Toward a 'chron-sensus' on neuroimmunomodulation, with 'modulation' operationally and inferentially defined.
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Biomedical subjects
Publications and source records attributed to F Halberg.
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Adrenalectomy predisposed the C3HeB/FeJ Mouse to tumor from a low dose of tumor cells, derived from a C3H spontaneous mammary adenocarcinoma. Sham surgery had a similar effect. In contrast, ovariectomized females, intact females, and male mice did not allow the low dose of cells to develop into a tumor. In order to better understand the role of hormones on the immune system controlling tumor growth, normal C3HeB/FeJ mice were studied for the effect of corticosterone or estradiol on splenic lymphocyte surface antigen expression. Adrenalectomy and ovariectomy caused a decrease in the percentage of all T cell subclasses and an increase in absolute numbers of immunoglobulin-bearing cells. Reconstitution of ovariectomized mice with estradiol did not significantly alter lymphocyte cell surface antigen expression. In contrast, injection of corticosterone into adrenalectomized mice brought these values to normal. Further study on normal mice placed on a 12:12-hr light:dark schedule showed that the hours after lights on (HALO) had a significant effect (analysis of variance) on body temperature, percentage of splenic B cells, T pan, T helper and T suppressor cells, and absolute numbers of T pan cells. Brain dehydroepiandrosterone sulfate correlated positively with T pan lymphocytes, but showed no significant effect on HALO. In contrast, body temperature showed a strong circadian rhythm (P less than 0.001). In addition, the presentation of estrus was circadian rhythmic (P = 0.003) with 58% of mice in estrus at 16 HALO and only 8% at 4 HALO. Multiple regression analysis revealed body temperature was strongly associated with absolute numbers of splenic T lymphocytes and their subsets, as well as percentage of B lymphocytes, Thy 1.2-, and Lyt-2-bearing cells. Similarly, HALO and estrous cycle stage were associated with percentage of T helper cells. The data showed that body temperature and hormones were associated with the cell surface antigens on lymphocytes and suggest that they affect lymphocyte function.
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Urinary melatonin excretion is lower in East-Asian (Japanese) than in North-American (whites of mixed ethnic origin) women. Moreover, a statistically significant circadian rhythm is demonstrated by population-mean cosinor in the data pool from both groups of women. Furthermore, statistical significance characterizes interactions of effects from geographic differences (between ethnic groups) with temporal factors. Such spatio-temporal interactions await further scrutiny with a view inter alia of carcinogenesis as it is influenced by a spectrum of intermodulating rhythms.
Studies in this laboratory on the nuclear binding sites (acceptors) for progesterone receptor in the developed chick oviduct have resulted in the detection of seasonal variations in the levels and functions of the receptor. Cytosol preparations obtained from the chick oviducts during the winter/spring period between January and May display reduced receptor levels as well as a loss of the capacity of the receptor to bind to nuclear "acceptor" sites in vitro. The binding of [3H]P-R to whole chromatin or purified acceptor proteins reannealed to DNA display the same rhythm. No such rhythm is detected for the binding of P-R to pure DNA. Computer analysis of the data, using least squares method to fit the data to cosine curves, shows a significant fit indicating a circannual rhythm in P-R binding to the acceptor protein-DNA complex but not to pure DNA. The nuclear binding in vivo, achieved by injecting [3H]progesterone into the wing vein and analyzing the radioactivity localized in the oviduct nuclei, also displays a similar rhythm. These results support that native nuclear acceptor sites for progesterone in the chick oviduct represent protein-DNA complexes and not pure DNA. The failure of P-R to bind the nuclear acceptor sites in vivo and in vitro during this period can be explained by the two subunit hypothesis of Schrader and O'Malley, whereby one of the two subunits is absent or inactive during this period.
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Autorhythmometry of blood pressure by an individual over an age-span of 67 to 72 years showed a strong circadian rhythm superimposed upon significant circaseptan and circannual rhythms. Automatic BP monitoring with an Arteriosonde throughout 24-hour spans on 4 separate occasions, before and during treatment, also indicated a prominent circadian BP rhythm and a treatment-related reduction in circadian mesor. The concept of a blood pressure mesor reference for the antimesor-hypertensive treatment constitutes a valuable guideline in the control of "familial" mesor-hypertension.
During the span from 50 to 100 days and beyond, the male stroke-prone Okamoto rat develops systolic blood pressure measures in excess of 200 mm Hg. In the course of developing such a marked elevation in systolic blood pressure mean, this intermittently handled male Okamoto rat exhibits a statistically significant circadian rhythm with large amplitude. This amplitude may represent, at least in part, a response to intermittent handling; it is several times larger than the amplitude for spontaneously mesor-hypertensive (but not stroke-prone) female animals of the same age.
Methods are presented for qualifying clinical reference intervals, for individuals as well as peer groups, according to circadian and other rhythms, using chronobiologically-defined single samples or time series.