Joshua L. Bonkowsky

Axon routing across the midline controlled by the Drosophila Derailed receptor

In nervous systems with symmetry about the midline, many neurons project axons from one side to the other. Although several of the components controlling midline crossing have been identified, little is known about how axons choose the appropriate pathway when crossing. For example, in the Drosophila embryo axons cross the midline in one of two distinct tracts, the anterior or posterior commissure (AC or PC, respectively). Here we show that the Derailed (Drl) receptor tyrosine kinase is expressed by neurons that project in the AC, and that in the absence of Drl such neurons often project abnormally into the PC. Conversely, misexpression of Drl in PC neurons forces them to cross in the AC. The behaviour of Drl-misexpressing neurons and the in vivo binding pattern of a soluble Drl receptor probe indicate that Drl acts as a guidance receptor for a repellent ligand present in the PC. Our results show that Drl is a novel component in the control of midline crossing.

Hypoxaemia in acute respiratory and non-respiratory illnesses in neonates and children in a developing country

Aims: To determine, in sick neonates and children requiring admission to a hospital in the highlands of Papua New Guinea: (1) the incidence and severity of hypoxaemia; (2) the proportion with hypoxaemia who do not fulfil criteria for acute lower respiratory infection (ALRI); and (3) the power of clinical signs to predict hypoxaemia, according to age and disease category. Methods: Age dependent normal values for transcutaneous oxygen saturation (Spo2) were established in 218 well neonates and children in Goroka. A total of 491 sick neonates and children were then studied on presentation to the paediatric department at Goroka Hospital. Results: A total of 257 sick neonates and children (52%) were hypoxaemic. Hypoxaemia was present in 179/245 (73%) with clinical criteria for ALRI; 79/246 (32%) with non-ALRI illnesses (including meningitis, septicaemia, severe malnutrition, low birth weight, birth asphyxia, and congenital syphilis) were also hypoxaemic. For children aged 1 month to 5 years with ALRI, the clinical signs best predicting hypoxaemia were cyanosis, respiratory rate >60, poor feeding, or reduced spontaneous activity; in those without ALRI the best predictors were cyanosis, respiratory rate >60 per minute, and inability to feed, but the positive predictive value was much lower than for children with ALRI. For neonates cyanosis was predictive of hypoxaemia, but tachypnoea or inability to feed were not. Conclusions: Hypoxaemia is an under recognised complication of non-ALRI illnesses in children and in sick neonates in developing countries. Use of algorithms with high sensitivity for the recognition of hypoxaemia, and protocols for administration of oxygen to neonates, and to children with non-ALRI illnesses, might substantially reduce case fatality.

Death, Child Abuse, and Adverse Neurological Outcome of Infants After an Apparent Life-Threatening Event

OBJECTIVES. Apparent life-threatening events in infants constitute a significant challenge for health care providers. Apparent life-threatening event evaluation and management are poorly defined, and outcomes have not been clearly determined. Our objectives were to characterize short- and long-term risks for death, child abuse, and abnormal neurological outcomes of infants after an apparent life-threatening event and to identify clinical features that are predictive of these outcomes. METHODS. We collected data from infants ages birth to 12 months of age who were hospitalized after an apparent life-threatening event during a 5-year time period. Patients were evaluated for subsequent death, child abuse, or adverse neurological outcome (chronic epilepsy or developmental delay). RESULTS. A total of 471 patients met inclusion criteria and were followed an average of 5.1 years. Two patients died after developing chronic epilepsy and severe developmental delay. Fifty-four (11%) patients were diagnosed as being a victim of child abuse, but only 2 were identified at initial presentation. There were 23 (4.9%) patients with adverse neurological outcomes, including 17 (3.6%) with chronic epilepsy and 14 (3.0%) with developmental delay. Of those who developed chronic epilepsy, 71% returned within 1 month of the initial apparent life-threatening event with a second event. Neurological evaluation at the time of the apparent life-threatening event had low yield for predicting those who would develop chronic epilepsy. CONCLUSIONS. Infants who suffer an apparent life-threatening event are at risk for subsequent child abuse and adverse neurological outcomes. Deaths were uncommon and only occurred in the setting of severe developmental delay and seizure disorders. Neurological evaluation during hospitalization for a first apparent life-threatening event is of low yield, but close follow-up is essential.

Trends in Resource Utilization by Children with Neurological Impairment in the United States Inpatient Health Care System: A Repeat Cross-Sectional Study

Jay Berry and colleagues report findings from an analysis of hospitalization data in the US, examining the proportion of inpatient resources attributable to care for children with neurological impairment.

Heightened neurologic complications in children with pandemic H1N1 influenza

The 2009 pandemic influenza A (H1N1) has been recognized to cause neurological complications including seizures and encephalopathy. We identified 18 children with 2009 H1N1 influenza and neurological complications from first and second wave activity, and compared characteristics to seasonal influenza. Seizures, encephalopathy, and status epilepticus were common presentations. Focal neurological symptoms persisted in 22% of patients at discharge. Compared to seasonal influenza, patients with pandemic 2009 influenza were more likely to have encephalopathy, focal neurological findings, aphasia, and abnormal electroencephalographic findings. In addition, we noted a trend toward heightened neurological complications following second wave influenza activity. ANN NEUROL 2010

The burden of inherited leukodystrophies in children.

Objectives: Leukodystrophies are diseases of the white matter for which data concerning clinical characteristics, incidence, disease burden, and description of outcomes are sparse. The purpose of our study was to determine the incidence and most common types of inherited leukodystrophies in a population, the mortality and time course of deaths, common neurologic features in patients, and health care costs associated with leukodystrophies. Methods: We conducted a retrospective, hospital- and clinic-based surveillance of inherited leukodystrophies among children younger than 18 years presenting to a regional childrens hospital. We enrolled children evaluated from January 1, 1999, through December 31, 2007; clinical information was obtained from medical records. We calculated incidence based on state birth rates. Results: A total of 122 children with an inherited leukodystrophy were identified; 542 patients were excluded. A total of 49% had epilepsy, 43% required a gastrostomy tube, and 32% had a history of developmental regression. Mortality was 34%; average age at death was 8.2 years. No final diagnosis was reported in 51% of patients. The most common diagnoses were metachromatic leukodystrophy (8.2%), Pelizaeus-Merzbacher disease (7.4%), mitochondrial diseases (4.9%), and adrenoleukodystrophy (4.1%). Endocrine abnormalities and hypoplastic cerebellum were noted in significant portions of patients (15% and 14%). Average yearly per-patient medical costs were

The conserved dopaminergic diencephalospinal tract mediates vertebrate locomotor development in zebrafish larvae.

22,579. Population incidence was 1 in 7,663 live births. Conclusions: Inherited leukodystrophies are associated with substantial morbidity and mortality in children. Overall population incidence is higher than generally appreciated (1 in 7,663 live births). Most leukodystrophies remain undiagnosed, but a logical algorithm based on prevalence could aid testing.

Netrin-DCC, Robo-Slit, and Heparan Sulfate Proteoglycans Coordinate Lateral Positioning of Longitudinal Dopaminergic Diencephalospinal Axons

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 (D4R) 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 D4R 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 D4R agonism. We conclude that the dopaminergic otpb population, via the DDT, is responsible for spinal D4R 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.

Molecular cloning and developmental expression of foxP2 in zebrafish

Longitudinal axons provide connectivity between remote areas of the nervous system. Although the molecular determinants driving commissural pathway formation have been well characterized, mechanisms specifying the formation of longitudinal axon tracts in the vertebrate nervous system are largely unknown. Here, we study axon guidance mechanisms of the longitudinal dopaminergic (DA) diencephalospinal tract. This tract is established by DA neurons located in the ventral diencephalon and is thought to be involved in modulating locomotor activity. Using mutant analysis as well as gain of function and loss of function experiments, we demonstrate that longitudinal DA axons navigate by integrating long-range signaling of midline-derived cues. Repulsive Robo2/Slit signaling keeps longitudinal DA axons away from the midline. In the absence of repulsive Robo2/Slit function, DA axons are attracted toward the midline by DCC (deleted in colorectal cancer)/Netrin1 signaling. Thus, Slit-based repulsion counteracts Netrin-mediated attraction to specify lateral positions of the DA diencephalospinal tract. We further identified heparan sulfate proteglycans as essential modulators of DA diencephalospinal guidance mechanisms. Our findings provide insight into the complexity of positioning far-projecting longitudinal axons and allow us to provide a model for DA diencephalospinal pathfinding. Simultaneous integrations of repulsive and attractive long-range cues from the midline act in a concerted manner to define lateral positions of DA longitudinal axon tracts.

Cerebral Sinovenous Thrombosis in Children: Another Reason to Treat Iron Deficiency Anemia

Forkhead domain transcription factors are a large gene family with multiple roles in development. FOXP2, a recently identified member of this family, has been shown to be critical for normal development of language in humans, but little is known of its broader function during nervous system development. We report here the cloning of foxP2, the zebrafish ortholog of FOXP2. Zebrafish FoxP2 is highly conserved in its zinc‐finger and forkhead domains, but lacks the large glutamine repeat characteristic of its orthologs. In examining the spatial and temporal distribution of foxP2 during development, we find that it is specifically expressed in many domains of the nervous system, including the telencephalon, diencephalon, cerebellum, hindbrain, tectum, retinal ganglion cells, and spinal cord. Thus, in addition to specific roles in language development, foxP2 likely has a more general conserved role in nervous system development. Developmental Dynamics 234:740–746, 2005.