Genetic and environmental influences on human cord blood leptin concentration.

OBJECTIVE: To examine in a population sample of cord blood the time structure (chronome) of leptin, an adipocyte-derived hormone, and to assess any effect of a familial history of noninsulin-dependent diabetes mellitus and obesity, separately, on both the maternal and the paternal side. SUBJECTS AND METHODS: Leptin concentration was determined in cord blood from 93 infants. Effects of gender, gestational age, birth weight, maternal weight, familial antecedents of obesity and noninsulin-dependent diabetes mellitus, and circadian and about-yearly stage were assessed by linear regression and ANOVA. RESULTS: Cord blood leptin concentration is elevated in the presence of a family history of obesity on the paternal side, but not on the maternal side. Leptin concentrations are higher in spring and summer than in fall and are higher in infants born before noon. In keeping with earlier work, leptin concentration in cord blood correlates positively with birth weight and height and is higher in infants who are appropriate for or large for gestational age than in infants who are small for gestational age or born prematurely. DISCUSSION: Changes along the scales of the day and the seasons point to synchronizing environmental as well as genetic influence. An association of cord blood leptin concentration with obesity on the paternal side may help clarify the role of leptin in parental contributions to human obesity and may prompt focus on cholesterol metabolism.

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.

About-half-weekly (circasemiseptan) component of the endothelin-1 (ET-1) chronome and vascular disease risk.

Plasma ET-1 was measured around the clock on different calendar dates in healthy subjects and in subjects with diabetes and/or with high blood pressure and/or a history of vascular complications (HVDR). A transverse approach, with each subject contributing a single 24-h mean, assessed any about-weekly or half-weekly variation in ET-1. A circasemiseptan component resolved by single cosinor for nondiabetic (but not for diabetic) HVDR subjects (p = 0.010) differs in its timing of overall high values (p < 0.050) from that found in healthy subjects (p = 0.006). The results are aligned with circasemiseptan patterns in other circulatory variables and morbidity/mortality statistics.

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.

Influence of non-insulin-dependent diabetes mellitus on plasma endothelin-1 levels in patients with advanced atherosclerosis.

Endothelin-1 (ET-1) is an endothelium-derived vasoactive peptide with mitogen properties. Increased circulating ET-1 levels were found in patients with atherosclerosis as well as in patients with non-insulin-dependent diabetes mellitus (NIDDM) suggesting a role in the pathogenesis of these disorders. The aim of the present study was to ascertain the influence of the NIDDM on plasma ET-1 levels in patients with advanced atherosclerotic lesions. The circulating ET-1 levels were measured in 16 NIDDM patients (68.4 +/- 8.4 years) with macroangiopathy and in ten patients (65.3 +/- 11 years) with atherosclerosis without NIDDM. Twenty-two healthy subjects (43.1 +/- 18.3 years) served as controls. Circulating ET-1 levels were higher in NIDDM patients (6.8 +/- 2.8 pg/mL) than both controls (3.1 +/- 1 pg/mL; p < 0.001) and patients with vascular disease but without NIDDM (4.7 +/- 1.6 pg/mL; p < 0.04). No significant relationship was found between age and ET-1 concentrations, and no differences were noted between men and women in the control group. This study demonstrated that circulating ET-1 levels are increased in patients with atherosclerosis and that those with NIDDM showed the highest ET-1 levels. These observations strongly support a role for ET-1 in the pathogenesis of atherosclerosis and also suggest that this peptide may be involved in the development of atherosclerotic lesions in the NIDDM. We speculated that chronic exposure to hyperinsulinemia and hypertriglyceridemia in the diabetic patients could account for the increased ET-1 levels found in these patients.

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.

The endogenous secretion rate of human calcitonin in normal conditions.

This paper presents a study on secretion rate for calcitonin in normal healthy subjects, evaluated by an indirect method. A specific radioimmunoassay for monomeric calcitonin was used and the obtained results are lower than those reported by Kanis in 1982. In normal healthy subjects the secretion rate for calcitonin is 1.4 MRC U/day, i.e. ten times less than the value calculated by Kanis. These results will be able to clarify the role of calcitonin and its effects in normal conditions and in several osteoarticular and metabolic bone diseases.

Temporal aspects of the pathophysiology of human ulcer disease.

In this paper, a peptic ulcer is considered from the perspective that it is representative of a heterogeneous group of multifactorial determined or influenced disorders having a common pathomorphologic expression. This heterogeneity involves pathophysiological attributes, including both functional (including secretory and motility events and their respective driving mechanisms) and morphologic alterations that relate to mucosal resistance. Patients with duodenal ulcer (DU) have been observed to exhibit alterations, in comparison to normal subjects, in the circadian rhythm characteristics of several gastrointestinal functions. Prominent among these are altered amplitudes of several circadian-organized gastric variables, such as intragastric pH, gastrin, pepsinogen and gastric mitotic index. With respect to any given variable, a reduced group amplitude (a measure of one-half the peak-trough difference of a 24-hr rhythm) could signify an increased dispersion of acrophases (the location of the peak of a circadian rhythm along the 24-hr time scale) reflecting interindividual variation in synchronization schedules, sleep-wake patterns, or chronobiologic alterations. A reduced interindividual amplitude further supports the concept of the heterogeneity of peptic disease. A decrease in the intraindividual amplitude of certain gastric rhythms implies an altered temporal pattern over the 24 hr. This is consistent with the hypothesis of a decrease in the amount of time available for recovery of a given function or set of integrated functions, and hence, increased susceptibility to mucosal injury. Normal high-amplitude variation in gastrointestinal functioning over the 24 hr appears to be required for natural restoration of the gut.

Prominent circadian absorption of intranasal salmon calcitonin (SCT) in healthy subjects.

In young healthy subjects salmon calcitonin (SCT), intranasally administered, increased in serum as a function of the drug administration time. The serum concentration of a 400 IU SCT dose monitored 10 min after dosing was statistically more significant when inhaled at 0000 than at other, more conventional, administration times (morning or evening). Following dosing at certain times during the day, the serum SCT was less or even questionable with the dose and under the study conditions selected. Dosing without consideration of timing may lead to reduced effect or lack of effect or perhaps ambiguity or controversy regarding the possible circumstance of a "non-absorbent subject". The circadian frequency appears to be a critical determinant of intranasal SCT absorption suggesting administration time to be an important factor in the cost/benefit ratio without the unpleasant side effects sometimes experienced through parenteral routes.

Angiopathy affects circulating endothelin-1 levels in type 2 diabetic patients.

To evaluate the role of endothelin-1 (ET-1), a vasoconstrictor and mitogenic peptide synthesized by endothelial cells, on the endothelial dysfunction in non-insulin-dependent diabetic (type 2) patients, we have measured the circulating ET-1 levels in 25 patients with and without clinically evident vascular complications and in a control group. Circulating ET-1 levels were significantly higher in diabetic patients with angiopathy than in diabetics without angiopathy and in controls (7.02 +/- 2.9 pg/ml vs 4.4 +/- 1.1 pg/ml and 3.08 +/- 0.7 pg/ml, respectively; P < 0.001). No difference was demonstrated between diabetic patients without angiopathy and controls. These findings suggest that ET-1 may be a marker for arterial vascular disease only in patients with overt angiopathy. It is unclear whether it participates in the endothelial injury process or it is merely released from damaged endothelial cells.

Chronome assessment of circulating melatonin in humans.

BACKGROUND: Melatonin (MEL) production occurs mainly during the dark span. A prominent circadian variation is demonstrated in both blood and urine in humans. MATERIALS AND METHODS: The circadian, circannual, age and gender patterns of MEL were concomitantly investigated in 40 men and 132 women, each providing blood samples every 4 hours for 24 hours for conventional and cosinor analysis. RESULTS: Circulating MEL is circadian periodic (P < 0.001), peaking at night. The MESOR (rhythm-adjusted mean) is higher in women than in men. The circadian amplitude decreases with age. Both are modulated by a circannual variation, the MESOR peaking in winter (P < 0.001) and the circadian amplitude in summer (P < 0.05). CONCLUSIONS: Samples, unqualified as to gender, age and/or season, incompletely characterize the circadian MEL patterns. This chronome approach detects changes that may escape detection otherwise, checking whether a value is too high or too low, and also whether "swinging" occurs to the right extent.

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.

Evidence for bone mass and body fat distribution relationship in postmenopausal obese women.

The measurement of bone mass, a reliable predictor of osteoporotic fractures, in obese subjects has yielded conflicting results and bone mass has been reported to be elevated, normal or decreased. These observations indicate that factors other than body weight may be involved in the less risk for osteoporosis in obese subjects. In order to clarify the role of body fat distribution on bone density we studied sixty postmenopausal overweight/obese women with Body Mass Index (BMI) over 25 kg/m(2). Thirty five age-matched, nonobese postmenopausal women, served as controls. Bone mineral density (BMD) was measured at the proximal and ultradistal non dominant forearm using a double energy X-ray absorption (DEXA) apparatus. The waist/hip circumferences ratio (WHR) was used, in obese group, as an anthropometric estimation of the abdominal (WHR>0.85) to lower-extremity (WHR>0.85) fat proportion. The results were analyzed by Student t-test, ANOVA, and multiple linear regression analysis. No difference was found in BMD between obese group and controls, but a highly significant (P<0.001) positive correlation has been documented between proximal and ultradistal radius bone mineral density and waist/hip ratio in the obese group. Instead not significant correlation was found with BMI. Regional fat topography may influence the bone mass independently of total adiposity and visceral fat was the primary parameter accounting for higher bone mineral density values. These finding suggest that women with android-like obesity are protected from osteoporosis.

[Melatonin: a popular hormone]. / Melatonina: un ormone di successo.

This contribution makes an attempt to critically reassess the impressive career of melatonin (MEL) from a stepchild of hormone research to a best-seller of drug marketing. Melatonin, the hormone of the pineal gland, provides temporal information on diurnal and seasonal variation to the body and brain and it is involved in the synchronization of many different aspects of circadian systems to the light-dark cycle. In addition to these receptor-mediated functions, MEL may act as a modulator of intracellular signal transduction to enhance or suppress the responses of many different cells to other incoming signals. Melatonin is also a potent scavenger of reactive oxygen species and may thus protect cells and tissues against radical-mediated damages. The production of MEL declines with increasing age, and circulating MEL levels are affected by certain pharmacological or physiological manipulations. Animal and cell culture experiments suggest that MEL may have beneficial effects on certain aspects of aging and age-associated diseases. Of particular interest in this respect are reports on the influence of MEL on the brain and the immune system. The sole sufficiently investigated indication in humans is the treatment of certain sleep disorders from the group of sleep-wake-rhythm disturbances. These manifest themselves by sleep time of the day, i.e. in shift workers, after flights across time zones and in some aged persons. Clinical studies need to be performed in order to identify possible side effects of long-term MEL treatment. Serious concerns are raised about the use of uncontrolled, impure, or partially degraded MEL preparations.

Chronobiology in epidemiology and preventive medicine.

Many of the known cardiovascular risk factors, such as hormones, metabolic parameters, lifestyle, blood pressure, fibrinogenesis, fibrinolytic activity, etc., and also the reactivity of the organism to stimuli, are periodical and therefore require adequate measures at specific times in appropriate frequencies. The presence of circadian, circannual or other wide frequency rhythms may lead to contradiction in the evaluation of a potential risk factor. Chronobiological analysis shows fine differences within a "risk variable", defining some characters which may imply the alteration of a parameter only at certain times. Periodical risk factors may therefore be foreseen and sometimes prevented. Moreover, chronobiological approach may show another peculiar relation between risk factors; this is the so-called chronorisk. The convergence, in certain periods of time, of the phases of various risk factors, may strengthen their combined value. On the other hand, the phases of the protective factors, in the same period of time, may contribute to reduce or strengthen this combined value. From this point of view combined risk, apparently unimportant, appears highly increased, as compared with the normal homeostatic value. At equal levels of risk factors, different distribution and amplitude of the phases implies great differences in final combined risk values. Acute heart attack has a daily, seasonal and perhaps ultradian rhythm; other cardiological events, such as angina pectoris and sudden death, have circadian rhythms. Also cerebral vascular events have daily, seasonal, weekly and monthly variations. The periodical variations of acute vascular events and of the related risk factors, near and far, implies many complex interrelations in timing of biological structures, which are still perceived by the physician only as "noise".

Chronomes, time structures, for chronobioengineering for "a full life".

Week-long or longer monitoring of blood pressure and heart rate, coupled to time-structure analyses, can help detect disease-risk elevations, as a warning of the need for a preventive prehabilitation. Within the normal range of physiologic variation, computer methods quantify time structures, or chronomes, that can serve as reference values. The major applied purpose for mapping chronomes is the detection of disease-risk syndromes such as blood pressure "overswinging" and heart rate "underswinging." Too much blood pressure variability (circadian hyperamplitude tension; CHAT), is a risk factor for vascular disease. Other risk syndromes are chronome alterations of heart rate variability (CAHRVs), consisting of a loss of "jitter", i.e., a reduced standard deviation of heart rate or of alterations in the spectral element of the heart-rate-variability chronome, such as in the correlation dimension, an endpoint of deterministic chaos. These alterations can again serve for prehabilitation. On the basic side, the spectral element of the heart-rate-variability chronomes extends from focus on the heartbeat's period of about 1 second to periods in heart rate and its standard deviation that are numerical equivalents of about 10.5- and about 21-year cycles of solar activity. A seemingly unnatural physiologic rhythm or pattern (such as one of 81.6 hours) may correspond numerically to a purely physical environmental rhythm. For example, interplanetary magnetic storms, with their cycles as external chronome components, trigger myocardial infarctions, strokes, and traffic accidents. The systematic monitoring of external rhythms along with physiologic ones for the concurrent analysis of rhythms with longer and longer periods could detect alterations anywhere in and between the 1 cycle/sec and the 1 cycle/10.5- or 21-years regions of the spectrum. Chronobiomimetic engineering for discovering both instantaneous and long-term chronorisk alterations can provide warnings of increased risk. If risk-lowering therapy is then instituted automatically, instrumented health care will be extended beyond the pacemaker-cardioverter-defibrillator, which focuses on the frequency of 1 cycle/sec. Instrumentation that automatically detects blood pressure that varies too much and heart rate that varies too little is needed for prompting prophylactic CHAT and CAHRV treatment. A database of reference values that can be used for chronodiagnosis is now accumulating.

[Melatonin and seasonal depression]. / Melatonina e depressione stagionale.

Melatonin (MEL) hypothesis in seasonal affective disorders (SAD) is supported by: a) historical hint; b) circadian and seasonal MEL periodicity with evidence that the SAD is related to photoperiod; c) relationship between incidence and severity of SAD and latitude; d) the response to bright artificial light (ineffective in depression) which mimics summer time; e) MEL administration can induce some symptoms of the SAD; f) several antidepressant drugs increase MEL plasma levels. Several of these findings are disproved: the light acts independently from the MEL, some antidepressant agents act without modifying MEL levels; a consistent alteration in MEL secretion within SAD has not been convincingly demonstrated. Relationship between incidence and severity of SAD and latitude suggests a new potential implication of MEL in SAD. The daytime melatonin values reflect changes along the scale of a year in sunshine. Accordingly, the about-yearly periodicity, much larger in amplitude than the half-yearly component, yields ratios smaller than unity. By contrast during darkness an about-half-yearly component is more prominent. As the aurora zone is approached, the intensity of magnetic disturbances increases. Thus, the intensity of these two variables shows inverse relationships with latitude and geomagnetic field decreases plasma levels of MEL and inhibits MEL function.

Vascular damage and not hypertension per se influences endothelin-1 plasma levels in patients with non insulin dependent diabetes mellitus.

Several reports indicate higher endothelin-1 (ET-1) levels in patients with non insulin dependent diabetes mellitus (NIDDM), although this finding has not been confirmed by other studies. The discrepancy may be partially explained by the frequent coexistence in NIDDM patients of other pathologies, such as essential hypertension, and by the presence of diabetic vascular complications or renal failure, able, per se, to increase ET-1 circulating levels. This study aimed to evaluate the influence of arterial hypertension and/or of diabetic angiopathy on ET-1 circulating levels in a group of NIDDM patients. We measured ET-1 plasma concentrations in three groups of subjects: a) 22 NIDDM patients with or without hypertension and with or without vascular complications; b) 11 hypertensive patients; c) 14 age-matched healthy volunteers. Plasma ET-1 concentrations were significantly higher in NIDDM patients with angiopathy (7.3 +/- 0.7 pg/ml, mean +/- Standard Error; p < 0.001) than diabetics without angiopathy (4.4 +/- 0.53 pg/ml), hypertensive patients (4.7 +/- 0.85 pg/ml) and healthy subjects (3.1 +/- 0.19 pg/ml). This report indicates that increased plasma ET-1 levels in NIDDM patients may be ascribed only to those with vascular compliances, while hypertension, per se, does not affect ET-1 plasma levels in these patients.

Serum beta-endorphin increase after intravenous histamine treatment of chronic daily headache.

Histamine is able to induce spontaneous-like headache attacks in migraine and cluster headache subjects. Therefore, it has been considered as a possible agent in the pathogenesis of headache. Histamine desensitization is used for the treatment of cluster and other chronic headaches like migrains with interparoxysmal headache. However, it is unknown whether desensitization plays a role in headache improvement. Since a disfunction of the opioid system has been considered responsible for idiopathic headache and since low beta-endorphin levels have been demonstrated in some idiopathic headaches, particularly in migraine with interparoxysmal headache, we planned this study to verify if histamine therapy is able to modify serum beta-endorphin concentrations. For this purpose, we studied 24 healthy control subjects and 36 patients suffering from migraine with interparoxysmal headache refractory to conventional therapies. Patients showed baseline serum beta-endorphin levels significantly lower than healthy control subjects and treatment with histamine for 15 days increased their beta-endorphin concentrations. We believe that histamine treatment can activate the opioid endogenous system. However, the therapeutic effect of histamine remains to be verified by evaluating the correlation between beta-endorphin levels and headache improvement.