Mutation at the Evi1 locus in Junbo mice causes susceptibility to otitis media.

Otitis media (OM), inflammation of the middle ear, remains the most common cause of hearing impairment in children. It is also the most common cause of surgery in children in the developed world. There is evidence from studies of the human population and mouse models that there is a significant genetic component predisposing to OM, yet nothing is known about the underlying genetic pathways involved in humans. We identified an N-ethyl-N-nitrosourea-induced dominant mouse mutant Junbo with hearing loss due to chronic suppurative OM and otorrhea. This develops from acute OM that arises spontaneously in the postnatal period, with the age of onset and early severity dependent on the microbiological status of the mice and their air quality. We have identified the causal mutation, a missense change in the C-terminal zinc finger region of the transcription factor Evi1. This protein is expressed in middle ear basal epithelial cells, fibroblasts, and neutrophil leukocytes at postnatal day 13 and 21 when inflammatory changes are underway. The identification and characterization of the Junbo mutant elaborates a novel role for Evi1 in mammalian disease and implicates a new pathway in genetic predisposition to OM.

Educational skills: long-term outcome and predictors following paediatric traumatic brain injury.

Given that reading, spelling and arithmetic skills are acquired through childhood, their development may be compromised following a childhood traumatic brain injury (TBI). The present study examined educational skills (reading accuracy, spelling and arithmetic) at a mean follow-up interval of 6.8 years post-injury in children who had sustained a mild, moderate, or severe TBI at two ages: 'Young' (age at injury: 3-7 years, n = 48) and 'Old': (age at injury: 8-12 years, n = 36). Comparisons between the young and old TBI groups resulted in inconsistent findings. While a dose-response relationship for severity was evident for the young group, this was not always the case for the old group. Significant predictors of outcome included both severity and acute intellectual function.

Outcome and predictors of functional recovery 5 years following pediatric traumatic brain injury (TBI).

OBJECTIVES: The aim was to examine functional outcomes following traumatic brain injury (TBI) during early childhood, to investigate impairments up to 5 years postinjury and identify predictors of outcome. METHODS: The study compared three groups of children (mild = 11, moderate = 22, severe = 15), aged 2.0-6.11 years at injury, to a healthy control group (n = 17). Using a prospective, longitudinal design, adaptive abilities, behavior, and family functioning were investigated acutely, 6, 30 months and 5 years postinjury, with educational progress investigated at 30 months and 5 years postinjury. RESULTS: A strong association was suggested between injury severity and outcomes across all domains. Further, 5-year outcomes in adaptive and behavioral domains were best predicted by preinjury levels of child function, and educational performance by injury severity. CONCLUSION: Children who sustain a severe TBI in early childhood are at greatest risk of long-term impairment in day-to-day skills in the long-term postinjury.

Understanding predictors of functional recovery and outcome 30 months following early childhood head injury.

Much is known about outcome following traumatic brain injury (TBI) in school-age children; however, recovery in early childhood is less well understood. Some argue that such injuries should lead to good outcome, because of the plasticity of the developing brain. Other purport that the young brain is vulnerable, with injury likely to result in a substantial impairment (H. G. Taylor & J. Alden, 1997). The aim of this study was to examine outcomes following TBI during early childhood, to plot recovery over the 30 months postinjury, and to identify predictors of outcome. The study compared 3 groups of children sustaining mild, moderate, and severe TBI, ages 2.0 to 6.11 years at injury, with healthy controls. Groups were comparable for preinjury adaptive and behavioral function, psychosocial characteristics, age, and gender. Results suggested a strong association between injury severity and outcomes across all domains. Further, 30-month outcome was predicted by injury severity, family factors, and preinjury levels of child function. In conclusion, children with more severe injuries and lower preinjury adaptive abilities, and whose families are coping poorly, are at greatest risk of long-term impairment in day-to-day skills, even several years postinjury.

Thirty month outcome from early childhood head injury: a prospective analysis of neurobehavioural recovery.

Traumatic brain injury (TBI) is a common cause of acquired disability during childhood. While much is now known about outcome following TBI in the school-aged population, recovery in infants and young children is less well documented. The aim of this study was to examine neurobehavioural function following TBI during early childhood, to plot recovery over the 30 months post-injury and to identify predictors of outcome. The study compared three groups of children, sustaining injuries of different severity (mild = 14, moderate = 46, severe = 24), aged 2.0-6.11 years at injury, with a healthy control group (n = 33). The groups were similar with respect to pre-injury adaptive and behavioural function, psychosocial characteristics, age and gender. Using a prospective, longitudinal design, intellectual, language and memory functions were investigated acutely post-injury and again at 12 and 30 months post-injury. Results suggested a strong association between injury severity across all neurobehavioural domains. Further, 30 month outcome was predicted by multiple factors including injury severity, socio-economic status, pre-injury adaptive abilities and age, with pre-injury child behaviour and specific lesion characteristics playing surprisingly little role. In conclusion, children with more severe injuries, lower pre-injury adaptive abilities and lower socio-economic status are at greatest risk of long-term neurobehavioural impairment, even several years post-injury.

Selective changes in executive functioning ten years after severe childhood traumatic brain injury.

Pediatric traumatic brain injury (TBI) impacts on children's executive functions, but little is known of how such deficits evolve in the long term. Forty adolescents with TBI were assessed ten years post-injury and compared to 19 typically developing participants on a range of executive measures (attentional control, cognitive flexibility, goal setting, information processing). Children with mild or moderate TBI performed within age expectations on all tests; however, those with severe injuries had poorer performance on goal setting and processing speed tasks. Childhood TBI may result in subtle lasting changes in complex executive skills, which could require ongoing support into adulthood.

Intellectual outcome from preschool traumatic brain injury: a 5-year prospective, longitudinal study.

INTRODUCTION: Traumatic brain injury (TBI) is a common, acquired disability that may be used as a model to understand the impact of early brain injury on brain structure and function. To date, few studies have followed very young children over time after insult. OBJECTIVE: To plot recovery and outcome of intellectual ability after early TBI over the 5 years after injury, and to identify predictors of outcome including injury, sociodemographic and preinjury characteristics, and acute functional recovery. DESIGN: Children aged between 2 and 7 years who were diagnosed with TBI (N = 54) were consecutively recruited on admission to the Royal Children's Hospital, Victoria, Australia, to participate in a prospective, longitudinal study. Our study had a between-factor design that used injury severity as the independent variable. The participants were categorized into groups according to injury severity (mild, moderate, or severe), and were compared with healthy control participants (n = 16) at the acute time point, and at 12 months, 30 months, and 5 years after injury. Intellectual measures, including verbal and nonverbal skills, attention, and processing speed, were administered. RESULTS: Children with severe injuries demonstrated slower recovery and poorer cognitive outcomes up to 5 years after injury than did those who were observed for less severe injuries. Recovery trajectories were associated with injury severity over the first 30 months after injury, with the greatest deterioration in function observed for more severe injuries. From 30 months to 5 years after injury, progress was stable. Only injury severity (as determined by the Glasgow Coma Scale score) and acute cognitive performance were strong predictors of 5-year outcomes. CONCLUSIONS: This study has confirmed the high risk of persisting and global deficits associated with severe brain insult in early childhood. Contrary to previous speculation about "growing into deficits," children with severe brain insults have more protracted recovery periods but do not continue to lose ground compared with their peers. By 30 months after insult, recovery seems to stabilize and children begin to make appropriate developmental gains.

Children's attentional skills 5 years post-TBI.

OBJECTIVE: While a small number of research papers have reported findings on attentional deficits following pediatric traumatic brain injury (TBI), no study to date has reported findings in this area at 5 years post-TBI in very young children. This study examined attentional skills in a group of children who had sustained a mild, moderate, or severe TBI between the ages of 2 and 7 years. METHODS: The sample comprised 70 children, 54 of these had sustained a TBI and 16 the non-injured control group. Children were assessed 5 years post-TBI, with focus on tests of attentional ability. RESULTS: Attentional and processing speed (PS) deficits do occur and persist up to 5 years post-TBI, particularly following severe TBI in early childhood. Predictors of attentional outcomes varied depending on the component of attention investigated. CONCLUSIONS: Those skills developing or emerging at time of injury (e.g., sustained attention, shifting attention, divided attention, PS) are more compromised and may not develop at a normal rate of post-injury.

Long-term outcomes of surgical tongue reduction in Beckwith-Wiedemann syndrome.

BACKGROUND: Surgical tongue reduction is often performed in Beckwith-Wiedemann syndrome when macroglossia results in abnormal tongue function or cosmesis; however, no published studies have examined the long-term outcomes of this procedure. METHODS: Patients older than 18 years with Beckwith-Wiedemann syndrome who had previously undergone surgical tongue reduction at the Royal Children's Hospital in Melbourne underwent assessment of speech and tongue function, mobility, sensation, and cosmesis. These assessments were performed by questionnaire on 11 subjects and by formal medical and speech pathology review in four of these 11 subjects. RESULTS: Eleven patients aged 19 to 31 years completed responses by means of questionnaire. The most common self-reported abnormalities were continued disproportionate tongue bulk (91 percent), abnormal tongue appearance (82 percent), specific speech sound errors (73 percent), and a short tongue tip (55 percent). Formal assessments investigated speech, swallowing, taste, and tongue mobility in four quite different subjects. One of these four subjects had no detectable deficits in tongue function. All 11 patients were of normal intelligence and did not report significant difficulties in their day-to-day life that were attributable to their macroglossia or tongue reduction surgery. CONCLUSIONS: Pediatric patients with symptomatic macroglossia requiring surgical tongue reduction may not achieve complete normality in tongue function and appearance in adulthood. It is important that surgical tongue reduction addresses the global nature of the macroglossia and aims to retain a tapered tongue tip with length sufficient to permit normal tongue movements.

Functional plasticity or vulnerability after early brain injury?

CONTEXT: Traumatic brain injury (TBI) is a common, acquired, childhood disability that may be used as a model to understand more completely the impact of early brain injury on both brain structure and day-to-day function. Contrary to previously held views of the "plasticity" of the young brain, recent research suggests that such early insults may have a profound impact on development. To date, these suggestions remain largely untested. OBJECTIVES: To plot changes in cognitive abilities after childhood TBI over the 30 months after injury and to examine the impact of age at injury on cognitive outcomes. DESIGN: Prospective longitudinal study. SETTING: Royal Children's Hospital, Victoria, Australia. MAIN OUTCOME MEASURES: Global intellectual ability, verbal and nonverbal skills, attention, and processing speed. PARTICIPANTS: A total of 122 children admitted to the hospital with a diagnosis of TBI were divided according to injury age, ie, young (age: 3-7 years) or old (age: 8-12 years), and injury severity (mild, moderate, or severe) and were evaluated acutely and at 12 and 30 months after injury. An additional sample of children injured before 3 years of age (n = 27) was compared with these groups with respect to global intellectual ability only. RESULTS: A clear relationship was documented between injury severity and cognitive performance. For children who sustained severe injury, younger age at injury was associated with minimal, if any, recovery after injury, but better outcomes were observed after severe TBI among older children. Age at injury was not predictive of outcomes for children with mild or moderate TBI, although infants (age: 0-2.11 years) with moderate TBI showed poorer outcomes than did older children with injury of similar severity. CONCLUSIONS: Findings support a "double-hazard" model for severe and early brain insults and add to the ongoing debate regarding cerebral plasticity, suggesting that, contrary to traditional views, young children who sustain severe TBI in early childhood or moderate or severe TBI in infancy may be particularly vulnerable to significant residual cognitive impairment. From a clinical perspective, results indicate that long-term follow-up monitoring and management should be targeted to this high-risk group.

Mutant analysis reveals whirlin as a dynamic organizer in the growing hair cell stereocilium.

Little is known of the molecular processes that lead to the growth of stereocilia on the surface of hair cells in the inner ear. The PDZ protein whirlin is known, by virtue of the whirler mutation, to be involved in the process of stereocilia elongation and actin polymerization in the sensory hair cells of mammals. We have investigated the function of whirlin and its putative interacting partner, myosin XVa, in the stereocilium using relevant mice mutants. We raised an antibody that detects the short isoform of the whirlin protein which has been demonstrated to rescue the stereocilia growth defect in the whirler mutant. We show that whirlin localizes at the tips of stereocilia. Expression of whirlin is dynamic during stereocilia growth, demonstrating an ordered appearance and fade-out across the stereocilia rows and revealing a novel molecular gradation of process traversing the stereocilia bundle. Fade-out of whirlin in inner hair cells precedes that of outer hair cells, consistent with the earlier maturation of inner hair cell stereocilia. In myosin XVa mutants in which stereocilia are shortened, whirlin expression in the stereocilia tips is stalled and fade-out is accelerated. In whirlin mutants, myosin XVa is still expressed in stereocilia, but its appearance at the stereocilia tip is delayed. The data indicate that whirlin expression is a critical and dynamic organizer for stereocilia elongation and actin polymerization.