Impact of the Use of Simulated Patients in Basic First Aid Training on Laypeople Knowledge, Skills, and Self-efficacy: A Controlled Experimental Study.

BACKGROUND: First aid training is a cost-effective way to improve public health, but the most effective methods to teach first aid are currently unclear. The aim of this research was to investigate the added value of simulated patients during first aid certification trainings. METHODS: Occupational first aid trainings organized by the Belgian Red Cross between September 2018 and August 2019 were allocated to either training with a simulated patient or regular training, for the topics "stroke" and "burns." Participants' knowledge and self-efficacy related to these topics were assessed at baseline, directly after training and after 1 year. First aid skills for "stroke" and "burns" and participant satisfaction were assessed after training. Knowledge and self-efficacy were measured via a questionnaire, and skills were assessed during a practical skills test. Data were analyzed using generalized linear mixed model analyses. RESULTS: A total of 1113 participants were enrolled, 403 in the simulated patient group and 710 in the control group. First aid knowledge and self-efficacy increased strongly immediately after training. These increases did not differ between groups, nor did the level of practical skills. The simulated patient group had a significantly increased retention in first aid knowledge after 1 year, compared with control, while retention in self-efficacy did not differ. Participant satisfaction with training was similar between groups. CONCLUSIONS: Using simulated patients during occupational first aid trainings for laypeople did not improve outcomes immediately after training but did improve retention of first aid knowledge after 1 year. These results support the use of simulated patients during first aid training.

Mass gathering events: a retrospective analysis of the triage categories, type of injury or medical complaint and medical usage rates.

BACKGROUND: Adequate on-site first aid delivery at mass gatherings (MGs) is one of the cornerstones to ensure safe and healthy MGs. We investigated medical usage rates, frequency of triage categories and type of injury or medical complaint, among attendees at MGs in Belgium. METHODS: We analysed the Medical Triage and Registration Informatics System database, which includes prospectively collected person-level data regarding individuals visiting on-site posts at MGs in Belgium. MGs attended by >10 000 people and organised ≥5 times between 2009 and 2018 were included. We determined the proportion of patients in each triage category ('first aid' vs 'medical condition' vs 'medical emergency' vs 'no treatment') and each type of injury or medical complaint, and we calculated patient presentation rate (PPR) and transfer to hospital rate (TTHR). RESULTS: Twenty-eight MGs, totalling 194 events, were included involving 148 265 patient visits. 'First aid' was the most common triage category (80%, n=118 514). The need for a nurse/physician ('medical condition'), and for the treatment of life-threatening conditions ('medical emergency') was rare (8.9%, n=13 052, and 0.6%, n=860, of all patient presentations, respectively), but remarkably higher during indoor electronic dance music (EDM) events (17.8% (n=26 391) and 4.0% (n=5930), of all patient presentations, respectively). 'Skin wounds' were the most common injury category (42.4%, n=62 275). 'Respiratory problems', 'neurological problems', 'intoxication', 'heart complaints' and 'gastrointestinal complaints' were more frequent during indoor (electronic) dance, whereas 'burns', 'fracture/contusion' and 'skin wounds' were higher during outdoor music, sports events and city festivals, respectively. PPR (per 10 000 attendees) was highest for outdoor EDM and outdoor music (median 130 (IQR 79) and 129 (IQR 104), respectively). TTHR (per 10 000 attendees) was highest for indoor EDM (median 4.4 (IQR 8.5)). CONCLUSION: Medical usage rates, proportion of patients in triage and injury or medical complaint categories varied across different MG categories, suggesting opportunities for planning medical coverage at these events.

Predicting medical usage rate at mass gathering events in Belgium: development and validation of a nonlinear multivariable regression model.

BACKGROUND: Every year, volunteers of the Belgian Red Cross provide onsite medical care at more than 8000 mass gathering events and other manifestations. Today standardized planning tools for optimal preventive medical resource use during these events are lacking. This study aimed to develop and validate a prediction model of patient presentation rate (PPR) and transfer to hospital rate (TTHR) at mass gatherings in Belgium. METHODS: More than 200,000 medical interventions from 2006 to 2018 were pooled in a database. We used a subset of 28 different mass gatherings (194 unique events) to develop a nonlinear prediction model. Using regression trees, we identified potential predictors for PPR and TTHR at these mass gatherings. The additional effect of ambient temperature was studied by linear regression analysis. Finally, we validated the prediction models using two other subsets of the database. RESULTS: The regression tree for PPR consisted of 7 splits, with mass gathering category as the most important predictor variable. Other predictor variables were attendance, number of days, and age class. Ambient temperature was positively associated with PPR at outdoor events in summer. Calibration of the model revealed an R2 of 0.68 (95% confidence interval 0.60-0.75). For TTHR, the most determining predictor variables were mass gathering category and predicted PPR (R2 = 0.48). External validation indicated limited predictive value for other events (R2 = 0.02 for PPR; R2 = 0.03 for TTHR). CONCLUSIONS: Our nonlinear model performed well in predicting PPR at the events used to build the model on, but had poor predictive value for other mass gatherings. The mass gathering categories "outdoor music" and "sports event" warrant further splitting in subcategories, and variables such as attendance, temperature and resource deployment need to be better recorded in the future to optimize prediction of medical usage rates, and hence, of resources needed for onsite emergency medical care.

Best Available Evidence on Communicative First Aid Interventions by Laypeople for Preventing and Relieving Posttraumatic Stress Disorder-Related Symptomatology Following Traumatic Events.

Trauma-exposed individuals are at risk of developing mental health problems, including posttraumatic stress disorder (PTSD). As an exposed individual's friend or family member may be the first person to provide posttrauma relief, informing and training laypeople in psychosocial first aid may benefit mental health outcomes of trauma-exposed individuals. We aimed to (a) collect the best available evidence on communication as a first aid intervention in assisting individuals following traumatic events and (b) formulate practical recommendations. Systematic literature searches were conducted in three databases (March 2019). Following study selection, the extracted data were tabulated and synthesized narratively. The evidence was appraised according to the GRADE methodology and evaluated by a multidisciplinary expert panel to formulate recommendations for practice. Out of 1,724 articles, no experimental studies were identified, showing a complete lack of high-quality controlled studies on the efficacy of communicative practices. However, when lower-quality study designs were included, nine cross-sectional studies constituted the best available evidence. The studies suggested that positive communication by family members, r = -.38, aOR = 0.26, ß = -.22, p < .001-p < .05, and expressive coping by the victim, ß = -.62, p < .001, were associated with PTSD diagnosis and/or symptom severity; however, the evidence was of very low certainty. The expert panel took the methodological limitations into account when formulating weak practical recommendations. Cross-sectional studies currently provide the best possible evidence for developing guidelines on psychosocial first aid. High-quality controlled studies are needed to establish casual associations and identify the most effective interventions.

Aged Tmem106b knockout mice display gait deficits in coincidence with Purkinje cell loss and only limited signs of non-motor dysfunction.

Genetic variants in TMEM106B are a major risk factor for several neurodegenerative diseases including frontotemporal degeneration, limbic-predominant age-related TDP-43 encephalopathy, Parkinson's disease, late-onset-Alzheimer's disease and constitute a genetic determinant of differential aging. TMEM106B encodes an integral lysosomal membrane protein but its precise physiological function in the central nervous system remains enigmatic. Presently, we aimed to increase understanding of TMEM106B contribution to general brain function and aging. We analyzed an aged cohort of Tmem106b knockout-, heterozygote and wild-type mice in a behavioral test battery including assessments of motor function as well as, social, emotional and cognitive function. Aged Tmem106b knockout (KO) mice displayed diverse behavioral deficits including motor impairment, gait defects and reduced startle reactivity. In contrast, no prominent deficits were observed in social, emotional or cognitive behaviors. Histologically, we observed late-onset loss of Purkinje cells followed by reactive gliosis in the cerebellum, which likely contributed to progressive decline in motor function and gait defects in particular. Reactive gliosis was not restricted to the cerebellum but observed in different areas of the brain including the brain stem and parts of the cerebral cortex. Surviving Purkinje cells showed vacuolated lysosomes in the axon initial segment, implicating TMEM106B-dependent lysosomal trafficking defects as the underlying cause of axonal and more general neuronal dysfunction contributing to behavioral impairments. Our experiments help to elucidate how TMEM106B affects spatial neuronal homeostasis and exemplifies a critical role of TMEM106B in neuronal cells for survival.

Factors affecting mental health of health care workers during coronavirus disease outbreaks (SARS, MERS & COVID-19): A rapid systematic review.

INTRODUCTION: The novel Coronavirus Disease (COVID-19) outbreak currently puts health care workers at high risk of both physical and mental health problems. This study aimed to identify the risk and protective factors for mental health outcomes in health care workers during coronavirus epidemics. METHODS: A rapid systematic review was performed in three databases (March 24, 2020) and a current COVID-19 resource (May 28, 2020). Following study selection, study characteristics and effect measures were tabulated, and data were synthesized by using vote counting. Meta-analysis was not possible because of high variation in risk factors, outcomes and effect measures. Risk of bias of each study was assessed and the certainty of evidence was appraised according to the GRADE methodology. RESULTS: Out of 2605 references, 33 observational studies were selected and the identified risk and protective factors were categorized in ten thematic categories. Most of these studies (n = 23) were performed during the SARS outbreak, seven during the current COVID-19 pandemic and three during the MERS outbreak. The level of disease exposure and health fear were significantly associated with worse mental health outcomes. There was evidence that clear communication and support from the organization, social support and personal sense of control are protective factors. The evidence was of very low certainty, because of risk of bias and imprecision. CONCLUSION: Safeguarding mental health of health care workers during infectious disease outbreaks should not be treated as a separate mental health intervention strategy, but could benefit from a protective approach. This study suggests that embedding mental health support in a safe and efficient working environment which promotes collegial social support and personal sense of control could help to maximize resilience of health care workers. Low quality cross-sectional studies currently provide the best possible evidence, and further research is warranted to confirm causality.

The mental health impact of the covid-19 pandemic on healthcare workers, and interventions to help them: A rapid systematic review.

The covid-19 pandemic has heavily burdened healthcare systems throughout the world. We performed a rapid systematic review to identify, assess and summarize research on the mental health impact of the covid-19 pandemic on HCWs (healthcare workers). We utilized the Norwegian Institute of Public Health's Live map of covid-19 evidence on 11 May and included 59 studies. Six reported on implementing interventions, but none reported on effects of the interventions. HCWs reported low interest in professional help, and greater reliance on social support and contact. Exposure to covid-19 was the most commonly reported correlate of mental health problems, followed by female gender, and worry about infection or about infecting others. Social support correlated with less mental health problems. HCWs reported anxiety, depression, sleep problems, and distress during the covid-19 pandemic. We assessed the certainty of the estimates of prevalence of these symptoms as very low using GRADE. Most studies did not report comparative data on mental health symptoms before the pandemic or in the general population. There seems to be a mismatch between risk factors for adverse mental health outcomes among HCWs in the current pandemic, their needs and preferences, and the individual psychopathology focus of current interventions.

Arylsulfatase K inactivation causes mucopolysaccharidosis due to deficient glucuronate desulfation of heparan and chondroitin sulfate.

Mucopolysaccharidoses comprise a group of rare metabolic diseases, in which the lysosomal degradation of glycosaminoglycans (GAGs) is impaired due to genetically inherited defects of lysosomal enzymes involved in GAG catabolism. The resulting intralysosomal accumulation of GAG-derived metabolites consequently manifests in neurological symptoms and also peripheral abnormalities in various tissues like liver, kidney, spleen and bone. As each GAG consists of differently sulfated disaccharide units, it needs a specific, but also partly overlapping set of lysosomal enzymes to accomplish their complete degradation. Recently, we identified and characterized the lysosomal enzyme arylsulfatase K (Arsk) exhibiting glucuronate-2-sulfatase activity as needed for the degradation of heparan sulfate (HS), chondroitin sulfate (CS) and dermatan sulfate (DS). In the present study, we investigated the physiological relevance of Arsk by means of a constitutive Arsk knockout mouse model. A complete lack of glucuronate desulfation was demonstrated by a specific enzyme activity assay. Arsk-deficient mice show, in an organ-specific manner, a moderate accumulation of HS and CS metabolites characterized by 2-O-sulfated glucuronate moieties at their non-reducing ends. Pathophysiological studies reflect a rather mild phenotype including behavioral changes. Interestingly, no prominent lysosomal storage pathology like bone abnormalities were detected. Our results from the Arsk mouse model suggest a new although mild form of mucopolysacharidose (MPS), which we designate MPS type IIB.

The FTLD Risk Factor TMEM106B Regulates the Transport of Lysosomes at the Axon Initial Segment of Motoneurons.

Genetic variations in TMEM106B, coding for a lysosomal membrane protein, affect frontotemporal lobar degeneration (FTLD) in GRN- (coding for progranulin) and C9orf72-expansion carriers and might play a role in aging. To determine the physiological function of TMEM106B, we generated TMEM106B-deficient mice. These mice develop proximal axonal swellings caused by drastically enlarged LAMP1-positive vacuoles, increased retrograde axonal transport of lysosomes, and accumulation of lipofuscin and autophagosomes. Giant vacuoles specifically accumulate at the distal end and within the axon initial segment, but not in peripheral nerves or at axon terminals, resulting in an impaired facial-nerve-dependent motor performance. These data implicate TMEM106B in mediating the axonal transport of LAMP1-positive organelles in motoneurons and axonal sorting at the initial segment. Our data provide mechanistic insight into how TMEM106B affects lysosomal proteolysis and degradative capacity in neurons.

Post-weaning infant-to-mother bonding in nutritionally independent female mice.

Infant-parent attachment is highly selective and continues beyond essential care in primates, most prominently in humans, and the quality of this attachment crucially determines cognitive and emotional development of the infant. Altricial rodent species such as mice (Mus musculus) display mutual recognition and communal nursing in wild and laboratory environments, but parental bonding beyond the nursing period has not been reported. We presently demonstrated that socially and nutritionally independent mice still prefer to interact selectively with their mother dam. Furthermore, we observed gender differences in the mother-infant relationship, and showed disruption of this relationship in haploinsufficient Nbea+/- mice, a putative autism model with neuroendocrine dysregulation. To our knowledge, this is the first observation of murine infant-to-mother bonding beyond the nursing period.

Early Cognitive and Behavioral Deficits in Mouse Models for Tauopathy and Alzheimer's Disease.

Neurocognitive disorders, among which Alzheimer's disease (AD), have become one of the major causes of death in developed countries. No effective disease-modifying therapy is available, possibly because current treatments are administered too late to still be able to intervene in the disease progress. AD is characterized by a gradual onset with subclinical neurobiological and behavioral changes that precede diagnosis with years to even decades. The earlier the diagnosis, the earlier potential treatments can be tested and started. Mouse models are valuable to study the possible causes underlying early phases of neuropathology and their reflection in behavior and other biomarkers, to help improve preclinical detection and diagnosis of AD. Here, we assessed cognitive functioning and social behavior in transgenic mice expressing tau pathology only (Tau-P301L) or a combination of amyloid and tau pathology [amyloid precursor protein (APP)-V717I × Tau-P301L]. The mice were subjected to a variety of behavioral tasks at an age of 3-6 months, i.e., at an early phase of their AD-like pathology. We hypothesized that compared to age-matched wild-type controls, transgenic mice would show specific impairments in both cognitive and non-cognitive tasks. In line with our expectations, transgenic mice showed decreased cognitive flexibility in the Morris water maze, decreased exploratory behavior, decreased performance in a nesting task, and increased anxiety-like behavior. In accordance with the amyloid-cascade hypothesis, some of the behavioral measures showed more severe deficits in APP-V717I × Tau-P301L compared to Tau-P301L mice, indicating an exacerbation of disease processes due to the co-occurrence of amyloid and tau pathology. Our study supports the use of behavioral markers as early indicators of ongoing AD pathology during the preclinical phase.

Microglia lacking a peroxisomal ß-oxidation enzyme chronically alter their inflammatory profile without evoking neuronal and behavioral deficits.

BACKGROUND: Microglia play a central role in most neurological disorders, but the impact of microgliosis on brain environment and clinical functions is not fully understood. Mice lacking multifunctional protein-2 (MFP2), a pivotal enzyme in peroxisomal ß-oxidation, develop a fatal disorder characterized by motor problems similar to the milder form of MFP2 deficiency in humans. The hallmark of disease in mice is the chronic proliferation of microglia in the brain, but molecular pathomechanisms that drive rapid clinical deterioration in human and mice remain unknown. In the present study, we identified the effects of specific deletion of MFP2 from microglia in the brain on immune responses, neuronal functioning, and behavior. METHODS: We created a novel Cx3cr1-Mfp2-/- mouse model and studied the impact of MFP2 deficiency on microglial behavior at different ages using immunohistochemistry and real-time PCR. Pro- and anti-inflammatory responses of Mfp2-/- microglia were assessed in vitro and in vivo after stimulation with IL-1ß/INFγ and IL-4 (in vitro) and LPS and IL-4 (in vivo). Facial nerve axotomy was unilaterally performed in Cx3cr1-Mfp2-/- and control mice, and microglial functioning in response to neuronal injury was subsequently analyzed by histology and real-time PCR. Finally, neuronal function, motor function, behavior, and cognition were assessed using brainstem auditory evoked potentials, grip strength and inverted grid test, open field exploration, and passive avoidance learning, respectively. RESULTS: We found that Mfp2-/- microglia in a genetically intact brain environment adopt an inflammatory activated and proliferative state. In addition, we found that acute inflammatory and neuronal injury provoked normal responses of Mfp2-/- microglia in Cx3cr1-Mfp2-/- mice during the post-injury period. Despite chronic pro-inflammatory microglial reactivity, Cx3cr1-Mfp2-/- mice exhibited normal neuronal transmission, clinical performance, and cognition. CONCLUSION: Our data demonstrate that MFP2 deficiency in microglia causes intrinsic dysregulation of their inflammatory profile, which is not harmful to neuronal function, motor function, and cognition in mice during their first year of life.

Neuronal Dysfunction and Behavioral Abnormalities Are Evoked by Neural Cells and Aggravated by Inflammatory Microglia in Peroxisomal ß-Oxidation Deficiency.

It is becoming evident that microglia, the resident immune cells of the central nervous system (CNS), are active contributors in neurological disorders. Nevertheless, the impact of microgliosis on neuropathology, behavior and clinical decline in neuropathological conditions remains elusive. A mouse model lacking multifunctional protein-2 (MFP2), a pivotal enzyme in peroxisomal ß-oxidation, develops a fatal disorder characterized by motor problems similar to the milder form of human disease. The molecular mechanisms underlying neurological decline in men and mice remain unknown. The hallmark of disease in the mouse model is chronic proliferation of microglia in the brain without provoking neuronal loss or demyelination. In order to define the contribution of Mfp2-/- neural cells to development of microgliosis and clinical neuropathology, the constitutive Mfp2-/- mouse model was compared to a neural selective Nestin-Mfp2-/- mouse model. We demonstrate in this study that, in contrast to early-onset and severe microgliosis in constitutive Mfp2-/- mice, Mfp2+/+ microglia in Nestin-Mfp2-/- mice only become mildly inflammatory at end stage of disease. Mfp2-/- microglia are primed and acquire a chronic and strong inflammatory state in Mfp2-/- mice whereas Mfp2+/+ microglia in Nestin-Mfp2-/- mice are not primed and adopt a minimal activation state. The inflammatory microglial phenotype in Mfp2-/- mice is correlated with more severe neuronal dysfunction, faster clinical deterioration and reduced life span compared to Nestin-Mfp2-/- mice. Taken together, our study shows that deletion of MFP2 impairs behavior and locomotion. Clinical decline and neural pathology is aggravated by an early-onset and excessive microglial response in Mfp2-/- mice and strongly indicates a cell-autonomous role of MFP2 in microglia.

Sensorimotor and Neurocognitive Dysfunctions Parallel Early Telencephalic Neuropathology in Fucosidosis Mice.

Fucosidosis is a lysosomal storage disorder (LSD) caused by lysosomal α-L-fucosidase deficiency. Insufficient α-L-fucosidase activity triggers accumulation of undegraded, fucosylated glycoproteins and glycolipids in various tissues. The human phenotype is heterogeneous, but progressive motor and cognitive impairments represent the most characteristic symptoms. Recently, Fuca1-deficient mice were generated by gene targeting techniques, constituting a novel animal model for human fucosidosis. These mice display widespread LSD pathology, accumulation of secondary storage material and neuroinflammation throughout the brain, as well as progressive loss of Purkinje cells. Fuca1-deficient mice and control littermates were subjected to a battery of tests detailing different aspects of motor, emotional and cognitive function. At an early stage of disease, we observed reduced exploratory activity, sensorimotor disintegration as well as impaired spatial learning and fear memory. These early markers of neurological deterioration were related to the respective stage of neuropathology using molecular genetic and immunochemical procedures. Increased expression of the lysosomal marker Lamp1 and neuroinflammation markers was observed throughout the brain, but appeared more prominent in cerebral areas in comparison to cerebellum of Fuca1-deficient mice. This is consistent with impaired behaviors putatively related to early disruptions of motor and cognitive circuits particularly involving cerebral cortex, basal ganglia, and hippocampus. Thus, Fuca1-deficient mice represent a practical and promising fucosidosis model, which can be utilized for pathogenetic and therapeutic studies.

Long-term enzyme replacement therapy improves neurocognitive functioning and hippocampal synaptic plasticity in immune-tolerant alpha-mannosidosis mice.

Alpha-mannosidosis is a glycoproteinosis caused by deficiency of lysosomal acid alpha-mannosidase (LAMAN), which markedly affects neurons of the central nervous system (CNS), and causes pathognomonic intellectual dysfunction in the clinical condition. Cognitive improvement consequently remains a major therapeutic objective in research on this devastating genetic error. Immune-tolerant LAMAN knockout mice were developed to evaluate the effects of enzyme replacement therapy (ERT) by prolonged administration of recombinant human enzyme. Biochemical evidence suggested that hippocampus may be one of the brain structures that benefits most from long-term ERT. In the present functional study, ERT was initiated in 2-month-old immune-tolerant alpha-mannosidosis mice and continued for 9months. During the course of treatment, mice were trained in the Morris water maze task to assess spatial-cognitive performance, which was related to synaptic plasticity recordings and hippocampal histopathology. Long-term ERT reduced primary substrate storage and neuroinflammation in hippocampus, and improved spatial learning after mid-term (10weeks+) and long-term (30weeks+) treatment. Long-term treatment substantially improved the spatial-cognitive abilities of alpha-mannosidosis mice, whereas the effects of mid-term treatment were more modest. Detailed analyses of spatial memory and spatial-cognitive performance indicated that even prolonged ERT did not restore higher cognitive abilities to the level of healthy mice. However, it did demonstrate marked therapeutic effects that coincided with increased synaptic connectivity, reflected by improvements in hippocampal CA3-CA1 long-term potentiation (LTP), expression of postsynaptic marker PSD-95 as well as postsynaptic density morphology. These experiments indicate that long-term ERT may hold promise, not only for the somatic defects of alpha-mannosidosis, but also to alleviate cognitive impairments of the disorder.

Progressive leukoencephalopathy impairs neurobehavioral development in sialin-deficient mice.

Slc17a5-/- mice represent an animal model for the infantile form of sialic acid storage disease (SASD). We analyzed genetic and histological time-course expression of myelin and oligodendrocyte (OL) lineage markers in different parts of the CNS, and related this to postnatal neurobehavioral development in these mice. Sialin-deficient mice display a distinct spatiotemporal pattern of sialic acid storage, CNS hypomyelination and leukoencephalopathy. Whereas few genes are differentially expressed in the perinatal stage (p0), microarray analysis revealed increased differential gene expression in later postnatal stages (p10-p18). This included progressive upregulation of neuroinflammatory genes, as well as continuous down-regulation of genes that encode myelin constituents and typical OL lineage markers. Age-related histopathological analysis indicates that initial myelination occurs normally in hindbrain regions, but progression to more frontal areas is affected in Slc17a5-/- mice. This course of progressive leukoencephalopathy and CNS hypomyelination delays neurobehavioral development in sialin-deficient mice. Slc17a5-/- mice successfully achieve early neurobehavioral milestones, but exhibit progressive delay of later-stage sensory and motor milestones. The present findings may contribute to further understanding of the processes of CNS myelination as well as help to develop therapeutic strategies for SASD and other myelination disorders.

A mouse model for fucosidosis recapitulates storage pathology and neurological features of the milder form of the human disease.

Fucosidosis is a rare lysosomal storage disorder caused by the inherited deficiency of the lysosomal hydrolase α-L-fucosidase, which leads to an impaired degradation of fucosylated glycoconjugates. Here, we report the generation of a fucosidosis mouse model, in which the gene for lysosomal α-L-fucosidase (Fuca1) was disrupted by gene targeting. Homozygous knockout mice completely lack α-L-fucosidase activity in all tested organs leading to highly elevated amounts of the core-fucosylated glycoasparagine Fuc(α1,6)-GlcNAc(ß1-N)-Asn and, to a lesser extent, other fucosylated glycoasparagines, which all were also partially excreted in urine. Lysosomal storage pathology was observed in many visceral organs, such as in the liver, kidney, spleen and bladder, as well as in the central nervous system (CNS). On the cellular level, storage was characterized by membrane-limited cytoplasmic vacuoles primarily containing water-soluble storage material. In the CNS, cellular alterations included enlargement of the lysosomal compartment in various cell types, accumulation of secondary storage material and neuroinflammation, as well as a progressive loss of Purkinje cells combined with astrogliosis leading to psychomotor and memory deficits. Our results demonstrate that this new fucosidosis mouse model resembles the human disease and thus will help to unravel underlying pathological processes. Moreover, this model could be utilized to establish diagnostic and therapeutic strategies for fucosidosis.

Brain endothelial TAK1 and NEMO safeguard the neurovascular unit.

Inactivating mutations of the NF-κB essential modulator (NEMO), a key component of NF-κB signaling, cause the genetic disease incontinentia pigmenti (IP). This leads to severe neurological symptoms, but the mechanisms underlying brain involvement were unclear. Here, we show that selectively deleting Nemo or the upstream kinase Tak1 in brain endothelial cells resulted in death of endothelial cells, a rarefaction of brain microvessels, cerebral hypoperfusion, a disrupted blood-brain barrier (BBB), and epileptic seizures. TAK1 and NEMO protected the BBB by activating the transcription factor NF-κB and stabilizing the tight junction protein occludin. They also prevented brain endothelial cell death in a NF-κB-independent manner by reducing oxidative damage. Our data identify crucial functions of inflammatory TAK1-NEMO signaling in protecting the brain endothelium and maintaining normal brain function, thus explaining the neurological symptoms associated with IP.

Anti-inflammatory Therapy With Simvastatin Improves Neuroinflammation and CNS Function in a Mouse Model of Metachromatic Leukodystrophy.

Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by a functional deficiency of the lysosomal enzyme arylsulfatase A. The prevailing late-infantile variant of MLD is characterized by widespread and progressive demyelination of the central nervous system (CNS) causing death during childhood. In order to gain insight into the pathomechanism of the disease and to identify novel therapeutic targets, we analyzed neuroinflammation in two mouse models reproducing a mild, nondemyelinating, and a more severe, demyelinating, variant of MLD, respectively. Microgliosis and upregulation of cytokine/chemokine levels were clearly more pronounced in the demyelinating model. The analysis of the temporal cytokine/chemokine profiles revealed that the onset of demyelination is preceded by a sustained elevation of the macrophage inflammatory protein (MIP)-1α followed by an upregulation of MIP-1ß, monocyte chemotactic protein (MCP)-1, and several interleukins. The tumor necrosis factor (TNF)-α remains unchanged. Treatment of the demyelinating mouse model with the nonsteroidal anti-inflammatory drug simvastatin reduced neuroinflammation, improved the swimming performance and ataxic gait, and retarded demyelination of the spinal cord. Our data suggest that neuroinflammation is causative for demyelination in MLD mice and that anti-inflammatory treatment might be a novel therapeutic option to improve the CNS function of MLD patients.