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Biomedical subjects

F Halberg

Publications and source records attributed to F Halberg.

At least 217 records · Page 12Linked to original sources
PubMed1982

Circadian stage dependence of cis-diamminedichloroplatinum lethal toxicity in rats.

Renal physiology is circadian rhythmic. The major toxicity of cis-diamminedichloroplatinum (cisplatin) is irreversible renal damage. A single dose of cisplatin (11 mg/kg) was given to groups of standardized female Fischer 344 rats at one of six equispaced circadian stages. A statistically significant effect of time of injection upon tolerance was found by chi 2 analysis. Differences of 3- to 8-fold in survival rate of 50% mortality and a nearly 3-fold difference in long-term survival depended on circadian timing of cisplatin administration. Cisplatin timing resulting in optimal tolerance was similar from study to study. Additional 0.9% NaCl solution was administered with cisplatin in three experiments and resulted in an increase in overall mean survival time. It also resulted in an amplification of the survival rhythm without changing its timing. The increase in survival resulting from 0.9% NaCl solution loading, when compared to controls receiving cisplatin alone, was also highly time dependent. A 52% improvement in mean survival time was achieved in those animals receiving cisplatin and 0.9% NaCl solution at the most favorable circadian stage, as compared to a 20% improvement when this regimen was administered at an inopportune circadian stage. The safest time for cisplatin administration is near the midactivity span, shortly after the maximum of the circadian rhythm in rectal temperature.

Animals↗
PubMed1982

Reduction of cis-diamminedichloroplatinum nephrotoxicity in rats by optimal circadian drug timing.

A prominent circadian rhythm in the nephrotoxicity of a therapeutic dose of cis-diamminedichloroplatinum (cisplatin) is demonstrated in female Fischer rats. Rats were randomized to receive two doses of either cisplatin or 0.9% NaCl solution 14 days apart at the times of either high or low values in their circadian rhythm of urinary volume. Toxicity was assessed by measuring changes in body weight and changes in the 24-hr means of urinary volume, blood urea nitrogen, and urinary beta-N-acetylglucosaminidase (NAG) activity. Toxicity was least in rats which received the drug near the circadian maximum of urinary volume. Conversely, rats which received the same dose of drug near the circadian minimum of urinary volume lost more weight and exhibited a 2-fold increase in the 24-hr mean of urinary volume, a 3-fold rise in the 24-hr mean of blood urea nitrogen, and a 5-fold increase in the 24-hr mean of urinary NAG activity. A positive correlation between urinary NAG at the time of cisplatin administration and the extent of cisplatin nephrotoxicity was demonstrated (p less than 0.02). A correlation also was found between tissue NAG concentration and tissue uptake of cisplatin (p less than 0.001). A marked circadian rhythm of NAG activity in proximal tubular cells may contribute to the prominent circadian rhythm in murine renal tolerance for cisplatin.

Acetylglucosaminidase↗
PubMed1981

[Plasma cortisol concentrations and circadian rhythm in healthy young Japanese and caucasians (author's transl)].

We report herein a method of solid-phase radioimmunoassay (RIA) for assessment of plasma cortisol concentration using 125I-labeled ligand [CORTCTK-125]. Plasma cortisol concentrations and its circadian rhythm in healthy young Japanese and American whie women were also evaluated using CORTCTK-125. Nineteen Japanese women, of an average age of 20.3 +/- 0.1 years, and 12 Caucasians of mixed ethnic origin (Minnesota), average 20.0 +/- 0.5 years, were studied using a similar protocol. The distribution of the menstrual stage of the two groups was similar. Blood was drawn from each subject into EDTA containers at 4-hour intervals starting at 0800 on one day and was continued for the ensuing 24 hours. The samples were immediately placed in a refrigerated centrifuge at 4 degrees C, and then stored at -20 degrees C until the assay. The samples from Minnesota were packed in dry ice and brought by air to Japan. Determinations of plasma cortisol concentration in samples from both groups were carried out at Kyushu University. Advantages of the solid-phase RIA method are as follows: (1) 0.05 ml of plasma or serum was sufficient for determination of plasma cortisol concentrations, (2) no other solvents or solutions for the extraction or purification were required, (3) the procedure was simple and readily facilitated, and (4) the concentration of cortisol in heparin-plasma was somewhat higher than that in serum or EDTA-plasma, but there was no statistical difference. Plasma cortisol concentrations in the samples from the Japanese (19.73 +/- 1.44 on the first and 18.94 +/- 1.32 microgram/dl on the second day) and that of the American group (17.48 +/- 2.38 and 19.37 +/- 2.16 microgram/dl, respectively) at 0800 was similar. The average value of 7 determinations at 4-hour intervals was 11.01 +/- 2.00 microgram/dl in the Japanese and 10.29 +/- 1.05 microgram/dl in the American group. A remarkable and similar circadian rhythm was observed in both groups with a peak at 0800 and with nadirs at 2000 in the Japanese (4.80 +/- 0.45 microgram/dl) and 2400 in the American group (5.18 +/- 0.83 microgram/dl). There were statistically significant differences between the values at the peak and the nadir. The related subjects were then classified into Group-F (9 subjects) and Group-T (9); the former included high body mass index [BMI: body weight(kg)/body height(m)2] of more than 24.0, and the latter included a relatively lower BMI of less than 21.5. The circadian rhythm of both groups revealed a similar pattern, whereas plasma cortisol concentration was always higher in Group-F than in Group-T, at all 7 determinations. There were no significant differences except for the value at 0400. Furthermore, the average values of plasma cortisol concentration and circadian rhythm were compared; the group with a larger body surface area (BSA) (Group-L) and the group with a smaller BSA (Group-S). No difference was found in the plasma cortisol concentration of Group-L and -S, and the circadian rhythm was similar in both groups...

Adult↗
PubMed1981

Circadian aspects of serum prolactin and TSH lowering by bromocriptine in patients with prostatic hypertrophy.

Bromocriptine mesylate lowers the serum concentration of prolactin and TSH in patients with prostatic hypertrophy as a function of drug administration time. The effect of a 2.5-mg dose in lowering these two hormones in presumably similar patients is statistically highly significant and relatively large at unusual test times (in the evening); at other, conventional test or administration times (early morning or midday), it is smaller, questionable, or not demonstrable with the dose and conditions used. Dosing without timing may lead to reduced effect or lack of effect, ambiguity and controversy, and lack of timing may account for the circumstance that an effect of bromocriptine upon TSH in human serum was not previously established. Rigorous assessment of the effect of bromocriptine mesylate upon circulating TSH and prolactin requires consideration of the entire spectrum of rhythms, ultradian and infradian as well as circannual. The circadian approach here analyzed represents a step toward that goal and indicates that the circadian frequency is a critical determinant of this response. Manipulation of TSH concentration in serum, in turn, is of interest in view of the demonstrated alteration of the circannual TSH rhythm in patients with prostatic cancer.

Aged↗
PubMed1981

Circadian variations in cardiovascular parameters during sleep deprivation. A noninvasive study of young healthy men.

Twelve subjects were kept awake for 64 h under conditions of isolation from external time cues. Activity was sedentary and kept as constant as possible over time, as was intake of food and drink. Cardiovascular variables--blood pressure, heart rate, contractility (IJ-amplitude from ballistocardiogram), T-wave amplitude, QRS, PQ and QT intervals--were assessed every 3 h. At the same intervals, urine samples for catecholamine analysis were obtained. Data were analyzed by analysis of variance and cosinor techniques. Adrenaline excretion showed a pronounced circadian rhythm. Noradrenaline excretion and IJ amplitude showed much weaker rhythmicity, statistically significant only with the cosinor technique. The remaining variables showed no rhythmicity with either technique. It was concluded that constant conditions (including sleep deprivation) markedly disturb or even obliterate the circadian rhythms of cardiovascular variables and urinary noradrenaline excretion. It was also concluded that most of the amplitude of cardiovascular circadian rhythms measured under habitual sleep/wake conditions must be due to the alternation between sleeping and waking. The present data do not, however, rule out the existence of selfsustained circadian rhythmicity in cardiovascular variables; a design including continuous wakefulness may well have concealed endogenous low-amplitude rhythms.

Adult↗
PubMed1981

Ageing and circadian rhythm of plasma renin and aldosterone.

Five men and 8 women, 60-69 yr of age, and 4 men and 5 women, 17-37 yr of age, volunteered for this exploration of possible age-related changes in circadian-rhythm (CR) characteristics of radioimmunoassayable plasma renin (PRA) and aldosterone (PA). Blood was drawn at 06.00, 08.00, 12.00, 18.00, 20.00 and 24.00 from recumbent subjects on a habitual sodium intake of 120-140 mEq/24 h. Time-qualified data of PRA and PA, fitted by a 24-h cosine curve, were summarized by a population mean-cosinor method. Circadian characteristics were compared by a multivariate analysis using Hotelling's t2 test. Rhythmometry reveals in the elderly women a lower mesor (P less than 0.001) and amplitude (P = 0.036) of the CR in PRA and a higher mesor and amplitude (P = 0.021 and P = 0.020, respectively) of the PA-CR. The PRA acrophase is delayed (P less than 0.001) in the elderly women (04.40 vs. 08.04) while the timing of the PA acrophase is similar in the age groups of women compared (05.52 vs. 05.20). These differences found in women were not observed in the smaller groups of men. The seventh decade of life may be characterized by an internal circadian desynchronization between the major components of the renin-angiotensin-aldosterone system. A sex-dependent amplification of the extent of circadian variation in aldosterone may precede a decrease in the circadian amplitude occurring during the eighth decade of life, as a sign of the adrenopause in women.

Adolescent↗
PubMed1981

Changes with age characterize circadian rhythm in telemetered core temperature of stroke-prone rats.

In a stroke-prone (SP) strain of laboratory rats, aging is associated with quantifiable changes of the circadian rhythm in body core temperature: (1) its timing becomes less tight, as revealed by a larger standard error of the acrophase (the peak in the 24-hour cosine function best approximating all data) and (2) the acrophase in old SPs occurs earlier than in young ones--quite apart from (3) a decrease in circadian amplitude reported earlier. These results gain particularly in interest in the context of the recent finding that a large (approximately 90 degrees) acrophase-advance is associated with bilateral lesions of the suprachiasmatic nuclei in inbred (non-SP) Fischer rats. These observations may be of interest to those developing models of aging functions in disorders with blood pressure elevation.

Aging↗
PubMed1981

Familial and individualized longitudinal autorhythmometry for 5 to 12 years and human age effects.

Statistically significant and biologically interesting changes (no decrease and even an increase) with age may characterize peak expiratory flow. This variable and others were investigated in the same persons by dense measurements for several years. A possible health benefit from the monitoring of personal health thus becomes apparent. The relative prominence of changes in body core temperature and 2-min estimation with circadian rhythms, as compared to those with aging is of basic interest. The population-based presumption that aging necessarily involves an increase in overall-systolic and diastolic blood pressure is here aligned with an unusually well documented exception to this view.

Adolescent↗
PubMed1981

Circadian rhythms of plasma renin, aldosterone and cortisol on habitual and low dietary sodium intake.

To examine the effects of reducing sodium intake upon the renin-angiotensin-aldosterone system (RAAS), 5 healthy men and 5 healthy women, 17-37 years old, living under standardized conditions, were sampled around the clock, once on habitual and once on restricted sodium intake. Plasma renin activity (PRA), aldosterone (PA) and cortisol (PC) were determined by radioimmunoassay. All three variables were found to exhibit a statistically significant circadian rhythm, both on habitual and restricted salt intake. After salt restriction, an increase in midline-estimating statistic of rhythm (mesor) of PRA and PA, but not of PC, was observed. The acrophase (an estimate of the time of high values) for PC lagged behind that for PRA and PA. This difference in acrophase was of specially high statistical significance when subjects were on a sodium-restricted diet. These results demonstrate the importance of inferential statistical so-called rhythmometric methods: parameters such as the acrophase can also be used for the assessment of novel effects and for a quantification in time. The derivation of confidence intervals for each rhythm parameter allows one to verify that a given variable exhibits values bracketing an average not only between a higher and a lower, but also between an earlier and a later limit. Changes that may involve only the acrophase, such as a lead or lag, as here noted, are then detected and are of factual as well as methodological interest.

Adolescent↗
PubMed1981

Characterisation of breast skin temperature rhythms of women in relation to menstrual status.

Circadian breast skin temperature rhythms were characterised throughout the menstrual cycle, for various locations on the left breast of ambulatory women. All subjects exhibited highly significant circadian rhythms (P less than 0.001). Changes in rhythm parameters, such as the mesor, amplitude and acrophase, were observed during the menstrual cycle. No consistent trend in these rhythm parameters was observed between subjects in relation to menstrual cycle stage. Experimental and statistical techniques used to characterise circadian rhythms in pre-menopausal women were applied to a post-menopausal woman with primary breast cancer. Comparison of rhythm parameters associated with the tumour area and corresponding site on the contralateral breast showed abnormal thermal characteristics such as elevated mesor values, decreased amplitude as well as changes in the timing of the acrophase. These properties may be exploited for the early detection of breast cancer. The project also involved the design and testing of an ambulatory device, known as the 'chronobra', for the measurement of breast skin temperature. The performance of the chronobra was in close agreement with reliable, conventional equipment. The chronobra now allows studies of breast skin temperature rhythms associated with breast disease to be extended.

Adolescent↗
PubMed1981

Mammary cancer risk: circulating TSH and prolactin, fibrocystic breast disease in chronoepidemiologic perspective.

Classical epidemiology associates human breast cancer with several risk factors including, among others, so-called preclinical hypothyroidism, fibrocystic disease of the breast (FM), and hyperprolactinemia. Relationships among FM, hyperprolactinemia, and thyroid function are of interest because of the possibility of multiple risk combinations. Prolactin and TSH (the latter as a presumed index of preclinical hypothyroidism) undergo rhythmic changes and hence should be chronobiologically investigated. Serum samples obtained at 4-hour intervals throughout a 24-hour span from 23 healthy women and from 25 women with FM (histologically verified) here summarized suggest that circadian mesor-hyperprolactinemia is a feature associated with FM. In a broader context, however, such impressions and an often considered modest impairment of thyroid function in some patients must be viewed in the light of new chronobiologic rules. These include a reciprocity of the circannual amplitudes of TSH and prolactin in relation to breast cancer risk, revealed by cooperative studies. A yet broader chronoepidemiologic view reveals that the reciprocal relation of the circannual amplitudes of circulating TSH and prolactin is (sex) inverted in patients with cancer of the prostate.

Adult↗
PubMed1980

Amplitude-reduction and acrophase-advance of circadian mitotic rhythm in corneal epithelium of mice with bilaterally lesioned suprachiasmatic nuclei.

Lesions of the suprachiasmatic nuclei (SCN) have been reported to disrupt or abolish circadian rhythms of motor activity and body temperature as well as of several neuroendocrine functions. This study was undertaken to determine any effect the SCN may have on the prominent circadian rhythm characteristic of the mitotic index of the corneal epithelium. Singly caged adult mice of both sexes were fed ad libitum and standardized to 12 hours of light alternating with 12 hours of darkness. Animals were divided into experimental and control groups. Later they were killed in subgroups at the time intervals of 0800, 1200, 1000, 0000, 0400 hour. Mitotic counts were determined on both right and left corneas of all mice. The data were plotted separately for both groups and reflect colony variation. We conclude that major lesioning of the SCN or tis efferent projections disturbed but did not abolish the rhythm. In animals with unilateral lesions of the SCN, the mitotic index was consistently lower in the ipsilateral cornea. The mitotic index for animals with lesions which missed the SCN or its efferent projections did not differ from controls. The nuclei appear to function as pace-resetters and amplifiers of the rhythm studied.

Animals↗
PubMed1980

Differences and similarities among circadian characteristics of plasma renin activity in healthy young women in Japan and the United States.

A circadian rhythm of plasma activity (PRA) was demonstrated for both Japanese and North American women, the latter mostly Caucasians of mixed ethnic origin. The results were based on blood samples withdrawn at 4-hour intervals during a 24-hour span (in March 1978) from 20 subjects from Fukuoka (average age 20.4 +/- 0.1 years) and 16 subjects from Minneapolis (average age 20.2 +/- 0.4 years). The rhythms in the two populations showed similarities in some characteristics and differences in others. The timing of high values, i.e., of acrophases, objectively assessed by curve-fitting (and of corresponding 95 per cent confidence limits) was at 07(36) (05(00), 10(16) and 06(32) (03(00), 10(00) for Japan and USA, respectively. As objective measures of the extent of predictable rhythmic change mean amplitudes, in nanograms per milliliter per hour (ng/ml/hour), were similar (0.31 and 0.32); a statistically significant difference (P less than 0.05) was found in mean amplitudes expressed as percentage of the rhythm-adjusted average. Mean rhythm-adjusted average values (mesors) were lower in women from Japan than in those from the United States: (1.64 +/- 0.14 and 2.39 +/- 0.23 ng/ml/hour, respectively; P less than 0.01). A statistically significant difference in dietary salt, indicated by differences between the Japanese and North American women in the urinary excretion of sodium and chloride (P less than 0.05), almost certainly contributed to these results.

Adolescent↗
PubMed1980

Circadian placebo and ACTH effects on urinary cortisol in arthritics.

The effect of placebo and ACTH-1-17 (Synchrodyn, Hoechst) upon urinary free cortisol was examined at 5 different circadian stages on 10 men with Steinbrocker Stage II-III rheumatoid arthritis. A mean cosinor analysis of urinary cortisol data from the subjects prior to treatment with either ACTH or placebo revealed a statistically highly-significant rhythm. A circadian variation in a response of urinary free cortisol to a placebo was also seen. Moreover, the response of the midline-estimating statistic of rhythm (rhythm-adjusted circadian average) of urinary free cortisol to ACTH-1-17 by patients with rheumatoid arthritis is circadian rhythmic. This reactivity rhythm is out of phase with the spontaneous rhythm in urinary cortisol acrophases-in the tests limited thus far to midsummer. The further assessment of the circadian component in the context of broader interactions by rhythms with other frequencies in various conditions in health and disease is warranted by the demonstration of rhythms here presented for men with rheumatoid arthritis.

Adrenal Glands↗
PubMed1980

Rhythm-adjusted age effects in a concomitant study of twelve hormones in blood plasma of women.

The concentrations of luteinizing hormone, prolactin, estrone, estradiol, 17-hydroxyprogestrone, cortisol, aldosterone, dehydroepiandrosterone, thyrotropic hormone, triiodothyronine, thyroxin and insulin were determined in blood plasma obtained from women aged 15 to 59 years. Blood was sampled at intervals of 20 to 100 min throughout 24-hour spans in each of the four seasons and (in the case of cycling women) in four different stages of the menstrual cycle. With such sampling allowing for rhythmic and other fluctuations over a broad time scale it was possible to demonstrate statistically significant effects of age on hormones associated with the menstrual cycle (luteinizing hormone, prolactin, estrone, estradiol and 17-hydroxyprogesterone) and on dehydroepiandrosterone, but not on the remainder. The amplitude of circadian rhythms in several of the hormones also varied with age, thus affirming the value of sampling throughout this particular rhythm.

Adolescent↗
PubMed1980

Circannual rhythms in steroid receptor concentration and nuclear binding in the chick oviduct.

For 3 yr, 1-yr synchronized circannual rhythms were found for the chick oviduct weights, amounts of soluble protein, concentrations of the progesterone receptor in this organ, and capacity of this steroid-receptor complex in cytosol in bind in vitro to deoxyribonucleoprotein acceptor sites. By fitting the data with 1-yr cosine curves, statistically significant circannual rhythms were described for all of these rhythms, with high values occurring in the late summer and low ones in the late winter. Interestingly, no statistically significant rhythms were described for the binding of the progesterone-receptor complex to pure DNA. By analyzing both receptor and nuclear protein preparations isolated at different times of the year, changes in the receptor were found to underlie the rhythms in nuclear binding in vitro. Studies in vivo revealed similar rhythms for the nuclear translocation and binding of both progesterone and estrogen and for the progesterone-induced changes in RNA polymerase II activity. In each instance, marked reductions in nuclear binding and steroid-induced changes in the polymerase activity occurred in the late winter. Blood levels of the 3H-labeled steroids did not vary throughout the year, so differences in whole body metabolism and disposition of the steroids were ruled out as factors in the in vivo rhythms. These results support the validity of the cell-free binding assays and the hypothesis that certain protein-DNA complexes, and not pure DNA, represent the natural acceptor sites for the progesterone receptor. Furthermore, these rhythms emphasize the fact that steroid receptors are not constant entities but change in both amount and function. Although the exact cause of these rhythms in the progesterone receptor is not understood, a rhythm in estrogen action on the oviduct is strongly suggested. These rhythms in the steroid receptors may play a role in seasonal reproduction and molting in animals.

Animals↗