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While certain circadian hormonal changes are prominent, their predictable assessment requires a standardization of conditions of sampling. The 24-hour rhythm in circulating corticosterone of rodents, known since the 1950s, was studied as a presumed proxy for stress on 108 rats divided into 9 groups of 6 male and 9 groups of 6 female animals sampled every 4 hours for 24 hours. In a first stress study, the "no-rhythm" (zero-amplitude) assumption failed to be rejected at the 5% probability level in the two control groups and in 16 out of the 18 groups considered. A circadian rhythm could be detected with statistical significance, however, in three separate follow-up studies in the same laboratory, each on 168 rats kept on two antiphasic lighting regimens, with 4-hourly sampling for 7 or 14 days. In the first stress study, pooling of certain groups helped the detection and assessment of the circadian corticosterone rhythm. Without extrapolating to hormones other than corticosterone, which may shift more slowly or adjust differently and in response to different synchronizers, the three follow-up studies yielded uncertainty measures (95% confidence intervals) for the point estimate of its circadian period, of possible use in any future study as a reference standard. The happenstance of a magnetic disturbance at the start of two follow-up studies was associated with the detection of a circasemiseptan component, raising the question whether a geomagnetic disturbance could be considered as a "load". Far beyond the limitations of sample size, the methodological requirements for standardization in the experimental laboratory concerning designs of studies are considered in the context of models of depression. Lessons from nature's unforeseen geomagnetic contribution and from human studies are noted, all to support the advocacy, in the study of loads, of sampling schedules covering more than 24 hours.

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.

Time structurally (chronomically) interpreted half-hourly monitoring of blood pressure (BP) and heart rate (HR) for at least 7 days and preferably for 17 days is recommended, separately for a diagnosis of BP disorders and when necessary again for the same or longer spans for treatment, whenever a positive diagnosis of a disorder is made. In this study, 30 clinically healthy subjects underwent 7-day monitoring and provided a series of findings, including the detection of Circadian Hyper-Amplitude-Tension (CHAT), that is blood pressure overswinging, which carries a high risk of hard cardiovascular events. The results specifically bear upon south-east Asian-Indian immigrants. They show that cardiovascular disease risk increases with age, with a positive family history of hypertension and/or other cardiovascular diseases and even with the duration of stay in the USA. A relation to body mass index is also shown. Such monitoring for prehabilitation may eventually reduce the need for rehabilitation.

The effect of aging on blood pressure (BP) and heart rate (HR) was investigated in a cross-sectional study in the high-altitude community of Leh, Ladakh (altitude: 3524 m) and a Japanese community in U town, Hokkaido (altitude: 25 m). BP and HR were obtained in a sitting position from 332 subjects 13-81 years of age in Ladakh, and from 216 Japanese citizens, 24-79 years of age. Measurements were taken after a 2-min rest, using a semi-automated BP device (UA-767 PC, A and D Co. LTD, Tokyo). High-altitude people showed higher diastolic BP and HR values than lowland people (83.2 vs. 76.9 mmHg and 78.6 vs. 69.2 bpm, P < 0.001), but no difference in systolic BP. Highland people also showed a steeper BP increase with age than the lowland people (systolic BP: 0.7476 vs. 0.3179 mmHg/year, P < 0.0005; diastolic BP: 0.3196 vs. 0.0750 mmHg/year, P < 0.001). This chronoecologic investigation in Ladakh examined the circulation as a physiological system at high-altitude. Our data indicate the need for a more comprehensive cardiovascular assessment for a better diagnosis and a more fruitful treatment. Longitudinal observations of effects of socio-ecologic factors on the cardiovascular system should help prevent strokes and other cardiovascular events, especially at high altitude.

The predictive value of blood pressure (BP), heart rate (HR), and catecholamines in terms of any subsequent development of cardiovascular disease was investigated. Systolic (S) and diastolic (D) BP, HR, epinephrine (E) and norepinephrine (NE) were measured three times a year in 1980, 1984, and 1989 on 20 clinically healthy subjects, 18 patients with ‘essential hypertension’, and 22 patients with angina pectoris. Of the 22 patients in the latter group, 15 died during a 2-year follow-up (1990–1991). Each individual data series was analyzed by single cosinor to assess the circannual variation. Results were summarized by population-mean cosinor for each group. Parameter tests were used to compare the circannual rhythm characteristics among the different patient groups. A circannual rhythm was invariably demonstrated on a group basis (P < 0.05). Differences in MESOR and/or circannual amplitude were found among the different groups. In particular, patients with angina pectoris who will die within the 2-year follow-up differ in terms of their E and NE from all other patient groups, a difference already detected at the beginning of the study, more than 10 years before they die. A similar separation is not achieved in terms of BP or HR.

We examine whether autism may be influenced by non-photic environmental factors, among others, in a California database consisting of the number of cases added quarterly to the system between 1993 and 2004. Instead of a precise calendar (1.0)-year-long spectral component, we detect unseen primarily helio- and geomagnetic signatures, including a newly discovered near-transyear of 1.09-year length. In this case, it overrides any undetected seasonal effects, the topic of much previous unrewarding research, also analyzed herein without overcoming the limitation by stacking. Since we could not get additional data on autism, data on suicides, the final "detachment" and failure to bond, were also analyzed, again revealing a spectrum of non-photic signatures. What we do not see and do not anticipate can exist and can override the seasons, as resolved time-microscopically by chronomics, the study of chronomes (time structures). Just as spatial microscopy and electron microscopy resolved infectious agents, so does microscopy in time resolve the signature of environmental agents in human behavior in health and disease.

Several cohort studies have examined the association of carotid intima-media thickness (IMT) with the risk of stroke or myocardial infarction in apparently healthy persons. We investigated the predictive value of IMT of cardiovascular mortality in elderly community-dwelling people, beyond the prediction provided by age and MMSE. assessed by means of a multivariate Cox model. Carotid IMT and plaque were evaluated bilaterally with ultrasonography in 298 people older than 75 years ( 120 men and 178 women, average age: 79.6 years). The LILAC study started on July 25, 2000. Consultations were repeated every year. The follow-up ended on November 30, 2004. During the mean follow-up span of 1152 days, 30 subjects (21 men and nine women) died. Nine deaths were attributable to cardiovascular causes Imyocardial infarction: two men and three women; stroke: two men and two women). The age- and MMSE-adjusted relative risk (RR) and 95% confidence interval (95% CI) of developing all-cause mortality was assessed. A 0.3 mm increase in left IMT was associated with a RR of predicted 1.647 (1.075-2.524), and a similar increase in right IMT with a RR of 3.327 (1.429-7.746). For cardiovascular mortality, the corresponding RR values were 2.351 (1.029-5.372) and 2.890 (1.059-7.891), respectively. Carotid IMT assessed by ultrasonography is positively associated with an increased risk of all-cause and cardiovascular death in elderly community-dwelling people.

Objectives. To investigate whether Schumann resonance (SR) affects blood pressure (BP), heart rate (HR), and depression and, if so, whether the putative BP reactivity to SR (BPR-SR) is associated with health-related lifestyle (HLS), disease-related illnesses (DRI), and depression. Methods. A sample of 56 adults in Urausu, Hokkaido, Japan, wore an ambulatory BP monitor, except for the time in the shower, for seven consecutive days. They completed the Geriatric Depression Scale-Short Form and a health survey questionnaire on HLS and DRI. Group mean differences and within-individual differences in systolic (S) and diastolic (D) BP, mean arterial pressure (MAP), double product (DP), and HR were, respectively, compared between normal and enhanced SR days, using Student's t-test. Correlations between BPR-SR and other characteristics (i.e. age, gender, HLS, DRI, subjective health, and depression) were analyzed, using Pearson's product moment correlation. Results and discussion. Group mean SBP, DBP, MAP, and DP for enhanced SR days were lower than those for normal days (P=0.005–0.036). DRI was negatively associated with BPR-SR in SBP, DBP, MAP, and DP (P=0.003–0.024), suggesting a better health status for those who showed lower BP on enhanced SR days. HLS was negatively associated with BPR-SR in DBP and MAP (P=0.016–0.029). Males showed higher BPR-SR in DBP and MAP than females (P=0.004–0.016). Neither subjective health nor depression was significantly associated with BPR-SR. Future studies based on larger sample sizes are planned to see whether possible health effects can be generalized.

We investigated the predictive value of arterial stiffness to assess cardiovascular risk in elderly community-dwelling people by means of a multivariate Cox model. In 298 people older than 75 years (120 men and 178 women, average age: 79.6 years), brachial-ankle pulse wave velocity (baPWV) was measured between the right arm and ankle in a supine position. The LILAC study started on July 25, 2000, consultation was repeated yearly, and the last follow-up ended on November 30, 2004. During this follow-up span of 1227 days, there were nine cardiovascular deaths, the cause of death being myocardial infarction for two men and three women or stroke for two men and two women. In Cox proportional hazard models, baPWV as well as age, Mini-Mental State Examination (MMSE), Hasegawa Dementia Scale Revised (HDSR) and the low-frequency/high-frequency (LF/HF) ratio showed a statistically significant association with the occurrence of cardiovascular death. A two-point increase in MMSE and HDSR score significantly protected against cardiovascular death, the relative risk (RR) being 0.776 (P = 0.0369) and 0.753 (P = 0.0029), respectively. The LF/HF ratio also was significant (P = 0.025), but the other indices of HRV were not. After adjustment for age and HDSR, a 200 cm/s increase in baPWV was associated with a 30.2% increase in risk (RR = 1.302, 95% CI: 1.110-1.525), and a 500 cm/s increase in baPWV with a 93.3% increase in risk (RR = 1.933, 95% CI: 1.300-2.874, P = 0.0011), whereas the LF/HF ratio was no longer associated with a statistically significant increase in cardiovascular mortality. In elderly community-dwelling people, arterial stiffness measured by means of baPWV predicted the occurrence of cardiovascular death beyond the prediction provided by age, gender, blood pressure and cognitive functions, baPWV should be added to the cardiovascular assessment in various clinical settings, including field medical surveys and preventive screening. The early detection of risk by chronomics allows the timely institution of prophylactic measures, thereby shifting the focus from rehabilitation to prehabilitation medicine, as a public service to several Japanese towns.

Depression, which is a risk factor for cardiac morbidity and mortality, is not an unusual occurrence among individuals with coronary heart disease (CHD), but evidence concerning its role in the pathogenesis of this condition is less clear. Ambulatory blood pressure monitoring (ABPM) has become an important tool in the diagnosis and management of hypertension. Several previous studies have indicated that various kinds of target organ damage and cardiovascular morbidity are more strongly associated with a diagnosis by ABPM than through spot-checks in a clinical setting. This study investigated whether depressive mood was associated with changes in the about-weekly (circaseptan) and half-weekly (circasemiseptan) variations in blood pressure (BP) and heart rate (HR), including a BP surge on Mondays, in community-dwelling subjects monitored chronomically for the time structure (chronome) of their BP and HR variabilities. From April 2001 to April 2003, 217 subjects (85 men and 132 women; mean age: 56.8 +/- 11.3 yr) from U town, Hokkaido (latitude: 43.45 degrees N, longitude: 141.85 degrees E), self-monitored their BP and HR for 7 days starting around 11 a.m. on Thursday, and took readings at 30-minute intervals between 7 a.m. and 10 p.m., then at 60-minute intervals between 10 p.m. and 7 a.m. The data were retrieved and analyzed on a PC with appropriate commercial software (TM-2430-15; AD Co., Japan). Subjects were asked about 15 items on a depression rating scale through a self-administered questionnaire. When the score amounted to 5 or higher, subjects were considered to be depressive. Student's t-test, a one-way analysis of variance (ANOVA), and cosinor methods with parametric tests were also used. A p-value below 0.05 was considered to indicate statistical significance (below 0.10: borderline statistical significance). Depression rating scales were obtained for 192 out of the 217 subjects enrolled in this study. Depression scores were () 5 in 72 subjects. The average values of systolic (S) and diastolic (D) BP were statistically significantly higher in depressed subjects (SBP: 129.2 vs 124.5 mmHg; p = 0.034; DBP: 79.0 vs 76.5 mmHg; p = 0.041). The 7-day average for HR did not differ between subjects with depression scores of5 or5. DBP dipping was less in the depressed subjects (16.30 vs 18.22%; p = 0.048). The dipping ratios of SBP and HR showed no statistically significant difference. In the group with depression scores of5, HR variability (estimated by the SD of HR and HR dip) was higher during vacations and lower on Mondays. The 24-h BP measures showed a novelty effect and a surge on Mondays. In the depressed group, a prominent circaseptan rhythm appeared to replace the novelty effect, vacation dip, and Monday surge. The results of this investigation indicate the clinical importance of the monitoring of depressed subjects. Fewer than 7 days of monitoring means a greater risk of false diagnosis, and thus a therapeutic decision including potentially unnecessary or inappropriate long-term treatment. Records shorter than 7 days would not have detected circaseptan BP dysrhythmia associated with a depressive state. Prominent circaseptans can provide new indications on the mechanisms underlying the strong relation between depression and adverse cardiac events. Future studies should aim at determining whether the treatment of depression, especially from the standpoint of a chronodiagnosis and chronotherapy, can reduce the incidence of adverse cardiac events, and whether this depends upon restoring normal BP and HR variability, i.e. anormal BP and HR chronome.

Renal excretion in experimental hypertensive rats implanted with encapsulated human atrial natriuretic peptide (hANP)-producing cells is circadian periodic. Chinese hamster ovary (CHO) cells transfected with the plasmid hANP-cDNA were encapsulated in biocompatible polycaprolactone capsules for intraperitoneal implantation into two-kidney, one-clip (2K1C) hypertensive rats. During a 12:12 light-dark cycle, as compared to control CHO cells, the implantation of encapsulated hANP-producing CHO cells was associated with an increase in the net excretion of water, sodium and potassium, and with a reversal of the advanced circadian phases related to renovascular hypertension in 2K1C rats. The increase in blood pressure postimplantation was delayed, and increases in renal blood flow, glomerular filtration rate, sodium output, urinary excretion and urinary cyclic GMP concentrations were also found. Implantation of encapsulated hANP-producing cells affects circadian rhythms in kidney excretion functions of 2K1C rats, and may be useful for the treatment of cardiovascular disease.

It is becoming recognized that geomagnetic activity may influence biological processes, including the incidence of various human diseases. There is evidence that heart rate variability (HRV) may serve not only as an index of autonomic coordination of the circulation, but also as a powerful predictor of risk in apparently healthy subjects. This study focuses on the effects of geomagnetic disturbance on HRV, by comparing different indices of HRV of young, healthy men living in a subarctic area on days of low (Ap; 0-7), middle (Ap; 7-20), and high (Ap; 20-45) geomagnetic activity. The effect of geomagnetic disturbance on HRV is examined on the basis of 7-day records by Holter ECG, obtained longitudinally on 5 clinically healthy men, 21-31 years of age, in Alta, Norway (70 degree N). Frequency- and time-domain measures of HRV were analyzed for each subject on separate 24-hour spans. A graded alteration of HRV endpoints was found in association with increased geomagnetic activity. As time-domain measures of HRV, SDNNIDX and the 90% length of the Lorenz plot decreased statistically significantly on days with increased geomagnetic disturbance (p = 0.0144 and p = 0.0102, respectively). A graded decrease in frequency-domain HRV measures was also validated statistically for the total spectral power (decrease of 18.1% and 31.6% on days when 7 < Ap < 20 and 20 < Ap < 45 versus days when Ap < 7; p = 0.0013). The decrease in spectral power was mainly found at frequencies below 0.04 Hz, in the "ultra-low-frequency" (0.0001-0.003 Hz; 18.1% and 27.5% decrease, respectively; p = 0.0102) and "very-low-frequency" (0.003-0.04 Hz; 12.9% and 28.6% decrease, respectively; p = 0.0209) regions of the spectrum. The decrease in spectral power was much less pronounced around 10.5 sec ("low frequency"; N.S.) and around 3.6 sec ("high frequency"; N.S.). Evidence is provided here that HRV decreases on magnetically disturbed days, and that it does so in a dose-dependent fashion, HRV being depressed more on days when 20 < Ap < 45 than on days when 7 < Ap < 20, by comparison with days when Ap < 7. This graded response of HRV to geomagnetic activity should encourage us to search for human magnetoreceptors and for a better understanding of putative mechanisms of magnetoreception.

Population studies show the direct benefit from self-measurement for guiding the treatment of patients with severe hypertension; they also separate groups of children with a positive vs. negative family history of high blood pressure, despite the difficulty of obtaining valid readings during the rest/sleep span, which are needed for a reliable estimation of the circadian parameters. From the viewpoint of preventive maintenance, a 67-year-old woman monitored her blood pressure and heart rate around the clock for 7 days, using concomitantly an ambulatory monitor and a manual instrument. Self-measurement profiles were repeated on several occasions. The results are compared with those of a 62-year-old woman who followed the same initial 7-day protocol. The estimation of the circadian blood pressure pattern differed between the profiles obtained with an ambulatory monitor and by self-measurement. The differences, relatively small in one subject, were much larger for the other subject. Provided the results are chronobiologically analyzed and interpreted in the light of reference limits which are specific to self-measurement series as well as for gender, age and times of sampling, systematic self-measurement of blood pressure may yield a reliable assessment of the circadian variation for some, but not for all, individuals. For those who have been validated in at least one 7-day/24-h profile, occasional automatic ambulatory profiles are tentatively recommended as the main approach, with complementary systematic self-measurement when automatic instruments are scarce. For those with discrepant results, automatic monitoring is invariably recommended.

To study the interactions among the natural physical environmental cycles and human infradian components of heart rate (HR) and HR variability (HRV), a healthy 49-year-old man in Kiev, who had monitored his electrocardiogram (ECG) around the clock earlier for 50 days, added at a later date with the same ambulatorily wearable device, a record of 70 days. The mean value of the R-R intervals (R-R), their standard deviation (SDNN) and other HRV endpoints, computed over consecutive 5-min intervals, served as markers of the subject's functional associations with the amplitude of fluctuations in atmospheric pressure (FAP) and the planetary Kp index of geomagnetic disturbance. About-weekly and half-weekly cycles in HRV endpoints indicate a reduction in physiological 'preparedness', here described as 'dynamics', of the subject investigated on Saturdays and Sundays and a sharp increase in 'dynamics' on Mondays. The waveform of the weekly oscillation seemed to be influenced by ambient air temperature and FAP. On Mondays, an FAP amplification or a temperature rise was accompanied by a significant decrease in R-R and SDNN, indicating an aggravation of a 'Monday effect' in physiological 'dynamics'. HRV endpoints also revealed about-5-day and about-12-day cyclic components similar to those found in FAP. The infradian pattern in a 70-day record differed from one found earlier in a 50-day record of the same subject. Changes in the natural physical environment (past as well as present), especially in air temperature and FAP, likely influence(d) if not synchronize(d) the amplitude and waveform of infradian weekly and half-weekly physiological cycles. Some of these infradians, their wobbly nature notwithstanding, may have been built into our temporal make-up by an evolutionary integration of life in the non-stationary quasi-periodic natural physical environment, which continues to contribute to variability.

Background. Physical environmental variables, such as the natural variation in the geomagnetic field in and around the earth, influence biological processes and human health. The effect of geomagnetic disturbances on heart rate variability (HRV) in healthy students in a subarctic area is studied herein. Subjects and methods. Seven-day records by Holter ECG were obtained from eight clinically healthy subjects in Alta, Norway (70 N). Frequency- and time-domain measures of HRV were compared between 24-hour spans of high geomagnetic disturbance versus quiet conditions. Results. A 5.9% increase in the 24-hour average of HR (P = 0.020) and a 25.2% decrease in HRV (P = 0.002) were documented on days of high geomagnetic disturbance. The decrease in spectral power was found primarily at frequencies lower than 0.04 Hz and was not statistically significant around 3.6 sec. Conclusions. The physiological mechanism involved may be other than the parasympathetic, usually identified with spectral power centered around 3.6 sec, a spectral region wherein no statistically significant differences were found.

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 Tromso. 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.

The long-acting calcium antagonist nifedipine reduces the incidence of stroke in Eastern Asia, as shown by the Shanghai Trial Of Nifedipine in the Elderly (STONE) and the Systolic Hypertension in China (Syst-China) trials. Recent trials in Japan have shown that benidipine may be more efficient than the former drug in preventing strokes in the elderly. Benidipine, commonly prescribed in Japan for a definite depressor effect, reportedly without causing remarkable fluctuations in blood pressure (BP), is investigated herein from a chronobiological viewpoint. Eighteen subjects (nine women and nine men, 39 to 87 years of age) with essential hypertension (office and ambulatory systolic, S/diastolic, D BP values above 160/95 mm Hg and 130/80 mm Hg, respectively) were enrolled in this investigation. Ambulatory BP was monitored at 30-min intervals for at least 24 h (ABPM-630, Colin Medical) before and after 4 weeks of crossover treatment with nifedipine tablets (twice daily, 20 mg/d) and benidipine (once daily, 4 mg/d, in the morning). The results indicate that: 1) benidipine and nifedipine reduce 24-h daytime (10:00-20:00) and nighttime (00:00-06:00) averages of SBP and DBP (P0.001); 2) the circadian double amplitude of BP is decreased after treatment with benidipine (from 28.6 to 21.1 mm Hg SBP and from 19.7 to 15.2 mm Hg DBP; P0.05), while the day-night difference in SBP is increased after treatment with nifedipine (18.6 vs 27.9 mm Hg, P0.01); and 3) the increase in the day-night difference of heart rate (HR) is significant after treatment with benidipine (13.6 vs 18.8 beats per minute, bpm; P0.05), but not with nifedipine. We have previously evaluated the usefulness of the circadian amplitude of BP as a prognostic tool of cardiovascular outcome, and found that an excessive circadian SBP or DBP amplitude was associated with an increased risk of vascular disease. The fact that benidipine reduces the circadian BP amplitude may be one reason for the superiority of this treatment over nifedipine in preventing an adverse outcome. A reduced heart rate variability (HRV) also predicts adverse cardiovascular outcomes in patients with overt cardiovascular disease and in hypertensive subjects. The fact that benidipine increases the day-night difference in HR may be another reason for the positive effects of this treatment.

About 7-day (circaseptan) components, found at different levels of organization, notably in relation to growth, regeneration, repair and development, are often viewed as reflecting no more than the 7-day societal schedule, ample evidence for a built-in feature notwithstanding. Herein, we resolve circaseptans in geomagnetic pulsations recorded by a stand-alone magnetometer residing in Antarctica, far away from societal influences. Human physiological data, collected in the neonatal intensive care unit, show by intra-class correlation analysis that the nonlinearly assessed circaseptan period of heart rate, diastolic blood pressure and body weight is more similar between same-gender twins than among twin pairs, lending additional support for the endogenicity of circaseptans. Like circadians, about-weekly features in environmental variables such as geomagnetic pulsations were genetically acquired in the course of evolution.

Factors other than light may affect variations in melatonin, including disturbances in the geomagnetic field. Such a possibility was tested in Alta, Norway, located at latitude 70 degrees N, where the aurora borealis is a result of large changes in the horizontal component (H) of the geomagnetic field. Geomagnetic disturbances are felt more strongly closer to the pole than at lower latitudes. Also noteworthy in Alta is the fact that the sun does not rise above the horizon for several weeks during the winter. To examine whether changes in geomagnetic activity influence the secretion of melatonin, saliva was collected from 25 healthy subjects in Alta several times during the day-night and at different times of the year. Single cosinor analyses yielded individual estimates of.the circadian amplitude and MESOR of melatonin. A 3-hour mean value for the local geomagnetic activity index, K, was used for approximately the same 24-hour span. A circadian rhythm was found to characterize both melatonin and K, the peak in K (23:24) preceding that of melatonin (06:08). During the span of investigation, a circannual variation also characterized both variables. Correlation analyses suggest that changes in geomagnetic activity had to be of a certain magnitude to affect the circadian amplitude of melatonin. If large enough (> 80 nT/3 h), changes in geomagnetic activity also significantly decreased salivary melatonin concentration.

The aim of this study was to assess any variation in positive, negative and total affect recorded longitudinally; to compare the results with those from prior transverse or hybrid population studies, based on the same or a different method of mood rating; and to test for any association of mood with cardiovascular, hormonal and geophysical variables monitored concomitantly. The study approach was as follows. A clinically healthy 34-year-old man filled out the positive and negative affective scale (PANAS) questionnaire five times a day for 86 days. Systolic (S) and diastolic (D) blood pressure (BP) and heart rate (HR) were also measured automatically at 30-minute intervals with an ambulatory monitor from May 19 to June 29, 2000, while different endpoints of heart rate variability (HRV) were also determined at 5-minute intervals from beat-to-beat electrocardiogram (ECG) monitoring for 42 days between May 3 and June 14, 2000, with only short interruptions while the subject took a shower and changed ECG tapes. Saliva samples were collected at the times of mood ratings for one month for later determination of melatonin and cortisol concentrations. Intervals of 24 hours of the record of each variable displaced in increments of 24 hours were analyzed by chronobiologic serial section at a trial period of 24 hours to assess the circadian characteristics as they changed from one day to another. Estimates of the midline-estimating statistic of rhythm (MESOR) and circadian amplitude and acrophase obtained on consecutive days were correlated among variables to assess any associations. The findings were as follows. Overall, a circadian rhythm was demonstrated for all variables. A positive association was noteworthy between the circadian amplitude of negative affect and the MESOR of both SBP (r= 0.363; P= 0.029) and DBP (r= 0.389; P= 0.019), suggesting that BP is raised in the presence of large swings in negative affect. Needing further validation was a weak association between the MESOR of negative affect and the circadian amplitude of SBP (r= - 0.272; P = 0.108), suggesting a lowering of the circadian SBP amplitude in the presence of a strong negative affect. Of further interest was the lack of a statistically significant relation between positive and negative affect, not only in terms of the MESOR but also in terms of the circadian amplitude.

Time patterns in nocturnal concentrations of circulating melatonin of children are quantified in 8 girls and 8 boys, 8.7-16.8 yr of age, classified by Tanner pubertal stage. Between 1900 and 0700 h, each provided blood samples at 30-min intervals for melatonin RIA. Associations with gender, body mass index, and chronological and pubertal age determined by multiple linear regression and ANOVA reveal that the area under the curve of 12-h melatonin concentrations was affected by pubertal rather than chronological age, an effect to which data collected during darkness contributed the most. Each data series was also analyzed by a least squares spectrum at frequencies of 1-20 cycles/day. Ultradian changes with periods of 3.4 and 1.5 h, putatively associated with rapid eye movement sleep cycles, characterize nocturnal melatonin in boys and girls.

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.

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; p0.001) for ischaemic stroke and 6.9 (2.9 to 16.3; p0.001) for nephropathy. In MESOR-hypertensives, the relative risk for ischaemic stroke and nephropathy is 6.3 (p0.005) and 4.0 (p0.05), 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 (p0.05). 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.

Heart rate variability (HRV) during 30 minute's recovery from a 30-minute exercise was established for 6 healthy men 23-30 years old. The exercise-recovery schedule was performed at 8 circadian stages over 11 days for each subject and analyzed over consecutive 5-minute segments. The local K index for the time of the recovery was recorded as a variable for geomagnetic activity. Pooling all HRV values across the different times into recovery, the relation of HRV to local K is found to be non-linear. A quadratic model fitted to the pooled HRV values is statistically significant. The present study indicates that during recovery from exercise, the effect of geomagnetic disturbances on HRV is non-linear. A non-linear relation of HRV with respect to geomagnetic activity deserves further work to determine whether it can account for discrepant findings of an effect of magnetic storms on the incidence of myocardial infarctions, for which a decreased HRV is a predictor.

Col. Eugene L. (Gene) Kanabrocki, PhD, commanding officer of the 361st Medical Laboratory of the U.S. Army Reserve, together with Col. Lawrence E. (Larry) Scheving, Professor at the University of Arkansas, initiated in May 1969 a linked cross-sectional (hybrid) study at Fort Sam Houston, TX, to examine the oscillatory (circadian) nature of many physiological variables in a group of 13 army men, 22-28 years of age, anticipating that such data would serve, as indeed they did, as time-specified reference values in future investigations of health and aging. In the initial study, 36 variables were examined around the clock in observations at 3-hour intervals. In subsequent 24-hour profiles, mapped in May of 1971 (mostly on new, young subjects, and not officially part of the Aging Project), 1979, 1988, 1993, 1998 and 2003, additional subjects and variables were included. The follow-up studies were conducted at the Hines VA Medical Center in Hines, Illinois. Of the original 13 subjects, four were measured in all 6 studies and another four in 5 of the 6 studies. Three of the eight became diabetic (Type II) and three had vascular circulatory problems. Presently, a bank of circadian data for 187 medically relevant variables of blood (plasma or serum), saliva, urine, vital signs and other variables on the same subjects covers a span of 34 years. Dr. Robert B. Sothern (RBS), of the University of Minnesota, USA, the major analyst of Gene's investigations, in addition to being an add-on subject as he was in three studies, set up the half-hourly monitoring of blood pressure (BP) and heart rate (HR) in the 2003 study that yielded the data suggesting that the standard deviations (SD) of systolic (S) and diastolic (D) BP and HR are infl uenced by a magnetic storm. Since the standard deviation rather than the amplitude of a vascular spectral component was affected, we may be dealing with a stochastic rather than frequency window-dependent resonance with a magnetic storm. Gene and RBS also found (p0.08) an about-decadal signature of solar activity in long-acting natriuretic peptide (LANP), vessel dilator (VSDL), insulin, LH, prolactin, T3 uptake and, most importantly, in melatonin (p=0.004), noted solely to constitute a stimulus for follow-up studies, even when resonance occurs in an anticipated Horrebow-Schwabe circadecadal window gauged by relative sunspot (Wolf) numbers and involves many endocrine variables, as anticipated on the basis of independent evidence in melatonin and cortisol. The wealth of circadian information collected in these studies by Gene constitutes a treasure trove of unique advances in the battle of the normal range, with solid contributions also by Prof. Germaine Cornélissen of the University of Minnesota, USA, and by Prof. Ramon C. Hermida of the University of Vigo, Spain.

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.

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 (P0.05), 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.

This study aimed at examining any relation between the circadian variation in blood pressure (BP) in human pregnancy and fetal growth. A prospective study included 52 pregnant women monitored during the third trimester of pregnancy. There were 33 uncomplicated pregnancies with normal fetal growth (Group 1) and 19 pregnancies complicated by intrauterine growth retardation (IUGR), confirmed at birth (Group 2). Ten women (five in each group) had pregnancy-induced hypertension. All women were hospitalized and followed a similar daily routine. BP was recorded with an automatic wearable device. Measurements were obtained every 20 min for 24 +/- 1 h. BP profiles were analyzed by conventional statistical methods and by cosinor, involving the least squares fit of cosine curves with an anticipated period (24 h) to the data. BP parameters, fetal outcome, demographic and obstetric characteristics were compared between the two groups. Logistic regression and multivariate analyses were used to assess factors putatively associated with fetal outcome. The circadian amplitude of diastolic BP was found to be larger in normotensive women with IUGR. As gauged by odds ratios (OR), the circadian amplitude of diastolic BP (OR = 1.7, 95% CI: 1.1-2.8; P = 0.03) and hematocrit (OR = 1.4, 95% CI: 1.0-1.9; P = 0.04) were the only variables positively and independently associated with IUGR. In the presence of maternal hypertension, the circadian amplitude of systolic BP was negatively associated with IUGR (OR = 0.7, 95% CI: 0.5-1.0; P = 0.03). A larger circadian variation in diastolic BP, rather than a difference in the mean value of systolic or diastolic BP, was found to be statistically significantly associated with IUGR. This study adds another condition in which the circadian BP amplitude constitutes a harbinger of elevated risk, apart from an association with a shortened lifespan in the absence or presence of malignant hypertension and with an increased risk of stroke and nephropathy reported earlier.

Aim. Fractal analysis of heart rate (HR) variability (HRV) has been used as a new approach to evaluate the risk of mortality in various patient groups. Aim of this study is to examine the prognostic power of detrended fluctuation analysis (DFA) and traditional time- and frequency-domain analyses of HR dynamics as predictors of mortality among elderly people in a community. Methods. We examined 298 people older than 75 years (average age: 79.6 years) and 1-h ambulatory ECG was monitored. During the last 10 min, deep respiration (6-s expiration and 4-s inspiration) was repeated six times in a supine position. Time-domain and frequency-domain measures were determined by the maximum entropy method. Scaling exponents of short-term ( 11 beats, alpha 2) were determined by the DFA method. Six estimates, obtained from 10-min segments, were averaged to derive mean values for the entire recording span. These average values were denoted Alpha 1 and Alpha 2, estimates obtained during the first 10-min segment Alpha 1 S and Alpha 2 S, and those during the last 10-min segment Alpha 1E and Alpha 2E, respectively. The LILAC study started on July 25, 2000 and ended on November 30, 2004. We used Cox regression analysis to calculate relative risk (RR) and 95% confidence interval (CI) for all-cause mortality. Significance was considered at a value of P Results. Gender, age and Alpha 2E showed a statistically significant association with all-cause mortality. In univariate analyses, gender was significantly associated with all-cause mortality, being associated with a RR of 3.59 (P = 0.00136). Age also significantly predicted all-cause mortality and a 5-year increase in age was associated with a RR of 1.49 (P = 0.01809). The RR of developing all-cause mortality predicted by a 0.2-unit increase in Alpha 2E was 0.58 (P = 0.00390). Other indices of fractal analysis of HRV did not have predictive value. In multivariate analyses, when both Alpha 2E and gender were used as continuous variables in the same model, Alpha 2E remained significantly associated with the occurrence of all-cause mortality (P = 0.02999). After adjustment for both gender and age, a 0.2-unit increase in Alpha 2E was associated with a RR of 0.61 (95% CI: 0.42−0.90, p = 0.01151). Conclusion. An intermediate-term fractal-like scaling exponent of RR intervals was a better predictor of death than the traditional measures of HR variability in elderly community-dwelling people. It is noteworthy that the longer-term (alpha 2) rather than the short-term fractal component (alpha 1) showed predictive value for all-cause mortality, which suggests that an increase in the randomness of intermediate-term HR behavior may be a specific marker of neurohumoral and sympathetic activation and therefore may also be associated with an increased risk of mortality.

Effects of high altitude on arterial stiffness and neuro-cardio-pulmonary function were studied. Blood pressure (BP) and heart rate (HR) were measured in a sitting position on resting Ladakhis, living at an altitude of 3250-4647 m (Phey village, 3250 m: 17 men and 55 women; Chumathang village, 4193 m: 29 men and 47 women; Sumdo village, 4540 m: 38 men and 57 women; and Korzok village, 4647 m: 84 men and 70 women). The neuro-cardio-pulmonary function, including the Kohs block design test, the Up and Go, the Functional Reach and the Button tests, was examined in 40 elderly subjects (19 men and 21 women, mean age: 74.7 +/- 3.3 years) in Leh, Ladakh (altitude: 3524 m), for comparison with 324 elderly citizens (97 men and 227 women, mean age: 80.7 +/- 4.7 years) of Tosa, Japan (altitude: 250 m). Cardio-Ankle Vascular Index (CAVI) was measured as the heart-ankle pulse wave velocity (PWV) in these subjects using a VaSera CAVI instrument (Fukuda Denshi, Tokyo). SpO(2) decreased while Hb and diastolic BP increased with increasing altitude. At higher altitude, residents were younger and leaner. Women in Leh vs. Tosa had a poorer cognitive function, estimated by the Kohs block design test (3.7 +/- 3.6 vs. 16.4 +/- 9.6 points, P < 0.0001) and poorer ADL functions (Functional Reach: 13.7 +/- 7.0 cm vs. 25.3 +/- 8.7 cm, P < 0.0001; Button test: 22.5 +/- 4.8 vs. 14.8 +/- 5.7 s, P < 0.0001). Time estimation was shorter at high altitude (60-s estimation with counting: 41.1% shorter in men and 23.0% shorter in women). A higher voltage of the QRS complex was observed in the ECG of Leh residents, but two times measurement of CAVI showed no statistically significant differences between Leh and Tosa (two times of CAVI measures; 9.49 vs. 10.01 m/s and 9.41 vs. 10.05 m/s, respectively), suggesting that most residents succeed to adapt sufficiently to the high-altitude environment. However, correlation of CAVI with age shows several cases who show an extreme increase in CAVI. Thus, for the prevention of stroke and other adverse cardiovascular outcomes, including dementia, CAVI may be very useful, especially at high altitude. In conclusion, elderly people living at high altitude have a higher risk of cardiovascular disease than low-latitude peers. To determine how these indices are associated with maintained cognitive function deserves further study by the longitudinal follow-up of these communities in terms of longevity and aging in relation to their neuro-cardio-pulmonary function.

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”.

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.

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.

By means of a multivariate Cox model, we investigated the predictive value of a depressive mood on vascular disease risk in middle-aged community-dwelling people. In 224 people (88 men and 136 women; mean age: 56.8 +/- 11.2 years) of U town, Hokkaido (latitude: 43.45 degrees N, longitude: 141.85 degrees E), a chronoecological health watch was started in April 2001. Consultations were repeated every 3 months. Results at the November 30, 2004 follow-up are presented herein. 7-day/24-h blood pressure (BP) and heart rate (HR) monitoring started on a Thursday, with readings taken at 30-min intervals between 07:00 h and 22:00 h and at 60-min intervals between 22:00 h and 07:00 h. Data stored in the memory of the monitor (TM-2430-15, A and D company, Japan) were retrieved and analyzed on a personal computer with a commercial software for this device. Subjects were asked to answer a self-administered questionnaire inquiring about 15 items of a depression scale, at the start of study and again after 1-2 years. Subjects with a score higher by at least two points at the second versus first screening were classified as having a depressive mood. The other subjects served as the control group. The mean follow-up time was 1064 days, during which four subjects suffered an adverse vascular outcome (myocardial infarction: one man and one woman; stroke: two men). Among the variables used in the Cox proportional hazard models, a depressive mood, assessed by the Geriatric Depression Scale (GDS), as well as the MESOR of diastolic (D) BP (DBP-MESOR) and the circadian amplitude of systolic (S) BP (SBP-Amplitude) showed a statistically significant association with the occurrence of adverse vascular outcomes. The GDS score during the second but not during the first session was statistically significantly associated with the adverse vascular outcome. In univariate analyses, the relative risk (RR) of developing outcomes was predicted by a three-point increase in the GDS scale (RR = 3.088, 95% CI: 1.375-6.935, P = 0.0063). Increases of 5 mmHg in DBP-MESOR and of 3 mmHg in SBP-Amplitude were associated with RRs of 2.143 (95% CI: 1.232-3.727, P = 0.0070) and 0.700 (95% CI: 0.495-0.989, P = 0.0430), respectively. In multivariate analyses, when both the second GDS score and the DBP-MESOR were used as continuous variables in the same model, GDS remained statistically significantly associated with the occurrence of cardiovascular death. After adjustment for DBP-MESOR, a three-point increase in GDS score was associated with a RR of 2.172 (95% CI: 1.123-4.200). Monday endpoints of the 7-day profile showed a statistically significant association with adverse vascular outcomes. A 5 mmHg increase in DBP on Monday was associated with a RR of 1.576 (95% CI: 1.011-2.457, P = 0.0446). The main result of the present study is that in middle-aged community-dwelling people, a depressive mood predicted the occurrence of vascular diseases beyond the prediction provided by age, gender, ABP, lifestyle and environmental conditions, as assessed by means of a multivariate Cox model. A depressive mood, especially enhanced for 1-2 years, was associated with adverse vascular outcomes. Results herein suggest the clinical importance of repetitive assessments of a depressive mood and the need to take sufficient care of depressed subjects. Another result herein is that circadian and circaseptan characteristics of BP variability measured 7-day/24-h predicted the occurrence of vascular disease beyond the prediction provided by age, gender, depressive mood and lifestyle, as assessed by means of a multivariate Cox model. Earlier, we showed that the morning surge in BP on Mondays was statistically significantly higher compared with other weekdays. Although a direct association between the Monday surge in BP and cardiovascular events could not be demonstrated herein, it is possible that the BP surge on Monday mornings may also trigger cardiovascular events. We have shown that depressive people exhibit a more prominent circaseptan variation in SBP, DBP and the double product (DP) compared to non-depressed subjects. In view of the strong relation between depression and adverse cardiac events, studies should be done to ascertain that depression is properly diagnosed and treated. Chronodiagnosis and chronotherapy can reduce an elevated blood pressure and improve the altered variability in BP and HR, thus reducing the incidence of adverse cardiac events. This recommendation stands at the basis of chronomics, focusing on prehabilitation in preference to rehabilitation, as a public service offered in several Japanese towns.

Several kinds of health consultation and rehabilitation for functional disorders aimed at stroke prevention and maintenance of cognitive function in an elderly population in Hokkaido county, Japan. Changes in cardiovascular and neurobehavioral endpoints between 2000 and 2002 were assessed in 72 of 115 subjects over 75 years of age. Direct social intervention, including lifestyle modification can have a positive impact, notably on subjects with cardiovascular disorders.

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.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).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.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.

A new insofar as chronobiologic therapeutic approach by atrial natriuretic peptide (ANP) for hypertension and/or congestive heart failure (CHF) is based on the release of ANP from ANP cDNA transfected Chinese Hamster Ovary (CHO) cells encapsulated in polycaprolactone (PCL) tubes. ANP secretion was maintained for at least 6 months. The encapsulated cells remained viable during culturing. Control cells without transferred ANP cDNA were negative. ANP secretion is circadian periodic, peaking around 04:18, shifted to around 07:56 by melatonin treatment. The encapsulation technique, based on principles of chronotherapy, may provide a more efficient gene therapy, applicable for eventual human implantation of gene transferred cells.

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.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.Each variable underwent circadian variation (por = 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.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.

Effects of geomagnetic disturbance on heart rate variability (HRV), the 1/ f fractal scaling in particular, are being assessed in adults living at high latitude, where magnetic storms are more frequent and more intense than at lower latitudes. The latter may constitute a signal or a proxy, and possibly a mechanism underlying both undesirable and desirable effects, depending upon circumstances yet to be elucidated. Any circadecadal stage-dependence of morbidity and/or mortality from certain conditions such as myocardial infarctions remains to be studied in both adult and pediatric populations. Further work could thus examine whether any associations of geomagnetic disturbances may account, at least in part, through effects upon the circulation, for long-term infra-annual changes, possibly anchored in the population’s gene pool, observed in a number of anthropologic measurements at birth as well as in other population statistics. In order to assess the development of several chronome components of the electrocardiogram (ECG), around-the-clock ambulatory ECG were recorded from 19 infants (25 days–3 months of age), 22 children (3–9 years of age), 18 boys and girls (10–14 years of age), pubertal boys (15–20 years of age), and 10 young men (21–29 years of age). Time– and frequency-domain measures of HRV were obtained by spectral analysis, using the maximal entropy method (MEM). The frequency of detection of the circadian, circasemidian and circaoctohoran components, with periods of about 24, 12 and 8 h, respectively, was compared among the five groups for several HRV endpoints, notably 1/ f fractal scaling, total spectral power within a 5–min span, and its distribution into several frequency regions. A circadian component is already detectable in a sizeable proportion of infants and children for most of the HRV indices considered. The incidence of detection of the circadian component increases with age for the spectral power in different frequency regions, notably around 10.5 s (“LF”) and around 3.6 s (“HF”); it peaks around puberty for 1/ f in our data; and it did not detectably change with age for the total spectral power. Similar changes with age are not observed for the circasemidian or circaoctohoran components. The latter characterizes primarily 1/ f and less so the about 3.6 s power (“HF”). Several aspects of the HRV chronome may thus develop differently as a function of age. In 2000, we began a community-based study named “Longitudinal Investigation of Longevity and Aging in Hokkaido County (LILAC study)”. The ambulatory blood pressure (BP) of middle-aged subjects, aged 40–74 years, was monitored 7–day/24–h, and the cardiovascular and neurobehavioral functions of elderly people above 75 years were evaluated. Our goal was the prevention of stroke and myocardial infarction and the decline in cognitive function of the elderly in a community. Of 115 elderly people recruited in a longitudinal community-based study in 2000, 72 completed yearly follow-ups in 2002. A cardiovascular score based on BP, pulse wave velocity, and 1–h ECG-based HRV endpoints served to distinguish between normal, mildly disordered, or disordered participants. A comparison of cognitive function in 2002 vs. 2000, assessed with the MMSE, HDSR, the Up & Go and Functional Reach tests, gauged any effect of social intervention. Cognitive function was maintained or improved, especially for people suffering from hypertension, tachycardia, or a decreased HRV, suggesting that cardiovascular function is a major factor affecting cognitive function.

The synchronization of biological circadian and circannual rhythms is broadly viewed as a result of photic solar effects. Evidence for non-photic solar effects on biota is also slowly being recognized. The ultrastructure of cardiomyocytes from rabbits, the time structure of blood pressure and heart rate of neonates, and the heart rate variability of human adults on earth and in space were examined during magnetically disturbed and quiet days, as were morbidity statistics. Alterations in both the about-daily (circadian) and about-weekly (circaseptan) components are observed during disturbed vs. quite days. The about-weekly period of neonatal blood pressure correlates with that of the local geomagnetic disturbance index K. Circaseptans which are seen early in human life and in various other forms of life, including unicells, may provide information about the possible site(s) of life's origins from an integrative as well as adaptive evolutionary perspective.

To eventually build a scientific bridge to religion by examining whether non-photic, non-thermic solar effects may influence (religious) motivation, invaluable yearly world wide data on activities from 1950 to 1999 by Jehovah's Witnesses on behalf of their church were analyzed chronobiologically. The time structure (chronome) of these archives, insofar as it is able to be evaluated in yearly means for up to half a century, was assessed. Least squares spectra in a frequency range from one cycle in 42 to one in 2.1 years of data on the average number of hours per month spent in work for the church, available from 103 different geographic locations, as well as grand totals also including other sites, revealed a large peak at one cycle in about 21 years. The non-linear least squares fit of a model consisting of a linear trend and a cosine curve with a trial period of 21.0 years, numerically approximating that of the Hale cycle, validated the about 21.0-year component in about 70% of the data series, with the non-overlap of zero by the 95% confidence interval of the amplitude estimate. Estimates of MESOR (midline-estimating statistic of rhythm, a rhythm (or chronome) adjusted mean), amplitude and period were further regressed with geomagnetic latitude. The period estimate did not depend on geomagnetic latitude. The about 21.0-year amplitude tends to be larger at low and middle than at higher latitudes and the resolution of the about 21.0-year cycle, gauged by the width of 95% confidence intervals for the period and amplitude, is higher (the 95% confidence intervals are statistically significantly smaller) at higher than at lower latitudes. Near-matches of periods in solar activity and human motivation hint that the former may influence the latter, while the dependence on latitude constitutes evidence that geomagnetic activity may affect certain brain areas involved in motivation, just as it was earlier found that it is associated with effects on the electrocardiogram and anthropometry.

Helio-geomagnetic influences on the human circulation are investigated on the basis of an 11-year-long record from a clinically healthy cardiologist, 35 years of age at the start of monitoring. He measured his blood pressure and heart rate around the clock with an ambulatory monitor programmed to inflate an arm cuff, mostly at intervals of 15–30 minutes, with only few interruptions, starting in August 1987. While monitoring is continuing, data collected up to July 1998 are analyzed herein by cosinor rhythmometry and cross-spectral coherence with matching records of solar activity, gauged by Wolf numbers (WN) and of the geomagnetic disturbance index, K p . A direct association between heart rate (HR) and WN is found to be solar cycle stage-dependent, whereas an inverse relationship between heart rate variability (HRV) and WN is found consistently. An inverse relation is also observed between WN and the variability in systolic blood pressure (SBP), and to a lesser extent, diastolic blood pressure (DBP). Moreover, HR is cross-spectrally coherent with WN at a frequency of one cycle in about 7.33 months. The results support previously reported associations on morbidity and mortality statistics, extending their scope to human physiology monitored longitudinally.

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.

Meteorotropic associations of heart rate (HR) and HR variability (HRV) were investigated in a clinically healthy 48-year-old man in Kiev. His electrocardiogram (ECG) was determined over 50 days by fitting him with an ambulatorily wearable device; various natural physical environmental variables were also monitored. The mean inter-beat interval, the standard deviation of these intervals, the spectral power in several frequency ranges, the power ratio of the approx. 10.5-s/approx. 3.6-s spectral components and other aspects of HRV were computed over consecutive 14.4-min intervals. Together with ordinary meteorological variables, geomagnetic disturbances (GMD) and fluctuations of atmospheric pressure (FAP) in the range 0.01–0.10 Hz (10–100 s) were measured. The assessable infradian spectra (with frequencies lower than 1 cycle/28 hours) of all HRV parameters showed two major components with periods of about 3.5 and 10 days. Two environmental variables, FAP and wind speed (with which FAP is closely related), revealed both of these rhythms and showed the greatest cross-spectral coherence (0.70–0.98) with corresponding oscillations of HRV. Less specific but statistically significant product-moment correlations with major HRV indices were also found; most of these were with FAP, but correlations with air temperature, humidity, wind speed and geomagnetic disturbances were also found. Long-term ECG recording, essential in the detection of infradian rhythms, proved to be sensitive to physical environmental variables, notably meteorological ones. FAP, usually neglected since its role has not been considered in previous biometeorological studies, or some factor closely related to FAP is probably involved in synchronizing or influencing the approximately 3.5-day HR and HRV rhythms in humans.

This article is a follow-up on a 1998 article in JADA. The blood pressure, or BP, of 23 of 24 normotensive patients was monitored at 15-minute intervals for a total of nine days, in three consecutive sessions of four, two and three days, respectively, separated by a few weeks.Twelve patients were reached by phone seven years after the prior chronobiologically interpreted monitoring to ascertain their cardiovascular status since the initial monitoring.Only two of the 12 patients reached in follow-up had abnormalities in all three sessions, and only these two patients reported having experienced an adverse vascular event (one a myocardial infarction, the other coronary artery bypass graft surgery). The difference in outcome between the patients with chronobiological abnormality in all three sessions vs. the pool of those with abnormality in only two, one or none of the sessions is statistically significant.Even a five-day (and sometimes a longer) profile, while greatly preferred to single measurements, may not suffice for a definitive diagnosis of certain patients. Retrospectively, the 864 measurements, on the average, on each person in our study could have served for a recommendation to each person. Chronobiologically interpreted BP and heart rate monitoring for a week or longer as a start detects high-risk states that may be missed by conventional casual measurements that are rarely accompanied by one-day profiles.The dentist has an important opportunity for conveying the importance of monitoring BP and heart rate for a week to detect an abnormal variability, and for implementing this monitoring. Dentists can educate patients regarding the need for screening and for interpreting the results for variability, and contribute to their overall health by referring them to their physicians when treatment is indicated.

The circadian periodicity of urinary output, creatinine (Cr) and 5-hydroxyindole acetic acid (5-HIAA) excretion was studied under near-tropical conditions in 130 healthy volunteers (65 men and 65 women, 16–75 years of age) with a diurnal activity from about 06:30 to about 22:00 and nocturnal rest. These volunteers were divided into 4 groups, 16–30, 31–45,46–60 and 61–75 years of age, comprising 20, 20,15 and 10 participants of each gender, respectively. A marked circadian rhythm was recorded for urine volume, Cr and 5-HIAA excretion in healthy Indians of different ages. The acrophase tended to be delayed in the older age group. The relative amplitude decreased with advancing age, notably in women. Overall, men produced a larger urine volume as compared to women. Excretions of Cr and 5-HIAA in healthy Indian volunteers of different ages may be influenced by diet, societal relations, climate and/or geographic location. The contribution of such factors in metabolism and degradation warrants further study.

The heart rate and axilliary temperature of 17 patients with schizophrenia were measured every 3 hours during waking for 4 days. In 28 profiles, large inter- and intra-individual variations notwithstanding, relations between the time structures (chronomes) of heart rate and axillary temperature are assessed and further examined from the viewpoint of their bearing on the severity of the patients's condition.