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Alternative splicing plays a critical role in mouse neurodevelopment, regulating neurogenesis, cortical lamination, and synaptogenesis, yet few human neurodevelopmental disorders are known to result from pathogenic variation in splicing regulator genes. Nuclear Speckle Splicing Regulator Protein 1 (NSRP1) is a ubiquitously expressed splicing regulator not known to underlie a Mendelian disorder.

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Lymphocytic meningoradiculitis (Bannwarth syndrome) is a rare manifestation of Lyme neuroborreliosis in children. It is the most common clinical manifestation of early Lyme neuroborreliosis in adults in European countries where the disease is endemic but is rare in children. We report an imported case of Bannwarth syndrome in a pediatric patient and review the literature for other pediatric cases reported.

A 15-year-old healthy, active girl presented with acute bilateral upper extremity tingling and hand weakness while playing golf; within several hours, she developed numbness and weakness in all limbs. She denied preceding trauma and bowel/bladder incontinence. Examination showed global weakness, normal tone and reflexes, a C5 sensory level, and decreased light touch/temperature/pinprick in all limbs. Neuroimaging revealed an anterior spinal artery cervical cord infarct (figure), along with a degenerative disk, attributed to fibrocartilaginous embolism.

In carriers of deletion and duplication at 16p11.2, we found reciprocal neuroanatomical abnormalities and determined that these abnormalities were associated with cognitive and behavioral impairments.

The Royal Commission into Institutional Responses to Child Sexual Abuse has proposed major reforms to the tendency and coincidence rules for child sexual assault proceedings. These recommendations rest chiefly on a commissioned research study into juror reasoning examining 10 different trial types that reflect different evidentiary and procedural contexts. These variations include single complainant trials, some with and some without tendency and/or relationship evidence, and also joint trials where jurors hear from three child sexual assault complainants. This two-part article critically examines aspects of the proposed legislative reforms and the research study upon which it relies. Our conclusion is that there is grave danger that the proposed Bill risks converting well-intentioned aspirations into new injustices. [ABSTRACT FROM AUTHOR]

Advanced brain imaging of neonatal macrostructure and microstructure, which has prognosticating importance, is more frequently being incorporated into multi-center trials of neonatal neuroprotection. Multicenter neuroimaging studies, designed to overcome small sample sized clinical cohorts, are essential but lead to increased technical variability. Few harmonization techniques have been developed for neonatal brain microstructural (diffusion tensor) analysis. The work presented here aims to remedy two common problems that exist with the current state of the art approaches: 1) variance in scanner and protocol in data collection can limit the researcher's ability to harmonize data acquired under different conditions or using different clinical populations. 2) The general lack of objective guidelines for dealing with anatomically abnormal anatomy and pathology. Often, subjects are excluded due to subjective criteria, or due to pathology that could be informative to the final analysis, leading to the loss of reproducibility and statistical power. This proves to be a barrier in the analysis of large multi-center studies and is a particularly salient problem given the relative scarcity of neonatal imaging data. We provide an objective, data-driven, and semi-automated neonatal processing pipeline designed to harmonize compartmentalized variant data acquired under different parameters. This is done by first implementing a search space reduction step of extracting the along-tract diffusivity values along each tract of interest, rather than performing whole-brain harmonization. This is followed by a data-driven outlier detection step, with the purpose of removing unwanted noise and outliers from the final harmonization. We then use an empirical Bayes harmonization algorithm performed at the along-tract level, with the output being a lower dimensional space but still spatially informative. After applying our pipeline to this large multi-site dataset of neonates and infants with congenital heart disease (n = 398 subjects recruited across 4 centers, with a total of n = 763 MRI pre-operative/post-operative time points), we show that infants with single ventricle cardiac physiology demonstrate greater white matter microstructural alterations compared to infants with bi-ventricular heart disease, supporting what has previously been shown in literature. Our method is an open-source pipeline for delineating white matter tracts in subject space but provides the necessary modular components for performing atlas space analysis. As such, we validate and introduce Diffusion Imaging of Neonates by Group Organization (DINGO), a high-level, semi-automated framework that can facilitate harmonization of subject-space tractography generated from diffusion tensor imaging acquired across varying scanners, institutions, and clinical populations. Datasets acquired using varying protocols or cohorts are compartmentalized into subsets, where a cohort-specific template is generated, allowing for the propagation of the tractography mask set with higher spatial specificity. Taken together, this pipeline can reduce multi-scanner technical variability which can confound important biological variability in relation to neonatal brain microstructure.

IMPORTANCE Patients with rare diseases and complex clinical presentations represent a challenge for clinical diagnostics. Genomic approaches are allowing the identification of novel variants in genes for very rare disorders, enabling a molecular diagnosis. Genomics is also revealing a phenotypic expansion whereby the full spectrum of clinical expression conveyed by mutant alleles at a locus can be better appreciated. OBJECTIVE To elucidate the molecular cause of a complex neuropathy phenotype in 3 patients by applying genomic sequencing strategies. DESIGN, SETTING, AND PARTICIPANTS Three affected individuals from 2 unrelated families presented with a complex neuropathy phenotype characterized by axonal sensorimotor neuropathy and microcephaly. They were recruited into the Centers for Mendelian Genomics research program to identify the molecular cause of their phenotype. Whole-genome, targeted whole-exome sequencing, and high-resolution single-nucleotide polymorphism arrays were performed in genetics clinics of tertiary care pediatric hospitals and biomedical research institutions. MAIN OUTCOMES AND MEASURES Whole-genome and whole-exome sequencing identified the variants responsible for the patients’ clinical phenotype. RESULTS We identified compound heterozygous alleles in 2 affected siblings from 1 family and a homozygous nonsense variant in the third unrelated patient in the vaccinia-related kinase 1 gene (VRK1). In the latter subject, we found a common haplotype on which the nonsense mutation occurred and that segregates in the Ashkenazi Jewish population. CONCLUSIONS AND RELEVANCE We report the identification of disease-causing alleles in 3 children from 2 unrelated families with a previously uncharacterized complex axonal motor and sensory neuropathy accompanied by severe nonprogressive microcephaly and cerebral dysgenesis. Our data raise the question of whether VRK1 mutations disturb cell cycle progression and may result in apoptosis of cells in the nervous system. The application of unbiased genomic approaches allows the identification of potentially pathogenic mutations in unsuspected genes in highly genetically heterogeneous and uncharacterized neurological diseases.

This article examines the central role that credibility assessment plays in refugee determinations. It draws on the authors' own empirical study, Tales of the Unexpected, to display the complex ways in which applicants' poor mental health can affect their capacity to present a 'coherent and plausible‘ account of their experiences. The authors then explore the significant issues arising from the tendency revealed in the Tales study for decision makers to dismiss expert opinions expressed in reports tendered by applicants from psychologists specialising in cross-cultural mental health assessment. For example, consider the decision maker who observed that[The] psychologist reported that the Applicant was suffering from post-traumatic stress disorder and depression and that this psychological state was likely to affect his ability to answer questions at an RRT hearing …. [Nevertheless] [Mr S] did not display any difficulty in understanding or answering questions. … He [appeared] alert, engaged, and is clearly an intelligent man. I do not accept that he had any difficulty in understanding proceedings or answering questions.5

This article examines the central role that credibility assessment plays in refugee determinations. It draws on the authors' own empirical study, Tales of the Unexpected, to display the complex ways in which applicants' poor mental health can affect their capacity to present a 'coherent and plausible‘ account of their experiences. The authors then explore the significant issues arising from the tendency revealed in the Tales study for decision makers to dismiss expert opinions expressed in reports tendered by applicants from psychologists specialising in cross-cultural mental health assessment. For example, consider the decision maker who observed that[The] psychologist reported that the Applicant was suffering from post-traumatic stress disorder and depression and that this psychological state was likely to affect his ability to answer questions at an RRT hearing …. [Nevertheless] [Mr S] did not display any difficulty in understanding or answering questions. … He [appeared] alert, engaged, and is clearly an intelligent man. I do not accept that he had any difficulty in understanding proceedings or answering questions.5

OBJECTIVE: Cerebral atrophy is a prominent feature in adults with systemic lupus erythematosus (SLE). We assessed cerebral and cerebellar volume loss on clinically acquired brain magnetic resonance imaging (MRI) scans of children and adolescents with SLE. METHODS: We abstracted information on disease course for patients who underwent clinical brain MRI during the period 2002–2008. We completed qualitative assessments of volume loss and measured corpus callosum thickness and ventricular enlargement for patients with lupus and controls. RESULTS: Forty-nine children underwent brain MRI during the review period due to clinical indications. The lupus cohort was predominantly female and ethnically diverse. Mean age at imaging was 15.3 ± 2.6 years and mean disease duration was 30.6 ± 33.3 months. Findings suggestive of cerebral and cerebellar volume loss were seen respectively in 89.8% and 91.8% of lupus patients. Cerebral volume loss was moderate or severe in 26.5% of children. Cerebellar volume loss was moderate in 20.4% of these patients. Linear measurement means reflected corpus callosum thinning and ventricular enlargement in lupus patients. Volume loss was observed in newly diagnosed patients prior to corticosteroid use. Disease duration and corticosteroid use did not predict the severity of volume loss. There were statistically significant differences in linear imaging measurements comparing lupus patients to 14 similar-age controls. CONCLUSION: Regional volume loss was observed in most adolescents with lupus undergoing clinical brain MRI scans. As in other pediatric conditions with inflammatory or vascular etiologies, these findings may be reflecting disease-associated neuronal loss and not solely the effects of corticosteroid.

No Abstract.

Diffusion tensor imaging (DTI) is a recent imaging technique that assesses the microstructure of the cerebral white matter (WM) based on anisotropic diffusion (i.e., water molecules move faster in parallel to nerve fibers than perpendicular to them). Fractional anisotropy (FA), which ranges from 0 to 1.0, increases with myelination of WM tracts and is sensitive to diffuse axonal injury (DAI) in adults with traumatic brain injury (TBI). However, previous DTI studies of pediatric TBI were case reports without detailed outcome measures. Using mean FA derived from DTI fiber tractography, we compared DTI findings of the corpus callosum for 16 children who were at least 1 year (mean 3.1 years) post-severe TBI and individually matched, uninjured children. Interexaminer and intraexaminer reliability in measuring FA was satisfactory. FA was significantly lower in the patients for the genu, body, and splenium of the corpus callosum. Higher FA was related to increased cognitive processing speed and faster interference resolution on an inhibition task. In the TBI patients, higher FA was related to better functional outcome as measured by the dichotomized Glasgow Outcome Scale (GOS). FA also increased as a function of the area of specific regions of the corpus callosum such as the genu and splenium, and FA in the splenium was reduced with greater volume of lesions in this region. DTI may be useful in identifying biomarkers related to DAI and outcome of TBI in children.

In vivo MRI volumetric analysis enables investigators to evaluate the extent of tissue loss following traumatic brain injury (TBI). However, volumetric studies of pediatric TBI are sparse, and there have been no volumetric studies to date in children examining specific subregions of the prefrontal and temporal lobes. In this study, MRI volumetry was used to evaluate brain volume differences in the whole brain, and prefrontal, temporal, and posterior regions of children following moderate to severe TBI as compared to uninjured children of similar age and demographic characteristics. The TBI group had significantly reduced whole brain, and prefrontal and temporal regional tissue volumes as well as increased cerebrospinal fluid (CSF). Confidence interval testing further revealed group differences on gray matter (GM) and white matter (WM) in the superior medial and ventromedial prefrontal regions, WM in the lateral frontal region, and GM, WM, and CSF in the temporal region. Whole brain volume and total brain GM were reduced, and total ventricular volume, total CSF volume, and ventricle-to-brain ratio (VBR) were increased in the TBI group. Additional analyses comparing volumetric data from typically developing children and subgroups of TBI patients with and without regional focal lesions suggested that GM loss in the frontal areas was primarily attributable to focal injury, while WM loss in the frontal and temporal lobes was related to both diffuse and focal injury. Finally, volumetric measures of preserved frontotemporal tissue were related to functional recovery as measured by the Glasgow Outcome Scale (adapted for children) with greater tissue preservation predicting better recovery.

Selective learning (SL), the ability to select items to learn from among other items, engages cognitive control, which is purportedly mediated by the frontal cortex and its circuitry. Using incentive‐based auditory word recall and expository discourse tasks, we studied the efficiency of SL in children ages 6 to 16 years who had sustained severe traumatic brain injury (TBI) at least 1 year earlier. We hypothesized that SL would be compromised by severe TBI. Results indicated that children with severe TBI performed significantly worse than age‐matched typically developing children on word‐ and discourse‐level measures of SL efficiency with no significant group differences in number of items recalled from auditory word lists or declarative facts. We conclude that severe TBI disrupts incentive‐based cognitive control processes, possibly due to involvement of frontal neural networks. Ann Neurol 2004; 56: 847–853

We compare etomidate to pentobarbital for sedation of children for head and neck computed tomography imaging.

To evaluate effects of unilateral frontal lesions on psychosocial and global outcome of traumatic brain injury (TBI) in children, Study 1 compared matched groups of 22 school aged children who had sustained TBI either with or without unilateral frontal lesions. Study 2 evaluated effects of unilateral extrafrontal lesions in 18 TBI patients as compared with 18 nonlesional TBI patients. Communication, Daily Living, and Socialization domains and the Maladaptive Behavior Scale of the Vineland Adaptive Behavior Scales (VABS) were used to assess psychosocial outcome, and the Glasgow Outcome Scale (GOS) measured global outcome. All patients underwent magnetic resonance imaging at least 3 months post injury. Children with frontal lesions had worse scores on the Daily Living and Socialization domains and a higher frequency of maladaptive behavior than those without frontal lesions, but there was no difference in cognitive function. Disability was twice as common in the frontal lesion group relative to children without frontal lesions. Volume of frontal lesion was related to the Socialization domain. Side of lesion had no effect, nor did presence of an extrafrontal lesion (Study 2). Unilateral frontal lesions adversely affect late psychosocial outcome of TBI in children. (JINS, 2004, 10, 305–316.)

Only the metopic suture normally fuses during early childhood; all other cranial sutures normally fuse much later in life. Despite this, metopic synostosis is one of the least common forms of craniosynostosis. The temporal sequence of normal physiologic metopic suture fusion remains undefined and controversial. Therefore, diagnosis of metopic synostosis on the basis of computed tomography images alone can prove misleading. The present study sought to determine the normal sequence of metopic suture fusion and characterize both endocranial and ectocranial suture morphology. An analysis of computed tomography scans of 76 trauma patients, ranging in age from 10 days to 18 months, provided normative craniofacial data that could be compared to similar data obtained from the preoperative computed tomography scans of 30 patients who had undergone surgical treatment for metopic synostosis. Metopic suture fusion was complete by 6 to 8 months in all nonsynostotic patients, with initiation of suture fusion evident as early as 3 months of age. Fusion was found to commence at the nasion, proceed superiorly in progressive fashion, and conclude at the anterior fontanelle. Although an endocranial ridge was not commonly seen in synostotic patients, an endocranial metopic notchwas virtually diagnostic of premature suture fusion and was seen in 93 percent of synostotic patients. A metopic notch was not seen in anynonsynostotic patient. The morphologic and normative craniofacial data presented permit diagnosis of metopic synostosis based on computed tomography images obtained beyond the normal fusion period.

The migration or passive intracranial translocation of microplates and screws in the pediatric craniofacial patient has been reported. A retrospective review was undertaken to clarify the incidence of microplate translocation and identify potential clinical implications. Computed tomographic imaging demonstrated internalization of microfixation in 14 of 27 pediatric patients. Statistically significant factors for microplate translocation include longer plates (p< 0.05) and those placed in the temporal region (p< 0.001). Younger patients and those with syndromic craniofacial dysostosis also had a higher incidence of translocation. Specific complications relating to the translocation of microplates were not found in any patient. The direct effects of translocated microplates and screws on the underlying brain and dura remain unclear.

Activated protein C resistance caused by an Arg506Gln mutation in the factor V gene (factor V Leiden mutation) is the most common cause of familial thrombosis. This mutation is associated with arterial and venous thromboembolic disease in neonates, infants, and children, but is not a significant risk factor for ischemic stroke in adults. We report on 3 babies with different neonatal cerebrovascular disorders including ischemic infarction and hemorrhagic stroke who are heterozygous for factor V Leiden mutation. One infant had multiple thrombi in the fetal placental vasculature. This is the first reported association between hemiplegic cerebral palsy, placental thrombosis, and factor V Leiden mutation. We suspect that activated protein C resistance may be an important cause of in utero cerebrovascular disease and hemiplegic cerebral palsy.

Many remedial reading programs and procedures used today are woefully inadequate. Often the teacher and the students share the frustration of confusion and inadequate progress. This article examines two questions: (1) the reasons for such high rates of failure as well as (2) strategies to improve the quality of remedial instruction. Through work with student teachers placed in remedial situations, ten areas have been identified that are vital to successful remediation. Specific examples are given of ways to insure success in each area based on a theoretical view of reading as an active, thinking process influenced by the child's conceptual abilities and language experience.

Digital subtraction angiography is able to provide simultaneous information on renal structure and function. Thirteen normal patients were investigated. Parametric analysis was performed and a set of normal ranges was established for T-1/2 max, T-max, and renal-artery-to-renal-vein peak-to-peak transit time. Cases are presented to show that the technique is capable of identifying the normal kidney and differentiating it from abnormalities of intrarenal perfusion based on the detailed analysis of the vascular nephrogram.

Abstract: Mice selectively bred for sensitivity (COLD) or insensitivity (HOT) to the hypothermic effect of ethanol were tested in three tasks purported to assess ethanol's hedonic properties: place conditioning, taste conditioning, and ethanol drinking. In the place conditioning task, distinctive tactile (floor) stimuli were differentially paired with injection of ethanol (2.25 g/kg) or saline, and preference for the tactile stimuli was assessed during a choice test without ethanol. In the taste conditioning task, fluid-deprived mice were given repeated access to saccharin followed by injection of ethanol (2.25 g/kg). In the drinking task, mice were given access on alternate days to a single drinking tube containing water or ethanol in a concentration that gradually increased from 1 to 12% (v/v) over days. HOT mice showed greater conditioned preference for ethanol-paired tactile cues, greater aversion for ethanol-paired flavor cues, and drank less ethanol at concentrations above 5% than COLD mice. HOT mice also showed higher levels of ethanol-stimulated activity than COLD mice. Control experiments indicated that the lines did not differ in initial preference for the tactile and flavor stimuli used in the conditioning tasks. Because the same line differences were seen in mice selected from two genetically independent populations, these studies offer strong evidence of genetic correlations between ethanol's thermal effect and its effect on activity, place conditioning and taste conditioning. Evidence of a genetic correlation between ethanol's thermal effect and ethanol drinking, however, is weaker since it is based on a line difference observed in only one of the genetic replicates. In general, these findings suggest commonality in the biological mechanisms underlying ethanol's thermal effect and its effect in each behavioral task. This overall pattern of genetic correlations might indicate that these tasks measure the same motivational effect of ethanol.

This study will examine the premise that reading is often the victim of a separate, but equal doctrine in four year colleges. Because of this, great confusion exists as to its role in the university. In order to support reading's integral role in college success, several things will be explored. First, there is an overview of reading programs found in four year institutions. Next, the research looks at specific strategies needed to identify the interactive process between text and reader. Finally, the research outlines several existing university programs that are successful in providing help in these important reading and learning strategies by tying instruction to specific academic content. The overwhelming evidence suggests that universities can no longer ignore the complex issue of reading as it relates to the various disciplines. No longer can they use the band-aid approach of separate reading labs when major surgery within the curriculum is required.

Rapid advances, in respect of the visual and auditory systems, have occurred in neuroimaging over the past year in the area of so-called 'functional imaging', and in particular of functional magnetic resonance imaging. This has been accelerated by the introduction of echo-planar imaging, which allows for the very fast acquisition (< 100 ms/image) of multislice images. Radiology is no longer just a question of interpreting anatomy, for, with the ability to combine structure with function, we are now able to extract physiological information. This opens up exciting possibilities for advances in the field of neuroscience, and functional imaging will therefore form the main thrust of this review.

No relevant conflicts of interest to declare.

The stress-inducible transcription factor, NF-κB, plays an important in role in B-cell malignancies, regulating expression of a plethora of genes including those that drive proliferation, apoptosis and survival. Non-canonical (’alternative’) NF-κB signalling, resulting in processing of the p100 subunit to p52 and dimerization with RelB, is less well-studied than the canonical pathway. Previous studies on NF-κB signalling, particularly in CLL, showed that the RelA (canonical) subunit is highly expressed and associated with poor outcome. In multiple myeloma and lymphoma, mutations in genes that alter NF-κB activity (NOTCH1, BIRC3, MYD88, TRAF2/3) can promote cell survival, by increasing activation of the CD40 receptor or NIK (NF-κB-inducing kinase), resulting in constitutive non-canonical NF-κB signalling. More recently, a comprehensive study showed that recurrent mutations in TRAF3, BIRC3 and NFKB2, all of which regulate non-canonical NF-κB signalling, also occur in CLL (Puente XS et al, Nature 2015). Taken together, these data suggest that non-canonical NF-κB signalling is important in CLL and that this pathway represents a novel therapeutic target. We hypothesised that receptor-activated proliferation in CLL cells is reliant on non-canonical NF-κB-regulated gene transcription, and that targeting this pathway would decrease CLL cell survival. Since the IKKα kinase phosphorylates p100, which in turn leads to active p52/RelB dimers in the nucleus, it is a key driver of the non-canonical signalling pathway. We used cell line models and patient-derived CLL cells to evaluate a series of selective, first-in-class IKKα inhibitors.

No relevant conflicts of interest to declare.

Abstract 867

No relevant conflicts of interest to declare.