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A test of the relative merits of timed melatonin for the treatment of cardiac ischemia as well as hypertension refractory to other drugs is documented against the background of earlier chronobiological studies on blood pressure (BP), disease risks, circadian hyper-amplitude-tension and melatonin effects broadly.

A circadian rhythm in serum leptin, measured every 4 h for 24 h, characterizes normal-weight women (N = 14), and women with gynoid (N = 17) or android (N = 26) obesity, peaking around midnight (P < 0.05), but differing by about 3 h between android and gynoid women (P < 0.01). Obesity is associated with a higher MESOR (rhythm-adjusted mean; P < 0.001) and a smaller relative circadian amplitude (P < 0.05). Gynoid obesity is associated with a larger circadian amplitude of cortisol (P < 0.05), whereas android obesity is associated with a larger circadian amplitude and a higher MESOR of insulin (P < 0.05). Understanding putative mechanisms underlying different body fat distribution may lead to improved chronotherapeutic measures.

Geomagnetic activity has a strong half-yearly but no precise yearly component in its spectrum, as Armin Grafe suggested nearly half a century ago. We have postulated elsewhere that non-photic cycles such as those in geomagnetics may have signatures in the biosphere and vice versa that biological rhythms have likely counterparts in the physical environment. Accordingly, we document phenomena characterized by a prominent about half-yearly variation, re-analyzed to constitute the start of a transdisciplinary chronomic (time structural) map, aligning these conditions with a half-yearly cycle in the geomagnetic index Kp. At least some biospheric phenomena fitted concomitantly with 1- and 0.5-year cosine curves exhibit an amplitude (A) ratio of A(0.5-year)/A(1-year) larger than unity. Methodologically, it is pertinent that even if data were read off published graphs, the resulting analyses were practically the same as those in the original data received subsequently. The main point is a circasemiannual pattern in status epilepticus, in several morbid oral conditions, in the cell density of vasopressin-containing neurons in the human suprachiasmatic nuclei (SCN), in circulating melatonin at middle latitudes at night during years of minimal solar activity or around noon at high latitudes, and in an unusual circasemiannual aspect of a birth-month-dependence of human longevity. Others have asked whether annual rhythms in human reproduction are biological, sociological or both. We show some other possibilities herein, involving the physical environment, hardly to be neglected in the case of open systems. As to almost certainly multifactorial circasemiannual rhythms, geomagnetics may also be a signal, a proxy or a putative, at least partial mechanism. Geomagnetic activity is related in its turn to solar and galactic activity, and may be a marker for other cyclic events that affect the biosphere. The similarity of cycle lengths in itself can only be a hint prompting the search for causal relations.

An inferential statistical quantification of chronomes (time structures) in the range of everyday physiology has earlier revealed changes affecting the circadian amplitude of melatonin in the absence of changes in the chronome-adjusted mean value (MESOR) or in the acrophase. A chrono-meta-analysis of published data on patients with the Smith-Magenis syndrome herein quantifies the average extent of shift in the acrophase of the circadian melatonin rhythm, reported earlier by others time-macroscopically as an antiphase. Time-microscopically, the phase shift averages 9.6 +/- 0.9 h. Circadian melatonin ecphasia complements blood pressure ecphasia in non-insulin-dependent diabetes mellitus, associated with autonomic dysfunction. The shift in phase of the peak melatonin secretion from the night into the day, associated with specific genetic findings, raises basic questions concerning the designation of melatonin as a hormone associated with darkness. Whether a resetting of the circadian acrophase beyond providing melatonin for sleep improvement can provide benefit remains to be investigated.

Taking the heart rate (HR) for one cycle, whether to examine behavior in the region of periods of 1 s, 1 day, 1 week, 1.3 or 10.5 years, etc., is hazardous. Replications, when possible are mandatory for examining altered variability, whatever the period(s) involved may be. This replication in the individual, and across individuals when the periods are long, measured in decades, may serve for diagnosis and treatment. This rule applies in particular to a seemingly transient circadian hyper-amplitude-tension (CHAT), an over peer-threshold variability in blood pressure (BP), based on the fit of a 24-h cosine curve to time series of appropriate length, rather than to a mere snapshot covering just a single day or week. Transient CHAT may turn into intermittent CHAT, as determined in two cases presented herein. One case of transient CHAT could be so named after a successful treatment (Rx) change eliminated CHAT as an effect validated by monitoring at 30-min intervals for a 7-day span on a new treatment. CHAT disappeared for over 300 consecutive half-hourly measurements, but thereafter it reappeared. During the ensuing nearly continuously monitored 5 years, CHAT continued to appear and disappear sometimes without a treatment change. In another case, which was responsive to a change in the timing of medication, CHAT also disappeared and thereafter reappeared. In a short-term perspective of weeks or months of monitoring, CHAT seemed to be transient, but further monitoring again revealed it to be intermittent. Cases of intermittent CHAT require follow-up for outcomes by comparison with the population at large. Miniaturized instrumentation for their detection should be a high priority, but it must be realized that the automatic ambulatorily functioning monitors, available at 10% of the regular price through a BIOCOS project (corne001@umn.edu), already signify great progress, as compared to previously used manual measurements made around the clock by hypertensive opinion leaders in medicine from diagnosis to death. On automatically collected time series of BP and HR, gliding pergressive spectral windows as such, or such pergressive windows aligned further with global spectral windows, visualize the changing dynamics involved in health and disease, in the steps of Werner Menzel and Paolo Scarpelli.

We reported a female patient with unrecognized celiac disease and multiple extra intestinal manifestations, mainly related to a deranged immune function, including macroamilasemia, macrolipasemia, IgA nephropathy, thyroiditis, and anti-b2-glicoprotein-1 antibodies, that disappeared or improved after the implementation of a gluten-free diet.

We reported a case of non-Hodgkin's lymphoma where liver involvement was the predominant clinical manifestation. A 27-year old man presented with markedly elevated serum aspartate aminotrasferase, alanine aminotransferase and lactate dehydrogenase, reduced prothrombin activity, thrombocytopenic purpura and hepato-splenomegaly without adenopathy. Viral, toxic, autoimmune and metabolic liver diseases were excluded. Bone marrow biopsy showed an intracapillary infiltration of T-lymphocytes with no evidence of lipid storage disease. Because of a progressive spleen enlargement, splenectomy was performed. Histological examination showed lymphomatous intrasinuses invasion of the spleen. Immunohistochemical investigation revealed the T phenotype of the neoplastic cells: CD45+, CD45RO+, CD3+, CD4-, CD8-, TIA1-. About 50 % of the lymphoid cells expressed CD56 antigen. The diagnosis of hepatosplenic T cell lymphoma was done. The patient was treated with chemotherapy, which induced a complete remission. Eighteen months later, he had a first relapse with increased aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, thrombocytopenic purpura and blast in the peripheral blood. In spite of autologous bone marrow transplantation, he died twenty months after the diagnosis. Even in the absence of a mass lesion or lymphoadenopathy, hepatosplenic T-cell lymphoma should be considered in the differential diagnosis of a patient whose clinical course is atypical for acute hepatic dysfunction.

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.

Melatonin was not considered for a long time in medical culture and scientific research for the difficulties encountered in study protocols and for the obscure relevance in clinical practice. Today the pineal hormone has reached a great popularity, may be not strictly corresponding to the important role played in the regulation of many system function and the commercial diffusion has become extremely wide in some countries.

Objective: To evaluate whether in healthy postmenopausal women endothelial substances such as endothelin-1 (ET-1) and nitric oxide are related to cardiovascular risk factors and can be influenced by estradiol replacement., Design: A cross-sectional evaluation and a randomized, double-blind, placebo-controlled study with cross-over., Methods: In 20 healthy postmenopausal women it was investigated the relation of ET-1 and NOx with age, BMI, 24-h blood pressure, lipid and glucose metabolism, and coagulation parameters. In addition, in the same women, the role played by estrogens on circulating ET-1 and stable derivatives of nitric oxide (nitrite/nitrates) was investigated by administering for 2 months transdermal estradiol (50 microg/day) vs. placebo., Results: ET-1 and NOx were inversely related to each other (r=0.458; P=0.016). Multivariate analysis of regression showed that ET-1 levels were related directly to LDL-cholesterol (r=0.585; P=0.0005) and protein C (r=0.516; P=0.0008), and inversely to insulin (r=0.488; P=0.0065). The ratio NOx/ET-1 was directly related to HDL-cholesterol (r=0.441; P=0.005). The above relations were not influenced by estradiol. Indeed, in comparison to placebo, transdermal estradiol, besides reducing nocturnal systolic (P=0.002) and diastolic (P=0.03) blood pressure, did not modify ET-1 or NOx levels, as well as, any of the parameters considered., Conclusions: The relation of several cardiovascular risk factors with ET-1 and NOx/ET-1 suggests a primary role for these endothelial products in the determination of the cardiovascular risk of women. The present data do not support a role for transdermal estradiol in modifying ET-1 or NOx levels of healthy postmenopausal women.

Background: A number of qualitative and quantitative changes in hormonal secretion pattern have been found in subjects suffering from neoplastic disease. The aim of this study was to evaluate the presence of alterations in neuro-endocrine system function and in the pattern of endocrine secretion in patients with lung cancer., Methods: Cortisol, melatonin, growth hormone (GH), insulin-like growth factor I (IGF-I), thyrotropin-releasing hormone (TRH), thyroid-stimulating-hormone (TSH), and free thyroxine (FT4) serum levels were measured on blood samples collected every four hours for 24 hours from ten healthy old 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 and mean diurnal and nocturnal levels were compared and the presence of circadian rhythmicity was evaluated., Results: When hormone levels were expressed as area under the curve GH levels were higher (p=0.004) and IGF-I levels were lower (p=0.006) in patients with lung cancer than in normal subjects. The evaluation of melatonin/cortisol ratio in all subjects showed a significant difference between the control group and the group of cancer patients (p<0.05). When we compared mean diurnal levels (mean of 06.00-10.00-14.00h) GH levels were higher (p<0.0001) and IGF I levels were lower (p<0.0001) in cancer patients; when we compared mean nocturnal levels (mean of 18.00-22.00-02.00h) cortisol (p=0.03), TRH (p=0.02), and GH (p=0.001) levels were higher in cancer patients, while melatonin (p=0.04), TSH (p=0.04) and IGF I (p<0.0001) levels were higher in control subjects. A clear circadian rhythm was validated for time related changes of cortisol, melatonin, TRH, TSH and GH in control subjects and for time related changes of melatonin in cancer patients., Conclusion: These data suggest that lung cancer patients show alterations of hormone secretion and neuroendocrine system function.

For advanced colorectal carcinoma, two new drugs, raltitrexed (TOM) and oxaliplatin (L-OHP), have recently shown interesting results. Preclinical and clinical studies suggest that this combination, because of its favorable toxicity profile, high response rate and convenient schedule of administration, can be administered successfully in this disease. In our phase II study, 37 non pre-treated patients with metastatic colorectal carcinoma were treated with TOM (3 mg/m(2)) and L-OHP (130 mg/m(2)) every 3 weeks. In total, 222 cycles were administered; all patients received at least 2 cycles (median 6, range 2-8). There were two complete and 14 partial responses for an overall response rate of 43% (95% CI 27-69%). The median time to response was 2.5 months (range 2-4) and the median duration was 10.3 months (range 5-18). Twelve of the 23 (52%) patients with symptomatic colorectal cancer were classified as clinical benefit responders for at least 4 weeks during the study period. Treatment was well tolerated, and both acute, essentially hematologic, and cumulative hepatic and neurologic toxicities were manageable and reversible. Response rate and toxic effects observed during this study warrant additional studies comparing this TOM-L-OHP regimen with CPT-11 and/or capacitebine-containing regimens in metastatic colorectal carcinoma., (Copyright 2002 Lippincott Williams & Wilkins.)

System time is defined as the duration (T) and sampling density (deltat) of a given study. A time horizon is obtained by combining analytical results on endpoints of time structures (chronomes), usually on control groups, from accumulating diverse studies carried out with drastically different values of T and deltat. These two design considerations depend upon and are limited by resources. The desideratum of a small At e.g., for studies of chaotic endpoints, limits T, e.g., has thus far precluded a continuous mapping of decadal cycles in endpoints such as the approximate entropy or the correlation dimension. Time horizons are being documented for an increasing number of variables that undergo cycles with infra-annual frequencies - with one cycle in about one, two and/or five decades - in the biosphere as in the environment. These infra-annuals, in and around us, modulate ultra-annuals, including circadians, as well as about 7-day (circaseptan) and about half-yearly (circasemiannual) cycles, all prominent, e.g., in geophysical and biospheric specta. Neglect of infra-annual chronomics can lead to blunders. A statistically highly significant decrease in the excretion of steroidal metabolites (or in heart rate variability) may be misinterpreted as premature aging if it lasts for several years, and may be unnecessarily acted upon, e.g., by drugs. The decrease, however, may only be transient, occurring only during a given stage of a circadecadal cycle, and it may be followed for the next several years by an also spurious "rejuvenation", possibly misinterpreted as a drug effect. When recognized as the alternating stages of decadal cycles and assessed with an affordable deltat, infra-annuals of variables involved in major problems of our day, including homicides and wars, may lead us to manipulable internal or external mechanisms, and thus, eventually, possibly to countermeasures to crime and terror as well as to the optimization of aims such as spirituality.

An 80-year-old woman was admitted to the Traumatologic Hospital of Florence because of bilateral post-traumatic humeral fractures. Subcutaneous calcium heparin was immediately administered to prevent deep venous thrombosis. Nine days later, the patient was referred to the Internal Medicine Unit because of severe immune-mediated heparin-induced thrombocytopenia and bilateral deep venous thrombosis. Heparin therapy was immediately discontinued, and the patient was switched to warfarin therapy. Diagnosis of heparin-induced thrombocytopenia was confirmed by positivity of anti-heparin-PF4 antibodies. On the second day of warfarin therapy, bilateral limb venous gangrene with a high risk of limb amputation appeared. To reduce thrombin generation, i.e., the mechanism by which heparin-induced thrombocytopenia induces thrombotic events, intravenous treatment with dermatan sulphate and low-dose urokinase was initiated. After 10 days of treatment, the limb venous gangrene disappeared, and low-dose warfarin therapy was again introduced. The patient was discharged 40 days after admission, and a Doppler ultrasound study showed only minimal signs of deep vein thrombosis in the right popliteal veins. Although in Italy the use of dermatan sulphate has been limited to the prevention of deep vein thrombosis, this case shows that it should be considered a useful agent for the treatment of thrombotic complications secondary to heparin-induced thrombocytopenia. Patients with acute immune-mediated heparin-induced thrombocytopenia should not be treated with warfarin alone. Frequent platelet count monitoring from day 5 of heparin treatment remains the best means of early detection of immune-mediated heparin-induced thrombocytopenia.

To assess whether an increased production of nitric oxide is involved in the circulatory and renal alterations of cirrhosis, we evaluated systemic hemodynamics (echocardiography), renal hemodynamics, and sodium handling (lithium clearance method), plasma renin activity (PRA), aldosterone (PAC), and norepinephrine in 7 patients (3 men, mean age 65 +/- 2 years) with compensated cirrhosis, portal hypertension, and hyperdynamic circulation during intravenous N(G)-monomethyl-L-arginine (L-NMMA) (3 mg/kg bolus plus 0.05 mg/kg. min for 120 minutes) or placebo (the vehicle) in a randomized, placebo-controlled, crossover study. Administration of L-NMMA resulted in significant reductions in plasma and urinary nitrite levels and plasma cyclic guanosine monophosphate (cGMP), indicating effective inhibition of nitric oxide synthase. L-NMMA also significantly reduced cardiac index (-13%) and increased systemic vascular resistance (+26%), arterial pressure (+9%), renal blood flow (+12%), glomerular filtration rate (+12%), and sodium excretion (+25%). Changes in sodium excretion were caused by both enhanced filtered sodium load and reduced sodium reabsorption in the proximal tubule. Plasma norepinephrine significantly decreased in response to L-NMMA, and there was a trend for reductions in PRA and PAC. Placebo had no appreciable effect on any of the measured parameters. These results indicate that in patients with compensated cirrhosis, portal hypertension and hyperdynamic circulation inhibition of nitric oxide synthase corrects the altered systemic hemodynamics and improves renal function and sodium excretion.

Time patterns in nocturnal concentrations of circulating melatonin of children are quantified in 8 girls and 8 boys, 8.7-16.8 yr of age, classified by Tanner pubertal stage. Between 1900 and 0700 h, each provided blood samples at 30-min intervals for melatonin RIA. Associations with gender, body mass index, and chronological and pubertal age determined by multiple linear regression and ANOVA reveal that the area under the curve of 12-h melatonin concentrations was affected by pubertal rather than chronological age, an effect to which data collected during darkness contributed the most. Each data series was also analyzed by a least squares spectrum at frequencies of 1-20 cycles/day. Ultradian changes with periods of 3.4 and 1.5 h, putatively associated with rapid eye movement sleep cycles, characterize nocturnal melatonin in boys and girls.

Magnetic storms trigger myocardial infarctions with mechanisms relating to heart rate variability. Solar cycle-to-solar cycle differences and solar cycle stage dependence shown herein may resolve prior controversy and serve to advocate coordinated worldwide systematically aligned biological and physical monitoring. * This paper was originally invited by the historian-geophysicist Wilfried SCHRöDER of Bremen, Germany, for his biographical "Encounters," and is to serve as an update on the project on the BIOsphere and the Cosmos (BIOCOS) and its offspring ICEHRV (Dr. Kuniaki Otsuka's International Chronome Ecologic Study of Heart Rate Variability). It is intended for distribution at a NATO conference on space weather hazards, organized by Dr. Ioannis Daglis, June 18-29, 2000.

The spectrum of biological rhythms is extended far beyond circadians, circannuals, and ultradians, such as 1.5-hourly melatonin and 8-hourly endothelin-1 (ET-1) rhythms by statistics of natality, growth, morbidity, and mortality, some covering decades or centuries on millions of individuals. These reveal infradian cycles to be aligned with half-weekly rhythms in ET-1, weekly and half-yearly ones in melatonin, and even longer--about 50-, about 20-, and about 10-year cycles found in birth statistics. About daily, weekly, yearly, and ten-yearly patterns are also found in mortality from myocardial infarctions; the 10-yearly ones are also in heart rate and its variability; in steroid excretion, an aspect of resistance, for example, to bacteria; and in the genetic changes of the bacteria themselves. Automatic physiological measurements cover years and, in one case, cover a decade; the latter reveal an about 10-year (circadecennial) cycle. ECGs, covering months beat-to-beat, reveal circaseptans, gaining prominence in response to magnetic storms or after coronary artery bypass grafting. A spectrum including cycles from fractions of 1 Hz to circasemicentennians is just one element in biological time structures, chronomes. Chaos, trends, and any unresolved variability are the second to fourth elements of chronomes. Intermodulations, feedsidewards, account for rhythmically and thus predictably recurring quantitive differences and even for opposite treatment effects of the same total dose(s) of (1) immunomodulators inhibiting or stimulating DNA labeling of bone in health or speeding up versus slowing down a malignant growth and thus shortening or lengthening survival time, or (2) raising or lowering blood pressure or heart rate in the vascular aspect of the body's defense. Latitude-dependent competing photic and nonphotic solar effects upon the pineal are gauged by alternating yearly (by daylight) and half-yearly (by night) signatures of circulating melatonin at middle latitudes and by half-yearly signatures at noon near the pole. These many (including novel near 10-yearly) changes, for example, in 17-ketosteroid excretion, heart rate, heart rate variability, and myocardial infarction in us and those galactic, solar, and geophysical ones around us have their own special signatures and contribute to a cosmo-vasculo-immunity and, if that fails, to a cosmo(immuno?) pathology.

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.

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.

The circadian rhythm of serum melatonin of 39 cancer patients is compared with that of 28 healthy subjects matched by gender and age. Each subject provided 6 blood samples at 4-hour intervals for determination of melatonin by RIA. After log10-transformation, data series were analyzed by single and population-mean cosinor and compared between the two groups and among patients subgrouped by cancer site, stage and treatment. A circadian rhythm (P<0.001) is demonstrated for both groups, with a contributing 12-hour harmonic (P<0.001). In the absence of a difference in MESOR, the circadian amplitude of the cancer patients is smaller than that of the healthy subjects (P=0.003). Numerically, nocturnal (00:00 and 04:00) melatonin concentrations are lower and daytime (08:00-20:00) melatonin concentrations are higher in the cancer patients than in the healthy subjects (P=0.032 at 12:00 and P=0.058 at 16:00). In the age ranges examined, no differences are found with age in either group or by gender in health. No differences are found among cancer patients subgrouped either by site, stage (localized vs. metastasized) or treatment. If these results are validated, other Janus-like (two-faced: stimulation or inhibition, depending on chronome stage) effects of malignancy should be taken into consideration for screening and for timing treatment.

Brunetto Tarquini became professor of medical semeiotics and cardiology in 1981, and chief of an internal medicine department in 1990, a position he held until his untimely death. As director of the Inter-University Center for Clinical Chronobiology and as coordinator of a post-doctoral school in chronobiology, Brunetto influenced many young Italian physicians. He became the leader of a budding specialty of chronomedicine, coordinating an international group. His focus included temporal aspects of vascular diseases from womb-to-tomb as well as oncological risk factors. His research thus ranged from neonatology over neuroendocrinology to geriatrics, by studies on the pineal in particular, documenting the signature of heliogeomagnetic master switches for circulating human melatonin.

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.

The abundance of endothelial cells in bone marrow and the proximity of these cells to osteoclasts and osteoblasts suggest a role for endothelin-1 (ET-1) on bone metabolism. In vitro, the direct contact with bone endothelial cells induces osteoclastic progenitors to differentiate into mature elements. Recently it has been reported that ET-1 inhibits osteoclastic bone resorption and cell mobility through a specific receptor on osteoclasts; other authors demonstrated that ET-1 exerts a mitogenic activity on osteoblast-like cells (MC3T3) by stimulating tyrosin phosphorylation. We measured ET-1 circulating levels in patients with active Paget's bone disease, a condition with accelerated bone turnover. For the study we recruited 11 patients with Paget's bone disease (5F, 6M; mean age 68.2 +/- 3.6) in the acute stage of the disease; 10 healthy subjects (7F, 3M; mean age 66.5 +/- 3.9) were also enrolled as controls. Plasma ET-1 levels were measured with RIA kits provided by Nichols Institute. Patients showed significantly (P < 0.01) higher ET-1 circulating levels than controls (6.35 +/- 1.9 versus 3.4 +/- 1.2 pg/ml) with a positive correlation (r = 0.63; P = 0.038) with serum alkaline phosphatase (ALP), but not with urinary hydroxyproline. The higher levels of ET-1 in our patients suggest a physiopathological role for this peptide in the disease and, could perhaps represent a new useful marker of Paget's bone disease activity.

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.

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.

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.

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.

Individuals with constitutional trisomy 21 (Down syndrome) are at increased risk of developing acute leukaemias, both of myeloid and lymphoid lineage. Although the cause of leukaemia in Down syndrome (DS) remains unknown, potential candidate genes include the ones on chromosome 21, and in particular AML1, the rearrangement of which in the t(8,21) is associated with the French-American-British (FAB) classification M2 subtype of acute myeloid leukaemia (AML) in the general population and has been described in Down patients with AML-M2. Recently, a new rearrangement involving AML1, the t(12;21), producing the TEL/AML1 hybrid transcript, has been described by molecular analysis as the most recurrent genetic lesion in childhood acute lymphoblastic leukemia (ALL). In order to investigate whether the t(12;21) could give a molecular clue as to the precise basis of the etiologic association between DS and acute lymphoblastic leukemia, we tested a series of 11 consecutive cases of ALL in DS children for the presence of the TEL/AML1 transcript, by RT-PCR analysis. We report absence of the TEL/AML1 rearrangement among the 11 cases tested. This data may be suggestive of alternative pathways involved in the pathogenesis of ALL in children with constitutional trisomy 21.

The t(12;21)(p13;q22) translocation has been described recently as the most recurrent genetic lesion in paediatric acute lymphoblastic leukaemias (ALLs). It has also been associated with B-precursor lineage involvement and good outcome. We tested 51 diagnostic paediatric ALLs and found 11 cases with molecular evidence of the t(12;21). Interestingly, amongst t(12;21) positive patients, we report three cases with hybrid phenotype, and two cases showing an aggressive and fatal disease. Our data show that the t(12;21) does not represent an independent good-risk indicator. Long follow-ups and additional molecular investigations are needed to assess the prognostic and pathogenetic relevance of t(12;21) in childhood ALLs.

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.

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.

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.

The Authors report their personal experience with postoperative neuroradiologic studies in surgical patients with a herniated disk and/or degenerative cervical spondylosis. Twenty-six patients were enrolled: 16 of them underwent anterior diskectomy, 7 posterior decompressive laminectomy and 3 vertebral body removal. The patients were submitted to pre- and postoperative MRI with high field equipment (Signa 1.5 T, General Electrics), using sagittal SE T1- (TR/TE 360/15), PD and T2-weighted (TR/TE/FA 2000/40/120) sequences and T2-weighted GE axial sequences (TR/TE/FA 400/34/30). FSE sequences (TR/TE/ETL 4000/95/8) were used in 15 cases instead of the above T2-weighted SE sequences. The main postoperative MR findings were analyzed. In particular, the morphological and signal features of bone grafts, of vertebral end-plates, of the subchondral bone and of the surgical site were studied. After anterior diskectomy, the most frequent MR features were massive signal changes in the bone graft and lower vertebral plates, which were hypointense in T1 and hyperintense in T2; the adjacent subchondral bone also exhibited signal changes. Other postoperative MR findings accounted for early postoperative mobility (4 cases of persistent myelomalacia and 3 of bone graft fracture with consequent spinal instability) and late mobility (2 cases of herniated disk, 5 of spinal stenosis and one pseudomeningocele). The main limitation of MRI in postoperative cervical spine studies was the presence of ferromagnetic artifacts during SE, and even more GE, sequences; these artifacts were the main cause of misdiagnoses. In our experience, this troublesome limitation was overcome with FSE sequences but diagnostic accuracy remained poor in 4 patients. MRI, thanks to its multiparametric and multiplanar yield, is the gold standard for the examination of several early and late postoperative features and of postoperative mobility in the cervical spine. Moreover, T2-weighted FSE acquisitions are better than conventional SE to this purpose, because examination time is shorter, myelographic effect is improved and the sensitivity to ferromagnetic artifacts reduced.

Functional parameters of diluted Hb-A have been determined before and after addition of catalase and disodium-EDTA to the samples. There are no important differences between the results drawn from catalase added samples and catalase free ones, except for the fact the met-Hb level at pH 7.8 is significantly lower in the samples containing catalase. On the contrary, catalase is almost ineffective against met-Hb at pH 6.8, whereas its activity at pH 7.3 is rather modest. Another limitation is that catalase remains active against met-Hb for not more than 15-20 minutes after addition to the sample, which is just the time necessary for one complete (manual) oximetry.

The occurrence of t(1;19) translocation was investigated by reverse transcriptase-polymerase chain reaction (RT-PCR) for the E2A/PBX1 hybrid message in a panel of 37 consecutive childhood acute lymphoblastic leukemias (ALLs). Three patients with B-precursor ALL were found to be positive at diagnosis and were re-tested during follow-up to assess the presence of minimal residual disease (MRD). Two of them became PCR-negative during treatment, whereas one remains positive 3 years after diagnosis. Since all three patients are presently in clinical and hematological complete remission, PCR detection of persistent E2A/ PBX1 transcript does not seem to affect significantly the DFS at 3 years. However, the predictivity for an eventual late relapse still remains to be assessed.

This study was aimed at investigating if fast spin echo (FSE) pulse sequences can increase the diagnostic capabilities of MRI in the patients with degenerative disease of the postoperative cervical spine, considering their lower magnetic susceptibility than that of conventional spin echo (SE) sequences. The patient population consisted of 15 patients submitted to diskectomy after Cloward and Caspar. MR images were acquired with a 1.5-T unit (Signa, General Electric) with T2-weighted FSE versus conventional T1- and T2-weighted SE images. Thanks to fewer metallic artifacts, FSE images of the postoperative cervical spine yielded more pieces of information than conventional SE sequences in demonstrating the spine and its content. The best results were obtained in the patients with canal stenosis (8 patients) and myelomalacia (2 patients). In addition, the myelographic effect, another major semiologic feature of the FSE technique, provided further diagnostic information in these patients. Moreover, shorter examination times resulted in better patients tolerance, especially in those with recent surgery. Finally, reducing motion, blood flow or CSF flow artifacts definitely improved FSE image quality.

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.

A major application of Magnetic Resonance Imaging (MRI) consists in the "myelographic effect", characterized by high signal intensity of the CSF, which permits to visualize spinal subarachnoid spaces and nerve root sheaths. Such new ultrafast pulse sequences as fast spin echo (FSE) further enhance CSF high signal intensity. In addition, suppressing background with the fat suppression technique and with maximum intensity projection (MIP), a particular algorithm already used in MR angiography, FSE sequences yield 3D myelography-like images. Our study was aimed at assessing the clinical role and the reliability of this technique. Our preliminary experience is based on 21 patients with pain in the lower back and legs and on 5 healthy volunteers; all the myelography-like images were obtained with a 1.5-T MR system (Signa, General Electric). The parameters for FSE myelography-like images included: TR = 6000, TE = 200, ETL = 32, thickness = 3 mm, matrix = 256 x 224, Nex = 4, FOV = 20 cm, fat presaturation, no phase wrap, acquisition time = 2 min 58 s. MR myelography sequences were acquired after a standard FSE T1/T2-weighted exam. MR-myelography results confirmed the diagnosis of disk herniation made on conventional T1/T2-weighted images, especially in thecal sac compression and/or amputation of nerve root sheaths. MR myelography appeared to be especially useful in migrated disk herniation or in abnormal origin of nerve roots. Moreover, it allowed full and panoramic visualization of the subarachnoid spaces and excellent definition of the thecal sac, nerve roots and nerve root sheaths. In one patient only movement artifacts affected image quality. To conclude, even though it fails to yield any functional information, MR myelography appears to be an easy, rapid and noninvasive support to conventional MRI of the lumbar spine, to replace conventional myelography.