Endothelin-1's chronome indicates diabetic and vascular disease chronorisk.

Plasma endothelin-1 was measured around the clock in 72 subjects. Cosinor methods were used to assess circadian and other recurrent variation and trends, that is, the time structure (chronome) of this peptide. Multifactorial analyses of variance and linear regressions assessed chronome alterations associated with different risk factors: diabetes, obesity, high cholesterol, high blood pressure, vascular disease, smoking, and age. The rhythm-adjusted mean (MESOR) of endothelin-1 is elevated in diabetes and vascular disease. Diabetes is also associated with a larger circadian amplitude. A circadian variation in a subgroup of low-risk subjects is modulated by components with both lower and higher frequency.

Serum melatonin in multiple myeloma: natural brake or epiphenomenon?

Melatonin (MEL), the main hormone produced by the pineal gland, seems to exert antineoplastic activity both in vitro and in vivo. Moreover, several studies reported increased melatonin blood levels in cancer patients. Plasma melatonin concentrations were determined in 46 patients with multiple myeloma and in 31 age matched healthy subjects (57.8 +/- 6.9 versus 55.2 +/- 8.9 years). Venous blood was drawn between 7.30 and 9.30 a.m. and melatonin was assayed using a commercially available radioimmunoassay. The data were analysed by Student's t test and results reported as mean values +/- standard deviation. The patients with multiple myeloma showed significantly higher mean melatonin serum levels than healthy subjects (21.6 +/- 13.5 versus 12.1 +/- 4.8 pg/ml; p < 0.001). This behaviour could actually represent a phenomenon secondary to an altered endocrine-metabolic balance caused by an increased demand of the developing tumor. On the other hand, the increased melatonin secretion might be considered as a compensatory mechanism due to its antimitotic action and therefore as an effort to secrete substances capable of regulating neoplastic growth.

Daytime circulating melatonin levels in smokers.

AIMS AND BACKGROUND: Melatonin secretion is required to be a potential inhibitor of the development and growth of tumors, and cigarette smoking is a well established risk factor for cancer at various sites. METHODS: Circulating melatonin levels of 20 smokers and 20 non smokers (controls), sampled at the same hour from awaking in order to obtain a comparable circadian synchronization, were compared. RESULTS: Our data showed higher melatonin circulating levels in smokers (17.44 +/- 1.8 pg/ml) than in nonsmokers (9.77 +/- 1.4 pg/ml). CONCLUSIONS: The causes, mechanism and meaning of this phenomenon are still unknown. The most attractive hypothesis considers higher melatonin levels in smokers as an attempt to counterbalance cellular growth stimulus, a natural "brake" mechanism to restrain the proliferation of normally differentiated tissues: smoke is a prominent risk factor for several different tumors.

Chronobiology, growth hormone and healthy and malignant growth.

Chronobiology, the computer-aided science (logos) of life (bios) in time (chronos), provides novel concepts, tools and facts for those concerned with mitosis, growth and growth hormone (GH). GH concentrations in human plasma demonstrate a statistically significant circadian rhythm on a 6h as well as on a 24h rest-activity cycle. On a 24h routine of light (L) and darkness (D), alternating at 12h intervals, and in continuous D, circadian mitotic rhythms in mice persist as a feature of growth or regeneration. A circadian cell cycle commences with an increase in phospholipid labeling, followed by an increase in cytoplasmic RNA formation, preceding, in regular sequences, an increase in nuclear DNA formation and the next mitotic peak in those cells that are dividing in a growing or regenerating (reversibly "post-mitotic') rodent liver. About 5-day (presumably estral) and about 7-day (circaseptan) components as well as circadians are resolved as a spectrum of mitotic rhythms in rodent cornea. The effects of hormones such as GH or a synthetic ACTH analogue, ACTH 1-17, depend upon the circadian cell cycle stages when the agent is administered. No effect or statistically significant effect can be the result only of 1) the timing of a fixed dose of GH or 2) of the timing of the samples taken to investigate any effect. For both the timing of administration and the assessment of effects, a multifrequency spectrum of rhythms, if taken into account, can provide (in lieu of a considerable and often formidable source of variation) a new critical dimension of growth and development.

Ultradian (12-hr) significant component in serum prolactin of healthy women and patients with fibrocystic mastopathy.

The 4-hr sampling schedule for a single day demonstrated a prominent circadian rhythm of prolactin (PRL) in clinically healthy women and in mastopathy (FM) patients (with mesor hyperprolactinemia). This chapter reports on differences in time series of serum PRL observed between FM patients and healthy women in the follicular and luteal phases. Thirteen FM patients and six healthy women (controls) were sampled at intervals of 60 min for 24 hr in the two phases of the menstrual cycle. Serum PRL was determined by RIA. The results from spectral analysis of these data showed prominent circadian rhythms and an ultradian (12-hr) significant component in the PRL of controls and FM patients in both phases of the menstrual cycle. The acrophases of the 12-hr rhythms, however, clearly differed in controls and FM patients.

Intragastric pH continuously monitored in health and in gastric diseases: chronobiologic assessment.

Some gastric diseases clinically show ultradian, circadian, and circannual periodicities. We continuously monitored, during a single 24-hr span, with a fully electronic, solid-state portable recorder, endoluminal gastric pH in five healthy subjects, in some patients with gastric diseases including duodenal ulcer and gastric cancer, and in high-risk persons prone to develop duodenal ulcer and gastric cancer. The daily schedule and the timing of standardized meals for each subject were strictly verified. All stored data (300 time points/subject) were decoded, read, and analyzed by an inferential statistical method to estimate the rhythm parameters. The intragastric dense pH samples showed highly significant circadian and ultradian (8-hr) rhythms in all investigated subjects, but rhythm parameters differed in pre- and in overt pathology.

Calcitonin in a chronoepidemiologic perspective.

Calcitonin seasonal (circannual) variations in apparently healthy women and in women suffering from breast cancer in different evolutive-TNM-stage, were studied. Annual values are higher in patients with breast cancer, but there is no correlation with metastases. A significant calcitonin circannual rhythm with acrophase in winter was detectable in controls but not in breast cancer patients. The circannual rhythm obliteration could be a predictive signal of disease and not only metastatic disease.

Circadian rhythm in prostatic acid phosphatase (PAP): a potential tumor marker rhythm in prostatic cancer (PCa).

In order to define circadian states for an earlier diagnosis and for optimal response to treatment, the possibility of a circadian rhythm in serum PAP was investigated in subjects with and without prostatic cancer. Two groups of subjects were investigated: a. 12 patients affected by PCa, further subdivided in two subgroups: 1. without metastasis (6 patients) and 2. with metastatic disease (6 patients); b. 9 age-matched healthy control subjects. Controls and PCa patients were synchronized before starting the study with standardized meal times and nocturnal rest (22(00) to 06(00) ). Venous blood samples were drawn at prearranged hours (00(00), 04(00), 08(00), 12(00), 16(00), 20(00) ) for 24 consecutive hours. Each serum sample was assayed for PAP. Data on each group and subgroup were evaluated by conventional statistical analysis and by 'single' and 'population mean cosinor' to define rhythm parameters. PCa patients, as a single group, did not show a significant circadian PAP rhythm. A statistically significant circadian PAP rhythm was however detected in the subgroup without metastasis, on the contrary no rhythm was detected in the subgroup with metastatic disease. The potential of these rhythms as marker of cancer is noted.

Prolactin and prostate: a chronobiologic study.

A possible role of prolactin in prostatic disease has been claimed, but the results are so far misleading. Among the several factors that influence serum prolactin levels, temporal variations, notably circadian, are prominent. This paper shows an impairment in serum prolactin, chronobiologically investigated, in 12 patients with benign prostatic hypertrophy and in 7 patients with prostatic carcinoma. However, a single serum sample cannot be sufficient and may sometimes be misleading if not plotted with an adequate temporal reference standard (chronodesm).

Toward a medical prolepsis by chronobiology.

Medicine today strongly aims at prevention and optimization of diagnosis and therapy Studies tried staging and standardization of clinical trials in diseases and made search of markers for early diagnosis, prognosis and therapy. Moreover, risk factors and other variables such as predictors are now investigated more often in groups or populations of apparently healthy subjects, especially for such diseases as atherosclerosis and neoplasia. This new aspect of increasing interest may be defined as medical prolepsis (from the Greek pi rho ómicron lambda eta psi iota zeta = anticipated idea). It includes early signals of disease (protopathology) as well as other signals the host shows as defence or alarm reaction. Hence, we suggest a chronobiological approach in this field, which allows to quantify health and reveals more subtle differences in many physiological variables. According to these views, we reported studies concerning humoral markers and other parameters considered as risk factors both in atherosclerosis and in some endocrine tumors.

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.

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.

Circadian variation of serum prolactin and TSH of women in health or with mammary carcinoma, fibroadenoma or fibrocystic mastopathy.

Prolactin and TSH were determined in serum samples obtained at 4-hourly intervals throughout a 24-hour span from healthy women and from women with fibrocystic mastopathy, fibroadenoma or carcinoma of the breast. Data were subjected to analysis by the population mean-cosinor method. Differences in circadian mesor of prolactin among the 4 groups were statistically significant (P < .01), with healthy women having the lowest value. Prolactin amplitude differences among the groups were of borderline statistical significance (P = .05), while no differences in circadian acrophase were apparent. No statistically significance differences in TSH circadian mesor, amplitude or acrophase could be demonstrated. Individual values from subjects with breast disease were compared with time-qualified tolerance intervals based on data from healthy subjects. If these results can be corroborated on larger populations, sampling about 3 hours after arising may best detect an abnormal serum prolactin elevation. Results from this and other studies indicate the need for multi-variable and multifrequency investigations of breast disease.

Circadian variation in urinary melatonin in clinically healthy women in Japan and the United States of America.

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.

Iron metabolism: clinical chronobiological aspects.

Some features of clinical chronobiology are suggested on the basis of studies on the function of time in relation to various parameters of iron metabolism and factors associated with iron metabolism. In particular, so-called normal values, loading tests and the administration of iron (Eryfer) and chelating agents are reviewed in chronobiological terms. Some changes in the rhythms of iron metabolism are also discussed.