Origins and Proliferative States of Human Oligodendrocyte Precursor Cells.

Human cerebral cortex size and complexity has increased greatly during evolution. While increased progenitor diversity and enhanced proliferative potential play important roles in human neurogenesis and gray matter expansion, the mechanisms of human oligodendrogenesis and white matter expansion remain largely unknown. Here, we identify EGFR-expressing "Pre-OPCs" that originate from outer radial glial cells (oRGs) and undergo mitotic somal translocation (MST) during division. oRG-derived Pre-OPCs provide an additional source of human cortical oligodendrocyte precursor cells (OPCs) and define a lineage trajectory. We further show that human OPCs undergo consecutive symmetric divisions to exponentially increase the progenitor pool size. Additionally, we find that the OPC-enriched gene, PCDH15, mediates daughter cell repulsion and facilitates proliferation. These findings indicate properties of OPC derivation, proliferation, and dispersion important for human white matter expansion and myelination.

Growth Failure Prevalence in Neonates with Gastroschisis : A Statewide Cohort Study.

OBJECTIVES: To perform a multicenter study to assess growth failure in hospitalized infants with gastroschisis. STUDY DESIGN: This study included neonates with gastroschisis within sites in the University of California Fetal Consortium. The study's primary outcome was growth failure at hospital discharge, defined as a weight or length z score decrease >0.8 from birth. Regression analysis was performed to assess changes in z scores over time. RESULTS: Among 125 infants with gastroschisis, the median gestational age was 37 weeks (IQR 35-37). Length of stay was 32 days (23-60); 55% developed weight or length growth failure at discharge (28% had weight growth failure, 42% had length growth failure, and 15% had both weight and length growth failure). Weight and length z scores at 14 days, 30 days, and discharge were less than birth (P < .01 for all). Weight and length z scores declined from birth to 30 days (-0.10 and -0.11 z score units/week, respectively, P < .001). Length growth failure at discharge was associated with weight and length z score changes over time (P < .05 for both). Lower gestational age was associated with weight growth failure (OR 0.70 for each gestational age week, 95% CI 0.55-0.89, P = .004). CONCLUSIONS: Growth failure, in particular linear growth failure, is common in infants with gastroschisis. These data suggest the need to improve nutritional management in these infants.

Nonimmune hydrops fetalis: identifying the underlying genetic etiology.

PURPOSE: Numerous etiologies may lead to nonimmune hydrops fetalis (NIHF), and the underlying cause often remains unclear. We aimed to determine the proportion of NIHF cases in which the etiology was clearly determined in a large, contemporary, and diverse cohort, as well as to describe the etiologies with a focus on genetic causes. METHODS: Retrospective review of NIHF cases between 2015 and 2017 from the five University of California Fetal-Maternal Consortium sites. Singleton pregnancies with prenatally diagnosed NIHF were included, and cases with maternal alloimmunization were excluded. Cases were categorized as being of confirmed, suspected, or unknown etiology. RESULTS: Sixty-five NIHF cases were identified. Forty-six percent (30/65) remained of unknown etiology, while 9.2% (6/65) had a suspected etiology and 44.6% (29/65) were of confirmed etiology. Among confirmed cases, 11 resulted from aneuploidy; 7 from fetal structural anomalies; 2 each from fetal arrhythmia, Noonan syndrome, and generalized lymphatic dysplasia; and 1 each from arthrogryposis, parvovirus, neonatal alloimmune thrombocytopenia, fetal goiter, and Kasabach-Merritt syndrome. CONCLUSION: In this contemporary, multicenter study, the cause of prenatally diagnosed NIHF was confirmed in only 44% of cases, and a genetic etiology was found in only 25% of those that received standard of care genetic testing.

Comorbidities and Late Outcomes in Neonatal Pulmonary Hypertension.

Long-term outcomes of persistent pulmonary hypertension of newborn (PPHN) depend on disease severity, duration of ventilation, and associated anomalies. Congenital diaphragmatic hernia survivors may have respiratory morbidities and developmental delay. The presence of PPHN is associated with increased mortality in hypoxic-ischemic encephalopathy, though the effects on neurodevelopment are less clear. Preterm infants can develop pulmonary hypertension (PH) early in the postnatal course or later in the setting of bronchopulmonary dysplasia (BPD). BPD-PH is associated with higher mortality, particularly within the first year. Evidence suggests that both early and late PH in preterm infants are associated with neurodevelopmental impairment.

Neonatal Seizures.

Neonatal seizures are common among patients with acute brain injury or critical illness and can be difficult to diagnose and treat. The most common etiology of neonatal seizures is hypoxic-ischemic encephalopathy, with other common causes including ischemic stroke and intracranial hemorrhage. Neonatal clinicians can use a standardized approach to patients with suspected or confirmed neonatal seizures that entails laboratory testing, neuromonitoring, and brain imaging. The primary goals of management of neonatal seizures are to identify the underlying cause, correct it if possible, and prevent further brain injury. This article reviews recent evidence-based guidelines for the treatment of neonatal seizures and discusses the long-term outcomes of patients with neonatal seizures.

Association between consensus-based nutrition pathway and growth faltering in infants with gastroschisis: A retrospective cohort study.

BACKGROUND: The University of California Fetal Consortium published that 55% of infants with gastroschisis develop growth faltering by hospital discharge. To address this problem, we developed a nutrition pathway emphasizing (1) early provision of parenteral macronutrients, (2) use of human milk, and (3) growth faltering treatment. This study's goals were to assess adherence to and efficacy of this pathway in infants with gastroschisis across six California hospitals. METHODS: In 2015, the consortium standardized the care for infants with gastroschisis. To decrease growth faltering rates, between 2019 and 2020, nutrition guidelines were proposed, discussed, revised, and initiated. This study's primary outcome was weight or linear growth faltering (z score decline ≥0.8 in weight or length) at hospital discharge. Adherence measures were assessed. RESULTS: One hundred twenty-six infants with gastroschisis were born prepathway; 52 were born postpathway. Median gestational age was similar between cohorts. Adherence to components of the pathway ranged from 58% to 95%. The proportion of infants with weight or linear growth faltering at discharge was lower after pathway initiation (59.4% vs 36.2%, P = 0.0068). Adjusting for gestational age and fetal growth restriction, the pathway was associated with decreased weight or linear growth faltering (odds ratio [OR] 0.35 [0.16-0.75], P = 0.0060) and decreased linear growth faltering (OR 0.24 [0.096-0.56], P = 0.0062) at discharge. Hypertriglyceridemia, cholestasis, and days to full feeds were similar to published cohorts. CONCLUSION: Fewer infants with gastroschisis experienced weight or length growth faltering at hospital discharge following the implementation of a multicenter nutrition pathway.

High continuous positive airway pressures versus non-invasive positive pressure ventilation in preterm neonates: protocol for a multicentre pilot randomised controlled trial.

INTRODUCTION: Low pressure nasal continuous positive airway pressure (nCPAP) has long been the mainstay of non-invasive respiratory support for preterm neonates, at a constant distending pressure of 5-8 cmH2O. When traditional nCPAP pressures are insufficient, other modes including nasal intermittent positive pressure ventilation (NIPPV) are used. In recent years, high nCPAP pressures (≥9 cmH2O) have also emerged as an alternative. However, the comparative benefits and risks of these modalities remain unknown. METHODS AND ANALYSIS: In this multicentre pilot randomised controlled trial, infants <29 weeks' gestational age (GA) who either: (A) fail treatment with traditional nCPAP or (B) being extubated from invasive mechanical ventilation with mean airway pressure ≥10 cmH2O, will be randomised to receive either high nCPAP (positive end-expiratory pressure 9-15 cmH2O) or NIPPV (target mean Paw 9-15 cmH2O). Primary outcome is feasibility of the conduct of a larger, definitive trial as assessed by rates of recruitment and protocol violations. The main secondary outcome is failure of assigned treatment within 7 days postrandomisation. Multiple other clinical outcomes including bronchopulmonary dysplasia will be ascertained. All randomised participants will be analysed using intention to treat. Baseline and demographic variables as well as outcomes will be summarised and compared using univariate analyses, and a p<0.05 will be considered significant. ETHICS AND DISSEMINATION: The trial has been approved by the respective research ethics boards at each institution (McMaster Children's Hospital: Hamilton integrated REB approval #2113; Royal Alexandra Hospital: Health Research Ethics Board approval ID Pro00090244; Westmead Hospital: Human Research Ethics Committee approval ID 2022/ETH01343). Written, informed consent will be obtained from all parents/guardians prior to study enrolment. The findings of this pilot study will be disseminated via presentations at national and international conferences and via publication in a peer-reviewed journal. Social media platforms including Twitter will also be used to generate awareness. TRIAL REGISTRATION NUMBER: NCT03512158.

Adherence to and outcomes of a University-Consortium gastroschisis pathway.

BACKGROUND: Our multi-institutional university consortium implemented a gastroschisis pathway in 2015 to standardize and improve care by promoting avoidance of routine intubation and paralysis during silo placement, expeditious abdominal wall closure, discontinuation of antibiotics/narcotics within 48 h of closure, and early initiation/advancement of feeds. METHODS: Adherence to the gastroschisis pathway was prospectively monitored. Outcomes for the contemporary cohort (2015-2018) were compared with a historical cohort (2007-2012). RESULTS: Good adherence to the pathway was observed for 70 cases of inborn uncomplicated gastroschisis. The contemporary cohort had significantly lower median mechanical ventilator days (2 versus 5; p < 0.01) and antibiotic days (5.5 versus 9; p < 0.01) as well as earlier days to initiation of feeds (12 versus 15; p < 0.01). However, no differences were observed in length of stay (28 versus 29 days; p = 0.70). A skin closure technique was performed in 66% of the patients, of which 46% were performed at bedside without intubation, the assistance of an operating-room team, or general anesthesia. CONCLUSION: In this study, adherence to a clinical pathway for gastroschisis across different facilities was feasible and led to reduction in exposure to mechanical ventilation and antibiotics. The adoption of a bedside skin closure technique appears to facilitate compliance with the pathway. LEVEL OF EVIDENCE: Level II/III TYPE OF STUDY: Prospective comparative study with historical cohort.

The Impact of Telemedicine on Transfer Rates of Newborns at Rural Community Hospitals.

BACKGROUND AND OBJECTIVE: Telemedicine may have the ability to reduce avoidable transfers by allowing remote specialists the opportunity to more effectively assess patients during consultations. In this study, we examined whether telemedicine consultations were associated with reduced transfer rates compared to telephone consultations among a cohort of term and late preterm newborns. We hypothesized that neonatologist consultations conducted over telemedicine would result in fewer interfacility transfers than consultations conducted over telephone. METHODS: We collected data on all newborns who received a neonatal telemedicine or telephone consultation at 6 rural hospitals in northern and central California between August 2014 and June 2018. We used adjusted analyses to compare transfer rates between telemedicine and telephone cohorts. RESULTS: A total of 317 patients were included in the analysis; 89 (28.1%) of these patients received a telemedicine consultation and 228 (71.9%) received a telephone consultation only. The overall transfer rate was 77.0%. Patient consultations conducted using telemedicine were significantly less likely to result in a transfer than patient consultations conducted using the telephone (64.0% vs 82.0%, P = .001). After controlling for 5-minute Apgar score, birthweight, gestational age, site of consultation, and Transport Risk Index of Physiologic Stability score, the odds of transfer for telemedicine consultations was 0.48 (95% confidence interval: 0.26, 0.90, P = .02). CONCLUSIONS: Our findings suggest that telemedicine may have the potential to reduce potentially avoidable transfers of term and late preterm newborns. Future research on potentially avoidable transfers and patient outcomes is needed to better understand the ways in which telemedicine affects clinical decision-making.

Pbx3 is required for normal locomotion and dorsal horn development.

The transcription cofactor Pbx3 is critical for the function of hindbrain circuits controlling respiration in mammals, but the perinatal lethality caused by constitutively null mutations has hampered investigation of other roles it may play in neural development and function. Here we report that the conditional loss of Pbx3 function in most tissues caudal to the hindbrain resulted in progressive deficits of posture, locomotion, and sensation that became apparent during adolescence. In adult mutants, the size of the dorsal horn of the spinal cord and the numbers of calbindin-, PKC-gamma, and calretinin-expressing neurons in laminae I-III were markedly reduced, but the ventral cord and peripheral nervous system appeared normal. In the embryonic dorsal horn, Pbx3 expression was restricted to a subset of glutamatergic neurons, but its absence did not affect the initial balance of excitatory and inhibitory interneuron phenotypes. By embryonic day 15 a subset of Meis(+) glutamatergic neurons assumed abnormally superficial positions and the number of calbindin(+) neurons was increased three-fold in the mutants. Loss of Pbx3 function thus leads to the incorrect specification of some glutamatergic neurons in the dorsal horn and alters the integration of peripheral sensation into the spinal circuitry regulating locomotion.

Amyloid-beta, tau alterations and mitochondrial dysfunction in Alzheimer disease: the chickens or the eggs?

Alzheimer disease (AD) is defined pathologically and diagnostically defined by amyloid-beta senile plaques and neurofibrillary tangles (NFT) composed of tau. From the time of their original description nearly a century ago, a major focus has been to understand the role that these lesions play in the pathogenesis of the disease. The majority favors the notion that these lesions cause the disease and therefore attempts at therapeutic intervention are focused on preventing lesions formation. However, this rationale may be misguided since new evidence from our laboratories and others suggest that the lesions not only occur as a by-product of the fundamental disease process but also that they may be protective.

The role of iron and copper in the aetiology of neurodegenerative disorders: therapeutic implications.

Abnormalities in the metabolism of the transition metals iron and copper have been demonstrated to play a crucial role in the pathogenesis of various neurodegenerative diseases. Metal homeostasis as it pertains to alterations in brain function in neurodegenerative diseases is reviewed in this article in depth. While there is documented evidence for alterations in the homeostasis, redox-activity and localisation of transition metals, it is also important to realise that alterations in specific copper- and iron-containing metalloenzymes appear to play a crucial role in the neurodegenerative process. These changes provide the opportunity to identify pathways where modification of the disease process can occur, potentially offering opportunities for clinical intervention. As understanding of disease aetiology evolves, so do the tools with which diseases are treated. In this article, we examine not only the possible mechanism of disease but also how pharmaceuticals may intervene, from direct and indirect antioxidant therapy to strategies involving gene therapy.

The state versus amyloid-beta: the trial of the most wanted criminal in Alzheimer disease.

Investigators studying the primary culprit responsible for Alzheimer disease have, for the past two decades, primarily focused on amyloid-beta (Abeta). Here, we put Abeta on trial and review evidence amassed by the prosecution that implicate Abeta and also consider arguments and evidence gathered by the defense team who are convinced of the innocence of their client. As in all trials, the arguments provided by the prosecution and defense revolve around the same evidence, with opposing interpretations. Below, we present a brief synopsis of the trial for you, the jury, to decide the verdict. Amyloid-beta: guilty or not-guilty?

Sonic hedgehog is a potent inducer of rat oligodendrocyte development from cortical precursors in vitro.

Sonic Hedgehog (Shh) induces oligodendrocyte development in the ventral neural tube and telencephalon but its role in oligodendrocyte generation in dorsal telencephalon is debated. Transcripts for Shh and its receptor complex were detected in subventricular zone and neocortex from E17 to birth. As Shh is not yet expressed in E15 neocortex, we grew E15 cortical precursors (CP) into neurospheres in the presence of recombinant Octyl-Shh (O-Shh). After sphere adhesion and removal of O-Shh, enhanced neurite outgrowth and cell migration were already observed at 3 h. Three days after O-Shh treatment, oligodendrocyte progenitors (OP) emerged and continued to increase in number for 7 days while the ratio of neuronal cells decreased compared to control. Shh selectively triggered mitosis of OP but not neuronal progenitors and enhanced growth of neonatal OP. Thus Shh in E15-17 embryonic neocortex can signal CP to adopt an oligodendrocyte fate and favors expansion of this lineage.