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The emergence and international spread of neurovirulent circulating vaccine-derived polioviruses (cVDPVs) across multiple countries in Africa and Asia in recent years pose a major challenge to the goal of eradicating all forms of polioviruses. Approximately 90% of all cVDPV outbreaks are caused by the type 2 strain of the Sabin vaccine, an oral live, attenuated vaccine; cVDPV outbreaks typically occur in areas of persistently low immunization coverage (1). A novel type 2 oral poliovirus vaccine (nOPV2), produced by genetic modification of the type 2 Sabin vaccine virus genome (2), was developed and evaluated through phase I and phase II clinical trials during 2017-2019. nOPV2 was demonstrated to be safe and well-tolerated, have noninferior immunogenicity, and have superior genetic stability compared with Sabin monovalent type 2 (as measured by preservation of the primary attenuation site [domain V in the 5' noncoding region] and significantly lower neurovirulence of fecally shed vaccine virus in transgenic mice) (3-5). These findings indicate that nOPV2 could be an important tool in reducing the risk for generating vaccine-derived polioviruses (VDPVs) and the risk for vaccine-associated paralytic poliomyelitis cases. Based on the favorable preclinical and clinical data, and the public health emergency of international concern generated by ongoing endemic wild poliovirus transmission and cVDPV type 2 outbreaks, the World Health Organization authorized nOPV2 for use under the Emergency Use Listing (EUL) pathway in November 2020, allowing for its first use for outbreak response in March 2021 (6). As required by the EUL process, among other EUL obligations, an extensive plan was developed and deployed for obtaining and monitoring nOPV2 isolates detected during acute flaccid paralysis (AFP) surveillance, environmental surveillance, adverse events after immunization surveillance, and targeted surveillance for adverse events of special interest (i.e., prespecified events that have the potential to be causally associated with the vaccine product), during outbreak response, as well as through planned field studies. Under this monitoring framework, data generated from whole-genome sequencing of nOPV2 isolates, alongside other virologic data for isolates from AFP and environmental surveillance systems, are reviewed by the genetic characterization subgroup of an nOPV working group of the Global Polio Eradication Initiative. Global nOPV2 genomic surveillance during March-October 2021 confirmed genetic stability of the primary attenuating site. Sequence data generated through this unprecedented global effort confirm the genetic stability of nOPV2 relative to Sabin 2 and suggest that nOPV2 will be an important tool in the eradication of poliomyelitis. nOPV2 surveillance should continue for the duration of the EUL., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Isobel M. Blake, John Konz, Andrew Macadam, Javier Martin, John Modlin, and M. Steven Oberste report institutional support from the Bill and Melinda Gates Foundation. Andrew Macadam reports support for travel to consortium meetings from the Bill and Melinda Gates Foundation and PATH. Lester M. Shulman is an independent consultant for the McKing Consulting Corporation, an unpaid member of the Israel National Certification Committee for Polio, and a volunteer member of the Emergency Response Team for the current cVDPV3 polio outbreak in Israel. No other potential conflicts of interest were reported.

Introduction. Global poliovirus eradication is a public health emergency of international concern. The acute flaccid paralysis (AFP) surveillance programme in South Africa has been instrumental in eliminating polioviruses and keeping the country poliovirus free. Gap statement. The sensitivity of surveillance for polioviruses by every African country is of global interest in the effort to ensure global health security from poliovirus re-emergence. Aim. To describe the epidemiology of polioviruses from AFP cases and environmental samples in South Africa and to report the performance of the AFP surveillance system for the years 2016-2019 against targets established by the World Health Organization (WHO). Methods. Stool specimens from AFP or suspected AFP cases were received and tested as per WHO guidelines. Environmental samples were gathered from sites across the Gauteng province using the grab collection method. Concentration was effected by the two-phase polyethylene glycol method approved by the WHO. Suspected polioviruses were isolated in RD and/or L20B cell cultures through identification of typical cytopathic effects. The presence of polioviruses was confirmed by intratypic differentiation PCR. All polioviruses were sequenced using the Sanger method, and their VP1 gene analysed for mutations. Results. Data from 4597 samples (2385 cases) were analysed from the years 2016-2019. Two cases of immunodeficiency-associated vaccine-derived poliovirus (iVDPV) type 3 were detected in 2017 and 2018. A further 24 Sabin type 1 or type 3 polioviruses were detected for the 4 years. The national surveillance programme detected an average of 3.1 cases of AFP/100 000 individuals under 15 years old (2.8/100 000-3.5/100 000). The stool adequacy of the samples received was 53.0 % (47.0-55.0%), well below the WHO target of 80 % adequacy. More than 90 % of results were released from the laboratory within the turnaround time (96.6 %) and non-polio enteroviruses were detected in 11.6 % of all samples. Environmental surveillance detected non-polio enterovirus in 87.5 % of sewage samples and Sabin polioviruses in 12.5 % of samples. Conclusion. The AFP surveillance programme in South Africa is sensitive to detect polioviruses in South Africa and provided no evidence of wild poliovirus or VDPV circulation in the country.

Enterovirus D68 (EV-D68) causes outbreaks of respiratory illness, and there is increasing evidence that it causes outbreaks of acute flaccid myelitis (AFM). There are no licensed therapies to prevent or treat EV-D68 infection or AFM disease. We isolated a panel of EV-D68-reactive human monoclonal antibodies that recognize diverse antigenic variants from participants with prior infection. One potently neutralizing cross-reactive antibody, EV68-228, protected mice from respiratory and neurologic disease when given either before or after infection. Cryo-electron microscopy studies revealed that EV68-228 and another potently neutralizing antibody (EV68-159) bound around the fivefold or threefold axes of symmetry on virion particles, respectively. The structures suggest diverse mechanisms of action by these antibodies. The high potency and effectiveness observed in vivo suggest that antibodies are a mechanistic correlate of protection against AFM disease and are candidates for clinical use in humans with EV-D68 infection., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background and Aim of the Work: The International Health Regulations Emergency Committee declared in 2014 that poliovirus circulation is a public health emergency of international concern. In 2017 and 2018 Italy was classified at intermediate risk of poliovirus reintroduction based on suboptimal poliovirus surveillance. Acute flaccid paralysis active surveillance is the gold standard in the polio eradication process. The aims of this study were to investigate the causes of reduced acute flaccid paralysis case reporting in Emilia-Romagna in the last few years (step 1) and to study a public health intervention to restore an adequate level of acute flaccid paralysis surveillance in that region (step 2)., Methods: In the first step a context analysis was performed by analysing the 2015-2017 Hospital Discharge Registers in Emilia-Romagna with the ICD-9-CM differential diagnosis codes for acute flaccid paralysis. Data from context analysis was then used to plan a new regional collaborative network of acute flaccid paralysis active surveillance., Results: The active surveillance network was, at the end of the study, composed by 49 doctors from both hospital administrations and clinical wards from 4 University Hospitals and 7 Local Health Authorities throughout the Region. In 15 months, 7 acute flaccid paralysis cases have been reported; 85,7% received a full clinical and virological investigation and 83,3% completed the 60 day's follow-up. The mean response to each e-mail was 48,5% (SD 7,5%)., Conclusions: In 2019, the Emilia-Romagna's active surveillance system reached the sensitivity, completeness of case investigation and follow-up required to achieve the minimum levels for certification standard surveillance.

Rabies has two distinct clinical syndromes, encephalitic (or 'furious') and paralytic (or 'dumb'). The paralytic form presents as acute flaccid myelitis and is more common in patients who received post-exposure anti-rabies vaccination without rabies immunoglobulins. We have recently had the opportunity to manage a middle-aged man presenting as 'dumb' paralytic rabies.

Spinal cord injury (SCI) is a devastating neurologic disorder that often leads to permanent disability, and there is no effective treatment for it. High mobility group box-1 (HMGB1) is a damage-associated molecular protein that triggers sterile inflammation upon injuries. We have previously shown that two administrations of neutralizing monoclonal antibody (mAb) against HMGB1 (immediately after (0 h) and 6 h after) SCI dramatically improves functional recovery after SCI in mice. However, when considering clinical application, 0 h after SCI is not practical. Therefore, in this study, we examined the therapeutic time window of the mAb administration. Injection at 3 h after SCI significantly improved the functional recovery comparably to injection immediately after SCI, while injection at 6 h was less effective, and injection at 9 or 12 h had no therapeutic effect. We also found beneficial effects of injection at 3 h after injury on blood-spinal cord barrier maintenance, inflammatory-related gene expression and preservation of the damaged spinal cord tissue. Taken together, our results suggest that a single administration of anti-HMGB1 mAb within a proper time window could be a novel and potential therapeutic strategy for SCI., (Copyright © 2018 Elsevier B.V. and Japan Neuroscience Society. All rights reserved.)

Objective: Current constraints aim to minimize the risk of radiation myelitis by the use of restrictive maximal spinal cord doses, commonly 50 Gy. However, several studies suggested that a dose-volume effect could exist. Based on these observations, we evaluated patients receiving potentially excessive doses to the spinal cord within minimal volumes., Patients and Methods: Patients receiving radiotherapy between June 2010 and May 2015 using the Novalis TM (Varian, Palo Alto, CA, USA; Brainlab, Heimstetten, Germany) radiosurgery system were retrospectively analyzed. A total of 56 patients with 62 treated lesions that had been prescribed radiation doses close to the spinal cord potentially higher than the common 50 Gy 2‑Gy equivalent-dose (EQD2) constraint were selected for further analysis. Of these patients, 26 with 31 lesions had no history of previous irradiation, while 30 patients with 31 lesions had been previously irradiated within the treatment field., Results: According to different dose evaluation approaches (spinal canal, spinal cord contour), 16 and 10 out of 31 primary irradiated lesions infringed constraints. For the 16 lesions violating spinal canal doses, the maximum doses ranged from 50.5 to 61.9 Gy EQD2. Reirradiated lesions had an average and median cumulative dose of 70.5 and 69 Gy, respectively. Dose drop-off was steep in both groups. Median overall survival was 17 months. No radiation myelitis or radiomorphological alterations were observed during follow-up., Conclusion: This study adds to the increasing body of evidence indicating that excessive spinal cord doses within a minimal volume, especially in a reirradiation setting with topographically distinct high-point doses, may be given to patients after careful evaluation of treatment- and tumor-associated risks.

Targeting posttraumatic inflammation is crucial for improving locomotor function. SIRT1 has been shown to play a critical role in disease processes such as hepatic inflammation, rheumatoid arthritis, and acute lung inflammation by regulating inflammation. However, the role of SIRT1 in spinal cord injury (SCI) is unknown. We hypothesized that SIRT1 plays an important role in improving locomotor function after SCI by regulating neuroinflammation. In this study, we investigate the effect of SIRT1 in SCI using pharmacological intervention (SRT1720) and the Mx1-Cre/loxP recombination system to knock out target genes. First, we found that SIRT1 expression at the injured lesion site of wild-type (WT) mice (C57BL/6) decreased 4 h after SCI and lasted for 3 d. Moreover, administration of SRT1720, an agonist of SIRT1, to WT mice significantly improved functional recovery for up to 28 d after injury by reducing the levels of proinflammatory cytokines, the number of M1 macrophages, the number of macrophages/microglia, and the accumulation of perivascular macrophages. In contrast, administration of SRT1720 to SIRT1 knock-out (KO) mice did not improve locomotor recovery or attenuate inflammation. Furthermore, SIRT1 KO mice exhibited worse locomotor recovery, increased levels of inflammatory cytokines, and more M1 macrophages and perivascular macrophages than those of WT mice after SCI. Together, these findings indicate that SRT1720, an SIRT1 agonist, can improve functional recovery by attenuating inflammation after SCI. Therefore, SIRT1 is not only a protective factor but also an anti-inflammatory molecule that exerts beneficial effects on locomotor function after SCI. SIGNIFICANCE STATEMENT Posttraumatic inflammation plays a central role in regulating the pathogenesis of spinal cord injury (SCI). Here, new data show that administration of SRT1720, an SIRT1 agonist, to wild-type (WT) mice significantly improved outcomes after SCI, most likely by reducing the levels of inflammatory cytokines, the number of macrophages/microglia, perivascular macrophages, and M1 macrophages. In contrast, SIRT1 KO mice exhibited worse locomotor recovery than that of WT mice due to aggravated inflammation. Taken together, the results of this study expand upon the previous understanding of the functions and mechanisms of SIRT1 in neuroinflammation following injury to the CNS, suggesting that SIRT1 plays a critical role in regulating neuroinflammation following CNS injury and may be a novel therapeutic target for post-SCI intervention., (Copyright © 2017 the authors 0270-6474/17/372916-15$15.00/0.)

Experimental autoimmune encephalomyelitis (EAE) is a demyelinating pathology of the central nervous system (CNS) used as a model to study multiple sclerosis immunopathology. EAE has also been extensively employed to evaluate potentially therapeutic schemes. Considering the presence of an immune response directed to heat shock proteins (hsps) in autoimmune diseases and the immunoregulatory potential of these molecules, we evaluated the effect of a previous immunization with a genetic vaccine containing the mycobacterial hsp65 gene on EAE development. C57BL/6 mice were immunized with 4 pVAXhsp65 doses and 14 days later were submitted to EAE induction by immunization with myelin oligodendrocyte glycoprotein (MOG 35-55 ) emulsified in Complete Freund's Adjuvant. Vaccinated mice presented significant lower clinical scores and lost less body weight. MOG 35-55 immunization also determined less inflammation in lumbar spinal cord but did not change CD4+CD25+Foxp3+ T cells frequency in spleen and CNS. Infiltrating cells from the CNS stimulated with rhsp65 produced significantly higher levels of IL-10. These results suggest that the ability of pVAXhsp65 vaccination to control EAE development is associated with IL-10 induction., Competing Interests: The authors declare no conflict of interests.

Current therapies to limit the neural tissue destruction following the spinal cord injury are not effective. Our recent studies indicate that the injury to the white matter of the spinal cord results in a severe inflammatory response where macrophages phagocytize damaged myelin and the fluid-filled cavity of injury extends in size with concurrent and irreversible destruction of the surrounding neural tissue over several months. We previously established that a high dose of 4mg/rat of dexamethasone administered for 1 week via subdural infusion remarkably lowers the numbers of infiltrating macrophages leaving large amounts of un-phagocytized myelin debris and therefore inhibits the severity of inflammation and related tissue destruction. But this dose was potently toxic to the rats. In the present study the lower doses of dexamethasone, 0.125-2.0mg, were administered via the subdural infusion for 2 weeks after an epidural balloon crush of the mid-thoracic spinal cord. The spinal cord cross-sections were analyzed histologically. Levels of dexamethasone used in the current study had no systemic toxic effect and limited phagocytosis of myelin debris by macrophages in the lesion cavity. The subdural infusion with 0.125-2.0mg dexamethasone over 2 week period did not eliminate the inflammatory process indicating the need for a longer period of infusion to do so. However, this treatment has probably lead to inhibition of the tissue destruction by the severe, prolonged inflammatory process., (Copyright © 2015 Polish Neurological Society. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.)

There is much evidence to suggest that brain-derived neurotrophic factor (BDNF) is a prominent candidate in promoting neuroprotection, axonal regeneration, and synaptic plasticity following spinal cord injury (SCI). Although some evidence indicates that BDNF has potent anti-oxidative effects and may be involved in the regulation of the immune response, the effects of BDNF in the inflammatory response during the course of secondary damage after SCI is still unclear. The present study was designed to investigate the effects of BDNF with a special focus on their effect on macrophage polarization after SCI. Adult C57 mice underwent T10 spinal cord clip compression injury and received lenti-BDNF vector injections at the epicenter of the lesion site. Four days later, total BDNF levels were greatly increased in animals that received lenti-BDNF injections. Confocal imaging showed that more than 80 % of the lenti-virus infected cells were CD11b-positive macrophages. In addition, the expression of arginase-1 and CD206 (associated with M2 macrophage phenotype) significantly increased in the animals that received lenti-BDNF injections compared with those that received lenti-EGFP injections. On the contrary, the expression of CD16/32 and inducible nitric oxide synthase (M1 phenotype marker) was down-regulated as demonstrated using flow cytometry and immunohistochemistry. Furthermore, the production of interleukin 1β and tumor necrosis factor alpha was significantly reduced whereas the levels of interleukin 10 and interleukin 13 were elevated in subjects that received lenti-BDNF vector injections. The time course of functional recovery revealed that gradual recovery was observed in the subacute phase in lenti-BDNF group, little improvement was observed in lenti-EGFP group. At the axonal level, significant retraction of the CST axons were observed in lenti-EGFP injected animals relative to lenti-BDNF group by biotinylated dextran amine tracing. In addition, compared to lenti-BDNF group markedly demyelination was observed in the lenti-EGFP group using luxol fast blue staining. In conclusion, we found that BDNF could promote the shift of M1 to M2 phenotype and ameliorate the inflammatory microenvironment. Furthermore, the roles of BDNF in immunity modulation may enhance neuroprotective effects and partially contribute to the locomotor functional recovery after SCI.

This study was aimed to evaluate the effect of Angelica Sinensis on experimental rat models in which spinal cord injury was induced by studying different factors. Different factors causing inflammation play a key role in pathophysiology of SCI. Here three groups of rats (n=15, each was used). These included a sham control group where only laminectomy was performed, SCI group where SCI was induced and AS/SCI group where although SCI was induced but Angelica Sinensis was also administered to study its effect and draw a comparison with control. The expression of I-kBα and NF-kB p65 was also studied using western blotting and after recording optical density (OD) values of western blots. MPO activity was used to measure the effect of 20 mg/kg Angelica Sinensis. The levels of proinflammatory cytokines TNF-α, IL-1β and IL-6 were also studied. As compared with SCI group and sham control it was observed that Angelica Sinensis significantly reduced the expression of I-kBα and NF-kB p65, (P<0.05), while MPO activity was also significantly reduced. Proinflammatory cytokine level was also reduced in treated group as compared to both other groups. On the basis of this study we concluded that the use of 20 mg/kg Angelica Sinensis in rat models can attenuate the secondary damage caused by SCI and thus help in controlling the pathology of SCI in rats.

Trauma in spinal cord injury often results in massive damage to the white matter and in damage to myelin that results in a severe phagocyte-rich infiltration apparently directed at removing immunologically toxic myelin debris. In the epidural balloon crush injury to the rat cranial thoracic spinal cord, the dorsal column was crushed, which at one week post-op resulted in its obliteration by a severe infiltration by a virtually pure population of macrophages that internalized all damaged myelin. A week-long subdural infusion of dexamethasone, a stable synthetic corticosteroid, resulted in remarkable inhibition of the macrophage infiltration of the crush cavity and in the lack of removal of myelin debris by phagocytosis. In this study we demonstrated that spinal cord injury results in a severe inflammatory response directed at massively damaged myelin, and we inhibited this response with a subdural infusion of a powerful anti-inflammatory drug, dexamethasone.

Rheumatoid arthritis (RA) is the most common inflammatory disease of the cervical spine (CS). After hands and feet, CS is the most commonly involved segment, being present in more than half of the patients with RA. Especially in the CS, RA may cause degeneration of ligaments, leading to laxity, instability and subluxation of the vertebral bodies. This is often asymptomatic or symptoms are erroneously attributed to peripheral manifestations. Otherwise, this may cause compression of spinal cord (SC) and medulla oblongata leading to severe neurologic deficits and even sudden death. Owing to its potentially debilitating and life-threatening sequelae, inevitable progression once neurologic deficits occur and the poor medical condition of afflicted patients, CS involvement remains a priority in the diagnosis and its treatment will remain a challenge. The surgical approach aims a solid fixation of the upper cervical spine, giving stability, preventing neurologic deterioration and injury to the SC, leading to improved neurologic function, vascular integrity and maintenance of sagittal balance. The recent advances in surgical techniques, complete understanding of the anatomy and precise preoperative evaluation led to safer and more effective procedures that have decreased complication rates. Based on the fact that when a patient becomes myelopathic the rate of long-term mortality increases and the chance of neurologic recovery decreases, many authors agree that early surgical intervention, before the onset of neurologic deficits, gives a more satisfactory outcome. However, the timing when a prophylactic stabilization should occur is poorly defined, and so, patients with radiographic instability but without evidence of neurologic deficit are still the most difficult to manage.

The pathophysiology of spinal cord injury (SCI) involves post-traumatic inflammation and glial scarring which interfere with repair and recovery. Self-assembling peptides (SAPs) are molecules designed for tissue engineering. Here, we tested the performance of K2(QL)6K2 (QL6), a SAP that attenuates inflammation and glial scarring, and facilitates functional recovery. We injected QL6 into the spinal cord tissue of rats 24 h after clip compression SCI. QL6 led to a significant reduction in post-traumatic apoptosis, inflammation and astrogliosis. It also resulted in significant tissue preservation as determined by quantitative histomorphometry. Furthermore, QL6 promoted axonal preservation/regeneration, demonstrated by BDA anterograde and Fluorogold retrograde tracing. In vitro experiments found that a QL6 scaffold enhanced neuronal differentiation and suppressed astrocytic development. The electrophysiology confirmed that QL6 led to significant functional improvement of axons, including increased conduction velocity, reduced refractoriness and enhanced high-frequency conduction. These neuroanatomical and electrophysiological improvements were associated with significant neurobehavioral recovery as assessed by the Basso-Beattie-Bresnahan technique. As the first detailed examination of the pathophysiological properties of QL6 in SCI, this work reveals the therapeutic potential of SAPs, and may suggest an approach for the reconstruction of the injured spinal cord., (Copyright © 2013 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Inflammation plays an important role in the pathogenesis of secondary damage after spinal cord injury (SCI). Previous studies have suggested that nuclear factor-erythroid 2-related factor 2 (Nrf2), a pleiotropic transcription factor, may play a key role in modulating inflammation in a variety of experimental models. This study evaluated the neuroprotective role of Nrf2 in the inflammatory response after SCI in mice., Materials and Methods: Nrf2-deficient (Nrf2(-/-)) and wild-type (Nrf2(+/+)) mice spinal cord compression injury was induced by the application of vascular clips (force of 10 g) to the dura. Sulforaphane (SFN) was used to activate Nrf2 after SCI. Inflammatory cytokines, NF-κB activity, histologic injury score, dying neurons count in grey matter, water content of impaired spinal cord, and Basso open-field motor score (BMS) were assessed to determine the extent of SCI-mediated damage., Results: The results showed that SFN activated Nrf2 in impaired spinal cord tissue, improved hindlimb locomotor function assessed by BMS, reduced inflammatory damage, histologic injury, dying neurons count, and spinal cord edema caused by SCI. Nrf2(-/-) mice demonstrated more severe neurologic deficit and spinal cord edema after SCI and did not benefit from the protective effect of SFN., Conclusions: Taken together, our results suggest that Nrf2 may represent a strategic target for SCI therapies., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Spinal cord injury (SCI) has a significant impact on quality of life, expectancy, and economic burden, with considerable costs associated with primary care and loss of income. The complex pathophysiology of SCI may explain the difficulty in finding a suitable therapy for limiting neuronal injury and promoting regeneration. Although innovative medical care, advances in pharmacotherapy have been limited. The aim of the present study was to carefully investigate molecular pathways and subtypes of glial cells involved in the protective effect of PEA on inflammatory reaction associated with an experimental model of SCI. The compression model induced by applying an aneurysm clip to the spinal cord in mice is closer to the human situation, since it replicates the persistence of cord compression. Spinal cord trauma was induced in mice by the application of vascular clips to the dura via a four-level T5-T8 laminectomy. Repeated PEA administration (10 mg/kg i.p., 6 and 12 h after SCI) significantly reduced the degree of the severity of spinal cord trauma through the reduction of mast cell infiltration and activation. Moreover, PEA treatment significantly reduced the activation of microglia and astrocytes expressing cannabinoid CB(2) receptor after SCI. Importantly, the protective effect of PEA involved changes in the expression of neurotrophic factors, and in spinal cord dopaminergic function. Our results enhance our understanding about mechanisms related to the anti-inflammatory property of the PEA suggesting that this N-acylethanolamine may represent a crucial therapeutic intervention both diminishing the immune/inflammatory response and promoting the initiation of neurotrophic substance after SCI., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Mechanical damage to the spinal cord initiates a secondary injury cascade that results in ischemia, disturbances in ion concentrations, excitotoxicity, production of reactive oxygen species, inflammation, and apoptosis. Over weeks to months a glial scar forms, and scarring can result in the development of syringomyelia. In the early phase of the disease, treatment should focus on maintaining systemic blood pressure and oxygenation, decompression of the spinal cord, and stabilization, if indicated. There are currently no proven neuroprotective drug therapies for limiting secondary damage, but blinded clinical trials are underway. Transplantation with olfactory ensheathing cells and mesenchymal stem cells show promise, as do potassium channel antagonists. Canine clinical trials of these therapies are ongoing., (Copyright 2010 Elsevier Inc. All rights reserved.)

Demyelination and neurodegeneration is a major contributor in the progression of disability in multiple sclerosis (MS). Thus, the development of therapies that are neuroprotective has elicited considerable interests. Estrogens and estrogen receptor (ER) ligand treatments are promising treatments to prevent MS-induced neurodegeneration and a multicenter phase II clinical trial of estriol as a beneficial therapy in MS is underway. Here, we discuss studies performed in our laboratory that examined the effects of ER ligands in the inflammatory/demyelinating disorder experimental autoimmune encephalomyelitis (EAE), a model of MS. Administration of estriol or 17beta-estradiol reduced clinical severity and this clinical disease improvement was associated with favorable changes in cytokine production. There was a significant decrease of neuronal pathology in gray matter along with myelin and axon preservation in white matter of spinal cords of mice with EAE. In subsequent experiments, we contrasted the results of ERalpha versus ERbeta ligand treatment. While ERalpha ligand treatment was anti-inflammatory, ERbeta ligand treatment was not. ERbeta ligand treatment nevertheless reduced demyelination and preserved axon numbers in white matter and prevented neuronal abnormalities in gray matter. Clinically, ERalpha ligand treatment abrogated the disease at the onset, while ERbeta ligand treatment had no effect at disease onset, but promoted recovery. Thus, unlike ERalpha ligand treatment, ERbeta ligand treatment was protective at the level of the target organ, independent of anti-inflammatory effects in the peripheral immune system. ERbeta ligand treatment should be considered as a potential neuroprotective agent for MS and other neurodegenerative diseases, particularly since breast and uterine cancer are mediated through ERalpha.

Objective: To use magnetic resonance imaging (MRI) to characterize secondary injury immediately after spinal cord injury (SCI), and to show the effect of hypertonic saline on MRI indices of swelling, edema, and hemorrhage within the cord., Design: A prospective, randomized, placebo-controlled study., Setting: Research laboratory., Subjects: Twelve adult Long-Evans female rats., Interventions: Rats underwent a unilateral 12.5 mm SCI at vertebral level C5. Animals were administered 0.9% NaCl (n = 6) or 5% NaCl (n = 6) at 1.4 mL/kg intravenously every hour starting 30 minutes after SCI. Immediately after SCI, rats were placed in a 4.7T Bruker MRI system and images were obtained continuously for 8 hours using a home-built transmitter/receiver 3 cm Helmholtz coil. Rats were killed 8 hours after SCI., Measurements and Main Results: Quantification of cord swelling and volumes of hypointense and hyperintense signal within the lesion were determined from MRI. At 36 minutes after SCI, significant swelling of the spinal cord at the lesion center and extending rostrally and caudally was demonstrated by MRI. Also, at this time point, a hypointense core was identified on T1, PD, and T2 weighted images. Over time this hypointense core reduced in size and in some animals was no longer visible by 8 hours after SCI, although histopathology demonstrated presence of red blood cells. A prominent ring of T2-weighted image hyperintensity, characteristic of edema, surrounded the hypointense core. At the lesion center, this rim of edema occupied the entire unilateral injured cord and in all animals extended to the contralateral side. Administration of HS resulted in increased serum [Na], attenuation of cord swelling, and decreased volume of hypointense core and edema at the last time points., Conclusions: We were able to use MRI to detect rapid and acute changes in the evolution of tissue pathophysiology, and show potentially beneficial effects of hypertonic saline in acute cervical SCI.

Although it has been long believed that the damaged central nervous system does not regenerate upon injury, there is an emerging hope for regeneration-based therapy of the damaged central nervous system (CNS) due to the progress of developmental biology and regenerative medicine including stem cell biology. In this review, we have summarized recent studies aimed at the development of regeneration-based therapeutic approaches for spinal cord injuries, including therapy with anti-inflammatory cytokines, transplantation of neural stem/precursor cells and induction of axonal regeneration.

The ten-years experience of acute flaccid paralysis (AFP) surveillance in Belarus has been summarized. Among 456 AFP cases reported from 1996 to 2005, 11 were classified as vaccine-associated paralytic poliomyelitis (VAPP), 445--as non-polio AFP. The risk of VAPP for the period 1996-2001 was 1 case per 745,000 used doses of oral poliovaccine (OPV). For the recipients of OPV the risk was 1 case per 911,700 doses and for the first-dose recipients--1 case per 96,000 doses. The high incidence of VAPP was a reason for implementation of sequential polio vaccination schedule in 2000. Guillain-Barre syndrome dominated among non-polio AFP (39.3% of cases); more rare were traumatic neuritis (27.9% of cases), transient monoparalysis (12.1%), myelitis (7.6%). Non-polio AFP differed from VAPP by following epidemiological and virological characteristics: predominance of previously repeatedly vaccinated against poliomyelitis; development of paralysis in long-term period after vaccination; isolation of non-polio viruses belonged to three serotypes of Coxsackie B viruses (B1, B4, B6) and six serotypes of Echo viruses (6, 7, 11, 14, 24, 25) in 8.1% of cases; absence of typical for polio residual paralyses in patients who excreted vaccine polioviruses.

Viral gene delivery for spinal cord injury (SCI) is a promising approach for enhancing axonal regeneration and neuroprotection. An understanding of spatio-temporal transgene expression in the spinal cord is essential for future studies of SCI therapies. Commonly, intracellular marker proteins (e.g., EGFP) were used as indicators of transgene levels after viral delivery, which may not accurately reflect levels of secreted transgene. This study examined transgene expression using ELISA after viral delivery of D15A, a neurotrophin with BDNF and NT-3 activities, at 1, 2, and 4weeks after in vivo and ex vivo delivery using lentiviral, adenoviral, and retroviral vectors. Further, the inflammatory responses and viral infection patterns after in vivo delivery were examined. Lentiviral vectors had the most stable pattern of gene expression, with D15A levels of 536 +/- 38 and 363 +/- 47 pg/mg protein seen at 4 weeks after the in vivo and ex vivo delivery, respectively. Our results show that protein levels downregulate disproportionately to levels of EGFP after adenoviral vectors both in vivo and ex vivo. D15A dropped from initial levels of 422 +/- 87 to 153 +/- 18 pg/mg protein at 4 weeks after in vivo administration. Similarly, ex vivo retrovirus-mediated transgene expression exhibited rapid downregulation by 2 weeks post-grafting. Compared to adenoviral infection, macrophage activation was attenuated after lentiviral infection. These results suggest that lentiviral vectors are most suitable in situations where stable long-term transgene expression is needed. Retroviral ex vivo delivery is optional when transient expression within targeted spinal tissue is desired, with adenoviral vectors in between.

Oxidative stress plays an important role in the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). Bilirubin is regarded today as a potent antioxidant. Recent studies show that the potent antioxidant actions of bilirubin reflect an amplification mechanism whereby biliverdin reductase (BVR) physiologically regenerates bilirubin in a catalytic cycle. We hypothesized that BVR might prove to be a new effective target for the treatment of free radical-mediated diseases. In this study, we demonstrated that treatment with BVR ameliorated both clinical and pathological signs of EAE more efficiently than treatments with traditional antioxidant enzymes. In vitro, interference with cellular BVR activity by siRNA elicited greater increases in reactive oxygen species and cell death than interference with the activities of other antioxidant enzymes. Further studies showed that BVR surpasses other enzymes by the multifactorial functions of its only end product, bilirubin, including anti-complement activity, and an activity that inhibits antibody-dependent cell-mediated cytotoxicity of lymphocytes. Since BVR regenerates bilirubin in a redox cycle without significantly increasing the concentration of bilirubin, our results suggest that BVR may represent a novel strategy for the treatment of multiple sclerosis and other oxidative stress-mediated diseases.

The accumulation of inflammatory cells in the lesion of a spinal cord injury (SCI) enhances secondary damage, resulting in further neurological impairment. High-dose methylprednisolone (MP) treatment is the only accepted treatment for inflammation secondary to human SCI but is minimally effective. Using a rat SCI model, we devised an anti-inflammatory treatment to block the infiltration of neutrophils and hematogenous monocyte/macrophages over the first 2 days postinjury by targeting the CD11dCD18 integrin. Anti-CD11d mAb administration following SCI effectively reduced neutrophil and macrophage infiltrate into lesions by 70% and 36%, respectively, over the first 72 h post-SCI. MP also reduced neutrophil and macrophage infiltrate by 60% and 28%, respectively, but by different mechanisms. The immunosuppression caused by anti-CD11d treatment was not sustained, as inflammatory cell numbers were not different from those observed in untreated SCI control animals at 7 days postinjury. In contrast, in MP-treated animals, the number of macrophages was still suppressed in the lesion while neutrophil numbers were significantly increased. These results suggest that anti-CD11d mAb treatment following SCI will minimize the destructive actions associated with early, uncontrolled leukocyte infiltration into the lesion while permitting the positive wound healing effects of macrophages at later time points.

We reviewed our experience treating head and neck malignancies junctioning over the spinal cord using asymmetric collimation. The mean dose delivered to the cord was 43.28 Gy above to the junction, 40.36 Gy below it. With a median follow-up of 20 months, none of our 32 patients developed radiation myelitis.

Normal tissue injury may lead to severe, life threatening, late side effects after therapeutic use of irradiation. Neurological complications caused by radiation of the spinal cord are ascribed to progressive, irreversible damage to the vasculature. Hyperbaric oxygen (HBO) is known to induce angiogenesis in irradiated tissue and has been proven to reduce late radiation injury in several normal tissues when applied during the latent period before complications become manifest. In the present study: (1). the prophylactic potential of HBO; (2). optimal timing of HBO therapy after spinal cord irradiation, i.e. during the latent period; and (3). effect of HBO on the re-irradiation tolerance of the spinal cord were investigated. The rat cervical spinal cord was locally X-ray irradiated with ten fractions of 6.5 Gy in 11 days. Five treatment groups (n=10) included: irradiation alone and irradiation followed by 30 HBO treatments (100% oxygen at 240 kPa for 90 min) during latency, with HBO starting either immediately, 5, 10 or 15 weeks after the primary irradiation course. One year after the primary treatment, the same spinal cord volume was re-irradiated with 20 Gy single dose. During life span, the animals were observed on the incidence of myelitis and the duration of the latent period. The actuarial analysis revealed no significant difference in neurological complications free survival between the irradiation alone and the irradiation+HBO treatment groups. A tendency towards radiosensitization was found in the group in which the primary irradiation course was immediately followed by the HBO treatment course. The data show that HBO applied during the latent period of progressively developing irradiation damage to the spinal cord does not increase the re-irradiation tolerance of this tissue.

Purpose: To evaluate the risk of developing radiation myelitis after a cervical spinal cord dose of 50.6 Gy given via 1.1 Gy b.i.d. fractionation during a prospective, randomised trial of hyperfractionated radiation therapy (HFX RT) to a total dose of 77 Gy given in 70 fractions of 1.1 Gy b.i.d., with and without concurrent low-dose, daily cisplatin (CDDP) for head and neck cancer., Methods: Of 130 patients with locally advanced, unresectable, nonmetastatic squamous cell carcinoma of the head and neck (SCC H&N) who entered a prospective, randomised trial, 101 patients received 50.6 Gy to a portion of their spinal cord and survived > 1 year following the beginning of therapy. Forty-five patients were treated with HFX RT alone and fifty-six patients also received CDDP., Results: None of these 101 patients developed cervical radiation myelitis. Therefore, it was not possible to investigate the influence of potentially contributing factors on the occurrence of radiation myelitis, such as interfraction interval, cord length, and administration of concurrent CDDP., Conclusions: Given the increasing number of studies with both altered fractionated regimens and concurrent radio-chemotherapy in SCC H&N, new studies with more patients are needed to gain better insight into the risks of developing cervical radiation myelitis.

Clinically effective drug treatments for spinal cord injury (SCI) remain unavailable. Agmatine, an NMDA receptor antagonist and inhibitor of nitric oxide synthase (NOS), is an endogenous neuromodulator found in the brain and spinal cord. Evidence is presented that agmatine significantly improves locomotor function and reduces tissue damage following traumatic SCI in rats. The results suggest the importance of future therapeutic strategies encompassing the use of single drugs with multiple targets for the treatment of acute SCI. The therapeutic targets of agmatine (NMDA receptor and NOS) have been shown to be critically linked to the pathophysiological sequelae of CNS injury and this, combined with the non-toxic profile, lends support to agmatine being considered as a potential candidate for future clinical applications.

This animal study was designed to investigate HBO as a treatment or prophylaxis for radiation myelitis. All animals received identical spinal cord radiation doses of 69 Gy in 10 daily fractions. Group I received no HBO; group II began HBO at the onset of signs of myelitis; group III received HBO with prophylactic intent beginning 6 wk after irradiation; and group IV received both modalities on the same day, but radiation always preceded HBO by at least 4 h. HBO consisted of 90 min oxygen at 2.4 atm abs for 20 daily treatments. Animals were objectively assessed for the loss of certain neurologic reflexes indicative of four levels of myelitis. Although all animals progressed to severe myelitis, group III animals had group-averaged levels of myelitis consistently less than control. The differences were statistically significant for several weeks. Group IV animals progressed to severe myelitis much more rapidly than any other group. Additional study is justified by this trial. Key questions to be answered include the optimal timing of HBO to produce a beneficial rather than detrimental effect.