Experimental evidence supporting a global melt layer at the base of the Earth's upper mantle.

The low-velocity layer (LVL) atop the 410-km discontinuity has been widely attributed to dehydration melting. In this study, we experimentally reproduced the wadsleyite-to-olivine phase transformation in the upwelling mantle across the 410-km discontinuity and investigated in situ the sound wave velocity during partial melting of hydrous peridotite. Our seismic velocity model indicates that the globally observed negative Vs anomaly (-4%) can be explained by a 0.7% melt fraction in peridotite at the base of the upper mantle. The produced melt is richer in FeO (~33 wt.%) and H2O (~16.5 wt.%) and its density is determined to be 3.56-3.74 g cm-3. The water content of this gravitationally stable melt in the LVL corresponds to a total water content in the mantle transition zone of 0.22 ± 0.02 wt.%. Such values agree with estimations based on magneto-telluric observations.

First steps to define murine amniotic fluid stem cell microenvironment.

Stem cell niche refers to the microenvironment where stem cells reside in living organisms. Several elements define the niche and regulate stem cell characteristics, such as stromal support cells, gap junctions, soluble factors, extracellular matrix proteins, blood vessels and neural inputs. In the last years, different studies demonstrated the presence of cKit+ cells in human and murine amniotic fluid, which have been defined as amniotic fluid stem (AFS) cells. Firstly, we characterized the murine cKit+ cells present both in the amniotic fluid and in the amnion. Secondly, to analyze the AFS cell microenvironment, we injected murine YFP+ embryonic stem cells (ESC) into the amniotic fluid of E13.5 wild type embryos. Four days after transplantation we found that YFP+ sorted cells maintained the expression of pluripotency markers and that ESC adherent to the amnion were more similar to original ESC in respect to those isolated from the amniotic fluid. Moreover, cytokines evaluation and oxygen concentration analysis revealed in this microenvironment the presence of factors that are considered key regulators in stem cell niches. This is the first indication that AFS cells reside in a microenvironment that possess specific characteristics able to maintain stemness of resident and exogenous stem cells.

ARMC5 mutation analysis in patients with primary aldosteronism and bilateral adrenal lesions.

Idiopathic hyperaldosteronism (IHA) due to bilateral adrenal hyperplasia is the most common subtype of primary aldosteronism (PA). The pathogenesis of IHA is still unknown, but the bilateral disease suggests a potential predisposing genetic alteration. Heterozygous germline mutations of armadillo repeat containing 5 (ARMC5) have been shown to be associated with hypercortisolism due to sporadic primary bilateral macronodular adrenal hyperplasia and are also observed in African-American PA patients. We investigated the presence of germline ARMC5 mutations in a group of PA patients who had bilateral computed tomography-detectable adrenal alterations. We sequenced the entire coding region of ARMC5 and all intron/exon boundaries in 39 patients (37 Caucasians and 2 black Africans) with confirmed PA (8 unilateral, 27 bilateral and 4 undetermined subtype) and bilateral adrenal lesions. We identified 11 common variants, 5 rare variants with a minor allele frequency <1% and 2 new variants not previously reported in public databases. We did not detect by in silico analysis any ARMC5 sequence variations that were predicted to alter protein function. In conclusion, ARMC5 mutations are not present in a fairly large series of Caucasian patients with PA associated to bilateral adrenal disease. Further studies are required to definitively clarify the role of ARMC5 in the pathogenesis of adrenal nodules and aldosterone excess in patients with PA.

Peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE in individuals with neck or mediastinal paraganglioma (PGL).

Paragangliomas (PGLs) are neuroendocrine tum-ors that arise embryologically from the neural crest. Sympathetic PGLs can be located in the thoracic-abdominal region while parasympathetic PGLs are mainly situated in the head and neck region. Most PGLs are sporadic, but in 30% of cases they are hereditary (associated with mutations of SDHB, SDHC, SDHD, SDHAF2, SDHA, TMEM, MAX, and VHL); they can be classified into 4 different paraganglioma syndromes: PGL1, PGL2, PGL3, and PGL4. Surgery is the treatment of choice for both sympathetic and parasympathetic PGLs. Other types of treatment include medical agents (such as gemcitabine, cisplatin, or sunitinib) and radiotherapy (external-beam radiotherapy or stereotactic surgery). Surgery and radiotherapy, however, can cause important side effects such as vascular complications and peripheral nerve damage (hypoglossal, recurrent laryngeal, glossopharyngeal, and vagus). Another possible treatment option is the use of peptide receptor radionuclide therapy (PRRT), including PRRT with 177Lu-DOTATATE. We studied 4 patients with hereditary nonmetastatic paraganglioma syndrome type 1 (PGL1), with progressive disease, in whom surgical excision was not possible. They were treated with 177Lu-DOTATATE (3-5 cycles) and all had a partial response (PR) or a stable disease (SD) to the treatment. In conclusion, a good alternative treatment when surgical or radiation therapy are contraindicated could be radiometabolic therapy with 177Lu-DOTATATE.

Role of ultrasound and color Doppler imaging in the detection of carotid paragangliomas.

INTRODUCTION: Carotid body paragangliomas (PGLs) are highly vascularized lesions that arise from the paraganglia located at the carotid bifurcation. PURPOSE: To evaluate the usefulness of gray-scale ultrasound (US) and color Doppler ultrasound (CDUS) in the detection and follow-up of carotid PGLs of the neck. MATERIALS AND METHODS: The authors retrospectively reviewed US and CDUS examinations of the neck performed in 40 patients with PGL syndrome type 1 and single or bilateral neck PGLs confirmed by CT or MRI; the patients had a total of 60 PGLs of the neck. US and CDUS outcome was compared to the outcome of second-line imaging techniques such as magnetic resonance imaging (MRI) or computed tomography (CT). The following findings were considered: presence/absence of focal lesions at US imaging and difference in maximum diameter of the lesion measured at US and MRI/CT. Results were compared using the Student's t-test. RESULTS: Of the 60 PGLs of the neck only 5 (8.3%) were not visualized at US or CDUS examination. The difference in maximum diameter of these lesions measured at CT/MRI and US/CDUS ranged between -5 mm and +16 mm (mean difference 2.2 ± 6.0). This difference was statistically significant (p = 0.008). CONCLUSIONS: US and CDUS are useful methods for identifying carotid PGLs also measuring less than 10 mm in diameter. However, diagnostic accuracy of US and CDUS is reduced in the measurement of the exact dimensions of the lesions.

Genetics of adrenal tumors.

The impact of genetics and genomics on clinical medicine is becoming more and more important. Endocrinology pioneered the development of molecular medicine, but also the study of adrenal tumors had a great impact in this field. Particularly important was the detection of genetics of tumors derived from the adrenal medulla, as well as that of those derived from the sympathetic and parasympathetic paraganglia. The identification of mutations in one of the several pheochromocytoma/paraganglioma susceptibility genes may indicate a specific clinical management drive. Less well understood is the genetics of adrenal cortex tumors, in particular adrenocortical carcinoma, a rare and particularly aggressive disease. There are only a few examples of hereditary transmission of adrenocortical carcinoma, but the analysis of low penetrance genes by genome wide association study may enable us to discover new genetic mechanisms responsible for adrenocortical-derived tumors.

Cardiovascular risk factors and ultrasound evaluation of intima-media thickness at common carotids, carotid bulbs, and femoral and abdominal aorta arteries in patients with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

CONTEXT: In congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, a tendency for obesity, high insulin, and high 24-h blood pressure levels has been reported in children and adolescents. Increased intima-media thickness (IMT) is considered a measure of subclinical atherosclerosis and a predictor of myocardial infarction and stroke. OBJECTIVE: The objective of the study was to evaluate glucose metabolism, lipid profile, IMT of the abdominal aorta, right and left common carotids, carotid bulbs, and common femoral arteries in adult CAH patients. SUBJECTS: Nineteen (10 females, nine males; 28 +/- 3.5 yr) patients (12 salt wasting and seven simple virilizing) and 19 (10 females, nine males) healthy subjects matched for anthropometric parameters (age, sex, body mass index, smoking habit, waist to hip ratio, and blood pressure). METHODS: Glucose metabolism was studied using the oral glucose tolerance test and the homeostasis model assessment-insulin resistance. The echo-Doppler was used for arterial ultrasound. 17-Hydroxyprogesterone, androstenedione, testosterone, ACTH, plasma renin activity, total and high-density lipoprotein cholesterol, and triglycerides were measured. RESULTS: CAH patients had significantly higher fasting plasma insulin (11.6 +/- 6.20 microU/ml vs 5.18 +/- 2.4 microU/ml; P < 0.0001) and homeostasis model assessment-insulin resistance than controls (2.46 +/- 1.92 vs 1.12 +/- 0.58; P = 0.0033). IMT of the studied arteries was higher in CAH patients than controls. There was no correlation between IMT and cumulative glucocorticoid doses and androgen levels. CONCLUSION: A reduced insulin sensitivity and increased IMT were demonstrated in adults with CAH, who consequently need a follow-up for cardiovascular risk.

Fine analysis of the short arm of chromosome 1 in sporadic and familial pheochromocytoma.

OBJECTIVE: Despite the very recent discovery that about 25% of apparently sporadic forms of pheochromocytoma are actually due to germline mutations of RET, VHL, SDHB or SDHD genes, the genetic bases of the tumourigenesis of this type of cancer are still incompletely understood. Recent studies provided evidence that a new tumour suppressor gene, mapping on the short arm of chromosome 1, could be involved in early tumourigenesis of pheochromocytoma. DESIGN: We have performed a fine analysis of loss of heterozygosity (LOH) of this region. In particular, we have analysed 31 highly polymorphic microsatellites distributed at 3.8 Mege base (Mb) mean intervals along the short arm of the chromosome 1 in paired samples of DNA extracted from peripheral blood lymphocytes and tumour tissues. PATIENTS: The study was carried out on 38 patients with pheochromocytoma that had been grouped, by careful clinical and molecular investigation, in the following classes: 21 sporadic, five multiple endocrine neoplasia type 2 (MEN2), two type 1 neurofibromatosis (NF1), five von Hippel-Lindau (VHL), one somatic VHL mutated and four nonsyndromic familial cases. RESULTS: In 12/21 sporadic cases (57.1%), in 4/5 MEN2 (80%), 2/4 non-syndromic familial cases (50%), and in 2/2 NF1 (100%), the entire short arm was deleted, while in 6/21 sporadic (28.6%) and 1/5 MEN2 (20%) cases a partial deletion was detected. On the other hand, none of the five cases due to VHL mutation (either germline or somatic) had LOH at chromosome 1. In total, complete or partial deletion of 1p was detected in 27/38 (71%) of the cases. The most frequently deleted marker was D1S2890, which maps at 1p32.1. This region, which spans from 50 to 62 Mb from telomere, was therefore further investigated with markers located at a mean interval of 1.3 Mb in the subset of cases that showed a partial deletion of 1p. This analysis showed that a small region between 55.1 and 59.0 Mb was most frequently missing, which could therefore contain a novel pheochromocytoma locus. CONCLUSIONS: The results presented here confirm that the short arm of chromosome 1 harbours one or more genes responsible for the development of pheochromocytoma and suggest that one of them could map in a 3.9-Mb fragment between 1p32.3 and 1p32.1.

Diastematomyelia in an adult. Case report.

An adult with diastematomyelia underwent a full neuroradiological study (myelography with jopamidolo plus computed tomography) followed by surgery. The value of the neuroradiological study, especially to the surgeon, is emphasised.

[Indications and results of surgical treatment of spontaneous intracerebral hematomas]. / Indicazioni e risultati del trattamento chirurgico degli ematomi intracerebrali spontanei.

A series of 96 cases of spontaneous intracerebral haematoma, 82 of them operated on, is reported. The results are discussed in relation to the site of the haemorrhage, the aetiology, the patient's age, general and neurological conditions, and the time gap between haemorrhage and operation.