RESUMEN
Repetitive mild traumatic brain injury (mTBI) in children and adolescents leads to acute and chronic neurologic sequelae and is linked to later life neurodegenerative disease. However, the biological mechanisms connecting early life mTBI to neurodegeneration remain unknown. Using an adolescent mouse repetitive closed head injury model that induces progressive cognitive impairment in males and anxiety in females in the absence of overt histopathology, we examined transcriptional and translational changes in neurons isolated from sham and injured brain in the chronic phase after injury. At 14 months, single-nuclei RNA sequencing of cortical brain tissue identified disruption of genes associated with neuronal proteostasis and evidence for disrupted ligand-receptor signaling networks in injured mice. Western blot analysis of isolated neurons showed evidence of inflammasome activation and downstream IL-1ß processing, as previously demonstrated in acute CNS injury models, and accumulation of misfolded, hyperphosphorylated tau, and changes in expression of proteins suggestive of impaired translation in males but not in females. At 6 months, injured IL-1 receptor 1 (IL-1R1) KO mice, which are protected from postinjury cognitive deficits, had decreased accumulation of pro-IL-1ß and misfolded tau in cortex and cerebellum, suggesting that IL-1R1 is upstream of inflammasome priming (defined as increase in pro-IL-1ß) and abnormal tau phosphorylation. Together, our findings provide evidence for neuronal inflammasome activation and impaired proteostasis as key mechanisms linking repetitive mTBI in adolescence to later life neurologic dysfunction and neurodegeneration.SIGNIFICANCE STATEMENT Repetitive mild closed head injury in adolescent male mice leads to impaired proteostasis, tau phosphorylation, and inflammasome activation in neurons later in adulthood through mechanisms involving IL-1 receptor 1. The data are the first to link repetitive mild traumatic brain injury in adolescence to neurodegeneration and suggest molecular targets and pathways to prevent neurologic sequelae in the chronic period after injuries.
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Conmoción Encefálica , Enfermedades Neurodegenerativas , Tauopatías , Animales , Conmoción Encefálica/complicaciones , Conmoción Encefálica/patología , Modelos Animales de Enfermedad , Femenino , Inflamasomas , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedades Neuroinflamatorias , Proteostasis , Receptores de Interleucina-1 , Tauopatías/patologíaRESUMEN
Auditory experience drives neural circuit refinement during windows of heightened brain plasticity, but little is known about the genetic regulation of this developmental process. The primary auditory cortex (A1) of mice exhibits a critical period for thalamocortical connectivity between postnatal days P12 and P15, during which tone exposure alters the tonotopic topography of A1. We hypothesized that a coordinated, multicellular transcriptional program governs this window for patterning of the auditory cortex. To generate a robust multicellular map of gene expression, we performed droplet-based, single-nucleus RNA sequencing (snRNA-seq) of A1 across three developmental time points (P10, P15, and P20) spanning the tonotopic critical period. We also tone-reared mice (7 kHz pips) during the 3-d critical period and collected A1 at P15 and P20. We identified and profiled both neuronal (glutamatergic and GABAergic) and nonneuronal (oligodendrocytes, microglia, astrocytes, and endothelial) cell types. By comparing normal- and tone-reared mice, we found hundreds of genes across cell types showing altered expression as a result of sensory manipulation during the critical period. Functional voltage-sensitive dye imaging confirmed GABA circuit function determines critical period onset, while Nogo receptor signaling is required for its closure. We further uncovered previously unknown effects of developmental tone exposure on trajectories of gene expression in interneurons, as well as candidate genes that might execute tonotopic plasticity. Our single-nucleus transcriptomic resource of developing auditory cortex is thus a powerful discovery platform with which to identify mediators of tonotopic plasticity.
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Corteza Auditiva , Núcleo Celular/metabolismo , ARN , Análisis de la Célula Individual/métodos , Transcriptoma/genética , Animales , Corteza Auditiva/crecimiento & desarrollo , Corteza Auditiva/metabolismo , Regulación del Desarrollo de la Expresión Génica/genética , Glutamato Descarboxilasa/genética , Glutamato Descarboxilasa/metabolismo , Ratones , Receptores Nogo/genética , Receptores Nogo/metabolismo , ARN/análisis , ARN/genética , ARN/metabolismo , Análisis de Secuencia de ARN/métodosRESUMEN
BACKGROUND: During the COVID-19 pandemic, thousands of pregnant women have been infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The implications of maternal SARS-CoV-2 infection on fetal and childhood well-being need to be characterized. We aimed to characterize the fetal immune response to maternal SARS-CoV-2 infection. METHODS: We performed single-cell RNA-sequencing and T cell receptor sequencing on cord blood mononuclear cells (CBMCs) from newborns of mothers infected with SARS-CoV-2 in the third trimester (cases) or without SARS-CoV-2 infection (controls). RESULTS: We identified widespread gene expression changes in CBMCs from cases, including upregulation of interferon-stimulated genes and major histocompatibility complex genes in CD14+ monocytes, transcriptional changes suggestive of activation of plasmacytoid dendritic cells, and activation and exhaustion of natural killer cells. Lastly, we observed fetal T cell clonal expansion in cases compared to controls. CONCLUSIONS: As none of the infants were infected with SARS-CoV-2, our results suggest that maternal SARS-CoV-2 infection might modulate the fetal immune system in the absence of vertical transmission. IMPACT: The implications of maternal SARS-CoV-2 infection in the absence of vertical transmission on fetal and childhood well-being are poorly understood. Maternal SARS-CoV-2 infection might modulate the fetal immune system in the absence of vertical transmission. This study raises important questions about the untoward effects of maternal SARS-CoV-2 on the fetus, even in the absence of vertical transmission.
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COVID-19 , Complicaciones Infecciosas del Embarazo , Niño , Femenino , Feto , Humanos , Inmunidad , Inmunofenotipificación , Recién Nacido , Transmisión Vertical de Enfermedad Infecciosa , Pandemias , Embarazo , Complicaciones Infecciosas del Embarazo/epidemiología , SARS-CoV-2RESUMEN
Children who require surgery in the newborn period are at risk for long-term neurodevelopmental impairment (NDI). There is growing evidence that surgery during this critical window of neurodevelopment gives rise to an increased risk of brain injury, predisposing to neurodevelopmental challenges including motor delays, learning disabilities, executive function impairments, and behavioral disorders. These impairments can have a significant impact on the quality of life of these children and their families. This review explores the current literature surrounding the effect of neonatal surgery on neurodevelopment, as well as the spectrum of proposed mechanisms that may impact neurodevelopmental outcomes. The goal is to identify modifiable risk factors and patients who may benefit from close neurodevelopmental follow-up and early referral to therapy.
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Lesiones Encefálicas , Trastornos Mentales , Niño , Recién Nacido , Humanos , Calidad de Vida , Derivación y Consulta , Factores de RiesgoRESUMEN
Regulation of gene expression is primarily controlled by changes in the proteins that occupy genes' regulatory elements. We developed genomic locus proteomics (GLoPro), in which we combine CRISPR-based genome targeting, proximity labeling, and quantitative proteomics to discover proteins associated with a specific genomic locus in native cellular contexts.
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Proteína 9 Asociada a CRISPR/metabolismo , ADN-(Sitio Apurínico o Apirimidínico) Liasa/metabolismo , Inmunoprecipitación de Cromatina , Endonucleasas , Genoma , Genómica , Células HEK293 , Humanos , Enzimas Multifuncionales , Reacción en Cadena de la Polimerasa , Ingeniería de ProteínasRESUMEN
Coordinated changes in gene expression underlie the early patterning and cell-type specification of the central nervous system. However, much less is known about how such changes contribute to later stages of circuit assembly and refinement. In this study, we employ single-cell RNA sequencing to develop a detailed, whole-transcriptome resource of gene expression across four time points in the developing dorsal lateral geniculate nucleus (LGN), a visual structure in the brain that undergoes a well-characterized program of postnatal circuit development. This approach identifies markers defining the major LGN cell types, including excitatory relay neurons, oligodendrocytes, astrocytes, microglia, and endothelial cells. Most cell types exhibit significant transcriptional changes across development, dynamically expressing genes involved in distinct processes including retinotopic mapping, synaptogenesis, myelination, and synaptic refinement. Our data suggest that genes associated with synapse and circuit development are expressed in a larger proportion of nonneuronal cell types than previously appreciated. Furthermore, we used this single-cell expression atlas to identify the Prkcd-Cre mouse line as a tool for selective manipulation of relay neurons during a late stage of sensory-driven synaptic refinement. This transcriptomic resource provides a cellular map of gene expression across several cell types of the LGN, and offers insight into the molecular mechanisms of circuit development in the postnatal brain.
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Regulación del Desarrollo de la Expresión Génica , Cuerpos Geniculados/embriología , Cuerpos Geniculados/fisiología , Neuronas/fisiología , Sinapsis/fisiología , Transcriptoma , Animales , Axones/fisiología , Encéfalo/embriología , Perfilación de la Expresión Génica , Ratones , Microscopía Electrónica de Rastreo , Neurogénesis , Retina/fisiología , Análisis de Secuencia de ARN , Programas Informáticos , Vías Visuales/fisiologíaRESUMEN
OBJECTIVES: Extracorporeal membrane oxygenation is an established therapy for cardiac and respiratory failure unresponsive to usual care. Extracorporeal membrane oxygenation mortality remains high, with ongoing risk of death even after successful decannulation. We describe occurrence and factors associated with mortality in children weaned from extracorporeal membrane oxygenation. DESIGN: Retrospective cohort study. SETTING: Two hundred five extracorporeal membrane oxygenation centers reporting to the Extracorporeal Life Support Organization. SUBJECTS: Eleven thousand ninety-six patients, less than 18 years, supported with extracorporeal membrane oxygenation during 2007-2013, who achieved organ recovery before decannulation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Primary outcome was hospital mortality less than or equal to 30 days post extracorporeal membrane oxygenation decannulation. Among 11,096 patients, indication for extracorporeal membrane oxygenation cannulation was respiratory (6,206; 56%), cardiac (3,663; 33%), or cardiac arrest (extracorporeal cardiopulmonary resuscitation, 1,227; 11%); the majority were supported with venoarterial extracorporeal membrane oxygenation at some stage in their course (8,576 patients; 77%). Mortality was 13%. Factors associated with mortality included younger age (all < 1 yr categories compared with older, p < 0.05), lower weight among neonates (≤ 3 vs > 3 kg; p < 0.001), mode of extracorporeal membrane oxygenation support (venoarterial extracorporeal membrane oxygenation compared with venovenous extracorporeal membrane oxygenation, p < 0.001), longer admission to extracorporeal membrane oxygenation cannulation time (≥ 28 vs < 28 hr; p < 0.001), cardiac and extracorporeal cardiopulmonary resuscitation compared with respiratory extracorporeal membrane oxygenation (both p < 0.001), extracorporeal membrane oxygenation duration greater than or equal to 135 hours (p < 0.001), preextracorporeal membrane oxygenation hypoxemia (PO2 ≤ 43 vs > 43 mm Hg; p < 0.001), preextracorporeal membrane oxygenation acidemia (p < 0.001), and extracorporeal membrane oxygenation complications, particularly cerebral or renal (both p < 0.001). CONCLUSIONS: Despite extracorporeal membrane oxygenation decannulation for organ recovery, 13% of patients die in hospital. Mortality is associated with patient factors, preextracorporeal membrane oxygenation illness severity, and extracorporeal membrane oxygenation management. Evidence-based strategies to optimize readiness for extracorporeal membrane oxygenation decannulation and postextracorporeal membrane oxygenation decannulation care are needed.
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Oxigenación por Membrana Extracorpórea/mortalidad , Mortalidad Hospitalaria , Unidades de Cuidado Intensivo Pediátrico/estadística & datos numéricos , Desconexión del Ventilador/mortalidad , Factores de Edad , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Factores de TiempoRESUMEN
Hypotension is a common problem in neonates with complex underlying pathophysiology. Although treatment of low blood pressure is common, clinicians must use all available information to target neonates with compromised perfusion. Pharmacotherapy should be tailored to the specific physiologic perturbations of the individual neonate. Dopamine is the most commonly utilized agent and may be the most appropriate agent for septic shock with low diastolic blood pressure. However, alternative therapies should be considered for other etiologies of hypotension, including milrinone and vasopressin for persistent pulmonary hypertension of the newborn and dobutamine for patent ductus arteriosus. Additional studies are required to refine the approach to neonatal hypotension and document the long-term outcomes of treated neonates.
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Presión Sanguínea , Dobutamina/uso terapéutico , Dopamina/uso terapéutico , Hipotensión , Milrinona/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Cardiotónicos/uso terapéutico , Conducto Arterioso Permeable/complicaciones , Humanos , Hipotensión/diagnóstico , Hipotensión/etiología , Hipotensión/fisiopatología , Hipotensión/terapia , Recién Nacido , Efectos Adversos a Largo Plazo , Choque Séptico/complicacionesRESUMEN
BACKGROUND: Ebstein anomaly and tricuspid valve dysplasia are rare congenital tricuspid valve malformations associated with high perinatal mortality. The literature consists of small, single-center case series spanning several decades. We performed a multicenter study to assess the outcomes and factors associated with mortality after fetal diagnosis in the current era. METHODS AND RESULTS: Fetuses diagnosed with Ebstein anomaly and tricuspid valve dysplasia from 2005 to 2011 were included from 23 centers. The primary outcome was perinatal mortality, defined as fetal demise or death before neonatal discharge. Of 243 fetuses diagnosed at a mean gestational age of 27±6 weeks, there were 11 lost to follow-up (5%), 15 terminations (6%), and 41 demises (17%). In the live-born cohort of 176 live-born patients, 56 (32%) died before discharge, yielding an overall perinatal mortality of 45%. Independent predictors of mortality at the time of diagnosis were gestational age <32 weeks (odds ratio, 8.6; 95% confidence interval, 3.5-21.0; P<0.001), tricuspid valve annulus diameter z-score (odds ratio, 1.3; 95% confidence interval, 1.1-1.5; P<0.001), pulmonary regurgitation (odds ratio, 2.9; 95% confidence interval, 1.4-6.2; P<0.001), and a pericardial effusion (odds ratio, 2.5; 95% confidence interval, 1.1-6.0; P=0.04). Nonsurvivors were more likely to have pulmonary regurgitation at any gestational age (61% versus 34%; P<0.001), and lower gestational age and weight at birth (35 versus 37 weeks; 2.5 versus 3.0 kg; both P<0.001). CONCLUSION: In this large, contemporary series of fetuses with Ebstein anomaly and tricuspid valve dysplasia, perinatal mortality remained high. Fetuses with pulmonary regurgitation, indicating circular shunt physiology, are a high-risk cohort and may benefit from more innovative therapeutic approaches to improve survival.
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Anomalía de Ebstein/mortalidad , Válvula Tricúspide/anomalías , Aborto Eugénico , Adulto , Peso al Nacer , Cateterismo Cardíaco , Procedimientos Quirúrgicos Cardíacos/estadística & datos numéricos , Síndrome de Down/complicaciones , Síndrome de Down/mortalidad , Anomalía de Ebstein/diagnóstico por imagen , Anomalía de Ebstein/embriología , Anomalía de Ebstein/cirugía , Femenino , Edad Gestacional , Cardiopatías Congénitas/diagnóstico por imagen , Cardiopatías Congénitas/embriología , Cardiopatías Congénitas/mortalidad , Cardiopatías Congénitas/cirugía , Mortalidad Hospitalaria , Humanos , Recién Nacido , Recien Nacido Prematuro , Enfermedades del Prematuro/mortalidad , Masculino , Cuidados Paliativos , Derrame Pericárdico/etiología , Embarazo , Resultado del Embarazo , Estudios Retrospectivos , Factores de Riesgo , Resultado del Tratamiento , Válvula Tricúspide/fisiopatología , Válvula Tricúspide/cirugía , Insuficiencia de la Válvula Tricúspide/etiología , Insuficiencia de la Válvula Tricúspide/cirugía , Ultrasonografía Prenatal , Adulto JovenRESUMEN
OBJECTIVES: There is a paucity of data regarding the impact of extracorporeal membrane oxygenation support, adequacy of surgical repair, and timing of intervention for residual structural lesions in neonates cannulated to extracorporeal membrane oxygenation after cardiac surgery. Our goal was to determine how these factors were associated with survival. DESIGN: Retrospective study. SETTING: Cardiovascular ICU. SUBJECTS: Neonates (≤ 28 d old) with congenital heart disease cannulated to extracorporeal membrane oxygenation after cardiac surgery during 2006-2013. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Eighty-four neonates were cannulated to venoarterial extracorporeal membrane oxygenation after cardiac surgery. Survival to discharge was 50%. There was no difference in survival based on surgical complexity and those with single or biventricular congenital heart disease. Prematurity (≤ 36 wk gestation; odds ratio, 2.33; p = 0.01), preextracorporeal membrane oxygenation pH less than or equal to 7.17 (odds ratio, 2.01; p = 0.04), need for inotrope support during extracorporeal membrane oxygenation (odds ratio, 3.99; p = 0.03), and extracorporeal membrane oxygenation duration greater than 168 hours (odds ratio, 2.04; p = 0.04) were all associated with increased mortality. Although preextracorporeal membrane oxygenation lactate was not significantly different between survivors and nonsurvivors, unresolved lactic acidosis greater than or equal to 72 hours after cannulation (odds ratio, 2.77; p = 0.002) was associated with increased mortality. Finally, many patients (n = 70; 83%) were noted to have residual lesions after cardiac surgery, and time to diagnosis or correction of residual lesions was significantly shorter in survivors (1 vs 2 d; p = 0.02). CONCLUSIONS: Our data suggest that clearance of lactate is an important therapeutic target for patients cannulated to extracorporeal membrane oxygenation. In addition, timely identification of residual lesions and expedient interventions on those lesions may improve survival.
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Procedimientos Quirúrgicos Cardíacos , Oxigenación por Membrana Extracorpórea/mortalidad , Cardiopatías Congénitas/cirugía , Mortalidad Hospitalaria , Cuidados Posoperatorios/mortalidad , Oxigenación por Membrana Extracorpórea/efectos adversos , Oxigenación por Membrana Extracorpórea/métodos , Femenino , Estudios de Seguimiento , Humanos , Recién Nacido , Masculino , Cuidados Posoperatorios/efectos adversos , Cuidados Posoperatorios/métodos , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Epoxyeicosatrienoic acids (EETs), lipid mediators produced by cytochrome P450 epoxygenases, regulate inflammation, angiogenesis, and vascular tone. Despite pleiotropic effects on cells, the role of these epoxyeicosanoids in normal organ and tissue regeneration remains unknown. EETs are produced predominantly in the endothelium. Normal organ and tissue regeneration require an active paracrine role of the microvascular endothelium, which in turn depends on angiogenic growth factors. Thus, we hypothesize that endothelial cells stimulate organ and tissue regeneration via production of bioactive EETs. To determine whether endothelial-derived EETs affect physiologic tissue growth in vivo, we used genetic and pharmacological tools to manipulate endogenous EET levels. We show that endothelial-derived EETs play a critical role in accelerating tissue growth in vivo, including liver regeneration, kidney compensatory growth, lung compensatory growth, wound healing, corneal neovascularization, and retinal vascularization. Administration of synthetic EETs recapitulated these results, whereas lowering EET levels, either genetically or pharmacologically, delayed tissue regeneration, demonstrating that pharmacological modulation of EETs can affect normal organ and tissue growth. We also show that soluble epoxide hydrolase inhibitors, which elevate endogenous EET levels, promote liver and lung regeneration. Thus, our observations indicate a central role for EETs in organ and tissue regeneration and their contribution to tissue homeostasis.
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Eicosanoides/farmacología , Células Endoteliales/metabolismo , Compuestos Epoxi/farmacología , Neovascularización Fisiológica/fisiología , Regeneración/fisiología , Animales , Cromatografía Liquida , Eicosanoides/metabolismo , Epóxido Hidrolasas/antagonistas & inhibidores , Compuestos Epoxi/metabolismo , Ojo/irrigación sanguínea , Inmunohistoquímica , Riñón/fisiología , Hígado/fisiología , Pulmón/fisiología , Ratones , Ratones Transgénicos , Neovascularización Fisiológica/efectos de los fármacos , Receptor TIE-2/genética , Regeneración/efectos de los fármacos , Espectrometría de Masas en TándemRESUMEN
The anemia of sickle cell disease is associated with a severe inflammatory vasculopathy and endothelial dysfunction, which leads to painful and life-threatening clinical complications. Growing evidence supports the anti-inflammatory properties of ω-3 fatty acids in clinical models of endothelial dysfunction. Promising but limited studies show potential therapeutic effects of ω-3 fatty acid supplementation in sickle cell disease. Here, we treated humanized healthy and sickle cell mice for 6 weeks with ω-3 fatty acid diet (fish-oil diet). We found that a ω-3 fatty acid diet: (i) normalizes red cell membrane ω-6/ω-3 ratio; (ii) reduces neutrophil count; (iii) decreases endothelial activation by targeting endothelin-1 and (iv) improves left ventricular outflow tract dimensions. In a hypoxia-reoxygenation model of acute vaso-occlusive crisis, a ω-3 fatty acid diet reduced systemic and local inflammation and protected against sickle cell-related end-organ injury. Using isolated aortas from sickle cell mice exposed to hypoxia-reoxygenation, we demonstrated a direct impact of a ω-3 fatty acid diet on vascular activation, inflammation, and anti-oxidant systems. Our data provide the rationale for ω-3 dietary supplementation as a therapeutic intervention to reduce vascular dysfunction in sickle cell disease.
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Anemia de Células Falciformes/dietoterapia , Antiinflamatorios/farmacología , Vasos Sanguíneos/efectos de los fármacos , Suplementos Dietéticos , Ácidos Grasos Omega-3/farmacología , Anemia de Células Falciformes/metabolismo , Anemia de Células Falciformes/patología , Animales , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/patología , Modelos Animales de Enfermedad , Endotelina-1/antagonistas & inhibidores , Endotelina-1/biosíntesis , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Endotelio Vascular/patología , Membrana Eritrocítica/efectos de los fármacos , Membrana Eritrocítica/patología , Humanos , Hipoxia/dietoterapia , Hipoxia/metabolismo , Hipoxia/patología , Ratones , Ratones Transgénicos , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Neutrófilos/patología , Oxígeno/efectos adversosRESUMEN
OBJECTIVES: The objective of this study was to describe our single-institution experience with prenatal atrial septal stent placement for fetuses with hypoplastic left heart syndrome and an intact atrial septum (HLHS/IAS). BACKGROUND: Infants born with HLHS/IAS are at high risk for neonatal death, despite maximal postnatal therapy. Prenatal atrial septoplasty by static balloon dilation has been effective in decompressing the left atrium (LA) in utero, but several factors have limited the size of septal defects. We attempted to overcome the limitations of balloon septoplasty using transcatheter atrial septal stents. METHODS: All records from our institution of fetuses with HLHS/IAS that underwent prenatal atrial septal stent placement were reviewed, including operative notes and echocardiograms. RESULTS: Nine fetuses between 24 and 31 weeks gestation with HLHS/IAS underwent attempted fetal atrial septal stent placement. A stent was deployed across the atrial septum in five fetuses, with four fetuses demonstrating flow across the stent at the time of intervention. In four cases, stent placement failed due to malposition or embolization, but in three of the four cases, atrial balloon septoplasty at the same in-utero procedure successfully and acutely decompressed the LA. There were no maternal complications. There was one fetal demise. The remaining eight fetuses survived to delivery, but four died in the neonatal period (two of which had been stented). CONCLUSIONS: Ultrasound-guided atrial septal stent placement is feasible in some fetuses with HLHS/IAS. Visualization of the septum and catheter tip is critical to technical success. Additional experience is necessary to determine the clinical impact of this intervention. © 2013 Wiley Periodicals, Inc.
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Tabique Interatrial/cirugía , Cateterismo Cardíaco/métodos , Corazón Fetal/cirugía , Defectos del Tabique Interatrial/cirugía , Síndrome del Corazón Izquierdo Hipoplásico/cirugía , Stents , Tabique Interatrial/diagnóstico por imagen , Tabique Interatrial/embriología , Ecocardiografía Doppler , Femenino , Corazón Fetal/diagnóstico por imagen , Estudios de Seguimiento , Edad Gestacional , Defectos del Tabique Interatrial/diagnóstico por imagen , Defectos del Tabique Interatrial/embriología , Humanos , Síndrome del Corazón Izquierdo Hipoplásico/diagnóstico por imagen , Síndrome del Corazón Izquierdo Hipoplásico/embriología , Embarazo , Diseño de Prótesis , Resultado del Tratamiento , Ultrasonografía PrenatalRESUMEN
BACKGROUND: To determine the effect of docosahexaenoic acid (DHA) on the growth of human melanoma in vitro and in vivo and to better understand the potential role of the G protein-coupled receptors (GPRs) in mediating this effect. MATERIALS AND METHODS: For in vitro studies, human melanoma and control fibroblast cells were treated with DHA and TAK-875 (selective GPR40 agonist) and a cell viability assay was performed to determine cell counts. A murine subcutaneous xenograft model of human melanoma was used to test the effect of dietary treatment with an omega-3 fatty acid (FA) rich diet compared with an omega-6 FA rich diet on the growth of human melanoma in vivo. A similar animal model was used to test the effect of oral TAK-875 on the growth of established melanoma tumors in vivo. RESULTS: DHA has an inhibitory effect on the growth of human melanoma both in vitro and in vivo. Tumors from animals on the omega-3 FA rich diet were 69% smaller in weight (P = 0.005) and 76% smaller in volume compared with tumors from animals on the omega-6 FA rich diet. TAK-875 has an inhibitory effect on the growth of human melanoma both in vitro and in vivo. Tumors from animals treated with TAK-875 were 46% smaller in weight (P = 0.07), 62% smaller in volume (P = 0.03), and grew 77% slower (P = 0.04) compared with the placebo group. CONCLUSIONS: DHA and TAK-875 have a profound and selective inhibitory effect on the growth of human melanoma both in vitro and in vivo.
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Benzofuranos/uso terapéutico , Ácidos Docosahexaenoicos/uso terapéutico , Melanoma Experimental/dietoterapia , Melanoma Experimental/tratamiento farmacológico , Receptores Acoplados a Proteínas G/metabolismo , Sulfonas/uso terapéutico , Animales , Benzofuranos/farmacología , Línea Celular Tumoral , Ácidos Docosahexaenoicos/farmacología , Humanos , Melanoma Experimental/metabolismo , Ratones , Receptores Acoplados a Proteínas G/agonistas , Sulfonas/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Childhood blood pressure (BP) is an important determinant of adult cardiovascular disease. Prenatal exposure to methylmercury through maternal fish consumption has been reported to increase the BP of children years later. METHODS: Mother-child pairs were enrolled from Project Viva, a prospective cohort study in Massachusetts. From second trimester maternal blood samples, we measured erythrocyte mercury concentration. Systolic BP in children, measured up to 5 times per visit in early and mid-childhood (median ages 3.2 and 7.7 years), was the primary outcome. We used mixed-effect regression models to account for variation in the number of BP measurements and to average effects over both time points. RESULTS: Among 1103 mother-child pairs, mean (SD) second trimester total erythrocyte mercury concentration was 4.0 (3.9)ng/g among mothers whose children were assessed in early childhood and 4.0 (4.0)ng/g for children assessed in mid-childhood. Mean (SD) offspring systolic BP was 92.1 (10.4)mm Hg in early childhood and 94.3 (8.4)mm Hg in mid-childhood. After adjusting for mother and infant characteristics, mean second trimester blood mercury concentration was not associated with child systolic BP (regression coefficient, 0.1mm Hg; 95% CI, -1.3 to 1.5 for quartile 4 vs. quartile 1) at either time period. Further adjusting for second trimester maternal fish consumption, as well as docosahexaenoic acid and eicosapentaenoic acid consumption, did not substantially change the estimates. CONCLUSIONS: The results of this study demonstrate an absence of association between childhood blood pressure and low-level mercury exposure typical of the general US population.
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Presión Sanguínea/efectos de los fármacos , Compuestos de Metilmercurio/envenenamiento , Efectos Tardíos de la Exposición Prenatal/sangre , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Adulto , Niño , Preescolar , Femenino , Sangre Fetal/fisiología , Humanos , Masculino , Exposición Materna , Compuestos de Metilmercurio/sangre , Embarazo , Estudios ProspectivosRESUMEN
The mammalian central nervous system coordinates a network of signaling pathways and cellular interactions, which enable a myriad of complex cognitive and physiological functions. While traditional efforts to understand the molecular basis of brain function have focused on well-characterized proteins, recent advances in high-throughput translatome profiling have revealed a staggering number of proteins translated from non-canonical open reading frames (ncORFs) such as 5' and 3' untranslated regions of annotated proteins, out-of-frame internal ORFs, and previously annotated non-coding RNAs. Of note, microproteins < 100 amino acids (AA) that are translated from such ncORFs have often been neglected due to computational and biochemical challenges. Thousands of putative microproteins have been identified in cell lines and tissues including the brain, with some serving critical biological functions. In this perspective, we highlight the recent discovery of microproteins in the brain and describe several hypotheses that have emerged concerning microprotein function in the developing and mature nervous system.
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OBJECTIVE: Blood product transfusion is a common practice in infants with hypoxic-ischemic encephalopathy (HIE) undoing therapeutic hypothermia (TH). The advantages and disadvantages of conservative or liberal transfusion practices in this fragile population are unknown. Study aims to characterize the transfusion practices in infants with HIE and investigate the association with outcome. STUDY DESIGN: We conducted a retrospective cohort study at a single level IV NICU, evaluating transfusion thresholds, as well as the association between hematological abnormalities or blood product transfusions and outcomes in infants admitted with HIE. RESULT: By univariate analysis, FFP transfusion was associated with increased in-hospital death. However, multivariate analysis adjusting for HIE severity demonstrated no association between hematological abnormality or blood product transfusion and death, nor with neurodevelopmental impairment. CONCLUSION: No association was found between hematological blood product transfusion and death or neurodevelopmental impairment in a retrospective single NICU study of infants with HIE.
RESUMEN
Antenatal administration of extracellular vesicles from amniotic fluid stem cells (AFSC-EVs) reverses features of pulmonary hypoplasia in models of congenital diaphragmatic hernia (CDH). However, it remains unknown which lung cellular compartments and biological pathways are affected by AFSC-EV therapy. Herein, we conducted single-nucleus RNA sequencing (snRNA-seq) on rat fetal CDH lungs treated with vehicle or AFSC-EVs. We identified that intra-amniotically injected AFSC-EVs reach the fetal lung in rats with CDH, where they promote lung branching morphogenesis and epithelial cell differentiation. Moreover, snRNA-seq revealed that rat fetal CDH lungs have a multilineage inflammatory signature with macrophage enrichment, which is reversed by AFSC-EV treatment. Macrophage enrichment in CDH fetal rat lungs was confirmed by immunofluorescence, flow cytometry, and inhibition studies with GW2580. Moreover, we validated macrophage enrichment in human fetal CDH lung autopsy samples. Together, this study advances knowledge on the pathogenesis of pulmonary hypoplasia and further evidence on the value of an EV-based therapy for CDH fetuses.
Asunto(s)
Líquido Amniótico , Vesículas Extracelulares , Pulmón , Vesículas Extracelulares/metabolismo , Animales , Líquido Amniótico/citología , Líquido Amniótico/metabolismo , Pulmón/patología , Pulmón/metabolismo , Ratas , Humanos , Células Madre/metabolismo , Inflamación/metabolismo , Inflamación/patología , Hernias Diafragmáticas Congénitas/metabolismo , Hernias Diafragmáticas Congénitas/patología , Hernias Diafragmáticas Congénitas/terapia , Femenino , Macrófagos/metabolismo , Modelos Animales de Enfermedad , Diferenciación Celular , Feto , Embarazo , Trasplante de Células Madre/métodosRESUMEN
Parenteral nutrition (PN)-associated liver disease (PNALD) is a life-threatening complication of the administration of PN. The development of PNALD may be partly due to the composition of the lipid emulsion administered with PN: soybean oil-based lipid emulsions (SOLE) are associated with liver disease, while fish oil-based lipid emulsions (FOLE) are associated with prevention and improvement of liver disease. The objective of this study was to determine how the choice of lipid emulsion modified the production of bioactive lipid mediators (LMs). We utilized a mouse model of steatosis to study the differential effect of FOLE and SOLE. We subsequently validated these results in serum samples from a small cohort of human infants transitioning from SOLE to FOLE. In mice, FOLE was associated with production of anti-inflammatory, proresolving LMs; SOLE was associated with increased production of inflammatory LMs. In human infants, the transition from SOLE to FOLE was associated with a shift toward a proresolving lipidome. Together, these results demonstrate that the composition of the lipid emulsion directly modifies inflammatory homeostasis.