Diagnosing vascular variability anomalies, not only MESOR-hypertension.

Chronobiology is the study of biological rhythms. Chronomics investigates interactions with environmental cycles in a genetically coded autoresonance of the biosphere with wrangling space and terrestrial weather. Analytical global and local methods applied to human blood pressure records of around-the-clock measurements covering decades detect physiological-physical interactions, a small yet measurable response to solar and terrestrial magnetism. The chronobiological and chronomic interpretation of ambulatory blood pressure monitoring (C-ABPM) records in the light of time-specified reference values derived from healthy peers matched by sex and age identify vascular variability anomalies (VVAs) for an assessment of cardio-, cerebro-, and renovascular disease risk. Even within the conventionally accepted normal range, VVAs have been associated with a statistically significant increase in risk. Long-term C-ABPM records help to "know ourselves," serving for relief of psychological and other strain once transient VVAs are linked to the source of a load, prompting adjustment of one's lifestyle for strain reduction. Persistent circadian VVAs can be treated, sometimes by no more than a change in timing of the daily administration of antihypertensive medication. Circadian VVA assessment is an emergency worldwide, prompted in the United States by 1,000 deaths per day every day from problems related to blood pressure. While some heads of state met under United Nation and World Health Organization sponsorship to declare that noncommunicable diseases are a slow-motion disaster, a resolution has been drafted to propose C-ABPM as an added tool complementing purely physical environmental monitoring to contribute also to the understanding of social and natural as well as personal cataclysms.

Toward a personalized chronotherapy of high blood pressure and a circadian overswing.

Timing can greatly affect the response to a stimulus, including antihypertensive medications. Herein, we assess the response of 30 patients to losartan/hydrochlorothiazide (L/H), administered for at least 1 month at a given circadian stage to each patient, this stage being changed during consecutive spans to cover six treatment times from awakening to bedtime at approximately 3-hour intervals. At the end of each stage, each patient underwent a 7-day around-the-clock ambulatory blood pressure (BP) profile, analyzed chronobiologically. A larger reduction of the midline estimating statistic of rhythm (MESOR; a rhythm-adjusted mean) of diastolic BP was achieved by L/H administration in the early morning for more patients (P < .05), while treatment upon awakening was the best choice for most patients to reduce the circadian amplitude of BP the most (P < .01). The optimal treatment time varied considerably among patients, however. Special attention should be given to the effect on the circadian amplitude since treatment can increase it above a threshold, beyond which there is a marked increase in cardiovascular disease risk. The results indicate the desirability to individualize the optimization of the antihypertensive effect of L/H by timing along the circadian scale.

IL-15 receptor deletion results in circadian changes of locomotor and metabolic activity.

Interleukin-15 (IL-15) is a cytokine produced in the normal brain that acts on its specific receptor IL-15Ralpha and co-receptors IL-2Rbeta and IL-2Rgamma in neuronal cells. The functions of the cerebral IL-15 system, however, are not yet clear. To test the hypothesis that IL-15Ralpha regulates metabolic activity and body temperature, we quantified the specific metabolic phenotype of IL-15Ralpha knockout mice. These normal-appearing mice were leaner with lower fat composition. During the entire circadian cycle, the knockout mice had a significantly higher acrophase in locomotor activity and heat dissipation. During the light phase, there was significantly greater food intake, oxygen consumption, and carbon dioxide production. The difference in the dark and light phases suggests that IL-15Ralpha participates in circadian rhythm regulation. The higher oxygen consumption in the light phase indicates adaptive thermogenesis in the knockout mice. The body temperature of the receptor knockout mice was significantly higher than the control in the light phase, and this was mainly caused by a large difference occurring between 0600 and 0900 h. In addition to the metabolic chamber studies and circadian rhythm analyses, qPCR of hypothalamic homogenates indicated higher mRNA expression of orexin and transient receptor potential vanilloid 4 cation channels. Consistent with a direct role of IL-15Ralpha in the hypothalamus, IL-15 treatment of the wild-type mice induced c-Fos expression in the preoptic area. We conclude that activation of hypothalamic neurons by IL-15 in mice contributes to thermoregulation and modifies the metabolic phenotype.

Chronotherapy by Ribozyme Targeted to Telomerase in Nude Mice with a Transplanted Tumor: Model for Human Hepatic Cancer / 航天医学与医学工程

Objective To investigate therapeutic autcomes of using telomerase inhibitors to treat cancer at the presumably most and least opportune circadian stages basing on our earlier study. Methods Twenty-four BALB/C nude mice were synchronized to a regimen of LD12:12 for 4 wk. Hepatic cancer cells (SMMC-7721) were implanted into both flanks of each mouse.Two weeks after transplantation,the hTERT-5'RZ was used to treat the hepatic cancer transplanted into the nude mice daily for two weeks,the injection times being either 9 or 21 HALO.Results The tumorinhibition ratio of mice treated at 21 HALO (65%) was statistically significantly higher than that of mice treated at 9 HALO (48%). Telomerase activity was also reduced to a greater extent in mice treated withhTERT-5'RZ at 21 than at 9 HALO, that was at the time of maximal circadian telomerase activity. Conclusion Injection of ribozyme targeted to telomerase during the tumor's DNA synthesis is associated with a betterinhibition of tumor growth and a better therapeutic outcome in hepaticcancer.

Cancer chronomics I. Origins of timed cancer treatment: early marker rhythm-guided individualized chronochemotherapy.

A 21-year old patient who presented in 1973 with a rare and highly malignant ovarian endodermal sinus tumor with spillage into the peritoneal cavity is alive and well today after receiving chronochemotherapy. During the first four courses of treatment, medications were given at different circadian stages. Complete blood counts and marker variables such as mood, vigor, nausea, and temperature were monitored around the clock and analyzed by cosinor to seek times of highest tolerance. Remaining treatment courses were administered at a time corresponding to the patient's best drug tolerance, rather than extrapolating the timing of optimal cyclophosphamide administration from also-implemented parallel laboratory studies on mice. Notwithstanding remaining hurdles in bringing chronochemotherapy to the clinic for routine care, merits of marker rhythm-guided chronotherapy documented in this and other case reports have led to the doubling of the two-year disease-free survival of patients with large perioral tumors in a clinical trial.

Cancer chronomics II. Origins of timing cancer treatment.

This paper is a memorial to Mikhail Victorovich Berezkin (MVB) (10 April 1940 - 16 January 2005), an enthusiastic advocate of chrono-oncology. It illustrates his early dose- and circadian time-response curves, limited as yet by a 4-timepoint approach, provides a list of his publications, and offers a succinct overview of individualized marker rhythm-guided oncotherapy.

Cancer chronomics III. Chronomics for cancer, aging, melatonin and experimental therapeutics researchers.

This position paper documents the merit of including for basic and clinical investigations the mapping of circadian and other rhythms and yet broader chronomes, time structures in and around us. Chronobiometry used herein relies on inferential statistical methods and on materials documented earlier. The circadian amplitude of melatonin is shown to relate both to cancer risk and to the presence of overt cancer, when no differences are found in the 24-hour average of melatonin. Optimization of treatment by timing, thoroughly documented along the circadian scale earlier, could be broadened to include optimization along the scale of the week, and eventually beyond. In both cases, reliance on marker rhythmometry is advocated. More generally, the limits of knowledge are expanded by considering already mapped spectral components and their characteristics that can be influenced by the dynamics of heliogeomagnetic signals heretofore unassessed.

About 21-year hale cyclic signature in agriculture complement those in biomedicine.

Data on total cultivated area and total production of wheat and rye, barley and two-row barley, corn, soya and sunflower in Romania (1968-2000) are re-analyzed from the viewpoint of chronomics. An about 10.7-year component is detected with borderline statistical significance. A 3-component model consisting of cosine curves, with periods of 3.62, 2.48 and 2.15 years, accounts for 27% of the overall variability. Transdisciplinary chronomics is advocated to systematically map predictable dynamics in agriculture such as Hale-like cycles in corn and soja and their interactions with chronomes of external environmental factors.

100 or 30 years after Janeway or Bartter, Healthwatch helps avoid 'flying blind'.

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

Melatonin, refractory hypertension, myocardial ischemia and other challenges in nightly blood pressure lowering.

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

Chronomics: circadian and circaseptan timing of radiotherapy, drugs, calories, perhaps nutriceuticals and beyond.

We suggest a putative benefit from timing nutriceuticals (substances that are both nutrients and pharmaceuticals) such as antioxidants for preventive or curative health care, based on the proven merits of timing nutrients, drugs, and other treatments, as documented, i.a., in India. The necessity of timing melatonin, a major antioxidant, is noted. A protocol to extend the scope of chronoradiotherapy awaits testing. Imaging in time by mapping rhythms and broader time structures, chronomes, for earliest diagnoses, for example detection of vascular disease risk, is recommended. The study of rhythms and broader chronomes leads to a dynamic functional genomics, guided by imaging in time of free radicals and antioxidants, amongst many other variables.

Effects of autogenic training and antihypertensive agents on circadian and circaseptan variation of blood pressure.

Even when the daily blood pressure mean is acceptable, too large a circadian amplitude of blood pressure largely increases cardiovascular disease risk. Autogenic training (N = 11), a non-pharmacologic intervention capable of lowering an excessive blood pressure variability, may be well-suited for MESOR-normotensive patients diagnosed with circadian-hyper-amplitude-tension (CHAT). Not all anti-hypertensive drugs affect blood pressure variability. Accordingly, long-acting carteolol (N = 11) and/or atenolol (N = 8) may be preferred to captopril retard (N = 13), nilvadipine (N = 8), or amlodipine (N = 7) for midline-estimating statistic of rhythm (MESOR)-hypertensive patients with CHAT. Prospective outcome studies are needed to assess whether the relative merits of these treatments are in keeping with their effects on blood pressure and blood pressure variability.

Effects of diaphragmatic breathing on ambulatory blood pressure and heart rate.

Psychological procedures, such as self-hypnosis in the form of autogenic training, have been proposed for correcting a deviant, e.g., high blood pressure (BP). In view of the overwhelming evidence for the circadian (CD) stage dependence of any treatment effects, the CD stage dependence of the effects of diaphragmatic breathing (DB) on BP and heart rate (HR) was explored in data from a clinically healthy normotensive subject who, following 3 weeks of ambulatory monitoring as a reference standard, measured BP and HR with a manual monitor at 1-min intervals for 5 min before and after DB (three deep diaphragmatic breaths) and who performed DB for about 2 weeks at about 2-h intervals while awake. The 3-week data series were analyzed by cosinor, involving the least-squares fit of cosine curves with periods of 24, 12 and 168 h. A CD rhythm was detected for BP and HR (P < 0.001 in each case), peaking in the afternoon. Some about-weekly (circaseptan; CS) BP rhythms and 12-h (circasemidian) components were also statistically significant. DB was found to reduce systolic (S) BP. Overall, SBP decreased by 5.9 +/- 0.8 mmHg (P < 0.001) and diastolic (D) BP by 1.4 +/- 0.8 mmHg (P < 0.005), while HR remained at about the same average. The effect of DB on BP was CD-dependent, the largest response occurring in the afternoon, 2-3 h before the peaks in SBP and DBP found in the reference data of the same subject. There was also a 5-10% decrease in SBP around the weekend (Friday, Saturday and Sunday). The results on a single subject suggest the need to collect similar data on others for optimizing by clock-hour, day of the week, and eventually by the marker rhythms BP and/or HR the best times for DB and other procedures. The personalized best time for people on different work/rest schedules for relaxation may be several hours before their BP has reached its highest point in the 24-h span. HR may serve as a marker for DB timing, but the effect on HR of DB was only of borderline statistical significance in the subject investigated.

Circadian telomerase activity and DNA synthesis for timing peptide administration.

DNA synthesis and telomerase activity were assessed in nude mice transplanted with hepatic carcinoma. Hepatic cancer cells (SMMC-7721) were implanted into both flanks of each of 14 BALB/C mice synchronized in 12 h of light alternating with 12 h of darkness (LD12:12) for 4 weeks. At 7 timepoints, tumor samples were collected for measurement of cellular DNA content by flow cytometry and telomerase activity by PCR-ELISA assay. Cosinor analyses determine a 24-h rhythm for all variables, showing a similar timing for the DNA-synthesis phase and telomerase activity. These results provide a model for exploring optimal timing of chronotherapy with peptides, especially for treatment with telomerase inhibitors.

Salivary CA130 with and without unilateral autonomic parotid denervation of rats fed different diets.

BACKGROUND: Tumor markers such as CA130 can be determined in human whole saliva. Saliva represents an attractive body fluid for longitudinal studies. MATERIALS AND METHODS: CA130 was determined in parotid saliva from 8 rats fed different diets, with or without autonomic denervation. RESULTS: CA130 could be determined in parotid saliva of rats, irrespective of diet and/or autonomic denervation. Whether the numerical decrease in CA130 observed after autonomic denervation is statistically significant requires further work. CONCLUSIONS: Since salivary CA130 has been shown to decrease following treatment with anti-cancer drugs in humans, the ability to determine this tumor marker in rat saliva opens new opportunities for optimizing cancer chronotherapy in the experimental laboratory.