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M Mannelli

Publications and source records attributed to M Mannelli.

At least 37 records · Page 2Linked to original sources
PubMed2000

Relative expression of the RET9 and RET51 isoforms in human pheochromocytomas.

Activating mutations of the RET oncogene cause the inheritance of multiple endocrine neoplasia type 2 (MEN2). The RET pre-mRNA is spliced into several transcripts coding for multiple isoforms, including Ret9 and Ret51. When harboring activating mutations in the cytoplasmic region, the Ret51 protein displays a higher in vitro transforming efficiency as compared to the corresponding Ret9 isoform. We investigated whether a more transforming isoform was preferentially expressed in MEN2 tumors as compared to normal tissues or sporadic pheochromocytomas. By quantitative RNases protection assays, we measured the absolute abundance of the 3' splice variants in pheochromocytomas and in normal tissues. The proportion of RET51 transcripts was highly dispersed between tumors and normal tissues. In familial tumors the proportion of RET51 transcripts was significantly larger (48.1%) than in sporadic tumors (36.75%). This result suggests that the preferential expression of the Ret51 protein isoform, even though moderate, is a growth advantage for MEN2 tumors.

Adrenal Gland Neoplasms↗
PubMed2000

Telomerase activity is significantly enhanced in malignant adrenocortical tumors in comparison to benign adrenocortical adenomas.

Telomerase is an enzyme that causes short repeated sequence addition to the ends of chromosomes, thereby preventing their shortening during cell division and counteracting cell senescence. Telomerase activity is generally absent in adult differentiated cells, whereas it has been demonstrated in tumor cells, suggesting that its presence might be considered an index of malignancy. To evaluate whether telomerase might be considered a good predictive index of malignancy in adrenocortical tumors, we measured telomerase activity in 11 adrenal adenomas and 7 carcinomas obtained at surgery, using an original quantitative method. Telomerase activity was significantly higher (P<0.001) in carcinomas than in adenomas (median, 15.2 ng DNA/microg protein; range, 9.0-27.6 vs. 2.0; range, 0-8.3), and no overlap was observed between the 2 groups. In carcinomas, telomerase activity was significantly correlated with tumor diameter (r = 0.939; P<0.0001), whereas in adenomas it was not. The results of this study suggest that quantitative telomerase measurement may represent a useful tool to differentiate malignant from benign adrenocortical tumors.

Adenoma↗
PubMed1999

In vivo evidence that endogenous dopamine modulates sympathetic activity in man.

Dopamine receptors type 2 (D2)-like receptor blockers cause an increase in the norepinephrine response to intense physical exercise. However, during intense physical exercise, D2-like antagonists also cause an increase in the epinephrine response, which itself might cause an increase in plasma norepinephrine through the activation of beta2 presynaptic receptors. Therefore, we evaluated the effect of domperidone, a D2-like antagonist, on the norepinephrine response to physical exercise in 6 Addison patients (3 were adrenalectomized and 3 had adrenal tuberculosis). In these patients, the norepinephrine increase observed during exercise was significantly higher after the administration of domperidone than a placebo (F=4,328; P<0.001). Because peripheral plasma norepinephrine does not reflect the sympathetic tone to the heart accurately, we evaluated the effect of domperidone administration (20 mg orally) on the sympathovagal balance, which was measured by the ratio between the high- and low-frequency components of heart rate variability, in 9 normal volunteers in the supine and sitting positions. When compared with placebo, domperidone caused a significant increase in the low/high frequency ratio (P<0.05) in the sitting position without modifying basal and stimulated norepinephrine plasma levels or blood pressure. These data support a role for endogenous dopamine in modulating norepinephrine release by human sympathetic nerves in vivo.

Adrenal Gland Diseases↗
PubMed1999

Pheochromocytoma in Italy: a multicentric retrospective study.

OBJECTIVE: To conduct an epidemiological study on pheochromocytoma in Italy. METHODS: Data on 284 patients with pheochromocytoma observed between 1978 and 1997 were collected from 18 Italian centers through a questionnaire reporting epidemiological, clinical, laboratory, radiological and surgical data. RESULTS: 53.6% of the patients were females and 46.4% were males. Thirty-two tumors were discovered as incidental adrenal masses. The most frequent referred symptoms were palpitations (58.1%), headache (51.9%), sweating (48. 8%) and anxiety (35.3%). Their association was present only in 15.5% of patients. Paroxysmal symptoms were reported in 67.1% and hypertensive crises in 59.7% of patients. Normal blood pressure (systolic and diastolic) was present both in the supine and upright positions in 21.1% of patients. Among laboratory assays, urinary vanylmandelic acid (VMA) was the most widely used (58.1%) and was the least sensitive (25% of false negative results). Basal plasma catecholamines were found to be normal in 11.3% of patients but were always elevated when sampled during a hypertensive paroxysm. A clonidine suppression test was performed in 38 patients with no adverse side effects. It gave a false negative response in 2 patients. A glucagon test was performed in 21 patients. It was interrupted for acute hypertension in 52.4% of patients. Only 5/21 patients were normotensive and had normal basal plasma catecholamines. In these patients the test gave a positive response in four (80%). CT (79.6%) and I-MIBG scintigraphy (68.5%) were the most widely used methods for tumor localization. CT sensitivity was 98.9% for intra-adrenal and 90.9% for extra-adrenal tumors. MIBG sensitivity was 88.5%. In the 263 patients who underwent surgery, the tumor was intra-adrenal in 89.4%, extra-adrenal in 8.5%, intra- and extra-adrenal in 2.1%, and bilateral in 11.0% of patients. Malignancy was reported in 9.9% of cases. Surgery caused remission of hypertension in 59.3%, improvement in 26.8%, and no changes in 13. 9% of patients. In the last group the interval between initial symptoms and diagnosis was significantly longer. CONCLUSIONS: The present study confirms that the clinical presentation of pheochromocytoma is variable and aspecific. Normotension is often present and often the tumor is discovered incidentally. An indication for the routine use of screening methods more sensitive than urinary VMA is strongly suggested. The clonidine test was found to be safe and should be preferred to the glucagon test which has to be restricted to very selected patients. CT and MIBG scintigraphy are almost always successful in localizing the tumor. Reversal of hypertension by surgery seems to depend on an early diagnosis.

Adolescent↗
PubMed1999

Angiotensin II stimulates the synthesis and secretion of vascular permeability factor/vascular endothelial growth factor in human mesangial cells.

The aim of the present study was to evaluate the role of angiotensin II (AngII) in regulating both the gene expression and secretion of vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) in human mesangial cells (HMC) in culture. Densitometric analysis of Northern blot experiments demonstrated that AngII increases VPF/VEGF mRNA in a dose-dependent manner. The levels of VPF/VEGF mRNA in HMC exposed for 3 h to 10 nM, 100 nM, and 1 microM AngII were, respectively, 1.5-, 2.3-, and 1.6-fold higher than control cells (P < 0.05, P < 0.0001, and P < 0.05, respectively). This effect was blocked by the pretreatment with losartan (1 microM) (P < 0.005), a selective antagonist of the AngII AT1 receptor. Reverse transcription-PCR performed in HMC using oligonucleotide primers specific for all VPF/VEGF mRNA splicing variants detected three bands corresponding to VEGF 189, 165, and 121. Exposure of the cells to 100 nM AngII resulted in an increase of all the mRNA transcripts. Furthermore, in situ hybridization experiments showed that the levels of hybridization signals for VPF/VEGF mRNA resulted consistently higher in HMC exposed for 3 h to AngII (100 nM) than in control cells. The effects of AngII on the secretion of VPF/VEGF peptide in the culture medium of HMC were assessed using an enzyme-linked immunosorbent assay method. When different concentrations of AngII were tested in 3-h stimulation periods, the percentage of increase in the levels of released VPF/VEGF was significantly higher than control cells for AngII concentrations of 100 nM (62 +/- 11% mean +/- SD, P < 0.0001) and 1 microM (17.3 +/- 10.9%, P < 0.01). The pretreatment of HMC with losartan (1 microM) prevented the increase of VPF/VEGF secretion induced by AngII (100 nM) (AngII 54.7 +/- 3.9 pg/microg DNA versus AngII + losartan 37.8 +/- 3.6 pg/microg DNA, mean +/- SD, P < 0.005). VPF/VEGF protein was time dependently released in the culture medium under basal, steady-state conditions. Compared with control cells, AngII (100 nM) caused a significant increase in the levels of released VPF/VEGF after 3 and 6 h (control 33.8 +/- 1.7 pg/microg DNA at 3 h, 42.1 +/- 1.1 at 6 h, and 117.7 +/- 10 at 24 h; AngII 54.7 +/- 3.9 at 3 h, P < 0.0001, 61.6 +/- 8.7 at 6 h, P < 0.05, and 144.7 +/- 22.7 at 24 h, NS; mean +/- SD). According to the results obtained from enzyme-linked immunosorbent assay experiments, Western blot analysis showed that the intensity of the 19-kD band corresponding to VPF/VEGF was 1.5-fold higher in AngII (100 nM)-treated HMC than in control cells. Similarly, immunocytochemistry on HMC demonstrated an increase in intracellular VPF/VEGF immunostaining in response to AngII treatment (100 nM) compared with control cells. This study demonstrated that in HMC, AngII augmented the levels of VPF/VEGF gene expression and stimulated the synthesis and secretion of its peptide by activating AT1 receptors. Through these mechanisms, AngII may affect the functions of endothelial cells during the development of renal diseases involving the glomerulus.

Angiotensin II↗
PubMed1998

Effects of clonidine on power spectral analysis of heart rate variability in mild essential hypertension.

Patients with essential hypertension often show alterations of the autonomic nervous system. We evaluated the sympathetic and parasympathetic drive to the heart in 12 mildly hypertensive patients and 9 healthy subjects by power spectral analysis of heart rate variability. All subjects underwent measurements of RR interval, low (LF) and high frequency (HF) components of heart rate variability, LF/HF ratio and blood pressure in the resting and sitting positions, both before and after oral clonidine (300 microg), a central sympatholytic agent. In the supine position before clonidine, hypertensive patients had higher blood pressure and lower HF values than healthy subjects. Clonidine induced increases in RR interval and HF in both groups, while LF and LF/HF ratio decreased in healthy subjects, but not in hypertensive patients. On assuming the sitting position, both groups showed reductions in RR and HF and increments in LF and LF/HF. In healthy subjects, the response to the postural challenge was unaffected by clonidine. In contrast, hypertensive patients showed no changes in LF and LF/HF ratio, and a significantly lower decrease in HF. These differences were probably due to the existence of two subsets of patients, one exhibiting similar responses to clonidine as healthy subjects, and the other showing no appreciable response to the drug. These results suggest that hypertensive patients have an altered sympatho-vagal balance to the heart, which can be unmasked by clonidine. This phenomenon should be taken into account to achieve a better control of the overall cardiovascular risk of hypertensive patients.

Administration, Oral↗
PubMed1998

Different effects of atrial and C-type natriuretic peptide on the urinary excretion of endothelin-1 in man.

1. Following the observation that brain natriuretic peptide enhances the urinary excretion rate of endothelin-1, the relationship between natriuretic peptides and urinary endothelin-1 was further investigated. Six healthy volunteers received, on three different occasions, increasing doses of atrial or C-type natriuretic peptide (0, 2 and 4 pmol.min-1.kg-1 for 1 h each), or placebo.2. Atrial natriuretic peptide caused significant increases in the urinary excretion of cGMP, sodium and endothelin-1, without affecting plasma endothelin-1, renal plasma flow, glomerular filtration rate and urine flow rate. C-type natriuretic peptide did not modify any of these parameters. During atrial natriuretic peptide infusion, urinary endothelin-1 directly correlated with plasma atrial natriuretic peptide, urinary cGMP and sodium excretion.3. These results indicate that enhancement of the urinary excretion of endothelin-1 by natriuretic peptides is dose-dependent and somewhat related to their ability to bind to natriuretic peptide receptors A, activate guanylate cyclase and induce a natriuretic response.

Adult↗
PubMed1998

Effects of acute clonidine administration on power spectral analysis of heart rate variability in healthy humans.

1. To investigate the relationship between the autonomic drive to the heart and heart rate variability, as evaluated by power spectral analysis, we studied the effect of clonidine (300 microg), a central sympatholytic agent, on heart rate variability. 2. Six healthy subjects (mean age 31 +/- 3 years) were studied in the supine and the sitting position (15 min each) on two different occasions, respectively, before and after clonidine administration. Using an autoregressive approach, the low frequency (LF) and the high frequency (HF) components of power spectral analysis were measured, and their ratio was calculated. Blood pressure was monitored throughout the study and plasma catecholamines were measured at the end of each period. 3. Before clonidine, assumption of the sitting position induced increases in LF, LF/HF ratio, blood pressure and plasma noradrenaline. Clonidine induced remarkable reductions in the normalized values of the LF component and the LF/HF ratio in both the resting and the sitting position (supine: LF = -68%, LF/HF ratio = -80%; sitting: LF = -23%, LF/HF ratio = -55%) without affecting the central frequencies of LF and HF components. Blood pressure and plasma catecholamines also significantly decreased after clonidine. 4. These results support the hypothesis that the LF component of HRV, expressed in normalized units, is an indicator of the sympathetic control of the heart. In addition, this component seems to be largely of central origin, because it is markedly reduced by the central sympatholytic action of clonidine.

Adult↗
PubMed1998

Low-dose C-type natriuretic peptide does not affect cardiac and renal function in humans.

In experimental animals, C-type natriuretic peptide (CNP) has vasodilating, hypotensive, and natriuretic activities. The role of circulating CNP in the overall regulation of cardiac and renal function in humans is less defined, in both health and disease. We measured cardiac volumes, diastolic and systolic functions, systemic (Doppler echocardiography) and renal hemodynamics, intrarenal sodium handling (lithium clearance method), plasma and urinary cGMP, plasma renin concentration, and plasma aldosterone level in six healthy volunteers (mean age, 33+/-3 years) receiving CNP (2 and 4 pmol/kg per minute for 1 hour each) in a single-blind, placebo-controlled, random-order, crossover study. During CNP infusion, plasma CNP increased from 1.17+/-0.23 to 41.52+/-4.61 pmol/L (ie, 4- to 10-fold higher levels than those observed in disease states) without affecting plasma and urinary cGMP, cardiac volumes, dynamics of left and right heart filling, cardiac output, arterial pressure, renal hemodynamics, intrarenal sodium handling, sodium excretion, or plasma levels of renin and aldosterone. The finding that increments in plasma CNP within the pathophysiological range have no effects on systemic hemodynamics, renal function, or the renin-angiotensin system do not support the hypothesis that CNP may act as a circulating hormone in humans.

Adult↗
PubMed1997

Pheochromocytoma crisis caused by contemporary ergotamine, caffeine, and nimesulide administration.

Pheochromocytoma is a rare tumor that secretes excess catecholamines. Pheochromocytoma crises may be precipitated by the use of several drugs. This article describes the case of a patient affected by pheochromocytoma in whom multiple organ failure developed after contemporary administration of ergotamine, caffeine, and nimesulide. The patient recovered completely long after surgical intervention.

Adrenal Gland Neoplasms↗
PubMed1997

Localization of endothelin-converting enzyme-1 in human kidney.

The distribution of endothelin-converting enzyme-1 (ECE-1) mRNA and protein was investigated in human kidney excised because of renal tumors. ECE-1 immunoreactivity was detected by immunohistochemistry throughout the different areas of the kidney in the vascular and tubular structures. In the cortex, ECE-1 immunostaining was present in the endothelial surface of arcuate and interlobular arteries and in arterioles. Weak specific immunoreactivity was present over some proximal and distal tubules. Few endothelial glomerular cells contained ECE-1 protein. In the medulla, ECE-1 immunoreactivity was observed in the vasa recta bundles and capillaries. ECE-1 immunostaining was also detected in the outer and inner medullary collecting ducts and thin limbs of Henle's loops. Immunohistochemical detection of the von Willebrand factor on adjacent sections confirmed the endothelial nature of the vascular cells that exhibited ECE-1 immunostaining. The distribution patterns of ECE-1 mRNA, investigated by in situ hybridization, appeared similar to that obtained by immunohistochemistry in the cortical and medullary vasculature and in different portions of the nephron. Northern blot and densitometric analyses demonstrated that ECE-1 mRNA levels were quantitatively similar in both the renal cortex and medulla. These results demonstrate that vascular endothelial and tubular epithelial cells in the cortex and medulla of the human kidney synthesize ECE-1, which, in turn, may play an important role in regulating endothelin production in physiological and pathological conditions.

Adult↗
PubMed1997

Urinary endothelin-1 excretion is enhanced by low-dose infusion of brain natriuretic peptide in normal humans.

To evaluate the functional relationship between cardiac natriuretic peptides and endothelin-1 within the human kidney, we studied the effects exerted by infusion of brain natriuretic peptide on urinary endothelin-1 excretion. We studied twice in a single-blind manner five normal volunteers who received a constant infusion of 5% dextrose (250 mL/h) or human brain natriuretic peptide-32 at a dose of 4 pmol/kg per minute. Blood samples were drawn at intervals for measurement of hematocrit and concentrations of creatinine, electrolytes, brain natriuretic peptide, and endothelin-1. Urine was collected an intervals for measurement of flow rate and concentrations of creatinine, sodium, cGMP, and endothelin-1. Blood pressure and heart rate were measured every 15 minutes. Placebo administration did not change blood pressure, heart rate, or any of the other parameters measured in plasma and urine. As expected, brain natriuretic peptide infusion caused significant increases in its own plasma levels (basal versus peak levels [mean +/- SD], 1.45 +/- 0.20 versus 50.5 +/- 6.0 pmol/L, P < .01), in urinary cGMP (0.75 +/- 0.16 versus 1.92 +/- 0.81 fmol/min, P < .05), and in urinary sodium excretion (140.0 +/- 38.7 versus 624.2 +/- 181.6 mumol/min, P < .01). In addition, it caused an increase in urinary endothelin-1 excretion (4.32 +/- 2.11 versus 19.67 +/- 9.52 fmol/min, P < .05), without modifying plasma endothelin-1, blood pressure, heart rate, creatinine clearance, and urinary flow rate. Our data indicate that brain natriuretic peptide, at plasma levels comparable to those observed in patients with heart failure, causes a significant increase in urinary but not plasma endothelin-1, thus demonstrating a functional link between cardiac natriuretic peptides and renal release of endothelin-1.

Adult↗
PubMed1997

Characterizing an ectopic secreting carcinoid with indium-111-DTPA-D-Phe-pentetreotide.

UNLABELLED: This report describes a technique that increases the specificity of 111In-pentetreotide as evaluated in a patient with ectopic Cushing syndrome. METHODS: Two separate SPECT studies were performed with different pharmacologic protocols, both including treatment with cold octreotide. The imaging protocol provides acquisitions at 4 and 24 hr after injection. The quantitative approach was based on the ROI activity (manually designed) of an area of pathological lung uptake (ROI-T) versus background (ROI-NT). Histological, histochemical and specific mRNA measurements confirmed the presence of an SSR2 receptor carcinoid in the lung. RESULTS: The time course of ROI-T/ROI-NT is a linear increase between 4 and 24 hr. Washout with cold octreotide diminished the ROI-T activity content and the saturation protocol increased ROI-T/ROI-NT, confirming the specific nature of the uptake. CONCLUSION: Displacement and saturation protocols in 111In-pentetreotide imaging demonstrated the specificity of tumor binding.

ACTH Syndrome, Ectopic↗
PubMed1996

Impaired cardiovascular autonomic response to passive tilting in cirrhosis with ascites.

The autonomic regulation of cardiovascular function was evaluated in 15 cirrhotic patients with ascites and in 13 healthy subjects by the autoregressive power spectral analysis (PSA) of the intervals between adjacent R waves of the electrocardiogram (RR) interval and arterial pressure variability. Total power, low frequency (LF; index of the sympathetic activity of the heart and circulation), and high frequency (HF; index of vagal tone to the heart) components of the RR interval, systolic, and diastolic arterial pressure were evaluated in the supine position and during passive tilting, together with plasma norepinephrine levels. In the supine position, no significant differences in the PSA data were observed between the control subjects and cirrhotic patients, who had higher plasma norepinephrine levels. In healthy subjects, tilting was associated with an increase in the LF of the RR interval and arterial pressure and a decrease in the HF of the RR interval. In contrast, patients with cirrhosis showed a decrease of both LF and HF. Consequently, the LF/HF ratio significantly increased in healthy subjects, whereas it was unchanged in cirrhotic patients. The LF component of the diastolic pressure also decreased during tilting in cirrhotic patients. Plasma norepinephrine increased after tilting in both groups. These results indicate that the autonomic response to passive tilting is impaired in cirrhotic patients with ascites at both the cardiac and vascular levels, as a result of an altered sympatho-vagal balance, with reduced sympathetic predominance. These alterations occurred despite an appropriate response to the tilting of plasma norepinephrine, pointing to a receptorial or postreceptorial site of the autonomic impairment.

Adult↗
PubMed1995

Systemic hemodynamics and renal function during brain natriuretic peptide infusion in patients with essential hypertension.

We assessed the cardiovascular and renal effects of human brain natriuretic peptide (BNP) infused at a dose inducing an increase in plasma BNP to pathophysiologic levels, in eight hypertensive patients in a randomized, placebo-controlled, cross-over study. Left ventricular performance, cardiac output (echocardiography), heart rate, arterial pressure, glomerular filtration rate (GFR; creatinine clearance), sodium excretion, intrarenal sodium handling (lithium clearance method), and urine flow rate were measured in the infusion and postinfusion periods (1 h each), together with plasma BNP and the urinary excretion rate of cGMP. Plasma BNP levels increased from 2.90 +/- 0.74 to 36.43 +/- 5.51 pmol/L (P < .01) at the end of the infusion and were still elevated at the end of the postinfusion period (7.03 +/- 1.41 pmol/L, P < .05). The urinary excretion of cGMP was also significantly higher during BNP infusion. Left ventricular performance, cardiac output, arterial pressure, and peripheral vascular resistance were not affected by BNP. Peptide infusion induced a significant increase in GFR (placebo, 115 +/- 24; BNP, 147 +/- 19 mL/min), sodium excretion (placebo, 129 +/- 40; BNP, 243 +/- 60 mumol/min), and urine flow rate. All these effects were observed also in the postinfusion period. The natriuretic effect of BNP was attributable to both an increase in filtered sodium load and a reduction of distal sodium reabsorption. These results suggest that BNP may contribute to maintain renal function and sodium excretion in patients with essential hypertension.

Adult↗
PubMed1995

In-vivo studies on ovarian insulin-like growth factor I concentrations in human preovulatory follicles and human ovarian circulation.

In some recent hypotheses, the ovary has been indicated as a source of insulin-like growth factor (IGF)-I, with synthesis regulated from local steroidal and non-steroidal substances. We measured IGF-I concentrations in both serum and follicular fluid of women undergoing in-vitro fertilization (IVF) and embryo transfer, in both induced and spontaneous cycles. It was found that serum and follicular IGF-I concentrations were correlated with follicular morphology, oocyte maturity, steroid concentrations and clinical characteristics of IVF cycles. In addition, we measured IGF-I concentrations in both peripheral and ovarian circulation to gain further detailed information on the contribution of the ovary to IGF-I production. The results of our study support the hypothesis that follicular IGF-I is probably derived by diffusion from peripheral circulation and that local production appears unlikely.

Adult↗
PubMed1995

Role for endogenous dopamine in modulating sympathetic-adrenal activity in humans.

Dopamine (DA) is synthesized and secreted in central as well as peripheral nervous system and in the adrenal medulla. Neuronal DA receptors, which have been characterized as D2 receptors, mediate an inhibition of adenylate cyclase and are located prejunctionally on sympathetic nerve endings and on chromaffin cells. Their pharmacological activation causes an inhibition of in vitro and in vivo norepinephrine (NE) release from sympathetic nerve terminals and an inhibition of in vitro epinephrine (E) release from the adrenal medulla. Endogenous DA, co-secreted with the other catecholamines (CA), modulates sympathetic-adrenal discharge only during high sympathetic stimulation through an autocrine mechanism, limiting excessive sympathetic adrenal discharge. Also pheochromocytoma cells synthesize and express D2 receptors. In patients with pheochromocytoma D2 antagonists cause hypertensive crises but the mechanism mediating this effect is still unknown as well as whether endogenous DA might modulate tumoral secretion.

Adrenal Gland Neoplasms↗