Extracellular Vesicles: Therapeutic Potential in Central Nervous System Trauma by Regulating Cell Death.

CNS (central nervous system) trauma, which is classified as SCI (spinal cord injury) and TBI (traumatic brain injury), is gradually becoming a major cause of accidental death and disability worldwide. Many previous studies have verified that the pathophysiological mechanism underlying cell death and the subsequent neuroinflammation caused by cell death are pivotal factors in the progression of CNS trauma. Simultaneously, EVs (extracellular vesicles), membrane-enclosed particles produced by almost all cell types, have been proven to mediate cell-to-cell communication, and cell death involves complex interactions among molecules. EVs have also been proven to be effective carriers of loaded bioactive components to areas of CNS trauma. Therefore, EVs are promising therapeutic targets to cure CNS trauma. However, the link between EVs and various types of cell death in the context of CNS trauma remains unknown. Therefore, in this review, we summarize the mechanism underlying EV effects, the relationship between EVs and cell death and the pathophysiology underlying EV effects on the CNS trauma based on information in published papers. In addition, we discuss the prospects of applying EVs to the CNS as feasible therapeutic strategies for CNS trauma in the future.

Advances in Optogenetics Applications for Central Nervous System Injuries.

Injuries to the central nervous system (CNS) often lead to severe neurological dysfunction and even death. However, there are still no effective measures to improve functional recovery following CNS injuries. Optogenetics, an ideal method to modulate neural activity, has shown various advantages in controlling neural circuits, promoting neural remapping, and improving cell survival. In particular, the emerging technique of optogenetics has exhibited promising therapeutic methods for CNS injuries. In this review, we introduce the light-sensitive proteins and light stimulation system that are important components of optogenetic technology in detail and summarize the development trends. In addition, we construct a comprehensive picture of the current application of optogenetics in CNS injuries and highlight recent advances for the treatment and functional recovery of neurological deficits. Finally, we discuss the therapeutic challenges and prospective uses of optogenetics therapy by photostimulation/photoinhibition modalities that would be suitable for clinical applications.

Nerve recovery from treatment with a vascularized nerve graft compared to an autologous non-vascularized nerve graft in animal models: A systematic review and meta-analysis.

BACKGROUND: Treatment of nerve injuries proves to be a worldwide clinical challenge. Vascularized nerve grafts are suggested to be a promising alternative for bridging a nerve gap to the current gold standard, an autologous non-vascularized nerve graft. However, there is no adequate clinical evidence for the beneficial effect of vascularized nerve grafts and they are still disputed in clinical practice. OBJECTIVE: To systematically review whether vascularized nerve grafts give a superior nerve recovery compared to non-vascularized nerve autografts regarding histological and electrophysiological outcomes in animal models. MATERIAL AND METHODS: PubMed and Embase were systematically searched. The inclusion criteria were as follows: 1) the study was an original full paper which presented unique data; 2) a clear comparison between a vascularized and a non-vascularized autologous nerve transfer was made; 3) the population study were animals of all genders and ages. A standardized mean difference and 95% confidence intervals for each comparison was calculated to estimate the overall effect. Subgroup analyses were conducted on graft length, species and time frames. RESULTS: Fourteen articles were included in this review and all were included in the meta-analyses. A vascularized nerve graft resulted in a significantly larger diameter, higher nerve conduction velocity and axonal count compared to an autologous non-vascularized nerve graft. However, during sensitivity analysis the effect on axonal count disappeared. No significant difference was observed in muscle weight. CONCLUSION: Treating a nerve gap with a vascularized graft results in superior nerve recovery compared to non-vascularized nerve autografts in terms of axon count, diameter and nerve conduction velocity. No difference in muscle weight was seen. However, this conclusion needs to be taken with some caution due to the inherent limitations of this meta-analysis. We recommend future studies to be performed under conditions more closely resembling human circumstances and to use long nerve defects.

Upper Cervical Trauma.

Craniocervical injuries (CCJs) account for 10% to 30% of all cervical spine trauma. An increasing number of patients are surviving these injuries due to advancements in automobile technology, resuscitation techniques, and diagnostic modalities. The leading injury mechanisms are motor vehicle crashes, falls from height, and sports-related events. Current treatment with urgent rigid posterior fixation of the occiput to the cervical spine has resulted in a substantial reduction in management delays expedites treatment of CCJ injuries. Within CCJ injuries, there is a spectrum of instability, ranging from isolated nondisplaced occipital condyle fractures treated nonoperatively to highly unstable injuries with severely distracted craniocervical dissociation. Despite the evolution of understanding and improvement in the management of cases regarding catastrophic failure to diagnose, subsequent neurologic deterioration still occurs even in experienced trauma centers. The purpose of this article is to review the injuries that occur at the CCJ with the accompanying anatomy, presentation, imaging, classification, management, and outcomes.

Thoracolumbar Spine Trauma.

Thoracolumbar spine trauma can result in potentially life-threatening consequences and requires careful management to ensure good outcomes. The purpose of this chapter is to discuss the anatomy, diagnostic tools, non-operative, and operative treatments important when addressing thoracolumbar trauma.

Magnetically guided targeted delivery of erythropoietin using magnetic nanoparticles: Proof of concept.

The objective of this proof-of-concept study was to demonstrate the targeted delivery of erythropoietin (EPO) using magnetically guided magnetic nanoparticles (MNPs).MNPs consisting of a ferric-ferrous mixture (FeCl3·6H2O and FeCl2·4H2O) were prepared using a co-precipitation method. The drug delivery system (DDS) was manufactured via the spray-drying technique using a nanospray-dryer. The DDS comprised 7.5 mg sodium alginate, 150 mg MNPs, and 1000 IU EPO.Scanning electron microscopy revealed DDS particles no more than 500 nm in size. Tiny particles on the rough surfaces of the DDS particles were composed of MNPs and/or EPO, unlike the smooth surfaces of the only alginate particles. Transmission electron microscopy showed the tiny particles from 5 to 20 nm in diameter. Fourier-transform infrared spectroscopy revealed DDS peaks characteristic of MNPs as well as of alginate. Thermal gravimetric analysis presented that 50% of DDS weight was lost in a single step around 500°C. The mode size of the DDS particles was approximately 850 nm under in vivo conditions. Standard soft lithography was applied to DDS particles prepared with fluorescent beads using a microchannel fabricated to have one inlet and two outlets in a Y-shape. The fluorescent DDS particles reached only one outlet reservoir in the presence of a neodymium magnet. The neurotoxicity was evaluated by treating SH-SY5Y cells in 48-well plates (1 × 10 cells/well) with 2 µL of a solution containing sodium alginate (0.075 mg/mL), MNPs (1.5 mg/mL), or sodium alginate + MNPs. A cell viability assay kit was used to identify a 93% cell viability after MNP treatment and a 94% viability after sodium alginate + MNP treatment, compared with the control. As for the DDS particle neurotoxicity, a 95% cell viability was noticed after alginate-encapsulated MNPs treatment and a 93% cell viability after DDS treatment, compared with the control.The DDS-EPO construct developed here can be small under in vivo conditions enough to pass through the lung capillaries with showing the high coating efficiency. It can be guided using magnetic control without displaying significant neurotoxicity in the form of solution or particles.

Current status of pediatric neurocritical care in Argentina. / Estado actual del soporte neurológico crítico en pediatría en la Argentina.

INTRODUCTION: Patients with neurocritical injuries account for 10-16 % of pediatric intensive care unit (PICU) admissions and frequently require neuromonitoring. OBJECTIVE: To describe the current status of neuromonitoring in Argentina. METHODS: Survey with 37 questions about neuromonitoring without including patients' data. Period: April-June 2017. RESULTS: Thirty-eight responses were received out of 71 requests (14 districts with 11 498 annual discharges). The PICU/hospital bed ratio was 21.9 (range: 4.2-66.7). Seventy-four percent of PICUs were public; 61 %, university-affiliated; and 71 %, level I. The availability of monitoring techniques was similar between public and private (percentages): intracranial pressure (95), electroencephalography (92), transcranial Doppler (53), evoked potentials (50), jugular saturation (47), and bispectral index (11). Trauma was the main reason for monitoring. CONCLUSION: Except for intracranial pressure and electroencephalography, neuromonitoring resources are scarce and active neurosurgery availability is minimal. A PICU national registry is required.

Introducción. Los pacientes con lesiones neurocríticas representan el 10-16 % de los ingresos a unidades de cuidados intensivos pediátricas (UCIP) y, frecuentemente, requieren neuromonitoreo. Objetivo. Describir el estado actual del neuromonitoreo en la Argentina. Métodos. Encuesta con 37 preguntas sobre neuromonitoreo sin incluir datos de pacientes. Período: abril-junio, 2017. Resultados. Se recibieron 38 respuestas a 71 solicitudes (14 distritos con 11 498 egresos anuales). La relación camas de UCIP/hospitalarias fue 21,9 (rango: 4,2-66,7). El 74 % fueron públicas; el 61 %, universitarias, y el 71 %, nivel 1. La disponibilidad fue similar entre públicas y privadas (porcentajes): presión intracraneana (95), electroencefalografía (92), doppler transcraneano (53), potenciales evocados (50), saturación yugular (47) e índice bispectral (11). El principal motivo de monitoreo fue trauma. Conclusión. Excepto la presión intracraneana y la electroencefalografía, los recursos de neuromonitoreo son escasos y la disponibilidad de neurocirugía activa es mínima. Se necesita un registro nacional de UCIP.

Developing a Guideline for Neurotrauma in Nigeria.

BACKGROUND: The Nigerian Academy of Neurological Surgeons in 2019 resolved to standardize the practice of neurosurgery in Nigeria. It set up committees to standardize the various aspects of neurosurgery, such as neurotrauma, pediatrics, functional, vascular, skull base, brain tumor, and spine. The Committee on Neurotrauma convened and resolved to study most of the available protocols and guidelines in use in different parts of the world. OBJECTIVE: To formulate a standard protocol for the practice of neurotrauma care within the Nigerian locality. METHODS: The Committee split its membership into 3 subcommittees to cover the various aspects of the Neurotrauma Guidelines, such as neurotrauma curriculum, standard neurotrauma management protocols, and neurotrauma registry. Each subcommittee was to research on available models and formulate a draft for Nigerian neurotrauma. RESULTS: All the 3 subcommittees had their reports ready on schedule. Each concurred that neurotrauma is a major public health challenge in Nigeria. They produced 3 different drafts on the 3 thematic areas of the project. The subcommittees are: 1. Subcommittee on Fellowship, Training and Research Curriculum; 2. Subcommittee on Standard Protocols and Management Guidelines; and 3. Subcommittee of the Nigerian Neurotrauma Registry. CONCLUSION: The committee concluded that a formal protocol for neurotrauma care is long overdue in Nigeria for the standardization of all aspects of neurotrauma. It then recommended the adoption of these guidelines by all institutions offering services in Nigeria using the management protocols, opening a registry, and mounting researches on the various aspects of neurotrauma.

Magnetic resonance imaging of enhanced nerve repair with mesenchymal stem cells combined with microenvironment immunomodulation in neurotmesis.

INTRODUCTION: The immuno-microenvironment of injured nerves adversely affects mesenchymal stem cell (MSC) therapy for neurotmesis. Magnetic resonance imaging (MRI) can be used noninvasively to monitor nerve degeneration and regeneration. The aim of this study was to investigate nerve repair after MSC transplantation combined with microenvironment immunomodulation in neurotmesis by using multiparametric MRI. METHODS: Rats with sciatic nerve transection and surgical coaptation were treated with MSCs combined with immunomodulation or MSCs alone. Serial multiparametric MRI examinations were performed over an 8-week period after surgery. RESULTS: Nerves treated with MSCs combined with immunomodulation showed better functional recovery, rapid recovery of nerve T2, fractional anisotropy and radial diffusivity values, and more rapid restoration of the fiber tracks than nerves treated with MSCs alone. DISCUSSION: Transplantation of MSCs in combination with immunomodulation can exert a synergistic repair effect on neurotmesis, which can be monitored by multiparametric MRI.

Assessment of Acute Kidney Injury in Neurologically Injured Patients Receiving Hypertonic Sodium Chloride: Does Chloride Load Matter?

Background: Increasing evidence suggests that large-volume infusions of 0.9% sodium chloride (NaCl) for resuscitation are associated with hyperchloremic metabolic acidosis, renal vasoconstriction, and increased risk of acute kidney injury (AKI). Patients with neurological injury may require hypertonic NaCl for therapeutic hypernatremia, treatment of cerebral salt wasting, hyponatremia, or elevated intracranial pressure. Consequently, this increased exposure to chloride may result in an increased risk for development of AKI. Objective: The primary aim of this study was to describe the risk for development of AKI in neurologically injured patients receiving large volumes of intravenous hypertonic NaCl. Methods: This single-center, retrospective study looked at neurologically injured patients who received hypertonic NaCl and sodium acetate. Data were collected to assess renal function, hyperchloremia, and acidemia. Receiver operating characteristic (ROC) curve analysis was used to determine the predictive association between the amount of daily and overall chloride exposure and development of AKI. Results: A total of 301 patients were screened, and of those, 142 were included. Of the 142 patients included, 13% developed AKI, and 38% developed hyperchloremia. Additionally, 32% of patients were switched from NaCl to sodium acetate after an average of 3.4 ± 1.5 days of NaCl therapy. The ROC curve demonstrated that if patients received greater than 2055 mEq of chloride over 7 days, they were more likely to develop AKI (sensitivity 72%, specificity 70%; P = 0.002; area under the curve = 0.7). Conclusion and Relevance: Neurologically injured patients receiving hypertonic sodium therapy with a high chloride load are at risk of developing hyperchloremia and AKI.

Therapeutic use of extracellular mitochondria in CNS injury and disease.

In the central nervous system (CNS), neuronal functionality is highly dependent on mitochondrial integrity and activity. In the context of a damaged or diseased brain, mitochondrial dysfunction leads to reductions in ATP levels, thus impairing ATP-dependent neural firing and neurotransmitter dynamics. Restoring mitochondrial ability to generate ATP may be a basic premise to restore neuronal functionality. Recently, emerging data in rodent and human studies suggest that mitochondria and its components are surprisingly released into extracellular space and potentially transferred between cells. Transferred mitochondria may support oxidative phosphorylation in recipient cells. In this mini-review, we (a) survey recent findings in cell to cell mitochondrial transfer and the presence of cell-free extracellular mitochondria and its components, (b) review experimental details of how to detect extracellular mitochondria and mitochondrial transfer in the CNS, (c) discuss strategies and tissue sources for mitochondria isolation, and (d) explore exogenous mitochondrial transplantation as a novel approach for CNS therapies.

Systemic Immune Response to Traumatic CNS Injuries-Are Extracellular Vesicles the Missing Link?

Inflammation following traumatic injury to the central nervous system (CNS) persists long after the primary insult and is known to exacerbate cell death and worsen functional outcomes. Therapeutic interventions targeting this inflammation have been unsuccessful, which has been attributed to poor bioavailability owing to the presence of blood-CNS barrier. Recent studies have shown that the magnitude of the CNS inflammatory response is dependent on systemic inflammatory events. The acute phase response (APR) to CNS injury presents an alternative strategy to modulating the secondary phase of injury. However, the communication pathways between the CNS and the periphery remain poorly understood. Extracellular vesicles (EVs) are membrane bound nanoparticles that are regulators of intercellular communication. They are shed from cells of the CNS including microglia, astrocytes, neurons and endothelial cells, and are able to cross the blood-CNS barrier, thus providing an attractive candidate for initiating the APR after acute CNS injury. The purpose of this review is to summarize the current evidence that EVs play a critical role in the APR following CNS injuries.

[Conservative Treatment of Thoracic and Lumbar Vertebral Fractures - what's it all about?] / Konservative Behandlung von Wirbelfrakturen in BWS und LWS ­ was geht wie?

The basis for assessing thoracolumbar vertebral body fractures are two established classification systems. Important, especially in terms of further treatment, is the distinction between osteoporotic and healthy bones. The AO Spine classification offers a comprehensive tool for healthy bones to reliably specify the morphological criterias (alignment, integrity of the intervertebral disc, fragment separation, stenosis of the spinal canal). In addition to the fracture morphology, the OF classification for osteoporotic fractures includes patient-specific characteristics to initiate adequate therapy. In general an adequate pain therapy is required for early rehabilitation. While in the bone healthy population, physiotherapy reduces the risk of muscle deconditioning, in the osteoporotic population it additionally serves to prevent subsequent fractures. Unlike osteoporotic patients, bone healthy patients with vertebral fractures should not undergo a corset/orthosis treatment.

Crowdfunding for stem cell-based interventions to treat neurologic diseases and injuries.

OBJECTIVE: To characterize the marketplace for direct-to-consumer (DTC) unproven stem cell-based interventions (SCBI) for neurologic diseases and injuries using crowdfunding data. METHODS: Search terms were developed from previous empirical studies of DTC businesses and the International Classification of Diseases-11 for neurologic diseases and used to query GoFundMe's internal search engine. Campaigns initiated November 2017-2018 and seeking SCBI for neurologic diseases and injuries (n = 1,030) were reviewed to identify the number of donors, number of Facebook shares, recipient location, funding pledged, funding requested, underlying neurologic condition, treatment location, and treatment facility name. RESULTS: A total of 1,030 crowdfunding campaigns for SCBI for neurologic diseases and injuries requested $33,449,979 and received $5,057,069 from 38,713 donors. The most common neurologic condition identified was multiple sclerosis (MS) (n = 404, 35.5%). Of campaigns naming specific destination facilities (n = 392), the most common clinical settings identified were the Stem Cell Institute in Panama City, Panama (n = 91, 23.2%), StemGenex in San Diego, California (n = 44, 11.2%), and Clinica Ruiz in Puebla, Mexico (n = 36, 9.2%). CONCLUSIONS: MS dominated the total number of crowdfunding campaigns. Most campaigns were linked to individuals from regions geographically proximal to destination facilities advertising SCBI for particular neurologic diseases. Most of the clinical destinations were located in comparatively high-income countries such as the United States, Mexico, and Panama. These findings provide considerable insight into the DTC marketplace for SCBI. Analysis of crowdfunding campaigns can be used to develop more targeted patient education initiatives and health policies related to domestic and international travel for unproven SCBI.

Advances of tooth-derived stem cells in neural diseases treatments and nerve tissue regeneration.

Nerous system diseases, both central and peripheral, bring an incredible burden onto patients and enormously reduce their quality of life. Currently, there are still no effective treatments to repair nerve lesions that do not have side effects. Stem cell-based therapies, especially those using dental stem cells, bring new hope to neural diseases. Dental stem cells, derived from the neural crest, have many characteristics that are similar to neural cells, indicating that they can be an ideal source of cells for neural regeneration and repair. This review summarizes the neural traits of all the dental cell types, including DPSCs, PDLCs, DFCs, APSCs and their potential applications in nervous system diseases. We have summed up the advantages of dental stem cells in neural repair, such as their neurotrophic and neuroprotective traits, easy harvest and low rejective reaction rate, among others. Taken together, dental stem cells are an ideal cell source for neural tissue regeneration and repair.

Do Neural Stem Cells Have a Choice? Heterogenic Outcome of Cell Fate Acquisition in Different Injury Models.

The adult mammalian central nervous system (CNS) is generally considered as repair restricted organ with limited capacities to regenerate lost cells and to successfully integrate them into damaged nerve tracts. Despite the presence of endogenous immature cell types that can be activated upon injury or in disease cell replacement generally remains insufficient, undirected, or lost cell types are not properly generated. This limitation also accounts for the myelin repair capacity that still constitutes the default regenerative activity at least in inflammatory demyelinating conditions. Ever since the discovery of endogenous neural stem cells (NSCs) residing within specific niches of the adult brain, as well as the description of procedures to either isolate and propagate or artificially induce NSCs from various origins ex vivo, the field has been rejuvenated. Various sources of NSCs have been investigated and applied in current neuropathological paradigms aiming at the replacement of lost cells and the restoration of functionality based on successful integration. Whereas directing and supporting stem cells residing in brain niches constitutes one possible approach many investigations addressed their potential upon transplantation. Given the heterogeneity of these studies related to the nature of grafted cells, the local CNS environment, and applied implantation procedures we here set out to review and compare their applied protocols in order to evaluate rate-limiting parameters. Based on our compilation, we conclude that in healthy CNS tissue region specific cues dominate cell fate decisions. However, although increasing evidence points to the capacity of transplanted NSCs to reflect the regenerative need of an injury environment, a still heterogenic picture emerges when analyzing transplantation outcomes in injury or disease models. These are likely due to methodological differences despite preserved injury environments. Based on this meta-analysis, we suggest future NSC transplantation experiments to be conducted in a more comparable way to previous studies and that subsequent analyses must emphasize regional heterogeneity such as accounting for differences in gray versus white matter.

Rotary jet-spun porous microfibers as scaffolds for stem cells delivery to central nervous system injury.

Stem cell transplantation is a promising strategy to treat brain injuries. However, cell-based therapies are limited because poor local cell engraftment. Here, we present a polylactic acid (PLA) scaffold to support mesenchymal stem cells (MSCs) delivery in stroke. We isolated bone marrow MSCs from adult C57/Bl6 mice, cultured them on PLA polymeric rough microfibrous (PRM) scaffolds obtained by rotary jet spinning, and transplanted over the brains of adult C57/Bl6 mice, carrying thermocoagulation-induced cortical stroke. No inflammatory response to PRM was found. MSCs transplantation significantly reduced the area of the lesion and PRM delivery increased MSCs retention at the injury site. In addition, PRM upregulated α6-integrin and CXCL12 production, which may be the cause for greater cell retention at the lesion site and may provide additional benefit to MSCs transplantation procedures. We conclude that PRM scaffolds offer a promising new system to deliver stem cells to injured areas of the brain.

An update on the management of adult traumatic nerve injuries-replacing old paradigms: A review.

Acute nerve injuries are routinely encountered in multisystem trauma patients. Advances in surgical treatment of nerve injuries now mean that good outcomes can be achieved. Despite this, old mantras associated with management of nerve injuries, including "wait a year to see if recovery occurs" and "there's nothing we can do", persist. Practicing by these mantras places these patients at a disadvantage. Changes begin to occur in the nerve, neuromuscular junction, and muscle from the moment a nerve injury occurs. These changes can become irreversible approximately 18 to 24 months following denervation. Thus, it is a race to reestablish a functional nerve-muscle connection before these irreversible changes. Good outcomes rely on appropriate acute management and avoiding delays in care. Primary nerve surgery options include direct primary repair, nerve graft repair, and nerve transfer. Acute management of nerve injuries proceeds according to the rule of 3's and requires early cooperation between trauma surgeons who recognize the nerve injury and consultant nerve surgeons. Care of patients with acute traumatic nerve injuries should not be delayed. Awareness of current management paradigms among trauma surgeons will help facilitate optimal upfront management. With the ever-expanding surgical options for management of these injuries and the associated improvement of outcomes, early multidisciplinary approaches to these injuries have never been more important. Old mantras must be replaced with new paradigms to continue to see improvements in outcomes for these patients. The importance of this review is to raise awareness among trauma surgeons of new paradigms for management of traumatic nerve injuries.