Hope Center member publications

Vitamin A1/A2 chromophore exchange: Its role in spectral tuning and visual plasticity
(2021) Developmental Biology, 475, pp. 145-155. 

Corbo, J.C.

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, 63110, United States

Abstract
Vertebrate rod and cone photoreceptors detect light via a specialized organelle called the outer segment. This structure is packed with light-sensitive molecules known as visual pigments that consist of a G-protein-coupled, seven-transmembrane protein known as opsin, and a chromophore prosthetic group, either 11-cis retinal (‘A1’) or 11-cis 3,4-didehydroretinal (‘A2’). The enzyme cyp27c1 converts A1 into A2 in the retinal pigment epithelium. Replacing A1 with A2 in a visual pigment red-shifts its spectral sensitivity and broadens its bandwidth of absorption at the expense of decreased photosensitivity and increased thermal noise. The use of vitamin A2-based visual pigments is strongly associated with the occupation of aquatic habitats in which the ambient light is red-shifted. By modulating the A1/A2 ratio in the retina, an organism can dynamically tune the spectral sensitivity of the visual system to better match the predominant wavelengths of light in its environment. As many as a quarter of all vertebrate species utilize A2, at least during a part of their life cycle or under certain environmental conditions. A2 utilization therefore represents an important and widespread mechanism of sensory plasticity. This review provides an up-to-date account of the A1/A2 chromophore exchange system. © 2021

Author Keywords
Chromophore;  Cones;  Opsins;  Photoreceptors;  Porphyropsin;  Retina;  Rods;  Sensory plasticity;  Spectral tuning;  Visual ecology;  Visual pigments;  Visual plasticity;  Vitamin A1;  Vitamin A2

Funding details
National Institutes of HealthNIHEY025196, EY026672, EY030075

Document Type: Article
Publication Stage: Final
Source: Scopus

Immune activation during Paenibacillus brain infection in African infants with frequent cytomegalovirus co-infection
(2021) iScience, 24 (4), art. no. 102351, . 

Isaacs, A.M.^a b , Morton, S.U.^c d , Movassagh, M.^e , Zhang, Q.^f , Hehnly, C.^g h , Zhang, L.^g , Morales, D.M.ⁱ , Sinnar, S.A.^j k , Ericson, J.E.^l , Mbabazi-Kabachelor, E.^m , Ssenyonga, P.^m , Onen, J.^m , Mulondo, R.^m , Hornig, M.ⁿ , Warf, B.C.^o , Broach, J.R.^g h , Townsend, R.R.^f , Limbrick, D.D., Jr.ⁱ , Paulson, J.N.^p , Schiff, S.J.^j q

^a Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Department of Clinical Neurosciences, University of Calgary, Calgary, AB T2N 1N4, Canada
^c Division of Newborn Medicine, Boston Children’s Hospital, Boston, MA 02115, United States
^d Department of Pediatrics, Harvard Medical School, Boston, MA 02115, United States
^e Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, United States
^f Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
^g Institute for Personalized Medicine, Pennsylvania State University, Hershey, PA 17033, United States
^h Department of Biochemistry and Molecular Biology, Pennsylvania State University, State College, PA 16801, United States
ⁱ Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO 63110, United States
^j Center for Neural Engineering, Pennsylvania State University, State College, PA 16801, United States
^k Department of Medicine, Pennsylvania State University College of Medicine, Hershey, PA 17033, United States
^l Department of Pediatrics, Pennsylvania State College of Medicine, Hershey, PA 17033, United States
^m CURE Children’s Hospital of Uganda, Mbale, Uganda
ⁿ Department of Epidemiology, Columbia University Mailman School of Public Health, New York, NY 10032, United States
^o Department of Neurosurgery, Harvard Medical School, Boston, MA 02115, United States
^p Department of Biostatistics, Product Development, Genentech Inc., South San Francisco, CA 94080, United States
^q Center for Infectious Disease Dynamics, Departments of Neurosurgery, Engineering Science and Mechanics, and Physics, The Pennsylvania State University, University ParkPA 16802, United States

Abstract
Inflammation during neonatal brain infections leads to significant secondary sequelae such as hydrocephalus, which often follows neonatal sepsis in the developing world. In 100 African hydrocephalic infants we identified the biological pathways that account for this response. The dominant bacterial pathogen was a Paenibacillus species, with frequent cytomegalovirus co-infection. A proteogenomic strategy was employed to confirm host immune response to Paenibacillus and to define the interplay within the host immune response network. Immune activation emphasized neuroinflammation, oxidative stress reaction, and extracellular matrix organization. The innate immune system response included neutrophil activity, signaling via IL-4, IL-12, IL-13, interferon, and Jak/STAT pathways. Platelet-activating factors and factors involved with microbe recognition such as Class I MHC antigen-presenting complex were also increased. Evidence suggests that dysregulated neuroinflammation propagates inflammatory hydrocephalus, and these pathways are potential targets for adjunctive treatments to reduce the hazards of neuroinflammation and risk of hydrocephalus following neonatal sepsis. © 2021 The Authors

Author Keywords
Immunology;  Proteomics;  Transcriptomics

Funding details
396212
National Institutes of HealthNIH5DP1HD086071-05
National Cancer InstituteNCIP30 CA091842
National Institute of General Medical SciencesNIGMSP41 GM103422, R24GM136766
Medtronic
National Center for Advancing Translational SciencesNCATSUL1 TR000448
Institute of Clinical and Translational SciencesICTS
Pennsylvania State UniversityPSU

Document Type: Article
Publication Stage: Final
Source: Scopus

SARM1 is a metabolic sensor activated by an increased NMN/NAD+ ratio to trigger axon degeneration
(2021) Neuron, 109 (7), pp. 1118-1136.e11. Cited 1 time.

Figley, M.D.^a b , Gu, W.^c , Nanson, J.D.^c , Shi, Y.^d , Sasaki, Y.^b e , Cunnea, K.^f g , Malde, A.K.^d , Jia, X.^h , Luo, Z.^c , Saikot, F.K.^c , Mosaiab, T.^d , Masic, V.^d , Holt, S.^d , Hartley-Tassell, L.^d , McGuinness, H.Y.^c , Manik, M.K.^c , Bosanac, T.ⁱ , Landsberg, M.J.^c , Kerry, P.S.^f g , Mobli, M.^h , Hughes, R.O.ⁱ , Milbrandt, J.^b e , Kobe, B.^c , DiAntonio, A.^a b , Ve, T.^d

^a Department of Developmental Biology, Washington University School of Medicine in Saint Louis, St. Louis, MO, United States
^b Needleman Center for Neurometabolism and Axonal Therapeutics, Washington University School of Medicine in Saint Louis, St. Louis, MO, United States
^c School of Chemistry and Molecular Biosciences, Institute for Molecular Bioscience and Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, QLD 4072, Australia
^d Institute for Glycomics, Griffith University, Southport, QLD 4222, Australia
^e Department of Genetics, Washington University School of Medicine in Saint Louis, St. Louis, MO, United States
^f Evotec (UK) Ltd., 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, United Kingdom
^g Evotec SE, Manfred Eigen Campus, Essener Bogen 7, Hamburg, 22419, Germany
^h Centre for Advanced Imaging, University of Queensland, Brisbane, QLD 4072, Australia
ⁱ Disarm Therapeutics, a wholly owned subsidiary of Eli Lilly & Co., Cambridge, MA, United States

Abstract
Axon degeneration is a central pathological feature of many neurodegenerative diseases. Sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1) is a nicotinamide adenine dinucleotide (NAD+)-cleaving enzyme whose activation triggers axon destruction. Loss of the biosynthetic enzyme NMNAT2, which converts nicotinamide mononucleotide (NMN) to NAD+, activates SARM1 via an unknown mechanism. Using structural, biochemical, biophysical, and cellular assays, we demonstrate that SARM1 is activated by an increase in the ratio of NMN to NAD+ and show that both metabolites compete for binding to the auto-inhibitory N-terminal armadillo repeat (ARM) domain of SARM1. We report structures of the SARM1 ARM domain bound to NMN and of the homo-octameric SARM1 complex in the absence of ligands. We show that NMN influences the structure of SARM1 and demonstrate via mutagenesis that NMN binding is required for injury-induced SARM1 activation and axon destruction. Hence, SARM1 is a metabolic sensor responding to an increased NMN/NAD+ ratio by cleaving residual NAD+, thereby inducing feedforward metabolic catastrophe and axonal demise. © 2021 Elsevier Inc.

Author Keywords
allostery;  ARM domain;  cryo-EM;  NADase;  nicotinamide riboside;  TIR domain;  X-ray crystallography

Document Type: Article
Publication Stage: Final
Source: Scopus

CD11c+CD88+CD317+ myeloid cells are critical mediators of persistent CNS autoimmunity
(2021) Proceedings of the National Academy of Sciences of the United States of America, 118 (14), . 

Manouchehri, N.^a , Hussain, R.Z.^a , Cravens, P.D.^a , Esaulova, E.^b , Artyomov, M.N.^b , Edelson, B.T.^b , Wu, G.F.^b c , Cross, A.H.^c , Doelger, R.^a , Loof, N.^d , Eagar, T.N.^e , Forsthuber, T.G.^f , Calvier, L.^g h , Herz, J.^g h i j , Stüve, O.^k l

^a Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States
^b Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110
^c Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110
^d Moody Foundation Flow Cytometry Facility, Children’s Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States
^e Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX 77030
^f Department of Biology, University of Texas at San Antonio, San Antonio, TX 78249, Mexico
^g Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States
^h Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States
ⁱ Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States
^j Center for Neuroscience, Department of Neuroanatomy, Albert-Ludwigs University, Freiburg, 79085, Germany
^k Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75390;
^l Neurology Section, VA North Texas Health Care System, Dallas, United States

Abstract
Natalizumab, a humanized monoclonal antibody (mAb) against α4-integrin, reduces the number of dendritic cells (DC) in cerebral perivascular spaces in multiple sclerosis (MS). Selective deletion of α4-integrin in CD11c+ cells should curtail their migration to the central nervous system (CNS) and ameliorate experimental autoimmune encephalomyelitis (EAE). We generated CD11c.Cre+/-ITGA4fl/fl C57BL/6 mice to selectively delete α4-integrin in CD11c+ cells. Active immunization and adoptive transfer EAE models were employed and compared with WT controls. Multiparameter flow cytometry was utilized to immunophenotype leukocyte subsets. Single-cell RNA sequencing was used to profile individual cells. α4-Integrin expression by CD11c+ cells was significantly reduced in primary and secondary lymphoid organs in CD11c.Cre+/-ITGA4fl/fl mice. In active EAE, a delayed disease onset was observed in CD11c.Cre+/-ITGA4fl/fl mice, during which CD11c+CD88+ cells were sequestered in the blood. Upon clinical EAE onset, CD11c+CD88+ cells appeared in the CNS and expressed CD317+ In adoptive transfer experiments, CD11c.Cre+/-ITGA4fl/fl mice had ameliorated clinical disease phenotype associated with significantly diminished numbers of CNS CD11c+CD88+CD317+ cells. In human cerebrospinal fluid from subjects with neuroinflammation, microglia-like cells display coincident expression of ITGAX (CD11c), C5AR1 (CD88), and BST2 (CD317). In mice, we show that only activated, but not naïve microglia expressed CD11c, CD88, and CD317. Finally, anti-CD317 treatment prior to clinical EAE substantially enhanced recovery in mice. Copyright © 2021 the Author(s). Published by PNAS.

Author Keywords
biomarker;  CD317;  EAE;  multiple sclerosis;  myeloid cells

Document Type: Article
Publication Stage: Final
Source: Scopus

Hydrocephalus treatment in patients with craniosynostosis: an analysis from the Hydrocephalus Clinical Research Network prospective registry
(2021) Neurosurgical Focus, 50 (4), pp. 1-7. 

Bonfield, C.M.^a , Shannon, C.N.^a , Reeder, R.W.^b , Browd, S.^c , Drake, J.^d , Hauptman, J.S.^c , Kulkarni, A.V.^d , Limbrick, D.D.^e , McDonald, P.J.^f , Naftel, R.^a , Pollack, I.F.^g , Riva-Cambrin, J.^h , Rozzelle, C.ⁱ , Tamber, M.S.^f , Whitehead, W.E.^j , Kestle, J.R.W.^k , III, J.C.W.^a

^a Department of Neurosurgery, Vanderbilt University Medical Center, Nashville, Tennessee, United States
^b Departments of Pediatrics, Salt Lake City, Utah, United States
^c Department of Neurosurgery, University of Washington, Seattle, Washington, United States
^d Division of Neurosurgery, University of Toronto, Ontario, Canada
^e Department of Neurosurgery, Washington University School of Medicine in St. LouisMissouri, United States
^f Division of Neurosurgery, University of British Columbia, British Columbia, Vancouver, Canada
^g Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States
^h Division of Neurosurgery, University of Calgary, Alberta, Canada
ⁱ Department of Neurosurgery, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States
^j Department of Neurosurgery, Baylor College of Medicine, Houston, Texas
^k Department of Neurosurgery, University of Utah, Salt Lake City, Utah, United States

Abstract
Objective Hydrocephalus may be seen in patients with multisuture craniosynostosis and, less commonly, singlesuture craniosynostosis. The optimal treatment for hydrocephalus in this population is unknown. In this study, the authors aimed to evaluate the success rate of ventriculoperitoneal shunt (VPS) treatment and endoscopic third ventriculostomy (ETV) both with and without choroid plexus cauterization (CPC) in patients with craniosynostosis. Methods Utilizing the Hydrocephalus Clinical Research Network (HCRN) Core Data Project (Registry), the authors identified all patients who underwent treatment for hydrocephalus associated with craniosynostosis. Descriptive statistics, demographics, and surgical outcomes were evaluated. Results In total, 42 patients underwent treatment for hydrocephalus associated with craniosynostosis. The median gestational age at birth was 39.0 weeks (IQR 38.0, 40.0); 55% were female and 60% were White. The median age at first craniosynostosis surgery was 0.6 years (IQR 0.3, 1.7), and at the first permanent hydrocephalus surgery it was 1.2 years (IQR 0.5, 2.5). Thirty-three patients (79%) had multiple different sutures fused, and 9 had a single suture: 3 unicoronal (7%), 3 sagittal (7%), 2 lambdoidal (5%), and 1 unknown (2%). Syndromes were identified in 38 patients (90%), with Crouzon syndrome being the most common (n = 16, 42%). Ten patients (28%) received permanent hydrocephalus surgery before the first craniosynostosis surgery. Twenty-eight patients (67%) underwent VPS treatment, with the remaining 14 (33%) undergoing ETV with or without CPC (ETV ± CPC). Within 12 months after initial hydrocephalus intervention, 14 patients (34%) required revision (8 VPS and 6 ETV ± CPC). At the most recent follow-up, 21 patients (50%) required a revision. The revision rate decreased as age increased. The overall infection rate was 5% (VPS 7%, 0% ETV ± CPC). Conclusions This is the largest prospective study reported on children with craniosynostosis and hydrocephalus. Hydrocephalus in children with craniosynostosis most commonly occurs in syndromic patients and multisuture fusion. It is treated at varying ages; however, most patients undergo surgery for craniosynostosis prior to hydrocephalus treatment. While VPS treatment is performed more frequently, VPS and ETV are both reasonable options, with decreasing revision rates with increasing age, for the treatment of hydrocephalus associated with craniosynostosis. ©AANS 2021, except where prohibited by US copyright law

Author Keywords
craniosynostosis;  endoscopic third ventriculostomy;  hydrocephalus;  ventriculoperitoneal shunt

Funding details
National Institute of Neurological Disorders and StrokeNINDS1RC1NS068943-01, CER-1403-13857
Gerber Foundation1692-3638
Hydrocephalus AssociationHA

Document Type: Article
Publication Stage: Final
Source: Scopus

Dural augmentation approaches and complication rates after posterior fossa decompression for Chiari I malformation and syringomyelia: A Park-Reeves Syringomyelia Research Consortium study
(2021) Journal of Neurosurgery: Pediatrics, 27 (4), pp. 459-468. 

Yahanda, A.T.^a , David Adelson, P.^b , Hassan A. Akbari, S.^c , Albert, G.W.^d , Aldana, P.R.^e , Alden, T.D.^f , Anderson, R.C.E.^g , Bauer, D.F.^h , Bethel-Anderson, T.^a , Brockmeyer, D.L.ⁱ , Chern, J.J.^j , Couture, D.E.^k , Daniels, D.J.^l , Dlouhy, B.J.^m , Durham, S.R.ⁿ , Ellenbogen, R.G.^o , Eskandari, R.^p , George, T.M.^q , Grant, G.A.^r , Graupman, P.C.^s , Greene, S.^t , Greenfield, J.P.^u , Gross, N.L.^v , Guillaume, D.J.^w , Hankinson, T.C.^x , Heuer, G.G.^y , Iantosca, M.^z , Iskandar, B.J.^aa , Jackson, E.M.^ab , Johnston, J.M.^c , Keating, R.F.^ac , Krieger, M.D.^ad , Leonard, J.R.^ae , Maher, C.O.^af , Mangano, F.T.^ag , Gordon McComb, J.^ad , McEvoy, S.D.^a , Meehan, T.^a , Menezes, A.H.^m , O’Neill, B.R.^x , Olavarria, G.^ah , Ragheb, J.^ai , Selden, N.R.^aj , Shah, M.N.^ak , Shannon, C.N.^al , Shimony, J.S.^am , Smyth, M.D.^a , Stone, S.S.D.^an , Strahle, J.M.^a , Torner, J.C.^m , Tuite, G.F.^ao , Wait, S.D.^ap , Wellons, J.C., III^al , Whitehead, W.E.^aq , Park, T.S.^a , Limbrick, D.D., Jr.^a

^a Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
^b Division of Pediatric Neurosurgery, Barrow Neurological Institute at Phoenix Children’s Hospital, Phoenix, AZ, United States
^c Division of Pediatric Neurosurgery, University of Alabama at BirminghamAL, United States
^d Division of Neurosurgery, Arkansas Children’s Hospital, Little Rock, AR, United States
^e Division of Pediatric Neurosurgery, University of Florida College of Medicine, Jacksonville, FL, United States
^f Division of Pediatric Neurosurgery, Ann and Robert H. Lurie Children’s Hospital of ChicagoIL, United States
^g Division of Pediatric Neurosurgery, Department of Neurological Surgery, Children’s Hospital of New York, Columbia-Presbyterian, New York, NY, United States
^h Department of Neurosurgery, Dartmouth- Hitchcock Medical Center, Lebanon, NH, United States
ⁱ Division of Pediatric Neurosurgery, Primary Children’s Hospital, Salt Lake City, UT, United States
^j Division of Pediatric Neurosurgery, Children’s Healthcare of AtlantaGA, United States
^k Department of Neurological Surgery, Wake Forest University, School of Medicine, Winston-Salem, NC, United States
^l Department of Neurosurgery, Mayo Clinic, Rochester, MN, United States
^m Department of Neurosurgery, University of Iowa Hospitals and Clinics, Iowa City, IA, United States
ⁿ Department of Neurosurgery, University of Vermont, Burlington, VT, United States
^o Division of Pediatric Neurosurgery, Seattle Children’s Hospital, Seattle, WA, United States
^p Department of Neurosurgery, Medical University of South Carolina, Charleston, SC, United States
^q Division of Pediatric Neurosurgery, Dell Children’s Medical Center, Austin, TX, United States
^r Division of Pediatric Neurosurgery, Lucile Packard Children’s Hospital, Palo Alto, CA, United States
^s Division of Pediatric Neurosurgery, Gillette Children’s Hospital, St. Paul, MN, United States
^t Division of Pediatric Neurosurgery, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
^u Department of Neurological Surgery, Weill Cornell Medical College, NewYork-Presbyterian Hospital, New York, NY, United States
^v Department of Neurosurgery, University of Oklahoma, Oklahoma City, OK, United States
^w Department of Neurosurgery, University of Minnesota Medical School, Minneapolis, MN, United States
^x Department of Neurosurgery, Children’s Hospital Colorado, Aurora, CO, United States
^y Division of Pediatric Neurosurgery, Children’s Hospital of Pennsylvania, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^z Department of Neurosurgery, Penn State Milton S. Hershey Medical Center, Hershey, PA, United States
^aa Department of Neurological Surgery, University of Wisconsin at MadisonWI, United States
^ab Department of Neurosurgery, Johns Hopkins University, School of Medicine, Baltimore, MD, United States
^ac Department of Neurosurgery, Children’s National Medical Center, Washington, DC, United States
^ad Division of Pediatric Neurosurgery, Children’s Hospital of Los AngelesCA, United States
^ae Division of Pediatric Neurosurgery, Nationwide Children’s Hospital, Columbus, OH, United States
^af Department of Neurosurgery, University of Michigan, Ann Arbor, MI, United States
^ag Division of Pediatric Neurosurgery, Cincinnati Children’s Medical Center, Cincinnati, OH, United States
^ah Division of Pediatric Neurosurgery, Arnold Palmer Hospital for Children, Orlando, FL, United States
^ai Department of Neurological Surgery, University of Miami, School of Medicine, Miami, FL, United States
^aj Department of Neurological Surgery and Doernbecher Children’s Hospital, Oregon Health and Science University, Portland, OR, United States
^ak Division of Pediatric Neurosurgery, McGovern Medical School, Houston, TX, United States
^al Division of Pediatric Neurosurgery, Monroe Carell Jr. Children’s Hospital of Vanderbilt University, Nashville, TN, United States
^am Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^an Division of Pediatric Neurosurgery, Boston Children’s Hospital, Boston, MA, United States
^ao Department of Neurosurgery, Neuroscience Institute, All Children’s Hospital, St. Petersburg, FL, United States
^ap Carolina Neurosurgery and Spine Associates, Charlotte, NC, United States
^aq Division of Pediatric Neurosurgery, Texas Children’s Hospital, Houston, TX, United States

Abstract
OBJECTIVE Posterior fossa decompression with duraplasty (PFDD) is commonly performed for Chiari I malformation (CM-I) with syringomyelia (SM). However, complication rates associated with various dural graft types are not well established. The objective of this study was to elucidate complication rates within 6 months of surgery among autograft and commonly used nonautologous grafts for pediatric patients who underwent PFDD for CM-I/SM. METHODS The Park-Reeves Syringomyelia Research Consortium database was queried for pediatric patients who had undergone PFDD for CM-I with SM. All patients had tonsillar ectopia ≥ 5 mm, syrinx diameter ≥ 3 mm, and ≥ 6 months of postoperative follow-up after PFDD. Complications (e.g., pseudomeningocele, CSF leak, meningitis, and hydrocephalus) and postoperative changes in syrinx size, headaches, and neck pain were compared for autograft versus nonautologous graft. RESULTS A total of 781 PFDD cases were analyzed (359 autograft, 422 nonautologous graft). Nonautologous grafts included bovine pericardium (n = 63), bovine collagen (n = 225), synthetic (n = 99), and human cadaveric allograft (n = 35). Autograft (103/359, 28.7%) had a similar overall complication rate compared to nonautologous graft (143/422, 33.9%) (p = 0.12). However, nonautologous graft was associated with significantly higher rates of pseudomeningocele (p = 0.04) and meningitis (p < 0.001). The higher rate of meningitis was influenced particularly by the higher rate of chemical meningitis (p = 0.002) versus infectious meningitis (p = 0.132). Among 4 types of nonautologous grafts, there were differences in complication rates (p = 0.02), including chemical meningitis (p = 0.01) and postoperative nausea/ vomiting (p = 0.03). Allograft demonstrated the lowest complication rates overall (14.3%) and yielded significantly fewer complications compared to bovine collagen (p = 0.02) and synthetic (p = 0.003) grafts. Synthetic graft yielded higher complication rates than autograft (p = 0.01). Autograft and nonautologous graft resulted in equal improvements in syrinx size (p < 0.0001). No differences were found for postoperative changes in headaches or neck pain. CONCLUSIONS In the largest multicenter cohort to date, complication rates for dural autograft and nonautologous graft are similar after PFDD for CM-I/SM, although nonautologous graft results in higher rates of pseudomeningocele and meningitis. Rates of meningitis differ among nonautologous graft types. Autograft and nonautologous graft are equivalent for reducing syrinx size, headaches, and neck pain. © 2021 American Association of Neurological Surgeons. All rights reserved.

Author Keywords
Chiari I malformation;  Dural augmentation;  Duraplasty;  Park-Reeves;  Posterior fossa decompression;  Syringomyelia

Funding details
National Institutes of HealthNIHU54 HD087011
University of WashingtonUW
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD

Document Type: Article
Publication Stage: Final
Source: Scopus

Biochemical evaluation of intracerebroventricular rhNAGLU-IGF2 enzyme replacement therapy in neonatal mice with Sanfilippo B syndrome
(2021) Molecular Genetics and Metabolism, . 

Kan, S.-H.^a b , Elsharkawi, I.^c , Le, S.Q.^a c , Prill, H.^d , Mangini, L.^d , Cooper, J.D.^a c , Lawrence, R.^d , Sands, M.S.^c , Crawford, B.E.^d , Dickson, P.I.^a c

^a Department of Pediatrics, The Lundquist Institute (formally Los Angeles Biomedical Research Institute) at Harbor-UCLA Medical Center, Torrance, CA 90502, United States
^b CHOC Research Institute, Orange, CA 92868, United States
^c Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
^d Biology Research, BioMarin Pharmaceutical Inc., Novato, CA 94949, United States

Abstract
Mucopolysaccharidosis IIIB (MPS IIIB, Sanfilippo syndrome type B) is caused by a deficiency in α-N-acetylglucosaminidase (NAGLU) activity, which leads to the accumulation of heparan sulfate (HS). MPS IIIB causes progressive neurological decline, with affected patients having an expected lifespan of approximately 20 years. No effective treatment is available. Recent pre-clinical studies have shown that intracerebroventricular (ICV) ERT with a fusion protein of rhNAGLU-IGF2 is a feasible treatment for MPS IIIB in both canine and mouse models. In this study, we evaluated the biochemical efficacy of a single dose of rhNAGLU-IGF2 via ICV-ERT in brain and liver tissue from Naglu−/− neonatal mice. Twelve weeks after treatment, NAGLU activity levels in brain were 0.75-fold those of controls. HS and β-hexosaminidase activity, which are elevated in MPS IIIB, decreased to normal levels. This effect persisted for at least 4 weeks after treatment. Elevated NAGLU and reduced β-hexosaminidase activity levels were detected in liver; these effects persisted for up to 4 weeks after treatment. The overall therapeutic effects of single dose ICV-ERT with rhNAGLU-IGF2 in Naglu−/− neonatal mice were long-lasting. These results suggest a potential benefit of early treatment, followed by less-frequent ICV-ERT dosing, in patients diagnosed with MPS IIIB. © 2021 Elsevier Inc.

Author Keywords
Heparan sulfate;  Intracerebroventricular enzyme replacement therapy (ICV-ERT);  Mucopolysaccharidosis IIIB;  Neonatal mice;  Sanfilippo syndrome type B

Funding details
National Institutes of HealthNIHGM8432-27 /28, R01 NS088766, R61 NS111079-01
BioMarin Pharmaceutical

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Channelopathies in fragile X syndrome
(2021) Nature Reviews Neuroscience, . 

Deng, P.-Y., Klyachko, V.A.

Department of Cell Biology and Physiology, Washington University School of Medicine, St Louis, MO, United States

Abstract
Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and the leading monogenic cause of autism. The condition stems from loss of fragile X mental retardation protein (FMRP), which regulates a wide range of ion channels via translational control, protein–protein interactions and second messenger pathways. Rapidly increasing evidence demonstrates that loss of FMRP leads to numerous ion channel dysfunctions (that is, channelopathies), which in turn contribute significantly to FXS pathophysiology. Consistent with this, pharmacological or genetic interventions that target dysregulated ion channels effectively restore neuronal excitability, synaptic function and behavioural phenotypes in FXS animal models. Recent studies further support a role for direct and rapid FMRP–channel interactions in regulating ion channel function. This Review lays out the current state of knowledge in the field regarding channelopathies and the pathogenesis of FXS, including promising therapeutic implications. © 2021, Springer Nature Limited.

Funding details
National Institute of Neurological Disorders and StrokeNINDS

Document Type: Review
Publication Stage: Article in Press
Source: Scopus