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A novel therapy to promote axonal fusion in human digital nerves.
Bamba R, Waitayawinyu T, Nookala R, Riley DC, Boyer RB, Sexton KW, Boonyasirikool C, Niempoog S, Kelm ND, Does MD, Dortch RD, Shack RB, Thayer WP
(2016) J Trauma Acute Care Surg 81: S177-S183
MeSH Terms: Adolescent, Historically Controlled Study, Humans, Lacerations, Male, Nerve Regeneration, Peripheral Nerve Injuries, Peripheral Nerves, Polyethylene Glycols, Recovery of Function
Show Abstract · Added October 24, 2018
BACKGROUND - Peripheral nerve injury can have a devastating impact on our military and veteran population. Current strategies for peripheral nerve repair include techniques such as nerve tubes, nerve grafts, tissue matrices, and nerve growth guides to enhance the number of regenerating axons. Even with such advanced techniques, it takes months to regain function. In animal models, polyethylene glycol (PEG) therapy has shown to improve both physiologic and behavioral outcomes after nerve transection by fusion of a portion of the proximal axons to the distal axon stumps. The objective of this study was to show the efficacy of PEG fusion in humans and to retrospectively compare PEG fusion to standard nerve repair.
METHODS - Patients with traumatic lacerations involving digital nerves were treated with PEG after standard microsurgical neurorrhaphy. Sensory assessment after injury was performed at 1 week, 2 weeks, 1 month, and 2 months using static two-point discrimination and Semmes-Weinstein monofilament testing. The Medical Research Council Classification (MRCC) for Sensory Recovery Scale was used to evaluate the level of injury. The PEG fusion group was compared to patient-matched controls whose data were retrospectively collected.
RESULTS - Four PEG fusions were performed on four nerve transections in two patients. Polyethylene glycol therapy improves functional outcomes and speed of nerve recovery in clinical setting assessed by average MRCC score in week 1 (2.8 vs 1.0, p = 0.03). At 4 weeks, MRCC remained superior in the PEG fusion group (3.8 vs 1.3, p = 0.01). At 8 weeks, there was improvement in both groups with the PEG fusion cohort remaining statistically better (4.0 vs 1.7, p = 0.01).
CONCLUSION - Polyethylene glycol fusion is a novel therapy for peripheral nerve repair with proven effectiveness in animal models. Clinical studies are still in early stages but have had encouraging results. Polyethylene glycol fusion is a potential revolutionary therapy in peripheral nerve repair but needs further investigation.
LEVEL OF EVIDENCE - Therapeutic study, level IV.
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MeSH Terms
Comparison of three neurotropic viruses reveals differences in viral dissemination to the central nervous system.
Luethy LN, Erickson AK, Jesudhasan PR, Ikizler M, Dermody TS, Pfeiffer JK
(2016) Virology 487: 1-10
MeSH Terms: Animals, Cell Line, Central Nervous System, Cricetinae, HeLa Cells, Humans, Interferon Type I, Mice, Mice, Inbred C57BL, Mice, Knockout, Orthoreovirus, Mammalian, Peripheral Nerves, Poliomyelitis, Poliovirus, Receptor, Interferon alpha-beta, Reoviridae Infections, Sciatic Nerve, Yellow Fever, Yellow fever virus
Show Abstract · Added February 4, 2016
Neurotropic viruses initiate infection in peripheral tissues prior to entry into the central nervous system (CNS). However, mechanisms of dissemination are not completely understood. We used genetically marked viruses to compare dissemination of poliovirus, yellow fever virus 17D (YFV-17D), and reovirus type 3 Dearing in mice from a hind limb intramuscular inoculation site to the sciatic nerve, spinal cord, and brain. While YFV-17D likely entered the CNS via blood, poliovirus and reovirus likely entered the CNS by transport through the sciatic nerve to the spinal cord. We found that dissemination was inefficient in adult immune-competent mice for all three viruses, particularly reovirus. Dissemination of all viruses was more efficient in immune-deficient mice. Although poliovirus and reovirus both accessed the CNS by transit through the sciatic nerve, stimulation of neuronal transport by muscle damage enhanced dissemination only of poliovirus. Our results suggest that these viruses access the CNS using different pathways.
Copyright © 2015 Elsevier Inc. All rights reserved.
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19 MeSH Terms
Biophysical characterization of interactions between the C-termini of peripheral nerve claudins and the PDZ₁ domain of zonula occludens.
Wu J, Peng D, Zhang Y, Lu Z, Voehler M, Sanders CR, Li J
(2015) Biochem Biophys Res Commun 459: 87-93
MeSH Terms: Amino Acid Motifs, Claudin-1, Claudin-2, Claudin-3, Claudin-5, Claudins, Humans, Nuclear Magnetic Resonance, Biomolecular, Peripheral Nerves, Protein Structure, Secondary, Zonula Occludens-2 Protein
Show Abstract · Added February 5, 2016
Our recent study has shown that cellular junctions in myelin and in the epi-/perineruium that encase nerve fibers regulate the permeability of the peripheral nerves. This permeability may affect propagation of the action potential. Direct interactions between the PDZ₁ domain of zonula occludens (ZO₁ or ZO₂) and the C-termini of claudins are known to be crucial for the formation of tight junctions. Using the purified PDZ₁ domain of ZO₂ and a variety of C-terminal mutants of peripheral nerve claudins (claudin-1, claudin-2, claudin-3, claudin-5 in epi-/perineurium; claudin-19 in myelin), we have utilized NMR spectroscopy to determine specific roles of the 3 C-terminal claudin residues (position -2, -1, 0) for their interactions with PDZ₁ of ZO₂. In contrast to the canonical model that emphasizes the importance of residues at the -2 and 0 positions, our results demonstrate that, for peripheral nerve claudins, the residue at position -1 plays a critical role in association with PDZ₁, while the side-chain of residue 0 plays a significant but lesser role. Surprisingly, claudin-19, the most abundant claudin in myelin, exhibited no binding to ZO₂. These findings reveal that the binding mechanism of claudin/ZO in epi-/perineurium is distinct from the canonical interactions between non-ZO PDZ-containing proteins with their ligands. This observation provides the molecular basis for a strategy to develop drugs that target tight junctions in the epi-/perineurium of peripheral nerves.
Published by Elsevier Inc.
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11 MeSH Terms
S-adenosylmethionine levels regulate the schwann cell DNA methylome.
Varela-Rey M, Iruarrizaga-Lejarreta M, Lozano JJ, Aransay AM, Fernandez AF, Lavin JL, Mósen-Ansorena D, Berdasco M, Turmaine M, Luka Z, Wagner C, Lu SC, Esteller M, Mirsky R, Jessen KR, Fraga MF, Martínez-Chantar ML, Mato JM, Woodhoo A
(2014) Neuron 81: 1024-1039
MeSH Terms: Animals, Cell Differentiation, Cell Division, DNA Methylation, Female, Genomics, Male, Mice, Mice, Inbred C57BL, Mice, Obese, Myelin Sheath, Peripheral Nerves, Primary Cell Culture, Rats, S-Adenosylmethionine, Schwann Cells
Show Abstract · Added January 20, 2015
Axonal myelination is essential for rapid saltatory impulse conduction in the nervous system, and malformation or destruction of myelin sheaths leads to motor and sensory disabilities. DNA methylation is an essential epigenetic modification during mammalian development, yet its role in myelination remains obscure. Here, using high-resolution methylome maps, we show that DNA methylation could play a key gene regulatory role in peripheral nerve myelination and that S-adenosylmethionine (SAMe), the principal methyl donor in cytosine methylation, regulates the methylome dynamics during this process. Our studies also point to a possible role of SAMe in establishing the aberrant DNA methylation patterns in a mouse model of diabetic neuropathy, implicating SAMe in the pathogenesis of this disease. These critical observations establish a link between SAMe and DNA methylation status in a defined biological system, providing a mechanism that could direct methylation changes during cellular differentiation and in diverse pathological situations.
Copyright © 2014 Elsevier Inc. All rights reserved.
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16 MeSH Terms
Abnormal junctions and permeability of myelin in PMP22-deficient nerves.
Guo J, Wang L, Zhang Y, Wu J, Arpag S, Hu B, Imhof BA, Tian X, Carter BD, Suter U, Li J
(2014) Ann Neurol 75: 255-65
MeSH Terms: Action Potentials, Age Factors, Animals, Arthrogryposis, Axons, Disease Models, Animal, Gene Expression Regulation, HEK293 Cells, Hereditary Sensory and Motor Neuropathy, Humans, Junctional Adhesion Molecules, Mice, Mice, Transgenic, Mutation, Myelin Proteins, Myelin Sheath, Neural Conduction, Peripheral Nerves, Potassium, Tight Junction Proteins, Tight Junctions
Show Abstract · Added March 17, 2014
OBJECTIVE - The peripheral myelin protein-22 (PMP22) gene is associated with the most common types of inherited neuropathies, including hereditary neuropathy with liability to pressure palsies (HNPP) caused by PMP22 deficiency. However, the function of PMP22 has yet to be defined. Our previous study has shown that PMP22 deficiency causes an impaired propagation of nerve action potentials in the absence of demyelination. In the present study, we tested an alternative mechanism relating to myelin permeability.
METHODS - Utilizing Pmp22(+) (/) (-) mice as a model of HNPP, we evaluated myelin junctions and their permeability using morphological, electrophysiological, and biochemical approaches.
RESULTS - We show disruption of multiple types of cell junction complexes in peripheral nerve, resulting in increased permeability of myelin and impaired action potential propagation. We further demonstrate that PMP22 interacts with immunoglobulin domain-containing proteins known to regulate tight/adherens junctions and/or transmembrane adhesions, including junctional adhesion molecule-C (JAM-C) and myelin-associated glycoprotein (MAG). Deletion of Jam-c or Mag in mice recapitulates pathology in HNPP.
INTERPRETATION - Our study reveals a novel mechanism by which PMP22 deficiency affects nerve conduction not through removal of myelin, but through disruption of myelin junctions.
© 2014 American Neurological Association.
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21 MeSH Terms
Duration of upper and lower extremity peripheral nerve blockade is prolonged with dexamethasone when added to ropivacaine: a retrospective database analysis.
Rasmussen SB, Saied NN, Bowens C, Mercaldo ND, Schildcrout JS, Malchow RJ
(2013) Pain Med 14: 1239-47
MeSH Terms: Adult, Aged, Amides, Anesthetics, Local, Anti-Inflammatory Agents, Databases, Factual, Dexamethasone, Epinephrine, Female, Humans, Linear Models, Logistic Models, Male, Middle Aged, Nerve Block, Orthopedic Procedures, Pain, Postoperative, Patient Satisfaction, Peripheral Nerves, Postoperative Complications, Retrospective Studies, Ropivacaine, Sensation Disorders, Shoulder, Young Adult
Show Abstract · Added May 27, 2014
BACKGROUND - Dexamethasone, when added to local anesthetics, has been shown to prolong the duration of peripheral nerve blocks; however, there are limited studies utilizing large numbers of patients. The purpose of this study was to examine the effect of adding dexamethasone to ropivacaine on duration of nerve blocks of the upper and lower extremity.
METHODS - We reviewed 1,040 patient records collected in an orthopedic outpatient surgery center that had received an upper or lower extremity peripheral nerve block with ropivacaine 0.5% with or without dexamethasone and/or epinephrine. The primary outcome was duration of analgesia in upper or lower extremity blocks containing dexamethasone as an adjunct. Secondary outcomes included postoperative patient pain scores, satisfaction, and the incidence of block related complications. Linear and ordinal logistic regression models were used to examine the independent effect of dexamethasone on outcomes.
RESULTS - Dexamethasone was observed to increase median block duration by 37% (95% confidence interval: 31-43%). The increased block duration persisted within body regions (upper and lower) and across a range of block types. Dexamethasone was also observed to reduce pain scores on the day of surgery (P = 0.001) and postoperative day 1 (P < 0.001). There was no significant difference in duration of nerve blocks when epinephrine (1:400,000) was added to 0.5% ropivacaine with or without dexamethasone.
CONCLUSION - The addition of dexamethasone to 0.5% ropivacaine prolongs the duration of peripheral nerve blocks of both the upper and lower extremity.
Wiley Periodicals, Inc.
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25 MeSH Terms
Retinotopic maps in the pulvinar of bush baby (Otolemur garnettii).
Li K, Patel J, Purushothaman G, Marion RT, Casagrande VA
(2013) J Comp Neurol 521: 3432-50
MeSH Terms: Animals, Brain Mapping, Central Nervous System, Data Interpretation, Statistical, Electrodes, Implanted, Electrophysiological Phenomena, Female, Galago, Imaging, Three-Dimensional, Immunohistochemistry, Male, Microelectrodes, Peripheral Nerves, Photic Stimulation, Pulvinar, Retina, Vision, Ocular, Visual Cortex, Visual Pathways
Show Abstract · Added February 12, 2015
Despite its anatomical prominence, the function of the primate pulvinar is poorly understood. A few electrophysiological studies in simian primates have investigated the functional organization of pulvinar by examining visuotopic maps. Multiple visuotopic maps have been found for all studied simians, with differences in organization reported between New and Old World simians. Given that prosimians are considered closer to the common ancestors of New and Old World primates, we investigated the visuotopic organization of pulvinar in the prosimian bush baby (Otolemur garnettii). Single-electrode extracellular recording was used to find the retinotopic maps in the lateral (PL) and inferior (PI) pulvinar. Based on recordings across cases, a 3D model of the map was constructed. From sections stained for Nissl bodies, myelin, acetylcholinesterase, calbindin, or cytochrome oxidase, we identified three PI chemoarchitectonic subdivisions, lateral central (PIcl), medial central (PIcm), and medial (PIm) inferior pulvinar. Two major retinotopic maps were identified that cover PL and PIcl, the dorsal one in dorsal PL and the ventral one in PIcl and ventral PL. Both maps represent central vision at the posterior end of the border between the maps, the upper visual field in the lateral half and the lower visual field in the medial half. They share many features with the maps reported for the pulvinar of simians, including the location in pulvinar and the representation of the upper-lower and central-peripheral visual field axes. The second-order representation in the lateral map and a laminar organization are likely features specific to Old World simians.
Copyright © 2013 Wiley Periodicals, Inc.
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19 MeSH Terms
Pathological changes long after liver transplantation in a familial amyloidotic polyneuropathy patient.
Obayashi K, Ueda M, Oshima T, Kawahara S, Misumi Y, Yamashita T, Jono H, Yazaki M, Kametani F, Ikeda S, Ohya Y, Asonuma K, Inomata Y, Ando Y
(2012) BMJ Case Rep 2012:
MeSH Terms: Adult, Amyloid Neuropathies, Familial, Autopsy, Brain Chemistry, Fatal Outcome, Gastrointestinal Tract, Heart Ventricles, Humans, Kidney, Liver, Liver Transplantation, Lung, Male, Pancreas, Peripheral Nerves, Prealbumin, Thyroid Gland, Tongue
Show Abstract · Added February 11, 2015
Liver transplantation (LT) reportedly prolongs the survival of patients with familial amyloidotic polyneuropathy (FAP), a fatal hereditary systemic amyloidosis caused by mutant transthyretin (TTR). However, what happens in systemic tissue sites long after LT is poorly understood. In the present study, we report pathological and biochemical findings for an FAP patient who underwent LT and died from refractory ventricular fibrillation more than 16 years after FAP onset. Our autopsy study revealed that the distributions of amyloid deposits after LT were quite different from those in FAP amyloidogenic TTR V30M patients not having had LT and seemed to be similar to those observed in senile systemic amyloidosis (SSA), a sporadic systemic amyloidosis derived from wild-type (WT) TTR. Our biochemical examination also revealed that this patient's cardiac and tongue amyloid deposits derived mostly from WT TTR. We propose that FAP patients after LT may suffer from SSA-like WT TTR amyloidosis in systemic organs.
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18 MeSH Terms
Peripheral nerve and brain differ in their capacity to resolve N,N-diethyldithiocarbamate-mediated elevations in copper and oxidative injury.
Valentine HL, Viquez OM, Valentine WM
(2010) Toxicology 274: 10-7
MeSH Terms: Animals, Blotting, Western, Brain, Copper, Ditiocarb, Glutathione Transferase, Heme Oxygenase-1, Liver, Male, Mass Spectrometry, Myelin Sheath, Oxidation-Reduction, Oxidative Stress, Peripheral Nerves, Rats, Rats, Sprague-Dawley, Sciatic Nerve, Spinal Cord, Superoxide Dismutase, Superoxide Dismutase-1
Show Abstract · Added May 27, 2014
Previous studies have demonstrated that N,N-diethyldithiocarbamate (DEDC) elevates copper and promotes oxidative stress within the nervous system. However, whether these effects resolve following cessation of exposure or have the potential to persist and result in cumulative injury has not been determined. In this study, an established model for DEDC myelin injury in the rat was used to determine whether copper levels, oxidative stress, and neuromuscular deficits resolve following the cessation of DEDC exposure. Rats were exposed to DEDC for 8 weeks and then either euthanized or maintained for 2, 6 or 12 weeks after cessation of exposure. At each time point copper levels were measured by inductively coupled mass spectrometry to assess the ability of sciatic nerve, brain, spinal cord and liver to eliminate excess copper post-exposure. The protein expression levels of glutathione transferase alpha, heme oxygenase 1 and superoxide dismutase 1 in peripheral nerve and brain were also determined by western blot to assess levels of oxidative stress as a function of post-exposure duration. As an initial assessment of the bioavailability of the excess copper in brain the protein expression levels of copper chaperone for superoxide dismutase 1, and prion protein were determined by western blot as a function of exposure and post-exposure duration. Neuromuscular function in peripheral nerve was evaluated using grip strengths, nerve conduction velocities, and morphologic changes at the light microscope level. The data demonstrated that in peripheral nerve, copper levels and oxidative stress return to control levels within several weeks after cessation of exposure. Neuromuscular function also showed a trend towards pre-exposure values, although the resolution of myelin lesions was more delayed. In contrast, total copper and antioxidant enzyme levels remained significantly elevated in brain for longer post-exposure periods. The persistence of effects observed in brain suggests that the central nervous system is more susceptible to long-term cumulative adverse effects from dithiocarbamates. Additionally, significant changes in expression levels of chaperone for superoxide dismutase 1, and prion protein were observed consistent with at least a portion of the excess copper being bioactive.
2010 Elsevier Ireland Ltd. All rights reserved.
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20 MeSH Terms
Nitrogen substituent polarity influences dithiocarbamate-mediated lipid oxidation, nerve copper accumulation, and myelin injury.
Valentine HL, Viquez OM, Amarnath K, Amarnath V, Zyskowski J, Kassa EN, Valentine WM
(2009) Chem Res Toxicol 22: 218-26
MeSH Terms: Animals, Copper, Demyelinating Diseases, Ditiocarb, Ethylenebis(dithiocarbamates), Lipid Peroxidation, Male, Malondialdehyde, Mass Spectrometry, Myelin Sheath, Nitrogen, Oxidative Stress, Peripheral Nerves, Rats, Rats, Sprague-Dawley, Sarcosine, Thiocarbamates
Show Abstract · Added May 27, 2014
Dithiocarbamates have a wide spectrum of applications in industry, agriculture, and medicine, with new applications being investigated. Past studies have suggested that the neurotoxicity of some dithiocarbamates may result from copper accumulation, protein oxidative damage, and lipid oxidation. The polarity of a dithiocarbamate's nitrogen substituents influences the lipophilicity of the copper complexes that it generates and thus potentially determines its ability to promote copper accumulation within nerve and induce myelin injury. In the current study, a series of dithiocarbamate-copper complexes differing in their lipophilicity were evaluated for their relative abilities to promote lipid peroxidation determined by malondialdehyde levels generated in an ethyl arachidonate oil-in-water emulsion. In a second component of this study, rats were exposed to either N,N-diethyldithiocarbamate or sarcosine dithiocarbamate; both generated dithiocarbamate-copper complexes that were lipid- and water-soluble, respectively. Following the exposures, brain, tibial nerve, spinal cord, and liver tissue copper levels were measured by inductively coupled mass spectroscopy to assess the relative abilities of these two dithiocarbamates to promote copper accumulation. Peripheral nerve injury was evaluated using grip strengths, nerve conduction velocities, and morphologic changes at the light microscope level. Additionally, the protein expression levels of glutathione transferase alpha and heme-oxygenase-1 in nerve were determined, and the quantity of protein carbonyls was measured to assess levels of oxidative stress and injury. The data provided evidence that dithiocarbamate-copper complexes are redox active and that the ability of dithiocarbamate complexes to promote lipid peroxidation is correlated to the lipophilicity of the complex. Consistent with neurotoxicity requiring the formation of a lipid-soluble copper complex, significant increases in copper accumulation, oxidative stress, and myelin injury were produced by N,N-diethyldithiocarbamate but not by sarcosine dithiocarbamate.
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17 MeSH Terms