Cerebellar Purkinje cell activity regulates white matter response and locomotor function after neonatal hypoxia.

Neonatal hypoxia (Hx) causes white matter (WM) injury, particularly in the cerebellum. We previously demonstrated Hx-induced reduction of cerebellar Purkinje cell (PC) activity results in locomotor deficits. Yet, the mechanism of Hx-induced cerebellar WM injury and associated locomotor abnormalities remains undetermined.

Mesenchymal stem cell-derived small extracellular vesicles alleviate the immunometabolic dysfunction in murine septic encephalopathy.

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection that results in high mortality and long-term sequela. The central nervous system (CNS) is susceptible to injury from infectious processes, which can lead to clinical symptoms of septic encephalopathy (SE). SE is linked to a profound energetic deficit associated with immune dysregulation.

Hypercapnia Causes Injury of the Cerebral Cortex and Cognitive Deficits in Newborn Piglets.

In critically ill newborns, exposure to hypercapnia (HC) is common and often accepted in neonatal intensive care units to prevent severe lung injury. However, as a "safe" range of arterial partial pressure of carbon dioxide levels in neonates has not been established, the potential impact of HC on the neurodevelopmental outcomes in these newborns remains a matter of concern. Here, in a newborn Yorkshire piglet model of either sex, we show that acute exposure to HC induced persistent cortical neuronal injury, associated cognitive and learning deficits, and long-term suppression of cortical electroencephalogram frequencies.

Neuroprotective effect of Src kinase in hypoxia-ischemia: A systematic review.

Background: Hypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal morbidity and mortality worldwide. While the application of therapeutic hypothermia has improved neurodevelopmental outcomes for some survivors of HIE, this lone treatment option is only available to a subset of affected neonates. Src kinase, an enzyme central to the apoptotic cascade, is a potential pharmacologic target to preserve typical brain development after HIE.

Computational analysis of cortical neuronal excitotoxicity in a large animal model of neonatal brain injury.

Background: Neonatal hypoxic brain injury is a major cause of intellectual and developmental disability. Hypoxia causes neuronal dysfunction and death in the developing cerebral cortex due to excitotoxic Ca-influx. In the translational piglet model of hypoxic encephalopathy, we have previously shown that hypoxia overactivates Ca/Calmodulin (CaM) signaling via Sarcoma (Src) kinase in cortical neurons, resulting in overexpression of proapoptotic genes.

Basal forebrain magnocellular cholinergic systems are damaged in mice following neonatal hypoxia-ischemia.

Neonatal hypoxic-ischemic encephalopathy (HIE) causes lifelong neurologic disability. Despite the use of therapeutic hypothermia, memory deficits and executive functions remain severely affected. Cholinergic neurotransmission from the basal forebrain to neocortex and hippocampus is central to higher cortical functions.

Placental endocrine function shapes cerebellar development and social behavior.

Compromised placental function or premature loss has been linked to diverse neurodevelopmental disorders. Here we show that placenta allopregnanolone (ALLO), a progesterone-derived GABA-A receptor (GABAR) modulator, reduction alters neurodevelopment in a sex-linked manner. A new conditional mouse model, in which the gene encoding ALLO's synthetic enzyme (akr1c14) is specifically deleted in trophoblasts, directly demonstrated that placental ALLO insufficiency led to cerebellar white matter abnormalities that correlated with autistic-like behavior only in male offspring.

Disruption of neonatal Purkinje cell function underlies injury-related learning deficits.

It is hypothesized that perinatal cerebellar injury leads to long-term functional deficits due to circuit dysmaturation. Using a novel integration of GCaMP6f fiber photometry with automated measurement of cerebellar behavior using the ErasmusLadder, we causally link cerebellar injury to altered Purkinje cell responses during maladaptive behavior. Chemogenetic inhibition of neonatal Purkinje cells is sufficient to phenocopy the effects of perinatal cerebellar injury.

Epidermal Growth Factor Receptor Inhibition Reverses Cellular and Transcriptomic Alterations Induced by Hypoxia in the Neonatal Piglet Brain.

Acute hypoxia (HX) causes extensive cellular damage in the developing human cerebral cortex. We found increased expression of activated-EGFR in affected cortical areas of neonates with HX and investigated its functional role in the piglet, which displays a highly evolved, gyrencephalic brain, with a human-like maturation pattern. In the piglet, HX-induced activation of EGFR and Ca/calmodulin kinase IV (CaMKIV) caused cell death and pathological alterations in neurons and glia.

Unexpected Synergy: Macrophages and Schwann Cells Modulate Pathology in a Newborn Disease through a Shared Substrate.

Krabbe disease is characterized by GALC deficiency and Schwann cell impairment. In a recent issue of Neuron, Weinstock et al. (2020) show that hematopoietic stem cell transplantation, an established therapy, improves pathology in a mouse model through an unexpected GALC-dependent mechanism, i.

Drugs for the Prevention and Treatment of Bronchopulmonary Dysplasia.

Rates of bronchopulmonary dysplasia (BPD) are increasing. After preterm birth, there are important developmental periods in which neonates are more vulnerable to stressful events. These periods are opportunities for pharmacologic interventions.

Placental programming of neuropsychiatric disease.

The placenta is vital for fetal growth, and compromised function is associated with abnormal development, especially of the brain. Linking placental function to brain development is a new field we have dubbed neuroplacentology. Approximately 380,000 infants in the United States each year abruptly lose placental support upon premature birth, and more than 10% of pregnancies are affected by more insidious placental dysfunction such as preeclampsia or infection.

Association between hemoglobin concentrations at discharge from the neonatal intensive care unit with markers of neurodevelopmental outcomes in premature neonates.

Background: Premature neonates are often subjected to multiple transfusions with red blood cells during their hospitalization in the neonatal intensive care unit (NICU). The hemoglobin threshold for transfusion prior to discharge from the NICU varies significantly among different centers. The aim of the present study is to investigate the association between hemoglobin concentration at discharge with neurodevelopmental outcomes in premature neonates.

Hospital-Acquired Hyponatremia in Children Following Hypotonic versus Isotonic Intravenous Fluids Infusion.

Hypotonic solutions have been used in pediatrics for maintenance of intravenous (IV) hydration. However, recent randomized control trials and cohort studies have raised significant concerns for association with hospital-acquired hyponatremia (HAH). The study aimed to assess whether the use of hypotonic parenteral solutions (PS) compared with isotonic PS is associated with increased HAH risk in children with common pediatric conditions.

The Neurodevelopmental Perspective of Surgical Necrotizing Enterocolitis: The Role of the Gut-Brain Axis.

This state-of-the-art review article aims to highlight the most recent evidence about the therapeutic options of surgical necrotizing enterocolitis, focusing on the molecular basis of the gut-brain axis in relevance to the neurodevelopmental outcomes of primary peritoneal drainage and primary laparotomy. Current evidence favors primary laparotomy over primary peritoneal drainage as regards neurodevelopment in the surgical treatment of necrotizing enterocolitis. The added exposure to inhalational anesthesia in infants undergoing primary laparotomy is an additional confounding variable but requires further study.

Effect of Src Kinase inhibition on Cytochrome c, Smac/DIABLO and Apoptosis Inducing Factor (AIF) Following Cerebral Hypoxia-Ischemia in Newborn Piglets.

We have previously shown that cerebral Hypoxia-ischemia (HI) results in activation of Src kinase in the newborn piglet brain. We investigated the regulatory mechanism by which the pre-apoptotic proteins translocate from mitochondria to the cytosol during HI through the Src kinase. Newborn piglets were divided into 3 groups (n = 5/group): normoxic (Nx), HI and HI pre-treated with Src kinase inhibitor PP2 (PP2 + HI).

Effect of Intranasally Delivered rh-VEGF165 on Angiogenesis Following Cerebral Hypoxia-Ischemia in the Cerebral Cortex of Newborn Piglets.

Background: Vascular endothelial growth factor (VEGF) stimulates vascular genesis and angiogenesis. Cerebral Hypoxia-Ischemia (HI) leads to the reduction of vasculature in the cerebral cortex of newborn piglets.

Objective: The present study tests the hypothesis that post-hypoxia intranasal administration of recombinant human VEGF (rh-VEGF165) for 3 days increases the vascular density in the cerebral cortex of newborn piglets without promoting neovascularization.

FAK-Src-paxillin system expression and disease outcome in human neuroblastoma.

Background: Neuroblastoma (NB) often presents with metastatic disease and poor survival. The need for new prognostic markers remains invaluable. The FAK-Src-Paxillin protein system is associated with aggressive phenotype in adult malignancies but is largely unexplored in pediatric NB.

Effect of Concurrent Src Kinase Inhibition with Short-Duration Hypothermia on Ca2+/Calmodulin Kinase IV Activity and Neuropathology after Hypoxia-Ischemia in the Newborn Swine Brain.

Background: Hypoxia-ischemia (HI) results in increased activation of Ca2+/calmodulin kinase IV (CaM kinase IV) mediated by Src kinase. Therapeutic hypothermia ameliorates neuronal injury in the newborn.

Hypothesis: Inhibition of Src kinase concurrently with hypothermia further attenuates the hypoxia-induced increased activation of CaM kinase IV compared with hypothermia alone.

Foreign body injuries in children: Are the younger siblings doomed?

Background And Objectives: Foreign body injury (FBI) is a considerable public health issue for children. Although the relationships of FBI with age, gender, and objects of injury have been studied, the extent to which other demographic factors influence FBI is unclear. We hypothesized that the risk for FBI increases with the number of children in the household.

Obesity as a Risk Factor for Urinary Tract Infection in Children.

Childhood obesity is a nationwide epidemic with an estimated 16% to 18% of children and adolescents qualifying as obese and another 21% to 24% considered overweight. Obesity has been linked to an increased risk of developing serious infections. Healthcare Cost and Utilization Project-Kids' Inpatient Database 2009 was queried to analyze national trends in patient encounters, specifically those listing patients as comorbid obese and then identified those with urinary tract infection (UTI) as primary or secondary diagnosis.