Bruno Bagni

Circadian rhythm of calcitonin gene-related peptide in uncomplicated essential hypertension

Objective: To assess the existence of an altered circulating pattern of calcitonin gene-related peptide (CGRP) in hypertension. Design: The 24 h variation in plasma CGRP was measured and compared in 10 patients affected by uncomplicated essential hypertension and in nine age- and sex-matched healthy volunteers. The diurnal variations in blood pressure, atrial natriuretic peptide (ANP), plasma renin activity (PRA), plasma aldosterone and plasma cortisol were also assessed. Methods: Recumbency studies were performed under standardized, drug-free conditions beginning at 0800 h. Venous samples were drawn every 4h for 24 h and hormone levels were assessed with specific radioimmunoassays. The blood pressure was measured every 15min with a SpaceLabs 90207 monitor. Results: The mean 24-h plasma CGRP concentrations were significantly lower in the hypertensive group than in the control group. In both groups a circadian rhythm was present with the same pattern, but at a lower level in hypertension. A temporal sequence starting with the nocturnal rise in plasma CGRP concentrations and progressing with the elevations of ANP, PRA, and plasma aldosterone and cortisol was apparent in both groups. The nocturnal rise in the CGRP and ANP concentrations coincided with the blood pressure and the heart rate falls. Conclusions: Our data show that CGRP is lower than normal but maintains its circadian variability and its relationship with the diurnal variations in blood pressure and other hormones known to be active on the cardiovascular system.

Hypoparathyroidism in Beta-Thalassemia major

In the last 18 years, we have observed 24 cases of hypoparathyroidism (HPT) in β-thalassemia major. At present, 4.5% of patients followed regularly in our department have this complication. HPT is thought to be mainly the consequence of iron deposition in the parathyroid glands. The age of our patients when HPT was diagnosed ranged from 11 to 24 years (mean 16.5 years). Their serum ferri-tin levels ranged from 810 to 15,200 ng/ml (mean 3,772 ng/ml). The severity of HPT varied widely. In only 3 patients was hypocalcemia severe with signs of tetany, seizures or cardiac failure. The onset of HPT was preceded or followed in most patients by other endocrine and/or cardiac complications. We found no clear relationship between HPT and serum ferritin levels in our patients, suggesting either an individual sensitivity to iron toxicity or early damage of the parathyroid gland before chelation had reduced the iron overload. However, the diagnosis of no new cases of HPT in the last 3 years coinciding with the much improved regime of chelation therapy suggests that chelation may have helped to prevent the development of HPT.

Oxidative stress, body fat composition, and endocrine status in pre- and postmenopausal women.

Objective: To evaluate the role of menopause on the regional composition and distribution of fat in women and eventual correlations with the oxidative state. Design: In this observational clinical investigation, 90 women (classified for menopause status according to Stages of Reproductive Aging Workshop criteria) were evaluated for body mass composition and fat distribution by dual-energy x-ray absorptiometry and for oxidative status by determination of serum hydroperoxide levels and residual antioxidant activity. Results: Total body fat mass increases significantly in postmenopause (P < 0.05) by 22% in comparison with premenopause, with specific increases in fat deposition at the level of trunk (abdominal and visceral) (P < 0.001) and arms (P < 0.001). Concomitantly, the antioxidant status increases significantly (P < 0.001) by 17%. When data were adjusted for age by analysis of covariance, statistical significance disappeared for the increase in fat mass, but it was retained for antioxidant status (P < 0.05). Both antioxidant status and hydroperoxide level increased with trunk fat mass, as shown by linear correlation analysis (r = 0.46, P < 0.001 and r = 0.26, P < 0.05, respectively). Conclusions: The results of our investigation demonstrate that fat content increases in the upper part of the body (trunk and arms) in postmenopause and that age is the main determinant of this increase. During the comparison of premenopausal and postmenopausal women, we also detected a significant increase in antioxidant status. Apparently this change is mainly related to menopausal endocrine and fat changes.

Effect of different treatment regimes on linear growth and final height in β‐thalassaemia major

OBJECTIVE The clinical picture of thalassaemia major has changed progressively over the years. Our study is a retrospective analysis of data on growth in a group of patients who have completed puberty spontaneously and have attained their adult height. Our objective was to evaluate the effect of different transfusion regimes and desferrioxamine administration on the growth pattern in β thalassaemia major.

Primary hypothyroidism and the low T3 syndrome in thalassaemia major

Basal thyroid function was assessed from the serum thyroxine, triiodothyronine, and thyroid-stimulating hormone concentrations in 114 patients (mean age 13·6 years), designated group 1, with thalassaemia major. Forty of these patients were further evaluated (group 2) for serum-free thyroxine, and free and reverse triiodothyronine concentrations. The response of thyroid-stimulating hormone to thyrotrophin-releasing hormone was measured in 25 patients from this subgroup. Results were compared with those from 53 control subjects. Primary hypothyroidism, defined by a raised thyroid-stimulating hormone level above the upper range limit of 6·5 μIU/ml of the controls, was present in 17·5% of the 114 patients. In group 2 patients, a spectrum of thyroid disease spanning uncompensated and compensated primary hypothyroidism and decreased thyroid reserve was evident. The presence of primary hypothyroidism (uncompensated and compensated) was associated with an age of at least 10 years, an increased incidence of iron toxicity-related systemic complications, and an increased transfusion iron load, but not with an increased serum ferritin level. In the total 114 patients there were 9 who had the low triiodothyronine (sick euthyroid) syndrome. Primary hypothyroidism occurs in a significant proportion of thalassaemia major patients in the absence of obvious clinical signs of hypothyroidism; the low triiodothyronine syndrome associated with non-thyroidal disease is not uncommon.

Hormonal sensitivity of adenylate cyclase from human endometrium: Modulation by estradiol

In human endometria, a membrane-bound adenylate cyclase is present, which is recovered in high yield in a low-speed particulate fraction. Neither the specific activity of the enzyme nor the response to modifiers that act through the regulatory subunit of the complex, are modified during the proliferative or secretory phase of the cycle. Surprisingly, we found that in vitro treatment of secretory endometrial membranes with 17 beta-estradiol stimulates 3- to 4-fold the activity of adenylate cyclase. However this response does not occur on proliferative membranes. The activation by estradiol is independent of the presence of guanylylimidodiphosphate and is additive to that of the nucleotide. Possibly, as the consequence of the phenomenon, the concentration of cyclic AMP is significantly higher in curretage samples obtained from patients during the secretory rather than in the proliferative phase of the cycle. To our knowledge this is the first evidence of a target-cell membrane-directed effect of sex steroids in humans.

Gonadal function in patients with beta thalassaemia major.

Endocrine studies were made on 23 female patients aged 13 to 29 years, with delayed puberty or primary amenorrhoea and beta thalassaemia major, and 12 healthy controls, of whom six were prepubertal and six were in Tanners stage 3-4. Each patient and control received a single intravenous dose of 100 micrograms gonadotrophin releasing hormone (GnRH), and one week later, 10 U/kg body weight of human menopausal gonadotrophin (hMG) to stimulate ovarian function. The patients had decreased gonadotrophin reserves when compared with those of normal controls, only one of 23 patients had an intact luteinising hormone and follicle stimulating hormone response. Most of the thalassaemic patients with delayed puberty showed normal gonad response to human menopausal gonadotrophin (hMG), but three had very low responses, when compared with that of controls. The gonadal failure was even more severe in four of six patients with primary amenorrhoea. It is important to assess hypothalamic-pituitary-gonadal function in young women with beta thalassaemia major, so that those with glandular dysfunction may be started on replacement therapy.

Consistent Changes in the Circadian Rhythms of Blood Pressure and Atrial Natriuretic Peptide in Congestive Heart Failure

We demonstrated in previous works that the circadian rhythms of blood pressure (BP) and atrial natriuretic peptide (ANP) are antiphasic in normal subjects and in essential hypertension. The aim of the present study was to assess the circadian rhythms of BP and ANP in 20 patients with stable congestive heart failure (CHF), divided into two groups of 10 according to their New York Heart Association functional class. A matched control group of 10 normal volunteers was also studied. Noninvasive BP monitoring at 15-min intervals was performed for 24 h. Peripheral blood samples were also obtained at 4-h intervals starting from 08:00 h. The mean (+/- SEM) circadian mesors of ANP plasma levels were 13.4 +/- 1.7 pmol/L in the control group, 28.6 +/- 2.4 pmol/L in the group of 10 patients in class II, and 81.5 +/- 12 pmol/L in the group of 10 patients in class III-IV. In normal subjects, plasma ANP concentration was highest at 04:00 h (21.5 +/- 2.7 pmol/L) and lowest at 16:00 h (8.8 +/- 2.4 pmol/L; p less than 0.01). Both groups of patients with CHF showed no significant circadian change in the plasma levels of ANP and also a significantly blunted circadian rhythm of BP. Cosinor analysis confirmed the loss of the circadian rhythms of ANP and BP in CHF patients. Our findings support the existence of a causal relationship between the circadian rhythms of ANP and BP.

Circadian Rhythms of Atrial Natriuretic Peptide, Blood Pressure and Heart Rate in Normal Subjects

The occurrence and extent of a circadian rhythm in the circulating concentrations of atrial natriuretic peptide (ANP) is still a matter of controversy. In a group of hospitalized normal volunteers (6 men and 4 women, 16-76 years old), we investigated the circadian variability of ANP and its temporal relation with the circadian rhythms of blood pressure (BP) and heart rate (HR), by using a chronobiological inferential statistical method. At the end of a synchronizing period of 1 week (the diet and the daily schedule were standardized), the subjects underwent automatic BP and HR monitoring, and blood sampling for 24 h. A statistically significant mean circadian rhythm was demonstrated for ANP, BP, and HR. The mean circadian acrophase of ANP was calculated to occur around 4 a.m. BP and HR rhythms appeared to be in antiphase with ANP rhythm, i.e. the peak of BP and HR rhythms more or less coincided with a trough in ANP rhythm. ANP appears to be anticipatory in its circadian periodic rise to awakening. Therefore, postural changes cannot fully account for the diurnal variations observed.

17β-estradiol levels and oxidative balance in a population of pre-, peri-, and post-menopausal women

Background. The high incidence of various diseases observed in post-menopausal women has been widely associated to the decline of 17β-estradiol (E2) occurring in correspondence of menopausal transition. One of the mechanisms suggested to explain this link takes into account the ability of E2 to counteract oxidative stress (OS) which is believed to play an important role in several pathogenic processes. Aim. To investigate whether stages of womens life characterized by different levels of E2 influence OS. Subjects and methods. We conducted a cross sectional study of OS markers in 159 women subdivided in 65 pre-menopausal, 36 peri-menopausal, and 58 post-menopausal classified according to the Staging of Reproductive Aging Workshop (STRAW) criteria. E2, follicle-stimulating hormone, and markers of OS including hydroperoxides, thiols, uric acid, total and residual antioxidant power, were assessed. Results. After adjustment for covariates, only total antioxidant power was significantly different according to menopausal status (p <0.01), with lower value in pre- with respect peri- and post-menopausal women. No significant correlations between E2 levels and OS markers were detected. Conclusions. Endogen E2, and, consequently, its decline during menopausal transition, is not a determinant factor for OS.