Circaseptans

A "human" biologic week, as a feature of nature, not only culture, can be found in data from antiquity. In a histogram prepared by Hildebrandt and Bandt-Reges of the spans elapsed between the onset of symptoms and the "critical day" of fever recorded in their populations of patients by Hippocrates (c. 640 BC-c. 370 BC), Galen (c. 129-c. 200) and Avicenna (980-1037), peaks appear at 7 days and multiples of 7 days; we validate by [chi]² the non-randomness of the patterns (Figure 8/I; left). There is more modern evidence as well documenting the need to consider and to optimize concomitantly circaseptan and circadian drug administration patterns. It stems from studies on the immunomodulation of malignant growth (Figure 8/V) in LOU rats bearing an immunocytoma and kept on a schedule of light (L) and darkness (D) alternating at 12-hour intervals (LD12:12); the effect of a 7-day pre-treatment with lentinan (Rx) was compared to that of pre-treatment with saline (S): the growth of the malignant tumor was inhibited and survival time was lengthened when this immunomodulator was administered daily during L, the rat's resting span, in doses varying sinusoidally from day to day as a circadian-circaseptan chronotherapy (Chr); the rest span, however, is not the usual treatment time for humans, and a systematic sinusoidal variation of doses from day to day also is not the standard practice. When treatment was given (as would be convenient for humans) during the rat's usual activity span (D) according to the habitual equal daily doses (of many conventional human treatment schedules), i.e., homeostatically (H), tumor growth was accelerated and survival shortened.

Outcomes of immunotherapy, such as that by lentinan, depend on the chronome. Circadian and circaseptan components, and also circannual ones (not shown here), should underlie the design of treatment administration schedules. Many added developments contributed to the formulation of the chronome, a multifactorial multi-frequency rhythm and trend structure. These included 1) the need to treat according to a broader-than-circadian schedule; 2) the practicability of assessing the other components of a rhythm spectrum automatically by modern recorders; 3) the demonstration of the genetic basis of these rhythms; 4) the interdigitation of rhythms with a) trends of growth, development, maturation, as well as aging, and b) with trends accompanying an elevation of disease risk or illness and treatment; and 5) the response of rhythms and trends to influences from the solar system and from beyond.

The endogenicity of circaseptans is supported by their manifestation after a single stimulus. During the regeneration of the kidney after unilateral nephrectomy or contralateral ischemia studied by Hübner (not shown), there are sharp peaks occurring about every 7 days in DNA labelling and mitotic activity; cosinor analyses validate the circaseptans (Figure 8/II). An about-7-day pattern also characterizes the rejection episodes following the allografting of a kidney, a heart or a pancreas in rodents, or of the human kidney in different institutions and continents (Figure 8/I, right), irrespective of the day of the week when the surgery is performed.

The endogenicity of circaseptans is also supported by their free-running from the social 7-day routine. The urinary 17-ketosteroid excretion by a clinically healthy man (CH) living on a precise 7-day social routine is circaseptan-rhythmic for a decade, with a one-week synchronized period and a peak on Wednesdays or Thursdays, until massive doses of testosterone are self-administered, when the circaseptan acrophase starts drifting, scanning more than a full week over the ensuing several years: the circaseptan rhythm is then characterized by a period close to but statistically significantly shorter than precisely one week (Figure 8/III, top). The circaseptan advancing free-run is found in the presence of a delaying circasemiseptan, with a period slightly longer than 3.5 days (not shown). Supporting the endogenicity of circaseptans and circasemiseptans is their free-run. The observation that the circasemiseptan lengthens while the circaseptan shortens suggests some extent of independence of these two components from each other and certainly from urine volume that remains 7-day synchronized (Figure 8/III, second row).

Circaseptan (and circadian) components characterize the blood pressure and heart rate of a woman who became amenorrheic while spending over 100 days isolated in a cave without time cues (SF). Upon return to a societal routine, her circadians quickly resynchronized to the societal day (not shown), but her circaseptans failed to do so for weeks, until menstruation was reinduced by hormones (Figure 8/III, third row). That menstruation may synchronize circaseptans is also apparent in psychophysiologic data in health and in pre- or overt pathology. A phase-drifting, if not free-running, circaseptan is also found in the creatinine excretion rate of a patient with a müllerian-duct adenocarcinoma involving the ovary (EH) (Figure 8/IV).

Circaseptans are prominent in the blood pressure of babies at term (Figure 9/I, top). Circadian and circaseptan changes in several vital signs such as systolic and diastolic blood pressure of very pre-term babies (with a gestational age at birth less than 33 weeks), assessed during the first 3 weeks post-partum, show a circaseptan-over-circadian prominence. The circaseptan component of systolic blood pressure of a very pre-term baby predominates over the circadian one (Figure 9/I, second row) during his first 4 months of life. Ontogeny may reveal the basic nature of circaseptans both in terms of the prominence of the circaseptan amplitude (e.g., in respiratory rate; Figure 9/I, bottom) and the admittedly wobbly phase drift compatible with a free-run of the circaseptan period. Circaseptans and circasemiseptans also characterize the incidence of sudden infant death syndrome.

A large prominence of circaseptans is observed in morbidity/mortality statistics of all ages. Circannuals, circaseptans and circasemiseptans are found (along with circadians; not shown) in morbidity/mortality statistics of human sudden adult death, myocardial infarctions and strokes, among millions of other emergency situations (Figure 9/III). These circaseptans and circasemiseptans retain stable phase characteristics over time (Figure 9/II, middle) and represent a rather general feature, as suggested by a worldwide summary of the incidence of myocardial infarctions (Figure 9/II, bottom). Circaseptans and circasemiseptans are also prominent features of likely underlying mechanisms such as the glutathione content of human platelet-rich plasma in vitro (Figure 9/IV).