New therapeutics for the prevention or amelioration of fetal alcohol spectrum disorders: a narrative review of the preclinical literature.

Background: Ethanol consumption during pregnancy induces enduring detrimental effects in the offspring, manifesting as a spectrum of symptoms collectively termed as Fetal Alcohol Spectrum Disorders (FASD). Presently, there is a scarcity of treatments for FASD.Objectives: To analyze current literature, emphasizing evidence derived from preclinical models, that could potentially inform therapeutic interventions for FASD.Methods: A narrative review was conducted focusing on four prospective treatments: nutritional supplements, antioxidants, anti-inflammatory compounds and environmental enrichment. The review also highlights innovative therapeutic strategies applied during early (e.g. folate administration, postnatal days 4-9) or late (e.g. NOX2 inhibitors given after weaning) postnatal stages that resulted in significant improvements in behavioral responses during adolescence (a critical period marked by the emergence of mental health issues in humans).Results: Our findings underscore the value of treatments centered around nutritional supplementation or environmental enrichment, aimed at mitigating oxidative stress and inflammation, implying shared mechanisms in FASD pathogenesis. Moreover, the review spotlights emerging evidence pertaining to the involvement of novel molecular components with potential pharmacological targets (such as NOX2, MCP1/CCR2, PPARJ, and PDE1).Conclusions: Preclinical studies have identified oxidative imbalance and neuroinflammation as relevant pathological mechanisms induced by prenatal ethanol exposure. The relevance of these mechanisms, which exhibit positive feedback loop mechanisms, appear to peak during early development and decreases in adulthood. These findings provide a framework for the future development of therapeutic avenues in the development of specific clinical treatments for FASD.

Effect of plasma exchange with albumin replacement on albumin functionality and organ dysfunction in acute-on-chronic liver failure.

Background & Aims: Effective treatments for acute-on-chronic liver failure (ACLF) are a major unmet need. This proof-of-concept pilot study was aimed at evaluating the effects of plasma exchange (PE) with albumin 5% (PE-A5%) on albumin functional capacity and organ dysfunction in patients with ACLF. Methods: Ten adult patients were enrolled in a single-center phase II, prospective, open-label, non-controlled study. Six PE-A5% sessions were performed in 10 days followed by a 1-month follow-up visit. Albumin functional capacity and circulatory function were assessed, as were renal, cerebral, and liver function, and systemic inflammation. The main safety variable was the percentage of PE sessions associated with at least one procedure-related adverse event (AE). Results: Patients with ACLF showed lower albumin binding capacity, lower antioxidant capacity, and lower levels of albumin with preserved structure compared to healthy donors (n = 19). From baseline to day 11, PE-A5% treatment increased albumin levels and improved albumin binding capacity to Sudlow site II (15.3±1.6 mg/ml to 18.9±1.7 mg/ml; p = 0.003), fatty acid-binding capacity (8.2±1.4 µM to 3.1±1.5 µM; p = 0.013) and antioxidant capacity (human mercaptalbumin 9.5±1.5 mg/ml to 14.6±1.6 mg/ml; p = 0.001). Native albumin levels were increased throughout day 1-11 PE-A5% sessions (6.5±1.0 mg/ml to 10.2±1.4 mg/ml; p = 0.035). PE-A5% improved systemic hemodynamics (mean arterial pressure, heart rate, cardiac index), renal function (creatinine level, blood urea nitrogen), cerebral function (hepatic encephalopathy grade), liver parameters (transaminases, bilirubin) and inflammatory parameters (C-reactive protein, leukocyte count). All patients had at least one of the 78 AEs reported, mostly mild (product/procedure-related: 36%). Sixteen serious AEs were reported in eight patients (procedure/product-related: none). Conclusions: PE-A5% was a safe procedure associated with positive effects on albumin functionality, and circulatory, renal, cerebral, and liver function in patients with ACLF. Impact and implications: Acute-on-chronic liver failure (ACLF) is a clinical condition characterized by severe systemic inflammation, organ failure, and high mortality. Plasma exchange removes patient's plasma containing pathogenic substances, replacing it with 5% albumin and fresh frozen plasma (PE-A5%). In this study, cirrhotic patients with ACLF were treated with PE-A5%, which was a safe procedure that increased binding and antioxidant capacity of patients' albumin, while improving circulatory, kidney, brain, and liver functions. These beneficial effects could impact survival in ACLF. ClinicalTrialsgov Identifier: NCT01201720. EudraCT number: 2010-021360-15.

Evolution of lysine-specific demethylase 1 and REST corepressor gene families and their molecular interaction.

Lysine-specific demethylase 1A (LSD1) binds to the REST corepressor (RCOR) protein family of corepressors to erase transcriptionally active marks on histones. Functional diversity in these complexes depends on the type of RCOR included, which modulates the catalytic activity of the complex. Here, we studied the duplicative history of the RCOR and LSD gene families and analyzed the evolution of their interaction. We found that RCOR genes are the product of the two rounds of whole-genome duplications that occurred early in vertebrate evolution. In contrast, the origin of the LSD genes traces back before to the divergence of animals and plants. Using bioinformatics tools, we show that the RCOR and LSD1 interaction precedes the RCOR repertoire expansion that occurred in the last common ancestor of jawed vertebrates. Overall, we trace LSD1-RCOR complex evolution and propose that animal non-model species offer advantages in addressing questions about the molecular biology of this epigenetic complex.

Enfermedad renal: urinoma. A propósito de un caso / Renal disease: urinoma. Apropos of a case

Objetivo. Ecografía permite diagnosticar y seguir el progreso de las uropatías obstructivas incluyendo la aparición de urinomas. Sujeto y métodos. Presentamos un caso de hidronefrosis diagnosticado en segundo trimestre con evolución posterior a urinoma. Resultados. Paciente de 21,4 semanas de gestación (SG) se realiza ecografía observándose hidronefrosis izquierda grado II. A las 27.5SG se observó una hidronefrosis izquierda con colección líquida de 40×50×30mm retroperitoneal izquierda peri-renal con distorsión de la morfología del riñón desplazado medialmente compatible con urinoma. Conclusiones. La aparición prenatal de un urinoma se asocia a afectación postnatal en diferente grado de la función del riñón afectado (AU)

Objective. Fetal ultrasound enables us to diagnose and follow the progress of obstructive uropathies including the occurrence of fetal urinomas. Subject and methods. We report a case of hydronephrosis diagnosed in the second trimester with evolution urinoma. Results. Patient at 21.4 weeks’ gestation showed in fetal ultrasound a left hydronephrosis grade II. At 27.5w showed a left hydronephrosis with a retroperitoneal fluid collection perirenal 40×50×30mm and distortion of the kidney morphology compatible with urinoma. Conclusions. the prenatal occurrence of an urinoma is often associated with the postnatal absence of function of the involved kidney (AU)

Capacidad de unión de la albúmina al beta-amiloide / The capacity of albumin to bind to beta-amyloid

Introducción. Se ha descrito que la mayor parte del péptido beta-amiloide (Ab) plasmático se halla unido a albúmina (aprox. 90%) y que parece existir un equilibrio entre el Ab periférico y el cerebral, por lo que debería ser posible reducir sus niveles en sangre mediante el recambio plasmático con albúmina terapéutica que, a su vez, podría influir en el desalojo de Ab cerebral. En este estudio se realizó una caracterización del contenido y la capacidad de unión de la albúmina terapéutica al Ab. Materiales y métodos. Niveles de Ab1-40 y Ab1-42 en albúmina terapéutica (albúmina humana Grifols; n = 18 lotes), así como en plasma normal (n = 8) o de pacientes con enfermedad de Alzheimer (n = 45), se determinaron mediante ELISA. La capacidad de unión de la albúmina terapéutica a péptidos sintéticos con la secuencia primaria del Ab1-42 humano se determinó mediante resonancia de plasmones de superficie (SPR). Resultados. Los niveles tanto de Ab1-40 como de Ab1-42 en la albúmina terapéutica fueron siempre inferiores al último punto válido de la curva estándar (< 25 a < 63 pg/ml). Los niveles en plasma normal o de pacientes con enfermedad de Alzheimer oscilaron entre < 25 y 312 pg/ml para Ab1-40 y < 25 y 279,4 pg/ml para Ab1-42. Los experimentos de SPR confirmaron una alta afinidad de la albúmina terapéutica por el péptido Ab experimental. Conclusiones. La albúmina humana Grifols presenta un contenido indetectable de Ab e inferior al observado en plasma de controles normales y pacientes con enfermedad de Alzheimer, y además es capaz de unirse a péptidos con la secuencia del Ab1-42 humano (AU)

Introduction. Most plasma beta-amyloid peptide (Ab) has been described to circulate bound to albumin (aprox. 90%). Moreover, a balance between peripheral and brain Ab seems to exist, so a reduction of Ab levels in blood through plasma exchange with therapeutic albumin should induce a clearance of brain Ab. In this study, content of Ab in therapeutic albumin as well as its binding capacity were characterized. Materials and methods. Levels of Ab1-40 and Ab1-42 were determined by means of ELISA technique in therapeutic albumin (human albumin Grifols; n = 18 batches), in normal plasma (n = 8) and in plasma from patients with Alzheimer disease (n = 45). Binding capacity of therapeutic albumin to synthetic peptides containing the primary sequence of human Ab1-42 was determined by means of surface plasmon resonance (SPR) technique. Results. Both the Ab1-40 and Ab1-42 levels in therapeutic albumin were always lower than the last valid point measured in the standard curve (< 25 to < 63 pg/mL). Levels in normal plasma and in plasma from Alzheimer disease patients rantransport ged between < 25 to 312 pg/mL for Ab1-40, and < 25 to 279,4 pg/mL for Ab1-42. SPR studies confirmed the high affinity of therapeutic albumin for the experimental Ab peptide. Conclusions. Human albumin Grifols shows undetectable Ab levels, and lower to those observed in normal plasma and in plasma from patients with Alzheimer diisease. Moreover, it was able to bind peptides containing the sequence of human Ab1-42 (AU)