Bone damage in type 2 diabetes mellitus.

This review focuses on the mechanisms determining bone fragility in patients with type 2 diabetes mellitus (T2DM). Despite bone mineral density (BMD) is usually normal or more often increased in these patients, fracture incidence is high, probably because of altered bone "quality". The latter seems to depend on several, only partly elucidated, mechanisms, such as the increased skeletal content of advanced glycation end-products causing collagen deterioration, the altered differentiation of bone osteogenic cells, the altered bone turnover and micro-architecture. Disease duration, its severity and metabolic control, the type of therapy, the presence or absence of complications, as like as the other known predictors for falls, are all relevant contributing factors affecting fracture risk in T2DM. In these patients the estimate of fracture risk in the everyday clinical practice may be challenging, due to the lower predictive capacity of both BMD and risk factors-based algorithms (e.g. FRAX).

Approach in glucocorticoid-induced osteoporosis prevention: results from the Italian multicenter observational EGEO study.

Glucocorticoid-induced osteoporosis (GIO) is the most frequent cause of secondary osteoporosis. GIO is linked to glucocorticoids (GC) daily assumption with maximum effect within first months of treatment and decreasing to basal levels as the therapy is discontinued. In Italy, primary prevention of GIO is suggested when GC therapy (prednisone >5 mg/day or equivalent) is taken for longer than 3 months. Lazio GISMO (Italian Group for Study and Diagnosis of Bone Metabolism Diseases) group organized the GC and Osteoporosis Epidemiology study (EGEO) to evaluate physician's approach in preventing GIO. The study involved 19 osteoporosis centers. Patients taking long-term GC therapy were recruited and information collected: medical history and anthropometric data, GC therapy, primary disease, physician's specialty, osteopororosis screening, and pharmacological intervention. The study included 1334 patients. Mean age was 63 ± 13 yr; 243 (18%) patients had a history of falls from standing position in the previous 12 months, 78 (35%) vertebral fractures, 91 (41%) fractures other than vertebral, 27 (12%) femoral fractures, and 27 (12%) multiple sites fractures. The molecules of GC more often prescribed were prednisone and 6-metil prednisolone. One thousand and forty patients (78%) were taking GC for more than 6 months. GC therapy was prescribed more frequently by rheumatologists (62%). Antiosteoporotic drugs for GIO prevention were prescribed in 431 patients (32%). Among the patients, only 27% (360) received calcium and vitamin D supplements, and 39% (319) treated by rheumatologists received anti-resorptive drugs. In conclusion, our data show that in Italy, as already described elsewhere, only a small subpopulation of GC-treated patients was supported by an anti-osteoporotic therapy, indicating the need to further stimulate awareness of both patients and specialists, prescribing GC therapy, to an appropriate and prompt GIO prevention.

Chronic constipation in hypercalcemic patients with primary hyperparathyroidism.

BACKGROUND: Chronic constipation (C), among gastrointestinal symptoms, is commonly associated with primary hyperparathyroidism (PHPT) and probably attributable to hypercalcemia. OBJECTIVE OF THE STUDY: To evaluate in patients affected with PHPT the prevalence of C utilizing a validated questionnaire and the current prevalence of C compared to that observed in the past and to evaluate the relationship between C and the severity of PHPT. METHODS: 55 outpatients affected with PHPT, admitted to our Department of Internal Medicine and Medical Specialities in the years (2006-2009) were studied (group 1: 50 postmenopausal women and 5 men, mean age 61.9 +/- 9.4 years), together with 55 sex and age matched controls (group 2). Also considered were a group of PHPT patients observed, in the same ambulatory, during the years '70-'80 (group 3). A questionnaire, Rome II criteria, was administered and used to define C, whereas only anamneses were used to define C in group 3. RESULTS: The prevalence of C in patients with PHPT was 21.8% in group 1 vs 12.7% in group 2 (n.s.) and 32.7% in group 3. There is a decreasing trend in the prevalence of C in patients with PHPT as observed from 1970-89 to 2006-2009 (p < 0.05). The reduction of C was associated together with a significant reduction in the serum calcium level (p < 0.001). The presence of C vs its absence in patients with PHPT is characterized by higher values of calcemia (p < 0.001), ionized calcium (p < 0.001), and parathyroid hormone (p = 0.019). CONCLUSION: The actual prevalence of C in patients with PHPT is not significantly different from that found in the control group and is decreasing with respect to the past years. Moreover, C seems to be associated with the severity of the disease rather than with the diagnosis of PHPT per se.

Relation of adiponectin, visfatin and bone mineral density in patients with metabolic syndrome.

BACKGROUND: Adipose tissue has been suggested to influence bone density and metabolism through the effect of some adipokines. However, whether adiponectin and visfatin may correlate with bone metabolism is still unclear. AIM: The aim of this study was to investigate the relationship of adiponectin and visfatin with bone density in patients with metabolic syndrome (MS). SUBJECTS: We enroled 72 consecutive patients with MS (25 males, 47 females; mean age 58.14±11 yr) and 40 control subjects. METHODS: Plasma adiponectin and visfatin levels were measured. Bone mineral density (BMD) was assessed by dual energy X-ray absorptiometry (DXA) at the level of lumbar spine L2-L4 (BMD L2-L4) and femoral neck (BMD-Fn). RESULTS: MS patients had higher plasma visfatin and lower adiponectin levels than controls, (p<0.01 for both). Adiponectin was negatively correlated with BMD-Fn and BMD L2-L4 (r=-0.20, r=-0.24, respectively; p<0.05 for both) whereas plasma visfatin levels were positively correlated to BMD L2-L4 only in men (r=0.44; p<0.05). CONCLUSIONS: Our study shows that adiponectin and visfatin are oppositely associated with BMD. Although the mechanisms behind these correlations are unclear, a modulation of bone metabolism by these adipokines can be suggested.

Sporadic and hereditary primary hyperparathyroidism.

Primary hyperparathyroidism (PHPT) is a common endocrine disorder, particularly frequent in post-menopausal women. It is characterized by hypercalcemia with inappropriately high spontaneous plasma PTH. Singlegland adenoma is the most common cause (75- 85%). PHPT is usually a sporadic disease but in approximately <5% of cases, a familial hyperparathyroid syndrome is diagnosed. Familial hyperparathyroidism is a clinically and genetically heterogeneous group of disorders including: multiple endocrine neoplasia (MEN) type 1, MEN type 2A, MEN4, benign familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, hyperparathyroidism-jaw tumor syndrome, and familial isolated hyperparathyroidism. These syndromes show mendelian inheritance patterns and the main genes for most of them have been defined. The classic form of PHPT, which presents with hypercalcemia, kidney stones, and bone disease, is no longer common. Currently, there is an increasing interest in the subtle manifestations of PHPT, particularly the cardiovascular and neuropsychiatric manifestations. Parathyroidectomy is the definitive cure for PHPT even though patients with the asymptomatic form of the disease can be followed conservatively.

Skeletal turnover, bone mineral density, and fractures in male chronic abusers of alcohol.

BACKGROUND: Chronic alcohol abuse is a risk factor for osteoporosis and fractures, whose pathogenesis is still unclear. We investigated the influence of alcoholism and other risk factors on calcium and skeletal metabolism, bone mineral density (BMD), and fractures. MATERIALS AND METHODS: In 51 chronic male alcoholics without liver failure and 31 healthy controls, serum total and ionised calcium, phosphate, creatinine, 25-hydroxy vitamin D (25OHD), PTH, total (ALP) and bone-specific (BALP) alkaline phosphatase, osteocalcin (BGP), carboxy-terminal telopeptide of type I collagen (beta-CTx), osteoprotegerin (OPG) and receptor activator of nuclear factor kappa B ligand (RANKL) were assessed. In patients only, we also measured serum testosterone, 17-beta estradiol, LH, and IGF-I. BMD was measured by dual energy x-ray absorptiometry at lumbar spine (LS-) and femur [neck (FN-) and total hip (TF-)]. Vertebral fractures were identified by a semiquantitative method on thoraco-lumbar spine x-ray, non-vertebral fractures (as life-style factors) by history. RESULTS: Alcoholics were leaner, had significantly higher ALP and BALP, and lower BGP and 25OHD levels than controls. No significant difference in other calcium and bone metabolism parameters was found. OPG/RANKL ratio was significantly higher in alcoholics. Beta-CTx negatively correlated with abuse duration. OPG positively correlated with daily alcohol assumption and with indexes of liver cytolysis. Though LS-, FN- and TF-BMD of alcoholics and controls did not significantly differ, patients had a much higher prevalence of vertebral fractures. The same was found considering both vertebral and non-vertebral fractures. CONCLUSIONS: Ethanol-induced skeletal damage seems mainly dependent on negative effects on bone formation. Lifestyle factors and traumas likely contribute to the high fracture incidence of alcohol abusers, independently of BMD.

Metabolic bone diseases during long-term total parenteral nutrition.

Long-term total parenteral nutrition (TPN) is a procedure commonly applied to patients with advanced forms of intestinal malabsorption. Among TPN complications, bone metabolic diseases, such as osteoporosis and osteomalacia, are a common finding. Initially considered to be a manifestation of aluminium toxicity which followed massive contamination with the element of the solutions used in TPN, metabolic osteopathy during TPN is currently considered a multiform syndrome, with a multifactorial pathogenesis, which may manifest itself with vague or clear clinical pictures. In this review, we analyse clinical, pathogenetic, and therapeutic aspects of the most common bone metabolic diseases in patients undergoing long-term TPN.

Cyclical changes of vertebral body heights and bone loss in healthy women after menopause.

Annual changes in vertebral body heights (VHs) and lumbar bone mineral density (LBMD) were evaluated in 120 healthy pre- and post-menopausal women aged 45-74 years. Subjects were divided into groups according to menstrual status and years since menopause (YSM). Vertebral heights were evaluated, using radiological morphometry as the sum of anterior vertebral body heights (AVHs) from T4 to L5 at baseline and exactly 12 months later. Results indicate that the sum of VHs is inversely correlated with advancing age, and the decrease in VHs is not a constant process over time but rather exhibits cyclical damping oscillations. When log-linear trend of VH decrease was transformed into a constant considering annual percentage changes, the presence of a cyclical component of 7 years was evident. Employing a harmonic regression model, the cyclical component was also statistically significant on baseline data. The cyclical decrease of VHs corresponds to an analogous cyclical behavior of LBMD values. These results suggest that a lack of estrogen acts as a synchronizer on bone remodeling, triggering a latent cyclical rhythm of bone loss, accompanied by cyclical bone microarchitecture deterioration and consequent vertebral body deformities, which after menopause persists throughout life. The existence of a chronobiological rhythm of bone loss and trabecular bone strength reduction at vertebral level after menopause, if confirmed, could have important clinical implications.

Increased plasma levels of adrenomedullin, a vasoactive peptide, in patients with end-stage pulmonary disease.

AIM: To study adrenomedullin (AM) plasma levels in patients with severe lung disease and to analyze the relationship between AM and heart changes, hemodynamics and blood gases. METHODS: Case control study of 56 patients (36 men, 20 women) with severe lung disease and 9 control subjects (7 men, 2 women). Patients with end-stage pulmonary disease, including chronic obstructive pulmonary disease (COPD, n=11), cystic fibrosis (CF, 26), idiopatic pulmonary fibrosis (ILD, n=9), and idiopatic pulmonary arterial hypertension (PAH, n=10), who were evaluated for lung trasplantation between January 1997 and September 2000, and nine patients who underwent lung surgery for a solitary benign nodule. AM plasma levels in pulmonary artery (mixed venous blood, vein) and aorta or femoral artery (arterial, art), art and vein blood gases, pulmonary hemodynamics, systemic hemodynamics, two-dimensional transthoracic echocardiography and echo-Doppler study. RESULTS: Plasma AM (art and ven) levels were higher among patients' group compared to the controls (AMart p<0.02 and AMven p<0.04) for CF, ILD, PAH (AMart, pg ml(-1) Controls 13.7+/-3.6, COPD 22.8+/-6.2, CF 28.1+/-11.4, ILD 34.1+/-14.3, PAH 35.1+/-18.9; AMven, pg ml(-1) Controls 14.2+/-4.8, COPD 28.1+/-12.6, CF 31.7+/-14.1, ILD 38.7+/-16.5, PAH 40.1+/-4.4). We found with a trend towards higher concentration in ILD and PAH patients compared to COPD and CF but no statistical significant differences. Mixed-venous AM was higher than arterial AM in all groups resulting in AM uptake (AMPulmUp pg min(-1) Controls 4.8+/-22.6, COPD 21.1+/-44.9, CF 20.6+/-45.1, ILD 23.7+/-38.5, PAH 29.9+/-49.7). The univariate analysis showed a weak but significant correlation between AMart and mean systemic arterial pressure, heart rate, mean pulmonary arterial pressure and systemic vascular resistance. In the multivariate analysis, four variables emerged as independent factors of AMart including mean pulmonary arterial pressure, heart rate, mean systemic arterial pressure and left ventricular diastolic diameter (F=8.6, p<0.00001, r=0.60, r2=0.32). A similar weak correlation was apparent between AMven, systemic vascular resistance, and mean pulmonary arterial pressure. The results of multivariate analysis identify right atrial enlargement, mean right atrial pressure, heart rate and left ventricular dimensions as the only independent variables related to AMven (F=4.3, p<0.0004 r=0.56, r2=0.26). AM pulmonary uptake was significantly correlated with AMven (r=0.65), but not with hemodynamic, blood gas and echocardiographic variables. CONCLUSIONS: AM plasma levels are elevated in patients with severe lung disease in face of a preserved pulmonary uptake. These results suggest that the high AM plasma levels in patients with severe lung disease are not caused by a reduced pulmonary clearance, instead suggesting a systemic production.

Ambulatory monitoring of blood pressure (AMBP) in patients with primary hyperparathyroidism.

The purpose of our study was to evaluate the behaviour of blood pressure (BP) by ambulatory monitoring of blood pressure (AMBP) in 53 patients with primary hyperparathyroidism (PHPT) compared to 100 essential hypertensive (EH) and 31 healthy subjects (HS). The correlations between calcium-phosphorus metabolism and haemodynamic parameters in all groups are included in the study. AMBP was performed using the oscillometric technique (Space-Labs, 90207, Redmond, WA, USA) and the following AMBP parameters were evaluated: average day time systolic (S) and diastolic (D) blood pressure (BP) and heart rate (HR) (when awake), average night time SBP, DBP and HR (when asleep) and average 24-h-SBP, DBP and HR. The definition of 'dipper' or 'non-dipper' subjects was established if night time SBP and DBP fall was >10% and <10%, respectively. In total, 25 PHPT patients (47.2%) were hypertensive (HT-PHPT) and 28 PHPT (52.8%) were normotensive (NT-PHPT). Mean 24-h-SBP and DBP obtained by AMBP was higher in HT-PHPT (P < 0.05) and EH (P < 0.05) than in NT-PHPT and HS. The multiple linear regression has shown that in PHPT-HT patients ionized calcium is an independent factor for the rise of 24-h-DBP values (r: 0.497; P < 0.05) and daytime DBP values (r: 0.497; P < 0.05). In 56% of HT-PHPT patients there is an absence of physiological BP nocturnal fall ('non-dipper'), which is statistically significant (P < 0.05) compared with 'non-dipper' EH patients (30%). In conclusion, in our study the prevalence of hypertension in PHPT was 47%. AMBP revealed that the 'non-dipping 'pattern was much higher in HT-PHPT patients in respect to EH patients.

Acute hyperinsulinemia is associated with increased plasma adrenomedullin concentrations in uncomplicated obesity.

OBJECTIVE: Adrenomedullin (AM) is a potent hypotensive peptide which may be implicated in the insulin regulatory system. Acute hyperinsulinemia exerts no influence on plasma AM in normal subjects while no data on obese subjects has been reported. PURPOSE: The aim of the study was to investigate the effect of acute hyperinsulinemia on the plasma AM concentration in patients with uncomplicated obesity. RESEARCH METHODS: We measured the plasma AM levels in 23 obese subjects (BMI 41.9 +/- 9.8 kg/m2), 21 females and 2 males (mean age 31 +/- 7.2 years), before and during a euglycemic hyperinsulinemic clamp. The control group consisted of 43 healthy subjects (HS) (22 males and 21 females; mean age 38 +/- 12 years; BMI 23.3 +/- 3.2 kg/m2). RESULTS: Baseline plasma AM was found to be higher in obese subjects (20.4 +/- 8.4 pg/ml) than in normal subjects (11.3 +/- 0.8 pg/ml) (p < 0.001). A significant increase in the plasma AM levels was observed in obese subjects during acute hyperinsulinemia (from 20.4 +/- 8.4 pg/ml at 0 min to 26 +/- 8.9 pg/ml at 120 min, p < 0.02). Plasma AM concentrations were significantly correlated with insulin levels at 30 min (r = 0.44; p = 0.04) and 120 min (r = 0.40, p = 0.05) during the clamp. DISCUSSION: In conclusion, acute hyperinsulinemia induced a significant increase in the plasma levels of AM in uncomplicated obese subjects. Hyperinsulinemia may, at least in part, regulate levels of AM in obesity, explaining the high levels of the peptide in these subjects.

[Primary hyperparathyroidism]. / Iperparatiroidismo primitivo.

Primary hyperparathyroidism (PHPT) is characterized by excessive PTH secretion in respect to calcium homeostasis needs, due to parathyroid adenoma (80% of cases), hyperplasia (15-20%), or carcinoma (1-2%). In familial forms of PHPT, several mutations have an established role: menin gene for MEN type 1, RET for MEN type 2a, calcium-sensing receptor gene for familial hypocalciuric hypercalcemia, parafibromin gene for PHPT-jaw tumour and carcinoma. Etiology of sporadic adenomas (80% of PHPT cases) is less defined, being most commonly found a mutation of menin gene or activation of PRAD1 oncogene. In recent years, the classical features of the disease became less common. Typically, bone involvement is now represented by a reduced bone mass at skeletal sites more rich in cortical tissue. Prominently trabecular skeletal sites are relatively spared, because of the anabolic effects of a slight PTH excess on trabecular tissue. PHPT patients may have increased fracture risk, though it is not clear why bone damage is more severe in a subgroup of patients. Clinical features of hypercalcemia may be fatigue, anorexia, thirst, and polyuria. Vague neurological and psychiatric symptoms, such as weakness, anxiety, depression, paresthesias, and muscular cramps may ameliorate after parathyroidectomy. Recent reports indicate increased cardiovascular mortality in PHPT patients. Diagnosis is based on the detection of hypercalcemia, together with inappropriately high serum PTH levels. Preoperative localization of the diseased glands is mandatory in persistent or recurrent PHPT, as like as when minimally invasive surgery is planned. High resolution ultrasonography and SPECT double-phase 99m Tc-sestamibi scintigraphy are the most commonly employed techniques. Intraoperatory PTH assay may confirm successful surgery when serum concentrations decrease more than 50%. Surgical therapy is indicated in patients with renal or skeletal complications, such as in those with previous parathyrotoxic crisis. Many surgeons in recent years adopted minimally invasive parathyroidectomy. Medical treatment is an option for patients unwilling or unfitted for surgery because of severe concomitant diseases. Employed therapy includes estrogens, SERMs, bisphosphonates and calcimimetics.

Annual skeletal balance and metabolic bone marker changes in healthy early postmenopausal women: results of a prospective study.

The aim of this study was to establish the duration and annual rate of menopause-related bone loss and to investigate the relationship between bone turnover and bone loss in early healthy postmenopausal women. The rate of change in bone mineral density (BMD) at the lumbar spine and in bone turnover was measured twice at the exact interval of 12 months by dual-energy X-ray absorptiometry (DXA) and by the determination of plasma alkaline phosphatase levels (ALP) and fasting urinary hydroxyproline/creatinine ratio (OHPr/Cr), respectively, in 123 healthy premenopausal and postmenopausal women 45-60 years of age. The subjects were divided into nine groups according to their menstrual status and years since menopause (YSM). Annual bone loss at the lumbar spine of women who were menopausal for 1, 2, 3, 4, and 5 years was -2.62 +/- 0.37 (95% confidence interval -3.66, -1.58), -3.87 +/- 0.96 (-6.02, -1.73), -2.50 +/- 0. 37 (-3.29, -1.70), -2.86 +/- 0.73 (-4.44, -1.27), and -1.54 +/- 0.41 (-2.42, -0.66), respectively, and was significantly less than zero. But, the annual bone loss of women who were premenopausal or menopausal for 6, 7, and 8 years was -0.76 +/- 0.60 (-2.04, +0.53), -1.16 +/- 0.68 (-2.61, +0.29), 0.24 +/- 0.48 (-0.78, +1.26), and 0. 16 +/- 0.63 (-1.18, -1.49), respectively, and was not significantly different from zero. These results demonstrate that the early hormone-dependent bone loss commences in the first year after menopause and is arrested within 6 years after the onset of menopause. The overall bone loss for this phase is estimated to be approximately 15%. Annual change in ALP and OHPr/Cr seems to indicate that bone resorption prevails on bone formation in the first 2 YSM, whereas osteoblastic activity relatively prevails from YSM 3 to YSM 5, which explains the progressive repairing of the imbalance between bone resorption and formation.

Cyclical behavior of bone remodeling and bone loss in healthy women after menopause: results of a prospective study.

Annual changes in lumbar bone mineral density (LBMD) and bone remodeling markers were measured in 238 healthy pre- and postmenopausal women, aged 45-74 years. The subjects were divided into groups according to their menstrual status and years since menopause. The results obtained indicate that bone loss is not a constant process over time but rather exhibits cyclical damping oscillations. When the log-linear trend of LBMD decrement was transformed into a constant by considering annual percentage changes, the presence of a cyclical component of 7 years was evident. By employing a harmonic regression model, the cyclical component was also statistically significant on baseline data. The cyclical behavior of LBMD decrement corresponded to an analogous behavior of the bone remodeling markers. These results suggest that a lack of estrogen acts as a synchronizer on bone remodeling by triggering a latent cyclical rhythm of bone loss that persists throughout life after menopause. The existence of a chronobiological rhythm of bone loss starting after menopause, if confirmed, could have important clinical implications.

Absence of somatic mutations in natriuretic peptide receptor type A gene in human aldosterone-secreting adenomas.

Somatic mutations of genes codifying for key regulatory proteins are the cause of different types of hormone-secreting adenomas. Natriuretic peptides (NP) are the strongest inhibitors of aldosterone secretion but aldosterone-secreting adenomas (aldosteronomas) are resistant to this inhibition and have reduced binding sites for NPs. The objective of this study was to sequence the entire coding region of the NP receptor type A (NPRA, codified by the Npr1 gene) to find loss-of-function somatic mutations. Total RNA was extracted from eight aldosteronomas and cDNA was synthesized. NPRA mRNA expression was evaluated by Northern blot analysis and compared with beta-actin mRNA as the housekeeping gene. Twelve primer couples were designed on the basis of the Npr1 gene organization to amplify, by PCR, all 22 coding exons of the gene. The two strands of amplified DNAs were purified and directly sequenced by automated capillary sequencer. NPRA mRNA expression did not differ among aldosteronomas. Npr1 open reading frame sequences obtained from eight aldosteronomas did not contain any mutation. The coding sequences of all 22 exons were identical in all samples and identical to published sequences. In the 3'-untranslated region (3'-UTR) a new length difference 3C/4C polymorphism was found at position 15 129 (three adenomas were 3C/4C and two were 3C/3C). Such a 3C/4C polymorphism was present in genomic DNA from 80 control subjects (25, 4C/4C; 40, 3C/4C; 15, 3C/3C). Mutations in the coding exons of the Npr1 gene do not appear to be a common cause of aldosteronomas. Moreover, the exons of Npr1 encoding for the translated portion of mRNA do not appear to be prone to polymorphisms. The polymorphism identified in the 3'-UTR might affect mRNA stability resulting in lower receptor synthesis, but it is not likely to confer a predisposition to the development of aldosteronomas.

Adrenomedullin, a new peptide, in patients with insulinoma.

BACKGROUND: It has been demonstrated that adrenomedullin, a newly discovered peptide, affects the release of insulin from pancreatic islets cells, suggesting a role in the insulin-regulating system. OBJECTIVE: To investigate whether adrenomedullin secretion is modified in patients with insulin-secreting islet cell tumours. DESIGN: The study was performed in nine patients with surgically treated insulinoma. Circulating adrenomedullin was assayed using a specific radioimmunoassay and its localization and distribution in the tumour were determined by means of immunohistochemistry. RESULTS: Adrenomedullin concentrations were significantly greater in patients with insulinoma (6.6 +/- 3.2 fmol/ml) than in controls (2.1 +/- 1.1 fmol/ml). In six patients monitored before and after surgery, plasma adrenomedullin decreased from 6.3 +/- 2.9 fmol/ml to 3.0 +/- 1.6 fmol/ml. Immunoreactive adrenomedullin was localized exclusively in the tumours cells, whereas stroma, surrounding pancreas parenchyma and major ducts were negative for the peptide. CONCLUSIONS: Our findings indicate that circulating adrenomedullin is increased in insulinoma and that this increase is related to the neoplastic phenotype.

Adrenomedullin concentrations are elevated in plasma of patients with primary hyperparathyroidism.

The aim of the study was to evaluate plasma adrenomedullin (AM) concentration in primary hyperparathyroidism (PHP) and its effect on the regulation of blood pressure. Forty-one patients with PHP (25 normotensive and 16 hypertensive), and 31 healthy subjects (HS) were included in the study. As expected the total and ionized calcium and i-PTH serum levels were significantly higher in patients with PHP than in HS (P <.001). No significant difference was found in calcium-phosphorus metabolism parameters between normotensive and hypertensive PHP patients. Serum i-PTH levels correlated positively with systolic blood pressure (SBP) (r = 0.510; P <.02), diastolic blood pressure (DBP) (r = 0.586; P <.01) and heart rate (HR) (r = 0.486; P <.043) only in hypertensive PHP patients. Overall, mean plasma AM concentrations were significantly higher in PHP patients (16.1 +/- 7.9 pg/mL) than in HS (11.3 +/- 4.8 pg/mL) (P <.003) and correlated with i-PTH (r = 0.430; P <.005). However, in hypertensive PHP patients plasma AM levels (22.5 +/- 4.7 pg/mL) were higher than in normotensive PHP patients (11.6 +/- 1.8 pg/mL) (P <.001) and correlated with DBP (r = 0.902, P <.0029). In HS no correlation was found between plasma AM values and biohumoral, hormonal, or hemodynamic parameters. In conclusion, we demonstrated that in patients with PHP, plasma AM concentrations are increased and correlate with i-PTH and blood pressure values. We suggest that increased AM levels could be a compensatory factor in the defence mechanism against further blood pressure elevation.

Circulating adrenomedullin is increased in patients with corticotropin-dependent Cushing's syndrome due to pituitary adenoma.

It has been demonstrated that adrenomedullin, a newly discovered peptide with structural similarity to calcitonin gene-related peptide (CGRP), is expressed in pituitary gland and affects basal and corticotropin (ACTH)-releasing factor (CRF)-stimulated ACTH release in animals, thus suggesting its potential role in regulating the hypothalamus-pituitary-adrenal axis. To evaluate whether ACTH and cortisol levels affect adrenomedullin production in humans, we studied 14 patients with Cushing's syndrome due to pituitary adenoma and 8 patients with Cushing's syndrome due to adrenal tumor, with measurement of circulating adrenomedullin by a specific radioimmunoassay (RIA). Adrenomedullin concentrations were significantly higher in patients with pituitary adenoma (37.6 +/- 17.8 pg/mL) versus controls (13.7 +/- 6.1 pg/mL) and patients with adrenal adenoma (17.8 +/- 2.2 pg/mL). After pituitary surgical treatment, plasma adrenomedullin decreased significantly. In one patient with Cushing's syndrome due to pituitary adenoma who underwent simultaneous sampling of the inferior petrosal venous sinuses, the adrenomedullin concentration was significantly higher in plasma collected from the side with the adenoma and increased after CRF administration (delta increase, 42.6%), according to ACTH levels. Our findings indicate that circulating adrenomedullin is increased in Cushing's disease, and the pituitary gland may represent the site of the elevated production of adrenomedullin in this condition.

Clinical aspects of early increase in serum gamma-glutamyl transferase in cerebral infarction.

Gamma-glutamyl transferase (GGT) serum levels were measured in 42 female patients within 72 hours, and on day 10, after an ischaemic cerebral infarction (CI) and correlated with neurological impairment at admission and with mortality during hospitalization. Mean +/- SEM GGT serum value within 72 hours after CI was significantly higher compared to the mean +/- SEM value observed in control subjects (26.7 +/- 2.5 vs 16.5 +/- 1.2 U/L, P < 0.001) and it correlated with the severity of neurological status and with mortality. A positive correlation between GGT and creatine kinase (CK) serum levels was also observed (r = 0.47, P < 0.01). On day 10 after CI, normalization of serum GGT values was found. We conclude that GGT serum level increases in CI as a consequence of brain damage and that this increment may be considered as a clinical and prognostic unfavourable index of the disease.

Hypocalcemia and hypomagnesemia in cancer patients.

The aim of this study was to evaluate the incidence of hypocalcemia and hypomagnesemia and the relationship between calcium and magnesium serum levels in 82 hospitalized cancer patients, 61 of whom were in the terminal phase of the disease. The frequency of hypocalcemia and hypomagnesemia was 13.4% and 17.1% respectively. The incidence of hypocalcemia in patients with hypomagnesemia was 28.6%, while in those with normal or high magnesium serum levels it was 10.3%. The lowest magnesium serum level was observed in hypocalcemic patients. It may thus be concluded that hypocalcemia and hypomagnesemia are a frequent complication of malignant tumors mostly in the terminal stage of the disease, and that even hypomagnesemia could contribute to the development of tumor-associated hypocalcemia.