Ospedale San Raffaele IRCCS

San Raffaele Cimena, Italy

Ospedale San Raffaele IRCCS

San Raffaele Cimena, Italy
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PubMed | Li Ka Shing Knowledge Institute, Ospedale Fatebene Fratelli, The Second University of Naples, IRCCS San Martino IST and 21 more.
Type: | Journal: BMJ (Clinical research ed.) | Year: 2016

To test the optimal antithrombotic regimen in patients with acute coronary syndrome.Randomised controlled trial.Patients with acute coronary syndrome with and without ST segment elevation in 78 centres in Italy, the Netherlands, Spain, and Sweden.7213 patients with acute coronary syndrome and planned percutaneous coronary intervention: 4010 with ST segment elevation and 3203 without ST segment elevation. The primary study results in the overall population have been reported previously.Patients were randomly assigned, in an open label fashion, to one of two regimens: bivalirudin with glycoprotein IIb/IIIa inhibitors restricted to procedural complications or heparin with or without glycoprotein IIb/IIIa inhibitors.Primary endpoints were the occurrence of major adverse cardiovascular events, defined as death, myocardial infarction or stroke; and net adverse clinical events, defined as major bleeding or major adverse cardiovascular events, both assessed at 30 days. Analyses were performed by the principle of intention to treat.Use of a glycoprotein IIb/IIIa inhibitor in patients assigned to heparin was planned at baseline in 30.7% of patients with ST segment elevation, in 10.9% without ST segment elevation, and in no patients assigned to bivalirudin. In patients with ST segment elevation, major adverse cardiovascular events occurred in 118 (5.9%) assigned to bivalirudin and 129 (6.5%) assigned to heparin (rate ratio 0.90, 95% confidence interval 0.70 to 1.16; P=0.43), whereas net adverse clinical events occurred in 139 (7.0%) patients assigned to bivalirudin and 163 (8.2%) assigned to heparin (0.84, 0.67 to 1.05; P=0.13). In patients without ST segment elevation, major adverse cardiovascular events occurred in 253 (15.9%) assigned to bivalirudin and 262 (16.4%) assigned to heparin (0.97, 0.80 to 1.17; P=0.74), whereas net adverse clinical events occurred in 262 (16.5%) patients assigned to bivalirudin and 281 (17.6%) assigned to heparin (0.93, 0.77 to 1.12; P=0.43).A bivalirudin monotherapy strategy compared with heparin with or without glycoprotein IIb/IIIa inhibitors, did not result in reduced major adverse cardiovascular events or net adverse clinical events in patients with or without ST segment elevation.Trial RegistrationClinicalTrials.gov NCT01433627.


D'Andrea A.,The Second University of Naples | Nistri S.,CMSR Veneto Medica | Castaldo F.,The Second University of Naples | Galderisi M.,University of Naples Federico II | And 5 more authors.
International Journal of Cardiology | Year: 2012

Aims: To evaluate left ventricular (LV) systolic and diastolic myocardial function, and their relation to coronary flow reserve in patients with non-insulin-dependent diabetes mellitus (DM) and microvascular angina. Methods and results: We selected a population of 45 normotensive patients with DM (56.3 ± 8.2 years; 25 males) with LV ejection fraction > 50% and microvascular angina (anginal pain, positive imaging stress test and normal coronary angiography). Thirty-five age- and sex-matched healthy controls were also enrolled. All the patients underwent standard echocardiography, Tissue Doppler (TDI), two-dimensional strain (2DSE) imaging, and coronary flow reserve (CFR) measurement. LV myocardial early diastolic peak velocities (Em) and peak systolic 2DSE were reduced in both interventricular septum (IVS) and LV lateral wall (p < 0.01) in DM, as well as CFR (1.89 ± 0.7 vs 2.55 ± 0.56, p < 0.0001) compared with controls. By multivariate analysis, the independent determinants of Em were glycated haemoglobin (β coefficient = - 0.36; p < 0.01) and age (β = - 0.46, p < 0.001), while global longitudinal strain was predicted by glycated haemoglobin (β = 0.48, P < 0.001) and by the duration of the disease (β = 0.38, P < 0.005). An independent association between LV global longitudinal strain and CFR (β coefficient = - 0.47, p < 0.001) in DM patients was also evidenced. Conclusions: TDI, 2DSE and CFR are valuable non-invasive and easy-repeatable tools for detecting LV myocardial and coronary function in DM patients with microvascular angina. © 2011 Published by Elsevier Ireland Ltd.


D'Andrea A.,The Second University of Naples | Mele D.,Azienda Ospedaliera Universitaria Ferrara | Nistri S.,CMSR Veneto Medica | Riegler L.,The Second University of Naples | And 6 more authors.
European Heart Journal Cardiovascular Imaging | Year: 2013

AimsAsynchronous myocardial contraction adversely influences left ventricular (LV) function and is therefore associated with a poor prognosis in heart failure. Exercise-induced change in ventricular dyssynchrony may be an important determinant of dynamic changes in cardiac output and mitral regurgitation.Methods and resultsA prospective, longitudinal study was designed with pre-defined dyssynchrony index and outcome variables to test the hypothesis that dynamic dyssynchrony is associated with worse long-term event-free survival in patients with dilated cardiomyopathy (DCM) and 'narrow' QRS complex. One-hundred eighty patients (62 ± 8 years; 110 males) with NYHA class II-III, idiopathic DCM, ejection fraction ≤35%, and QRS duration <120 ms were selected. All the patients underwent standard Doppler echo, colour tissue velocity imaging (DTI), and supine bicycle exercise stress echocardiography. Cardiac synchronicity was defined, at rest and at peak exercise, as DTI velocity opposing-wall delay (significant if ≥65 ms). Outcome was defined as freedom from death, heart transplantation, or LV-assist device implantation, over a median follow-up of 48 months, and a Cox proportional hazards model was used for survival analysis. At baseline examination, DCM patients showed a reduced LV ejection fraction (31 + 4%). A significant electromechanical delay in 58 patients (32%). At the peak of physical exercise, a significant electromechanical delay was detected in 103 patients (57%). There were 41 events during the follow-up (23%): 28 cardiac deaths, 8 heart transplantations, and 5 LV-assist device implantations over 4 years. When adjusted for confounding baseline variables, LV end-diastolic volume, restrictive mitral flow pattern, severity of mitral regurgitation, and the presence of exercise-induced intraventricular dyssynchrony were the only independent determinants of an adverse outcome.ConclusionIn patients with idiopathic DCM and narrow QRS, the increase in echocardiographic dyssynchrony during exercise was the strongest predictor of less favourable event-free survival. © The Author 2012.


Pecori Giraldi F.,University of Milan | Pesce S.,University of Milan | Maroni P.,Instituto Galeazzi IRCCS | Pagliardini L.,University of Milan | And 3 more authors.
Journal of Neuroendocrinology | Year: 2010

Prepro-thyrotrophin-releasing hormone (TRH) (178-199), a 22-amino acid cleavage product of the TRH prohormone, has been postulated to act as an adrenocorticotrophin hormone (ACTH)-release inhibitor. Indeed, although in vitro evidence indicates that this peptide may inhibit basal and stimulated ACTH secretion in rodent anterior pituitary primary cultures and cell lines, not all studies concur and no study has as yet evaluated the effect of this peptide in Cushing's disease. The present study aimed to test the effect of preproTRH(178-199) in human tumoural corticotrophs. Twenty-four human ACTH-secreting pituitary tumours (13 macroadenomas, 11 microadenomas) were collected during surgery and incubated with 10 or 100 n. m preproTRH(178-199). ACTH secretion was assessed after 4 and 24 h of incubation by immunometric assay and expressed relative to levels observed in control, unchallenged wells (= 100%). Parallel experiments were performed in rat anterior pituitary primary cultures. A clear inhibition of ACTH secretion at 4 and 24 h was observed in 12 specimens (for 10 n. m ppTRH: 70 ± 4% control at 4 h and 83 ± 5% control at 24 h; for 100 n. m ppTRH: 70 ± 4% control at 4 h and 85 ± 5% control at 24 h), whereas a mild and short-lasting stimulatory effect was observed in three tumours and no changes in ACTH secretion in the remaining nine tumoural specimens. The inhibitory effect of preproTRH(178-199) was more evident in macroadenomas and significantly correlated with sensitivity to dexamethasone inhibition. Significant inhibition of ACTH secretion by preproTRH(178-199) in rat pituitary cultures was observed after 24 h of incubation. The present study conducted in a large series of human corticotroph tumours shows that preproTRH(178-199) inhibits tumoural ACTH secretion in a sizable proportion of specimens, in close relation to the size of the tumour and its sensitivity to glucocorticoid negative feedback. This appears a promising avenue of research and further studies are warranted to explore the full scope of preproTRH(178-199) as a regulator of ACTH secretion. © 2010 The Authors. Journal Compilation © 2010 Blackwell Publishing Ltd.


Cassarino M.F.,Instituto Auxologico Italiano IRCCS | Sesta A.,Instituto Auxologico Italiano IRCCS | Pagliardini L.,Instituto Auxologico Italiano IRCCS | Losa M.,Ospedale San Raffaele IRCCS | And 4 more authors.
Endocrine | Year: 2016

ACTH-secreting pituitary tumors are by definition partially autonomous, i.e., secrete ACTH independent of physiological control. However, only few, small-sized studies on proopiomelanocortin (POMC) and its regulation by corticotropin-releasing hormone (CRH) or glucocorticoids are available. Objective of the present study was to report on constitutive and CRH- and dexamethasone-regulated POMC, CRH (CRH-R1), and glucocorticoid receptor (NR3C1) gene expression in a large series of human corticotrope adenomas. Fifty-three ACTH-secreting adenomas were incubated with 10 nM CRH or 10 nM dexamethasone for 24 h. POMC, CRH-R1,NR3C1, and its alpha and beta isoforms were quantified and medium ACTH measured. Constitutive POMC expression proved extremely variable, with macroadenomas exhibiting higher levels than microadenomas. POMC increased during CRH in most specimens; conversely, changes induced by dexamethasone were varied, ranging from decrease to paradoxical increase. No correlation between POMC and ACTH was detected in any experimental condition. CRH-R1 expression was not linked to the response to CRH while NR3C1 was expressed at greater levels in specimens who failed to inhibit during dexamethasone; glucocorticoid receptor α was the more abundant isoform and subject to down-regulation by dexamethasone. Our results demonstrate a considerable variability in POMC expression among tumors and no correlation between POMC and ACTH, suggesting that POMC peptide processing/transport plays a major role in modulating ACTH secretion. Further, CRH-R1 and NR3C1 expression were not linked to the expected ligand-induced outcome, indicating that receptor signaling rather than abundance determines corticotrope responses. Our findings pave the way to new avenues of research into Cushing’s disease pathophysiology. © 2016 The Author(s)


Cassarino M.F.,Instituto Auxologico Italiano IRCCS | Sesta A.,Instituto Auxologico Italiano IRCCS | Pagliardini L.,Instituto Auxologico Italiano IRCCS | Losa M.,Ospedale San Raffaele IRCCS | And 4 more authors.
Pituitary | Year: 2014

Purpose: It is well known that methylation plays an important role in regulating tissue expression of proopiomelanocortin (POMC) and recent studies have shown that demethylation can occur also in vitro in neuroendocrine tumors. Aim of the present study was to evaluate whether inhibition of methylation modulates POMC expression and ACTH secretion by human corticotrope tumors. Methods: Twenty two ACTH-secreting pituitary tumors were incubated with 5-AZA-2′-deoxycytidine (AZA), an inhibitor of DNA-methyltransferases, with or without 10 nM corticotropin-releasing hormone (CRH). Both dose response (100 nM–10 μM AZA) and time course (4–96 h) experiments were carried out for measurement of ACTH secretion and POMC gene expression. Results: Incubation with AZA increased constitutive POMC expression and ACTH secretion by human corticotrope adenomas. The effect appeared most notable at 24 and 48 h with 1 μM AZA. Incubation with AZA did not exert an additional stimulatory effect on CRH-stimulated POMC and ACTH. Conclusions: The present study shows that AZA increases POMC gene expression and ACTH secretion in human pituitary ACTH-secreting tumors. This can be taken to indicate that mechanisms set into motion by AZA play a role in the regulation of ACTH secretion/POMC expression in tumoral corticotropes and paves the way to further studies in Cushing’s disease. © 2013, Springer Science+Business Media New York.

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