Pedro de Castro

Instituto de Investigación Sanitaria La Fe

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María Vázquez López

Hospital General Universitario Gregorio Marañón

Francisco Domı́nguez

Instituto de Investigación Sanitaria La Fe

Alicia Quiñonero

Valencian Infertility Institute

Estíbaliz Barredo Valderrama

Hospital General Universitario Gregorio Marañón

Roberto González-Martín

Instituto de Investigación Sanitaria La Fe

L. Escrich

Valencian Infertility Institute

Francisco Chamié

Laboratório Interinstitucional de e-Astronomia

Renata Mattos

Laboratório Interinstitucional de e-Astronomia

Luiz Carlos Simões

Instituto Nacional de Cardiologia

Samuel Ignacio Pascual Pascual

Hospital Universitario La Paz

Cooperative Institutions

Hospital General Universitario Gregorio Marañón

Centre for Biomedical Network Research on Rare Diseases

Instituto de Salud Carlos III

Valencian Infertility Institute

Hospital Sant Joan de Déu Barcelona

Instituto de Investigación Sanitaria La Fe

Hospital Materno-Infantil

Hospital Universitario La Paz

Centro de Investigación Biomédica en Red

Universitat de Barcelona

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Pharmacological interaction between valproic acid and carbapenem: What about levels in pediatrics?

European Journal of Paediatric Neurology (2014)

Ma Concepción Miranda Herrero Andrés J. Alcaraz Romero Vicente Escudero Vilaplana Sarah N. Fernández Cecilia M. Fernández-Llamazares

Valproic Acid

Carbapenem

Concomitant

Therapeutic index

Antiepileptic drug

Therapeutic Drug Monitoring

10.1016/j.ejpn.2014.12.010

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Citations (25)

Reabilitação vocal de laringectomizados com prótese traqueoesofágica

Revista Brasileira de Otorrinolaringologia (2001)

Claudiney Cândido Costa Abrão Rapoport José Francisco Salles Chagas Iára Bittante de Oliveira Pedro de Castro

Material: No período de 23 de fevereiro de 1999 a junho de 2000 foram estudados 23 pacientes submetidos à laringectomia total que receberam a prótese traqueoesofágica do tipo Blom-Singer Indeweling Low Presure, sendo 22 pacientes do sexo masculino, com faixa etária variando de 40 a 80 anos. O tempo de acompanhamento variou de 150 a 462 dias. Um paciente era do estádio clínico I, com comprometimento da comissura posterior; um, do estádio II, com lesão na subglote; 13, do estádio III; e sete do IV. Forma de estudo: Prospectivo clínico não randomizado. Método: A prótese foi locada concomitante à laringectomia em sete pacientes; secundariamente, com anestesia geral, em cinco; e, por endoscopia digestiva alta, sob sedação e anestesia local, em quatorze. Foram estudadas as complicações decorrentes da colocação e uso da prótese vocal, avaliação da qualidade da voz e da inteligibilidade de fala, utilizando parâmetro perceptivo-auditivo, antes e depois da fonoterapia e do tempo necessário para reabilitação vocal. Resultados: Houve três complicações pós-operatórias relacionadas com procedimento cirúrgico terapêutico, que impossibilitaram a reabilitação vocal; dos vinte possíveis de serem reabilitados com a prótese, dezoito se reabilitaram com índice de 90% de sucesso. O tempo médio para reabilitação variou de um a 65 dias. Conclusão: Concluímos que as complicações decorrentes da colocação e uso da prótese não inviabilizaram o sucesso do método; o tempo médio para aquisição da voz foi de sete dias; a qualidade vocal e a inteligibilidade de fala apresentaram melhora após a realização da fonoterapia, sem diferença estatística significativa; e a colocação secundária da prótese vocal, utilizando nova técnica, por endoscopia digestiva alta, mostrou-se mais eficaz em relação às técnicas convencionais.

10.1590/s0034-72992001000500017

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Tratamientos agudos de recanalización en el ictus arterial isquémico pediátrico posnatal. Código ictus pediátrico

Anales de Pediatría (2023)

Pedro de Castro María Vázquez López A. Gil Núñez A. Chacón Pascual M.C. Miranda Herrero

El ictus arterial isquémico infantil es una patología mucho menos conocida que en adultos debido a su menor frecuencia y a su diferente etiología. Sin embargo, es también una patología grave con una alta incidencia de secuelas severas y perennes, que sobrepasan el 50% de los casos. El manejo agudo del ictus arterial isquémico pediátrico posnatal (IAIPP) ha cambiado drásticamente en los últimos años, fundamentalmente en lo referente a los tratamientos de recanalización (trombólisis y terapias endovasculares). Estos tratamientos, que antes no se recomendaban en la edad infantil, se están afianzando cada vez más en la práctica diaria. Aunque los estudios realizados en niños no tienen un grado de evidencia alto por ser retrospectivos y porque el número de casos es bajo, soportan la idea de que dichos tratamientos son igual de seguros y eficaces que en los adultos siempre que se realicen con unos criterios de inclusión y exclusión determinados y dentro de un tiempo determinado desde el inicio de los síntomas (ventana terapéutica). En este artículo se revisa, a la luz de los conocimientos actuales, el manejo agudo del IAIPP. Debido a que la eficacia de estos tratamientos está íntimamente ligada al inicio precoz de los mismos, es necesaria la existencia de un código ictus infantil como ampliación del código ictus que se aplica a los adultos. Ha empezado a implantarse en España desde el año 2019 aunque todavía hay importantes zonas del país donde aún no se aplica. In children, arterial ischemic stroke is a much less understood disease compared to in adults due to its lower frequency and different aetiology. However, it is also a serious disease, with a high incidence of severe and permanent sequelae that exceeds 50% of total cases. The acute management of postnatal arterial ischaemic stroke (MNAIS) has changed drastically in recent years, chiefly on account of recanalization treatments (thrombolysis and endovascular therapies). These treatments, which used to not be recommended in childhood, are increasingly implemented in everyday clinical practice. Although the evidence from studies carried out in children is not of high quality due to their retrospective design and the small number of reported cases, they support the hypothesis that these treatments are as safe and effective as they are in adults as long as appropriate eligibility criteria are applied and they are used within a certain time from the onset of symptoms (therapeutic window). This article reviews the MNAIS based on the current scientific evidence. Since the efficacy of these treatments is highly dependent on their early initiation, a paediatric stroke code needs to be in place as an extension of the stroke code applied to adults. It has started to be introduced in Spain since 2019, although there are still large areas of the country where it has yet to be applied.

10.1016/j.anpedi.2023.05.005

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Deciphering the role of PGRMC2 in the human endometrium during the menstrual cycle and in vitro decidualization using an in vitro approach

Human Reproduction (2024)

Yassmin Medina-Laver Roberto González-Martín Pedro de Castro Indra Díaz-Hernández Pilar Alamá

Abstract STUDY QUESTION What is the human endometrial non-classical progesterone receptor (PGR) membrane component 2 (PGRMC2) expression pattern throughout the menstrual cycle and what role does it play during decidualization? SUMMARY ANSWER Endometrial PGRMC2 expression fluctuates during the human menstrual cycle and is abundantly expressed in human endometrial stromal cells (hEnSCs) during in vitro decidualization, process where PGRMC2 is involved in embryo implantation-related pathways. WHAT IS KNOWN ALREADY The endometrial response to progesterone is mediated by the classical and non-classical PGRs. We previously demonstrated that PGR membrane component 1 (PGRMC1) is critical for endometrial function, embryo implantation, and future placentation, however, the role(s) of PGRMC2, which is structurally similar to PGRMC1, have not been studied in the human endometrium. STUDY DESIGN, SIZE, DURATION This prospective study comprehensively evaluated the endometrial expression of PGRMC2 throughout the human menstrual cycle and during in vitro decidualization of hEnSCs (isolated from 77 endometrial biopsies that were collected from 66 oocyte donors), using immunohistochemistry, RT-qPCR, western blot, transcriptomic, and proteomic analyses. In addition, functional analysis was carried out to validate the implication of PGRMC2 in hEnSCs during embryo invasion using an in vitro outgrowth model. PARTICIPANTS/MATERIALS, SETTING, METHODS In vitro decidualization of hEnSCs was induced using co-treatment with cAMP and medroxyprogesterone 17-acetate progestin, and evaluated by measuring prolactin by ELISA and F-actin immunostaining. RT-qPCR was employed to compare expression with other PGRs. To reveal the function of PGRMC2 during the decidualization process, we specifically knocked down PGRMC2 with siRNAs and performed RNA-seq and quantitative proteomics techniques (SWATH-MS). The common differentially expressed genes (DEGs) and proteins (DEPs) were considered for downstream functional enrichment analysis. Finally, to verify its implication in the trophoblast invasion, an outgrowth model was carried out where hEnSCs with silenced PGRMC2 were co-cultured with human trophoblastic spheroids (JEG-3) following in vitro decidualization. MAIN RESULTS AND THE ROLE OF CHANCE In contrast to PGRMC1 and classical PGRs, endometrial PGRMC2 gene expression was significantly lower during the late- versus mid-secretory phase (P < 0.05). Accordingly, the elevated PGRMC2 protein abundance observed in the endometrial epithelial glands throughout the menstrual cycle dropped in the late secretory phase, when abundance decreased in all endometrial compartments. Nevertheless, PGRMC2 protein increased during the mid-secretory phase in stromal and glandular cells, and PGRMC2 mRNA (P < 0.0001) and protein (P < 0.001) levels were significantly enhanced in the membranes/organelles of decidualized hEnSCs, compared to non-decidualized hEnSCs. Notably, PGRMC1 and PGRMC2 mRNA were significantly more abundant than classical PGRs throughout menstrual cycle phases and in decidualized and non-decidualized hEnSCs (P < 0.05). RNA-seq and proteomics data revealed 4687 DEGs and 28 DEPs, respectively, in decidualized hEnSCs after PGRMC2 silencing. While functional enrichment analysis showed that the 2420 upregulated genes were mainly associated with endoplasmic reticulum function, vesicular transport, morphogenesis, angiogenesis, cell migration, and cell adhesion, the 2267 downregulated genes were associated with aerobic respiration and protein biosynthesis. The protein enrichment analysis showed that 4 upregulated and 24 downregulated proteins were related to aerobic respiration, cellular response, metabolism, localization of endoplasmic reticulum proteins, and ribonucleoside biosynthesis routes. Finally, PGRMC2 knockdown significantly compromised the ability of the decidualized hEnSCs to support trophoblast expansion in an outgrowth model (P < 0.05). LARGE-SCALE DATA Transcriptomic data are available via NCBI’s Gene Expression Omnibus (GEO) under GEO Series accession number GSE251843 and proteomic data via ProteomeXchange with identifier PXD048494. LIMITATIONS, REASONS FOR CAUTION The functional analyses were limited by the discrete number of human endometrial biopsies. A larger sample size is required to further investigate the potential role(s) of PGRMC2 during embryo implantation and maintenance of pregnancy. Further, the results obtained in the present work should be taken with caution, as the use of a pure primary endometrial stromal population differentiated in vitro does not fully represent the heterogeneity of the endometrium in vivo, nor the paracrine communications occurring between the distinct endometrial cell types. WIDER IMPLICATIONS OF THE FINDINGS The repression of endometrial PGRMC2 during the late- versus mid-secretory phase, together with its overexpression during decidualization and multiple implications with embryo implantation not only highlighted the unknown roles of PGRMC2 in female reproduction but also the potential to exploit PGRMC2 signaling pathways to improve assisted reproduction treatments in the future. STUDY FUNDING/COMPETING INTEREST(S) This research was funded by Instituto de Salud Carlos III (ISCIII) granted to F.D. (PI20/00405 and PI23/00860), co-funded by the European Union. Y.M.-L. was supported by a predoctoral research grant from Generalitat Valenciana (ACIF/2019/262). R.G.-M. was supported by Generalitat Valenciana (CIAPOT/2022/15). P.d.C. was supported by a predoctoral grant for training in research into health (PFIS FI20/00086) from the Instituto de Salud Carlos III. I.D.-H. was supported by the Spanish Ministry of Science, Innovation and Universities (FPU18/01550). A.P. was supported by the Instituto de Salud Carlos III (PFIS FI18/00009). This research was also supported by IVI Foundation-RMA Global (1911-FIVI-103-FD). The authors declare no conflict of interest.

Decidualization

Decidua

Progesterone receptor

10.1093/humrep/deae044

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UNRAVELLING THE TRANSCRIPTOMIC CONTRIBUTION OF THE MATERNAL HAPLOID GENOME IN EARLY EMBRYO DEVELOPMENT WITH A UNIPARENTAL SINGLE CELL LEVEL APPROACH

Fertility and Sterility (2023)

Pedro de Castro Xavier Vendrell L. Escrich N. Grau Nuria Soler Balaguer

Blastomere

Pronucleus

10.1016/j.fertnstert.2023.08.549

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Funciones visuoespaciales y prematuridad

Revista de Neurología (2014)

Ma Concepción Miranda Herrero Samuel Ignacio Pascual Pascual Estíbaliz Barredo Valderrama María Vázquez López Pedro de Castro

Visuospatial functions are very important in learning process and development of abstract thought during childhood. Several studies show that preterm and low birth weight infants obtain lower scores in test that assess cognitive functions, specially in the first year of life. These differences are attenuated over time, but a developmental delay that affects working memory and visuospatial process still persists. It is unclear what factors are involved in development of these functions, and pre- or perinatal factors may interfere with the proper conduct of the same, but have been described anatomical and physiological differences between the preterm and term brain that could explain somewhere in these alterations. The different selective vulnerability to hypoxia between immature brain in which preoligodendrocytes and subplate neurons predominate, and mature brain, determine differences in the pattern of injury from hypoxia with greater involvement of the periventricular white matter in preterm children. This lesional pattern leaves to a dysfunction in attentional and visuospatial process, due to the increased vulnerability of the regions involved in the dorsal pathway of visual processing. Funciones visuoespaciales y prematuridad.Durante la infancia, las funciones visuoespaciales son importantes en los procesos de aprendizaje y en el desarrollo del pensamiento abstracto. Diferentes estudios muestran que los niños prematuros o con bajo peso al nacer obtienen menores puntuaciones en los tests que valoran las funciones cognitivas, siendo estas diferencias mas pronunciadas durante el primer año de vida. Con el tiempo, estas diferencias se van atenuando, pero persiste un retraso madurativo que afecta a la memoria de trabajo y a los procesos visuoespaciales. No esta claro cuales son los factores implicados en el desarrollo de estas funciones y que factores pre o perinatales pueden interferir en su buen desarrollo, pero se han descrito diferencias anatomicas y fisiologicas entre el cerebro del niño pretermino y el termino que podrian explicar, en parte, alguna de estas alteraciones. La diferente vulnerabilidad selectiva a la hipoxia entre el cerebro inmaduro, en el que predominan las neuronas de la subplaca y los preoligodendrocitos, y el cerebro maduro del niño nacido a termino determinan diferencias en el patron de lesion por hipoxia con mayor afectacion de la sustancia blanca periventricular en el niño pretermino. Este patron lesional conlleva una disfuncion en los procesos atencionales y visuoespaciales debido a la mayor vulnerabilidad de las regiones que intervienen en la ruta dorsal del procesamiento visual.

Vulnerability

10.33588/rn.5909.2014208

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Citations (2)

Longitudinal profiling of human androgenotes through single-cell analysis unveils paternal gene expression dynamics in early embryo development

Human Reproduction (2024)

Xavier Vendrell Pedro de Castro L. Escrich N. Grau Roberto González-Martín

Abstract STUDY QUESTION How do transcriptomics vary in haploid human androgenote embryos at single cell level in the first four cell cycles of embryo development? SUMMARY ANSWER Gene expression peaks at the fourth cell cycle, however some androcytes exhibit unique transcriptional behaviors. WHAT IS KNOWN ALREADY The developmental potential of an embryo is determined by the competence of the oocyte and the sperm. However, studies of the contribution of the paternal genome using pure haploid androgenotes are very scarce. STUDY DESIGN, SIZE, DURATION This study was performed analyzing the single-cell transcriptomic sequencing of 38 androcytes obtained from 10 androgenote bioconstructs previously produced in vitro (de Castro et al., 2023). These results were analyzed through different bioinformatics software such as g: Profiler, GSEA, Cytoscape, and Reactome. PARTICIPANTS/MATERIALS, SETTING, METHODS Single cell sequencing was used to obtain the transcriptomic profiles of the different androcytes. The results obtained were compared between the different cycles studied using the DESeq2 program and functional enrichment pathways using g: Profiler, Cytoscape, and Reactome. MAIN RESULTS AND THE ROLE OF CHANCE A wave of paternally driven transcriptomic activation was found during the third-cell cycle, with 1128 upregulated and 225 downregulated genes and the fourth-cell cycle, with 1373 upregulated and 286 downregulated genes, compared to first-cell cycle androcytes. Differentially expressed routes related to cell differentiation, DNA-binding transcription, RNA biosynthesis and RNA polymerase II transcription regulatory complex, and cell death were found in the third and fourth with respect to the first-cell cycle. Conversely, in the fourth cell cycle, 153 downregulated and 332 upregulated genes were found compared with third cell cycle, associated with differentially expressed processes related to E-box binding and zinc finger protein 652 (ZNF652) transcription factor. Further, significant overexpression of LEUTX, PRAMEF1, DUXA, RFPL4A, TRIM43, and ZNF675 found in androgenotes, compared to biparental embryos, highlights the paternal contributions to zygote genome activation. LARGE SCALE DATA All raw sequencing data are available through the Gene Expression Omnibus (GEO) under accessions number: GSE216501. LIMITATIONS, REASONS FOR CAUTION Extrapolation of biological events from uniparental constructs to biparental embryos should be done with caution. Maternal and paternal genomes do not act independently of each other in a natural condition. The absence of one genome may affect gene transcription of the other. In this sense, the haploid condition of the bioconstructs could mask the transcriptomic patterns of the single cells. WIDER IMPLICATIONS OF THE FINDINGS The results obtained demonstrated the level of involvement of the human paternal haploid genome in the early stages of embryo development as well as its evolution at the transcriptomic level, laying the groundwork for the use of these bioconstructs as reliable models to dispel doubts about the genetic role played by the paternal genome in the early cycles of embryo development. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by Instituto de Salud Carlos III (ISCIII) through the project ‘PI22/00924’, co-funded by European Regional Development Fund (ERDF); ‘A way to make Europe’. F.D. was supported by the Spanish Ministry of Economy and Competitiveness through the Miguel Servet program (CPII018/00002). M.J.E. was supported by Instituto de Salud Carlos III (PI19/00577 [M.J.E.]) and FI20/00086. P.dC. was supported by a predoctoral grant for training in research into health (PFIS PI19/00577) from the Instituto de Salud Carlos III. All authors declare having no conflict of interest with regard to this trial.

Profiling (computer programming)

Developmental Biology

10.1093/humrep/deae072

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Relationship between IMC size and blastocyst diameter with euplody

Reproductive BioMedicine Online (2018)

Yolanda Cabello Daniel Ordoñez Celia Romero Aida Vaquero-Rey Pedro de Castro

Inner cell mass

Blastocyst Transfer

10.1016/j.rbmo.2018.04.025

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Evaluación precoz en la hipoxia perinatal. Marcadores pronósticos

Revista de Neurología (2000)

Luisa López Gómez Pedro de Castro AB Bernardo Atienza A. Megías Montijano D. Blanco Bravo

Perinatal asphyxia and its neurological signs are the most important cause of brain damage and neurological sequelae in full term newborn babies. Neuroprotection treatments currently being investigated promise to reduce such sequelae, but these treatments are not without risk and the patients involved should be selected.To analyze a scale composed of variables recorded from the start of delivery until the fourth hour of life, comparing the neurological evolution of the patients. By means of this scale we aim to establish a criterion for the selection of neonates with acute perinatal asphyxia, who would benefit from neuroprotector treatment.A retrospective study was made of 50 patients with the diagnosis of perinatal asphyxia. Our scale was formed of the following variables: intrauterine meconiorrhexis, pathological cardiotocographic recordings, resuscitation at birth, Apgar score at five minutes, pH of the umbilical artery blood, neurological examination, multisystemic involvement, seizures, persistent metabolic acidosis and need for mechanical ventilation during the first hours of life. The patients were followed up for at least one year by means of periodical studies (neurological examination and evaluation of psychomotor development according to the Brunnet Lezinne test). For statistical analysis we used the chi squared test, Fisher's exact test, Kruskal-Wallis test and the area beneath the ROC curve.The scale presented constitutes a rapid, easy method which is statistically significant for the selection of perinatal asphyxia of high neurological risk which would benefit from neuroprotector treatment after the event.

Perinatal asphyxia

Umbilical artery

Apgar score

Neurological examination

10.33588/rn.3112.2000262

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Citations (2)

Comparative single-cell transcriptomic profiles of human androgenotes and parthenogenotes during early development

Fertility and Sterility (2022)

Pedro de Castro Xavier Vendrell L. Escrich N. Grau Roberto González-Martín

Cell synchronization

10.1016/j.fertnstert.2022.12.027

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Citations (4)