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      Closing the Gap Between Mammalian and Invertebrate Peripheral Nerve Injury: Protocol for a Novel Nerve Repair


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          Outcomes after peripheral nerve injuries are poor despite current nerve repair techniques. Currently, there is no conclusive evidence that mammalian axons are capable of spontaneous fusion after transection. Notably, certain invertebrate species are able to auto-fuse after transection. Although mammalian axonal auto-fusion has not been observed experimentally, no mammalian study to date has demonstrated regenerating axolemmal membranes contacting intact distal segment axolemmal membranes to determine whether mammalian peripheral nerve axons have the intrinsic mechanisms necessary to auto-fuse after transection.


          This study aims to assess fusion competence between regenerating axons and intact distal segment axons by enhancing axon regeneration, delaying Wallerian degeneration, limiting the immune response, and preventing myelin obstruction.


          This study will use a rat sciatic nerve model to evaluate the effects of a novel peripheral nerve repair protocol on behavioral, electrophysiologic, and morphologic parameters. This protocol consists of a variety of preoperative, intraoperative, and postoperative interventions. Fusion will be assessed with electrophysiological conduction of action potentials across the repaired transection site. Axon-axon contact will be assessed with transmission electron microscopy. Behavioral recovery will be analyzed with the sciatic functional index. A total of 36 rats will be used for this study. The experimental group will use 24 rats and the negative control group will use 12 rats. For both the experimental and negative control groups, there will be both a behavior group and another group that will undergo electrophysiological and morphological analysis. The primary end point will be the presence or absence of action potentials across the lesion site. Secondary end points will include behavioral recovery with the sciatic functional index and morphological analysis of axon-axon contact between regenerating axons and intact distal segment axons.


          The author is in the process of grant funding and institutional review board approval as of March 2020. The final follow-up will be completed by December 2021.


          In this study, the efficacy of the proposed novel peripheral nerve repair protocol will be evaluated using behavioral and electrophysiologic parameters. The author believes this study will provide information regarding whether spontaneous axon fusion is possible in mammals under the proper conditions. This information could potentially be translated to clinical trials if successful to improve outcomes after peripheral nerve injury.

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          Remyelination therapies: a new direction and challenge in multiple sclerosis

          Restoring damaged myelin could reverse the neurological effects observed in patients with multiple sclerosis. In this Review, Yong and colleagues discuss the progress made in remyelinating therapies, including novel and potential repurposed agents, and highlight the challenges in preclinical and clinical development for such drugs.
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            Mechanisms of acute axonal degeneration in the optic nerve in vivo.

            Axonal degeneration is an initial key step in traumatic and neurodegenerative CNS disorders. We established a unique in vivo epifluorescence imaging paradigm to characterize very early events in axonal degeneration in the rat optic nerve. Single retinal ganglion cell axons were visualized by AAV-mediated expression of dsRed and this allowed the quantification of postlesional acute axonal degeneration (AAD). EM analysis revealed severe structural alterations of the cytoskeleton, cytoplasmatic vacuolization, and the appearance of autophagosomes within the first hours after lesion. Inhibition of autophagy resulted in an attenuation of acute axonal degeneration. Furthermore, a rapid increase of intraaxonal calcium levels following crush lesion could be visualized using a calcium-sensitive dye. Application of calcium channel inhibitors prevented crush-induced calcium increase and markedly attenuated axonal degeneration, whereas application of a calcium ionophore aggravated the degenerative phenotype. We finally demonstrate that increased postlesional autophagy is calcium dependent and thus mechanistically link autophagy and intraaxonal calcium levels. Both processes are proposed to be major targets for the manipulation of axonal degeneration in future therapeutic settings.
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              Median and ulnar nerve injuries: a meta-analysis of predictors of motor and sensory recovery after modern microsurgical nerve repair.

              The aim of this study was to quantify variables that influence outcome after median and ulnar nerve transection injuries. The authors present a meta-analysis based on individual patient data on motor and sensory recovery after microsurgical nerve repair. From 130 studies found after literature review, 23 articles were ultimately included, giving individual data for 623 median or ulnar nerve injuries. The variables age, sex, nerve, site of injury, type of repair, use of grafts, delay between injury and repair, follow-up period, and outcome were extracted. Satisfactory motor recovery was defined as British Medical Research Council motor scale grade 4 and 5, and satisfactory sensory recovery was defined as British Medical Research Council grade 3+ and 4. For motor and sensory recovery, complete data were available for 281 and 380 nerve injuries, respectively. Motor and sensory recovery were significantly associated (Spearman r = 0.62, p 40 years: odds ratio, 4.3; 95 percent confidence interval, 1.6 to 11.2), site (proximal versus distal: odds ratio, 0.46; 95 percent confidence interval, 0.20 to 1.10), and delay (per month: odds ratio, 0.94; 95 percent confidence interval, 0.90 to 0.98) were significant predictors of successful motor recovery. In ulnar nerve injuries, the chance of motor recovery was 71 percent lower than in median nerve injuries (odds ratio, 0.29; 95 percent confidence interval, 0.15 to 0.55). For sensory recovery, age (odds ratio, 27.0; 95 percent confidence interval, 9.4 to 77.6) and delay (per month: odds ratio, 0.92; 95 percent confidence interval, 0.87 to 0.98) were found to be significant predictors. In this individual patient data meta-analysis, age, site, injured nerve, and delay significantly influenced prognosis after microsurgical repair of median and ulnar nerve injuries.

                Author and article information

                JMIR Res Protoc
                JMIR Res Protoc
                JMIR Research Protocols
                JMIR Publications (Toronto, Canada )
                August 2020
                27 August 2020
                : 9
                : 8
                : e18706
                [1 ] Department of Plastic and Reconstructive Surgery University of Nevada Las Vegas Las Vegas, NV United States
                [2 ] Larner College of Medicine University of Vermont Burlington, VT United States
                Author notes
                Corresponding Author: Maxwell Vest maxwell.vest@ 123456unlv.edu
                Author information
                ©Maxwell Vest, Addison Guida, Cory Colombini, Kristina Cordes, Diana Pena, Marwa Maki, Michael Briones, Sabrina Antonio, Carmen Hollifield, Elli Tian, Lucas James, Christian Borashan, Johnnie Woodson, John Rovig, Hanaa Shihadeh, Alexander Karabachev, John Brosious, Ashley Pistorio. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 27.08.2020.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in JMIR Research Protocols, is properly cited. The complete bibliographic information, a link to the original publication on http://www.researchprotocols.org, as well as this copyright and license information must be included.

                : 13 March 2020
                : 12 June 2020
                : 22 June 2020
                : 23 June 2020

                wallerian degeneration,auto-fusion,peripheral nerve injury,nerves,surgery,intervention,rat model,nerve repair


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