Season's appreciations.

To follow the tradition set by the late Franz Halberg, highlights of research performed over the last year from his Minnesota Center are summarized. They illustrate the broad international cooperation enjoyed by his center and the diversity of applications of the discipline he founded. The results briefly summarized herein in the form of an annotated bibliography are a testimony that his legacy continues to live on and constitutes a tribute to his memory.

27-day cycles in human mortality: Traute and Bernhard Düll.

This tribute to her parents by one co-author (NDP) is the fruit of a more than a decade-long search by the senior author (FH) for the details of the lives of Bernhard and Gertraud ("Traute") Düll. These pioneers studied how space/terrestrial weather may differentially influence human mortality from various causes, the 27-day mortality pattern being different whether death was from cardiac or respiratory disease, or from suicide. FH is the translator of personal information about her parents provided by NDP in German. Figuratively, he also attempts to "translate" the Dülls' contribution in the context of the literature that had appeared before their work and after their deaths. Although the Dülls published in a then leading journal, among others (and FH had re-analyzed some of their work in a medical journal), they were unknown to academies or libraries (where FH had inquired about them). The Dülls thoroughly assembled death certificates to offer the most powerful evidence for an effect of solar activity reflected in human mortality, as did others before them. They went several steps further than their predecessors, however. They were the first to show possibly differential effects of space and/or Earth weather with respect to suicide and other deaths associated with the nervous and sensory systems vs. death from cardiac or respiratory disease as well as overall death by differences in the phase of a common 27-day cycle characterizing these mortality patterns. Furthermore, Bernhard Düll developed tests of human visual and auditory reaction time to study effects of weather and solar activity, publishing a book (his professorial dissertation) on the topic. His unpublished finding of an increased incidence of airplane crashes in association with higher solar activity was validated after his death, among others, by Tatiana Zenchenko and A. M. Merzlyi.

Egeson's (George's) transtridecadal weather cycling and sunspots.

In the late 19th century, Charles Egeson, a map compiler at the Sydney Observatory, carried out some of the earliest research on climatic cycles, linking them to about 33-year cycles in solar activity, and predicted that a devastating drought would strike Australia at the turn of the 20th century. Eduard Brückner and William J. S. Lockyer, who, like Egeson, found similar cycles, with notable exceptions, are also, like the map compiler, mostly forgotten. But the transtridecadal cycles are important in human physiology, economics and other affairs and are particularly pertinent to ongoing discusions of climate change. Egeson's publication of daily weather reports preceded those officially recorded. Their publication led to clashes with his superiors and his personal life was marked by run-ins with the law and, possibly, an implied, but not proven, confinement in an insane asylum and premature death. We here track what little is known of Egeson's life and of his bucking of the conventional scientific wisdom of his time with tragic results.

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.

CHRONOMICS AND GENETICS.

The mapping of time structures, chronomes, constitutes an endeavor spawned by chronobiology: chronomics. This cartography in time shows signatures on the surface of the earth, cycles, also accumulating in life on the earth's surface. We append a glossary of these and other cycles, the names being coined in the light of approximate cycle length. These findings are transdisciplinary, in view of their broad representation and critical importance in the biosphere. Suggestions of mechanisms are derived from an analytical statistical documentation of characteristics with superposed epochs and superposed cycles and other "remove-and-replace" approaches. These approaches use the spontaneously changing presence or absence of an environmental, cyclic or other factor for the study of any corresponding changes in the biosphere. We illustrate the indispensability of the mapping of rhythm characteristics in broader structures, chronomes, along several or all available different time scales. We present results from a cooperative cartography of about 10, about 20, and about 50-year rhythms in the context of a broad endeavor concerned with the Biosphere and the Cosmos, the BIOCOS project. The participants in this project are our co-authors worldwide, beyond Brno and Minneapolis; the studies of human blood pressure and heart rate around the clock and along the week may provide the evidence for those influences that Mendel sought in meteorology and climatology.

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.

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 of circulating plasma lipid peroxides and anti-oxidant enzymes and other related molecules in cirrhosis of liver. In the memory of late Shri Chetan Singh.

BACKGROUND: The chronome (from chronos, time, and nomos, rule; time structure) of lipid peroxidation and anti-oxidant defense mechanisms may relate to the efficacy and management of preventive and curative chronotherapy. PATIENTS AND METHODS: Thirty patients with liver cirrhosis, 25-45 years of age, and 60 age-matched clinically healthy volunteers were synchronized for 1 week with diurnal activity from about 06:00 to about 22:00 and nocturnal rest. Breakfast was around 08:30, lunch around 13:30 and dinner around 20:30. Drugs known to affect the free-radical system were not taken. Blood samples were collected at 6-h intervals for 24 h under standardized, presumably 24-h synchronized conditions. Determinations included plasma lipid peroxides, in the form of malondialdehyde (MDA), blood superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR) activities, and serum total protein, albumin, ascorbic acid, and uric acid concentrations. RESULTS: A marked circadian variation was demonstrated for each variable in each group by population-mean cosinor (P < 0.01). In addition to anticipated differences in overall mean value (MESOR), patients differed from healthy volunteers also in terms of their circadian pattern. CONCLUSION: Mapping the broader time structure (chronome) with age and multifrequency rhythm characteristics of antioxidants and pro-oxidants is needed for exploring their putative role as markers in the treatment and management of liver cirrhosis.

Incidence of sudden cardiac death, myocardial infarction and far- and near-transyears.

We analyzed cycles with periods, tau, in the range of 0.8-2.0 years, characterizing, mostly during 1999-2003, the incidence of sudden cardiac death (SCD), according to the International Classification of Diseases, 10th revision (ICD10), code I46.1. In the tau range examined, only yearly components could be documented in time series from North Carolina, USA; Tbilisi, Georgia; and Hong Kong, in the latter two locations based on relatively short time series. By contrast, in Minnesota, USA, we found only a component with a longer than (= trans) yearly (transyearly) tau of 1.39 years; the 95% confidence interval (CI) of the tau extended from 1.17 to 1.61 years, falling into the category of transyears (defined as a tau and a 95% CI between 1.0 and 2.0 years, with the limits of the 95% CI of the spectral component's tau overlapping neither of these lengths). During the same span from 1999 to 2003 in Arkansas, USA, a component of about 1-year in length was present, and in addition, one with a tau of 1.69 year with a CI extending from 1.29 to 2.07 years, a far-transyear candidate, far-transyears being defined as having a tau with a CI between 1.20 and 2.0 year, with the CI overlapping neither of these lengths. In the Czech Republic, there was also a calendar-yearly tau and one of 1.76 years. In the latter two geographic/geomagnetic areas, the about-yearly and the longer cycles' amplitudes were of similar prominence. The taus are only candidate transyears; the 95% CIs of their taus overlap the 2-year length. When a series on SCD from 1994 to 2003 from the Czech Republic was analyzed, the 95% CI of the transyear's tau no longer overlapped the 2-year length. Transyears were also found in the Czech Republic for myocardial infarctions (MI), meeting the original transyear definition in both a shorter and a longer series. Moreover, in the 1994-2003 series on MI from the Czech Republic, a near-transyear was also found, meeting the definition of a period with a 95% CI overlapping neither precisely 1.0 year nor 1.2 years, along with a far-transyear, defined as a tau between 1.2 and 2.0 years, again with the 95% CI covering neither of these lengths. Herein, we discuss near- and far-transyears more generally in the light of their background in physics and the concept of reciprocal cyclicities.

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.

AMBULATORY BLOOD PRESSURE MONITORING: THE NEED OF 7-DAY RECORD.

The need for systematic around-the-clock self-measurements of blood pressure (BP) and heart rate (HR), or preferably for automatic monitoring as the need arises and can be met by inexpensive tools, is illustrated in two case reports. Miniaturized unobtrusive, as yet unavailable instrumentation for the automatic measurement of BP and HR should be a high priority for both government and industry. Automatic ambulatorily functioning monitors already represent great progress, enabling us to introduce the concept of eventually continuous or, as yet, intermittent home ABPM. On BP and HR records, gliding spectra aligned with global spectra visualize the changing dynamics involved in health and disease, and can be part of an eventually automated system of therapy adjusted to the ever-present variability of BP. In the interim, with tools already available, chronomics on self- or automatic measurements can be considered, with analyses provided by the Halberg Chronobiology Center, as an alternative to "flying blind", as an editor put it. Chronomics assessing variability has to be considered.

UNTREATED TRANSIENT LONGER THAN 7-DAY CHAT, CIRCADIAN HYPER-AMPLITUDE TENSION, IN A 7-YEAR PERSPECTIVE.

The case report presented herein aims at promoting the awareness in medical, notably cardiological, practice of the importance of, first, collecting at least a week-long record of around-the-clock measurements of blood pressure (BP) and heart rate (HR) (and a much longer record if the 7 day record so indicates) and, second, of analysing the data chronobiologically in the light of reference values specified as a function of time, gender and age as a minimum. In addition to diagnosing deviations in a chronome (time structure)-adjusted mean value, a chronobiological approach identifies abnormalities in the variability of BP and/or HR, gauged by the circadian characteristics (double amplitude and acrophase, measures of the extent and timing of predictable change within a cycle) and by the standard deviation. A woman in presumably good health was 60 years of age at the start of intermittent monitoring over a 7 year span. The case report illustrates the extent to which a decision based on single BP readings and even on 24 hour averages may be misleading. Treatment based on an initial week-long monitoring may benefit from continued long-term monitoring.

Circadian periodicity of plasma lipid peroxides and other anti-oxidants as putative markers in gynecological malignancies.

BACKGROUND: The chronome (from chronos, time, and nomos, rule), or time structure, of lipid peroxidation and anti-oxidant defense mechanisms may relate to prevention and curative chronochemotherapeutic efficacy and management. PATIENTS AND METHODS: Newly diagnosed women with gynecological malignancies (N = 30), 30-60 years of age, and age-matched clinically healthy women (N = 35) provided blood samples every 6 hours for 24 hours under standardized conditions. Plasma malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR) activities, and serum ascorbate, urate and high-density lipoprotein cholesterol (HDL-C) concentrations were determined. RESULTS: Each variable underwent circadian variation (p < or = 0.002). Patients differed from controls by their overall chronome-adjusted mean value (MESOR) and by the circadian dynamics in the spectral element of their chronome. CONCLUSION: Chronomes of putative anti- and pro-oxidants should be mapped to explore their putative chemotherapeutic role as markers in cancer chronoprevention and management of established disease.

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.

Alternating light-darkness-influenced human electrocardiographic magnetoreception in association with geomagnetic pulsations.

Geomagnetic variations of partly interplanetary origin, with cyclic signatures in human affairs and pathology include the incidence of various diseases, regarding which this study of healthy subjects attempted to determine an underlying mechanism by worldwide archival and physiological monitoring, notably of heart rate variability (HRV). In the past half-century, the possible health and other hazards of natural, solar variability-driven temporal variations in the earth's magnetic field have become a controversial subject in view of the inconsistent results. Some well-documented claims of associations between geomagnetic storms and myocardial infarction or stroke have been rejected by a study based on more comprehensive data analyzed by rigorous methods - covering, however, only part of a solar cycle in only part of a hemisphere. It seems possible that inter-solar cycle and geographic variability, if not geographic differences, may account for discrepancies. Herein, we examine the start of a planetary study on any influence of geomagnetic disturbances that are most pronounced in the auroral oval, on human HRV. The magnetic field variations exhibit complex spectra and include the frequency band between 0.001-10 Hz, which is regarded as ultra-low frequency by physicists. Since the 'ultra-low-frequency' range, like other endpoints used in cardiology, refers to much higher frequencies than the about-yearly changes that are here shown to play a role in environmental-organismic interactions revealed by HRV, the current designations used in cardiology are all placed in quotation marks to indicate the need for possible revision. Whether or not this suggestion has an immediate response, we have pointed to a need for the development of instrumentation and software that renders the assessment of circadian, infradian and even infra-annual (truly low frequency) modulations routinely feasible. HRV was examined on the basis of nearly continuous 7-day records by ECG between December 10, 1998, and November 2, 2000, on 19 clinically healthy subjects, 21 to 54 years of age, in Alta, Norway. A geomagnetic record was obtained from the Auroral Observatory of the University of Tromsø. First, frequency-domain measures of HRV were compared for each person in 24-hour spans of high geomagnetic disturbance versus quiet conditions. Second, cross-spectra between geomagnetic activity and HRV measures were quantified via the squared coherence spectrum using 7-day time series. A 7.5% increase in the 24-hour average of heart rate, HR (P = 0.00020) and a decrease in HRV were documented on days of high geomagnetic disturbance. The decrease in HRV was validated statistically for the 'total frequency', 'TF' endpoint (18.6% decrease, P= 0.00009). The decrease in spectral power was found primarily in the 'circaminutan frequency', 'VLF' (21.9% decrease, P< 0.000001) in conjunction with the 'minutes-to-hours' component, ultra-low-frequency, 'ULF' (15.5% decrease, P= 0.00865) and circadecasecundan 'low frequency', 'LF' (14.2% decrease, P = 0.00187) regions of the spectrum. Power-law scaling of the power spectra did not show any statistically significant difference. It is noteworthy that most of the decrease in HRV, except for the circaminutan (VLF) component, was observed only in the season in which sunshine alternated with darkness (D/L), a finding suggesting a mechanism influenced by the alternation of light and darkness. The hypothesis of a light-dark-influenced magnetoreception was also supported by cross-spectral analysis. Group-averaged coherence at frequencies coincident with the geomagnetic Pc 6 pulsations (with periods ranging from 10 minutes to 5 hours) differed with a statistical significance (P < 0.000001) among the three natural lighting conditions, the association being weaker during UL or D/D than during D/L. By contrast, no statistically significant differences were found in terms of the circadian and circasemidian frequencies in relation to the alternation of sunshine with darkness or rather circannual rhythm stage. In conclusion, evidence is provided herein that an alteration of HRV is most apparent in the circaminutan ('VLF') region, which is clinically important, because a reduction in its power is a predictor of morbidity and mortality from cardiovascular disease. The circadecasecundan ('LF') component of HRV also decreased in association with geomagnetic disturbance, which may reflect an episodic alteration of arterial pressure related to changes in geomagnetic activity. Lastly, our study suggests the existence of a light-dark-influenced magnetoreception mechanism in humans involving mainly the Pc 6 band of the magnetic field.