Hypermelatoninemia in women with polycystic ovarian syndrome.
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Biomedical subjects
Publications and source records attributed to R Tarquini.
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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.
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.
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".
Rheumatoid arthritis and osteoarthritis, expression, respectively, of inflammatory and degenerative articular involvement, are the most important diseases affecting joint cartilage. Proteolytic enzymes are the effectors of the articular damage: their increased production by chondrocytes and synoviocytes leads to cartilage breakdown. These enzymes, whose structure and specific activities have been defined in the recent years, carry out their action in the extracellular matrix. They are characterized by the presence of a particular element at the active site, that allows to distinguish four different families. The most studied and the best known among them are metalloproteinases, represented by several enzymes with common features, and serinoproteinases, some members of which, particularly urokinase and tissue-type plasminogen activator, are recently indicated as potential responsible for articular destruction. Activators, and inhibitors of proteinases play a fundamental role: a fine balance, that controls the mechanisms of activation and inhibition, seems to take place at transcriptional level. Any factor able to modify the cellular shape and the cytoskeleton, gives rise to lytic enzyme expression at the genomic level. With the progress of knowledges, serinoproteinases are assuming an increasing relevance, particularly the components of the fibrinolytic pathway.
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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.
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.
The immune system plays an important role in the defense against neoplastic disease and immune responses show temporal changes related to circadian variations of antibodies, total lymphocytes in the peripheral blood and cell mediated immune responses. In this study we evaluate. lymphocyte subpopulations and interleukin-2 (IL-2) serum levels in peripheral blood samples collected at four-hour intervals for 24-hours starting at 06.00 h from ten healthy subjects aged 65-79 years (mean age +/- s.e. 67.28 +/- 3.11) and from ten subjects suffering from untreated non small cell lung cancer aged 65-78 years (mean age +/- s.e. 68.57 +/- 1.81). Areas under the curve, mean diurnal levels (mean of 06.00-10.00-14.00 h) and mean nocturnal levels (mean of 18.00-22.00-02.00 h) were calculated, and the presence of circadian rhythmicity was evaluate. When we compared AUC values there was a decrease in CD8bright (T suppressor subset) and an increase in CD16 (natural killer cells) and of IL-2 serum levels in cancer patients. When we compared mean diurnal levels, CD8 (T suppressor/cytotoxic subset) and CD8bright levels were lower, and CD16 levels were higher in cancer patients. When we compared mean nocturnal levels, CD16 and CD25 (T and B activated lymphocytes with expression of the a chain of IL-2 receptor) levels were higher, while CD8, CD8bright, CD20 (total B-cells), TcRd1 (epitope of the constant domain of d chain of T-cell receptor 1) and dTcS1 (epitope of the variable domain of d chain of T-cell receptor1) levels were lower in cancer patients. A clear circadian rhythm was validated for the time-qualified changes in CD4, CD20, HLA-DR with acrophase at night, and CD8, CD8 bright, CD8 dim, CD16, TcRd1 and dTcS1 with acrophase in the morning in the control group. A clear circadian rhythm was validated for the time-qualified changes in CD4 with acrophase at night, in the group of cancer patients. Results obtained in our study show that lung cancer is associated with anomalies of proportion and circadian variations of lymphocyte subsets that must be considered when adoptive immunotherapy has to be planned.
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.
Evidence here cited underlies resolutions at international meetings to initiate a chronobiology project for health improvement. This project demonstrates expeditiously the feasibility and the health benefits of incorporating chronomedical considerations in the diagnosis, treatment, and prevention of one (or a few closely related) vascular (and oncological) diseases, that have high awareness and importance in the public perspective. Thereby, chronomedicine should become a mainstream basic and applied speciality leading to continual improvement in national/international health status. Reference data obtained for health care can also serve to give a better understanding of the relationship between the terrestrial biosphere and cosmoi near and far.
AIMS AND BACKGROUND: Several studies have evidenced that IGF-1 may play a role in the growth regulation of many cancer cell lines, and recently GH and IGF-1 have been recognized as stimulators of lymphopoiesis and immune function. We investigated whether there are differences among health- old people and old people suffering from lung cancer at different stages of disease in the 24-hour secretory profiles of GH und IGF-1. METHODS: The study was carried out on seven healthy volunteers (mean age +/- s.e. 68.8 + 1.92), seven patients with I and II stage lung cancer (mean age +/- s.e. 67.2 +/- 0.80) and seven patients with III and IV stage lung cancer (mean age +/- s.e. 69.5 +/- 2.26). GH and IGF-1 serum levels were measured on blood samples collected every four hours for 24 hours; the area under the curve (AUC) and the presence of circadian rhythmicity were evaluated. RESULTS: A normal circadian rhythmicity was recognizable only for GH secretion in healthy subjects. A progressive increase of GH serum levels and a steady decrease of IGF-1 serum levels were observed in cancer patients in relation to advancing stage of neoplastic disease. CONCLUSIONS: Lung cancer is associated with an altered regulation of GH-IGF-1 system, that might play a role in the clinical course of neoplastic disease.
BACKGROUND: The host immune response is important in the natural history of neoplastic disease. In order to evaluate alterations of immune function associated with cancer we analyzed the nyctohemeral profile of lymphocyte subpopulations in peripheral blood of cancer patients. The study was carried out on seven healthy volunteers (mean age +/- s.e. 68.8 +/- 1.92), seven patients with I and II stage lung cancer (mean age +/- s.e. 67.2 +/- 0.80), seven patients with III and IV stage lung cancer (mean age +/- s.e. 69.5 +/- 2.26). The area under the curve (AUC) and the presence of circadian rhythmicity were evaluated. RESULTS: The most striking differences were a statistically significant decrease of CD8 (T suppressor/cytotoxic subset) and CD8bright (T suppressor subset) in cancer patients, with a loss of normal circadian rhythmicity, and a statistically significant increase of CD16 (natural killer cells) in cancer patients, especially with I and II stage disease, with a clear circadian rhythm present in all the groups. A statistically significant decrease of delta TcS1 (epitope of the variable domain of delta chain of T-cell receptor 1) was observed in the subjects with I and II stage lung cancer, with a loss of circadian rhythmicity in the two groups of cancer patients. TcR delta 1 (epitope of the constant domain of delta chain of T-cell receptor 1) was significantly decreased in cancer patients, but a clear circadian rhythm was present in these subjects. No significant differences among the groups were found in the values of CD2 (total T cells), CD4 (T helper/inducer subset), CD8dim (T cytotoxic subset), CD4/CD8 ratio, HLA-DR (B cells and activated T cells), CD20 (total B cells) and CD25 (T activated lymphocytes with expression of the alpha chain of interleukin-2 receptor). Nyctohemeral variations of CD2 in control subjects and in I-II stage cancer patients and of CD4 and CD20 in III-IV stage cancer patients presented circadian rhythmicity. CONCLUSIONS: The results suggest that lung cancer is associated with alterations in the proportions and nyctohemeral profiles of various lymphocyte subsets, related to the stage of disease and probably the expression of an altered immune function.
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.
In epidemiology of osteoporosis, obesity is to be considered one of its protecting factors. However there are in the literature discordant opinions: some authors describe a protective effect of obesity on the trabecular bone, others on the cortical one, others no effects at all and others finally a positive influence on both the trabecular and the cortical bone. However, only few studies on obesity's impact on bone metabolism are available. Bone mineral density at forearm and serum osteocalcin levels, a specific and sensitive marker of bone turn-over, in a group of postmenopausal obese women with those of a nonobese control group were compared. Obese women showed higher densitometric measurements than nonobese, but only the values of the third distal site of forearm resulted higher in a significant way. Serum osteocalcin values were similar between the two groups but the obese women showed a greater dispersion of the values (8.15 +/- 4.96 ng/ml) compared to nonobese (8.35 +/- 1.63 ng/ml). This high variability suggests an heterogeneity of bone turn-over in obese subjects and could explain the discordant results of the literature.
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.
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.