The orphan receptor APJ and its recently identified endogenous ligand, apelin, exhibit high levels of mRNA expression in the heart. However, the functional importance of apelin in the cardiovascular system is not known. In isolated perfused rat hearts, infusion of apelin (0.01 to 10 nmol/L) induced a dose-dependent positive inotropic effect (EC50: 33.1+/-1.5 pmol/L). Moreover, preload-induced increase in dP/dt(max) was significantly augmented (P<0.05) in the presence of apelin. Inhibition of phospholipase C (PLC) with U-73122 and suppression of protein kinase C (PKC) with staurosporine and GF-109203X markedly attenuated the apelin-induced inotropic effect (P<0.001). In addition, zoniporide, a selective inhibitor of Na+-H+ exchange (NHE) isoform-1, and KB-R7943, a potent inhibitor of the reverse mode Na+-Ca2+ exchange (NCX), significantly suppressed the response to apelin (P<0.001). Perforated patch-clamp recordings showed that apelin did not modulate L-type Ca2+ current or voltage-activated K+ currents in isolated adult rat ventricular myocytes. Apelin mRNA was markedly downregulated in cultured neonatal rat ventricular myocytes subjected to mechanical stretch and in vivo in two models of chronic ventricular pressure overload. The present study provides the first evidence for the physiological significance of apelin in the heart. Our results show that apelin is one of the most potent endogenous positive inotropic substances yet identified and that the inotropic response to apelin may involve activation of PLC, PKC, and sarcolemmal NHE and NCX.

This survey confirms that TMZ is established as first-line chemotherapeutic treatment of APT/PC. Clinically functioning tumours, low MGMT and concurrent radiotherapy were associated with a better response. The limited long-term effect of TMZ and the poor efficacy of other drugs highlight the need to identify additional effective therapies.

USP8 is frequently mutated in adenomas causing Cushing's disease, especially in those from female adult patients diagnosed at a younger age.

The average age for its diagnosis was 51 years, and no gender difference was observed. The average size of tumors was 10.2 cm. Congenital adrenal hyperplasia was associated to 10% of all cases analyzed, while other adrenal hypersecretory disorders (cortisol, aldosterone) were found in 7.5% of cases. Computed tomography and magnetic resonance imaging can be reliably used for its differential diagnosis. If the diagnosis of an adrenal myelolipoma is unambiguous, and no associated symptoms or hormonal activity are established, surgical intervention is usually not necessary.

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Background-Adrenomedullin (ADM), a new vasorelaxing and natriuretic peptide, may function as an endogenous regulator of cardiac function, because ADM and its binding sites have been found in the heart. We characterize herein the cardiac effects of ADM as well as the underlying signaling pathways in vitro. Methods and Results-In isolated perfused, paced rat heart preparation, infusion of ADM at concentrations of 0.1 to 1 nmol/L for 30 minutes induced a dose-dependent, gradual increase in developed tension, whereas proadrenomedullin N-20 (PAMP; 10 to 100 nmol/L), a peptide derived from the same gene as ADM, had no effect. The ADM-induced positive inotropic effect was not altered by a calcitonin gene-related peptide (CGRP) receptor antagonist, CGRP 8 -37 , or H-89, a cAMP-dependent protein kinase inhibitor. ADM also failed to stimulate ventricular cAMP content of the perfused hearts. Ryanodine (3 nmol/L), a sarcoplasmic reticulum Ca 2ϩ release channel opener, suppressed the overall ADM-induced positive inotropic effect. Pretreatment with thapsigargin (30 nmol/L), which inhibits sarcoplasmic reticulum Ca 2ϩ ATPase and depletes intracellular Ca 2ϩ stores, attenuated the early increase in developed tension produced by ADM. In addition, inhibition of protein kinase C by staurosporine (10 nmol/L) and blockade of L-type Ca 2ϩ channels by diltiazem (1 mol/L) significantly decreased the sustained phase of ADM-induced increase in developed tension. Superfusion of atrial myocytes with ADM (1 nmol/L) in isolated left atrial preparations resulted in a marked prolongation of action potential duration between 10 and Ϫ50 mV transmembrane voltage, consistent with an increase in L-type Ca 2ϩ channel current during the plateau. Conclusions-Our results show that ADM enhances cardiac contractility via cAMP-independent mechanisms including Ca 2ϩ release from intracellular ryanodine-and thapsigargin-sensitive Ca 2ϩ stores, activation of protein kinase C, and Ca 2ϩ influx through L-type Ca 2ϩ channels. (Circulation. 1998;97:1062-1070.)Key Words: adrenomedullin Ⅲ contractility Ⅲ calcium Ⅲ peptides Ⅲ signal transduction A drenomedullin is a newly discovered, potent, vasorelaxing and natriuretic peptide that was originally isolated from human pheochromocytoma.1 The peptide, consisting of 52 amino acids in humans and 50 amino acids in the rat, is classified in the CGRP family.2,3 ADM may function as a paracrine and/or autocrine factor in the regulation of cardiac function, because high mRNA expression, 4 a considerable amount of ADM-like immunoreactivity, 5-7 and a high level of 125 I-ADM binding 8 have been found in the heart. In agreement with this hypothesis, ADM has been reported to increase cardiac output and left ventricular contractility in vivo 9,10 and exert a direct inotropic effect in vitro.11 Recently, the plasma concentration of circulating ADM has been shown to be increased in patients with congestive heart failure.5,12-14 Moreover, Jougasaki et al 5 reported that immunohistochemical staining for ADM is significantly increased...

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Differential diagnosis of adrenocortical adenoma (ACA) and carcinoma is of pivotal clinical relevance, as the prognosis and clinical management of benign and malignant adrenocortical tumors (ACTs) is entirely different. Circulating microRNAs (miRNAs) are promising biomarker candidates of malignancy in several tumors; however, there are still numerous technical problems associated with their analysis. The objective of our study was to investigate circulating miRNAs in ACTs and to evaluate their potential applicability as biomarkers of malignancy. We have also addressed technical questions including the choice of profiling and reference gene used. A total of 25 preoperative plasma samples obtained from patients with ACAs and carcinomas were studied by microarray and quantitative real-time PCR. None of the three miRNAs (hsa-miR-192, hsa-mir-197 and hsa-miR-1281) found as differentially expressed in plasma samples in our microarray screening could be validated by quantitative real-time PCR. In contrast, of the selected eight miRNAs reported in the literature as differentially expressed in ACT tissues, five (hsa-miR-100, hsa-miR-181b, hsa-miR-184, hsa-miR-210 and hsamiR-483-5p) showed a statistically significant overexpression in adrenocortical cancer vs adenoma when normalized on hsa-miR-16 as a reference gene. Receiver operator characteristic analysis of data revealed that the combination of dCT hsa-miR-210 -dCT hsa-miR-181b and dCT hsa-miR-100 /dCT hsa-miR-181b showed the highest diagnostic accuracy (area under curve 0.87 and 0.85, respectively). In conclusion, we have found significant differences in expression of circulating miRNAs between ACAs and carcinomas, but their diagnostic accuracy is not yet high enough for clinical application. Further studies on larger cohorts of patients are needed to assess the diagnostic and prognostic potential application of circulating miRNA markers.