Massive Postpartum Hemorrhage: Protocol and Red Code

Postpartum hemorrhage (PPH) is the leading cause of maternal death. In developing countries, approximately 8% of maternal death is caused by PPH. Protocols should provide a standardized approach to evaluate and monitor the patients. A standard protocol must be recognized by the institution and must be accepted and known by all team members. Additionally, it is important to have a massive obstetric hemorrhage protocol (red code) for those patients with an important bleeding who require blood products available as soon as possible. In the red code activation protocol there are several key points to consider: the management algorithm must be known and accepted by all team members, a clear and effective communication between the team must be established and all the participants must know the role they play. Massive obstetric hemorrhage has a multidisciplinary implication: obstetricians, anesthesiologists, pediatricians, midwife, nurses, auxiliary staff, and laboratory blood bank staff. The active participation of the multidisciplinary team in simulations before the protocols implementation facilitates the evaluation of critical points and subsequent changes before their final application, the assessment of the adequacy of circuits and infrastructure, as well as a better protocols compliance

The frequency-following response (FFR) to speech stimuli: a normative dataset in healthy newborns

The Frequency-Following Response (FFR) is a neurophonic auditory evoked potential that reflects the efficient encoding of speech sounds and is disrupted in a range of speech and language disorders. This raises the possibility to use it as a potential biomarker for literacy impairment. However, reference values for comparison with the normal population are not yet established. The present study pursues the collection of a normative database depicting the standard variability of the newborn FFR. FFRs were recorded to /da/ and /ga/ syllables in 46 neonates born at term. Seven parameters were retrieved in the time and frequency domains, and analyzed for normality and differences between stimuli. A comprehensive normative database of the newborn FFR is offered, with most parameters showing normal distributions and similar robust responses for /da/ and /ga/ stimuli. This is the first normative database of the FFR to characterize normal speech sound processing during the immediate postnatal days, and corroborates the possibility to record the FFRs in neonates at the maternity hospital room. This normative database constitutes the first step towards the detection of early FFR abnormalities in newborns that would announce later language impairment, allowing early preventive measures from the first days of life

Models for the Study of Fetal Alcohol Spectrum Disorders: An Overview

Prenatal alcohol exposure is associated to different physical, behavioral, cognitive, and neurological impairments collectively known as fetal alcohol spectrum disorder. The underlying mechanisms of ethanol toxicity are not completely understood. Experimental studies during human pregnancy to identify new diagnostic biomarkers are difficult to carry out beyond genetic or epigenetic analyses in biological matrices. Therefore, animal models are a useful tool to study the teratogenic effects of alcohol on the central nervous system and analyze the benefits of promising therapies. Animal models of alcohol spectrum disorder allow the analysis of key variables such as amount, timing and frequency of ethanol consumption to describe the harmful effects of prenatal alcohol exposure. In this review, we aim to synthetize neurodevelopmental disabilities in rodent fetal alcohol spectrum disorder phenotypes, considering facial dysmorphology and fetal growth restriction. We examine the different neurodevelopmental stages based on the most consistently implicated epigenetic mechanisms, cell types and molecular pathways, and assess the advantages and disadvantages of murine models in the study of fetal alcohol spectrum disorder, the different routes of alcohol administration, and alcohol consumption patterns applied to rodents. Finally, we analyze a wide range of phenotypic features to identify fetal alcohol spectrum disorder phenotypes in murine models, exploring facial dysmorphology, neurodevelopmental deficits, and growth restriction, as well as the methodologies used to evaluate behavioral and anatomical alterations produced by prenatal alcohol exposure in rodents

Murine Models for the Study of Fetal Alcohol Spectrum Disorders: An Overview.

Prenatal alcohol exposure is associated to different physical, behavioral, cognitive, and neurological impairments collectively known as fetal alcohol spectrum disorder. The underlying mechanisms of ethanol toxicity are not completely understood. Experimental studies during human pregnancy to identify new diagnostic biomarkers are difficult to carry out beyond genetic or epigenetic analyses in biological matrices. Therefore, animal models are a useful tool to study the teratogenic effects of alcohol on the central nervous system and analyze the benefits of promising therapies. Animal models of alcohol spectrum disorder allow the analysis of key variables such as amount, timing and frequency of ethanol consumption to describe the harmful effects of prenatal alcohol exposure. In this review, we aim to synthetize neurodevelopmental disabilities in rodent fetal alcohol spectrum disorder phenotypes, considering facial dysmorphology and fetal growth restriction. We examine the different neurodevelopmental stages based on the most consistently implicated epigenetic mechanisms, cell types and molecular pathways, and assess the advantages and disadvantages of murine models in the study of fetal alcohol spectrum disorder, the different routes of alcohol administration, and alcohol consumption patterns applied to rodents. Finally, we analyze a wide range of phenotypic features to identify fetal alcohol spectrum disorder phenotypes in murine models, exploring facial dysmorphology, neurodevelopmental deficits, and growth restriction, as well as the methodologies used to evaluate behavioral and anatomical alterations produced by prenatal alcohol exposure in rodents

Global Retinoblastoma Presentation and Analysis by National Income Level.

Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale. Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. Design, Setting, and Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. Main Outcomes and Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low- and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI, 4.30-7.68]). Conclusions and Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs

Mouse model of fetal alcohol spectrum disorders according to two human alcohol drinking patterns and the role of epigallocatechin gallate in their prevention. Epigallocatechin gallate bioavailability study in humans

[eng] HYPOTHESIS: Prenatal alcohol exposure produces different degrees of fetal growth restriction, placental disorders, and brain impairments in humans depending on the type of exposure (acute or binge versus chronic moderate or Mediterranean). EGCG therapy administered under optimal pharmacokinetic conditions may attenuate these abnormalities. The specific hypotheses of this doctoral thesis are: 1. Binge human-like pattern of PAE produces more severe fetal growth restriction and placental disorders than Mediterranean PAE 2. Binge human-like pattern of PAE produces more severe brain impairment in comparison to Mediterranean PAE 3. EGCG therapy administered under optimal pharmacokinetic conditions may mitigate placental and brain alterations produced by PAE according to the two human-like drinking patterns (binge versus Mediterranean) 4. Highest plasma concentrations are reached with oral EGCG administration without food supplements 5. Food supplements improve the stability of oral EGCG administration. OBJECTIVES: The main objectives of this thesis are to evaluate the protective effect of EGCG on a FASD-like mouse model exposed to two human-like drinking patterns (acute or binge versus chronic moderate or Mediterranean) and assess the specific EGCG bioavailability profile in humans under different nutritional conditions. The specific objectives of this doctoral thesis are: 1. To assess the effects of binge versus Mediterranean alcohol exposure on fetal growth and placenta, based on fetal and placental weight and placental angiogenesis biomarkers 2. To analyze the effects of binge versus Mediterranean alcohol exposure on maturation, differentiation, and plasticity in fetal brain processes based on specific neuronal biomarkers 3. To study the protective effect of EGCG on fetal growth, placental development, and neurogenesis processes 4. To analyze the bioavailability of oral EGCG administered alone or with different food supplements in healthy volunteers 5. To evaluate the pharmacokinetic parameters of EGCG in healthy volunteers.[spa] INTRODUCCIÓN: Según la Organización Mundial de la Salud, la exposición prenatal a alcohol es la principal causa evitable de discapacidad intelectual en el mundo occidental, asociándose a diferentes alteraciones físicas y desórdenes neurológicos que conllevan alteraciones cognitivas y conductuales. El conjunto de estas alteraciones se denominan trastornos del espectro alcohólico fetal (TEAF). Los desórdenes relacionados con esta exposición a alcohol se asocian a importantes problemas en la esfera social y conlleva una serie de costes para el sistema de salud pública. Aunque el consumo del alcohol de forma aguda y compulsiva es el patrón de consumo más habitual, otros tipos de consumo, como el Mediterráneo (bajas dosis de forma continuada), son habituales en determinadas zonas geográficas. Sin embargo, se desconocen actualmente los mecanismos responsables de la toxicidad del alcohol. Los roedores como la cepa de ratón C57BL/6 permiten evaluar los efectos teratogénicos del alcohol según la dosis y el momento del desarrollo en que se administra, analizando comportamientos complejos similares a los humanos y terapias experimentales prometedoras. Las similitudes en las etapas del desarrollo neurológico en los ratones y humanos permiten llevar a cabo estos estudios, pero hay que tener en cuenta que en el ratón el equivalente al tercer trimestre de gestación humana ocurre en la etapa postnatal. La dismorfología facial debida a la exposición prenatal a alcohol aparece durante el equivalente al primer trimestre de gestación humana, pero el desarrollo neurológico ocurre continuamente durante toda la gestación, por lo que el consumo en cualquier momento del embarazo puede conducir a alteraciones en procesos claves como la proliferación, la migración, la diferenciación, la sinaptogénesis, la gliogénesis, la mielinización y la apoptosis en los linajes neuronales, que conllevan alteraciones neurológicas y del comportamiento. Por otro lado, el consumo prenatal de alcohol produce deficiencias nutricionales maternas y alteraciones en la angiogénesis e histología placentaria que conllevan a una restricción del crecimiento fetal. Actualmente no disponemos de ningún tratamiento específico para el TEAF, a parte del diagnóstico precoz y el tratamiento de los síntomas. La epigalocatequina galato (EGCG) es un flavonoide con poder antioxidante que se ha evaluado en el tratamiento de diversas patologías humanas. Dado que el alcohol produce un aumento de estrés oxidativo, la EGCG se plantea como una opción terapéutica para el TEAF. Algunos estudios han demostrado que la EGCG se puede distribuir en el cerebro embrionario y fetal mediante su administración a la gestante, pero es necesario conocer mejor su perfil farmacocinético. Actualmente no existe consenso sobre la concentración más adecuada de EGCG para obtener unos efectos terapéuticos óptimos. Conocer bien el perfil farmacocinético de la EGCG puede ser útil con el fin de utilizarlo en futuros ensayos clínicos. HIPÓTESIS: La exposición prenatal a alcohol produce diferente grado de restricción de crecimiento fetal, trastornos placentarios y desórdenes neurológicos según el patrón de consumo humano (agudo o binge versus moderado crónico o Mediterráneo). La terapia con EGCG administrada en las condiciones farmacocinéticas óptimas puede atenuar estas anomalías. OBJETIVOS: Los objetivos principales de esta tesis doctoral son evaluar el efecto protector de la terapia con EGCG en un modelo de TEAF en ratón de acuerdo con los dos patrones de consumo humano (agudo o binge versus moderado crónico o Mediterráneo), y analizar el perfil de biodisponibilidad específico de la EGCG en humanos bajo diferentes condiciones nutricionales. MÉTODOS: Para llevar a cabo los objetivos de esta tesis se realizó un estudio preclínico en modelo de ratón y un estudio prospectivo cruzado en humanos. En el estudio preclínico se utilizó la cepa de ratón C57BL/6. Se realizaron los apareamientos y el diagnóstico de gestación se llevó a cabo mediante la visualización de tapón espermático. Las ratonas gestantes fueron asignados aleatoriamente a 6 grupos experimentales: (1) control Mediterráneo (1,38 mg/kg maltodextrina); (2) etanol Mediterráneo (0,75 mg/kg etanol); (3) etanol Mediterráneo + antioxidante (0,75 mg/kg etanol + 30 mg/kg EGCG); (4) control binge (5,52 mg/kg maltodextrina); (4) etanol binge (3 mg/kg etanol); (6) etanol binge + EGCG (0,75 mg/kg etanol + 30 mg/kg EGCG). Las gestaciones se finalizaron mediante cesáreas el día 19 y se realizaron necropsias con obtención de placenta y tejido cerebral. Se analizó el crecimiento fetal, se realizó estudio de los fenómenos de angiogénesis en placenta (VEGF-A, PLGF y VEGF-R), del estrés oxidativo (Nrf2), y los procesos del desarrollo neurológico que incluyen la maduración (NeuN, DCX), diferenciación (GFAP) y plasticidad neuronal (BDNF) mediante técnicas de Western blot e inmunohistoquímica. Por último, se realizaron los análisis estadísticos correspondientes. En el estudio cruzado, se reclutaron prospectivamente diez voluntarios sanos (cinco mujeres y cinco hombres). Se realizaron tres series de experimentos clínicos con un período de descanso de siete días entre cada uno: (1) Teavigo® (extracto de EGCG) en ayunas; (2) Teavigo® con un desayuno estándar; y (3) FontUp® (Teavigo® en un preparado comercial con suplementos nutricionales). Se realizaron extracciones de sangre en los minutos 0, 30, 60, 90, 120, 180, 240 y 360 después de la administración de EGCG. La determinación de EGCG en plasma se realizó mediante el método analítico de cromatografía y espectrometría de masas UPLC-ESI-MS/MS. Se analizaron estadísticamente las siguientes variables farmacocinéticas: AUC0-360, Cmax, Cav, Cmin, T1/2 y Tmax. RESULTADOS PRINCIPALES: Respecto al estudio en el modelo animal objetivamos que cualquier patrón de consumo de alcohol (Mediterráneo o binge) produce efectos no deseados en la descendencia. Con la administración de dosis elevadas de alcohol encontramos una restricción de crecimiento fetal importante, sin embargo, las dosis más moderadas no fueron suficientes para sobrepasar el umbral requerido para que se produjera un déficit de crecimiento. Cualquier patrón de consumo produjo desequilibrios en la expresión de los factores angiogénicos en placenta (VEGF-A, VEGF-R) y desórdenes en los procesos del desarrollo neuronal, incluyendo la pérdida de neuronas maduras (NeuN), retraso en la maduración neuronal (DCX) y desórdenes en la diferenciación astrocitaria (GFAP). La exposición a alcohol continuada durante el desarrollo fetal puede conducir a una habituación en determinados procesos como la plasticidad neuronal (BDNF). El tratamiento con EGCG fue capaz de revertir las alteraciones del crecimiento fetal y desarrollo placentario, el estrés oxidativo, y los desórdenes en los procesos del desarrollo neurológico fetal. En el estudio cruzado para el análisis de la biodisponibilidad de la EGCG, con la administración de Teavigo® en ayunas se obtuvieron concentraciones más elevadas en plasma (evaluadas mediante AUC0-360, Cmax y Cav), tanto en hombres como en mujeres. Sin embargo, la variabilidad interindividual fue menor (T1/2 más elevada) con la administración de Teavigo® con un desayuno estándar y principalmente con el suplemento alimenticio FontUp®. CONCLUSIONES: Los resultados presentados en esta tesis apoyan el uso de la EGCG como un potencial tratamiento prenatal para las alteraciones en los procesos neuronales fetales, el desarrollo placentario y el crecimiento fetal producidas por la exposición prenatal a alcohol. Estos hallazgos suponen el punto de partida para plantear nuevas investigaciones sobre el efecto de la EGCG sobre los trastornos del comportamiento relacionados con el TEAF en el adulto. El conocimiento sobre las características farmacocinéticas de la EGCG permitirá su uso en la población gestante humana como una alternativa segura para el tratamiento de los problemas de salud derivados del consumo prenatal de alcohol

Epigallocatechin gallate ameliorates the effects of prenatal alcohol exposure in a fetal alcohol spectrum disorder-like mouse model

Fetal alcohol spectrum disorder is the main preventable cause of intellectual disability in the Western world. Although binge drinking is the most studied prenatal alcohol exposure pattern, other types of exposure, such as the Mediterranean, are common in specific geographic areas. In this study, we analyze the effects of prenatal alcohol exposure in binge and Mediterranean human drinking patterns on placenta and brain development in C57BL/6J mice. We also assess the impact of prenatal treatment with the epigallocatechin-3-gallate antioxidant in both groups. Study experimental groups for Mediterranean or binge patterns: (1) control; (2) ethanol; (3) ethanol + epigallocatechin-3-gallate. Brain and placental tissue were collected on gestational Day 19. The molecular pathways studied were fetal and placental growth, placental angiogenesis (VEGF-A, PLGF, VEGF-R), oxidative stress (Nrf2), and neurodevelopmental processes including maturation (NeuN, DCX), differentiation (GFAP) and neural plasticity (BDNF). Prenatal alcohol exposure resulted in fetal growth restriction and produced imbalances of placental angiogenic factors. Moreover, prenatal alcohol exposure increased oxidative stress and caused significant alterations in neuronal maturation and astrocyte differentiation. Epigallocatechin-3-gallate therapy ameliorated fetal growth restriction, attenuated alcohol-induced changes in placental angiogenic factors, and partially rescued neuronal nuclear antigen (NeuN), (doublecortin) DCX, and (glial fibrillary acidic protein) GFAP levels. Any alcohol consumption (Mediterranean or binge) during pregnancy may generate a fetal alcohol spectrum disorder phenotype and the consequences may be partially attenuated by a prenatal treatment with epigallocatechin-3-gallate

Effects of Microbiota Imbalance in Anxiety and Eating Disorders: Probiotics as Novel Therapeutic Approaches

Anxiety and eating disorders produce a physiological imbalance that triggers alterations in the abundance and composition of gut microbiota. Moreover, the gut–brain axis can be altered by several factors such as diet, lifestyle, infections, and antibiotic treatment. Diet alterations generate gut dysbiosis, which affects immune system responses, inflammation mechanisms, the intestinal permeability, as well as the production of short chain fatty acids and neurotransmitters by gut microbiota, which are essential to the correct function of neurological processes. Recent studies indicated that patients with generalized anxiety or eating disorders (anorexia nervosa, bulimia nervosa, and binge-eating disorders) show a specific profile of gut microbiota, and this imbalance can be partially restored after a single or multi-strain probiotic supplementation. Following the PRISMA methodology, the current review addresses the main microbial signatures observed in patients with generalized anxiety and/or eating disorders as well as the importance of probiotics as a preventive or a therapeutic tool in these pathologies

Effects of Microbiota Imbalance in Anxiety and Eating Disorders: Probiotics as Novel Therapeutic Approaches

Anxiety and eating disorders produce a physiological imbalance that triggers alterations in the abundance and composition of gut microbiota. Moreover, the gut–brain axis can be altered by several factors such as diet, lifestyle, infections, and antibiotic treatment. Diet alterations generate gut dysbiosis, which affects immune system responses, inflammation mechanisms, the intestinal permeability, as well as the production of short chain fatty acids and neurotransmitters by gut microbiota, which are essential to the correct function of neurological processes. Recent studies indicated that patients with generalized anxiety or eating disorders (anorexia nervosa, bulimia nervosa, and binge-eating disorders) show a specific profile of gut microbiota, and this imbalance can be partially restored after a single or multi-strain probiotic supplementation. Following the PRISMA methodology, the current review addresses the main microbial signatures observed in patients with generalized anxiety and/or eating disorders as well as the importance of probiotics as a preventive or a therapeutic tool in these pathologies

Effects of Antioxidant Intake on Fetal Development and Maternal/Neonatal Health during Pregnancy

During pregnancy, cycles of hypoxia and oxidative stress play a key role in the proper development of the fetus. Hypoxia during the first weeks is crucial for placental development, while the increase in oxygen due to the influx of maternal blood stimulates endothelial growth and angiogenesis. However, an imbalance in the number of oxidative molecules due to endogenous or exogenous factors can overwhelm defense systems and lead to excessive production of reactive oxygen species (ROS). Many pregnancy complications, generated by systemic inflammation and placental vasoconstriction, such as preeclampsia (PE), fetal growth restriction (FGR) and preterm birth (PTB), are related to this increase of ROS. Antioxidants may be a promising tool in this population. However, clinical evidence on their use, especially those of natural origin, is scarce and controversial. Following PRISMA methodology, the current review addresses the use of natural antioxidants, such as epigallocatechin gallate (EGCG), melatonin and resveratrol (RESV), as well as other classical antioxidants (vitamin C and E) during the prenatal period as treatment of the above-mentioned complications. We review the effect of antioxidant supplementation on breast milk in lactating mothers