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1. Guillain-Barré Syndrome Following Zika Virus Infection Is Associated With a Diverse Spectrum of Peripheral Nerve Reactive Antibodies

Author

Davies, Alexander J., Lleixà, Cinta, Siles, Ana M., Gourlay, Dawn S., Berridge, Georgina, Dejnirattisai, Wanwisa, Ramírez-Santana, Carolina, Anaya, Juan-Manuel, Falconar, Andrew K., Romero-Vivas, Claudia M., Osorio, Lyda, Parra, Beatriz, Screaton, Gavin R., Mongkolsapaya, Juthathip, Fischer, Roman, Pardo, Carlos A., Halstead, Susan K., Willison, Hugh J., Querol, Luis, and Rinaldi, Simon

Published
2023
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2. A Novel Cytotoxic Mechanism for Triple-Negative Breast Cancer Cells Induced by the Type II Heat-Labile Enterotoxin LT-IIc through Ganglioside Ligation.

Author

King-Lyons, Natalie D., Bhati, Aryana S., Hu, John C., Mandell, Lorrie M., Shenoy, Gautam N., Willison, Hugh J., and Connell, Terry D.

Subjects
TRIPLE-negative breast cancer, CYTOTOXINS, BREAST cancer, EPITHELIAL cells, CELL death
Abstract

Triple-negative breast cancer (TNBC), which constitutes 10–20 percent of all breast cancers, is aggressive, has high metastatic potential, and carries a poor prognosis due to limited treatment options. LT-IIc, a member of the type II subfamily of ADP-ribosylating—heat-labile enterotoxins that bind to a distinctive set of cell-surface ganglioside receptors—is cytotoxic toward TNBC cell lines, but has no cytotoxic activity for non-transformed breast epithelial cells. Here, primary TNBC cells, isolated from resected human tumors, showed an enhanced cytotoxic response specifically toward LT-IIc, in contrast to other enterotoxins that were tested. MDA-MB-231 cells, a model for TNBC, were used to evaluate potential mechanisms of cytotoxicity by LT-IIc, which induced elevated intracellular cAMP and stimulated the cAMP response element-binding protein (CREB) signaling pathway. To dissect the role of ADP-ribosylation, cAMP induction, and ganglioside ligation in the cytotoxic response, MDA-MB-231 cells were exposed to wild-type LT-IIc, the recombinant B-pentamer of LT-IIc that lacks the ADP-ribosylating A polypeptide, or mutants of LT-IIc with an enzymatically inactivated A1-domain. These experiments revealed that the ADP-ribosyltransferase activity of LT-IIc was nonessential for inducing the lethality of MDA-MB-231 cells. In contrast, a mutant LT-IIc with an altered ganglioside binding activity failed to trigger a cytotoxic response in MDA-MB-231 cells. Furthermore, the pharmacological inhibition of ganglioside expression protected MDA-MB-231 cells from the cytotoxic effects of LT-IIc. These data establish that ganglioside ligation, but not the induction of cAMP production nor ADP-ribosyltransferase activity, is essential to initiating the LT-IIc-dependent cell death of MDA-MB-231 cells. These experiments unveiled previously unknown properties of LT-IIc and gangliosides in signal transduction, offering the potential for the targeted treatment of TNBC, an option that is desperately needed. [ABSTRACT FROM AUTHOR]

Published
2024
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3. Schwann cell nodal membrane disruption triggers bystander axonal degeneration in a Guillain-Barre syndrome mouse model

Author

McGonigal, Rhona, Campbell, Clare I., Barrie, Jennifer A., Yao, Denggao, Cunningham, Madeleine E., Crawford, Colin L., Rinaldi, Simon, Rowan, Edward G., and Willison, Hugh J.

Subjects
Physiological aspects, Models, Development and progression, Risk factors, Injuries, Schwann cells -- Physiological aspects, Gangliosides -- Physiological aspects, Axons -- Injuries, Guillain-Barre syndrome -- Risk factors -- Development and progression -- Models
Abstract

Introduction Guillain-Barre syndrome (GBS) is a postinfectious autoimmune disorder affecting the peripheral nervous system (PNS) resulting in acute-onset paralysis (1). GBS comprises a spectrum of axonal and demyelinating variants that [...], In Guillain-Barre syndrome (GBS), both axonal and demyelinating variants can be mediated by complement-fixing anti-GM1 ganglioside autoantibodies that target peripheral nerve axonal and Schwann cell (SC) membranes, respectively. Critically, the extent of axonal degeneration in both variants dictates long-term outcome. The differing pathomechanisms underlying direct axonal injury and the secondary bystander axonal degeneration following SC injury are unresolved. To investigate this, we generated glycosyltransferase-disrupted transgenic mice that express GM1 ganglioside either exclusively in neurons [[GalNAcT.sup.-/-]-Tg(neuronal)] or glia [[GalNAcT.sup.-/-]-Tg(glial)], thereby allowing anti-GM1 antibodies to solely target GM1 in either axonal or SC membranes, respectively. Myelinated-axon integrity in distal motor nerves was studied in transgenic mice exposed to anti-GM1 antibody and complement in ex vivo and in vivo injury paradigms. Axonal targeting induced catastrophic acute axonal disruption, as expected. When mice with GM1 in SC membranes were targeted, acute disruption of perisynaptic glia and SC membranes at nodes of Ranvier (NoRs) occurred. Following glial injury, axonal disruption at NoRs also developed subacutely, progressing to secondary axonal degeneration. These models differentiate the distinctly different axonopathic pathways under axonal and glial membrane targeting conditions, and provide insights into primary and secondary axonal injury, currently a major unsolved area in GBS research.

Published
2022
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4. Diagnosis and management of Guillain–Barré syndrome in ten steps

Author

Leonhard, Sonja E., Mandarakas, Melissa R., Gondim, Francisco A. A., Bateman, Kathleen, Ferreira, Maria L. B., Cornblath, David R., van Doorn, Pieter A., Dourado, Mario E., Hughes, Richard A. C., Islam, Badrul, Kusunoki, Susumu, Pardo, Carlos A., Reisin, Ricardo, Sejvar, James J., Shahrizaila, Nortina, Soares, Cristiane, Umapathi, Thirugnanam, Wang, Yuzhong, Yiu, Eppie M., Willison, Hugh J., and Jacobs, Bart C.

Published
2019
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5. European Academy of Neurology/Peripheral Nerve Society Guideline on diagnosis and treatment of Guillain–Barré syndrome

Author

van Doorn, Pieter A., Van den Bergh, Peter Y.K., Hadden, Robert D.M., Avau, Bert, Vankrunkelsven, Patrik, Attarian, Shahram, Blomkwist-Markens, Patricia H., Cornblath, David R., Goedee, H. Stephan, Harbo, Thomas, Jacobs, Bart C., Kusunoki, Susumu, Lehmann, Helmar C., Lewis, Richard A., Lunn, Michael P., Nobile-Orazio, Eduardo, Querol, Luis, Rajabally, Yusuf A., Umapathi, Thirugnanam, Topaloglu, Haluk A., Willison, Hugh J., van Doorn, Pieter A., Van den Bergh, Peter Y.K., Hadden, Robert D.M., Avau, Bert, Vankrunkelsven, Patrik, Attarian, Shahram, Blomkwist-Markens, Patricia H., Cornblath, David R., Goedee, H. Stephan, Harbo, Thomas, Jacobs, Bart C., Kusunoki, Susumu, Lehmann, Helmar C., Lewis, Richard A., Lunn, Michael P., Nobile-Orazio, Eduardo, Querol, Luis, Rajabally, Yusuf A., Umapathi, Thirugnanam, Topaloglu, Haluk A., and Willison, Hugh J.

Abstract

Guillain–Barré syndrome (GBS) is an acute polyradiculoneuropathy. Symptoms may vary greatly in presentation and severity. Besides weakness and sensory disturbances, patients may have cranial nerve involvement, respiratory insufficiency, autonomic dysfunction and pain. To develop an evidence-based guideline for the diagnosis and treatment of GBS, using Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology a Task Force (TF) of the European Academy of Neurology (EAN) and the Peripheral Nerve Society (PNS) constructed 14 Population/Intervention/Comparison/Outcome questions (PICOs) covering diagnosis, treatment and prognosis of GBS, which guided the literature search. Data were extracted and summarised in GRADE Summaries of Findings (for treatment PICOs) or Evidence Tables (for diagnostic and prognostic PICOs). Statements were prepared according to GRADE Evidence-to-Decision (EtD) frameworks. For the six intervention PICOs, evidence-based recommendations are made. For other PICOs, good practice points (GPPs) are formulated. For diagnosis, the principal GPPs are: GBS is more likely if there is a history of recent diarrhoea or respiratory infection; CSF examination is valuable, particularly when the diagnosis is less certain; electrodiagnostic testing is advised to support the diagnosis; testing for anti-ganglioside antibodies is of limited clinical value in most patients with typical motor-sensory GBS, but anti-GQ1b antibody testing should be considered when Miller Fisher syndrome (MFS) is suspected; nodal–paranodal antibodies should be tested when autoimmune nodopathy is suspected; MRI or ultrasound imaging should be considered in atypical cases; and changing the diagnosis to acute-onset chronic inflammatory demyelinating polyradiculoneuropathy (A-CIDP) should be considered if progression continues after 8 weeks from onset, which occurs in around 5% of patients initially diagnosed with GBS. For treatment, the TF recommends intravenous

Published
2023

7. Post-Infectious Autoimmunity in the Central (CNS) and Peripheral (PNS) Nervous Systems: An African Perspective

Author

Ndondo, Alvin Pumelele, Eley, Brian, Wilmshurst, Jo Madeleine, Kakooza-Mwesige, Angelina, Giannoccaro, Maria Pia, Willison, Hugh J., Cruz, Pedro M. Rodríguez, Heckmann, Jeannine M., Bateman, Kathleen, Vincent, Angela, Ndondo, Alvin Pumelele, Eley, Brian, Wilmshurst, Jo Madeleine, Kakooza-Mwesige, Angelina, Giannoccaro, Maria Pia, Willison, Hugh J, Cruz, Pedro M Rodríguez, Heckmann, Jeannine M, Bateman, Kathleen, and Vincent, Angela

Subjects
Adult, Central Nervous System, Immunology, Àfrica, Communicable Diseases, COVID-19 (Malaltia), Communicable Disease, encephaliti, Central Nervous System Diseases, peripheral nervous system, Humans, Malalties transmissibles, Immunology and Allergy, neurological disorder, Child, Brain Diseases, post-infectiou, autoimmunity, Brain Disease, COVID-19, Peripheral Nervous System Diseases, encephalopathy, immunity, Sistema nerviós -- Malalties, Immunitat, Central Nervous System Disease, Africa, Encephalitis, Human
Abstract

The direct impact and sequelae of infections in children and adults result in significant morbidity and mortality especially when they involve the central (CNS) or peripheral nervous system (PNS). The historical understanding of the pathophysiology has been mostly focused on the direct impact of the various pathogens through neural tissue invasion. However, with the better understanding of neuroimmunology, there is a rapidly growing realization of the contribution of the innate and adaptive host immune responses in the pathogenesis of many CNS and PNS diseases.The balance between the protective and pathologic sequelae of immunity is fragile and can easily be tipped towards harm for the host. The matter of immune privilege and surveillance of the CNS/PNS compartments and the role of the blood-brain barrier (BBB) and blood nerve barrier (BNB) makes this even more complex. Our understanding of the pathogenesis of many post-infectious manifestations of various microbial agents remains elusive, especially in the diverse African setting. Our exploration and better understanding of the neuroimmunology of some of the infectious diseases that we encounter in the continent will go a long way into helping us to improve their management and therefore lessen the burden.Africa is diverse and uniquely poised because of the mix of the classic, well described, autoimmune disease entities and the specifically “tropical” conditions. This review explores the current understanding of some of the para- and post-infectious autoimmune manifestations of CNS and PNS diseases in the African context. We highlight the clinical presentations, diagnosis and treatment of these neurological disorders and underscore the knowledge gaps and perspectives for future research using disease models of conditions that we see in the continent, some of which are not uniquely African and, where relevant, include discussion of the proposed mechanisms underlying pathogen-induced autoimmunity. This review covers the following conditions as models and highlight those in which a relationship with COVID-19 infection has been reported: a) Acute Necrotizing Encephalopathy; b) Measles-associated encephalopathies; c) Human Immunodeficiency Virus (HIV) neuroimmune disorders, and particularly the difficulties associated with classical post-infectious autoimmune disorders such as the Guillain-Barré syndrome in the context of HIV and other infections. Finally, we describe NMDA-R encephalitis, which can be post-HSV encephalitis, summarise other antibody-mediated CNS diseases and describe myasthenia gravis as the classic antibody-mediated disease but with special features in Africa.

Published
2022
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8. Guillain-Barré Syndrome Following Zika Virus Infection Is Associated With a Diverse Spectrum of Peripheral Nerve Reactive Antibodies

Author

Davies, Alexander J., primary, Lleixà, Cinta, additional, Siles, Ana M., additional, Gourlay, Dawn S., additional, Berridge, Georgina, additional, Dejnirattisai, Wanwisa, additional, Ramírez-Santana, Carolina, additional, Anaya, Juan-Manuel, additional, Falconar, Andrew K., additional, Romero-Vivas, Claudia M., additional, Osorio, Lyda, additional, Parra, Beatriz, additional, Screaton, Gavin R., additional, Mongkolsapaya, Juthathip, additional, Fischer, Roman, additional, Pardo, Carlos A., additional, Halstead, Susan K., additional, Willison, Hugh J., additional, Querol, Luis, additional, and Rinaldi, Simon, additional

Published
2022
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10. Real time imaging of intra-axonal calcium flux in an explant mouse model of axonal Guillain-Barré syndrome

Author

Cunningham, Madeleine E., McGonigal, Rhona, Barrie, Jennifer A., Yao, Denggao, and Willison, Hugh J.

Subjects
Disease Models, Animal, Mice, Developmental Neuroscience, Neurology, Calpain, Gangliosides, Animals, Calcium, Complement System Proteins, Guillain-Barre Syndrome, Axons
Abstract

The acute motor axonal variant of Guillain-Barré syndrome is associated with the attack of motor axons by anti-ganglioside antibodies which activate complement on the axonal plasma membrane. Animal models have indirectly implicated complement pore-mediated calcium influx as a trigger of axonal damage, through the activation of the protease calpain. However, this calcium influx has never been imaged directly. Herein we describe a method to detect changes in intra-axonal calcium in an ex vivo mouse model of axonal Guillain- Barré syndrome and describe the influence of calcium on axonal injury and the effects of calpain inhibition on axonal outcome.\ud \ud Using ex vivo nerve-muscle explants from Thy1-TNXXL mice which axonally express a genetically encoded calcium indicator, we studied the effect of the binding and activation of complement by an anti-GD1b ganglioside antibody which targets the motor axon. Using live multiphoton imaging, we found that a wave of calcium influx extends retrogradely from the motor nerve terminal as far back as the large bundles within the muscle explant. Despite terminal complement pores being detectable only at the motor nerve terminal and, to a lesser degree, the most distal Node of Ranvier, disruption of axonal proteins occurred at more proximal sites implicating the intra-axonal calcium wave. Morphological analysis indicated two different types of calcium-induced changes: acutely, distal axons showed swelling and breakdown at sites where complement pores were present. Distally, in areas of raised calcium which lacked detectable complement pores, axons developed a spindly, vacuolated appearance suggestive of early signs of degeneration. All morphological changes were prevented with treatment with a calpain inhibitor.\ud \ud This is the first investigation of axonal calcium dynamics in a mouse model of Guillain-Barré syndrome and demonstrates the proximal reach of calcium influx following an injury which is confined to the most distal parts of the motor axon. We also demonstrate that calpain inhibition remains a promising candidate for both acute and sub-acute consequences of calcium-induced calpain activation.

Published
2022

11. SARM1 Depletion Slows Axon Degeneration in a CNS Model of Neurotropic Viral Infection

Author

Crawford, Colin L., Antoniou, Christina, Komarek, Lina, Schultz, Verena, Donald, Claire L., Montague, Paul, Barnett, Susan C., Linington, Christopher, Willison, Hugh J., Kohl, Alain, Coleman, Michael P., Edgar, Julia M., Coleman, Michael [0000-0002-9354-532X], and Apollo - University of Cambridge Repository

Subjects
tubulin (microtubules), Cellular and Molecular Neuroscience, nervous system, glia, neurofilament, nicotinamide adenine dinucleotide, Molecular Biology, Zika virus
Abstract

Zika virus (ZIKV) is a neurotropic flavivirus recently linked to congenital ZIKV syndrome in children and encephalitis and Guillain-Barré syndrome in adults. Neurotropic viruses often use axons to traffic to neuronal or glial cell somas where they either remain latent or replicate and proceed to infect new cells. Consequently, it has been suggested that axon degeneration could represent an evolutionarily conserved mechanism to limit viral spread. Whilst it is not known if ZIKV transits in axons, we previously reported that ZIKV infection of glial cells in a murine spinal cord-derived cell culture model of the CNS is associated with a profound loss of neuronal cell processes. This, despite that postmitotic neurons are relatively refractory to infection and death. Here, we tested the hypothesis that ZIKV-associated degeneration of neuronal processes is dependent on activation of Sterile alpha and armadillo motif-containing protein 1 (SARM1), an NADase that acts as a central executioner in a conserved axon degeneration pathway. To test this, we infected wild type and Sarm1 homozygous or heterozygous null cell cultures with ZIKV and examined NAD+ levels as well as the survival of neurons and their processes. Unexpectedly, ZIKV infection led to a rapid SARM1-independent reduction in NAD+. Nonetheless, the subsequent profound loss of neuronal cell processes was SARM1-dependent and was preceded by early changes in the appearance of β-tubulin III staining. Together, these data identify a role for SARM1 in the pathogenesis of ZIKV infection, which may reflect SARM1's conserved prodegenerative function, independent of its NADase activity.

Published
2022
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12. An International Perspective on Preceding Infections in Guillain-Barre Syndrome The IGOS-1000 Cohort

Author

Leonhard, Sonja E., van der Eijk, Annemiek A., Andersen, Henning, Antonini, Giovanni, Arends, Samuel, Attarian, Shahram, Barroso, Fabio A., Bateman, Kathleen J., Batstra, Manou R., Benedetti, Luana, van den Berg, Bianca, Van den Bergh, Peter, Burmann, Jan, Busby, Mark, Casasnovas, Carlos, Cornblath, David R., Davidson, Amy, Doets, Alex Y., van Doorn, Pieter A., de la Cour, Charlotte Dornonville, Feasby, Thomas E., Fehmi, Janev, Garcia-Sobrino, Tania, Goldstein, Jonathan M., Gorson, Kenneth C., Granit, Volkan, Hadden, Robert D. M., Harbo, Thomas, Hartung, Hans-Peter, Hasan, Imran, Holbech, Jakob, V, Holt, James K. L., Jahan, Israt, Islam, Zhahirul, Karafiath, Summer, Katzberg, Hans D., Kleyweg, Ruud P., Kolb, Noah, Kuitwaard, Krista, Kuwahara, Motoi, Kusunoki, Susumu, Luijten, Linda W. G., Kuwabara, Satoshi, Pan, Edward Lee, Lehmann, Helmar C., Maas, Marijke, Martin-Aguilar, Lorena, Al Miller, James, Mohammad, Quazi Deen, Monges, Soledad, Nedkova-Hristova, Velina, Nobile-Orazio, Eduardo, Pardo, Julio, Pereon, Yann, Querol, Luis, Reisin, Ricardo, Van Rijs, Wouter, Rinaldi, Simon, Roberts, Rhys C., Roodbol, Joyce, Shahrizaila, Nortina, Sindrup, Soren Hein, Stein, Beth, Cheng-Yin, Tan, Tankisi, Hatice, Tio-Gillen, Anne P., Tous, Maria J. Sedano, Verboon, Christine, Vermeij, Frederique H., Visser, Leo H., Huizinga, Ruth, Willison, Hugh J., Jacobs, Bart C., Leonhard, Sonja E., van der Eijk, Annemiek A., Andersen, Henning, Antonini, Giovanni, Arends, Samuel, Attarian, Shahram, Barroso, Fabio A., Bateman, Kathleen J., Batstra, Manou R., Benedetti, Luana, van den Berg, Bianca, Van den Bergh, Peter, Burmann, Jan, Busby, Mark, Casasnovas, Carlos, Cornblath, David R., Davidson, Amy, Doets, Alex Y., van Doorn, Pieter A., de la Cour, Charlotte Dornonville, Feasby, Thomas E., Fehmi, Janev, Garcia-Sobrino, Tania, Goldstein, Jonathan M., Gorson, Kenneth C., Granit, Volkan, Hadden, Robert D. M., Harbo, Thomas, Hartung, Hans-Peter, Hasan, Imran, Holbech, Jakob, V, Holt, James K. L., Jahan, Israt, Islam, Zhahirul, Karafiath, Summer, Katzberg, Hans D., Kleyweg, Ruud P., Kolb, Noah, Kuitwaard, Krista, Kuwahara, Motoi, Kusunoki, Susumu, Luijten, Linda W. G., Kuwabara, Satoshi, Pan, Edward Lee, Lehmann, Helmar C., Maas, Marijke, Martin-Aguilar, Lorena, Al Miller, James, Mohammad, Quazi Deen, Monges, Soledad, Nedkova-Hristova, Velina, Nobile-Orazio, Eduardo, Pardo, Julio, Pereon, Yann, Querol, Luis, Reisin, Ricardo, Van Rijs, Wouter, Rinaldi, Simon, Roberts, Rhys C., Roodbol, Joyce, Shahrizaila, Nortina, Sindrup, Soren Hein, Stein, Beth, Cheng-Yin, Tan, Tankisi, Hatice, Tio-Gillen, Anne P., Tous, Maria J. Sedano, Verboon, Christine, Vermeij, Frederique H., Visser, Leo H., Huizinga, Ruth, Willison, Hugh J., and Jacobs, Bart C.

Abstract

Background and Objectives Infections play a key role in the development of Guillain-Barre syndrome (GBS) and have been associated with specific clinical features and disease severity. The clinical variation of GBS across geographical regions has been suggested to be related to differences in the distribution of preceding infections, but this has not been studied on a large scale. Methods We analyzed the first 1,000 patients included in the International GBS Outcome Study with available biosamples (n = 768) for the presence of a recent infection with Campylobacter jejuni, hepatitis E virus, Mycoplasma pneumoniae, cytomegalovirus, and Epstein-Barr virus. Results Serologic evidence of a recent infection with C. jejuni was found in 228 (30%), M. pneumoniae in 77 (10%), hepatitis E virus in 23 (3%), cytomegalovirus in 30 (4%), and Epstein-Barr virus in 7 (1%) patients. Evidence of more than 1 recent infection was found in 49 (6%) of these patients. Symptoms of antecedent infections were reported in 556 patients (72%), and this proportion did not significantly differ between those testing positive or negative for a recent infection. The proportions of infections were similar across continents. The sensorimotor variant and the demyelinating electrophysiologic subtype were most frequent across all infection groups, although proportions were significantly higher in patients with a cytomegalovirus and significantly lower in those with a C. jejuni infection. C. jejuni-positive patients were more severely affected, indicated by a lower Medical Research Council sum score at nadir (p = 0.004) and a longer time to regain the ability to walk independently (p = 0.005). The pure motor variant and axonal electrophysiologic subtype were more frequent in Asian compared with American or European C. jejuni-positive patients (p < 0.001, resp. p = 0.001). Time to nadir was longer in the cytomegalovirus-positive patients (p = 0.004). Discussion Across geographical regions, the distribution o

Published
2022

13. Predicting Outcome in Guillain-Barre Syndrome International Validation of the Modified Erasmus GBS Outcome Score

Author

Doets, Alex Y., Lingsma, Hester F., Walgaard, Christa, Islam, Badrul, Papri, Nowshin, Davidson, Amy, Kusunoki, Susumu, Dimachkie, Mazen M., Waheed, Waqar, Kolb, Noah, Islam, Zhahirul, Mohammad, Quazi Deen, Harbo, Thomas, Sindrup, Soren H., Chavada, Govindsinh, Willison, Hugh J., Casasnovas, Carlos, Bateman, Kathleen, Miller, James A. L., van den Berg, Bianca, Verboon, Christine, Roodbol, Joyce, Leonhard, Sonja E., Benedetti, Luana, Kuwabara, Satoshi, Van den Bergh, Peter, Monges, Soledad, Marfia, Girolama A., Shahrizaila, Nortina, Galassi, Giuliana, Pereon, Yann, Burmann, Jan, Kuitwaard, Krista, Kleyweg, Ruud P., Marchesoni, Cintia, Tous, Maria J. Sedano, Querol, Luis, Illa, Isabel, Wang, Yuzhong, Nobile-Orazio, Eduardo, Rinaldi, Simon, Schenone, Angelo, Pardo, Julio, Vermeij, Frederique H., Lehmann, Helmar C., Granit, Volkan, Cavaletti, Guido, Gutierrez-Gutierrez, Gerardo, Barroso, Fabio A., Visser, Leo H., Katzberg, Hans D., Dardiotis, Efthimios, Attarian, Shahram, van der Kooi, Anneke J., Eftimov, Filip, Wirtz, Paul W., Samijn, Johnny P. A., Gilhuis, H. Jacobus, Hadden, Robert D. M., Holt, James K. L., Sheikh, Kazim A., Karafiath, Summer, Vytopil, Michal, Antonini, Giovanni, Feasby, Thomas E., Faber, Catharina G., Gijsbers, Cees J., Busby, Mark, Roberts, Rhys C., Silvestri, Nicholas J., Fazio, Raffaella, van Dijk, Gert W., Garssen, Marcel P. J., Straathof, Chiara S. M., Gorson, Kenneth C., Jacobs, Bart C., Doets, Alex Y., Lingsma, Hester F., Walgaard, Christa, Islam, Badrul, Papri, Nowshin, Davidson, Amy, Kusunoki, Susumu, Dimachkie, Mazen M., Waheed, Waqar, Kolb, Noah, Islam, Zhahirul, Mohammad, Quazi Deen, Harbo, Thomas, Sindrup, Soren H., Chavada, Govindsinh, Willison, Hugh J., Casasnovas, Carlos, Bateman, Kathleen, Miller, James A. L., van den Berg, Bianca, Verboon, Christine, Roodbol, Joyce, Leonhard, Sonja E., Benedetti, Luana, Kuwabara, Satoshi, Van den Bergh, Peter, Monges, Soledad, Marfia, Girolama A., Shahrizaila, Nortina, Galassi, Giuliana, Pereon, Yann, Burmann, Jan, Kuitwaard, Krista, Kleyweg, Ruud P., Marchesoni, Cintia, Tous, Maria J. Sedano, Querol, Luis, Illa, Isabel, Wang, Yuzhong, Nobile-Orazio, Eduardo, Rinaldi, Simon, Schenone, Angelo, Pardo, Julio, Vermeij, Frederique H., Lehmann, Helmar C., Granit, Volkan, Cavaletti, Guido, Gutierrez-Gutierrez, Gerardo, Barroso, Fabio A., Visser, Leo H., Katzberg, Hans D., Dardiotis, Efthimios, Attarian, Shahram, van der Kooi, Anneke J., Eftimov, Filip, Wirtz, Paul W., Samijn, Johnny P. A., Gilhuis, H. Jacobus, Hadden, Robert D. M., Holt, James K. L., Sheikh, Kazim A., Karafiath, Summer, Vytopil, Michal, Antonini, Giovanni, Feasby, Thomas E., Faber, Catharina G., Gijsbers, Cees J., Busby, Mark, Roberts, Rhys C., Silvestri, Nicholas J., Fazio, Raffaella, van Dijk, Gert W., Garssen, Marcel P. J., Straathof, Chiara S. M., Gorson, Kenneth C., and Jacobs, Bart C.

Abstract

Background and Objectives The clinical course and outcome of the Guillain-Barre syndrome (GBS) are diverse and vary among regions. The modified Erasmus GBS Outcome Score (mEGOS), developed with data from Dutch patients, is a clinical model that predicts the risk of walking inability in patients with GBS. The study objective was to validate the mEGOS in the International GBS Outcome Study (IGOS) cohort and to improve its performance and region specificity. Methods We used prospective data from the first 1,500 patients included in IGOS, aged >= 6 years and unable to walk independently. We evaluated whether the mEGOS at entry and week 1 could predict the inability to walk unaided at 4 and 26 weeks in the full cohort and in regional subgroups, using 2 measures for model performance: (1) discrimination: area under the receiver operating characteristic curve (AUC) and (2) calibration: observed vs predicted probability of being unable to walk independently. To improve the model predictions, we recalibrated the model containing the overall mEGOS score, without changing the individual predictive factors. Finally, we assessed the predictive ability of the individual factors. Results For validation of mEGOS at entry, 809 patients were eligible (Europe/North America [n = 677], Asia [n = 76], other [n = 56]), and 671 for validation of mEGOS at week 1 (Europe/North America [n = 563], Asia [n = 65], other [n = 43]). AUC values were >0.7 in all regional subgroups. In the Europe/North America subgroup, observed outcomes were worse than predicted; in Asia, observed outcomes were better than predicted. Recalibration improved model accuracy and enabled the development of a region-specific version for Europe/North America (mEGOS-Eu/NA). Similar to the original mEGOS, severe limb weakness and higher age were the predominant predictors of poor outcome in the IGOS cohort. Discussion mEGOS is a validated tool to predict the inability to walk unaided at 4 and 26 weeks in patients with GBS, a

Published
2022

14. Predicting Outcome in Guillain-Barré Syndrome: International Validation of the Modified Erasmus GBS Outcome Score

Author

Doets, A, Lingsma, H, Walgaard, C, Islam, B, Papri, N, Davidson, A, Yamagishi, Y, Kusunoki, S, Dimachkie, M, Waheed, W, Kolb, N, Islam, Z, Mohammad, Q, Harbo, T, Sindrup, S, Chavada, G, Willison, H, Casasnovas, C, Bateman, K, Miller, J, van den Berg, B, Verboon, C, Roodbol, J, Leonhard, S, Benedetti, L, Kuwabara, S, Van den Bergh, P, Monges, S, Marfia, G, Shahrizaila, N, Galassi, G, Péréon, Y, Bürmann, J, Kuitwaard, K, Kleyweg, R, Marchesoni, C, Sedano Tous, M, Querol, L, Illa, I, Wang, Y, Nobile-Orazio, E, Rinaldi, S, Schenone, A, Pardo, J, Vermeij, F, Lehmann, H, Granit, V, Cavaletti, G, Gutiérrez-Gutiérrez, G, Barroso, F, Visser, L, Katzberg, H, Dardiotis, E, Attarian, S, van der Kooi, A, Eftimov, F, Wirtz, P, Samijn, J, Gilhuis, H, Hadden, R, Holt, J, Sheikh, K, Karafiath, S, Vytopil, M, Antonini, G, Feasby, T, Faber, C, Gijsbers, C, Busby, M, Roberts, R, Silvestri, N, Fazio, R, van Dijk, G, Garssen, M, Straathof, C, Gorson, K, Jacobs, B, Doets, Alex Y, Lingsma, Hester F, Walgaard, Christa, Islam, Badrul, Papri, Nowshin, Davidson, Amy, Yamagishi, Yuko, Kusunoki, Susumu, Dimachkie, Mazen M, Waheed, Waqar, Kolb, Noah, Islam, Zhahirul, Mohammad, Quazi Deen, Harbo, Thomas, Sindrup, Soren H, Chavada, Govindsinh, Willison, Hugh J, Casasnovas, Carlos, Bateman, Kathleen, Miller, James A L, van den Berg, Bianca, Verboon, Christine, Roodbol, Joyce, Leonhard, Sonja E, Benedetti, Luana, Kuwabara, Satoshi, Van den Bergh, Peter, Monges, Soledad, Marfia, Girolama A, Shahrizaila, Nortina, Galassi, Giuliana, Péréon, Yann, Bürmann, Jan, Kuitwaard, Krista, Kleyweg, Ruud P, Marchesoni, Cintia, Sedano Tous, María J, Querol, Luis, Illa, Isabel, Wang, Yuzhong, Nobile-Orazio, Eduardo, Rinaldi, Simon, Schenone, Angelo, Pardo, Julio, Vermeij, Frederique H, Lehmann, Helmar C, Granit, Volkan, Cavaletti, Guido, Gutiérrez-Gutiérrez, Gerardo, Barroso, Fabio A, Visser, Leo H, Katzberg, Hans D, Dardiotis, Efthimios, Attarian, Shahram, van der Kooi, Anneke J, Eftimov, Filip, Wirtz, Paul W, Samijn, Johnny P A, Gilhuis, H Jacobus, Hadden, Robert D M, Holt, James K L, Sheikh, Kazim A, Karafiath, Summer, Vytopil, Michal, Antonini, Giovanni, Feasby, Thomas E, Faber, Catharina G, Gijsbers, Cees J, Busby, Mark, Roberts, Rhys C, Silvestri, Nicholas J, Fazio, Raffaella, van Dijk, Gert W, Garssen, Marcel P J, Straathof, Chiara S M, Gorson, Kenneth C, Jacobs, Bart C, Doets, A, Lingsma, H, Walgaard, C, Islam, B, Papri, N, Davidson, A, Yamagishi, Y, Kusunoki, S, Dimachkie, M, Waheed, W, Kolb, N, Islam, Z, Mohammad, Q, Harbo, T, Sindrup, S, Chavada, G, Willison, H, Casasnovas, C, Bateman, K, Miller, J, van den Berg, B, Verboon, C, Roodbol, J, Leonhard, S, Benedetti, L, Kuwabara, S, Van den Bergh, P, Monges, S, Marfia, G, Shahrizaila, N, Galassi, G, Péréon, Y, Bürmann, J, Kuitwaard, K, Kleyweg, R, Marchesoni, C, Sedano Tous, M, Querol, L, Illa, I, Wang, Y, Nobile-Orazio, E, Rinaldi, S, Schenone, A, Pardo, J, Vermeij, F, Lehmann, H, Granit, V, Cavaletti, G, Gutiérrez-Gutiérrez, G, Barroso, F, Visser, L, Katzberg, H, Dardiotis, E, Attarian, S, van der Kooi, A, Eftimov, F, Wirtz, P, Samijn, J, Gilhuis, H, Hadden, R, Holt, J, Sheikh, K, Karafiath, S, Vytopil, M, Antonini, G, Feasby, T, Faber, C, Gijsbers, C, Busby, M, Roberts, R, Silvestri, N, Fazio, R, van Dijk, G, Garssen, M, Straathof, C, Gorson, K, Jacobs, B, Doets, Alex Y, Lingsma, Hester F, Walgaard, Christa, Islam, Badrul, Papri, Nowshin, Davidson, Amy, Yamagishi, Yuko, Kusunoki, Susumu, Dimachkie, Mazen M, Waheed, Waqar, Kolb, Noah, Islam, Zhahirul, Mohammad, Quazi Deen, Harbo, Thomas, Sindrup, Soren H, Chavada, Govindsinh, Willison, Hugh J, Casasnovas, Carlos, Bateman, Kathleen, Miller, James A L, van den Berg, Bianca, Verboon, Christine, Roodbol, Joyce, Leonhard, Sonja E, Benedetti, Luana, Kuwabara, Satoshi, Van den Bergh, Peter, Monges, Soledad, Marfia, Girolama A, Shahrizaila, Nortina, Galassi, Giuliana, Péréon, Yann, Bürmann, Jan, Kuitwaard, Krista, Kleyweg, Ruud P, Marchesoni, Cintia, Sedano Tous, María J, Querol, Luis, Illa, Isabel, Wang, Yuzhong, Nobile-Orazio, Eduardo, Rinaldi, Simon, Schenone, Angelo, Pardo, Julio, Vermeij, Frederique H, Lehmann, Helmar C, Granit, Volkan, Cavaletti, Guido, Gutiérrez-Gutiérrez, Gerardo, Barroso, Fabio A, Visser, Leo H, Katzberg, Hans D, Dardiotis, Efthimios, Attarian, Shahram, van der Kooi, Anneke J, Eftimov, Filip, Wirtz, Paul W, Samijn, Johnny P A, Gilhuis, H Jacobus, Hadden, Robert D M, Holt, James K L, Sheikh, Kazim A, Karafiath, Summer, Vytopil, Michal, Antonini, Giovanni, Feasby, Thomas E, Faber, Catharina G, Gijsbers, Cees J, Busby, Mark, Roberts, Rhys C, Silvestri, Nicholas J, Fazio, Raffaella, van Dijk, Gert W, Garssen, Marcel P J, Straathof, Chiara S M, Gorson, Kenneth C, and Jacobs, Bart C

Abstract

Background and objectives: The clinical course and outcome of the Guillain-Barré syndrome (GBS) are diverse and vary among regions. The modified Erasmus GBS Outcome Score (mEGOS), developed with data from Dutch patients, is a clinical model that predicts the risk of walking inability in patients with GBS. The study objective was to validate the mEGOS in the International GBS Outcome Study (IGOS) cohort and to improve its performance and region specificity. Methods: We used prospective data from the first 1,500 patients included in IGOS, aged ≥6 years and unable to walk independently. We evaluated whether the mEGOS at entry and week 1 could predict the inability to walk unaided at 4 and 26 weeks in the full cohort and in regional subgroups, using 2 measures for model performance: (1) discrimination: area under the receiver operating characteristic curve (AUC) and (2) calibration: observed vs predicted probability of being unable to walk independently. To improve the model predictions, we recalibrated the model containing the overall mEGOS score, without changing the individual predictive factors. Finally, we assessed the predictive ability of the individual factors. Results: For validation of mEGOS at entry, 809 patients were eligible (Europe/North America [n = 677], Asia [n = 76], other [n = 56]), and 671 for validation of mEGOS at week 1 (Europe/North America [n = 563], Asia [n = 65], other [n = 43]). AUC values were >0.7 in all regional subgroups. In the Europe/North America subgroup, observed outcomes were worse than predicted; in Asia, observed outcomes were better than predicted. Recalibration improved model accuracy and enabled the development of a region-specific version for Europe/North America (mEGOS-Eu/NA). Similar to the original mEGOS, severe limb weakness and higher age were the predominant predictors of poor outcome in the IGOS cohort. Discussion: mEGOS is a validated tool to predict the inability to walk unaided at 4 and 26 weeks in patients with

Published
2022

15. The legacy of ZikaPLAN:a transnational research consortium addressing Zika

Author

Wilder-Smith, Annelies, Brickley, Elizabeth B., Ximenes, Ricardo Arraes de Alencar, Miranda-Filho, Demócrito de Barros, Turchi Martelli, Celina Maria, Solomon, Tom, Jacobs, Bart C., Pardo, Carlos A., Osorio, Lyda, Parra, Beatriz, Lant, Suzannah, Willison, Hugh J., Leonhard, Sonja, Turtle, Lance, Ferreira, Maria Lúcia Brito, de Oliveira Franca, Rafael Freitas, Lambrechts, Louis, Neyts, Johan, Kaptein, Suzanne, Peeling, Rosanna, Boeras, Deborah, Logan, James, Dolk, Helen, Orioli, Ieda M., Neumayr, Andreas, Lang, Trudie, Baker, Bonny, Massad, Eduardo, Preet, Raman, Wilder-Smith, Annelies, Brickley, Elizabeth B., Ximenes, Ricardo Arraes de Alencar, Miranda-Filho, Demócrito de Barros, Turchi Martelli, Celina Maria, Solomon, Tom, Jacobs, Bart C., Pardo, Carlos A., Osorio, Lyda, Parra, Beatriz, Lant, Suzannah, Willison, Hugh J., Leonhard, Sonja, Turtle, Lance, Ferreira, Maria Lúcia Brito, de Oliveira Franca, Rafael Freitas, Lambrechts, Louis, Neyts, Johan, Kaptein, Suzanne, Peeling, Rosanna, Boeras, Deborah, Logan, James, Dolk, Helen, Orioli, Ieda M., Neumayr, Andreas, Lang, Trudie, Baker, Bonny, Massad, Eduardo, and Preet, Raman

Abstract

Global health research partnerships with institutions from high-income countries and low- and middle-income countries are one of the European Commission's flagship programmes. Here, we report on the ZikaPLAN research consortium funded by the European Commission with the primary goal of addressing the urgent knowledge gaps related to the Zika epidemic and the secondary goal of building up research capacity and establishing a Latin American-European research network for emerging vector-borne diseases. Five years of collaborative research effort have led to a better understanding of the full clinical spectrum of congenital Zika syndrome in children and the neurological complications of Zika virus infections in adults and helped explore the origins and trajectory of Zika virus transmission. Individual-level data from ZikaPLAN`s cohort studies were shared for joint analyses as part of the Zika Brazilian Cohorts Consortium, the European Commission-funded Zika Cohorts Vertical Transmission Study Group, and the World Health Organization-led Zika Virus Individual Participant Data Consortium. Furthermore, the legacy of ZikaPLAN includes new tools for birth defect surveillance and a Latin American birth defect surveillance network, an enhanced Guillain-Barre Syndrome research collaboration, a de-centralized evaluation platform for diagnostic assays, a global vector control hub, and the REDe network with freely available training resources to enhance global research capacity in vector-borne diseases.

Published
2022

18. The role of gangliosides in the organisation of the node of Ranvier examined in glycosyltransferase transgenic mice

Author

McGonigal, Rhona and Willison, Hugh J.

Subjects
Nervous system, Genetically modified mouse, Histology, Mice, Transgenic, Ligands, chemistry.chemical_compound, Mice, Gangliosides, Glycosyltransferase, medicine, Transferase, Animals, Receptor, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Autoantibodies, Node of Ranvier, biology, Glycosyltransferases, Cell Biology, Axons, N-Acetylneuraminic Acid, Sialyltransferases, Sialic acid, Cell biology, medicine.anatomical_structure, chemistry, biology.protein, Anatomy, Glycolipids, NODAL, Developmental Biology
Abstract

Gangliosides are a family of sialic acid containing glycosphingolipids highly enriched in plasma membranes of the vertebrate nervous system. They are functionally diverse in modulating nervous system integrity, notably at the node of Ranvier, and also act as receptors for many ligands including toxins and autoantibodies. They are synthesised in a stepwise manner by groups of glycosyl- and sialyltransferases in a developmentally and tissue regulated manner. In this review, we summarise and discuss data derived from transgenic mice with different transferase deficiencies that have been used to determine the role of glycolipids in the organisation of the node of Ranvier. Understanding their role at this specialised functional site is crucial to determining differential pathophysiology following directed genetic or autoimmune injury to peripheral nerve nodal or paranodal domains, and revealing the downstream consequences of axo-glial disruption.

Published
2021

19. Guía basada en la evidencia. Diagnóstico y manejo del síndrome de Guillain-Barré en diez pasos = Evidence based guidelines. Diagnosis and management of Guillain-Barré syndrome in ten steps

Author

Leonhard, Sonja E., Mandarakas, Melissa R., de Assis Aquino Gondim, Francisco, Bateman, Kathleen, Brito Ferreira, Maria L., Cornblath, David R., Van Doorn, Pieter A., Dourado, Mario E., Hughes, Richard A.C., Islam, Badrul, Kusunoki, Susumu, Pardo, Carlos A., Reisin, Ricardo, Sejvar, James J., Shahrizaila, Nortina, Soares, Cristiane, Umapathi, Thirugnanam, Wang, Yuzhong, Yiu, Eppie M., Willison, Hugh J., and Jacobs, Bart C.

Abstract

Guillain-Barré syndrome (GBS) is a rare, but potentially fatal, immune-mediated disease of the peripheral nerves and nerve roots that is usually triggered by infections. The incidence of GBS can therefore increase during outbreaks of infectious diseases, as was seen during the Zika virus epidemics in 2013 in French Polynesia and in 2015 in Latin America. Diagnosis and management of GBS can be complicated as its clinical presentation and disease course are heterogeneous, and no international clinical guidelines are currently available. To support clinicians, especially in the context of an outbreak, we have developed a globally applicable guideline for the diagnosis and management of GBS. The guideline is based on current literature and expert consensus, and has a ten-step structure to facilitate its use in clinical practice. We first provide an introduction to the diagnostic criteria, clinical variants and differential diagnoses of GBS. The ten steps then cover early recognition and diagnosis of GBS, admission to the intensive care unit, treatment indication and selection, monitoring and treatment of disease progression, prediction of clinical course and outcome, and management of complications and sequelae.

Published
2021

20. Oligodendrocytes are susceptible to Zika virus infection in a mouse model of perinatal exposure: implications for CNS complications

Author

Schultz, Verena, Barrie, Jennifer A., Donald, Claire L., Crawford, Colin L., Mullin, Margaret, Anderson, Thomas J., Solomon, Tom, Barnett, Susan C., Linington, Christopher, Kohl, Alain, Willison, Hugh J., and Edgar, Julia M.

Abstract

Some children with proven intrauterine Zika virus (ZIKV) infection who were born asymptomatic subsequently manifested neurodevelopmental delays, pointing to impairment of development perinatally and postnatally. To model this, we infected postnatal day (P) 5–6 (equivalent to the perinatal period in humans) susceptible mice with a mammalian cell‐propagated ZIKV clinical isolate from the Brazilian outbreak in 2015. All infected mice appeared normal up to 4 days post‐intraperitoneal inoculation (dpi), but rapidly developed severe clinical signs at 5–6 dpi. All nervous tissue examined at 5/6 dpi appeared grossly normal. However, anti‐ZIKV positive cells were observed in the optic nerve, brain, and spinal cord; predominantly in white matter. Co‐labeling with cell type specific markers demonstrated oligodendrocytes and astrocytes support productive infection. Rarely, ZIKV positive neurons were observed. In spinal cord white matter, which we examined in detail, apoptotic cells were evident; the density of oligodendrocytes was significantly reduced; and there was localized microglial reactivity including expression of the NLRP3 inflammasome. Together, our observations demonstrate that a clinically relevant ZIKV isolate can directly impact oligodendrocytes. As primary oligodendrocyte cell death can lead later to secondary autoimmune demyelination, our observations may help explain neurodevelopmental delays in infants appearing asymptomatic at birth and commend lifetime surveillance.

Published
2021

21. Neuronally expressed a-series gangliosides are sufficient to prevent the lethal age-dependent phenotype in GM3-only expressing mice

Author

McGonigal, Rhona, Barrie, Jennifer A., Yao, Denggao, Black, Lauren E., McLaughlin, Mark, and Willison, Hugh J.

Subjects
lipids (amino acids, peptides, and proteins)
Abstract

Gangliosides are expressed on plasma membranes throughout the body and enriched in the nervous system. A critical role for complex a‐ and b‐series gangliosides in central and peripheral nervous system ageing has been established through transgenic manipulation of enzymes in ganglioside biosynthesis. Disrupting GalNAc‐transferase (GalNAc‐T), thus eliminating all a‐ and b‐series complex gangliosides (with consequent over‐expression of GM3 and GD3) leads to an age‐dependent neurodegeneration. Mice that express only GM3 ganglioside (double knockout produced by crossing GalNAc‐T‐/‐ and GD3 synthase‐/‐ mice, Dbl KO) display markedly accelerated neurodegeneration with reduced survival. Degenerating axons and disrupted to the node of Ranvier architecture are key features of complex ganglioside‐deficient mice. Previously, we have shown that reintroduction of both a‐ and b‐series gangliosides into neurons on a global GalNAcT ‐/‐ background is sufficient to rescue this age‐dependent neurodegenerative phenotype. To determine the relative roles of a‐ and b‐series gangliosides in this rescue paradigm, we herein reintroduced GalNAc‐T into neurons of Dbl KO mice, thereby reconstituting a‐series but not b‐series complex gangliosides. We assessed survival, axon degeneration, axo‐glial integrity, inflammatory markers, and lipid‐raft formation in these Rescue mice compared to wild type and Dbl KO mice. We found that this neuronal reconstitution of a‐series complex gangliosides abrogated the adult lethal phenotype in Dbl KO mice, and partially attenuated the neurodegenerative features. This suggests that whilst neuronal expression of a‐series gangliosides is critical for survival during ageing, it is not entirely sufficient to restore complete nervous system integrity in the absence of either b‐series or glial a‐series gangliosides.

Published
2021

22. Management of Drug Budgets

Author

Ballantyne, John P., Behan, Peter O., Bone, Ian, Durward, William F., Grosset, Donal, Kennedy, Peter G. E., Metcalfe, Richard A., O'Leary, Colin P., Petty, Richard H. K., Thomas, Myfanwy, Willison, Hugh J., Duncan, Roderick, and Wade, Alan G.

Published
1999

23. The legacy of ZikaPLAN: a transnational research consortium addressing Zika

Author

Wilder-Smith, Annelies, primary, Brickley, Elizabeth B., additional, Ximenes, Ricardo Arraes de Alencar, additional, Miranda-Filho, Demócrito de Barros, additional, Turchi Martelli, Celina Maria, additional, Solomon, Tom, additional, Jacobs, Bart C., additional, Pardo, Carlos A., additional, Osorio, Lyda, additional, Parra, Beatriz, additional, Lant, Suzannah, additional, Willison, Hugh J, additional, Leonhard, Sonja, additional, Turtle, Lance, additional, Ferreira, Maria Lúcia Brito, additional, de Oliveira Franca, Rafael Freitas, additional, Lambrechts, Louis, additional, Neyts, Johan, additional, Kaptein, Suzanne, additional, Peeling, Rosanna, additional, Boeras, Deborah, additional, Logan, James, additional, Dolk, Helen, additional, Orioli, Ieda M, additional, Neumayr, Andreas, additional, Lang, Trudie, additional, Baker, Bonny, additional, Massad, Eduardo, additional, and Preet, Raman, additional

Published
2021
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26. Anti-ganglioside antibody internalization attenuates motor nerve terminal injury in a mouse model of acute motor axonal neuropathy

Author

Fewou, Simon N., Rupp, Angie, Nickolay, Lauren E., Carrick, Kathryn, Greenshields, Kay N., Pediani, John, Plomp, Jaap J., and Willison, Hugh J.

Subjects
Physiological aspects, Research, Antibodies -- Physiological aspects -- Research, Guillain-Barre syndrome -- Research, Neurons -- Physiological aspects -- Research, Viral antibodies -- Physiological aspects -- Research
Abstract

Introduction The Guillain-Barre syndromes (GBSs) are acute, immune-mediated neuropathies affecting the peripheral nervous system (PNS), usually triggered by preceding infectious events including Campylobacter jejuni enteritis. In the acute motor axonal [...], In the Guillain-Barre syndrome subform acute motor axonal neuropathy (AMAN), Campylobacter jejuni enteritis triggers the production of anti-ganglioside Abs (AGAbs), leading to immune-mediated injury of distal motor nerves. An important question has been whether injury to the presynaptic neuron at the neuromuscular junction is a major factor in AMAN. Although disease modeling in mice exposed to AGAbs indicates that complement-mediated necrosis occurs extensively in the presynaptic axons, evidence in humans is more limited, in comparison to the extensive injury seen at nodes of Ranvier. We considered that rapid AGAb uptake at the motor nerve terminal membrane might attenuate complement-mediated injury. We found that PC12 rat neuronal cells rapidly internalized AGAb, which were trafficked to recycling endosomes and lysosomes. Consequently, complement-mediated cytotoxicity was attenuated. Importantly, we observed the same AGAb endocytosis and protection from cytotoxicity in live mouse nerve terminals. AGAb uptake was attenuated following membrane cholesterol depletion in vitro and ex vivo, indicating that this process may be dependent upon cholesterol-enriched microdomains. In contrast, we observed minimal AGAb uptake at nodes of Ranvier, and this structure thus remained vulnerable to complement-mediated injury. These results indicate that differential endocytic processing of AGAbs by different neuronal and glial membranes might be an important modulator of site-specific injury in acute AGAb-mediated Guillain-Barre syndrome subforms and their chronic counterparts.

Published
2012
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27. The GD1a glycan is a cellular receptor for adenoviruses causing epidemic keratoconjunctivitis

Author

Nilsson, Emma C., Storm, Rickard J., Bauer, Johannes, Johansson, Susanne M.C., Lookene, Aivar, Angstrom, Jonas, Hedenstrom, Mattias, Eriksson, Therese L., Frangsmyr, Lars, Rinaldi, Simon, Willison, Hugh J., Domellof, Fatima Pedrosa, Stehle, Thilo, and Arnberg, Niklas

Subjects
Care and treatment, Physiological aspects, Properties, Health aspects, Protein binding -- Health aspects, Glycoproteins -- Health aspects -- Properties, Epidemic keratoconjunctivitis -- Health aspects -- Care and treatment -- Physiological aspects, Keratoconjunctivitis -- Health aspects -- Care and treatment -- Physiological aspects
Abstract

EKC is caused mainly by three species D adenoviruses (Ad8, Adl9 and Ad37) and is recognized as a severe ocular disease for which no antiviral drugs are available (2,5,6). Common [...], Adenovirus type 37 (Ad37) is a leading cause of epidemic keratoconjunctivitis (EKC) (1,2), a severe and highly contagious ocular disease. Whereas most other adenoviruses infect cells by engaging CD46 or the coxsackie and adenovirus receptor (CAR), Ad37 binds previously unknown sialic acid-containing cell surface molecules (3,4). By glycan array screening, we show here that the receptor-recognizing knob domain of the Ad37 fiber protein specifically binds a branched hexasaccharide that is present in the GD1a ganglioside and that features two terminal sialic acids. Soluble GD1a glycan and GD1a-binding antibodies efficiently prevented Ad37 virions from binding and infecting corneal cells. Unexpectedly, the receptor is constituted by one or more glycoproteins containing the GD1a glycan motif rather than the ganglioside itself, as shown by binding, infection and flow cytometry experiments. Molecular modeling, nuclear magnetic resonance and X-ray crystallography reveal that the two terminal sialic acids dock into two of three previously established sialic acid-binding sites in the trimeric Ad37 knob. Surface plasmon resonance analysis shows that the knob-GD1a glycan interaction has high affinity. Our findings therefore form a basis for the design and development of sialic acid-containing antiviral drugs for topical treatment of EKC.

Published
2011
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28. The neuropathic potential of anti-GM1 autoantibodies is regulated by the local glycolipid environment in mice

Author

Greenshields, Kay N., Halstead, Susan K., Zitman, Femke M.P., Rinaldi, Simon, Brennan, Kathryn M., O'Leary, Colin, Chamberlain, Luke H., Easton, Alistair, Roxburgh, Jennifer, Pediani, John, Furukawa, Koichi, Furukawa, Keiko, Goodyear, Carl S., Plomp, Jaap J., and Willison, Hugh J.

Subjects
Physiological aspects, Research, Gangliosides -- Research -- Physiological aspects, Autoantibodies -- Physiological aspects -- Research, Membrane proteins -- Physiological aspects -- Research, Sialic acids -- Research -- Physiological aspects
Abstract

Introduction The sialic acid--containing glycosphingolipids known as gangliosides are concentrated in plasma membrane microdomains, where they modulate the topological organization and function of membrane proteins (1), (2). Their oligosaccharide head [...], Anti-GM1 ganglioside autoantibodies are used as diagnostic markers for motor axonal peripheral neuropathies and are believed to be the primary mediators of such diseases. However, their ability to bind and exert pathogenic effects at neuronal membranes is highly inconsistent. Using human and mouse monoclonal anti-GM1 antibodies to probe the GM1-rich motor nerve terminal membrane in mice, we here show that the antigenic oligosaccharide of GM1 in the live plasma membrane is cryptic, hidden on surface domains that become buried for a proportion of anti-GM1 antibodies due to a masking effect of neighboring gangliosides. The cryptic GM1 binding domain was exposed by sialidase treatment that liberated sialic acid from masking gangliosides including GD1a or by disruption of the live membrane by freezing or fixation. This cryptic behavior was also recapitulated in solid-phase immunoassays. These data show that certain anti-GM1 antibodies exert potent complement activation-mediated neuropathogenic effects, including morphological damage at living terminal motor axons, leading to a block of synaptic transmission. This occurred only when GM1 was topologically available for antibody binding, but not when GM1 was cryptic. This revised understanding of the complexities in ganglioside membrane topology provides a mechanistic account for wide variations in the neuropathic potential of anti-GM1 antibodies.

Published
2009

29. The role of gangliosides in the organisation of the node of Ranvier examined in glycosyltransferase transgenic mice.

Author

McGonigal, Rhona and Willison, Hugh J.

Subjects
*GANGLIOSIDES, *TRANSGENIC mice, *PERIPHERAL nerve injuries, *CELL membranes, *NERVOUS system, *GLYCOLIPIDS, *GLYCOSPHINGOLIPIDS
Abstract

Gangliosides are a family of sialic acid containing glycosphingolipids highly enriched in plasma membranes of the vertebrate nervous system. They are functionally diverse in modulating nervous system integrity, notably at the node of Ranvier, and also act as receptors for many ligands including toxins and autoantibodies. They are synthesised in a stepwise manner by groups of glycosyl‐ and sialyltransferases in a developmentally and tissue regulated manner. In this review, we summarise and discuss data derived from transgenic mice with different transferase deficiencies that have been used to determine the role of glycolipids in the organisation of the node of Ranvier. Understanding their role at this specialised functional site is crucial to determining differential pathophysiology following directed genetic or autoimmune injury to peripheral nerve nodal or paranodal domains, and revealing the downstream consequences of axo‐glial disruption. [ABSTRACT FROM AUTHOR]

Published
2022
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30. The legacy of ZikaPLAN: a transnational research consortium addressing Zika

Author

Wilder-Smith, Annelies, Brickley, Elizabeth B., Ximenes, Ricardo Arraes de Alencar, Miranda-Filho, Demócrito de Barros, Turchi Martelli, Celina Maria, Solomon, Tom, Jacobs, Bart C., Pardo, Carlos A., Osorio, Lyda, Parra, Beatriz, Lant, Suzannah, Willison, Hugh J., Leonhard, Sonja, Turtle, Lance, Ferreira, Maria Lúcia Brito, de Oliveira Franca, Rafael Freitas, Lambrechts, Louis, Neyts, Johan, Kaptein, Suzanne, Peeling, Rosanna, Boeras, Deborah, Logan, James, Dolk, Helen, Orioli, Ieda M., Neumayr, Andreas, Lang, Trudie, Baker, Bonny, Massad, Eduardo, Preet, Raman, Wilder-Smith, Annelies, Brickley, Elizabeth B., Ximenes, Ricardo Arraes de Alencar, Miranda-Filho, Demócrito de Barros, Turchi Martelli, Celina Maria, Solomon, Tom, Jacobs, Bart C., Pardo, Carlos A., Osorio, Lyda, Parra, Beatriz, Lant, Suzannah, Willison, Hugh J., Leonhard, Sonja, Turtle, Lance, Ferreira, Maria Lúcia Brito, de Oliveira Franca, Rafael Freitas, Lambrechts, Louis, Neyts, Johan, Kaptein, Suzanne, Peeling, Rosanna, Boeras, Deborah, Logan, James, Dolk, Helen, Orioli, Ieda M., Neumayr, Andreas, Lang, Trudie, Baker, Bonny, Massad, Eduardo, and Preet, Raman

Abstract

Global health research partnerships with institutions from high-income countries and low- and middle-income countries are one of the European Commission's flagship programmes. Here, we report on the ZikaPLAN research consortium funded by the European Commission with the primary goal of addressing the urgent knowledge gaps related to the Zika epidemic and the secondary goal of building up research capacity and establishing a Latin American-European research network for emerging vector-borne diseases. Five years of collaborative research effort have led to a better understanding of the full clinical spectrum of congenital Zika syndrome in children and the neurological complications of Zika virus infections in adults and helped explore the origins and trajectory of Zika virus transmission. Individual-level data from ZikaPLAN`s cohort studies were shared for joint analyses as part of the Zika Brazilian Cohorts Consortium, the European Commission-funded Zika Cohorts Vertical Transmission Study Group, and the World Health Organization-led Zika Virus Individual Participant Data Consortium. Furthermore, the legacy of ZikaPLAN includes new tools for birth defect surveillance and a Latin American birth defect surveillance network, an enhanced Guillain-Barre Syndrome research collaboration, a de-centralized evaluation platform for diagnostic assays, a global vector control hub, and the REDe network with freely available training resources to enhance global research capacity in vector-borne diseases.

Published
2021
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31. BAF45b is required for efficient zika virus infection of HAP1 cells

Author

Persson, B. David, Nord, Stefan, Lindquist, Richard, Danskog, Katarina, Överby, Anna K., Kohl, Alain, Willison, Hugh J., Lenman, Annasara, Arnberg, Niklas, Persson, B. David, Nord, Stefan, Lindquist, Richard, Danskog, Katarina, Överby, Anna K., Kohl, Alain, Willison, Hugh J., Lenman, Annasara, and Arnberg, Niklas

Abstract

The 2016 Zika virus (ZIKV) epidemic illustrates the impact of flaviviruses as emerging human pathogens. For unknown reasons, ZIKV replicates more efficiently in neural progenitor cells (NPCs) than in postmitotic neurons. Here, we identified host factors used by ZIKV using the NCI-60 library of cell lines and COMPARE analysis, and cross-analyzed this library with two other libraries of host factors with importance for ZIKV infection. We identified BAF45b, a subunit of the BAF (Brg1/Brm-associated factors) protein complexes that regulate differentiation of NPCs to post-mitotic neurons. ZIKV (and other flaviviruses) infected HAP1 cells deficient in expression of BAF45b and other BAF subunits less efficiently than wildtype (WT) HAP1 cells. We concluded that subunits of the BAF complex are important for infection of ZIKV and other flavivirus. Given their function in cell and tissue differentiation, such regulators may be important determinants of tropism and pathogenesis of arthropod-borne flaviviruses.

Published
2021
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33. Guía basada en la evidencia. Diagnóstico y manejo del síndrome de guillain-barré en diez pasos

Author

Leonhard, Sonja E., Mandarakas, Melissa R., Gondim, Francisco De Assis Aquino, Bateman, Kathleen, Ferreira, Maria L.Brito, Cornblath, David R., Van doorn, Pieter A., Dourado, Mario E., Hughes, Richard A.C., Islam, Badrul, Kusunoki, Susumu, Pardo, Carlos A., Reisin, Ricardo, Sejvar, James J., Shahrizaila, Nortina, Soares, Cristiane, Umapathi, Thirugnanam, Wang, Yuzhong, Yiu, Eppie M., Willison, Hugh J., Jacobs, Bart C., Leonhard, Sonja E., Mandarakas, Melissa R., Gondim, Francisco De Assis Aquino, Bateman, Kathleen, Ferreira, Maria L.Brito, Cornblath, David R., Van doorn, Pieter A., Dourado, Mario E., Hughes, Richard A.C., Islam, Badrul, Kusunoki, Susumu, Pardo, Carlos A., Reisin, Ricardo, Sejvar, James J., Shahrizaila, Nortina, Soares, Cristiane, Umapathi, Thirugnanam, Wang, Yuzhong, Yiu, Eppie M., Willison, Hugh J., and Jacobs, Bart C.

Abstract

Guillain-Barré syndrome (GBS) is a rare, but potentially fatal, immune-mediated disease of the peripheral nerves and nerve roots that is usually triggered by infections. The incidence of GBS can therefore increase during outbreaks of infectious diseases, as was seen during the Zika virus epidemics in 2013 in French Polynesia and in 2015 in Latin America. Diagnosis and management of GBS can be complicated as its clinical presentation and disease course are heterogeneous, and no international clinical guidelines are currently available. To support clinicians, especially in the context of an outbreak, we have developed a globally applicable guideline for the diagnosis and management of GBS. The guideline is based on current literature and expert consensus, and has a ten-step structure to facilitate its use in clinical practice. We first provide an introduction to the diagnostic criteria, clinical variants and differential diagnoses of GBS. The ten steps then cover early recognition and diagnosis of GBS, admission to the intensive care unit, treatment indication and selection, monitoring and treatment of disease progression, prediction of clinical course and outcome, and management of complications and sequelae.

Published
2021

34. Guillain-Barré syndrome during the Zika virus outbreak in Northeast Brazil:An observational cohort study

Author

Leonhard, Sonja E., Halstead, Susan, Lant, Suzannah B., Militão de Albuquerque, Maria de Fatima Pessoa, de Brito, Carlos Alexandre Antunes, de Albuquerque, Lívia Brito Bezerra, Ellul, Mark A., de Oliveira França, Rafael Freitas, Gourlay, Dawn, Griffiths, Michael J., de Miranda Henriques-Souza, Adélia Maria, de Morais Machado, Maria, Medialdea-Carrera, Raquel, Mehta, Ravi, da Paz Melo, Roberta, Mesquita, Solange D., Moreira, Álvaro J.P., Pena, Lindomar J., Santos, Marcela Lopes, Turtle, Lance, Solomon, Tom, Willison, Hugh J., Jacobs, Bart C., Brito Ferreira, Maria L., Leonhard, Sonja E., Halstead, Susan, Lant, Suzannah B., Militão de Albuquerque, Maria de Fatima Pessoa, de Brito, Carlos Alexandre Antunes, de Albuquerque, Lívia Brito Bezerra, Ellul, Mark A., de Oliveira França, Rafael Freitas, Gourlay, Dawn, Griffiths, Michael J., de Miranda Henriques-Souza, Adélia Maria, de Morais Machado, Maria, Medialdea-Carrera, Raquel, Mehta, Ravi, da Paz Melo, Roberta, Mesquita, Solange D., Moreira, Álvaro J.P., Pena, Lindomar J., Santos, Marcela Lopes, Turtle, Lance, Solomon, Tom, Willison, Hugh J., Jacobs, Bart C., and Brito Ferreira, Maria L.

Abstract

Objective: To determine the clinical phenotype of Guillain-Barré syndrome (GBS) after Zika virus (ZIKV) infection, the anti-glycolipid antibody signature, and the role of other circulating arthropod-borne viruses, we describe a cohort of GBS patients identified during ZIKV and chikungunya virus (CHIKV) outbreaks in Northeast Brazil. Methods: We prospectively recruited GBS patients from a regional neurology center in Northeast Brazil between December 2014 and February 2017. Serum and CSF were tested for ZIKV, CHIKV, and dengue virus (DENV), by RT-PCR and antibodies, and serum was tested for GBS-associated antibodies to glycolipids. Results: Seventy-one patients were identified. Forty-eight (68%) had laboratory evidence of a recent arbovirus infection; 25 (52%) ZIKV, 8 (17%) CHIKV, 1 (2%) DENV, and 14 (29%) ZIKV and CHIKV. Most patients with a recent arbovirus infection had motor and sensory symptoms (72%), a demyelinating electrophysiological subtype (67%) and a facial palsy (58%). Patients with a recent infection with ZIKV and CHIKV had a longer hospital admission and more frequent mechanical ventilation compared to the other patients. No specific anti-glycolipid antibody signature was identified in association with arbovirus infection, although significant antibody titres to GM1, GalC, LM1, and GalNAc-GD1a were found infrequently. Conclusion: A large proportion of cases had laboratory evidence of a recent infection with ZIKV or CHIKV, and recent infection with both viruses was found in almost one third of patients. Most patients with a recent arbovirus infection had a sensorimotor, demyelinating GBS. We did not find a specific anti-glycolipid antibody signature in association with arbovirus-related GBS.

Published
2021

35. Tetanus toxin is internalized by a sequential clathrin-dependent mechanism initiated within lipid microdomains and independent of epsin1

Author

Deinhardt, Katrin, Berninghausen, Otto, Willison, Hugh J., Hopkins, Colin R., and Schiavo, Giampietro

Subjects
Lipid metabolism -- Research, Neurotoxic agents -- Research, Bacterial toxins -- Research, Biological sciences
Abstract

Ligand--receptor complexes are internalized by a variety of endocytic mechanisms. Some are initiated within clathrin-coated membranes, whereas others involve lipid microdomains of the plasma membrane. In neurons, where alternative targeting to short- or long-range trafficking routes underpins the differential processing of synaptic vesicle components and neurotrophin receptors, the mechanism giving access to the axonal retrograde pathway remains unknown. To investigate this sorting process, we examined the internalization of a tetanus neurotoxin fragment (TENT [H.sub.c]), which shares axonal carriers with neurotrophins and their receptors. Previous studies have shown that the TeNT [H.sub.c] receptor, which comprises polysialogangliosides, resides in lipid microdomains. We demonstrate that TeNT [H.sub.c] internalization also relies on a specialized clathrin-mediated pathway, which is independent of synaptic vesicle recycling. Moreover, unlike transferrin uptake, this AP-2--dependent process is independent of epsin1. These findings identify a pathway for TENT, beginning with the binding to a lipid raft component (GD1b) and followed by dissociation from GD1b as the toxin internalizes via a clathrin-mediated mechanism using a specific subset of adaptor proteins.

Published
2006

36. Reply: Guillain-Barré syndrome, SARS-CoV-2 and molecular mimicry and Ongoing challenges in unravelling the association between COVID-19 and Guillain-Barré syndrome and Unclear association between COVID-19 and Guillain-Barré syndrome and Currently available data regarding the potential association between COVID-19 and Guillain-Barré syndrome

Author

Lunn, Michael P, primary, Carr, Aisling C, additional, Keddie, Stephen, additional, Pakpoor, Julia, additional, Pipis, Menelaos, additional, and Willison, Hugh J, additional

Published
2021
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38. Clinical evaluation and investigation of neuropathy

Author

Willison, Hugh J. and Winer, John B.

Subjects
Diagnosis, Development and progression, Research, Methods, Peripheral nervous system diseases -- Diagnosis -- Development and progression -- Research, Neurological research -- Methods -- Research, Clinical pathology -- Research -- Methods, Peripheral nerve diseases -- Diagnosis -- Development and progression -- Research
Abstract

The assessment and investigation of a possible neuropathy is one of the most common clinical problems facing the general neurologist. Studies of the prevalence of neuropathy in the community are [...]

Published
2003

39. Adenovirus type 21-associated acute flaccid paralysis during an outbreak of hand-foot-and-mouth disease in Sarawak, Malaysia. (Major Article)

Author

Ooi, Mong How, Wong, See Chang, Clear, Daniela, Perera, David, Krishnan, Shekhar, Preston, Teresa, Tio, Phaik Hooi, Willison, Hugh J., Tedman, Brian, Kneen, Rachel, Cardosa, Mary Jane, and Solomon, Tom

Subjects
Foot-and-mouth disease -- Research, Adenoviruses -- Research, Enteroviruses -- Research, Children -- Diseases, Paralysis -- Causes of, Health, Health care industry
Published
2003

40. Guillain-Barré Syndrome Outbreak in Peru 2019 Associated With Campylobacter jejuni Infection

Author

Ramos, Ana P., primary, Leonhard, Sonja E., additional, Halstead, Susan K., additional, Cuba, Mireya A., additional, Castañeda, Carlos C., additional, Dioses, Jose A., additional, Tipismana, Martin A., additional, Abanto, Jesus T., additional, Llanos, Alejandro, additional, Gourlay, Dawn, additional, Grogl, Max, additional, Ramos, Mariana, additional, Rojas, Jesus D., additional, Meza, Rina, additional, Puiu, Daniela, additional, Sherman, Rachel M., additional, Salzberg, Steven L., additional, Simner, Patricia J., additional, Willison, Hugh J., additional, Jacobs, Bart C., additional, Cornblath, David R., additional, Umeres, Hugo F., additional, and Pardo, Carlos A., additional

Published
2021
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42. Zika Virus Infection Leads to Demyelination and Axonal Injury in Mature CNS Cultures

Author

Schultz, Verena, primary, Cumberworth, Stephanie L., additional, Gu, Quan, additional, Johnson, Natasha, additional, Donald, Claire L., additional, McCanney, George A., additional, Barrie, Jennifer A., additional, Da Silva Filipe, Ana, additional, Linington, Christopher, additional, Willison, Hugh J., additional, Edgar, Julia M., additional, Barnett, Susan C., additional, and Kohl, Alain, additional

Published
2021
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45. Epidemiological and cohort study finds no association between COVID-19 and Guillain-Barré syndrome

Author

Keddie, Stephen, primary, Pakpoor, Julia, additional, Mousele, Christina, additional, Pipis, Menelaos, additional, Machado, Pedro M, additional, Foster, Mark, additional, Record, Christopher J, additional, Keh, Ryan Y S, additional, Fehmi, Janev, additional, Paterson, Ross W, additional, Bharambe, Viraj, additional, Clayton, Lisa M, additional, Allen, Claire, additional, Price, Olivia, additional, Wall, Jasmine, additional, Kiss-Csenki, Annamaria, additional, Rathnasabapathi, Devi Priya, additional, Geraldes, Ruth, additional, Yermakova, Tatyana, additional, King-Robson, Joshua, additional, Zosmer, Maya, additional, Rajakulendran, Sanjeev, additional, Sumaria, Sheetal, additional, Farmer, Simon F, additional, Nortley, Ross, additional, Marshall, Charles R, additional, Newman, Edward J, additional, Nirmalananthan, Niranjanan, additional, Kumar, Guru, additional, Pinto, Ashwin A, additional, Holt, James, additional, Lavin, Tim M, additional, Brennan, Kathryn M, additional, Zandi, Michael S, additional, Jayaseelan, Dipa L, additional, Pritchard, Jane, additional, Hadden, Robert D M, additional, Manji, Hadi, additional, Willison, Hugh J, additional, Rinaldi, Simon, additional, Carr, Aisling S, additional, and Lunn, Michael P, additional

Published
2020
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