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Osteoprotegerin (OPG) serves as a soluble decoy receptor for RANKL to inhibit osteoclast formation and activity. Hormones such as PTH and glucocorticoids have been reported to decrease OPG concentrations, while estrogens, transforming growth factor b, related bone morphogenic factor and thrombopoietin reportedly enhance the OPG production in the osteoblastic and bone stromal cells. Since bone turnover shows a prominent circadian rhythm in laboratory animals and humans, with bone resorption increasing at night, we investigated the time structure of circulating OPG concentrations in a group of nine healthy subjects (six women and three men; in the age range of 26-49 years). Blood samples for OPG determination were collected every 4 h for 24 h on the same day, starting at 08:00 in the morning. Data were analyzed by inferential statistical procedures, including the single and population-mean cosinor. A 12-h component was found to characterize serum OPG concentrations (P = 0.038) with peak concentrations around noon and midnight. No statistically significant circadian rhythm of OPG concentrations could be found by cosinor in our study population. The mean 24-h OPG concentration was higher in women than in men (mean +/- S.E.: 3.13 +/- 0.44 vs. 1.94 +/- 0.26 pmol/l, Student t = 2.325, P = 0.053). Since PTH concentrations also exhibit a bimodal pattern along the 24-h scale, PTH may be tested as a putative determinant of the observed changes in serum concentrations of osteoprotegerin.

A multi-center four-hourly sampling of many tissues for 7 days (00:00 on April 5-20:00 to April 11, 2004), on rats standardized for 1 month in two rooms on antiphasic lighting regimens happened to start on the day after the second extremum of a moderate double magnetic storm gauged by the planetary geomagnetic Kp index (which at each extremum reached 6.3 international [arbitrary] units) and by an equatorial index Dst falling to -112 and -81 nT, respectively, the latter on the first day of the sampling. Neuroendocrine chronomes (specifically circadian time structures) differed during magnetically affected and quiet days. The circadian melatonin rhythm had a lower MESOR and lower circadian amplitude and tended to advance in acrophase, while the MESOR and amplitude of the hypothalamic circadian melatonin rhythm were higher during the days with the storm. The circadian parameters of circulating corticosterone were more labile during the days including the storm than during the last three quiet days. Feedsidewards within the pineal-hypothalamic-adrenocortical network constitute a mechanism underlying physiological and probably also pathological associations of the brain and heart with magnetic storms. Investigators in many fields can gain from at least recording calendar dates in any publication so that freely available information on geomagnetic, solar and other physical environmental activity can be looked up. In planning studies and before starting, one may gain from consulting forecasts and the highly reliable nowcasts, respectively.

Longitudinal records of blood pressure (BP) and heart rate (HR) around the clock for days, weeks, months, years, and even decades obtained by manual self-measurements (during waking) and/or automatically by ambulatory monitoring reveal, in addition to well-known large within-day variation, also considerable day-to-day variability in most people, whether normotensive or hypertensive. As a first step, the circadian rhythm is considered along with gender differences and changes as a function of age to derive time-specified reference values (chronodesms), while reference values accumulate to also account for the circaseptan variation. Chronodesms serve for the interpretation of single measurements and of circadian and other rhythm parameters. Refined diagnoses can thus be obtained, namely MESOR-hypertension when the chronome-adjusted mean value (MESOR) of BP is above the upper limit of acceptability, excessive pulse pressure (EPP) when the difference in MESOR between the systolic (S) and diastolic (D) BP is too large, CHAT (circadian hyper-amplitude tension) when the circadian BP amplitude is excessive, DHRV (decreased heart rate variability) when the standard deviation (SD) of HR is below the acceptable range, and/or ecphasia when the overall high values recurring each day occur at an odd time (a condition also contributing to the risk associated with 'non-dipping'). A non-parametric approach consisting of a computer comparison of the subject's profile with the time-varying limits of acceptability further serves as a guide to optimize the efficacy of any needed treatment by timing its administration (chronotherapy) and selecting a treatment schedule best suited to normalize abnormal patterns in BP and/or HR. The merit of the proposed chronobiological approach to BP screening, diagnosis and therapy (chronotheranostics) is assessed in the light of outcome studies. Elevated risk associated with abnormal patterns of BP and/or HR variability, even when most if not all measurements lie within the range of acceptable values, becomes amenable to treatment as a critical step toward prevention (prehabilitation) to reduce the need for rehabilitation (the latter often after costly surgical intervention).

A test of the relative merits of timed melatonin for the treatment of cardiac ischemia as well as hypertension refractory to other drugs is documented against the background of earlier chronobiological studies on blood pressure (BP), disease risks, circadian hyper-amplitude-tension and melatonin effects broadly.

Geomagnetic activity has a strong half-yearly but no precise yearly component in its spectrum, as Armin Grafe suggested nearly half a century ago. We have postulated elsewhere that non-photic cycles such as those in geomagnetics may have signatures in the biosphere and vice versa that biological rhythms have likely counterparts in the physical environment. Accordingly, we document phenomena characterized by a prominent about half-yearly variation, re-analyzed to constitute the start of a transdisciplinary chronomic (time structural) map, aligning these conditions with a half-yearly cycle in the geomagnetic index Kp. At least some biospheric phenomena fitted concomitantly with 1- and 0.5-year cosine curves exhibit an amplitude (A) ratio of A(0.5-year)/A(1-year) larger than unity. Methodologically, it is pertinent that even if data were read off published graphs, the resulting analyses were practically the same as those in the original data received subsequently. The main point is a circasemiannual pattern in status epilepticus, in several morbid oral conditions, in the cell density of vasopressin-containing neurons in the human suprachiasmatic nuclei (SCN), in circulating melatonin at middle latitudes at night during years of minimal solar activity or around noon at high latitudes, and in an unusual circasemiannual aspect of a birth-month-dependence of human longevity. Others have asked whether annual rhythms in human reproduction are biological, sociological or both. We show some other possibilities herein, involving the physical environment, hardly to be neglected in the case of open systems. As to almost certainly multifactorial circasemiannual rhythms, geomagnetics may also be a signal, a proxy or a putative, at least partial mechanism. Geomagnetic activity is related in its turn to solar and galactic activity, and may be a marker for other cyclic events that affect the biosphere. The similarity of cycle lengths in itself can only be a hint prompting the search for causal relations.

An inferential statistical quantification of chronomes (time structures) in the range of everyday physiology has earlier revealed changes affecting the circadian amplitude of melatonin in the absence of changes in the chronome-adjusted mean value (MESOR) or in the acrophase. A chrono-meta-analysis of published data on patients with the Smith-Magenis syndrome herein quantifies the average extent of shift in the acrophase of the circadian melatonin rhythm, reported earlier by others time-macroscopically as an antiphase. Time-microscopically, the phase shift averages 9.6 +/- 0.9 h. Circadian melatonin ecphasia complements blood pressure ecphasia in non-insulin-dependent diabetes mellitus, associated with autonomic dysfunction. The shift in phase of the peak melatonin secretion from the night into the day, associated with specific genetic findings, raises basic questions concerning the designation of melatonin as a hormone associated with darkness. Whether a resetting of the circadian acrophase beyond providing melatonin for sleep improvement can provide benefit remains to be investigated.

Taking the heart rate (HR) for one cycle, whether to examine behavior in the region of periods of 1 s, 1 day, 1 week, 1.3 or 10.5 years, etc., is hazardous. Replications, when possible are mandatory for examining altered variability, whatever the period(s) involved may be. This replication in the individual, and across individuals when the periods are long, measured in decades, may serve for diagnosis and treatment. This rule applies in particular to a seemingly transient circadian hyper-amplitude-tension (CHAT), an over peer-threshold variability in blood pressure (BP), based on the fit of a 24-h cosine curve to time series of appropriate length, rather than to a mere snapshot covering just a single day or week. Transient CHAT may turn into intermittent CHAT, as determined in two cases presented herein. One case of transient CHAT could be so named after a successful treatment (Rx) change eliminated CHAT as an effect validated by monitoring at 30-min intervals for a 7-day span on a new treatment. CHAT disappeared for over 300 consecutive half-hourly measurements, but thereafter it reappeared. During the ensuing nearly continuously monitored 5 years, CHAT continued to appear and disappear sometimes without a treatment change. In another case, which was responsive to a change in the timing of medication, CHAT also disappeared and thereafter reappeared. In a short-term perspective of weeks or months of monitoring, CHAT seemed to be transient, but further monitoring again revealed it to be intermittent. Cases of intermittent CHAT require follow-up for outcomes by comparison with the population at large. Miniaturized instrumentation for their detection should be a high priority, but it must be realized that the automatic ambulatorily functioning monitors, available at 10% of the regular price through a BIOCOS project (corne001@umn.edu), already signify great progress, as compared to previously used manual measurements made around the clock by hypertensive opinion leaders in medicine from diagnosis to death. On automatically collected time series of BP and HR, gliding pergressive spectral windows as such, or such pergressive windows aligned further with global spectral windows, visualize the changing dynamics involved in health and disease, in the steps of Werner Menzel and Paolo Scarpelli.

System time is defined as the duration (T) and sampling density (deltat) of a given study. A time horizon is obtained by combining analytical results on endpoints of time structures (chronomes), usually on control groups, from accumulating diverse studies carried out with drastically different values of T and deltat. These two design considerations depend upon and are limited by resources. The desideratum of a small At e.g., for studies of chaotic endpoints, limits T, e.g., has thus far precluded a continuous mapping of decadal cycles in endpoints such as the approximate entropy or the correlation dimension. Time horizons are being documented for an increasing number of variables that undergo cycles with infra-annual frequencies - with one cycle in about one, two and/or five decades - in the biosphere as in the environment. These infra-annuals, in and around us, modulate ultra-annuals, including circadians, as well as about 7-day (circaseptan) and about half-yearly (circasemiannual) cycles, all prominent, e.g., in geophysical and biospheric specta. Neglect of infra-annual chronomics can lead to blunders. A statistically highly significant decrease in the excretion of steroidal metabolites (or in heart rate variability) may be misinterpreted as premature aging if it lasts for several years, and may be unnecessarily acted upon, e.g., by drugs. The decrease, however, may only be transient, occurring only during a given stage of a circadecadal cycle, and it may be followed for the next several years by an also spurious "rejuvenation", possibly misinterpreted as a drug effect. When recognized as the alternating stages of decadal cycles and assessed with an affordable deltat, infra-annuals of variables involved in major problems of our day, including homicides and wars, may lead us to manipulable internal or external mechanisms, and thus, eventually, possibly to countermeasures to crime and terror as well as to the optimization of aims such as spirituality.