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Cholesterol, an important physiological factor becomes atherogenic only when it is oxidized. All the risk factors such as Western diet, sedentary behavior, tobacco, pollutants, diabetes have the ability to increase and oxidize the cholesterol in our body which results in to atherothrombosis. Cholesterol is also important for the synthesis of steroids and steroid hormones, and for the bile and bile acid salts. Sterol plays also an important role in embryonic development. Recent evidence indicates that cholesterol homeostasis in the central nervous system has been associated with neurological, neurodegenerative, and neurodevelopmental disorders. Recently cholesterol has been indicated to maintain the cell membrane integrity of the epithelial cells of the beta cells of pancreas, which is helpful in the prevention of diabetes among patients receiving statins. In neuronal cell membrane phospholipids, it maintains the integrity of neurons and prevents depression and aggression among patients receiving hypocholesterolemic agents. Increased production of cholesterol has to be avoided because it forms solid crystals which are known to kill normal cells. Increased cholesterol in the tissues may also have adverse effects because if it is oxidized, it predisposes inflammation in the arteries and deposits in arteries, initiating atherosclerosis. Therefore regulation of cholesterol metabolism is achieved predominantly through repression of transcription of genes that govern the synthesis of cholesterol and its receptor-mediated uptake from plasma lipoproteins via low-density lipoprotein cholesterol receptors in the hepatocytes and macrophages. Hypercholesterolemia could be a function of the brain due to a disturbance in the central circadian clock, causing disturbed circadian energy metabolism. Psychological stress can also cause hypercholesterolemia, yet the pathophysiological mechanisms involved remain elusive. The macrophage-specific reverse cholesterol transport, by which the transfer of cholesterol from macrophage foam cells to liver and feces is completed, appears to be an important antiatherogenic pathway which is blocked due to mental stress resulting in to hypercholesterolemia. Studies link energy homeostasis to the circadian clock at the behavioral, physiological, and molecular levels, emphasizing that certain nutrients and the timing of food intake may play a significant role in the development of dyslipidemia and obesity with greater risk of cardiovascular diseases and type 2 diabetes including hypercholesterolemia. In brief, it is possible that autonomic dysfunction due to diet and lifestyle factors, mental stress and disturbance in the central circadian clock can contribute in the development of hypercholesterolemia as a function of the brain.

Mind-brain-body-gene framework, including the role of chrononutrition, is probably implicated in the genesis of functional gastrointestinal diseases (FGIDs). Emphasis was placed on psychosocial dysregulation, the bridging of the Cartesian Gap, and chronobiology viz. the way circadian and other rhythmic structures of the brain, e.g. suprachiasmatic nucleus, and gastrointestinal tract interact partially explaining the phrase "we are what and when we eat". Chronobiological concepts of strain and stress in the context of sensory pain and the time-qualified network of gut hormones and neuropeptides are discussed for melatonin, serotonin, ghrelin, leptin, vasoactive intestinal peptide, neuropeptide Y, orexins, and others. The Tsimtsoum evolutionary aspects of diet from Palaeolithic to modern man in the context of increased omega-3/omega-6 fatty acid ratio reduces proinflammatory responses, important in pre-metabolic syndrome and cardiovascular disease, and protects against neuropsychic disorders possibly (FGIDs). Gut micro-organisms either affect the lumen (food substrates) and mucosa, where they reflect immunological, metabolic and physiologic function and importance of these two ecosystems. The interaction between enteric and autonomic systems and associated regulatory effects on proliferative and secretary epithelial dynamics and optimization of permeability for food nutrients and possible modulation of inflammation is an active area of research. In summary, this paper has focussed on the need to understand the multifarious aspects of biological and environmental variability, principally hormones and neuropeptides, in the possible genesis of (FGIDs).

Cycles of about 35 years found in the climate by Bruckner and Egeson were aligned with periodic changes in the length of the solar cycle by the Lockyers. The solar-cycle length and climate were subsequently revisited without reference to any cyclicity or those who discovered it. The descriptive statistics of Bruckner and Lockyer were repeatedly questioned and, with notable exceptions, have been forgotten. Bruckner’s data, taken from his summary chart, are shown here for the first time inferentially statistically validated as nonstationary (to the point of intermittency) and, as transdisciplinary, extending from meteorology to 2556 years of international battles; to 2189 years of tree rings; to ∼900 years of northern lights; to 400 years of economics; to 173 years of military affairs; and to ∼40 years of helio-, interplanetary- and geomagnetics matching a longitudinal record by a healthy individual who self-measured his heart rate and mental functions (with a 1-min time estimation), among other variables. Space weather, mirrored in the circulation of human blood, can be tracked biologically as a dividend from self-assessed preventive health care including the automatically and ambulatory-recorded heart rate and blood pressure for detecting and treating heretofore ignored vascular variability disorders. A website providing free analyses for anyone (in exchange for their data) could serve any community with computer-savvy members and could start focusing the attention of the population at large on problems of societal as well as individual health. Space weather was found to affect the human cardiovascular system, and it has been supposed that data on space weather can be inversely assimilated from biological self-monitoring data.

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.

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.

Objective. This study investigates how the shortening or lengthening of the circadian period of the environmental lighting schedule affects the circadian and extra-circadian structure of locomotor activity in mice, with particular focus on the circasemiseptan, circaseptan, and circadecadian components with anticipated periods of about 3.5, 7, and 10 days, respectively. Methods. The locomotor activity of mice kept on different light – dark (LD) cycles was automatically monitored around the clock for about five weeks. The data were analyzed by linear – nonlinear rhythmometry. Results. As anticipated, in LD12:12, a prominent circadian rhythm was observed, with a marked 12-hour component qualifying the circadian waveform. By comparison, in LD10:10 and in LD14:14, the circadian rhythm had a reduced amplitude and a period close to that of the environmental synchronizer. Extra-circadian variation was then also demonstrated. In conclusion, circadian lighting schedules affect a broader-than-circadian time...

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.

Studies on Drosophila melanogaster have shown that the period gene, a circadian clock gene and essential component of the underlying molecular feedback loop, can influence behavioural responses to cocaine. The mouse homologues, mPer1 and mPer2, were also shown to modulate cocaine sensitization and reward. Reportedly, normal expression of the per gene is important for the development of cocaine sensitization in Drosophila and in the mouse. This study examines the role of mPer1 on morphine addiction by applying a ribozyme to interfere with the expression of mPer1 in the central nervous system of mice. A plasmid based on pcDNA3.1 was constructed, using the expression of a hammerhead ribozyme that can selectively cleave the mPer1 mRNA. The ribozyme's presence was associated with a statistically significant reduction in mPer1 mRNA. Mice treated with the ribozyme and morphine synchronously did not show any preference for the morphine-paired side, whereas the control mice did. These results suggest that...

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.

Looking back on our January 20–27, 2005 visit to India, it was a whirlwind trip, very rewarding, exciting and also strenuous, in particular for Franz and also for myself, though on a somewhat different level, since I was mainly free of responsibilities. We returned 3 days before I started this note, maybe not long enough to be able to attain a more settled impression and judgment. My main purpose is to give a descriptive report about Franz’ effort to bring advances made in mapping chronomes (time structures) into practice in areas with limited resources. In particular, we wish to bring diagnostic and preventive possibilities into the clinical armament by the timely recognition and treatment of otherwise silent yet greatly increased risks of heart and brain attacks.

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

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.

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.

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

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.

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 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.

Daily data on solar magnetism, available from May 1975 to April 2002, were analyzed by linear–nonlinear rhythmometry, with particular focus on the near-transyear, slightly longer than the calendar year. The time structure of solar magnetism is compared to that of solar activity, gauged by Wolf numbers. An about 27-day component corresponding to the solar rotation period, is common to both variables but differs in harmonic content. About 10-year component characterizes solar activity but not solar magnetism. A near-transyear with a period of about 1.05 years is detected in solar magnetism. In solar activity, a near-transyear is also found but its period of about 1.10 years is longer than that characterizing solar magnetism, and it may be paired with an about 0.9-year component to correspond to an about 10-year modulation in amplitude or phase of an about-yearly component.

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.

Aims: Velocity changes in the solar wind recorded by satellite (IMP8 and Wind) are characterized by a solar cycle–dependent ∼1.3-year component. The presence of any ∼1.3-year component in human blood pressure (BP) and heart rate (HR) and in mortality from myocardial infarction (MI) is tested and its relative prominence compared to the 1.0-year variation. Materials and Methods: Around-the-clock manual or automatic BP and HR measurements from four subjects recorded over 5–35 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 ∼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 the authors (JDR). Results: An ∼1.3-year component is resolved nonlinearly for MI, with a period of 1.23 (95% CI: 1.21, 1.26) years. 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 ∼1.3-year and 1.0-year components was shown by gliding spectra on actual and simulated data. Discussion and Conclusion: The shortest 5-year record (1998–2003) revealed an ∼1.3-year component closer to the solar wind speed period characterizing the entire available record (1994–2003) than the value for the concurrent 5-year span. Physiological variables may resonate with nonphotic environmental cycles that may have entered the genetic code during evolution.

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.

Population densities (PD) of capillaries (C) and endotheliocytes (E) were determined in pinnal dermis of C57BL mice before and after trauma. Moving (and overall) least-squares spectra before trauma detected in EPD (versus CPD) pronounced 3.5-day (circasemiseptan) and 8-h oscillations corresponding to components of the endothelin-1 chronome in human blood plasma reported earlier. Circadians were more pronounced in CPD. After trauma, circasemiseptan oscillations appeared also in CPD; their period gradually shortened and in two weeks split into about 2.5- and about 4.5-day oscillations; and circadian components became very pronounced. The pre-traumatic chronome was not restored within three weeks following trauma.

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.