The most conserved part of the vertebrate dopaminergic system is the orthopedia (otp)-expressing diencephalic neuronal population that constitutes the dopaminergic diencephalospinal tract (DDT). ...Although studies in the neonatal murine spinal cord in vitro suggest an early locomotor role of the DDT, the function of the DDT in developing vertebrates in vivo remains unknown. Here, we investigated the role of the DDT in the locomotor development of zebrafish larvae. To assess the development of the behavioral and neural locomotor pattern, we used high-throughput video tracking in combination with peripheral nerve recordings. We found a behavioral and neural correspondence in the developmental switch from an immature to mature locomotor pattern. Blocking endogenous dopamine receptor 4 (D(4)R) signaling in vivo either before or after the developmental switch prevented or reversed the switch, respectively. Spinal transections of post-switch larvae reestablished the immature locomotor pattern, which was rescued to a mature-like pattern via spinal D(4)R agonism. Selective chemogenetic ablation of otp b (otpb) neurons that contribute to the DDT perpetuated the immature locomotor pattern in vivo. This phenotype was recapitulated by diencephalic transections that removed the dopaminergic otpb population and was rescued to a mature-like locomotor pattern by D(4)R agonism. We conclude that the dopaminergic otpb population, via the DDT, is responsible for spinal D(4)R signaling to mediate the developmental switch to the mature locomotor pattern of zebrafish. These results, integrated with the mammalian literature, suggest that the DDT represents an evolutionarily conserved neuromodulatory system that is necessary for normal vertebrate locomotor development.
Care advances in the United States (US) have led to improved survival of children with neurological impairment (NI). Children with NI may account for an increasing proportion of hospital resources. ...However, this assumption has not been tested at a national level.
We conducted a study of 25,747,016 US hospitalizations of children recorded in the Kids' Inpatient Database (years 1997, 2000, 2003, and 2006). Children with NI were identified with International Classification of Diseases, 9th Revision, Clinical Modification diagnoses resulting in functional and/or intellectual impairment. We assessed trends in inpatient resource utilization for children with NI with a Mantel-Haenszel chi-square test using all 4 y of data combined. Across the 4 y combined, children with NI accounted for 5.2% (1,338,590) of all hospitalizations. Epilepsy (52.2% n = 538,978) and cerebral palsy (15.9% n = 164,665) were the most prevalent NI diagnoses. The proportion of hospitalizations attributable to children with NI did not change significantly (p = 0.32) over time. In 2006, children with NI accounted for 5.3% (n = 345,621) of all hospitalizations, 13.9% (n = 3.4 million) of bed days, and 21.6% (US$17.7 billion) of all hospital charges within all hospitals. Over time, the proportion of hospitalizations attributable to children with NI decreased within non-children's hospitals (3.0% n = 146,324 in 1997 to 2.5% n = 113,097 in 2006, p<.001) and increased within children's hospitals (11.7% n = 179,324 in 1997 to 13.5% n = 209,708 in 2006, p<0.001). In 2006, children with NI accounted for 24.7% (2.1 million) of bed days and 29.0% (US$12.0 billion) of hospital charges within children's hospitals.
Children with NI account for a substantial proportion of inpatient resources utilized in the US. Their impact is growing within children's hospitals. We must ensure that the current health care system is staffed, educated, and equipped to serve this growing segment of vulnerable children.
Postembryonic neurogenesis has been observed in several regions of the vertebrate brain, including the dentate gyrus and rostral migratory stream in mammals, and is required for normal behavior 1–3. ...Recently, the hypothalamus has also been shown to undergo continuous neurogenesis as a way to mediate energy balance 4–10. As the hypothalamus regulates multiple functional outputs, it is likely that additional behaviors may be affected by postembryonic neurogenesis in this brain structure. Here, we have identified a progenitor population in the zebrafish hypothalamus that continuously generates neurons that express tyrosine hydroxylase 2 (th2). We develop and use novel transgenic tools to characterize the lineage of th2+ cells and demonstrate that they are dopaminergic. Through genetic ablation and optogenetic activation, we then show that th2+ neurons modulate the initiation of swimming behavior in zebrafish larvae. Finally, we find that the generation of new th2+ neurons following ablation correlates with restoration of normal behavior. This work thus identifies for the first time a population of dopaminergic neurons that regulates motor behavior capable of functional recovery.
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•Dopaminergic th2+ neurons in the zebrafish hypothalamus arise from Dlx+ precursors•th2+ neurons are continuously generated into adulthood and recover after ablation•Swim frequency is decreased by ablation and increased by activation of th2+ neurons•Recovery of th2+ neurons correlates with restoration of swim behavior
McPherson et al. show that dopaminergic th2+ neurons in zebrafish are continuously generated into adulthood and use opto- and pharmacogenetic techniques to demonstrate their function in swimming. They find that recovery of th2+ neurons after ablation correlates with the restoration of normal swimming behavior.
Objectives
Cerebral X-linked adrenoleukodystrophy (cALD) is an inflammatory demyelination of the brain that can lead to death unless treated by hematopoietic stem cell transplantation. Survival and ...improved outcomes for cerebral adrenoleukodystrophy are associated with hematopoietic stem cell transplantation at earliest evidence of disease on magnetic resonance imaging (MRI). Our goal was to determine average duration between diagnosis of cALD and hematopoietic stem cell transplantation.
Methods
This was a retrospective review of data of patients aged 18 years or younger, using a nationwide administrative health care database (Pediatric Health Information System), with an International Classification of Diseases, Tenth Revision (ICD-10) diagnosis of adrenoleukodystrophy. Time range was October 1, 2015, through June 30, 2021. We determined time to hematopoietic stem cell transplantation by duration between index brain MRI and a code for hematopoietic stem cell transplantation.
Results
We identified 27 patients with cerebral adrenoleukodystrophy. Total charges for the cohort was $53 million. Time to transplant averaged 97 days. For Hispanic patients, time to transplant was 117 days, compared with 80 days for White, non-Hispanic patients. Comparison of different hospitals showed significant variability in time to hematopoietic stem cell transplantation.
Discussion
We found that time to hematopoietic stem cell transplantation was >3 months for patients with cerebral adrenoleukodystrophy in the hospitals we evaluated. We noted differences in average time by race/ethnicity and by hospital. Our findings suggest opportunity to reduce time to transplant in cerebral adrenoleukodystrophy.
To describe the usefulness of rapid whole genome sequencing (rWGS) in a cohort of children presenting with acute liver dysfunction.
This was a retrospective, population-based cohort study conducted ...at Primary Children's Hospital in Salt Lake City, Utah. Children meeting criteria for acute liver dysfunction who received rWGS between August 2019 and December 2021 were included. rWGS was performed on blood samples from the patient and parents (1 or both depending on availability). The clinical characteristics of patients with positive rWGS results were compared with those with negative results.
Eighteen patients with pediatric acute liver dysfunction who had rWGS were identified. The median turnaround time from the date rWGS testing was ordered to the date an initial report was received was 8 days with a shorter turnaround time in patients with a diagnostic rWGS (4 days vs 10 days; P = .03). A diagnostic result was identified in 7 of 18 patients (39%). Subsequently, 4 patients in this cohort, who had negative rWGS results, were found to have a toxic exposure accounting for their liver dysfunction. With removal of these patients, the diagnostic rate of rWGS was 7 of 14 (50%). The use of rWGS led to a change in management for 6 of 18 patients (33%).
We found that rWGS provided a diagnosis in up to 50% of pediatric acute liver dysfunction. rWGS allows for higher diagnostic rates in an expedited fashion that affects clinical management. These data support the routine use of rWGS for life-threatening disorders in children, specifically acute liver dysfunction.
Hypoxic injury to the developing brain increases the risk of permanent behavioral deficits, but the precise mechanisms of hypoxic injury to the developing nervous system are poorly understood. In ...this study, we characterized the effects of developmental hypoxia (1% pO
2
from 24 to 48 h post-fertilization, hpf) on diencephalic dopaminergic (DA) neurons in larval zebrafish and the consequences on the development of swimming behavior. Hypoxia reduced the number of diencephalic DA neurons at 48 hpf. Returning zebrafish larvae to normoxia after the hypoxia (i.e., hypoxia-recovery, HR) induced reactive oxygen species (ROS) accumulation. Real-time qPCR results showed that HR caused upregulation of proapoptotic genes, including
p53
and
caspase3
, suggesting the potential for ROS-induced cell death. With HR, we also found an increase in TUNEL-positive DA neurons, a persistent reduction in the number of diencephalic DA neurons, and disrupted swimming development and behavior. Interestingly, post-hypoxia (HR) with the antioxidant N-acetylcysteine partially restored the number of DA neurons and spontaneous swimming behavior, demonstrating potential recovery from hypoxic injury. The present study provides new insights for understanding the mechanisms responsible for motor disability due to developmental hypoxic injury.
Objective:
The purpose of our study was to understand the healthcare burden and incidence of Krabbe disease (Krabbe).
Methods:
Retrospective analysis of Krabbe patients identified October 1, 2015 ...through December 31, 2020, ages birth through age 3, evaluated in two national databases. We estimated point prevalence and incidence from year 2016 data.
Results:
We identified 98 unique Krabbe patients with 736 visits including 260 were inpatient admissions. Total healthcare charges were $51.5 million dollars. We determined a point prevalence of 34 68 Krabbe patients in 2016 ages 0 3 years. This estimates a birth incidence of ~1 in 310,000 live births. Significance: Krabbe disease patients had over $51 million in health care charges and hundreds of hospitalizations. Estimated prevalence and birth incidence is similar to rates observed from newborn screening. Our findings show the tremendous health impacts of Krabbe disease, and provide guidance for efforts in screening and treatment planning.
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