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In a group of patients affected with psoriatic arthritis the effects of the association between gold salts (GS) and somatostatin (SOM), in comparison with two groups treated with SOM and GS respectively, were investigated. Sixty patients with psoriatic arthritis were selected and randomly allocated in three groups of twenty patients each. Group 1 received SOM infusion (250 micrograms/h for 96 h) and was assessed at baseline and 1, 15, 30, 60, 90 and 120 days after; Group 2 received intramuscular GS and was assessed at baseline, four months later, and then every month for four months; Group 3 received GS for 8 months; at the fourth month SOM was infused (as in Group 1) and the patients assessed at baseline four months later and then as Group 1. Assessment was made with the Ritchie index, pain scale and morning stiffness evaluation. Growth hormone was assayed in Group 1 every 4 h for 24 h the day before and the day after SOM infusion. The association between GS and SOM demonstrated a particular analgesic activity, effective on joint pain and tenderness, that lasted for all four months of follow-up. SOM showed a good response only after 15 and 30 days, and GS proved to be effective at about the sixth month of treatment. Side effects were reported in Group 1 (abdominal cramps, mild erythrodermia and supraventricular arrhythmia). A growth hormone circadian rhythm was found in psoriatic patients both before and after SOM treatment. The beneficial effect of the SOM/GS combination is demonstrated in psoriatic arthritis.(ABSTRACT TRUNCATED AT 250 WORDS)

Lung involvement in children affected with Systemic Sclerosis (SSc) has been studied. We used ventilation and perfusion scans and compared the results to those obtained with traditional pulmonary function tests. The vascular pulmonary area was examined with a gama-camera after infusion of 99mTc microspheres, while the alveolo-capillary membrane and the airways were investigated after administration of a radioaerosol, (99mTc DTPA). Pulmonary function tests revealed either alteration of the airways or a considerable involvement of the alveolo-capillary membrane in two patients. On the other hand ventilation scan showed airways alterations and a severe decrease of the alveolocapillary permeability in all patients. Our study indicates that ventilation scans may be useful in the diagnosis of early modifications of the lung function also in paediatric age and may complement the data obtained from traditional function tests.

The fibrinolytic activity (FA) has been studied on the synovial membrane obtained from 16 patients with osteoarthritis (OA), 20 patients with rheumatoid arthritis (RA) and 11 control subjects. Todd's autohistographic method, modified by Lotti, was used to investigate the FA and the monoclonal antibodies against u-PA and t-PA were used to identify the main plasminogen activator. Our results show that the FA is increased in the synovial membrane of patients with OA in comparison with the synovial FA of control subjects. In the synovial membranes from patients with RA, the FA shows different results: in some specimens FA is increased, and in others it is diminished or similar, compared with FA of samples from healthy controls. Thus, our data on synovial FA in OA confirm the previous reports, performed in vitro, on the activation of the plasmin system in this degenerative disease. The activity of the fibrinolytic system seems to participate in the cartilage degeneration and, via the activation of collagenase, to perpetuate the cartilage damage.

Decreased levels of angiotensin converting enzyme plasma activity were found in systemic sclerosis. No relationship with clinical characteristics of the disease and increased von Willebrand factor antigen concentration (a widely accepted marker of endothelial injury) were statistically demonstrated. An inverse relationship between the reduced activity of the enzyme and erythrocyte sedimentation rate was detected (r = 0.410, p less than 0.05). We hypothesize that in systemic sclerosis, angiotensin converting enzyme activity might be affected by a decrease in endothelial production or by interference of circulating factors. Further studies are needed to determine if angiotensin converting enzyme activity could be used as a marker of endothelial injury in scleroderma.

Rhythm parameters of peripheral arterial rest blood flow (RF) as a potential predictor of peripheral arterial disease (PAD) have been investigated. Three groups of subjects have been studied: a. six apparently healthy subjects; b. seven high risk (hypertension, diabetes, hypercholesterolaemia, hypertriglyceridaemia, erythrocytosis) subjects; c. four occlusive PAD selected patients with one 'pre-symptomatic' leg. RF has been measured by 'strain-gauge plethysmography' every min for 25 min, 4 times/day. Right fore-arm, right leg and left leg have been assessed. Data have been analyzed by 'single and population mean cosinor'. Significant circadian rhythms have been detected in apparently healthy subjects. Mesor and amplitude can differ according to single individual's area. Mesor is higher in upper limb. RF circadian rhythm parameters differ in subjects with various vascular risk load. Sometimes, PAD-symptomatic limb shows higher mesor than pre-symptomatic one, suggesting conditions of reactive post-ischemic hyperemia or a role of RF in PAD. Circadian dyschronia can be detected in PAD limbs but also in high risk subjects, perhaps an example of chronoprotopathology. These results suggest the possibility of a clinical use of RF rhythm parameters as predictors of vascular protopathology.

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

At present, neonates are being given screening tests for relatively rare diseases, such as phenylketonuria. The time has come to give emphasis to assessing the risk for major handicapping diseases, such as coronary heart disease, stroke, and certain diseases of the kidney. Modern technology for blood pressure and heart rate monitoring and data analysis provides noninvasive means to determine when preventive measures are indicated.

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

A group of 12 presumably healthy subjects was standardized for 7 days with rest time extending from 22.00 to 05.00. Meals were scheduled at 08.00-08.30, 12.00-12.30, 17.30-18.00 and the amounts consumed were standardized and measured. Each subject was sampled at 4-hour intervals throughout one 24-hour period; this involved the measurement of body temperature, radial pulse, blood pressure. In addition a sample of blood was collected at each time point and subsequently total, direct and indirect bilirubin measurement was made on each sample of serum. All data were analized by macroscopic approach (chronograms) and by mean cosinor. A circadian rhythm is detected in total, direct and indirect serum bilirubin.

Two groups of subjects (one consisting of fourteen apparently healthy subjects, the other of fourteen patients with peptic ulcers) were kept for a least 7 days on the same living schedule (nocturnal sleep for 22(00) to 05(00) and meals standardized at 08(00)-08(30), 12(00)-12(30), 17(30)-18(00)). During 24 hors, samples of venous blood were obtained from each subject every 4 hours for the serum gastrin radioimmunoassay. The results were analyzed by mean cosinor method. The control group has a statistically significant circadian rhythm, while we were not able to detect a circadian rhythm in the patients with duodenal ulcers. The daily mean of serum gastrin levels appears to be significantly reduced in the ulcer group.

The mean conisor technique reveals statistically significant circadian rhythms for serum concentrations of iron, chloride, cortisol, PBI, the fibrinolytic activity of blood, urinary iron excretion and gastric acid secretion in studies covering a 24-h span for presumably healthy subjects. Quantification of these rhythms provides internationally comparable reference values both for the conventional clinical laboratory and for any special chronobiologic applications.

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

The lymphocyte surface phenotype of lymph nodes from patients with larynx or urinary bladder carcinoma was investigated by using a panel of monoclonal antibodies. The phenotype pattern of lymphocytes from lymph nodes invaded by malignant cells (as assessed by histopathology) was different from that of the cells from noninvaded or normal control nodes. Although the proportion of natural killer cells or macrophages was similar in the 3 groups of lymph nodes, invaded lymph nodes contained a higher proportion of T-cells and a lower B-cell percentage. Furthermore, cells from invaded nodes comprised 15-20% of T3+ T8+ cells that coexpressed the M1 marker and, to some extent, also the Leu 7 marker. A large proportion of cells with multiple markers were activated, as shown by the expression of Tac and HLA-DR antigens. In 2 patients activated T8+ cells expressing also M1 and Leu 7 markers infiltrated the tumor site. The presence of these activated cells both in involved nodes and tumor mass may indicate that they originate in response to cancer.

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

A group of 8 patients (M) with liver cirrhosis were studied. Each subject was standardized with rest time extending from 22,00 to 05,00 and meals scheduled at 08,00-08,30, 12,00-12,30, 17,30-18,00. Then was sampled at 04,00, 08,00 12,00, 16,00, 20,00, 24,00. In each sample of serum were determined iron, T.I.B.C. and L.I.B.C. All data were analyzed by macroscopic approach (chronograms) and by mean cosinor. A significant circadian rhythm was detected in all parameters, with a statistically valid difference between normal subjects and patients with liver cirrhosis in the mesor of T.I.B.C. and L.I.B.C.

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

Blood pressure and heart rate were oscillometrically monitored with an automatic Nippon Colin instrument (Komaki, Japan) and were also self-measured by a 20-year-old man treated with an inhalant-decongestant containing an adrenergic and a corticosteroid analog. The subject also collected 24-hr urines for aldosterone determination. An elevation of urinary aldosterone excretion was observed compared to the usual value range of a peer group. After removal of the drug, urinary aldosterone dropped as did urinary potassium, whereas plasma potassium rose. Chronobiologic serial sections, carried out to follow the time course of blood pressure and heart rate, showed decreasing trends in MESOR after discontinuance of treatment. A decrease in the hyperbaric index, a measure of blood pressure excess over 24 hr, was also observed. Another subject treated with the same and a third treated with a similar inhalant-decongestant, who also monitored their blood pressures automatically and/or with self-measurements, showed similar effects: a decrease in blood pressure after removal of treatment and an increase in blood pressure when (for testing only) treatment was briefly resumed.

The inhibitory effect exerted upon the cyclic activity of the adrenal cortex by a synthetic steroid analog (dexamethasone-21-phosphate) administered at different circadian stages, has been studied previously. Reexamination of the same data by microscopic methods herein provides two sets of objective quantitative endpoints for further studies, namely 1. the characteristics of a rhythm isolated from a superimposed trend as well as noise, and 2. the endpoints of the trend itself. These endpoints quantify the effect of dose and, with the appropriate dose, the optimal timing for a given purpose may also be found.