Syringomyelia

Spinal Cord Image Denoising Using Dncnn Algorithm

Background: Spinal image denoising plays a vital role in the accurate diagnosis of disc herniation (DH).

Objective: Traditional denoising algorithms perform less due Limited Directional Selectivity problem and do not adequately capture directional information in pixels. Traditional algorithms' edge representation and texture details are insufficient for the earlier detection of DH. Limited Directional Selectivity leads to inaccurate diagnosis and classification of Disc Herniation (DH) stages. The DH stages are (i) Degeneration (ii) Prolapse (iii) Extrusion and (iv) Sequestration. Moreover, detection of DH size below 2mm using MR image is the major problem.

Methods: To solve the above problem, spinal cord MR images fed to the proposed Parrot optimization tuned Denoising Convolutional Neural Network (Po- DnCNN) algorithm for perspective enhancement of nucleus pulposus region in the spinal cord, vertebrae. The perspective enhancement of Spinal cord image led to the accurate classification of stages and earlier detection of DH by using the proposed Hippopotamus optimization- Fast Hybrid Vision Transformer (Ho–FastViT) algorithm. For this study, spinal cord MR images are obtained from the Grand Challenge website – SPIDER dataset.

Results: The proposed Po-DnCNN method and Ho-FastViT results are analysed quantitatively and qualitatively based on the edge, contrast, classification of the stage, and enhancement of the projected nucleus pulposus region in the spinal cord and vertebrae. The predicted DH results using the proposed method are compared with the manual Pfirrman Grade value of the spinal card method.

Conclusion: Proposed method is better than traditional methods for earlier detection of DH. Po-DnCNN and Ho-FastViat methods give high accuracy of about 98% and 97% compared to traditional methods.

Distinguishing Intramedullary Spinal Cord Neoplasms from Non-Neoplastic Conditions by Analyzing the Classic Signs on MRI in the Era of AI

Intramedullary lesions can be challenging to diagnose, given the wide range of possible pathologies. Each lesion has unique clinical and imaging features, which are best evaluated using magnetic resonance imaging. Radiological imaging is unique with rich, descriptive patterns and classic signs-which are often metaphorical. In this review, we present a collection of classic MRI signs, ranging from neoplastic to non-neoplastic lesions, within the spinal cord. The Differential Diagnosis (DD) of intramedullary lesions can be narrowed down by careful analysis of the classic signs and patterns of involvement in the spinal cord. Furthermore, the signs are illustrated memorably with emphasis on the pathophysiology, mimics, and pitfalls. Artificial Intelligence (AI) algorithms, particularly deep learning, have made remarkable progress in image recognition tasks. The classic signs and related illustrations can enhance a pattern recognition approach in diagnostic radiology. Deep learning can potentially be designed to distinguish neoplastic from non-neoplastic processes by pattern recognition of the classic MRI signs.

Drug-Induced Peripheral Neuropathy: Diagnosis and Management

Peripheral neuropathy comes in all shapes and forms and is a disorder which is found in the peripheral nervous system. It can have an acute or chronic onset depending on the multitude of pathophysiologic mechanisms involving different parts of nerve fibers. A systematic approach is highly beneficial when it comes to cost-effective diagnosis. More than 30 causes of peripheral neuropathy exist ranging from systemic and auto-immune diseases, vitamin deficiencies, viral infections, diabetes, etc. One of the major causes of peripheral neuropathy is drug-induced disease, which can be split into peripheral neuropathy caused by chemotherapy or by other medications. This review deals with the latest causes of drug-induced peripheral neuropathy, the population involved, the findings on physical examination and various workups needed and how to manage each case.

Polyphenols as Potential Therapeutics for Pain and Inflammation in Spinal Cord Injury

Spinal cord injury (SCI) and associated pain and inflammation caused by trauma or infection are serious health care issues world-wide. The various inflammatory, redox-sensitive and apoptotic events are contributing factors, but altered neuronal function, axonal degeneration, activated microglia, endothelial cells, astrocytes, fibroblasts, pericytes, Schwann cells, and meningeal cells are major players in its pathogenesis. Further, monocytes and neutrophil infiltration get recruited and facilitate the release of chemokines, cytokines, and other mediators of inflammation. This event leads to the production of different amino acids, neuropeptides kinin, prostaglandins, prostacyclin, thromboxane, leukotrienes, bradykinin, histamine, matrix metal proteinases, and serotonin that stimulate nerve endings and manifest the inflammation and pain processes, etc. Arachidonic acid (AA), NF-kB, NLRP3 inflammasome, and nitric oxide pathways along with P2X7 receptor and ion channel transient receptor potential (TRP) vanilloid are some of the recently explored targets for modulation of pain and inflammation in SCI. Till now, NSAIDs, opioids, antidepressants, anticonvulsants, NMDA antagonists, α2-adrenergic agonists, and GABA-receptor agonists are used for the management of these pathological conditions. However, these drugs are associated with various side effects. Additionally, the number of available animal models for SCI has enhanced the understanding of the complex pathological mechanisms involved in the generation of chronic inflammatory pain in SCI. These findings enable us to identify and validate several potent natural analgesic-anti-inflammatory drug candidates with minimal side effects. However, these compounds have been studied in preclinical models and shown promising results, but no clinical studies have been performed. Therefore, a detailed exploration of these natural compounds is important for bringing them from bench to bedside.

Occipital Encephalocele: Cause, Incidence, Neuroimaging and Surgical Management

Aims: To review and present the current knowledge of incidence, signs and symptoms, diagnosis and treatment of the occipital encephalocele.

Background: Encephalocele (E) is a defect of the neural tube that refers to congenital malformations featured by skull defect and dura with extracranial spread of intracranial structures. Occipital encephalocele (OE) are the most common form of this congenital disorder and are manifested as a swelling of different sizes over the occipital bone in the midline. Proper diagnosis and treatment is highly important in the management of this congenital malformation of brain.

Objective: To review and present the current knowledge of incidence, signs and symptoms, diagnosis and treatment of the occipital encephalocele.

Methods: We conducted a search of case reports or case-series of patients by the use of electronic databases: Pub Med, Medline, Index Medicus, Scorpus. The key words were: encephalocele, occipital encephalocele, neural tube defect, congenital malformation. The search was updated to December 31, 2018. Papers published in English were the only source of information.

Results: Occipital encephalocelle are more frequent in females than in males. The incidence is between 1 in 3000 to 1 in 10,000 live births; approximately 90% of them involve the midline. Magnetic resonance imaging is the method of choice in diagnosis and surgery is the best option for the treatment of OE. Overall morbidity and mortality is still high in spite of advenced surgical management, but have been significantly improved in recent years thanks to sophisticated highresolution imaging, adequate and proper surgical treatment and decent post-operative care.

Conclusion: Occipital encephalocele is the most common form of encephalocele. The diagnosis is mostly based by the use of neuroimaging techniques. Operation is the best option for treatment. Overall morbidity and mortality is still high, but have been significantly improved in recent years thanks to sophisticated high-resolution imaging, adequate and proper surgical treatment and decent post-operative care.

Mannitol Reduces Spinal Cord Edema in Rats with Acute Traumatic Spinal Cord Injury

Background: The research about anti-edema effects of mannitol on acute traumatic spinal cord injury (SCI) in rats is rare.

Objective: This study aimed to explore the effect of mannitol on spinal cord edema after SCI in rats.

Methods: Seventy-eight adult female rats were assigned to three groups randomly: a sham control group (n = 18), a contusion and normal saline contrast group (n=30), and a contusion and mannitol treatment group (n=30). We used the open-field test to estimate the functional recovery of rats weekly. Spinal cord water content was measured to determine the spinal cord edema. The ultrastructure features of the injured dorsolateral spinal cord were determined on the 7th day after SCI by HE staining.

Results: The mannitol group had greatly improved Basso-Beattie-Bresnahan (BBB) scores when compared with the saline contrast group. The spinal cord water content was increased significantly after SCI, and there was no significant difference in the water content between the NaCl and mannitol groups 1 day after SCI. The water content at 3 and 7 days after SCI was significantly lower in the mannitol group than in the NaCl group (p < 0.05). Mannitol can reduce spinal cord edema by increasing the number of red blood cells in the injured spinal cord and decrease the ratio (dorsoventral diameter/ mediolateral diameter) of spinal cord 7 days post-SCI.

Conclusion: Mannitol increases recovery of motor function in rats, reduces spinal cord edema and increases the number of red blood cells in the injured spinal cord, decreasing the ratio of spinal cord to reduce pressure.

FBXW7alpha Promotes the Recovery of Traumatic Spinal Cord

Background: White matter damage and neuronal cell death are incurred by spinal cord injury (SCI). FBXW7α, an important mediator of cell division and growth was investigated to explore its role in repairing the traumatic spinal cord in rats. Underlying mechanisms such as oxidative stress and inflammasomes signaling were also studied.

Methods: Spinal cord injury in rats was established by longitudinal surgical incision from the lower to mid-thoracic vertebrae on the backside, followed by 20-g weight placed on the exposed Th12 surface for 30 min. AAV-delivered FBXW7α and -sh-FBXW7α were intrathecally injected into the rat spinal cord. Indices of oxidation, neurotrophic factors, and pyroptosis were measured by Western blot, Elisa, and RT-PCR.

Results: We found the overexpression of FBXW7α in spinal cord rescue neuronal death triggered by the injury. Specifically, the nutritional condition, oxidative stress, and pyroptosis were improved. A synchronization of BNDF and GDNF expression patterns in various groups indicated the secretion of neurotrophic factors affect the outcome of SCI. The SOD1, CAT, and GSH-px were suppressed after trauma but all restored in response to FBXW7α overexpression. Inflammasomes-activated pyroptosis was incurred after the injury, and relevant biomarkers such as GSDMD, caspase-1, caspase- 11, IL-1β, and IL-18 were down-regulated after the introduction of FBXW7α into the injured cord. Additionally, up-regulating FBXW7α also repaired the mitochondria dysfunction.

Conclusion: Our data indicate FBXW7α probably serves as an important molecular target for the therapy of spinal cord injury.

Neurobehavioral Consequences Associated with Long Term Tramadol Utilization and Pathological Mechanisms

Tramadol is a synthetic analog of codeine used to treat pain of moderate to severe intensity and is reported to have neurotoxic potential. At therapeutic dose, tramadol does not cause major side effects in comparison to other opioid analgesics, and is useful for the management of neurological problems like anxiety and depression. Long term utilization of tramadol is associated with various neurological disorders like seizures, serotonin syndrome, Alzheimer’s disease and Parkinson’s disease. Tramadol produces seizures through inhibition of nitric oxide, serotonin reuptake and inhibitory effects on GABA receptors. Extensive tramadol intake alters redox balance through elevating lipid peroxidation and free radical leading to neurotoxicity and produces neurobehavioral deficits. During Alzheimer’s disease progression, low level of intracellular signalling molecules like cGMP, cAMP, PKC and PKA affect both learning and memory. Pharmacologically tramadol produces actions similar to Selective Serotonin Reuptake Inhibitors (SSRIs), increasing the concentration of serotonin, which causes serotonin syndrome. In addition, tramadol also inhibits GABAA receptors in the CNS has been evidenced to interfere with dopamine synthesis and release, responsible for motor symptoms. The reduced level of dopamine may produce bradykinesia and tremors which are chief motor abnormalities in Parkinson’s Disease (PD).

The Application of Neural Stem/Progenitor Cells for Regenerative Therapy of Spinal Cord Injury

Spinal cord injury (SCI) is a devastating event, and there are still no effective therapies currently available. Neural stem cells (NSCs) have gained increasing attention as promising regenerative therapy of SCI. NSCs based therapies of various neural diseases in animal models and clinical trials have been widely investigated. In this review we aim to summarize the development and recent progress in the application of NSCs in cell transplantation therapy for SCI. After brief introduction on sequential genetic steps regulating spinal cord development in vivo, we describe current experimental approaches for neural induction of NSCs in vitro. In particular, we focus on NSCs induced from pluripotent stem cells (PSCs). Finally, we highlight recent progress on the NSCs, which show great promise in the application to regeneration therapy for SCI.

Quality of Life in Individuals Affected by Arnold Chiari Malformation: Comparison and Validation of a Measurement Instrument

Background: Introduction. Arnold Chiari Malformation (ACM) type I is a pathology whose symptomatology has repercussions for the quality of life of those affected by it. Quality-of-life measurement instruments can allow the severity of the impact of Chiari type I malformation on patients’ lives to be monitored. The Chiari Symptom Profile (CSP) is a valid and reliable instrument designed for this purpose. The aim of the study was to adapt the CSP to Spanish and to explore the reliability and validity of this construct in the context of Spanish-speaking patients with ACM.

Methods: The English CSP instrument has a good internal validity and consistency. We used a standardized procedure for the linguistic validation of the translated scale. For the psychometric validation, we recruited 215 individuals with ACM and calculated the Cronbach&339;s alpha for the sample. The construct was validated by analyzing the age, sex, and presence of syringomyelia, as well as by correlating the results with the sickness impact profile 30 (SIP-30) questionnaire, which can also evaluate quality of life in this type of patient.

Results: The Spanish version of the CSP has good internal consistency and validity (Cronbach’s alpha of 0.90); age, sex, and the presence of syringomyelia does not significantly affect the quality of life of patients with ACM. There was a direct and significant correlation between the Spanish CSP and the validated SIP-30 questionnaire results (p < 0.05). Further analysis showed a positive correlation for the physical and psychological scopes of the CSP and SIP-30 questionnaires, but not for their functional and social scopes.

Conclusion: This version of the CSP is a valid and reliable instrument for measuring quality of life in patients with ACM in the Spanish context.

Structure-function Evaluation of Stem Cell Therapies for Spinal Cord Injury

Background: Spinal cord injuries (SCI) are prevalent, devastating for quality and expectancy of life, and cause heavy economic burdens. Stem cell therapies hold promise in complete structural and functional restoration of SCI.

Objective: This review focuses on the methods currently used to evaluate the stem cell therapies for SCI.

Results: Various kinds of stem cells involving embryonic stem cells (ESCs), bone marrow stromal cells (BMSCs), neural stem cells (NSCs) and induced pluripotent stem cells (iPSCs) are extensively used in regenerative research of SCI. For evaluation, the survival and integration of transplanted cells, spinal cord reconstruction and functional recovery all should be considered. Histological and histochemistrical, microscopic, and colorimetric assays, and real-time RT-PCR techniques are applied to determine the outcome. From the three main aspects-transplanted cells, spinal cord structure, and functional recovery-we summarize and discuss these methods with certain instances of applications in SCI models. Importantly, for the evaluations of function, neuronal transmitting, electrophysiological analysis and behavioral score are included.

Conclusion: Wider conjunction of established technologies, as well as the further development of nondestructive methods might make a big difference in testing stem cell therapies.

Mevalonate Cascade and Small Rho GTPase in Spinal Cord Injury

The mevalonate pathway has been extensively studied for its involvement in cholesterol synthesis. Inhibition of this pathway using statins (3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors; HMGR inhibitors) is the primarily selected method due to its cholesterol-lowering effect, making statins the most commonly used (86-94%) cholesterol-lowering drugs in adults. This pathway has several other by-products that are affected by statins including GTPase molecules (guanine triphosphate-binding kinases), such as Rho/Rho-associated coiled kinase (ROCK) kinases, that are implicated in other diseases, including those of the central nervous system (CNS). These molecules control several aspects of neural cell life including axonal growth, cellular migration, and cell death, and therefore, are of increasing interest in the field of spinal cord injury (SCI).

Limited regeneration capacity of nerve fibers in adult CNS has been considered the main obstacle for finding a SCI cure. Over the past two decades, the identity of inhibitory factors for regeneration has been widely investigated. It is well-established that the Rho/ROCK kinase system is specifically activated by the components of damaged spinal cord tissue, including oligodendrocytes and myelin, as well as extracellular matrix. This has led many groups to hypothesize that statin therapy may in fact enhance the current neurorestorative approaches. In this mini-review, a summary of SCI pathophysiology is discussed and the current literature targeting the regeneration obstacles in SCI are reviewed, with special attention to recent publications of the past decade. In addition, we focus on the current literature involving the use of pharmacological and molecular inhibitors of small GTPase molecules for treatment of neurotrauma. Inhibiting these molecules has been shown to increase neuroprotection, enhance axonal regeneration, and facilitate the implementation of cell replacement therapies. Based upon available literature, the need for clinical trials involving targeted inhibition of GTPase molecules remains strong. Some of these drugs are widely used for other diseases, and therefore re-purposing their application for neurotrauma can be fasttracked. These approaches can potentially modify the inhibitory environment of nervous tissue to allow the spontaneous repair capacity of injured tissue.

Spinal Cord Injury Changes Cytokine Transport

Here we summarize three aspects of our understanding of the interactions of cytokines and neurotrophic peptides/proteins with the blood-brain and bloodspinal cord barriers (BBB): (a) pharmacokinetic analysis that has been reported for native cytokines and neurotrophic peptides/proteins; (b) landmark work on conjugated proteins to enhance their delivery across the normal BBB; and (c) regulatory changes under pathophysiological conditions in rodents, particularly after spinal cord injury (SCI). First, though the BBB restricts the permeation of large proteins, some cytokines and neurotrophic peptides/proteins in the periphery can reach the central nervous system (CNS) by specific transport systems. Moreover, SCI and some other disease processes may regulate these transport systems. The significance of studies of the transport systems is obvious because of the biological impact of these molecules on the CNS in health and disease. We have characterized the pharmacokinetic characteristics of some stable cytokines and neurotrophic peptides/proteins in mice after intravenous administration and also in the setting of in situ brain perfusion. In the particular case of SCI, there are time- and regionspecific changes of BBB permeability and transport systems. Tumor necrosis factor-α, a cytokine with dual actions in regeneration of the spinal cord, has a slow basal influx into the brain and spinal cord. After SCI, the increase in the entry of tumor necrosis factor-α to the CNS differs from leakage after BBB disruption and is related to upregulation of the transport system in a unique temporal and regional pattern. Overall, the permeation of cytokines across the BBB can be mediated by specific transport systems. The regulation of transport in pathophysiological conditions affects the extent of neuroinflammation and is implicated in neuroregeneration.

Merging Transport Data for Choroid Plexus with Blood-Brain Barrier to Model CNS Homeostasis and Disease More Effectively

Robust modeling of CNS transport integrates molecular fluxes at the microvascular blood-brain barrier and epithelial choroid plexus blood-cerebrospinal fluid (CSF) barrier. Normal activity of solute transporters, channels and aquaporins, in the cerebral endothelium and choroidal epithelium, sets the microenvironment composition for neurons and glia. Conversely, perturbed transport/permeability at the barrier interfaces causes interstitial fluid dyshomeostasis (e.g. edema) arising in neural disorders. Critically-important transependymal solute/water distribution between brain and CSF needs more attention. This treatise encourages procuring transport data simultaneously for blood-brain barrier, blood-CSF barrier and CSF. In situ perfusion and multicompartmental analyses (tracers, microdialysis) provide dynamic assessments of molecular transfer among various CNS regions. Diffusion, active transport and convection are distorted by disease- and age-associated alterations in barrier permeability and CSF turnover (sink action). Clinical complications result from suboptimal conveyance of micronutrients (folate), catabolites (β-amyloid) and therapeutic agents (antibiotics) within the CNS. Neurorestorative therapies for stroke, traumatic brain injury, multiple sclerosis and brain tumors are facilitated by insight on molecular and cellular trafficking through the choroid plexus-CSF nexus. Knowledge is needed about fluxes of growth factors, neurotrophins, hormones and leukocytes from ventricular CSF into the hippocampus, subventricular zone and hypothalamus. CSF and brain removal of potentially toxic catabolites and neuropeptides merits further investigation to manage the degeneration of Alzheimer’s disease and normal pressure hydrocephalus. Novel therapies will rely on delineating peptide and drug distributions across the blood-brain barrier and choroid plexus-CSF, and how they modulate the intervening neural-glial networks and neurogenic sites. Multicompartmental transport modeling is key to devising specific pharmacologic targeting and thus impactful CSF translational research for CNS disorders.

Advanced Techniques for Imaging the Human Spinal Cord: Review of Literature

Despite the high sensitivity of magnetic resonance imaging (MRI) in detecting a wide spectrum of various pathological processes, the specificity of the method to differentiate among these pathologies and its ability to predict clinical outcomes has been rather below initial expectations. The main problem arises from the fact that most of the pathologies of the spinal cord manifest with a rather nonspecific increase of water protons, reflecting local oedema or gliosis. This is a common finding in most myelopathies, which does not allow a further differential diagnostic distinction in most cases. The use of contrast media improved the specificity of the method; however, it is still challenging to differentiate types of myelopathies. Advanced imaging methodologies such as functional MRI (fMRI), diffusion-weighted and -tensor imaging (DWI/DTI), Magnetic Resonance Spectroscopy (MRS) have been used in the evaluation of neurologic diseases in the brain and have gained increased acceptance among the clinicians for improving the specificity of MR technology and for their ability to better correlate with functional disabilities and clinical symptoms thus providing predictive information about potential outcome. Preliminary results show that, quantitative parameters extracted by these techniques from the spinal cord can provide surrogate markers of disability for determining prognosis as well. In this review, we focus on implementing advanced neuroimaging methodologies (DWI/DTI, fMRI and MRS) in imaging of the human spinal cord for better clinical assessment. Additionally, we review the recent imaging literature advances in this topics and their clinical applications.

Immunotherapy Strategies for Spinal Cord Injury

Regeneration in the central nervous system (CNS) of adult mammalian after traumatic injury is limited, which often causes permanent functional motor and sensory loss. After spinal cord injury (SCI), the lack of regeneration is mainly attributed to the presence of a hostile microenvironment, glial scarring, and cavitation. Besides, inflammation has also been proved to play a crucial role in secondary degeneration following SCI. The more prominent treatment strategies in experimental models focus mainly on drugs and cell therapies, however, only a few strategies applied in clinical studies and therapies still have only limited effects on the repair of SCI. Recently, the interests in immunotherapy strategies for CNS are increasing in number and breadth. Immunotherapy strategies have made good progresses in treating many CNS degenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), stroke, and multiple sclerosis (MS). However, the strategies begin to be considered to the treatment of SCI and other neurological disorders in recent years. Besides anti-inflamatory therapy, immunization with protein vaccines and DNA vaccines has emerged as a novel therapy strategy because of the simplicity of preparation and application. An inflammatory response followed by spinal cord injury, and is controled by specific signaling molecules, such as some cytokines playing a crucial role. As a result, appropriate immunoregulation, the expression of pro-inflammatory cytokines and anti-inflammatory cytokines may be an effective therapy strategy for earlier injury of spinal cord. In addition, myelinassociated inhibitors (MAIs) in the injured spinal cord, such as Nogo, myelin-associated glycoprotein (MAG) and oligodendrocyte- myelin glycoprotein (OMgp) are known to prevent axonal regeneration through their co-receptors, and to trigger demyelinating autoimmunity through T cell-mediated harmful autoimmune response. The antagonism of the MAIs through vaccinating with protein or DNA vaccines targeting Nogo, MAG, OMgp, and their co-receptors, may be an effective strategy for the treatment of SCI. However, immunotherapy such as anti-inflammtory therapy or vaccine targeting MAIs or their receptors, accompanied with the potential in risking autoimmune diseases. As a result, in order to optimize the anti-inflammtory therapy and design of protein or DNA vaccines for their use in the future clinical application, we need to further understand the possible mechanisms of neuroprotective immunity. This review presents recent advances in the development of immunotherapy strategies for the treatment of axonal degeneration and demyelination, and improvement of motor function after SCI.

A Review on Response of Immune System in Spinal Cord Injury and Therapeutic Agents useful in Treatment

Every year more than 12,000 people in US alone suffer from spinal cord injury. However, complete recovery of physical function is difficult due to multiple factors involved in disease progression. Currently available therapeutic regimens do not address all the factors concerned with the disease progression. The present review focuses mainly on the role of immune cells in progression of spinal cord injury and the drugs that target these immune cells. Literature search shows that inflammatory reactions and subsequent reactions that follow direct injury to spinal cord are sometimes responsible for the severity of the disease. Therefore, for design of proper treatment regimen a deep understanding in this area is required. Understanding the pathophysiology will help in creating delivery system that can target multiple factors involved in progression of spinal cord injury. A combination of various treatment strategies is required to reduce the disability in patients with spinal cord injury.

Nanofiber Scaffolds for Treatment of Spinal Cord Injury

Spinal cord injury (SCI) is a common neurologic disorder that results in loss of sensory function and mobility. It is well documented that tissue engineering is a potential therapeutic strategy for treatment of SCI. In this connection, various biomaterials have been explored to meet the needs of SCI tissue engineering and these include natural materials, synthetic biodegradable polymers and synthetic non- degradable polymers. Nanofiber scaffolds are newly emerging biomaterials that have been widely utilized in tissue engineering recently. In comparison to the traditional biomaterials, nanofibers have advantages in topography and porosity, thus mimicking the naturally occurring extracellular matrix. Besides, they exhibit excellent biocompatibility with low immunogenicity, and furthermore they are endowed with properties that help to bridge the lesion cavity or gap, and serve as an effective delivery system for graft cells or therapeutic drugs. This review summarizes some of the unique properties of nanofiber scaffolds which are critical to their potential application in treatment of injured spinal cord.

HDL Genetic Defects

High density lipoprotein cholesterol (HDL-C) and its related apolipoproteins form part of the reverse cholesterol transport system that removes excessive cholesterol from the periphery to the liver. Many transport proteins and enzymes that are involved in this process are susceptible to genetic defects that influence plasma HDL-C concentrations and HDL function.

The HDL-C concentration in the blood may not be as important as the function of this lipid fraction. The genetic defects affecting plasma HDL-C concentrations do not always show a consistent relationship with atherosclerosis.

Familial hypoalphalipoproteinaemia is associated with mutations in genes responsible for the transport proteins or the enzymes involved in the biogenesis of HDL-C. Inheritance of a Milano mutation of apolipoprotein A1 decreases the risk of atherosclerotic disease despite low circulating levels of HDL-C.

Tangier disease and Fish Eye disease are caused by mutations in the ATP binding cassette A1 (ABCA1), a transport protein, and lecithin cholesterol acyl transferase (LCAT), an enzyme, involved in the esterification of cholesterol, respectively. Patients with these conditions have very low levels of HDL-C concentration. The association between both these conditions and the risk of cardiovascular disease (CVD) is variable and inconsistent.

Understanding the molecular mechanism of HDL biogenesis not only helped in defining the pathophysiology of low and high HDL-C syndromes, but also in developing new treatment options to raise HDL-C levels.

A Valuable Animal Model of Spinal Cord Injury to Study Motor Dysfunctions, Comorbid Conditions, and Aging Associated Diseases

Most animal models of contused, compressed or transected spinal cord injury (SCI) require a laminectomy to be performed. However, despite advantages and disadvantages associated with each of these models, the laminectomy itself is generally associated with significant problems including longer surgery and anaesthesia (related post-operative complications), neuropathic pain, spinal instabilities, deformities, lordosis, and biomechanical problems, etc. This review provides an overview of findings obtained mainly from our laboratory that are associated with the development and characterization of a novel murine model of spinal cord transection that does not require a laminectomy. A number of studies successfully conducted with this model provided strong evidence that it constitutes a simple, reliable and reproducible transection model of complete paraplegia which is particularly useful for studies on large cohorts of wild-type or mutant animals - e.g., drug screening studies in vivo or studies aimed at characterizing neuronal and non-neuronal adaptive changes post-trauma. It is highly suitable also for studies aimed at identifying and developing new pharmacological treatments against aging associated comorbid problems and specific SCI-related dysfunctions (e.g., stereotyped motor behaviours such as locomotion, sexual response, defecation and micturition) largely related with ‘command centers’ located in lumbosacral areas of the spinal cord.

Restless Legs Syndrome in Multiple Sclerosis

There is a growing interest in sleep disorders in multiple sclerosis (MS) due to their high frequency and possible relationship to fatigue, a hallmark symptom in MS. Among them, insomnia and restless legs syndrome (RLS) are the most common ones. RLS is a sleep-related motor disorder characterized by a strong urge to move associated with uncomfortable sensations in the limbs. It is frequently under diagnosed in patients with MS although its course is often particularly severe. Several arguments support a symptomatic origin of RLS in MS patients. Independently of any causal relationship, the high prevalence of RLS in MS patients has clinical implications.

The purpose of the present review is (i) to summarize the epidemiological data and clinical characteristics of RLS in MS patients in order to increase sensitivity to this disorder; (ii) to document the substantial body of evidence in support of a symptomatic origin of RLS in MS and from this (iii) to delineate the proposition that MS may represent a clinical model to study RLS-associated pathological changes.

Regenerative Treatment in Spinal Cord Injury

Spinal cord injury is a devastating, traumatic event, and experienced mainly among young people. Until the modern era, spinal cord injury was so rapidly fatal that no seriously injured persons would survive long enough for regeneration to occur. Treatment of spinal cord injury can be summarized as follows: prevent further cord injury, maintain blood flow, relieve spinal cord compression, and provide secure vertebral stabilization so as to allow mobilization and rehabilitation, none of which achieves functional recovery. Previous studies have focused on analyzing the pathogenesis of secondary injury that extends from the injury epicenter to the periphery, as well as the tissue damage and neural cell death associated with secondary injury. Now, there are hundreds of current experimental and clinical regenerative treatment studies. One of the most popular treatment method is cell transplantation in injured spinal cord. For this purpose bone marrow stromal cells, mononuclear stem cells, mesenchymal stem cells, embryonic stem cells, neural stem cells, and olfactory ensheathing cells can be used. As a result, cell transplantation has become a promising therapeutic option for spinal cord injury patients. In this paper we discuss the effectiveness of stem cell therapy in spinal cord injury.

Adult Stem Cell Transplants for Spinal Cord Injury Repair: Current State in Preclinical Research

Spinal cord injury (SCI) is a traumatic disorder resulting in a functional deficit that usually leads to severe and permanent paralysis. After the initial insult to the spinal cord, additional structure and function are lost through an active and complex secondary process. Since there is not effective treatment for SCI, several strategies including cellular, pharmacological and rehabilitation therapies have been approached in animal models. Some of them have been proved in clinical trials. In this review we focus on the current state of cell therapies, particularly on cells from adult origin, assayed in preclinical research. Cell types used in SCI therapy include Schwann cells, olfactory ensheathing cells and adult stem cells, such as neural stem cells, umbilical cord blood derived cells, mesenchymal stem cells or induced pluripotent stem cells. There are not yet conclusive evidences on which types of glial or adult stem cells are most effective in SCI treatment. Their ability to incorporate into the damaged spinal cord, to differentiate into neural lineages, to exert neuroprotective effects, to promote regeneration of damaged axons, and to improve functional deficits are still discussed, before translation towards clinical use, as a single therapy or in combination with other strategies.

Current Status and Prospective Application of Stem Cell-Based Therapies for Spinal Cord Injury

Spinal cord injuries (SCIs) are a common form of trauma that leaves a huge trail of morbidity and human suffering in its wake. They occur mostly among the young, causing severe physical, psychological, social and economic burdens. The treatment of this condition has rather been disappointing; most of the management strategies being mainly supportive and prophylactic. In recent years there has been an emerging interest in the use of stem cells to regenerate the nervous tissue that has been damaged or lost. Although there has been much hype and unfounded hope, modest successes have been witnessed, and it is possible that these therapeutic strategies may have much more to offer in the future. This paper will review the current strategies of exploring cell-based therapies, mainly different types of stem cells to treat SCI along with the evidence that has been accumulated over the past decade in a rational bench-to-bedside approach. Furthermore, critical aspects such as the mode of delivery and ethical considerations are also discussed along with feasible suggestions for future translational research to provide a contextual picture of the current state of advancements in this field. The impediments to regeneration in the site of injury are briefly explained along with the benefits and drawbacks of different cell types used in the treatment of this condition. We hope that this review will offer a significant insight into this challenging clinical condition.

Gene Therapy Approaches for Neuroprotection and Axonal Regeneration after Spinal Cord and Spinal Root Injury

Recent understanding in pathophysiological mechanisms of spinal cord and spinal root injuries has facilitated the development of new strategies to promote neural repair. Gene therapy approaches have been viewed as the ideal means to achieve long-term local delivery of therapeutic molecules in the central nervous system (CNS). Ex vivo gene delivery offers the additional advantage of providing cellular support for regenerating axons. In this review, we summarize the studies on viral vector-mediated gene delivery to spinal cord in animal models, both in vivo and ex vivo. Most of the studies reported so far are aimed at delivery of various growth factors, such as neurotrophins and neuropoietic cytokines. Other molecules tested include those that interfere with intracellular processes to prevent cell death, or increase intrinsic regenerating state of injured neurons, or modify the CNS environment to make it permissive for axon growth. Several different combinatorial strategies involving gene delivery are also discussed as it has been recognized that successful neural repair may require the synergistic actions of multiple therapeutic managements.

Stem Cell Therapy for Spinal Cord Injury

Spinal cord injury (SCI) damages axons and disrupts myelination interrupting sensory and motor neuronal transmission to and from the brain. Patients suffering from SCI although continue to survive, are often left chronically disabled and with no promise of a cure. Advances in stem cell biology has opened up doors for the use of human embryonic, adult neural and induced pluripotent stem cell strategies for SCI. Despite great promise from animal research, clinical trials have been limited and the jury is still out on its safety and efficacy. This review discusses the advantages and disadvantages of the various stem cell types, barriers hindering translation from animal to humans, and the need for established guidelines for standardization of clinical trials ensuring subsequent implementation. Ultimately, unrealistic expectations of stem cell therapy (SCT) as the elixir for SCI should be managed. The success of SCT for SCI lies in the network of research scientists, medical professionals and patients working cooperatively to build up a knowledge-intensive platform for a comprehensive risk-benefit assessment of SCT for SCI.

CD133 Expressing Pericytes and Relationship to SDF-1 and CXCR4 in Spinal Cord Injury

Compression injury to the spinal cord (SC) results in vascular changes affecting the severity of the primary damage of the spinal cord. The recruitment of bone marrow (BM)-derived cells contribute to revascularization and tissue regeneration in a wide range of ischemic pathologies. Involvement of these cells in the vascular repair process has been investigated in an animal model of spinal cord injury (SCI). Temporal gene and protein expression of the BM-derived stem cell markers CD133 and CD34, of the mobilization factor SDF-1 and its receptor CXCR4 were determined following SC compression injury in rats. CD133 was expressed in uninjured tissue by cells surrounding arterioles identified as pericytes by co-expression of α-SMA. These cells mostly disappeared 2 days after injury but repopulated the tissue after 2 weeks. CD34 was expressed by endothelial cells and CD11b+ macrophages/microglia invading the injured tissue as observed 2 weeks following injury. SDF-1 was induced in reactive astrocytes and endothelial cells not until 2 weeks post-SCI. Comparison of the variation between CD34, CD133, CXCR4, and SDF-1 revealed a corresponding trend of CD133 with the SDF-1 expression. This study showed that resident microvascular CD133+ pericytes with presumptive stem cell potential are sensitive to SCI. Their decline following SCI and the delayed induction of SDF-1 may contribute to vessel destabilisation and inefficient revascularization. In addition, none of the analyzed markers could be assigned clearly to BM-derived cells. Together, our findings suggest that effective recruitment of pericytes may serve as a therapeutic option to improve microcirculation after SCI.

Long Term Recovery of Diaphragmatic Function in a Patient with Unilateral Diaphragmatic Pacemaker

Diaphragmatic pacing, also known as electrophrenic respiration or phrenic pacing has been used for quite some time in patients with respiratory failure due to diaphragmatic paralysis. We present a case of patient with respiratory insufficiency due to unilateral phrenic nerve injury as a result of radiation therapy for breast cancer. The patient had a diaphragmatic pacer inserted, with significant recovery on her symptoms. Three years after this procedure, the patient recovered her phrenic nerve function, and this was confirmed by nerve conduction study.

Inflammation: Beneficial or Detrimental After Spinal Cord Injury?

Spinal cord injury leads to a devastating cascade of secondary complications that eventually results in the formation of scar tissue many times the size of the original insult. Inflammation plays a very important role towards the development of such scar, but paradoxically, at the same time it has neuroprotective properties. Only recently have we understood enough about the relevant events to make the repair of injured spinal cords a reachable goal. Over the past decade, researchers have designed and tested numerous innovative therapeutic strategies, and many of such involve manipulation of the immune response. Interestingly, both immuno-stimulatory and immuno-suppressive interventions have shown positive results, which include the prevention of further tissue damage, prevention of secondary cell death and axonal degeneration, promotion of remyelination, stimulation of axonal regeneration, and facilitation of sensorimotor function recovery.

Pharmacological Neuroprotective Therapy for Acute Spinal Cord Injury: State of the Art

After spinal cord injury, a number of destructive events developed immediately after the primary insult increase tissue damage. Several therapeutic approaches are directed to neutralize these phenomena. The present manuscript revises diverse pharmacological treatments used to promote neuroprotection, both in clinical and experimental acute spinal cord injuries.

Eph/ephrin Signaling as a Potential Therapeutic Target After Central Nervous System Injury

Recent work indicates that the expression of Eph and ephrin proteins is upregulated after injury in the central nervous system (CNS). Although to date, much of the interest in these protein families in the nervous system has been on their roles during development, their presence in the adult CNS at multiple time points after injury suggest that they play significant roles in key aspects of the nervous systems response to damage. Several fundamental features of Eph and ephrin biology, such as bidirectional signaling, promiscuity of ligand-receptor binding, and potential cis regulation of function, present challenges for the formulation of rational and effective Eph/ephrin based strategies for CNS axon regeneration. However, recent work that have identified specific functions for individual Ephs and ephrins in injury-induced phenomena such as axon sprouting, cellular remodeling, and scar formation has begun to tease apart their contributions and may provide a number of potential entry points for beneficial therapeutic intervention.

Phosphodiesterase 5 Inhibitors in the Treatment of Erectile Dysfunction

Erectile dysfunction (ED) has multifactor pathogenesis, with neurological, vascular, endocrinological and psychogenic components described. However, about 50-85% of ED population report the presence of one or more comorbidities i.e. hypertension, diabetes, cardiovascular disease, dyslipidemia which all impair endothelial function and, erection is a basically vascular event that necessitates an intact endothelium to occur. Hence, ED may be mostly considered as the clinical manifestation of a disease affecting penile circulation as a part of a generalized vascular disorder due to atherosclerosis. Orally active drugs, i.e. phosphodiesterase type-5 inhibitors (PDE5-i), are a group of on-demand drugs licensed for ED treatment and appear to offer advantages over past therapies in terms of ease of administration and cost, and they are now widely advocated as first-line therapy. The recent discovery that chronic not on-demand administration of these drugs may improve erectile and endothelial response in men previously unresponding to on-demand regimes, opens a new scenario in the treatment of men with ED and comorbidities. Finally, the recent approval of PDE5-i sildenafil for the treatment of pulmonary arterial hypertension represents the new challenge for these class of drugs. Aim of this article will be to provide an update on the pathophysiology of ED and how to use of different available PDE5-i in approaching sexual dysfunctional men, pointing out on their characteristic of efficacy and safety and different indications in special subpopulations.

Back Pain in Children and Adolescents: Etiology, Clinical Approach and Treatment

The purpose of this systematic review is to investigate back pain as a clinical presentation in childhood and adolescence providing the clinician with a comprehensive approach, which will enable for an early recognition of those spinal disorders in need of more aggressive medical intervention. The current literature suggests that young people have a fairly high incidence of non-specific back pain, which seems to be much more frequent than traditionally reported. In schoolchildren, low back pain is mainly associated with psychosocial factors and seems to be mostly benign and selflimiting, therefore, only occasionally requiring medical attention. However, young patients who seek medical assistance, have a higher incidence of organic conditions that can manifest with spinal pain as their predominant symptom. The evaluation of a child or adolescent presenting with back pain can be a challenging task and requires skilled clinical expertise and a high index of suspicion. The physician should have a carefully planned strategy for assessing the pediatric spine patient, which should be accurate, reliable, consistent, and easily reproducible in delineating spinal pathologies. This should include a detailed history, physical examination, radiographic imaging, and appropriate diagnostic laboratory studies. A specific diagnosis will be established in at least 50% of the patients. In certain cases, an exact diagnosis cannot be made, and it is always advisable to re-evaluate the child after a period of initial observation. By then more serious problems will advance and become more obvious while minor symptoms not linked to an underlying pathology will resolve spontaneously. The authors did not receive grants or outside funding in support of their research or preparation of this manuscript. They did not receive payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or non-profit organization with which the authors are affiliated or associated.

L-Acetylcarnitine: A Proposed Therapeutic Agent for Painful Peripheral Neuropathies

During the past two decades, many pharmacological strategies have been investigated for the management of painful neuropathies. However, neuropathic pain still remains a clinical challenge. A combination of therapies is often required, but unfortunately in most cases adequate pain relief is not achieved. Recently, attention has been focused on the physiological and pharmacological effects of L-acetylcarnitine in neurological disorders. There are a number of reports indicating that L-acetylcarnitine can be considered as a therapeutic agent in neuropathic disorders including painful peripheral neuropathies. In this review article, we will examine the antinociceptive and the neuroprotective effects of Lacetylcarnitine as tested in clinical studies and in animal models of nerve injury.

Strategies to Create a Regenerating Environment for the Injured Spinal Cord

Spine cord injury (SCI) leads to devastating functional loss below the level of injury. Partially explained by the presence of a non-permissive environment, the injured spinal cord does not mount adequate regeneration to reestablish functional connections. Therefore, it is important to identify the cellular and molecular factors and their interactions that affect axonal regeneration within the changed environment. This review will discuss the current understanding of the neuronal and glial factors and the extracellular matrix in the spinal cord that inhibit axonal growth, and it will summarize some major approaches for facilitation of regeneration. The strategies are classified into the following categories: penetration of the blood-brain barrier; modulation of caspase activity to reduce apoptosis; stem cells and tissue implantation; administration of neurotrophic factors, including viral vector-mediated delivery; and modulation of the extracellular matrix. Although recent studies on genomic regulation and apoptosis have identified particularly important molecular targets, more is necessary to achieve long-term regeneration. A combination of the approaches targeting various aspects in the regenerating environment would be more effective than a single strategy. Overall, insights arising from the experimental results may eventually lead to better therapeutic intervention so as to lessen the functional disability and enhance the quality of life in patients with SCI.

Cell Elimination as a Strategy for Repair in Acute Spinal Cord Injury

Following injury, as part of the wound-healing process, cell proliferation occurs mostly to replace damaged cells and to reconstitute the tissue back to normal condition/function. In the spinal cord some of the dividing cells following injury interfere with the repair processes. This interference occurs at the later stages of wound healing (the third week after injury) triggering chronic inflammation and progressive tissue decay that is the characteristic pathology of spinal cord injury. Specific cell elimination within a critical time window after injury can lead to repair in the acutely injured spinal cord. Cell proliferation events can be manipulated/modified by x-irradiation. Clinically, numerous radiation protocols (i.e., radiation therapy) have been developed that specifically eliminate the rapidly dividing cells without causing any noticeable/significant damage to the tissue as a whole. Radiation therapy when applied within the critical time window after injury prevents the onset of chronic inflammation thus leading to repair of structure and function. Various aspects of the development of this cell-elimination strategy for repair in acute spinal cord injury by utilizing radiation therapy are being reviewed. Topics reviewed here: identifying the window of opportunity; and the beneficial repair effects of radiation therapy in a transection injury model and in a model relevant to human injury, the contusion injury model. The possible involvement of cellular components of the blood-spinal cord barrier as the trigger of chronic inflammation and/or target of the radiation therapy is discussed.

Neuroprotection and Regeneration Strategies for Spinal Cord Repair

The journey toward a cure for spinal cord injury (SCI) has taken many paths. In this article, we review these paths, and highlight the clinical applications of these experimental repair strategies. Initial strategies involved attempts at neuroprotection with steroids and other anti-inflammatory drugs. Other anti-ischemia treatments, agents to eliminate the damage from excitotoxicity, and anti-apoptotic agents were also tried. Another avenue involved enhancing the function of the remaining uninjured axons by measures to produce remyelination and medications to improve axonal conduction. In the last two decades there has been a major effort to enhance spinal cord axonal regeneration through a variety of techniques including neutralization of neurite inhibition, administration of neurotrophic factors, implantation of synthetic channels, and transplantation of a variety of cell types. Indeed, several of these strategies have been so promising in animals that clinicians have been stimulated to explore their potential human application. We also examine the different experimental models of SCI used to assess repair, and discuss how the injury model impacts on the assessment of axonal regeneration and functional recovery after SCI. The mechanisms of recovery that may be involved after SCI will be analyzed, and their relevance toward finding a cure for human SCI. Unfortunately, the goal of producing significant functional regeneration of the human spinal cord has not yet been achieved despite the many strategies that have been developed. It is our hope that improved understanding of the mechanisms underlying functional recovery will lead to successful therapeutic strategies in humans.

Neural Plasticity After Spinal Cord Injury

Spinal cord injury (SCI) has devastating physical and socioeconomical impact. However, some degree of functional recovery is frequently observed in patients after SCI. There is considerable evidence that functional plasticity occurs in cerebral cortical maps of the body, which may account for functional recovery after injury. Additionally, these plasticity changes also occur at multiple levels including the brainstem, spinal cord, and peripheral nervous system. Although the interaction of plasticity changes at each level has been less well studied, it is likely that changes in subcortical levels contribute to cortical reorganization. Since the permeability of the blood-brain barrier (BBB) is changed, SCI-induced factors, such as cytokines and growth factors, can be involved in the plasticity events, thus affecting the final functional recovery after SCI. The mechanism of plasticity probably differs depending on the time frame. The reorganization that is rapidly induced by acute injury is likely based on unmasking of latent synapses resulting from modulation of neurotransmitters, while the long-term changes after chronic injury involve changes of synaptic efficacy modulated by long-term potentiation and axonal regeneration and sprouting. The functional significance of neural plasticity after SCI remains unclear. It indicates that in some situations plasticity changes can result in functional improvement, while in other situations they may have harmful consequences. Thus, further understanding of the mechanisms of plasticity could lead to better ways of promoting useful reorganization and preventing undesirable consequences.

Research on the Possibility of Overcoming Traumatic Paraplegia and Its First Clinical Results

The interruption of the continuity of the spinal cord is still an incurable lesion. In contrast with the peripheral nerves, the axons regenerating from the mother cells of the brain do not progress inside the cord. The reasons of this “non-permissiveness” are still unclear. This article describes the attempts of the author to overcome this non-permissiveness by means of a research that began in 1980 on rats, and continued since 1993 on monkeys. Results of the research on experimental animals were good and convincing so that this operation has been performed on fully informed human being volunteers affected by total severance of the cord between T8 and T11. Results of the first clinical cases are presented regarding operations performed either by rerouting the ulnar nerve to the lower limbs, or connecting the rostral stump of the severed cord with peripheral nerves of the hip to obtain rudimentary, but efficient, walking. Recovery occurred well in advance of the expected time, and continued to improve up to allow the first patient operated on by connecting CNS with PNS to walk with sticks after having walked for some months with a walker. This connection functioned even if the axons activating the single muscles were from mother cells dispersed in different regions of the brain cortex. These cells fire together giving selective contraction of diverse muscles. Furthermore, function occurred although the upper motor neuron uses the neurotransmitter glutamate, whereas motor end plates use receptors for Acetilcholine. These data are under further investigation to determine whether the upper motor neuron changes the transmitter, or if the motor end changes its receptors (as seems to be by the first results).

Pathophysiology of Blood-Spinal Cord Barrier in Traumatic Injury and Repair

Blood-spinal cord barrier (BSCB) plays an important role in the regulation of the fluid microenvironment of the spinal cord. Trauma to the spinal cord impairs the BSCB permeability to proteins leading to vasogenic edema formation. Several endogenous neurochemical mediators and growth factors contribute to trauma induced BSCB disruption. Studies carried out in our laboratory suggest that those drugs and neurotrophic factors capable to attenuate the BSCB dysfunction following trauma are neuroprotective in nature. Whereas, agents that do not exert any influence on the BSCB disruption failed to reduce cell injury. These observations are in line with the idea that BSCB disruption plays an important role in the pathophysiology of spinal cord injuries. The probable mechanism(s) of trauma induced BSCB dysfunction and its contribution to cell injuries are discussed.

Endogenous and Exogenous CNS Derived Stem / Progenitor Cell Approaches for Neurotrauma

Neural stem/progenitor cells capable of generating new neurons and glia, reside in specific areas of the adult mammalian central nervous system (CNS), including the ependymal region of the spinal cord and the subventricular zone (SVZ), hippocampus, and dentate gyrus of the brain. Much is known about the neurogenic regions in the CNS, and their response to various stimuli including injury, neurotrophins (NFs), morphogens, and environmental factors like learning, stress, and aging. This work has shaped our current views about the CNSs potential to recover lost tissue and function post-traumatically and the therapies to support the intrinsic regenerative capacity of the brain or spinal cord. Recently, intensive research has explored the potential of harvesting, culturing, and transplanting neural stem/progenitors as a therapeutic intervention for spinal cord injury (SCI) and traumatic brain injury (TBI). Another strategy has focused on maximizing the potential of this endogenous population of cells by stimulating their recruitment, proliferation, migration, and differentiation in vivo following traumatic lesions to the CNS. The promise of such experimental treatments has prompted tissue and biomaterial engineers to implant synthetic three-dimensional biodegradable scaffolds seeded with neural stem/progenitors into CNS lesions. Although there is no definitive answer about the ideal cell type for transplantation, strong evidence supports the use of region specific neural stem/progenitors. The technical and logistic considerations for transplanting neural stem/progenitors are extensive and crucial to optimizing and maintaining cell survival both before and after transplantation, as well as for tracking the fate of transplanted cells. These issues have been systematically addressed in many animal models, that has improved our understanding and approach to clinical therapeutic paradigms.

Adult Stem Cell Application in Spinal Cord Injury

The mechanical force incurred by spinal cord injury results in degenerative neural tissue damage beyond the site of initial injury. By nature, the central nervous system (CNS) does not regenerate itself. Cell therapy, in particular, stem cell implantation has become a possible solution for spinal cord injury. Embryonic stem cells and fetal stem cells are the forefathers of the field of stem cell therapy. Isolation and preparation of specific populations of adult stem cells have evolved to the point of stable, long-term culturing with the capability to differentiate into neural phenotypes from all three of the neural lineages: neurons, astrocytes, and oligodendrocytes. Thus, adult stem cells will transcend ethical concerns, technical difficulties, and probably immunorejection. A variety of adult stem cells have been implanted in a rat model of spinal cord injury, ranging from olfactory ensheathing cells, cultured spinal cord stem cells, bone marrow derived stem cells, dermis derived stem cells, and a few others. Although no definite decisions on which adult stem cells are most effective for this CNS injury, their ability to incorporate into the spinal cord, differentiate, and to improve locomotor recovery hold promise for a cure.

Monitoring Cell Therapy Using Iron Oxide MR Contrast Agents

Given the remarkable progress that has recently been obtained in animal studies, the clinical use of stem and progenitor cells to correct or replace defective cell populations may soon become a reality. In order to develop effective cell therapies, the location and distribution of these cells must be determined in a non-invasive manner. Magnetic resonance (MR) tracking of magnetically labeled cells following transplantation or transfusion may fulfill this requirement. Indeed, a series of recent studies indicate that MRI cell tracking has great potential for further evaluation and optimization of cell therapy. Due to its biocompatibility and strong effects on T2(*) relaxation, iron oxide nanoparticles appear to be the contrast agent of choice, and several methods now exist to shuttle sufficient amount of these compounds into cells. Most of the tracking work has been carried out in disease models of the central nervous system, but, recently, the infarcted heart has also received attention. With its excellent spatial resolution and the ability to track labeled cells over prolonged periods of time, MR monitoring of cell therapy is likely to become an important technique in the foreseeable future.

Cardiovascular Alterations After Spinal Cord Injury: An Overview

The recent developments in the management of spinal cord injury (SCI) have led to a reduction in mortality and in the consequences, resulting from incomplete spinal cord damage in those who survive. In this respect, it is noteworthy that SCI not only results in paraplegia or tetraplegia, but also in systemic, cardiovascular and metabolic alterations secondary to autonomic dysfunction. After SCI there is a decrease in sympathetic discharge and an increase in parasympathetic drive, resulting in profound changes in arterial blood pressure and heart rate. When SCI is induced in experimental animals, an immediate hypotension occurs (acute phase) which has been attributed to an autonomic imbalance involving a predominance of parasympathetic activity. Subsequently, an episodic hypertension may develop (chronic phase) as a part of a condition denominated autonomic dysreflexia. This hypertension is caused by afferent stimulation below the level of injury and can be so severe that sometimes may lead to cerebral haemorrhage, seizures, and death. In the light of the above lines of evidence, experimental SCI may provide an ideal model to study the nature of cardiovascular mechanisms following traumatic injury. Thus, the present review will deal with an update of the possible cardiovascular complications associated to SCI (including spinal shock, autonomic dysreflexia, deep venous thrombosis, and risk for coronary heart disease). This will be discussed within the context of the development of drugs with potential therapeutic usefulness in the acute and chronic stages of SCI.

Cardiovascular Control After Spinal Cord Injury

Spinal cord injury (SCI) leads to profound haemodynamic changes. Constant outflows from the central autonomic pattern generators modulate the activity of the spinal sympathetic neurons. Sudden loss of communication between these centers and the sympathetic neurons in the intermediolateral thoracic and lumbar spinal cord leads to spinal shock. After high SCI, experimental data demonstrated a brief hypertensive peak followed by bradycardia with escape arrhythmias and marked hypotension. Total peripheral resistance and cardiac output decrease, while central venous pressure remains unchanged. The initial hypertensive peak is thought to result from direct sympathetic stimulation during SCI and its presence is anaesthetic agent dependent. Hypotension improves within days in most animal species because of reasons not totally understood, which may include synaptic reorganization or hyper responsiveness of α receptors. No convincing data has demonstrated that the deafferented spinal cord can generate significant basal sympathetic activity. However, with the spinal shock resolution, the deafferented spinal cord (in lesions above T6) will generate lifethreatening hypertensive bouts with compensatory bradycardia, known as autonomic hyperreflexia (AH) after stimuli such as pain or bladder / colonic distension. AH results from the lack of supraspinal control of the sympathetic neurons and altered neurotransmission (e.g. glutamatergic) within the spinal cord. Despite significant progress in recent years, further research is necessary to fully understand the spectrum of haemodynamic changes after SCI.

Neuropathic Pain: Some Clues for Future Drug Treatments

Neuropathic pain is still far from being adequately dealt with. Under this name, several clinical entities have been considered and most of them only share several painful ailments. At present, the available treatments can only alleviate the pain of roughly half of the patients, and their effectiveness is often limited by the appearance of the intolerable side effects. In this review, we will consider the pathophysiology of neuropathic pain to understand the basis of pharmacological treatments that are currently being investigated. Some examples of these drugs will also be considered.