do so at frequencies that have no precise human-made cyclic worldwide match.

The scope and the details of a newly developed actometer were introduced. We are able to select a desired threshold of gravity(g)-forces between 0.01g and 0.50g and to simultaneously monitor 3 kinds of activity along with an averaged g-force every minute. As a routine study, we monitored at settings of 0.01g, 0.05g and 0.20g and averaged on one channel. Part of the time, physical activity was monitored together with ambulatorily monitored blood pressure (BP) and the ECG, or at least heart rate (HR). Physical activity showed a circasemiseptan and circaseptan periodicity as well as the circadian component, especially in subjects with an irregular sleep-wakefulness life style. On the average, physical activity was greater on a working day than on a holiday. Everyday physical activity reflects in part the ability to exercise, and it is expected that this actometer can contribute or provide an objective individualized quality-of-life index. The effect of physical activity on circadian profiles of BP, HR and HR variability is also examined. We observed that BP started to increase several hours before getting up. This fact likely shows that there is an endogenous circadian rhythm in BP, independently of the sleep-wakefulness cycle. Lastly, we investigated the relationship between physical activity and HR in patients permanently paced; we confirmed that the DDDR pacing mode was more physiological than the VVI or VVIR mode. This newly developed actometer will bring about further progress in chronobiology.

Reference standards were sought for use in the search of any indications of myocardial damage by an alteration of the time structure, or chronome, of creatine phosphokinase (CPK) "MB" isoenzyme activity in the heart of the male Holtzman rat. 144 rats were kept on 6 lighting regimens staggered by 4 hours, 24 rats per chamber. On 8 consecutive days, hearts from 3 animals from each chamber were harvested and weighed. The left ventricle was dissected, homogenized in a buffer solution at 4 degrees C and stored frozen at -20 degrees C until analysis. A supernatant aliquot of each sample was analyzed by a discontinuous gradient elution from DEAE-Shephadex A-50 columns. The CPK isoenzymes were quantified by the Rosalki method. Results of the CPK assay from each time point were analyzed by linear and nonlinear least-squares rhythmometry. Among other components, a 168h or circaseptan rhythm characterized CPK activity in the heart of Holtzman rats. This component and other ultradian and circadian aspects of the time structure of rhythms and trends, the chronome of a given variable, may serve, by any eventual alteration of their dynamic characteristics, as gauges of potential cardiac damage prior to the occurrence of an increase in the overall mean of the enzymatic activity.

Several studies aimed at testing the effects of low-dose acetylsalicylic acid treatment (ASA, aspirin) in the prevention of preeclampsia conclude that beneficial effects of such treatment outweigh adverse ones. Since recent results suggest that desired effects upon lipoperoxides and beta-adrenergic receptors are dependent on the circadian timing of ASA administration, we aim to study if ASA therapy can be optimized by timing according to the rest-activity cycle. Accordingly, before conducting clinical trials on pregnant women, we have examined in clinically healthy subjects the possibility that effects of ASA upon blood pressure could indeed be time-dependent. We studied 55 healthy subjects (35 men and 20 women), 19-24 years of age (mean +/- SD: 20.9 +/- 1.8). Subjects were living on their usual diurnal waking (approximately 08:00 to approximately 24:00), nocturnal resting routine during sampling, following every-day life conditions without any restriction. The systolic, mean arterial and diastolic blood pressures and heart rates of each subject were automatically monitored every 30 min. for 48 hrs with an ABPM-630 Colin (Komaki, Japan) device before and after a one-week course of aspirin (500 mg/day). Subjects were randomly assigned to one of three groups, according to the circadian timing of administration of the daily dose of ASA: within two hours of awakening (R x 1), seven to nine hours after awakening (R x 2), or within two hours before bedtime (R x 3). The second blood pressure profile was obtained during the sixth and seventh days of treatment (to avoid differences in activity dependent on the day of the week). Results indicate a statistically significant blood pressure reduction (negative mean area between the blood pressure profiles obtained before and after aspirin administration) only when ASA was given seven to nine hours after awakening (R x 2; P = .012, .003, and .006 for systolic, mean arterial and diastolic blood pressure, respectively). These results were corroborated by a non-parametric (sign) test, also indicating the significant reduction in systolic and diastolic BP for R x 2 (P = .003 and .010, respectively). Non-invasive BP monitoring combined with the proper analysis of the time series thus obtained could then provide a cost-effective approach for testing the circadian optimization of long-term ASA administration for both cardiovascular disease prophylaxis and prevention of preeclampsia.

Whereas conventional time-unspecified single measurements of blood pressure and heart rate may mislead, influenced as they are, among other factors, by the individual's emotional state, position, diet and external stimuli generally, the chronobiologic evaluation of predictable variability in these physiologic variables assesses early cardiovascular disease risk in pregnancy by (a) the use of fully ambulatory devices and (b) the proper processing of the time series thus obtained. We have used this approach to quantify changes in 24-h synchronized circadian characteristics of cardiovascular variables in two consecutive pregnancies of a clinically healthy woman. The results were then compared with those obtained from data sampled after the second pregnancy. Blood pressure and heart rate were automatically monitored, at 1-h intervals, each time for at least 48 consecutive hours, and for a total of 76 days of monitoring in each pregnancy. Circadian parameters of those circulatory variables were computed for each 48-h profile of measurements by the least-squares fit of a 24-h cosine curve. Regression analysis of parameters thus obtained revealed patterns of variation of circadian rhythm-adjusted means and amplitudes with gestational age. In both pregnancies, the predictable variability of the circadian rhythm-adjusted mean of blood pressure can be approximated by a second-order polynomial model on gestational age: a steady linear decrease in systolic, mean arterial and diastolic blood pressures up to the 22nd week of pregnancy is followed by an increase up to the day of delivery. This pattern of variation is not found for data similarly sampled during non-pregnancy on the same woman. This longitudinal study confirms and extends to ambulatory everyday life conditions the predictable pregnancy-associated variability in blood pressure and heart rate and also allows the establishment of prediction and confidence limits for cardiovascular parameters in a healthy pregnancy.

The time has come for humans to return the debt to the many non-human species that were studied for the sake of humanity and to extend the motto of "doing unto oneself first what eventually is to be done to others" when the "others" are the patients of veterinarians. As physiologic monitoring benefits from advances in hardware and software, much chronobiologic information can be obtained on the chronomes of the different species cared for by veterinarians for a new health care focusing on prevention, implemented perhaps by recognizing and treating earliest rhythm alteration rather than merely the fact of overt disease.

A chronobiologic computerized modular health care (telehygiene) system for humans in extraterrestrial space 1) monitors and analyzes physiologic blood pressure, heart rate and other variation, including that in tumor markers; 2) recognizes earliest risk elevation by dynamic changes in the 'usual value' range (trend and rhythm alteration); 3) prompts timely and timed treatment for cardiovascular and emotional disease and malignancy prevention, and 4) serves for health improvement; the information from the system can also help optimize shift-work schedules for peak performance and provides endpoints of interest in basic science. The system exploits the chronome, a genetically anchored, habitat-synchronized structure of multifrequency rhythms and trends which is now documented (by longitudinal data series) to respond to magnetic disturbance in the solar system, with consequences expressed in catastrophic illness that is best prevented. Such a system, rated by peers as being of highest priority, could complement classical tools such as the stethoscope, proposed by the U.S. Johnson Space Center representative for use on the moon.

Background: Results from unpublished data on the incidence of adverse vascular events and from several published studies are reevaluated chronobiologically., Methods and Results: Cosinor methods indicate 1. a circadian variation in the incidence of paroxysmal supraventricular tachycardia (PST), of broadly classified ventricular arrhythmia (VAr), and of atrial fibrillation (AF); 2. a statistically significant difference in the timing of the circadian rhythm of PST and VAr versus that of AF; and 3. a further difference in the timing of these rhythms from that in the incidence of myocardial infarctions (MI). Electrocardiographic records for spans longer than 24h show the extent of day-to-day variability in circadian characteristics of the given patient and indicate the presence of even lower-frequency components, notably along the scale of a week, that may underlie weekly and half-weekly patterns of morbidity and mortality., Conclusion: Beyond alterations in the about 1-Hz periodicity of the heart, predictable changes along the scales of the day and the week may constitute a clue to the etiopathology of a given condition and provide a basis for treatment timing. The assessment of unfavorable changes in the lower frequency components may provide a lead time long enough to prompt the institution of preventive, rather than curative, intervention.

The realization of the implications of splitting the atom ended a tragic war. The nuclear age ensued. Likewise, a devastating escalation of health care costs could be ended by realizing the implications of splitting the normal range. Our currently disease-cure-oriented health care system does too little too late. Chronobiology could change this status quo into a system that recognizes risk early; it would gain new information from the resolution of predictable variations that take place within the physiologic range. Investment into vaccinations leads to returns in the form of savings in suffering and cost. A relatively modest investment into a 'Blood Pressure Health Start', pursued while chronobiology is being taught as an integral part in primary, secondary, higher and continued education, may not only drastically and in some respects promptly reduce the health care bill, but it would help the economy of the country that invests into the development of instrumentation for a chronobiologic systems approach. On the one hand, reducing the number of cases of catastrophic diseases, via improved diagnosis (to start with) of the blood pressure status, is likely to substantially reduce the budget deficit by reducing the legitimate and essential costs of care (to start with, of strokes and heart attacks, that kill more people than all other diseases combined and that have blood pressure disorders as their major risk factor). On the other hand, by implementing a novel health care system which also involves new technology that can become in demand worldwide, any trade balance will be improved.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical trials would gain from incorporating 'Phase 0' chronobiologic pilot designs both from the viewpoint of (statistical) power and cost-effectiveness. Herein, this statement is documented by power computations and is further illustrated by clinical examples answering specific questions. Power computations show the merits both of chronobiologic designs (that assign samples at equidistant intervals to cover one full cycle of anticipated pertinent rhythms) and of chronobiologic analyses (the cosinor versus the analysis of variance). Randomized clinical trials would gain from incorporating a concern for timing as well as dosing in all three stages of clinical trials (Phase I, II and III focusing on toxicity, efficacy and a comparison with the current best treatment, respectively) and could be cost-effectively preceded by 'Phase 0' trials so as to detect, sooner and with smaller sample sizes, desired or undesired effects that may otherwise be missed.

A chronobiologic approach is much more than fine-tuning that may perhaps be considered after a drug has been identified as useful; at very little cost at first, a Phase 0 chronobiologic trial may show that there is danger that a given drug may do more harm than good when administered at the wrong time. At least equally important, the chronobiologic approach may recognize the usefulness of a drug that is active only at the proper time. When different chronobiologic timing results in opposite effects from the same total weekly dose of the same drug, it is clear that timing cannot be separated from dosing. The time structure-adjusted pattern of drug administration can make the difference between the undesired stimulation of a malignant growth and shortening of survival time and the desired growth inhibition and prolongation of survival. The experience with lentinan, namely that this immunomodulating drug can stimulate as well as inhibit the development of a cancer, may apply to many more therapeutic agents in a day and age of biologic response modifiers. It is a point of particular importance that an immunostimulator ought not be given at a time when it can be an immunosuppressor. What is surprising to many under these circumstances is that chronobiologic designs are also cost-effective. Most scholars believe that if a test is carried out at six times, it will cost six times more, will require six times more patients and six times more work. We believe we have shown that the reverse holds true: if so, the discussion of the pros and cons of chronobiometry and of neglect thereof becomes one of ethics. Figures 1-5 depict the status quo. Examples have been given to show that some effects can be obtained only at certain times with the dose used. Figure 8 reveals the doubling of the desired anticancer effect by timing treatment according to an unspecific marker rhythm. The recognition of the power of chronobiologic designs coupled to the discovery of large-amplitude rhythms in non-invasively determined marker chronomes is a challenge that can be exploited, particularly in the treatment of cancer. Marker determinations are still expensive, but once the cost of their development is paid, a market is established, and the community is trained in self-help, the responsibility now assumed by most diabetic patients for themselves can also be shouldered by cancer patients.(ABSTRACT TRUNCATED AT 400 WORDS)

The blood pressure of 7 clinically healthy volunteering social drinkers was studied while they consumed, with a crossover design for 5 days, either 40 g of alcohol by day or fruit juice, with the two spans on alcohol and juice being separated by a one-week washout. Whereas the rhythm-adjusted mean was not changed, a clear statistically significant increase in the circadian double amplitude was found. The study provides a model for a rapidly achieved circadian amplitude hypertension which may precede an elevation of the overall blood pressure mean in the natural course of the disease.

Systolic (S) and diastolic (D) blood pressure (BP) and heart rate (HR) of clinically healthy children (24 boys and 15 girls) 3 to 7 years of age were measured with a standard mercury sphygmomanometer at 3-hour intervals for 24 hours in April 1991. The children slept and/or rested from 2100 to 0700 and napped from 1230 to 1530; they had meals at 0730, 1200 and 1800. A statistically significant circadian and about 12-hour (circasemidian) component of variation is documented for SBP and DBP of boys and girls and for HR of boys. No gender difference was found for the circadian and circasemidian components. A positive correlation with age is found for the MESOR and circadian amplitude of SBP and DBP (p < 0.05); a negative correlation with age is found for the MESOR of HR (p < 0.001).

Every 4 hours for 24 hours, 14 clinically healthy young individuals (6 women and 8 men), 26 +/- 4 years of age, measured systolic (S) and diastolic (D) blood pressure (BP) by sphygmomanometer and heart rate by ECG and did impedance cardiography under usual living conditions. Stroke volume (SV), cardiac output (CO) and total peripheral resistance (TPR) were calculated. Time series of SBP, DBP, HR, SV, CO and TPR were analyzed by single and population-mean cosinor. A circadian cardiovascular rhythm is demonstrated by rejection of the zero amplitude assumption in the population-mean cosinor test for SBP, DBP, HR, SV, CO and TPR (P < 0.01). TPR peaks around 0400 (-61 degrees from local midnight), in antiphase with all other variables, their acrophase occurring around 1600 (-240 degrees). A circadian rhythm of statistical significance or of borderline statistical significance is found for all variables except TPR in women. Circadian rhythm characteristics were otherwise mostly similar in men and women with a statistically significant gender difference found by parameter tests only for the MESOR and amplitude of SBP.

Cardiac function may vary predictably along the 1-year scale. A circannual rhythm, more or less in phase is documented for 5 echocardiographic variables in clinically healthy Japanese adults.

Twenty-four-hour blood pressure (BP) profiles of 56 patients diagnosed as 'hypertensive' by WHO criteria were analyzed by the fit of a 24-hour cosine curve according to the single cosinor method. A left ventricular mass index (LVMI) was also assessed by two-dimensional echocardiography on each patient as a gauge of target organ involvement. LVMI and the BP MESOR correlates positively for systolic, S (r = 0.324), mean arterial, MA (r = 0.334) and diastolic, D (r = 0.267) BP (P less than 0.05), yet no statistically significant linear correlation between LVMI and the circadian BP amplitude (one-half of predictable change) was found. When a second-degree polynomial regression was fitted to the circadian BP amplitudes, an association was found (SBP: R2 = 0.138, P = 0.02; MAP: R2 = 0.167, P = 0.01; DBP: R2 = 0.128, P less than 0.01). The corresponding curves were characterized by peaks in the circadian amplitudes of SBP, MAP and DBP around a value of LVMI between 110 and 120 g/m2. For further scrutiny, three subgroups had been formed on the basis of literature, a priori with respect to the LVMI (group 1: LVMI less than 100); group 2: 100 less than LVMI less than 130; group 3: 130 less than LVMI). For MESORs, there was no difference between groups 1 and 2, whereas the MESOR of group 3 were larger than the other two groups. The circadian BP amplitudes of group 2 were larger than those of the other two groups for SBP, MAP and DBP. An increasing LVMI precedes a definitive increase of BP MESOR and coincides with an increase in the circadian BP amplitude; thus an increase in extent of circadian changes can alert the self-monitoring population of a target organ involvement.

Rhythm characteristics of blood pressure (BP) and heart rate (Hr) of 11 healthy centenarians and 66 medical students are described. Each subject ambulatorily monitored measured BP and HR around the clock at 15-min intervals for 48 hours. Least-squares spectra were obtained by the fit of cosine curves (cosinor) and compared between the two populations. Confounding by geographic differences seems to be ruled out by comparisons with results from international data bases. A shift in prominence from the circadian domain to higher frequency harmonics was found for the BP but not for the HR of centenarians. In clinically mostly healthy centenarians, markers of primary aging may consist of a relatively low circadian BP and HR amplitude and a tendency toward internal and external desynchronization. Whether these chronobiologic changes with age are desirable, indifferent or undesirable can now be elucidated by outcome studies, in the light of the reference standards provided herein.

In a patient with a debulked müllerian adenocarcinoma involving the ovary, an elevated serum concentration of macrophage-colony stimulating factor (M-CSF) (5.3 ng/ml) was lowered into the range of the age- and gender-matched controls by a 24-hour infusion of 135 mg/m2 of taxol, as was a Ca125 of 1480 U/ml by three such taxol courses given at 3-week intervals (to 14 U/ml). A downward trend of M-CSF in serum with an about-14-hour ultradian modulation during the first chemotherapy course resembles that of the concomitantly assessed Ca125. A decreasing trend modulated by an about-half-weekly component is found in M-CSF of fractionated urines collected at spontaneous voidings around the clock for 5 days. M-CSF may serve as a chronobiologic marker for optimizing, on an individualized basis, 1) the infradian scheduling of chemotherapy courses and 2) the ultradian-circadian within-course time patterns. Timing based on markers of the anticancer effect aims at teh as-yet unattained transfer from rodent to human of cancer cures that were not previously feasible without chronobiologic considerations. This goal can be pursued with M-CSF as well as Ca125 and UGP as possibly complementary chronobiologic markers in a chronotherapy trial with taxol in humans.

One of us introduces a chronobiology course to students at the University of Milan, Italy, with a succinct statement that may well serve to summarize the foregoing 24 points. Its few lines distill the preceding details and formulate the raison d'être of Chronobiology: Chronobiology is: not only a science in its own right; not only a methodology; not only a new kind of statistical analysis; not just an aspect of biology, but a new way of invariably approaching any problem in biology, notably medicine.

Twelve endocrine variables in blood from a small number of clinically healthy adult women were sampled systematically around the clock and the seasons. Pattern discrimination methods singled out certain hormone values in certain seasons as classifiers for a high vs low risk of developing diseases associated with a high blood pressure. Further evidence in support of such classifiers is obtained on data from adolescent, menstrually cycling young adults and post-menopausal women, here analyzed as pool of series, with the scope of the data from any one age group greatly extended by a resampling procedure, namely, by bootstrapping. This mathematical approach was carried out on data series around the clock and seasons on several hormones as well as systolic and diastolic blood pressure. Classifier roles were strongly supported for plasma aldosterone and thyroid stimulating hormone, originally by an analysis of variance and, in the case of aldosterone, by circannual cosinor analysis and by numerical resampling. Circannual bootstrapping, a procedure recommended for broad routine use as a safeguard for hypothesis testing, was also done for plasma cortisol, dehydro-epi-androsterone sulfate and prolactin, variables for which (parametric) analyses of variance and cosinors did not reveal any difference between groups at high and low cardiovascular risk. In these instances, bootstrapping results are tentative and await further analyses. Results show the ability of circannual bootstrapping to detect outliers. Identification of classifiers provides cost-effective endocrine checks complementing the targeted automatic monitoring of blood pressure. Circannual indices for risk evaluation are, however, costly in several ways since it takes at least a year and quite a few samples to estimate them reliably. Accordingly, we also extended the scope of previous results by the application of an added procedure for circadian bootstrapping. With circadian as well as circannual bootstrapping, we here illustrate a major potential component of a system of chrono-engineering for health maintenance. This system should start with focus on the newborn. The results on adults here analyzed are likely to be more prominent in the neonate, to the extent that they are genetic in origin, yet amenable to modification by the extra-uterine environment.

Earlier, we described the format provided by an ambulatory blood pressure monitor, the ABPM-630 with a data handler (AA-200), manufactured by Colin Medical Instruments. A detailed procedure for data transfer from the memory cassette into the analyzer and into an IBM PC in a format compatible with programs in the Chronobiology Laboratories is provided with a brief description of the hardware used. Among several instruments available for ambulatory blood pressure and heart rate monitoring, the ABPM-630 has several advantages: it does not require electrodes (a merit it shares with other instruments); it is portable, even if there are smaller ones; it functions silently, being activated by a CO2 cartridge; and it provides data obtained by two methods, by auscultation and by oscillometry, in part as a backup for one another, depending on whether auditory or movement noise are within limits acceptable to the instrumentation. This feature renders it more likely that some record will be obtained. In our earlier publication, we had referred to and then briefly described a special program which converts the format of the data handler into a format acceptable for analyses with programs from the University of Minnesota Chronobiology Laboratories. Herein, the operation of transferring data from the ABPM-630 memory cassette to an IBM-compatible personal computer (PC) is described, with an indication further of the programs used in the Chronobiology Laboratories.

Interim chronobiologic cardiovascular reference data have been described; 353 clinically healthy Japanese subjects were monitored every 15 min for 24h on 2 occasions. Special attention was paid to the difference between metropolitan and rural areas. Not only the MESORs of SBP and DBP, but also the circadian amplitudes, were higher in the Tokyo than in a rural area (Komaki, Aichi Prefecture). Age-related alterations in the circadian profile of cardiovascular variables were noted for women but not for men. The average MESOR remained similar for SBP in men, whereas in women the average MESOR increased with advancing age in both urban and rural areas. The average circadian amplitude of SBP also increased with age in women, but not in men. No significant deviations of acrophase with age were found for SBP and DBP in men, whereas in rural women the acrophase tended to occur earlier with increasing age.

An elevation of systolic and diastolic bloodpressure to values regarded as abnormal ones on the basis of conventional criteria was recognized by self-measurement. For both systolic and diastolic blood pressure, the overall means adjusted for rhythms, the so-called mesors, also were elevated in the light of their response to treatment: these mesors were found to be lowered with statistical significance when values during treatment were compared by an objective test with values measured before treatment. Individualized rhythmometry quantitatively characterizes a predictalbe portion of the variability in human blood pressure and tests for the statistical significance of changes in blood pressure as a function of the treatment and also as a function of the circadian timing of such treatment. The case report thus illustrates an individualized chronotherapy of systolic and diastolic mesor-hypertension, diagnosed retrospectively from the tested effect of hydrochlorothiazide. In the case reported, and perhaps routinely, computer-analyzed self-measurements can serve 1) to prescribe the right kind and amount with the right timing, for a given therapy, and 2) for diagnosis and prevention as well (Meyer et al.; Halberg et al.).

In a series of experiments, male and female Sprague Dawley rats, kept in light (L) from 06(00) to 18(00) alternating with darkness (LD 12:12) inhaled different concentrations of carbon monoxide (50-1,700 ppm) at each of two test times, 12 h apart. A decrease in flow of CO2 (VCO2) resulting from CO inhalation was greater in the active dark (D) than resting light (L) span. Experimental hypoxic mortality of male and female mice also shows circadian variations, being greater in the D than in the L span. Moreover, a difference of mortality was observed betwen hypoxic exposures performed at 12(00) (in LD or DL) and hypoxic exposures performed at 00(00) (in LD or DL). Such results await tests of any extent to which they model responses of human beings to air pollution. In human beings any external environmental circadian, circaseptan and circannual variations in air pollution as such may serve to variable extent as socioeconomic synchronizers of innate rhythms with a corresponding frequency, rather than as solely generators of time patterns in any physiopathologic response to air pollution.

Data published earlier on a possible circadian variation in murine susceptibility to intravenously-administered ouabain and analyzed by conventional biometric methods, were reanalyzed by cosinor procedures. A statistically significant circadian rhythm could thus be demonstrated, contradicting the earlier conclusion that there was no circadian rhythm in susceptibility to ouabain when injected intravenously. Results from this reanalysis agreed with those from previous investigations in which ouabain was injected intraperitoneally or subcutaneously. Thus, a circadian rhythm characterizes murine susceptibility to ouabain given via 3 different routes.

A thermorhythmometric analysis was carried out on data from a patient who underwent a prophylactic subcutaneous mastectomy, subsequently to a preoperative mammogram revealing clustered small calcifications in the left breast. The patient self-measured surface temperature of each breast, above and below the nipple, at intervals of 75 +/- 10 min for 59 h while awake. In one location of each breast, the recording thermistor-probe was insulated for 21.5 h while other probe locations remained uninsulated. The overall rhythm-adjusted average surface temperature and the extent of predictable circadian variation differed with statistical significance when the two breasts were compared. The left breast exhibited a higher rhythm-adjusted mean temperature and a lower extent of predictable circadian variation, as compared to the contralateral breast. The interbreast differences of surface temperature also demonstrated a statistically significant rhythm. A review on results of rhythmometry of breast temperature was also carried out. The thermorhythmometric findings here reported must not necessarily be regarded as indicative of cancer; they may be found in non-cancerous subjects and may or may not reflect early pathology. The objective of this publication is to suggest that non-invasive mammary thermorhythmometry may complement clinical histopathology. This subject may exemplify a new principle awaiting scrutiny with much more extensive sampling and much longer follow-up, namely that chronopathology including chronoprotopathology, alongside established diagnostic procedures, may provide an indication for prophylactic intervention.

The bootstrap distribution of the difference in the circannual mesor of DHEA-S, TSH and LH between healthy adult women of a lowly or highly expansive personality, assessed by scale 9 of an abbreviated Minnesota Multiphasic Personality Inventory, validates the potential classifying role of these hormones, originally singled out by methods of pattern discrimination.

For melatonin (a chronomodulator of adrenal cortical function, immune phenomena and carcinogenesis), a circadian rhythm is demonstrated in aqueous pineal homogenate of domesticated B6D2F1 mice. Domestication as such does not eliminate a mechanism of cephalo-adrenal coordination.