Identification of occult metastases of medullary thyroid carcinoma by pentagastrin-stimulated intravenous calcitonin sampling followed by targeted surgery

BACKGROUND: High calcitonin (CT) serum levels suggest metastatic spread in medullary thyroid carcinoma (MTC) after thyroidectomy. In limited disease stages, however, morphological investigations including ultrasound, magnetic resonance imaging (MRI) and 18F-FDG positron emission tomography ([18F]FDG-PET) may often fail to identify exact tumour sites. OBJECTIVE: The aim of the present study was to establish an improved strategy to identify small cervical tumours by combining pentagastrin stimulation with bilateral cervical intravenous CT sampling followed by high-resolution ultrasound. DESIGN AND PATIENTS: Six MTC patients were examined, of whom five patients already had bilateral neck dissection. Five patients had sporadic MTC, and one patient suffered from MEN2a. RESULTS: Retrospective analysis of all patients revealed a highly sensitive positive correlation between an early calcitonin peak (20–40 s after pentagastrin injection) and site of cervical tumour affection. Postinterventional ultrasound examination of the affected regions of the neck revealed suspicious presence; in some cases small lymph nodes of less than 1 cm in size were then surgically excised. On histology, small tumours could be identified in four patients. Postsurgical examination revealed a clear decline of basal serum calcitonin levels in four patients (between −41% and −100%). In two patients CT normalized to baseline levels (< 10 pg/ml) and in another two patients CT rendered to near normal (14 and 17 pg/ml). CONCLUSION: Pentagastrin stimulation-based intravenous catheter sampling may be beneficial in the diagnostic work-up of MTC after thyroidectomy. Our data show that an early calcitonin peak (20–40 s after administration of pentagastrin) helps to identify tumour-affected regions

Mutations of the ret protooncogene in German multiple endocrine neoplasia families: Relation between genotype and phenotype.

It has been suggested that not only the position but also the nature of the mutations of the ret protooncogene strongly correlate with the clinical manifestation of the multiple endocrine neoplasm type 2 (MEN 2) syndrome. In particular, individuals with a Cys634-Arg substitution should have a greater risk of developing parathyroid disease. We, therefore, analyzed 94 unrelated families from Germany with inherited medullary thyroid carcinoma (MTC) for mutation of the ret protooncogene. In all but 1 of 59 families with MEN 2A, germline mutations in the extracellular domain of the ret protein were found. Some 81% of the MEN 2A mutations affected codon 634. Phenotype-genotype correlations suggested that the prevalence of pheochromocytoma and hyperparathyroidism is significantly higher in families with codon 634 mutations, but there was no correlation with the nature of the mutation. In all but 1 of 27 familial MTC (FMTC) families, mutations were detected in 1 of 4 cysteines in the extracellular domain of the ret protooncogene. Half of the FMTC mutations affected codon 634. Mutations outside of codon 634 occurred more often in FMTC families than in MEN 2A families. In all but 1 of 8 MEN 2B patients, de novo mutations in codon 918 were found. These data confirm the preferential localization of MEN 2-associated mutations and the correlation between disease phenotype and the position of the ret mutation, but there was no correlation between the occurrence of hyperparathyroidism or pheochromocytoma and the nature of the mutation

Internal gamma gamma-opacity in Active Galactic Nuclei and the consequences for the TeV observations of M87 and Cen A

Low Luminosity Active Galactic Nuclei (LLAGNs) possess the characteristic features of more luminous Active Galactic Nuclei (AGNs) but exhibit a much lower nuclear Halpha luminosity than their more luminous counterparts. M87 (NGC 4486) and Centaurus A (NGC 5128, CenA) are well-studied nearby LLAGNs. As an additional feature they show gamma-radiation up to TeV (10^{12}eV) energies, but the origin of this radiation is not resolved. The coincident observation of a radio and TeV flare in M87 suggests that the TeV radiation is produced within around 50-100 gravitational radii of the central supermassive black hole, depending on the assumed value of the mass of the black hole. Strong radiation fields can be produced in the central region of an (LL)AGN, e.g., by the accretion flow around the black hole, the jet plasma, or stars closely orbiting the black hole. These radiation fields can lead to the absorption of emitted TeV photons, and in fact high optical depths of such fields can make TeV detection from inner regions impossible. In this paper we consider the accretion flow around the black hole as the most prominent source for such a radiation field and we accordingly calculate the probability for absorption of TeV photons produced near the black holes in M87 and CenA assuming a low luminosity Shakura-Sunyaev Disk (SSD). We find that the results are very different for between the two LLAGNs. While the inner region of M87 is transparent for TeV radiation up to 15TeV, the optical depth in CenA is >> 1, leading to an absorption of TeV photons that might be produced near the central black hole. These results imply either that the TeV gamma production sites and processes are different for both sources, or that LLAGN black holes do not accrete (at least only) in form of a low luminosity SSD.Comment: accepted for publication in Ap

Threshold-Free Population Analysis Identifies Larger DRG Neurons to Respond Stronger to NGF Stimulation

Sensory neurons in dorsal root ganglia (DRG) are highly heterogeneous in terms of cell size, protein expression, and signaling activity. To analyze their heterogeneity, threshold-based methods are commonly used, which often yield highly variable results due to the subjectivity of the individual investigator. In this work, we introduce a threshold-free analysis approach for sparse and highly heterogeneous datasets obtained from cultures of sensory neurons. This approach is based on population estimates and completely free of investigator-set parameters. With a quantitative automated microscope we measured the signaling state of single DRG neurons by immunofluorescently labeling phosphorylated, i.e., activated Erk1/2. The population density of sensory neurons with and without pain-sensitizing nerve growth factor (NGF) treatment was estimated using a kernel density estimator (KDE). By subtraction of both densities and integration of the positive part, a robust estimate for the size of the responsive subpopulations was obtained. To assure sufficiently large datasets, we determined the number of cells required for reliable estimates using a bootstrapping approach. The proposed methods were employed to analyze response kinetics and response amplitude of DRG neurons after NGF stimulation. We thereby determined the portion of NGF responsive cells on a true population basis. The analysis of the dose dependent NGF response unraveled a biphasic behavior, while the study of its time dependence showed a rapid response, which approached a steady state after less than five minutes. Analyzing two parameter correlations, we found that not only the number of responsive small-sized neurons exceeds the number of responsive large-sized neurons—which is commonly reported and could be explained by the excess of small-sized cells—but also the probability that small-sized cells respond to NGF is higher. In contrast, medium-sized and large-sized neurons showed a larger response amplitude in their mean Erk1/2 activity

Correlation of RET somatic mutations with clinicopathological features in sporadic medullary thyroid carcinomas

Screening of REarranged during Transfection (RET) gene mutations has been carried out in different series of sporadic medullary thyroid carcinomas (MTC). RET-positive tumours seem to be associated to a worse clinical outcome. However, the correlation between the type of RET mutation and the patients' clinicopathological data has not been evaluated yet

RET Germline Mutations Identified by Exome Sequencing in a Chinese Multiple Endocrine Neoplasia Type 2A/Familial Medullary Thyroid Carcinoma Family

BACKGROUND: Whole exome sequencing provides a labor-saving and direct means of genetic diagnosis of hereditary disorders in which the pathogenic gene harbors a large cohort of exons. We set out to demonstrate a suitable example of genetic diagnosis of MEN 2A/FMTC (multiple endocrine neoplasia type 2/familial medullary thyroid carcinoma) using this approach. METHODOLOGY/PRINCIPAL FINDINGS: We sequenced the whole exome of six individuals from a large Chinese MEN2A/FMTC pedigree to identify the variants of the RET (REarranged during Transfection) protooncogene and followed this by validation. Then prophylactic or surgical thyroidectomy with modified or level VI lymph node dissection and adrenalectomy were performed for the carriers. The cases were closely followed up. Massively parallel sequencing revealed four missense mutations of RET. We unexpectedly discovered that the proband's daughter with MEN 2A-related MTC presented a novel p.C634Y/V292M/R67H/R982C compound mutation, due to the involvement of p.C634Y in the proband with MEN 2A and p.V292M/R67H/R982C in the proband's husband with FMTC. In the maternal origin, p.C634Y caused bilateral MTC in all 5 cases and bilateral pheochromocytoma in 2 of the 5; the earliest onset age was 28 years. In the paternal origin, one of the six p.V292M/R67H/R982C carriers presented bilateral MTC (70 years old), one only had bilateral C-cell hyperplasia (44 years), two had bilateral multi-nodules (46 and 48 years) and two showed no abnormality (22 and 19 years). CONCLUSIONS/SIGNIFICANCE: The results confirmed the successful clinical utility of whole exome sequencing, and our data suggested that the p.C634Y/V292M/R67H/R982C mutation of RET exhibited a more aggressive clinical phenotype than p.C634Y or p.V292M/R67H/R982C, while p.V292M/R67H/R982C presented a relatively milder pathogenicity of MTC and likely predisposed to FMTC

Predição do índice de conforto térmico em edificíos de escritório na Alemanha

Ladrões internacionais indicam quais são as exigências sobre conforto térmico que devem ser alcançadas em espaços de escritório. Elas se baseiam em um modelo desenvolvido pelo Prof. Paul Ole Fanger, no Centre for Indoor Environment and Energy, na Dinamarca. Hoje, quarenta anos de pesquisa mostram uma evolução desses indicadores. Este trabalho consiste no desenvolvimento de uma ferramenta para avaliar o conforto térmico em espaços de trabalho de edifícios de escritório. A metodologia baseia-se em medições e questionários realizados no local. Para o estudo de campo utiliza-se uma unidade móvel equipada com sensores e um questionário pelos quais se obtêm respostas dos usuários sobre a qualidade térmica do ambiente de trabalho. Levantam-se as condições térmicas de trinta edifícios de escritório na Alemanha com diferentes sistemas de climatização. A correlação entre os dados objetivos e subjetivos permite desenvolver uma fórmula que calcula o nível de insatisfação térmica em um ambiente determinado, em função de aspectos locais. Para os edifícios estudados, a temperatura de conforto é 23,3 ºC e o percentual mínimo de usuários insatisfeitos é de 7%, sendo 2,3 K (Kelvin) menor que o modelo de Fanger, o que é significativo no balanço energético dos edifícios localizados em um clima da Europa central

Measurement of the differential and total cross sections of the γd→K0Λ(p) reaction within the resonance region

We report the first measurement of differential and total cross sections for the ${\gamma}d \to K^0{\Lambda}(p)$ reaction, using data from the CLAS detector at the Thomas Jefferson National Accelerator Facility. Data collected during two separate experimental runs were studied with photon-energy coverage 0.8 - 3.6 GeV and 0.5 - 2.6 GeV, respectively. The two measurements are consistent giving confidence in the method and determination of systematic uncertainties. The cross sections are compared with predictions from the KAON-MAID theoretical model (without kaon exchange), which deviate from the data at higher W and at forward kaon angles. These data, along with previously published cross sections for $K^+ {\Lambda}$ photoproduction, provide essential constraints on the nucleon resonance spectrum. A first partial wave analysis has been performed that describes the data without the introduction of new resonances.Comment: 18 pages, 16 figures and data tabl

Determination of the proton spin structure functions for 0.05 < Q(2) < 5GeV(2) using CLAS

International audienceWe present the results of our final analysis of the full data set of g1p(Q2), the spin structure function of the proton, collected using CLAS at Jefferson Laboratory in 2000–2001. Polarized electrons with energies of 1.6, 2.5, 4.2, and 5.7 GeV were scattered from proton targets (NH315 dynamically polarized along the beam direction) and detected with CLAS. From the measured double spin asymmetries, we extracted virtual photon asymmetries A1p and A2p and spin structure functions g1p and g2p over a wide kinematic range (0.05 GeV2<Q2< 5 GeV2 and 1.08 GeV <W< 3 GeV) and calculated moments of g1p. We compare our final results with various theoretical models and expectations, as well as with parametrizations of the world data. Our data, with their precision and dense kinematic coverage, are able to constrain fits of polarized parton distributions, test pQCD predictions for quark polarizations at large x, offer a better understanding of quark-hadron duality, and provide more precise values of higher twist matrix elements in the framework of the operator product expansion