Restricted diffusion of the callosal splenium is highly specific for seizures in neonates.

BACKGROUND: To determine whether restricted diffusion of the callosal splenium is specific for seizure activity in neonates. METHODS: We performed a retrospective chart review of 123 neonates who had a diagnosis of hypoxic ischemic encephalopathy (HIE) who underwent therapeutic cooling and had magnetic resonance imaging (MRI) within the first 10 days of life. The regions examined for injury include the callosal splenium, cortex, deep gray matter, and subcortical white matter. Neurodevelopmental outcomes were secondarily assessed using the Bayley Scales of Infant Development at 12 to 18 months of age and > 18 months of age. APGAR scores and pH, two important markers of hypoxia/ischemia and encephalopathy, were also analyzed in relation to these outcomes. RESULTS: Approximately 41% of the neonates had at least one abnormal region on brain MRI, and 21% had abnormal signal in the splenium. Clinical and/or electrographic seizures were documented in 32%. Changes in the splenium had a sensitivity of 54%, specificity of 94%, and positive predictive value of 81% for seizure presence. The presence of seizures and splenium lesion was associated poor developmental outcomes at 12 to 18 months of age. APGAR scores at 10 minutes, but not lowest pH was associated with splenial changes. CONCLUSIONS: Restricted diffusion of the callosal splenium is specific for recent seizures in neonates with HIE. Seizures and splenial lesion represent risk factors for poor neurodevelopmental outcomes. Child neurologists and neonatologists should consider splenial signal abnormality in their assessment of neonates at risk for seizures and counsel families about likely outcomes accordingly.

Improved methods to characterize the length and quantity of highly unstable PolySialic acids subject category: (Carbohydrates, chromatographic techniques).

Polysialic acid (polySia) is a linear homopolymer of α2-8-linked sialic acids that is highly expressed during early stages of mammalian brain development and modulates a multitude of cellular functions. While degree of polymerization (DP) can affect such functions, currently available methods do not accurately characterize this parameter, because of the instability of the polymer. We developed two improved methods to characterize the DP and total polySia content in biological samples. PolySia chains with exposed reducing termini can be derivatized with DMB for subsequent HPLC analysis. However, application to biological samples of polySia-glycoproteins requires release of polySia chains from the underlying glycan, which is difficult to achieve without concurrent partial hydrolysis of the α2-8-linkages of the polySia chain, affecting its accurate characterization. We report an approach to protect internal α2-8sia linkages of long polySia chains, using previously known esterification conditions that generate stable polylactone structures. Such polylactonized molecules are more stable during acid hydrolysis release and acidic DMB derivatization. Additionally, we used the highly specific Endoneuraminidase-NF enzyme to discriminate polysialic acid and other sialic acid and developed an approach to precisely measure the total content of polySia in a biological sample. These two methods provide improved quantification and characterization of polySia.

A Case of Tuberculosis-Associated Acute Disseminated Encephalomyelitis in a Seven-Month-Old Infant.

A seven-month-old previously healthy female infant presented with acute onset encephalopathy and left focal weakness in the setting of three months of non-productive cough. She was diagnosed with pulmonary tuberculosis (TB), and neuroimaging showed multifocal non-enhancing T2 hyperintensities in the brain and longitudinal T2 hyperintensity in the spinal cord consistent with acute disseminated encephalomyelitis (ADEM). However, her cerebrospinal fluid (CSF) did not show evidence of TB infection. She was treated with high-dose steroids for five days with a steroid taper along with antitubercular medications with a remarkable recovery in gross motor function. This case suggests a previously unreported association between TB and an immune-mediated demyelinating syndrome in children that is clinically distinct from other more common forms of TB-associated central nervous system (CNS) complications.

Human-specific microglial Siglec-11 transcript variant has the potential to affect polysialic acid-mediated brain functions at a distance.

CD33-related Siglecs are often found on innate immune cells and modulate their reactivity by recognition of sialic acid-based "self-associated molecular patterns" and signaling via intracellular tyrosine-based cytosolic motifs. Previous studies have shown that Siglec-11 specifically binds to the brain-enriched polysialic acid (polySia/PSA) and that its microglial expression in the brain is unique to humans. Furthermore, human microglial Siglec-11 exists as an alternate splice form missing the exon encoding the last (fifth) Ig-like C2-set domain of the extracellular portion of the protein, but little is known about the functional consequences of this variation. Here, we report that the recombinant soluble human microglial form of Siglec-11 (hSiglec-11(4D)-Fc) binds endogenous and immobilized polySia better than the tissue macrophage form (hSiglec-11(5D)-Fc) or the chimpanzee form (cSiglec-11(5D)-Fc). The Siglec-11 protein is also prone to aggregation, potentially influencing its ligand-binding ability. Additionally, Siglec-11 protein can be secreted in both intact and proteolytically cleaved forms. The microglial splice variant has reduced proteolytic release and enhanced incorporation into exosomes, a process that appears to be regulated by palmitoylation of cysteines in the cytosolic tail. Taken together, these data demonstrate that human brain specific microglial hSiglec-11(4D) has different molecular properties and can be released on exosomes and/or as proteolytic products, with the potential to affect polySia-mediated brain functions at a distance.

Loss of NARS1 impairs progenitor proliferation in cortical brain organoids and leads to microcephaly.

Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Here, we identify biallelic missense and frameshift mutations in NARS1 in seven patients from three unrelated families with microcephaly and neurodevelopmental delay. Patient cells show reduced NARS1 protein, impaired NARS1 activity and impaired global protein synthesis. Cortical brain organoid modeling shows reduced proliferation of radial glial cells (RGCs), leading to smaller organoids characteristic of microcephaly. Single-cell analysis reveals altered constituents of both astrocytic and RGC lineages, suggesting a requirement for NARS1 in RGC proliferation. Our findings demonstrate that NARS1 is required to meet protein synthetic needs and to support RGC proliferation in human brain development.

Bi-allelic Loss of Human APC2, Encoding Adenomatous Polyposis Coli Protein 2, Leads to Lissencephaly, Subcortical Heterotopia, and Global Developmental Delay.

Lissencephaly is a severe brain malformation in which failure of neuronal migration results in agyria or pachygyria and in which the brain surface appears unusually smooth. It is often associated with microcephaly, profound intellectual disability, epilepsy, and impaired motor abilities. Twenty-two genes are associated with lissencephaly, accounting for approximately 80% of disease. Here we report on 12 individuals with a unique form of lissencephaly; these individuals come from eight unrelated families and have bi-allelic mutations in APC2, encoding adenomatous polyposis coli protein 2. Brain imaging studies demonstrate extensive posterior predominant lissencephaly, similar to PAFAH1B1-associated lissencephaly, as well as co-occurrence of subcortical heterotopia posterior to the caudate nuclei, "ribbon-like" heterotopia in the posterior frontal region, and dysplastic in-folding of the mesial occipital cortex. The established role of APC2 in integrating the actin and microtubule cytoskeletons to mediate cellular morphological changes suggests shared function with other lissencephaly-encoded cytoskeletal proteins such as α-N-catenin (CTNNA2) and platelet-activating factor acetylhydrolase 1b regulatory subunit 1 (PAFAH1B1, also known as LIS1). Our findings identify APC2 as a radiographically distinguishable recessive form of lissencephaly.

Evaluation of owners' attitudes towards veterinarian attire in the small animal specialty setting in North America.

Previous studies in human medicine have found that patients prefer their doctors to be more formally attired, and that this influences their trust and confidence in their physician. The purpose of this study was to evaluate how veterinarians' attire affected owners' impressions and trust in the small animal specialty medicine setting. A questionnaire based study conducted during a 2-month period at an urban based small animal private practice specialty hospital. Respondents completed a written survey after reviewing pictures of the same male and female veterinarian in five different dress styles. Respondents were asked for their preference for male and female veterinarian attire in different clinical scenarios and whether it would affect their willingness to discuss sensitive issues. Two hundred and thirty-eight questionnaires were completed during the study period with 76.1% of respondents being female. Female respondents did not have a preference to how a male or female veterinarian was attired with the attire examples provided. However, male respondents tended to have fairly equal response rates between no preference and preferring a male veterinarian to be in either clinical or professional attire. Male owners either had no preference or preferred their male veterinarian to be attired in clinical or professional attire and had no preference or preferred their female veterinarian to be clinical attire. Most respondents do not feel it is necessary for a veterinarian to wear a white coat or neck ties and most do not feel it is inappropriate for a veterinarian to wear blue jeans, have coloured hair, or have visible tattoos.

Clients' attitudes toward veterinarians' attire in the small animal emergency medicine setting.

OBJECTIVE To determine how veterinarians' attire affected clients' perceptions and trust in the small animal emergency medicine setting. DESIGN Cross-sectional study. SAMPLE 154 clients of a 24-hour small animal emergency clinic in a rural location. PROCEDURES A survey was administered to clients in the waiting room over a 1-month period to elicit their impressions of veterinarians' attire in various clinical scenarios and whether that attire would affect their perceptions. Respondents completed the survey after examining photographs of 1 male and 1 female veterinarian in 5 styles of attire (business, professional, surgical, clinical, and smart casual). RESULTS 83 (53.9%) respondents were female, and 71 (46.1%) were male; age was evenly distributed. Across all clinical scenarios, the most common response was no preference regarding the way a male or female veterinarian was dressed and that this attire would have no effect on the respondents' trust in their veterinarian. Most respondents were indifferent or preferred that their veterinarians not wear neckties and white coats. Twenty-six percent (40/154) of respondents indicated that they believed their veterinarian's attire would influence their opinion of the quality of care their pet received. CONCLUSIONS AND CLINICAL RELEVANCE In this small animal emergency medicine setting, most clients indicated no preference regarding their veterinarian's attire, yet approximately one-fourth indicated this attire would influence their perception of the quality of care their pet received. Further studies are warranted in other practice settings and locations to determine whether these findings are generalizable or unique to this particular setting.

Tumor-related epilepsy: epidemiology, pathogenesis and management.

INTRODUCTION: Seizure is a common comorbidity in patients with brain tumor. It may be the presenting symptom or develop after the tumor diagnosis. The underlying pathophysiology of brain tumor-related epilepsy remains poorly understood. METHODS: A comprehensive literature review of Pubmed English articles from 1980-2017 was performed to summarize current knowledge and treatment options of brain tumor-related epilepsy. RESULTS: Multiple factors have been found to contribute to tumor-related epilepsy, including tumor type, speed of tumor growth, location, and tumor burden. The underlying pathogenesis of epilepsy is not clear but perturbations in the peri-tumoral regions, both structural and cellular communications, have been implicated. CONCLUSIONS: Surgical and medical treatments of tumor-related epilepsy remain challenging as additional factors such as the extent of surgical resection, interactions with tumor-related oncological treatments and anti-epileptic medication related side effects need to be considered.

Hodgkin's lymphoma in an adolescent previously treated with surgical resection of third ventricular juvenile pilocytic astrocytoma.

We present a case of a 19-year-old man with cervical lymphadenopathy diagnosed with classical Hodgkin's lymphoma 9 years after gross total resection of a third ventricular juvenile pilocytic astrocytoma (JPA). Chemotherapy or radiation therapy was not a part of his initial JPA treatment. Owing to his two primary neoplasms, genetic testing was performed, which revealed heterozygous polymorphisms of unknown significance for CDH1 and p53, and negative BRAF mutation analysis. Our case reports development of classical Hodgkin's lymphoma after JPA in the absence of antecedent radiation and/or chemotherapy, and identifiable genetic predisposition.

The effect of insulin and insulin-like growth factors on hippocampus- and amygdala-dependent long-term memory formation.

Recent work has reported that the insulin-like growth factor 2 (IGF2) promotes memory enhancement. Furthermore, impaired insulin or IGF1 functions have been suggested to play a role in the pathogenesis of neurodegeneration and cognitive impairments, hence implicating the insulin/IGF system as an important target for cognitive enhancement and/or the development of novel treatments against cognitive disorders. Here, we tested the effect of intracerebral injections of IGF1, IGF2, or insulin on memory consolidation and persistence in rats. We found that a bilateral injection of insulin into the dorsal hippocampus transiently enhances hippocampal-dependent memory and an injection of IGF1 has no effect. None of the three peptides injected into the amygdala affected memories critically engaging this region. Together with previous data on IGF2, these results indicate that IGF2 produces the most potent and persistent effect as a memory enhancer on hippocampal-dependent memories. We suggest that the memory-enhancing effects of insulin and IGF2 are likely mediated by distinct mechanisms.

A positive autoregulatory BDNF feedback loop via C/EBPß mediates hippocampal memory consolidation.

Little is known about the temporal progression and regulation of the mechanisms underlying memory consolidation. Brain-derived-neurotrophic-factor (BDNF) has been shown to mediate the maintenance of memory consolidation, but the mechanisms of this regulation remain unclear. Using inhibitory avoidance (IA) in rats, here we show that a hippocampal BDNF-positive autoregulatory feedback loop via CCAAT-enhancer binding protein ß (C/EBPß) is necessary to mediate memory consolidation. At training, a very rapid, learning-induced requirement of BDNF accompanied by rapid de novo translation controls the induction of a persistent activation of cAMP-response element binding-protein (CREB) and C/EBPß expression. The latter, in turn, controls an increase in expression of bdnf exon IV transcripts and BDNF protein, both of which are necessary and, together with the initial BDNF requirement, mediate memory consolidation. The autoregulatory loop terminates by 48 h after training with decreased C/EBPß and pCREB and increased methyl-CpG binding protein-2, histone-deacetylase-2, and switch-independent-3a binding at the bdnf exon IV promoter.

Glucocorticoid receptors recruit the CaMKIIα-BDNF-CREB pathways to mediate memory consolidation.

Emotionally important events are well remembered. Although memories of emotional experiences are known to be mediated and modulated by stress hormones such as glucocorticoids, little is known about the underlying molecular mechanisms. We found that the hippocampal glucocorticoid receptors that are critically engaged during the formation of long-term inhibitory avoidance memory in rats were coupled to the activation of CaMKIIα, TrkB, ERK, Akt, PLCγ and CREB, as well as a to a substantial induction of Arc and synaptic GluA1. Most of these changes, which are initiated by a nongenomic effect of glucocorticoid receptors, were also downstream of the activation of brain-derived neurotrophic factor (BDNF). Hippocampal administration of BDNF, but not of other neurotrophins, selectively rescued both the amnesia and the molecular impairments produced by glucocorticoid receptor inhibition. Thus, glucocorticoid receptors mediate long-term memory formation by recruiting the CaMKIIα-BDNF-CREB-dependent neural plasticity pathways.

Memory enhancement: consolidation, reconsolidation and insulin-like growth factor 2.

Life and societies would change significantly if memory capacity or persistence in health and disease could be enhanced. It has been known for many years that memory can be improved and strengthened. Substances known to enhance memory include hormones, neurotransmitters, neuropeptides and metabolic substrates. Recently, attention has been given to identifying the molecular mechanisms and targets whereby memory enhancement can be achieved. One approach would be to target the physiological changes that are induced by learning and naturally required for memory strengthening via consolidation and reconsolidation. Here, we review approaches that boost memories by targeting the cAMP response element binding protein-CCAAT enhancer binding protein (CREB-C/EBP) pathway and/or its recently identified target gene insulin-like growth factor 2 (IGF2).

A critical role for IGF-II in memory consolidation and enhancement.

We report that, in the rat, administering insulin-like growth factor II (IGF-II, also known as IGF2) significantly enhances memory retention and prevents forgetting. Inhibitory avoidance learning leads to an increase in hippocampal expression of IGF-II, which requires the transcription factor CCAAT enhancer binding protein ß and is essential for memory consolidation. Furthermore, injections of recombinant IGF-II into the hippocampus after either training or memory retrieval significantly enhance memory retention and prevent forgetting. To be effective, IGF-II needs to be administered within a sensitive period of memory consolidation. IGF-II-dependent memory enhancement requires IGF-II receptors, new protein synthesis, the function of activity-regulated cytoskeletal-associated protein and glycogen-synthase kinase 3 (GSK3). Moreover, it correlates with a significant activation of synaptic GSK3ß and increased expression of GluR1 (also known as GRIA1) α-amino-3-hydroxy-5-methyl-4-isoxasolepropionic acid receptor subunits. In hippocampal slices, IGF-II promotes IGF-II receptor-dependent, persistent long-term potentiation after weak synaptic stimulation. Thus, IGF-II may represent a novel target for cognitive enhancement therapies.