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Glucocerebrosidosis (termed Gaucher disease in humans) is a lysosomal storage disease, caused by a deficiency of the enzyme glucocerebrosidase, which results in accumulation of the glycolipid substrate glucocerebroside in the macrophage-monocyte system. Three principal forms are recognized in humans, two being neuronopathic and resulting in neurodegeneration. Only two spontaneously arising cases have been described in domestic animals, one in a dog and the other in a flock of Southdown sheep. Since microglial activation is increasingly being recognized as having an important role in the pathogenesis of Gaucher disease and archival brains were available from lambs with type II glucocerebrosidosis, we wanted to determine whether microglia were activated in these brains. Ionized calcium binding adaptor molecule 1 (Iba1), a specific and the most widely expressed immunohistochemical marker of microglial activation, was used. Striking and widely distributed activation of microglia was demonstrated, suggesting that microglia actively participate in the development of neuropathological changes in ovine Gaucher disease. This aspect of Gaucher disease requires further study in any future cases detected in domestic animal species, including the mechanism by which this markedly increased Iba1 expression is related to disease progression., Competing Interests: Declaration of competing interests The authors declared no conflicts of interest in relation to the research, authorship and/or publication of this article., (Copyright © 2024 University of Adelaide. Published by Elsevier Ltd.. All rights reserved.)

Background: Sanfilippo syndrome (mucopolysaccharidosis type IIIA; MPS IIIA) is a childhood dementia caused by inherited mutations in the sulfamidase gene. At present, there is no treatment and children with classical disease generally die in their late teens. Intravenous or intra-cerebrospinal fluid (CSF) injection of AAV9-gene replacement is being examined in human clinical trials; evaluation of the impact on brain disease is an intense focus; however, MPS IIIA patients also experience profound, progressive photoreceptor loss, leading to night blindness., Aim: To compare the relative efficacy of the two therapeutic approaches on retinal degeneration in MPS IIIA mice., Methods: Neonatal mice received i.v. or intra-CSF AAV9-sulfamidase or vehicle and after 20 weeks, biochemical and histological evaluation of neuroretina integrity was carried out., Results: Both treatments improved central retinal thickness; however, in peripheral retina, outer nuclear layer thickness and photoreceptor cell length were only significantly improved by i.v. gene replacement. Further, normalization of endo-lysosomal compartment size and microglial morphology was only observed following intravenous gene delivery., Conclusions: Confirmatory studies are needed in adult mice; however, these data indicate that i.v. AAV9-sulfamidase infusion leads to superior outcomes in neuroretina, and cerebrospinal fluid-delivered AAV9 may need to be supplemented with another therapeutic approach for optimal patient quality of life., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Hampering assessment of treatment outcomes in gene therapy and other clinical trials in patients with childhood dementia is the lack of an objective, non-invasive measure of neurodegeneration. Optical coherence tomography (OCT) is a widely available, rapid, non-invasive, and quantitative method for examining the integrity of the neuroretina. Profound brain and retinal dysfunction occur in patients and animal models of childhood dementia, including Sanfilippo syndrome and we recently revealed a correlation between the age of onset and rate of progression of retinal and brain degeneration in sulfamidase-deficient Sanfilippo mice. The aim of the current study was to use OCT to visualise the discrete changes in retinal structure that occur during disease progression. A progressive decline in retinal thickness was readily observable in Sanfilippo mice using OCT, with differences seen in affected animals from 10-weeks of age. OCT applied to i.v. AAV9-sulfamidase-treated Sanfilippo mice enabled visualisation of improved retinal anatomy in living animals, an outcome confirmed via histology. Importantly, brain disease lesions were also ameliorated in treated Sanfilippo mice. The findings highlight the sensitivity, ease of repetitive use and quantitative capacity of OCT for detection of discrete changes in retinal structure and their prevention with a therapeutic. Combined with the knowledge that retinal and brain degeneration are correlated in Sanfilippo syndrome, OCT provides a window to the brain in this and potentially other childhood dementias., Competing Interests: Declaration of Competing Interest KMH, HB, LKW, DN, BK, PJT, MFS, GC, TM and RJC declare that they have no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Acute neuronopathic (type II) Gaucher disease (GD) is a devastating, untreatable neurological disorder resulting from mutations in the glucocerebrosidase gene (GBA1), with subsequent accumulation of glucosylceramide and glucosylsphingosine. Patients experience progressive decline in neurological function, with onset typically within the first three-to-six months of life and premature death before two years. Mice and drosophila with GD have been described, however little is known about the brain pathology observed in the naturally occurring ovine model of GD. We have characterised pathological changes in GD lamb brain and compared the histological findings to those in GD patient post-mortem tissue, to determine the validity of the sheep as a model of this disease. Five GD and five age-matched unaffected lamb brains were examined. We observed significant expansion of the endo/lysosomal system in GD lamb cingulate gyrus however TPP1 and cathepsin D levels were unchanged or reduced. H&E staining revealed neurons with shrunken, hypereosinophilic cytoplasm and hyperchromatic or pyknotic nuclei (red neurons) that were also shrunken and deeply Nissl stain positive. Amoeboid microglia were noted throughout GD brain. Spheroidal inclusions reactive for TOMM20, ubiquitin and most strikingly, p-Tau were observed in many brain regions in GD lamb brain, potentially indicating disturbed axonal trafficking. Our findings suggest that the ovine model of GD exhibits similar pathological changes to human, mouse, and drosophila type II GD brain, and represents a model suitable for evaluating therapeutic intervention, particularly in utero-targeted approaches., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2023. Published by Elsevier B.V. All rights reserved.)

Half of all reported violent incidents in healthcare settings occur in the emergency department (ED), so ED nurses are disproportionately affected by violence and aggression. Violence and aggression can cause physical injury, psychological harm, delays to patient care, eroded staff morale, increased sick leave and low staff retention. This article explores potential causes and risk factors for violent or aggressive behaviour from patients and visitors in the ED. It discusses risk assessment tools, management approaches and risk reduction strategies that can be used in the ED to tackle violence and aggression. The article also features a case study describing a successful small-scale trial of body-worn cameras at an East London ED., Competing Interests: None declared, (© 2021 RCN Publishing Company Ltd. All rights reserved. Not to be copied, transmitted or recorded in any way, in whole or part, without prior permission of the publishers.)