Administration of glucocorticoids is effective and necessary in various diseases, but the appearance of side effects may compromise its results. Timing as well as dosing designed to obtain, for the highest number of patients, maximal beneficial effects with minimal undesired effects, is particularly pertinent to long-term corticosteroid therapy, in view of the rhythms exhibited by the endogenous secretion of adrenal cortical and coordinating hormones, primarily ACTH. In experimental animals, properly-timed circadian treatment can be preferred to alternate-day treatment for avoiding certain side effects. To secure the desired effect each day rather than only on alternate days, a chronobiologically correct corticosteroid therapy seeks the best compromise between timing for most of the desired and least of the undesired effects. This was the aim in the design of a chronopluricorticoid drug, with the time specification on its label. The clinical use of this preparation allowed the inferential statistical demonstration of a rhythmic circadian organization maintained during therapy, while the pharmacological results gained were similar to those obtained by the conventional administration of larger doses of corticoids.

Adrenal Cortex↗

PubMedDate not supplied

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.

Animals↗

PubMedDate not supplied

Circaseptan (about-7-day) bioperiodicity--spontaneous and reactive--and the search for pacemakers.

A built-in (genetically determined) about-7-day (circaseptan) period comes to the fore as a desynchronized feature of human time structure in the urinary excretion of 17-ketosteroids by a clinical healthy man: during several years following an endocrine intervention (the self-administration of testosterone suppositories), a circaseptan rhythm (which during the preceding decade had revealed a period of precisely 7 days) deviated slightly, yet with statistical significance, from the environmental week. A second line of evidence for an intrinsic circaseptan component stems from the demonstration of statistically significant differences in timing of a circaseptan rhythm in springtail oviposition. A third line of evidence documents prominent circaseptan rhythmicity after the application of a single stimulus (devoid in itself of any circaseptan information). Such single stimulus induction, amplification and/or synchronization also documents the clinical and biologic importance of built-in circaseptan rhythms that were previously often misinterpreted as being purely reactive: a circaseptan spectral component is remarkably prominent in mammalian organ transplant rejection, both in the clinic and in the laboratory. In the latter case, in the absence of any weekly cycles in hospital routine, including treatment schedules, circaseptan components characterize the rejection of the rat kidney, pancreas and heart. Much additional information here reviewed reveals the occurrence of periods of about 7 days. Their implications for transplant and other chronoimmunology as well as biology in general, and their clinical applications in drug treatment, include the need to weld circaseptan timing to circadian timing and dosing. A dramatic documentation of this need stems from the circumstance that pretreatment for one week with the same total dose of the same substance (a polysaccharide - Lentinan) accelerates or retards cancerous growth (hence shortens or lengthens survival) as a function of interactive circaseptan and circadian rhythms.

17-Ketosteroids↗

PubMedDate not supplied

Circadian rhythms of adenosine deaminase activity in human erythrocytes: a transverse study on young, elderly and senile demented subjects.

Adenosine deaminase activity (ADA) was determined around the clock in human plasma from different groups of subjects: presumably clinically healthy women in Minneapolis, USA; healthy medical students, healthy elderly men and women, and mentally ill patients in Paris, France. In addition to analyses of variance, circadian characteristics were estimated individually and summarized by population-mean cosinor for each group. Technical and sampling considerations are documented: the individualized assessment of a circadian rhythm in adenosine deaminase is feasible in 8 out of 11 series from clinically healthy women covering 24h at 20-min intervals. A circadian population rhythm could be determined for the elderly men and women (p less than 0.05) and tentatively (p = 0.053) for the senile demented patients. A difference in circadian group rhythm characteristics found between the healthy elderly subjects and patients with senile dementia deserves further exploration.

Adenosine Deaminase↗

PubMedDate not supplied

Circadian effect of ACTH 1-17 on mitotic index of the corneal epithelium of BALB/C mice.

The objective was to determine the effect of ACTH 1-17, an adrenocorticotropin analogue, on the mitotic index in the corneal epithelium of mice standardized in 12 hr of light alternating with 12 hr darkness. A question asked was whether the time of administration along the 24-hr time scale influenced any response found. The findings showed that ACTH 1-17 could, depending upon when it was administered, bring about a statistically significant decrease, an increase or even no such change in the mitotic index. The greatest responses found were increases, especially when ACTH 1-17 was administered during the dark span. Also the time after injection when the responses occurred varied. The greatest response recorded was at 12 hr after injection when ACTH 1-17 was given at 2 hr into the dark with a 641% and a 718% increase with a low (0.02 IU/kg) and a higher (20 IU/kg) dose, respectively. A 3-way analysis of variance supported the conclusion that the kind-of-treatment, time-of-treatment and treatment-to-kill interval (sampling time) are important factors when determining any response to ACTH 1-17 on the mitotic index.

Adrenocorticotropic Hormone↗

PubMedDate not supplied

Effect of ACTH 1-17 at different circadian stages on [3H]TdR incorporation into DNA.

The objective was to determine the effect of adrenocorticotropin (ACTH 1-17) on the incorporation of [3H]TdR into DNA (DNA synthesis) in the tongue, esophagus and stomach of CD2F1 mice standardized to 12 hours of light alternating with 12 hours of darkness. A question asked was whether the time of administration along the 24-hour time scale influenced any response found. The response was complex as ACTH 1-17 was capable of bringing about statistically significant increases in the incorporation of [3H]TdR into DNA at certain times, decreases at other times, or no response at still another time. In general the most marked effects of 20 IU/kg of ACTH 1-17 when compared to controls, was to decrease DNA synthesis of as much as 60% 4 hours after administration at the end of the dark or beginning of the light span. A 2- and 3-way analysis of variance supported the conclusion that the kind-of-treatment, time-of-treatment and the interval-to-kill (Sampling time) as well as their interactions are important factors when determining any response of ACTH 1-17 or placebo.

Adrenocorticotropic Hormone↗

PubMedDate not supplied

Rewards in practice from chrono-meta-analyses 'recycling' heart rate, ectopy, ischemia and blood pressure information.

Previously published average curves of heart rate and duration of ischemia in patients with coronary artery disease, studied while on placebo or on treatment with either atenolol or diltiazem, are re-analysed for the assessment of about-daily (circadian) and about-weekly (circaseptan) changes in these variables and of any treatment effect on rhythm characteristics. In addition to circadians, a circaseptan pattern characterizes the duration of ischemia in all three aforementioned study stages. Both drugs decrease the duration of ischemia, atenolol, but not diltiazem, also affects the circadian amplitude and acrophase of this variable. A circaseptan pattern is also found for heart rate on placebo and on treatment with atenolol, but not with diltiazem. Both drugs lower heart rate and the circadian amplitude and 24-h standard deviation of heart rate, atenolol much more markedly than diltiazem. Circadian and circaseptan rhythm characteristics and their alterations with treatment serve to optimize treatment by timing its administration. Chronobiologic surveillance of variables that are being readily monitored as-one-goes by modern implantable devices can also serve for the validation of the effectiveness of drug and electrical therapy. Rhythm alterations, in turn, can provide the earliest warnings of an elevated disease risk and lead to an improved diagnosis.

Adult↗

PubMedDate not supplied

Excessive circadian amplitude of blood pressure increases risk of ischaemic stroke and nephropathy.

After 48-h ambulatory blood pressure monitoring, the incidence of ischaemic stroke, nephropathy, coronary heart disease and retinopathy was prospectively assessed for 6 years in 297 subjects, including 176 treated patients with an elevated blood pressure mean (MESOR-hypertensives). The relative risk associated with an excessive circadian blood pressure amplitude is 8.2 (95% confidence interval 3.1 to 21.7; p < 0.001) for ischaemic stroke and 6.9 (2.9 to 16.3; p < 0.001) for nephropathy. In MESOR-hypertensives, the relative risk for ischaemic stroke and nephropathy is 6.3 (p < 0.005) and 4.0 (p < 0.05), respectively. In MESOR-normotensives as well, an excessive circadian blood pressure amplitude is associated with a large increase in risk for ischaemic stroke and nephropathy (p < 0.05). An excessive circadian blood pressure amplitude is an entity in its own right that increases the risk of adverse vascular events irrespective of the blood pressure MESOR, age and the presence of other known risk factors. The diagnosis of this condition requires around-the-clock monitoring of blood pressure. The treatment of patients with this condition should aim not only at lowering the blood pressure mean but also at reducing blood pressure variability within 24 h.

Adult↗

PubMedDate not supplied

Individual assessment of antihypertensive response by self-starting cumulative sums.

A self-interpreted control chart, on an individualized basis, assesses the effect of a switch from beta-blockers to an angiotensin-converting enzyme (ACE)-inhibitor in a patient with occasional blood pressure (BP) excess. In dense and long data series, the BP and heart rate (HR) of this patient respond to the change in treatment by the test criterion of a self-starting Cumulative Sum (cusum), which reaches values outside a decision interval with a lowering of BP and an increase in HR and vice versa, at least for BP, after treatment cessation. Thereafter, minimal sampling requirements are sought in the same data by applying the same control chart approach to decimated data. Skeleton sampling schemes in a system of chronobiologic self-analysis and interpretation of manually recorded data obtained at strategically placed times (established on the basis of data decimations) could complement control charts that are used on a home computer or preferably would be built into the output of ambulatory monitors used at the outset as a minimum and routinely as an optimum.

Adrenergic beta-Antagonists↗

PubMedDate not supplied

Blood pressure variability assessed by semiautomatic and ambulatorily functional devices for home use.

As a basis for chronobiologic analyses and thereby for screening deviant blood pressure, measurements are advocated, preferably with ambulatorily functional instrumentation at half-hour intervals around-the-clock for an initial span of 7 days. When only manual instrumentation is available, 3-hourly measurements during waking and one measurement, preferably by a companion, around mid-sleep is recommended to detect a blood pressure disorder. Such screening is warranted for a reasonably reliable diagnosis, particularly in order to recognize circadian blood pressure overswinging (Circadian Hyper-Amplitude-Tension, CHAT) and to separate this new disease risk syndrome from an elevation of the time structure (chronome)-adjusted average (MESOR), that is MESOR-hypertension, and from the coexistence of the two foregoing conditions.

Adolescent↗

PubMedDate not supplied

Chronobiology in the diagnosis and treatment of mesor-hypertension.

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.).

Blood Pressure↗

PubMedDate not supplied

Chronomes, time structures, for chronobioengineering for "a full life".

Week-long or longer monitoring of blood pressure and heart rate, coupled to time-structure analyses, can help detect disease-risk elevations, as a warning of the need for a preventive prehabilitation. Within the normal range of physiologic variation, computer methods quantify time structures, or chronomes, that can serve as reference values. The major applied purpose for mapping chronomes is the detection of disease-risk syndromes such as blood pressure "overswinging" and heart rate "underswinging." Too much blood pressure variability (circadian hyperamplitude tension; CHAT), is a risk factor for vascular disease. Other risk syndromes are chronome alterations of heart rate variability (CAHRVs), consisting of a loss of "jitter", i.e., a reduced standard deviation of heart rate or of alterations in the spectral element of the heart-rate-variability chronome, such as in the correlation dimension, an endpoint of deterministic chaos. These alterations can again serve for prehabilitation. On the basic side, the spectral element of the heart-rate-variability chronomes extends from focus on the heartbeat's period of about 1 second to periods in heart rate and its standard deviation that are numerical equivalents of about 10.5- and about 21-year cycles of solar activity. A seemingly unnatural physiologic rhythm or pattern (such as one of 81.6 hours) may correspond numerically to a purely physical environmental rhythm. For example, interplanetary magnetic storms, with their cycles as external chronome components, trigger myocardial infarctions, strokes, and traffic accidents. The systematic monitoring of external rhythms along with physiologic ones for the concurrent analysis of rhythms with longer and longer periods could detect alterations anywhere in and between the 1 cycle/sec and the 1 cycle/10.5- or 21-years regions of the spectrum. Chronobiomimetic engineering for discovering both instantaneous and long-term chronorisk alterations can provide warnings of increased risk. If risk-lowering therapy is then instituted automatically, instrumented health care will be extended beyond the pacemaker-cardioverter-defibrillator, which focuses on the frequency of 1 cycle/sec. Instrumentation that automatically detects blood pressure that varies too much and heart rate that varies too little is needed for prompting prophylactic CHAT and CAHRV treatment. A database of reference values that can be used for chronodiagnosis is now accumulating.

Accidents, Traffic↗

PubMedDate not supplied

Enhanced circasemiseptan (about 3.5-day) variation in the heart rate of cancer patients?

In addition to prominent circadian and circannual components, an about half-weekly (circasemiseptan) pattern was shown earlier to characterize mitotic activity in cancer patients. A circasemiseptan variation in heart rate and circadian rhythms in heart rate and axillary temperature of cancer patients are assessed herein. These variables could be tested as putative marker rhythms for the optimization of radio- and/or chemotherapy by timing which, from a practical viewpoint, may be easier to implement along the scale of the week than that of the day.

Adolescent↗