Dietary influence on central nervous system myelin production, injury, and regeneration.

Oligodendrocytes not only produce myelin to facilitate nerve impulse conduction, but are also essential metabolic partners of the axon. Oligodendrocyte loss and myelin destruction, as occurs in multiple sclerosis (MS), leaves axons vulnerable to degeneration and permanent neurological deficits ensue. Many studies now propose that lifestyle factors such as diet may impact demyelinating conditions, including MS. Most prior reviews have focused on the regulatory role of diet in the inflammatory events that drive MS pathogenesis, however the potential for dietary factors to modulate oligodendrocyte biology, myelin injury and myelin regeneration remain poorly understood. Here we review the current evidence from clinical and animal model studies regarding the impact of diet or dietary factors on myelin integrity and other pathogenic features of MS. Some limited evidence exists that certain foods may decrease risk or influence the progression of MS, such as increased intake of fish or polyunsaturated fatty acids, caloric restriction and fasting-mimicking diets. In addition, evidence suggests adolescent obesity or insufficient vitamin D levels increase the risk for developing MS. However, no clear or consistent evidence exists that dietary components exacerbate disease progression. Cumulatively, current evidence highlights the need for more extensive clinical trials to validate dietary effects on MS and to identify diets or supplements that may be beneficial as food-based strategies in the management of MS alone or in combination with conventional disease modifying therapies.

A Retrospective Analysis of Adverse Events in Hyperbaric Oxygen Therapy (2012-2015): Lessons Learned From 1.5 Million Treatments.

OBJECTIVE: To describe the distribution and occurrence of adverse events recorded during hyperbaric oxygen (HBO) therapy from 2012 to 2015. In this analysis, events are defined as otic/sinus barotrauma, confinement anxiety, hypoglycemia, oxygen toxicity, pneumothorax, seizure, and shortness of breath. DATA AND ANALYSIS: The data for the analysis were drawn from a proprietary electronic health data system that contained information on 1,529,859 hyperbaric treatments administered during 53,371 treatment courses from 2012 to 2015 in outpatient wound care centers across the United States managed by Healogics, Inc, Jacksonville, Florida. RESULTS: Of the 1.5 million treatments included in the analysis, 0.68% were associated with an adverse event. Barotrauma and confinement anxiety were the most frequently reported events. Medically severe events were extremely uncommon, with fewer than 0.05 instances of oxygen toxicity per 1000 treatments and only 1 confirmed case of pneumothorax. CONCLUSIONS: Results indicate that the occurrence of adverse events associated with HBO therapy is infrequent and typically not serious. The findings of this study suggest that when administered according to the appropriate therapeutic protocols HBO therapy is a safe and low-risk intervention.

Treatment of Central Deafferentation and Trigeminal Neuropathic Pain by Motor Cortex Stimulation: Report of a Series of 20 Patients.

OBJECTIVE: Motor cortex stimulation (MCS) is an alternative treatment modality for central neuropathic pain, if conservative treatment failed. Study aim was outcome assessment after MCS. MATERIAL AND METHODS: This study is a retrospective case series review of patients who had undergone MCS for central pain (n = 8), deafferentation pain (n = 3) and neuropathic trigeminal pain (n = 9) between April 2001 and May 2011. In all patients, four contact-paddle electrodes were placed in the epidural space overlying the motor cortex via burr hole trepanation under local anesthesia. The follow-up period was 6 months to 6 years. Pain control was assessed by the visual analog scale (VAS). RESULTS: A total of 22 patients (11 men, 11 women) were treated; after trial stimulation two male patients were excluded for incompliance reasons. The mean patient age was 59.8 years (range: 31-79 years). In the central pain group, three patients reported complete, and four patients satisfactory pain control. In the trigeminal neuropathic pain group, seven patients reported complete, and two patients satisfactory pain control. In the deafferentation pain group, one patient reported complete, and two patients satisfactory pain control. None of the patients showed new neurologic deficits after the MCS. CONCLUSIONS: MCS is an effective treatment modality for central neuropathic pain and trigeminal pain with low morbidity and mortality. Future studies are necessary to evaluate and optimize this treatment option in more detail.

Role of Immune Cells in the Course of Central Nervous System Injury: Modulation with Natural Products.

Immune cells actively participate to the central nervous system (CNS) injury either damaging or protecting neural tissue with release of various mediators. Residential microglia and monocyte-derived macrophages play a fundamental role within the injured CNS and, here, special emphasis will be placed on M1 and M2 macrophages for their different functional activities. On the other hand, peripheral T regulatory (Treg) cells exert antiinflammatory activities in the diseased host. In this respect, activation of Treg cells by nutraceuticals may represent a novel approach to treat neuroinflammation. Omega-3 fatty acids and polyphenols will be described as substances endowed with antioxidant and anti-inflammatory activities. However, taking into account that Treg cells act in the later phase of CNS injury, favoring immune suppression, manipulation of host immune system with both substances requires caution to avoid undesired side effects.

Cerebrospinal fluid markers of central nervous system injury in decompression illness - a case-controlled pilot study.

INTRODUCTION: Decompression sickness (DCS) may cause a wide variety of symptoms, including central nervous system (CNS) manifestations. The main objective of this study was to examine whether DCS is associated with neuronal injury, and whether DCS could result in altered amyloid metabolism. METHODS: Seven, male divers with DCS and seven age-matched controls were included in the study. All the divers were treated by recompression but the controls did not receive hyperbaric oxygen. Cerebrospinal fluid (CSF) samples were collected 7-10 days after the diving injury and at three months follow-up. CSF biomarkers of neuronal injury, astroglial Injury/activation, and a range of markers of amyloid ß (Aß) metabolism, as well as two proinflammatory interleukins, were analysed using immunochemical methods. RESULTS: There were no significant differences in the best-established CSF markers of neuronal injury, total tau (T-tau) and neurofilament light, between DCS patients and controls or between the two sampling time points. Also, there were no significant changes in the astroglial or amyloid (Aß)-related markers between DCS patients and controls. However, the only diver with CNS symptoms had the highest levels of CSF T-tau, Aß38, Aß40 and Aß42. CONCLUSION: The results of our study speak against subclinical CNS injury or induction of inflammation or amyloid build-up in the brain among the six DCS patients without neurological symptoms. Further research, including on divers with CNS DCS, is justified.

Calreticulin contributes to C1q-dependent recruitment of microglia in the leech Hirudo medicinalis following a CNS injury.

BACKGROUND: The medicinal leech is considered as a complementary and appropriate model to study immune functions in the central nervous system (CNS). In a context in which an injured leech's CNS can naturally restore normal synaptic connections, the accumulation of microglia (immune cells of the CNS that are exclusively resident in leeches) has been shown to be essential at the lesion to engage the axonal sprouting. HmC1q (Hm for Hirudo medicinalis) possesses chemotactic properties that are important in the microglial cell recruitment by recognizing at least a C1q binding protein (HmC1qBP alias gC1qR). MATERIAL AND METHODS: Recombinant forms of C1q were used in affinity purification and in vitro chemotaxis assays. Anti-calreticulin antibodies were used to neutralize C1q-mediated chemotaxis and locate the production of calreticulin in leech CNS. RESULTS: A newly characterized leech calreticulin (HmCalR) has been shown to interact with C1q and participate to the HmC1q-dependent microglia accumulation. HmCalR, which has been detected in only some microglial cells, is consequently a second binding protein for HmC1q, allowing the chemoattraction of resident microglia in the nerve repair process. CONCLUSIONS: These data give new insight into calreticulin/C1q interaction in an immune function of neuroprotection, suggesting another molecular target to use in investigation of microglia reactivity in a model of CNS injury.

Integrated microfluidics platforms for investigating injury and regeneration of CNS axons.

We describe the development of experimental platforms to quantify the regeneration of injured central nervous system (CNS) neurons by combining engineering technologies and primary neuronal cultures. Although the regeneration of CNS neurons is an important area of research, there are no currently available methods to screen for drugs. Conventional tissue culture based on Petri dish does not provide controlled microenvironment for the neurons and only provide qualitative information. In this review, we introduced the recent advances to generate in vitro model system that is capable of mimicking the niche of CNS injury and regeneration and also of testing candidate drugs. We reconstructed the microenvironment of the regeneration of CNS neurons after injury to provide as in vivo like model system where the soluble and surface bounded inhibitors for regeneration are presented in physiologically relevant manner using microfluidics and surface patterning methods. The ability to control factors and also to monitor them using live cell imaging allowed us to develop quantitative assays that can be used to compare various drug candidates and also to understand the basic mechanism behind nerve regeneration after injury.

Optimizing the function of upstanding activities in adult patients with acquired lesions of the central nervous system by using the Bobath concept approach - A case report.

Nonspecific medical gymnastic therapy may help patients after stroke achieve certain results in terms of efficiency but not in terms of quality of movement. The goal of treatment by Bobath concept is development of movement (effectiveness) and optimization of movement (efficiency). This article presents the case of a 62-year old patient who had experienced a stroke and has difficulties with standing up activities. It underscores the importance of not only recovery of function but also optimization of the function in such patients.

Thresholds for thermal damage to normal tissues: an update.

The purpose of this review is to summarise a literature survey on thermal thresholds for tissue damage. This review covers published literature for the consecutive years from 2002-2009. The first review on this subject was published in 2003. It included an extensive discussion of how to use thermal dosimetric principles to normalise all time-temperature data histories to a common format. This review utilises those same principles to address sensitivity of a variety of tissues, but with particular emphasis on brain and testis. The review includes new data on tissues that were not included in the original review. Several important observations have come from this review. First, a large proportion of the papers examined for this review were discarded because time-temperature history at the site of thermal damage assessment was not recorded. It is strongly recommended that future research on this subject include such data. Second, very little data is available examining chronic consequences of thermal exposure. On a related point, the time of assessment of damage after exposure is critically important for assessing whether damage is transient or permanent. Additionally, virtually no data are available for repeated thermal exposures which may occur in certain recreational or occupational activities. For purposes of regulatory guidelines, both acute and lasting effects of thermal damage should be considered.

Neural plasticity: the biological substrate for neurorehabilitation.

Decades of basic science have clearly demonstrated the capacity of the central nervous system (CNS) to structurally and functionally adapt in response to experience. The field of neurorehabilitation has begun to use this body of work to develop neurobiologically informed therapies that harness the key behavioral and neural signals that drive neural plasticity. The present review describes how neural plasticity supports both learning in the intact CNS and functional improvement in the damaged or diseased CNS. A pragmatic, interdisciplinary definition of neural plasticity is presented that may be used by both clinical and basic scientists studying neurorehabilitation. Furthermore, a description of how neural plasticity may act to drive different neural strategies underlying functional improvement after CNS injury or disease is provided. The understanding of the relationship between these different neural strategies, mechanisms of neural plasticity, and changes in behavior may facilitate the development of novel, more effective rehabilitation interventions.

The receptor protein tyrosine phosphatase HmLAR1 is up-regulated in the CNS of the adult medicinal leech following injury and is required for neuronal sprouting and regeneration.

LAR-like receptor protein tyrosine phosphatases (RPTPs), which are abundantly expressed in the nervous systems of most if not all bilaterian animals thus far examined, have been implicated in regulating a variety of critical neuronal processes. These include neuronal pathfinding, adhesion and synaptogenesis during development and, in adult mammals, neuronal regeneration. Here we explored a possible role of a LAR-like RPTP (HmLAR1) in response to mechanical trauma in the adult nervous system of the medicinal leech. In situ hybridization and QPCR analyses of HmLAR1 expression in individual segmental ganglia revealed a significant up-regulation in receptor expression following CNS injury, both in situ and following a period in vitro. Furthermore, we observed up-regulation in the expression of the leech homologue of the Abelson tyrosine kinase, a putative signaling partner to LAR receptors, but not among other tyrosine kinases. The effects on neuronal regeneration were assayed by comparing growth across a nerve crush by projections of individual dorsal P neurons (P(D)) following single-cell injection of interfering RNAs against the receptor or control RNAs. Receptor RNAi led to a significant reduction in HmLAR1 expression by the injected cells and resulted in a significant decrease in sprouting and regenerative growth at the crush site relative to controls. These studies extend the role of the HmLARs from leech neuronal development to adult neuronal regeneration and provide a platform to investigate neuronal regeneration and gene regulation at the single cell level.

Therapeutic potential of melatonin in traumatic central nervous system injury.

A vast literature extolling the benefits of melatonin has accumulated during the past four decades. Melatonin was previously considered of importance to seasonal reproduction and circadian rhythmicity. Currently, it appears to be a versatile anti-oxidative and anti-nitrosative agent, a molecule with immunomodulatory actions and profound oncostatic activity, and also to play a role as a potent neuroprotectant. Nowadays, melatonin is sold as a dietary supplement with differential availability as an over-the-counter aid in different countries. There is a widespread agreement that melatonin is nontoxic and safe considering its frequent, long-term usage by humans at both physiological and pharmacological doses with no reported side effects. Endeavors toward a designated drug status for melatonin may be enormously rewarding in clinics for treatment of several forms of neurotrauma where effective pharmacological intervention has not yet been attained. This mini review consolidates the data regarding the efficacy of melatonin as an unique neuroprotective agent in traumatic central nervous system (CNS) injuries. Well-documented actions of melatonin in combating traumatic CNS damage are compiled from various clinical and experimental studies. Research on traumatic brain injury and ischemia/reperfusion are briefly outlined here as they have been recently reviewed elsewhere, whereas the studies on different animal models of the experimental spinal cord injury have been extensively covered in this mini review for the first time.

Psychoneuroimmunology and related mechanisms in understanding health disparities in vulnerable populations.

The nervous system as well as the endocrine system maintain extensive communication with the immune system through the influence of hormones and neurotransmitters and also by way of the hardwiring of sympathetic and parasympathetic nerves to the lymphoid organs. There is now convincing evidence that the communication between these three body systems is bidirectional. This chapter will provide a succinct review of how neuroendocrine and immune functions are affected in factors that impact vulnerability, such as aging, acute infection, and central nervous system injury. Given that the relevant literature on these topics is vast, the presentation in this chapter will serve to highlight primary references that reflect state of the science in these systems of focus.

Reduced axon sprouting after treatment that diminishes microglia accumulation at lesions in the leech CNS.

The role of mammalian microglia in central nervous system (CNS) repair is controversial. Microglia accumulate at lesions where they act as immune cells and phagocytize debris, and they may secrete neurotrophins, but they also produce molecules that can be cytotoxic, like nitric oxide (NO). To determine the importance of microglial accumulation at lesions on growth of severed CNS axons in the leech (Hirudo medicinalis), in which axon and synapse regeneration are notably successful even when isolated in tissue culture medium, microglial migration to lesions was reduced. Pressure (P) sensory neurons were injected with biocytin to reveal the extent of their sprouting 24 hours after lesioning. To reduce microglia accumulation at lesions, cords were treated for 3.5 hours with 3 mM ATP or 2 mM N(omega)-nitro-L-arginine methyl ester (L-NAME) or 50 microM Reactive blue-2 (RB2) beginning 30 minutes before injury. Lesioned controls were either not treated with drug or treated 3 hours later with one of the drugs, after the migration and subsequent accumulation of most microglia had occurred, but before the onset of axon sprouting, for a total of seven separate conditions. There was a significant reduction in total sprout lengths compared with controls when microglial accumulation was reduced. The results suggest that microglial cells are necessary for the usual sprouting of injured axons.

Rare but serious complications of acupuncture: traumatic lesions.

Acupuncture has a reputation among the public of being safe. Although recently performed prospective studies on the frequency of adverse effects of acupuncture found no severe complication, since 1965 many case reports of serious or even life-threatening incidents caused by acupuncture have appeared in the scientific literature. The most frequently reported complications are pneumothorax and lesions of the spinal cord. Severe injuries of peripheral nerves and blood vessels due to acupuncture seem to be very rare. Although case reports do not produce reliable data on the frequency of adverse events. information on sources of application errors can be extracted to increase the quality of acupuncture in education and therapy. All traumatic injuries described in this article could be avoided if practitioners had better anatomical knowledge, applied existing anatomical knowledge better, or both.

Complications and side effects of hyperbaric oxygen therapy.

BACKGROUND: Despite ongoing controversy, hyperbaric oxygen (HBO) therapy is frequently administered in various clinical situations. Probably because of the unique atmospheric conditions to which the patient is exposed, there are concerns about the safety aspects of this therapy. Possible complications during HBO therapy include barotraumatic lesions (middle ear, nasal sinuses, inner ear, lung, teeth), oxygen toxicity (central nervous system, lung), confinement anxiety, and ocular effects (myopia, cataract growth). METHODS: To analyze the medical safety of HBO therapy, this report reviewed complications and side effects of 782 patients treated for various indications with a total of 11,376 HBO therapy sessions within a multiplace chamber. The absolute treatment pressure was 240 or 250 kPa 114 or 15 msw). The compression was performed in a linear manner with 14 to 15 kPa (1.4 to 1.5 msw) x min(-1). All data were gathered prospectively within a special database. RESULTS: More than 17% of all patients experienced ear pain or discomfort as an expression of problems in equalizing the middle ear pressure. Most episodes were not related to a persistent eustachian tube dysfunction since they only occurred once. Barotraumatic lesions on visual otological examinations (ear microscopy) were verified in 3.8% of all patients. Patients with sensory deficits involving the ear region need special attention, because they seem to be at risk for rupture of the tympanic membrane (three cases documented). A barotrauma of the nasal sinuses occurred rarely and no barotraumatic lesions of the inner ear, lung, or teeth were noted. Oxygen toxicity of the CNS manifested by generalized seizures affected four patients without any recognizable risk factors or prodromes. None of the patients suffered recurrences or sequelae. Regular checks of the blood glucose in diabetics failed to reveal episodes of hypoglycemia as a cause for seizures. Lung function tests of patients undergoing prolonged treatment (average 52.8 sessions) did not deteriorate. CONCLUSION: Patients scheduled for HBO therapy need a careful pre-examination and monitoring. If safety guidelines are strictly followed, HBO therapy is a modality with an acceptable rate of complications. The predominant complication is represented by pressure equalization problems within the middle ear. Serious complications rarely occur.

Effects of whole-body hyperthermia on the canine central nervous system.

It has been reported that central nervous system (CNS) tissue may be more heat labile than other tissues of the body. However, no definite information has been available on how much heat CNS tissue can tolerate without sustaining damage during whole-body hyperthermia, especially in a chronic stage. In this study, whole-body hyperthermia was induced in dogs by extracorporeal heating of blood, to determine the effects 7 days after hyperthermia on the canine brain and spinal cord. The temperatures of both the brain and the spinal cord were raised to 42.0+/-0.1 degrees C and maintained at that level for 60 min. Seven days later, all of the dogs were sacrificed by transcardial perfusion using 10% formaldehyde phosphate buffer for microscopic examination. The thermal dose resulted in neither microscopic damage to the CNS nor neurological symptoms, as determined by comparison of microscopic and neurological findings with those of dogs whose brain and spinal cord temperatures were maintained at 37.0 degrees C for 60 min. The findings suggest that, for medical purposes, whole-body hyperthermia appears promising for application at a thermal dose of up to 42.0 degrees C for 60 min.

An immunohistochemical marker for Wallerian degeneration of fibers in the central and peripheral nervous system.

This work was prompted by the accidental observation that a newly developed, affinity purified polyclonal antibody against the C-terminus of the neuropeptide tyrosine (NPY) Y1-receptor protein decorates degenerating fibers in the central nervous system (CNS). This staining did not appear in control animals in which the antibody marked perikarya and dendrites at previously described locations [X. Zhang, L. Bao, Z.-Q. Xu, J. Kopp, U. Arvidsson, R. Elde, T. Hökfelt, Localization of neuropeptide Y Y1-receptors in the rat nervous system with special reference to somatic receptors on small dorsal root ganglion neurons, Proc. Natl. Acad. Sci. USA 91 (1994) 11738-11742]. Three models of experimental lesions were studied: sciatic nerve transection, spinal cord transection and parietal cortex thermocoagulation. In each model, animals were divided in groups (n=2) and processed for indirect immunofluorescence at different time intervals up to 28 days post-lesion (PL) (see below). All three experimental lesions produced a very intense immunolabeling of fibers in the projection pathways of the lesioned structures, strongly reminding of Wallerian degeneration (WD). In the sciatic nerve, the staining first appeared on day 1 PL, was strongly increased on day 3 PL, then declined after 7 days and had almost completely disappeared after 14 days. In the CNS, the staining appeared later and was first observed on day 3 PL and remained for a longer period, thus showing different time courses in the brain and spinal cord as compared to the sciatic nerve. The labeling was completely abolished, both in the CNS and in the sciatic nerve, by pre-incubation of the Y1-R antibody with the immunogenic peptide at a dilution of 10-6 M. The appearance of the staining and its time course strongly suggest that the process was related to degenerating axons. Although the protein actually detected remains to be determined, it is suggested that the staining ability of this antibody could be used as a positive marker of axonal degeneration following experimental or naturally occurring lesions of the nervous system.