CHRONOBIOLOGY OF HIGH BLOOD PRESSURE.

BIOCOS, the project aimed at studying BIOlogical systems in their COSmos, has obtained a great deal of expertise in the fields of blood pressure (BP) and heart rate (HR) monitoring and of marker rhythmometry for the purposes of screening, diagnosis, treatment, and prognosis. Prolonging the monitoring reduces the uncertainty in the estimation of circadian parameters; the current recommendation of BIOCOS requires monitoring for at least 7 days. The BIOCOS approach consists of a parametric and a non-parametric analysis of the data, in which the results from the individual subject are being compared with gender- and age-specified reference values in health.Chronobiological designs can offer important new information regarding the optimization of treatment by timing its administration as a function of circadian and other rhythms.New technological developments are needed to close the loop between the monitoring of blood pressure and the administration of antihypertensive drugs.

THE INCIDENCE OF SUDDEN CARDIAC DEATH IN AUSTRIA.

The aim of the study was to assess the time structure (chronome) of sudden cardiac death (SCD) in Austria. The daily incidence of SCD (ICD-10 I46.1) in Austria was obtained for the 4-year span from Jan 2002 to Dec 2005. Data were available separately for men and women. This data series was analyzed by linear-nonlinear rhythmometry. The major feature is the detection of a cis-half-year that is validated nonlinearly, the estimated period of the cis-half-year is 0.408 year (95% CI: 0.389, 0.426). It is concluded that the chronobiological analysis of sudden cardiac death in Austria showed the variability of total incidence with the period of a cis-half-year.

Circadian and extracircadian exploration during daytime hours of circulating corticosterone and other endocrine chronomes.

During 7 consecutive days, blood and several tissues were collected during daytime working hours only, three times per day at 4-h intervals from inbred Wistar rats, which had been previously standardized for 1 month in two rooms on a regimen of 12 h of light (L) alternating with 12 h of darkness (LD12:12). In one room, lights were on from 09:00 to 21:00 and in the other room, lights were on from 21:00 to 09:00 (DL12:12; reversed lighting regimen). This setup provides a convenient design to study circadian and extracircadian variations over long (e.g., 7-day) spans. Prior checking of certain circadian rhythms in animals reared in the room on reversed lighting (DL) as compared with animals in the usual (LD) regimen provided evidence that the 180 degrees phase-shift had occurred. These measurements were limited to the circadian (and not extended to infradian) variation. As marker rhythm, the core temperature of a subsample of rats was measured every 4 h around the clock (by night as well as by day) before the start of the 7-day sampling. An antiphase of the circadian rhythm in core temperature was thus demonstrated between rats in the LD vs. DL rooms. A sex difference in core temperature was also found in each room. A reversed rhythm in animals kept in DL and an antiphase between rats kept in DL vs. LD was again shown for the circulating corticosterone rhythm documented in subsamples of 8 animals of each sex sampled around the clock during the first approximately 1.5 day of the 7-day sampling. The findings were in keeping with the proposition that sampling rats at three timepoints 4 h apart during daytime from two rooms on opposite lighting regimens allows the assessment of circadian changes, the daytime samples from animals kept on the reversed lighting regimen accounting for the samples that would have to be obtained by night from animals kept in the room with the usual lighting regimen. During the 7-day-long follow-up, circadian and extracircadian spectral components were mapped for serum corticosterone, taking into account the large day-to-day variability. A third check on the synchronization of the animals to their respective lighting regimen was a comparison (and a good agreement) between studies carried out earlier on the same variables and the circadian results obtained on core temperature and serum corticosterone in this study as a whole. The present study happened to start on the day of the second extremum of a moderate double magnetic storm. The study of any associations of corticosterone with the storm is beyond our scope herein, as are the results on circulating prolactin, characterized by a greater variability and a larger sex difference than corticosterone. Sex differences and extracircadian aspects of prolactin and endothelin determined in the same samples are reported elsewhere, as are results on melatonin. Prior studies on melatonin were confirmed insofar as a circadian profile is concerned by sampling on two antiphasic lighting regimens, as also reported elsewhere. Accordingly, a circadian map for the rat will eventually be extended by the result of this study and aligned with other maps with the qualification of the unassessed contribution in this study of a magnetic storm.

Yearly and perhaps transyearly human natality patterns near the equator and at higher latitudes.

Data on the daily numbers of births in Davao, Philippines, available from 1993 to 2003 are re-analyzed herein by linear-nonlinear rhythmometry, as are data from Italy and Japan. A transyear, characterizing the solar wind and other non-photic physical environmental factors, corresponds to a spectral peak of the near-equatorial natality series. This component with a period of about 1.3 years is found to have an amplitude larger than the calendar year, the amplitude ratio being 134%. Whereas the transyear is validated nonlinearly, the 95% confidence interval for the period extending from 1.21 to 1.38 years and the 95% confidence interval for the amplitude not overlapping zero (P < 0.05), the annual variation is only demonstrable by linear least squares analysis. The results bring added evidence for an influence of non-photic environmental effects on human physiology, in this case data collected near the equatorial region, Davao being situated at 7 degrees N, 126 degrees E. They are in keeping with some degree of generality of a rule of reciprocity among mutually supporting physical and biological periodicities. They do not detract from the fact that in other longer data sets at higher latitudes, the calendar year, presumably reflecting climatic influences, dominates the spectrum.

Why continued surveillance? Intermittent blood pressure and heart rate abnormality under treatment.

Several opinion leaders have monitored their blood pressure systematically a sufficient number of times a day for chronomic (time structural) analyses, from the time of encountering chronobiology until their death; they set an example for others who also may not wish to base treatment on single spotchecks in a health care office. Such self-measurements, while extremely helpful, were not readily feasible without a noteworthy interruption of activities during waking as well as of sleep. New, relatively unobtrusive instrumentation now makes monitoring possible and cost-effective and will save lives. Illustrative results and problems encountered in an as-one-goes self-survey by GSK, a physician-scientist, are presented herein. Both MESOR-hypertension and CHAT (circadian hyper-amplitude-tension) can be intermittent conditions even under treatment, and treatment is best adjusted based on monitoring, rather than "flying blind".

Prokaryotic and eukaryotic unicellular chronomics.

An impeccable time series, published in 1930, consisting of hourly observations on colony advance in a fluid culture of E. coli, was analyzed by a periodogram and power spectrum in 1961. While the original senior author had emphasized specifically periodicity with no estimate of period length, he welcomed further analyses. After consulting his technician, he knew of no environmental periodicity related to human schedules other than an hourly photography. A periodogram analysis in 1961 showed a 20.75-h period. It was emphasized that "... the circadian period disclosed is not of exactly 24-h length." Confirmations notwithstanding, a committee ruled out microbial circadian rhythms based on grounds that could have led to a different conclusion, namely first, the inability of some committee members to see (presumably by eyeballing) the rhythms in their own data, and second, what hardly follows, that there were "too many analyses" in the published papers. Our point in dealing with microbes and humans is that analyses are indispensable for quantification and for discovering a biologically novel spectrum of cyclicities, matching physical ones. The scope of circadian organization estimated in 1961 has become broader, including about 7-day, about half-yearly, about-yearly and ex-yearly and decadal periodisms, among others. Microbial circadians have become a field of their own with eyeballing, yet time-microscopy can quantify characteristics with their uncertainties and can assess broad chronomes (time structures) with features beyond circadians. As yet only suggestive differences between eukaryotes and prokaryotes further broaden the perspective and may lead to life's sites of origin and to new temporal aspects of life's development as a chronomic tree by eventual rhythm dating in ontogeny and phylogeny.

Time microscopy for all kinds of data including circadian clock biology.

Data showing a rhythm to the naked eye prominently, barely or not at all were described as kinds A, B and C, respectively. Here, we document good agreement between estimates of maxima and minima with eyeballing and with the addition of point and interval estimates of parameters in kind A data. We also construct a chart that provides estimates of uncertainties that can be obtained objectively while they are more difficult to quantify subjectively; again there is agreement. Interval as point estimates of rhythm characteristics and parameter comparisons are useful in charting all kinds of data and become indispensable as we proceed from kind A to kind C data. Illustrations included herein from molecular biology apply equally to all aspects of transdisciplinary science.

Chronomics reveal and quantify circadian rhythmic melatonin in duodenum of rats.

A circadian rhythm is documented in duodenal melatonin in rats, peaking 16.8 hours after light onset. This component is more readily detected after log10-transformation of the data. It differs between male and female rats, females having a larger circadian amplitude and an earlier acrophase. The circadian rhythm in duodenal melatonin is also found to lead that of pineal melatonin. The results are qualified by the presence at the start of mapping of the second extremum of a double magnetic storm.

Chronomics affirm extending scope of lead in phase of duodenal vs. pineal circadian melatonin rhythms.

In Göttingen, Germany, circadian variations in melatonin had been determined time-macroscopically in pineal glands, blood plasma and duodenum of chicken and rats. When these data were meta-analyzed, they agreed with the results from an independent survey on tissues from rats collected in a laboratory in Pécs, Hungary. In the latter study, tissues were analyzed chemically in Bratislava, Slovakia, and numerically in Minneapolis, MN, USA, all by single- and multiple-component cosinor and parameter tests. In rats and chickens, these inferential statistical procedures clearly demonstrated a lead in phase of the 24-h cosine curves best fitting all of the duodenal vs. those best fitting all of the pineal melatonin values in each species in 2 geographic (geomagnetic) locations. The 24-h cosine curve of circulating melatonin was found to be in an intermediate phase position. Mechanisms of the phase differences and the contribution of gastrointestinal melatonin to circulating hormone concentrations are discussed.

Chronomics, neuroendocrine feedsidewards and the recording and consulting of nowcasts--forecasts of geomagnetics.

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.

Multiple resonances among time structures, chronomes, around and in US. Is an about 1.3-year periodicity in solar wind built into the human cardiovascular chronome?

AIMS: Velocity changes in the solar wind, recorded by satellite (IMP8 and Wind) are characterized by a solar cycle dependent approximately 1.3-year component. The presence of any approximately 1.3-year component in human blood pressure (BP) and heart rate (HR) and in mortality from myocardial infarction (MI) is tested and its relative prominence compared to the 1.0-year variation. MATERIALS AND METHODS: Around the clock manual or automatic BP and HR measurements from four subjects recorded over 5 to 35 years and a 29-year record of mortality from MI in Minnesota were analyzed by linear-nonlinear rhythmometry. Point and 95% confidence interval (CI) estimates were obtained for the approximately 1.3-year period and amplitude. The latter is compared with the 1.0-year amplitude for BP and HR records concurrent to the solar data provided by one of us (JDR). RESULTS: An approximately 1.3-year component is resolved nonlinearly for MI, with a period of 1.23 (95% CI: 1.21; 1.26) year. This component was invariably validated with statistical significance for BP and HR by linear rhythmometry. Nonlinearly, the 95% CI for the 1.3-year amplitude did not overlap zero in 11 of the 12 BP and HR series. Given the usually strong synchronizing role of light and temperature, it is surprising that 5 of the 12 cardiovascular series had a numerically larger amplitude of the 1.3-year versus the precise 1.0-year component. The beating of the approximately 1.3-year and 1.0-year components was shown by gliding spectra on actual and simulated data. DISCUSSION AND CONCLUSION: The shortest 5-year record (1998-2003) revealed an approximately 1.3-year component closer to the solar wind speed period characterizing the entire available record (1994-2003) than that for the concurrent 5-year span. Physiological variables may resonate with non-photic environmental cycles that may have entered the genetic code during evolution.

Chronomics.

Several international meetings have revealed an accumulating body of reference values for well-established about-daily and about-yearly rhythms of photic origin and evidence also for about-7-day, -27-day, -half-yearly, -10.5- and -21-yearly, and even -50-yearly rhythmicities in us as well as around us, as invisible non-photic heliogeophysical signatures possibly built into individuals and/or populations, complementing the biological year and day. In time series (biological or other) that are dense and sufficiently long, the characteristics of rhythms, chaos (deterministic and other) and trends can all be quantified as elements of structures called chronomes. Chronobiological methodology assesses uncertainties in comparisons of endpoints in all elements of chronomes, before and after: 1) changes in lifestyle, such as meal quality, quantity, timing and salting of the food; 2) preventive non-drug interventions to limit the risk of vascular disease; or 3) drug treatments for high-risk subjects as well as for those with actual vascular disease, all on a practicable, individualized and also a general population basis. A collateral hierarchy characterizes molecular to psychosocial aspects of living beings that are exposed to their socio-ecological environs and thus are synchronizable and/or otherwise manipulable by society, meals, lighting, heating, and non-photic, non-thermic environmental variations that become predictable to the extent that they appear to constitute cycles, yet adhere only to a statistical, rather than a deterministic causality. With this qualification, chronome mapping with outcomes could eventually serve an individualized optimization of lifestyle, for chronoprevention and chronotherapy as well as for inquiries into the evolution and future of life, a budding chronoastrobiology, in keeping with the original title of the conference.

Feedsidewards: intermodulation (strictly) among time structures, chronomes, in and around us, and cosmo-vasculo-neuroimmunity. About ten-yearly changes: what Galileo missed and Schwabe found.

The spectrum of biological rhythms is extended far beyond circadians, circannuals, and ultradians, such as 1.5-hourly melatonin and 8-hourly endothelin-1 (ET-1) rhythms by statistics of natality, growth, morbidity, and mortality, some covering decades or centuries on millions of individuals. These reveal infradian cycles to be aligned with half-weekly rhythms in ET-1, weekly and half-yearly ones in melatonin, and even longer--about 50-, about 20-, and about 10-year cycles found in birth statistics. About daily, weekly, yearly, and ten-yearly patterns are also found in mortality from myocardial infarctions; the 10-yearly ones are also in heart rate and its variability; in steroid excretion, an aspect of resistance, for example, to bacteria; and in the genetic changes of the bacteria themselves. Automatic physiological measurements cover years and, in one case, cover a decade; the latter reveal an about 10-year (circadecennial) cycle. ECGs, covering months beat-to-beat, reveal circaseptans, gaining prominence in response to magnetic storms or after coronary artery bypass grafting. A spectrum including cycles from fractions of 1 Hz to circasemicentennians is just one element in biological time structures, chronomes. Chaos, trends, and any unresolved variability are the second to fourth elements of chronomes. Intermodulations, feedsidewards, account for rhythmically and thus predictably recurring quantitive differences and even for opposite treatment effects of the same total dose(s) of (1) immunomodulators inhibiting or stimulating DNA labeling of bone in health or speeding up versus slowing down a malignant growth and thus shortening or lengthening survival time, or (2) raising or lowering blood pressure or heart rate in the vascular aspect of the body's defense. Latitude-dependent competing photic and nonphotic solar effects upon the pineal are gauged by alternating yearly (by daylight) and half-yearly (by night) signatures of circulating melatonin at middle latitudes and by half-yearly signatures at noon near the pole. These many (including novel near 10-yearly) changes, for example, in 17-ketosteroid excretion, heart rate, heart rate variability, and myocardial infarction in us and those galactic, solar, and geophysical ones around us have their own special signatures and contribute to a cosmo-vasculo-immunity and, if that fails, to a cosmo(immuno?) pathology.

Electrocardiogram of the humpback whale (Megaptera novaeangliae), with specific reference to atrioventricular transmission and ventricular excitation.

OBJECTIVES: The objective of the study was to record the electrocardiogram (ECG) of a large whale to obtain crucial data for comparative electrophysiologic analysis. BACKGROUND: The data were needed to establish the mismatch between heart size and PR interval and QRS duration in mammals. METHODS: In the waters off the coast of Newfoundland, in two humpback whales (Megaptera novaeangliae) with an estimated weight of 30,000 kg a 1-lead ECG was recorded, enabling reliable assessment of P waves and QRS complexes. RESULTS: It was found that both the PR interval (atrioventricular [AV] transmission time) and QRS duration (ventricular excitation) are extremely short for animals of this size. These findings are difficult, if not impossible, to explain on the basis of currently accepted electrophysiologic theories. However, the narrow QRS complex may be due to a very dense His-Purkinje network in the ventricular wall of whales. Alternative mechanisms that can explain the function of the mammalian AV node need to be considered and explored. CONCLUSIONS: The results of the study may be of value for the understanding of the ECG in humans.