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Juan M de Gandarias, Jon Irazusta, David Fernández, Enrique Echevarría, and Luis Casis

De Gandarias JM, Irazusta J, Fernández D, Echevarría E, Casis L. Brain Lys-aminopeptidase activity. Changes during cycle and pregnancy. Eur J Endocrinol 1994;130:373–7. ISSN 0804–4643

Lys-aminopeptidase activity levels during the estrous cycle (estrous and proestrous, in the morning and afternoon) and the pregnancy (2nd, 7th, 14th and 20th day postinsemination and the parturition day), in several areas of the rat brain, were studied in this research. The selected brain regions were the frontal, parietal and occipital cortices, olphactory bulbus, thalamus, hypothalamus, hippocampus, amygdala, striatum and pituitary gland. The most significant changes were shown in the hypothalamus and the pituitary gland. Thus, in these areas, the higher cyclic enzyme levels were found in the proestrous stage. During pregnancy, there was a rise on the 7th and 14th days, with a decrease on the 20th day. Also, similar changes in the occipital cortex, striatum, hippocampus and amygdala were appreciated, but fewer than those observed in the hypothalamus and the pituitary. In conclusion, the activity of the aminopeptidase under study fluctuates during the estrous cycle and during pregnancy, as well as in the hypothalamic–pituitary axis and also in several extrahypothalamic areas of the rat brain.

Luis Casis Saenz, Department of Physiology, Medical School, University of the Basque Country, PO Box 699, Bilbao, Spain

Free access

Eduardo Fernández-Rebollo, Olga Pérez, Cristina Martinez-Bouzas, Maria Carmen Cotarelo-Pérez, Intza Garin, Jose Luis Ruibal, Gustavo Pérez-Nanclares, Luis Castaño, and Guiomar Pérez de Nanclares

Context

The phenotypic variability of patients with syndromes presenting with dysmorphism makes clinical diagnosis difficult, leading to an exhaustive genetic study to determine the underlying mechanism so that a proper diagnosis could be established.

Objective

To genetically characterize siblings, the older sister diagnosed with Albright hereditary osteodystrophy and the younger one with CHARGE syndrome.

Design

Clinical case report.

Methods

Clinical, biochemical, and radiological studies were performed on the family. In addition, molecular genetic studies including sequencing of GNAS, typing of microsatellites on 2q and 21q, and multiplex ligation-dependent probe amplification of subtelomeric regions were performed, as well as confirmatory fluorescent in situ hybridization analysis.

Results

The genetic analysis revealed that both sisters presented a 2q37 deletion due to the maternal unbalanced segregation of a 2;21 translocation.

Conclusions

This is the first report of a 2q37 deletion where differential diagnosis of CHARGE syndrome is needed due to the appearance of choanal atresia.

Free access

Eduardo Fernández-Rebollo, Beatriz Lecumberri, Intza Garin, Javier Arroyo, Ana Bernal-Chico, Fernando Goñi, Rosa Orduña, Spanish PHP Group, Luis Castaño, and Guiomar Pérez de Nanclares

Purpose

Type I pseudohypoparathyroidism (PHP-I) can be subclassified into Ia and Ib, depending on the presence or absence of Albright's hereditary osteodystrophy's phenotype, diminished α-subunit of the stimulatory G protein (Gsα) activity and multihormonal resistance. Whereas PHP-Ia is mainly associated with heterozygous inactivating mutations in Gsα-coding exons of GNAS, PHP-Ib is caused by imprinting defects of GNAS. To date, just one patient with PHP and complete paternal uniparental disomy (UPD) has been described.

We sought to identify the underlining molecular defect in twenty patients with parathyroid hormone resistance, hypocalcemia and hyperphosphatemia, and abnormal methylation pattern at GNAS locus.

Methods

Microsatellite typing and comparative genome hybridization were performed for proband and parents.

Results

We describe four patients with partial paternal UPD of chromosome 20 involving pat20qUPD in one case, from 20q13.13-qter in two cases, and pat20p heterodisomy plus interstitial 20q isodisomy in one patient.

Conclusions

These observations demonstrate that mitotic recombination of chromosome 20 can also give rise to UPD and PHP, a situation similar to other imprinting disorders, such as Beckwith–Wiedemann syndrome or neonatal diabetes.

Free access

David Velázquez-Fernández, Stefano Caramuta, Deniz M Özata, Ming Lu, Anders Höög, Martin Bäckdahl, Catharina Larsson, Weng-Onn Lui, and Jan Zedenius

Background

The adrenocortical adenoma (ACA) entity includes aldosterone-producing adenoma (APA), cortisol-producing adenoma (CPA), and non-hyperfunctioning adenoma (NHFA) phenotypes. While gene mutations and mRNA expression profiles have been partly characterized, less is known about the alterations involving microRNA (miRNA) expression.

Aim

To characterize miRNA expression profile in relation to the subtypes of ACAs.

Subjects and methods

miRNA expression profiles were determined in 26 ACAs (nine APAs, ten CPAs, and seven NHFAs) and four adrenal references using microarray-based screening. Significance analysis of microarrays (SAM) was carried out to identify differentially expressed miRNAs between ACA and adrenal cortices or between tumor subtypes. Selected differentially expressed miRNAs were validated in an extended series of 43 ACAs and ten adrenal references by quantitative RT-PCR.

Results

An hierarchical clustering revealed separate clusters for APAs and CPAs, while the NHFAs were found spread out within the APA/CPA clusters. When NHFA was excluded, the clustering analysis showed a better separation between APA and CPA. SAM analysis identified 40 over-expressed and three under-expressed miRNAs in the adenomas as compared with adrenal references. Fourteen miRNAs were common among the three ACA subtypes. Furthermore, we found specific miRNAs associated with different tumor phenotypes.

Conclusion

The results suggest that miRNA expression profiles can distinguish different subtypes of ACA, which may contribute to a deeper understanding of ACA development and potential therapeutics.

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Sandra Rodríguez-Rodero, Paula Morales-Sánchez, Juan Ramón Tejedor, Andrés Coca-Pelaz, Cristina Mangas, Alfonso Peñarroya, Iván Fernández-Vega, Luís Fernández-Fernández, Carmen M Álvarez-López, Agustín F Fernández, Marina Arranz Álvarez, Aurora Astudillo, Pedro Pujante Alarcón, Cecilia Ragnarssön, Alberto Colina Alonso, Héctor Enrique Torres Rivas, Juan Pablo Rodrigo Tapia, Sandra Nieto Torrero, Yaiza Pedroche-Just, Rita María Regojo Zapata, Ana M Rodríguez-García, Anabel Abó, Milagros Balbín, Edelmiro Menéndez, Elías Delgado, and Mario F Fraga

Objective

The minimally invasive fine-needle aspiration cytology (FNAC) is the current gold standard for the diagnosis of thyroid nodule malignancy. However, the correct discrimination of follicular neoplasia often requires more invasive diagnostic techniques. The lack of suitable immunohistochemical markers to distinguish between follicular thyroid carcinoma and other types of follicular-derived lesions complicates diagnosis, and despite most of these tumours being surgically resected, only a small number will test positive for malignancy. As such, the development of new orthogonal diagnostic approaches may improve the accuracy of diagnosing thyroid nodules.

Design

This study includes a retrospective, multi-centre training cohort including 54 fresh-frozen follicular-patterned thyroid samples and two independent, multi-centre validation cohorts of 103 snap-frozen biopsies and 33 FNAC samples, respectively.

Methods

We performed a genome-wide genetic and epigenetic profiling of 54 fresh-frozen follicular-patterned thyroid samples using exome sequencing and the Illumina Human DNA Methylation EPIC platform. An extensive validation was performed using the bisulfite pyrosequencing technique.

Results

Using a random forest approach, we developed a three-CpG marker-based diagnostic model that was subsequently validated using bisulfite pyrosequencing experiments. According to the validation cohort, this cost-effective method discriminates between benign and malignant nodules with a sensitivity and specificity of 97 and 88%, respectively (positive predictive value (PPV): 0.85, negative predictive value (NPV): 0.98).

Conclusions

Our classification system based on a minimal set of epigenetic biomarkers can complement the potential of the diagnostic techniques currently available and would prioritize a considerable number of surgical interventions that are often performed due to uncertain cytology.

Significance statement

In recent years, there has been a significant increase in the number of people diagnosed with thyroid nodules. The current challenge is their etiological diagnosis to discount malignancy without resorting to thyroidectomy. The method proposed here, based on DNA pyrosequencing assays, has high sensitivity (0.97) and specificity (0.88) for the identification of malignant thyroid nodules. This simple and cost-effective approach can complement expert pathologist evaluation to prioritize the classification of difficult-to-diagnose follicular-patterned thyroid lesions and track tumor evolution, including real-time monitoring of treatment efficacy, thereby stimulating adherence to health promotion programs.

Free access

Antonio J Martínez-Fuentes, Marcelo Molina, Rafael Vázquez-Martínez, Manuel D Gahete, Luis Jiménez-Reina, Jesús Moreno-Fernández, Pedro Benito-López, Ana Quintero, Andrés de la Riva, Carlos Diéguez, Alfonso Soto, Alfonso Leal-Cerro, Eugenia Resmini, Susan M Webb, Maria C Zatelli, Ettore C degli Uberti, María M Malagón, Raul M Luque, and Justo P Castaño

Context

KISS1 was originally identified as a metastasis-suppressor gene able to inhibit tumor progression. KISS1 gene products, the kisspeptins, bind to a G-protein-coupled receptor (KISS1R, formerly GPR54), which is highly expressed in placenta, pituitary, and pancreas, whereas KISS1 mRNA is mainly expressed in placenta, hypothalamus, striatum, and pituitary.

Objective and design

KISS1/KISS1R pituitary expression profile, coupled to their anti-tumoral capacities, led us to hypothesize that this system may be involved in the biology of pituitary tumors. To explore this notion, expression levels of KISS1R and KISS1 were evaluated in normal and adenomatous pituitaries. Additionally, functionality of this system was assessed by treating dispersed pituitary adenoma cells in primary culture with kisspeptin-10 and evaluating intracellular calcium kinetics and apoptotic rate.

Results

Both KISS1 and KISS1R were expressed in normal pituitary, whereas this simultaneous expression was frequently lost in pituitary tumors, where diverse patterns of KISS1/KISS1R expression were observed that differed among distinct types of pituitary adenomas. Measurement of calcium kinetics revealed that kisspeptin-10 elicits a remarkable increase in [Ca2+]i in individual cells from four out of the five GH-producing adenomas studied, whereas cells derived from non-functioning pituitary adenomas (NFPA, n=45) did not respond. In contrast, kisspeptin-10 treatment increased the apoptotic rate in cells derived from both GH-producing and NFPA.

Conclusions

These results provide primary evidence that KISS1 and KISS1R expression can be differentially lost in pituitary tumor subtypes, where this system can exert functional, proapoptotic actions, and thereby offer novel insights to investigate the biology and therapeutic options to treat these tumors.

Restricted access

Silvia Patricia Alonso, Sergio Valdés, Cristina Maldonado-Araque, Ana Lago, Pilar Ocon, Alfonso Calle, Luis Castaño, Elías Delgado, Edelmiro Menéndez, Josep Franch-Nadal, Sonia Gaztambide, Juan Girbés, Felipe Chaves, Sara Garcia-Serrano, Eva Garcia-Escobar, José Carlos Fernandez-García, Gabriel Olveira, Natalia Colomo, and Gemma Rojo-Martínez

Objective

It has been proposed that a mild form of acquired resistance to thyroid hormone may occur in the general population. Its clinical significance remains largely unknown. The objective of the study was to explore whether a newly described thyroid hormone resistance index is associated with the risk of mortality in a sample of community-dwelling euthyroid subjects representative of the adult population of Spain.

Design

Longitudinal observational study including 3750 individuals, free of thyroid disease, TPO antibodies-negative (<50 IU/mL) and with TSH levels within the euthyroid range (≥0.5 and ≤5.0 mUI/mL) participating in the nationwide study Di@bet.es (2008–2010).

Methods

We used the Thyroid Feedback Quantile-based Index (TFQI) as a marker of resistance to thyroid hormone. The study population was grouped into categories according to their TFQI values at baseline. Fatal events were ascertained from the national death registry (end of follow-up December 2016).

Results

A total of 231 deaths were recorded during an average follow-up of 7.3 years. Compared with the category with the highest sensitivity to free thyroxine (TFQI ≤ p5) (reference), the relative risk of mortality in the categories with TFQI > p5 and ≤p25; >p25 and ≤p50; >p50 and ≤p75; >p75 and ≤p95 and >p95 were 1.01, (0.47–2.19), 1.42 (0.68–2.97), 1.54 (0.74–3.22), 1.47 (0.70–3.11) and 2.61 (1.16–5.89), respectively (P for trend 0.003). The association remained significant after multivariate adjustment of the data (P for trend 0.017).

Conclusions

A thyroid hormone resistance index focused on deviations of the average pituitary response to thyroid hormones may be associated with all-cause mortality independently of other conventional risk factors and comorbidities.