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Introduction: Energy-reducing spinal cord stimulation (SCS) approaches have the potential to impact patient experience with rechargeable and non-rechargeable SCS devices through reducing device recharge time or enhancing device longevity. This prospective, multi-center study evaluated the safety, effectiveness, and actual energy usage of differential target multiplexed (DTM) endurance therapy, a reduced energy DTM SCS derivative., Methods: Subjects who reported an overall pain visual analog score (VAS) of ≥6/10 cm and an Oswestry Disability Index score of 21-80 out of 100 at baseline with moderate to severe chronic, intractable back and/or leg pain were eligible. Evaluation visits occurred at 1, 3, 6, and 12 months post-device activation. The primary objective was to characterize change in overall pain intensity, as measured by VAS, from baseline to 3-month visit., Results: Fifty-seven subjects enrolled at 12 US sites from November 2020 through June 2021, 35 were implanted with a rechargeable SCS device, and 27 completed the 12-month visit. Subjects experienced a 50.4% mean reduction in overall pain from baseline at the 3-month follow-up that was sustained through 12 months. Additional outcomes including changes in overall, back, and leg pain intensity, quality of life, disability, therapy satisfaction, safety, and current battery usage are shown through 12-month follow-up., Conclusion: The use of DTM endurance SCS therapy in this study resulted in reductions in pain relief through 12 months, demonstrating that energy-reducing stimulation patterns can provide clinical benefit. Clinically effective, reduced energy SCS derivatives have the potential to impact patient experience through either reduced recharge requirements or increased device longevity., (© 2024 Medtronic and The Author(s). Pain Practice published by Wiley Periodicals LLC on behalf of World Institute of Pain.)

Objective: To investigate long-term explantation risks and causes for the explantation of neuromodulation devices for the treatment of chronic pain from different manufacturers., Methods: This retrospective analysis included patients implanted with a system for spinal cord stimulation (SCS) or dorsal root ganglion (DRG) stimulation at Sahlgrenska University Hospital between January 2012 and December 2022. Patient characteristics, explantation rates and causes for explantation were obtained by reviewing medical records., Results: In total, 400 patients were included in the study. Including all manufacturers, the cumulative explantation risk for any reason was 17%, 23% and 38% at 3, 5 and 10 years, respectively. Explantation risk due to diminished pain relief at the same intervals was 10%, 14% and 23%. A subgroup comparison of 5-year explantation risk using Kaplan-Meier analysis did not show a statistically significant difference between the manufacturers. In multivariable Cox regression analyses, there was no difference in explantation risk for any reason, but for explantation due to diminished pain relief, a higher risk was noted for Medtronic (preferably older types of SCS devices) and DRG stimulation. No other predictive factor for explantation was found., Conclusions: Although SCS and DRG stimulation are well-established and safe treatments for chronic pain, the long-term explantation risk remains high. The difference between manufacturers highlights the importance of technological evolution for improving therapy outcomes. Increased stringency in patient selection and follow-up strategies, as well as further development of device hardware and software technology for increased longevity, could possibly reduce long-term explantation risks., Competing Interests: Competing interests: KG has received lecture fees from Boston and Medtronic and has participated in advisory boards for Medtronic. None of these activities were related to the work presented in this paper. All other authors have no conflicts of interest to disclose., (© American Society of Regional Anesthesia & Pain Medicine 2024. Re-use permitted under CC BY. Published by BMJ.)

Objectives: Spinal cord stimulation (SCS) is a surgical treatment for severe, chronic, neuropathic pain. It is based on one to two lead(s) implanted in the epidural space, stimulating the dorsal column. It has long been assumed that when deactivating SCS, there is a variable interval before the patient perceives the return of the pain, a phenomenon often termed echo or carryover effect. Although the carryover effect has been problematized as a source of error in crossover studies, no experimental investigation of the effect has been published. This open, prospective, international multicenter study aimed to systematically document, quantify, and investigate the carryover effect in SCS., Materials and Methods: Eligible patients with a beneficial effect from their SCS treatment were instructed to deactivate their SCS device in a home setting and to reactivate it when their pain returned. The primary outcome was duration of carryover time defined as the time interval from deactivation to reactivation. Central clinical parameters (age, sex, indication for SCS, SCS treatment details, pain score) were registered and correlated with carryover time using nonparametric tests (Mann-Whitney/Kruskal-Wallis) for categorical data and linear regression for continuous data., Results: In total, 158 patients were included in the analyses. A median carryover time of five hours was found (interquartile range 2.5;21 hours). Back pain as primary indication for SCS, high-frequency stimulation, and higher pain score at the time of deactivation were correlated with longer carryover time., Conclusions: This study confirms the existence of the carryover effect and indicates a remarkably high degree of interindividual variation. The results suggest that the magnitude of carryover may be correlated to the nature of the pain condition and possibly stimulation paradigms., Clinical Trial Registration: The Clinicaltrials.gov registration number for the study is NCT03386058., Competing Interests: Conflict of Interest Bart Billet serves as a consultant for Abbott, Saluda, Bioelectronics, and Medtronic. Helga Angela Gulisano has received lecture fees from Medtronic. Jens Christian Hedemann Sørensen has received consulting fees from Novo Nordic and has a patent application for wireless brain-computer interface and stock options with Cenexum ApS and Neurizon ApS. Kaare Meier has received speaker’s fees from Abbott and has coownership of data base company Neurizon. Kliment Gatzinsky has received honoraria from Boston Scientific for lectures and serves on the advisory boards for Medtronic and Boston Scientific. Thomas Ruland reports consulting fees from Abbott. The remaining authors report no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Glioblastoma multiforme (GBM) is the most common and aggressive brain tumor in adults and is highly resistant to chemo- and radiotherapies. GBM has been associated with alterations in lipid contents, but lipid metabolism reprogramming in tumor cells is not fully elucidated. One of the key hurdles is to localize the lipid species that are correlated with tumor growth and invasion. A better understanding of the localization of abnormal lipid metabolism and its vulnerabilities may open up to novel therapeutic approaches. Here, we use time-of-flight secondary ion mass spectrometry (ToF-SIMS) to spatially probe the lipid composition in a GBM biopsy from two regions with different histopathologies: one region with most cells of uniform size and shape, the homogeneous part, and the other with cells showing a great variation in size and shape, the heterogeneous part. Our results reveal elevated levels of cholesterol, diacylglycerols, and some phosphatidylethanolamine in the homogeneous part, while the heterogeneous part was dominated by a variety of fatty acids, phosphatidylcholine, and phosphatidylinositol species. We also observed a high expression of cholesterol in the homogeneous tumor region to be associated with large cells but not with macrophages. Our findings suggest that ToF-SIMS can distinguish in lipid distribution between parts within a human GBM tumor, which can be linked to different molecular mechanisms.

Aim: The availability of long-term (>2 years) safety outcomes of spinal cord stimulation (SCS) remains limited. We evaluated safety in a global SCS registry for chronic pain. Methods: Participants were prospectively enrolled globally at 79 implanting centers and followed out to 3 years after device implantation. Results: Of 1881 participants enrolled, 1289 received a permanent SCS implant (1776 completed trial). The annualized rate of device explant was 3.5% (all causes), and 1.1% due to inadequate pain relief. Total incidence of device explantation >3 years was 7.6% (n = 98). Of these, 32 subjects (2.5%) indicated inadequate pain relief as cause for removal. Implant site infection (11 events) was the most common device-related serious adverse event (<1%). Conclusion: This prospective, global, real-world study demonstrates a high-level of safety for SCS with low rate of explant/serious adverse events. Clinical Trial Registration : NCT01719055 (ClinicalTrials.gov).

Objectives: To support rational decision-making on spinal cord stimulation (SCS), a European expert panel developed an educational e-health tool using the RAND/University of California at Los Angeles Appropriateness Method. This retrospective study aimed to determine the applicability and validity of the tool using data from patients for whom SCS had been considered., Materials and Methods: A total of 12 European implant centers retrieved data from 25 to 50 consecutive patients for whom SCS was considered in 2018-2019. For each patient, data were captured on the clinical and psychosocial variables included in the e-health tool, center decisions on SCS, and patient outcomes. Patient outcomes included global perception of effect by the patient and observer, and pain reduction (numeric pain rating scale) at six-month follow-up., Results: In total, 483 patients were included, of whom 133 received a direct implant, 258 received an implant after a positive trial, 32 had a negative trial, and 60 did not receive SCS for reasons other than a negative trial. The most frequent indication was persistent spinal pain syndrome type 1 and type 2 (74%), followed by neuropathic pain syndromes (13%), complex regional pain syndrome (12%), and ischemic pain syndromes (0.8%). Data on the clinical and psychosocial variables were complete for 95% and 93% of patients, respectively, and missing data did not have a significant impact on the study outcomes. In patients who had received SCS, panel recommendations were significantly associated with patient outcomes (p < 0.001 for all measures). Substantial improvement ranged from 25% if the e-health tool outcome was "not recommended" to 83% if SCS was "strongly recommended". In patients who underwent a trial (N = 290), there was 3% of trial failure when SCS was "strongly recommended" vs 46% when SCS was "not recommended"., Conclusions: Retrospective application of the e-health tool on patient data showed a strong relationship between the panel recommendations and both SCS trial results and treatment outcomes., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: A previously developed educational e-health tool considers both clinical and psychosocial factors when selecting patients with chronic pain for spinal cord stimulation (SCS). The validity of the composite recommendations was evaluated in a retrospective study, demonstrating a strong relationship with patient outcomes after SCS., Methods: An additional retrospective analysis was performed to determine the added value of a psychosocial evaluation as part of the decision-making process on SCS. Data concerned 482 patients who were considered for SCS in 2018-2019. The analysis focused on the relationship between the different layers of the tool recommendations (clinical, psychosocial, composite) with trial results and patient outcomes at 6 months after SCS. Of the initial study population, 381 patients underwent SCS and had follow-up data on at least one of three pain-related outcome measures., Results: Pain improvement was observed in 76% of the patients for whom SCS was strongly recommended based on merely the clinical aspects. This percentage varied by the level of psychosocial problems and ranged from 86% in patients without any compromising psychosocial factors to 60% in those with severe problems. Similarly, the severity of psychosocial problems affected trial results in patients for whom SCS was either recommended or strongly recommended., Conclusions: The strong relationship between psychosocial factors embedded in the SCS e-health tool and patient outcomes supports an integrated and multidisciplinary approach in the selection of patients for SCS. The educational e-health tool, combining both clinical and psychosocial aspects, is believed to be helpful for further education and implementation of this approach., Significance Statement: This study confirms the relevance of the psychosocial factors embedded in the educational SCS e-health tool (https://scstool.org/). The strong relationship between the severity of psychosocial factors with patient outcomes supports conducting a comprehensive psychological and behavioural assessment when determining the eligibility of patients for SCS., (© 2022 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC ®.)

Introduction: The International Neuromodulation Society convened a multispecialty group of physicians based on expertise with international representation to establish evidence-based guidance on the use of neurostimulation in the cervical region to improve outcomes. This Neurostimulation Appropriateness Consensus Committee (NACC) project intends to provide evidence-based guidance for an often-overlooked area of neurostimulation practice., Materials and Methods: Authors were chosen based upon their clinical expertise, familiarity with the peer-reviewed literature, research productivity, and contributions to the neuromodulation literature. Section leaders supervised literature searches of MEDLINE, BioMed Central, Current Contents Connect, Embase, International Pharmaceutical Abstracts, Web of Science, Google Scholar, and PubMed from 2017 (when NACC last published guidelines) to the present. Identified studies were graded using the US Preventive Services Task Force criteria for evidence and certainty of net benefit. Recommendations are based on the strength of evidence or consensus when evidence was scant., Results: The NACC examined the published literature and established evidence- and consensus-based recommendations to guide best practices. Additional guidance will occur as new evidence is developed in future iterations of this process., Conclusions: The NACC recommends best practices regarding the use of cervical neuromodulation to improve safety and efficacy. The evidence- and consensus-based recommendations should be utilized as a guide to assist decision making when clinically appropriate., (Copyright © 2021 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

Objectives: Repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex (M1) with frequencies 5-20 Hz is an expanding non-invasive treatment for chronic neuropathic pain (NP). Outcome data, however, show considerable inhomogeneity with concern to the levels of effect due to the great diversity of treated conditions. The aim of this review was to survey the literature regarding the efficacy and safety of M1 rTMS, and the accuracy to predict a positive response to epidural motor cortex stimulation (MCS) which is supposed to give a more longstanding pain relief., Methods: A systematic literature search was conducted up to June 2019 in accordance with the PRISMA guidelines. We used the PICO Model to define two specific clinical questions: (1) Does rTMS of M1 relieve NP better than sham treatment? (2) Can the response to rTMS be used to predict the effect of epidural MCS? After article selection, data extraction, and study quality assessment, the certainty of evidence of treatment effect was defined using the GRADE system., Results: Data on 5-20 Hz (high-frequency) rTMS vs. sham was extracted from 24 blinded randomised controlled trials which were of varying quality, investigated highly heterogeneous pain conditions, and used excessively variable stimulation parameters. The difference in pain relief between active and sham stimulation was statistically significant in 9 of 11 studies using single-session rTMS, and in 9 of 13 studies using multiple sessions. Baseline data could be extracted from 6 single and 12 multiple session trials with a weighted mean pain reduction induced by active rTMS, compared to baseline, of -19% for single sessions, -32% for multiple sessions with follow-up <30 days, and -24% for multiple sessions with follow-up ≥30 days after the last stimulation session. For single sessions the weighted mean difference in pain reduction between active rTMS and sham was 15 percentage points, for multiple sessions the difference was 22 percentage points for follow-ups <30 days, and 15 percentage points for follow-ups ≥30 days. Four studies reported data that could be used to evaluate the accuracy of rTMS to predict response to MCS, showing a specificity of 60-100%, and a positive predictive value of 75-100%. No serious adverse events were reported., Conclusions: rTMS targeting M1 can result in significant reduction of chronic NP which, however, is transient and shows a great heterogeneity between studies; very low certainty of evidence for single sessions and low for multiple sessions. Multiple sessions of rTMS can maintain a more longstanding effect. rTMS seems to be a fairly good predictor of a positive response to epidural MCS and may be used to select patients for implantation of permanent epidural electrodes. More studies are needed to manifest the use of rTMS for this purpose. Pain relief outcomes in a longer perspective, and outcome variables other than pain reduction need to be addressed more consistently in future studies to consolidate the applicability of rTMS in routine clinical practice., (© 2020 Kliment Gatzinsky et al., published by De Gruyter, Berlin/Boston.)

Background: Spinal cord stimulation (SCS) is an established treatment for chronic neuropathic, neuropathic-like and ischaemic pain. However, the heterogeneity of patients in daily clinical practice makes it often challenging to determine which patients are eligible for this treatment, resulting in undesirable practice variations. This study aimed to establish patient-specific recommendations for referral and selection of SCS in chronic pain., Methods: A multidisciplinary European panel used the RAND/UCLA Appropriateness Method (RUAM) to assess the appropriateness of (referral for) SCS for 386 clinical scenarios in four pain areas: chronic low back pain and/or leg pain, complex regional pain syndrome, neuropathic pain syndromes and ischaemic pain syndromes. In addition, the panel identified a set of psychosocial factors that are relevant to the decision for SCS treatment., Results: Appropriateness of SCS was strongly determined by the neuropathic or neuropathic-like pain component, location and spread of pain, anatomic abnormalities and previous response to therapies targeting pain processing (e.g. nerve block). Psychosocial factors considered relevant for SCS selection were as follows: lack of engagement, dysfunctional coping, unrealistic expectations, inadequate daily activity level, problematic social support, secondary gain, psychological distress and unwillingness to reduce high-dose opioids. An educational e-health tool was developed that combines clinical and psychosocial factors into an advice on referral/selection for SCS., Conclusions: The RUAM was useful to establish a consensus on patient-specific criteria for referral/selection for SCS in chronic pain. The e-health tool may help physicians learn to apply an integrated approach of clinical and psychosocial factors., Significance: Determining the eligibility of SCS in patients with chronic pain requires careful consideration of a variety of clinical and psychosocial factors. Using a systematic approach to combine evidence from clinical studies and expert opinion, a multidisciplinary European expert panel developed detailed recommendations to support appropriate referral and selection for SCS in chronic pain. These recommendations are available as an educational e-health tool (https://www.scstool.org/)., (© 2020 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC®.)

Background: Control of intracranial pressure (ICP) is a key element in neurointensive care for directing treatment decisions in patients with severe traumatic brain injury (TBI). The anti-inflammatory protein antisecretory factor (AF) has been demonstrated to reduce experimentally induced high ICP in animal models. This report describes the first steps to investigate the uptake, safety, and influence of AF for reduction of elevated ICP in patients with TBI in a clinical setting., Method: Four patients with severe TBI (Glasgow Coma Scale < 9) that required neurointensive care with ICP monitoring due to signs of refractory intracranial hypertension were investigated. One hundred milliliters of Salovum®, a commercially available egg yolk powder with high contents of AF peptides, was administrated either via nasogastric (patients 1 and 2) or rectal tube (patients 2, 3, and 4) every 8 h for 2 to 3 days as a supplement to the conventional neurointensive care. ICP was registered continuously. Plasma levels of AF were measured by enzyme-linked immunosorbent assay (ELISA) to confirm that Salovum® was absorbed appropriately into the bloodstream., Results: In the first two patients, we observed that when delivered by the nasogastric route, there was an accumulation of the Salovum® solution in the stomach with difficulties to control ICP due to impaired gastric emptying. Therefore, we tested to administer Salovum® rectally. In the third and fourth patients, who both showed radiological signs of extensive brain edema, ICP could be controlled during the course of rectal administration of Salovum®. The ICP reduction was statistically significant and was accompanied by an increase in blood levels of AF. No adverse events that could be attributed to AF treatment or the rectal approach for Salovum® administration were observed., Conclusions: The outcomes suggest that AF can act as a suppressor of high ICP induced by traumatic brain edema. Use of AF may offer a new therapeutic option for targeting cerebral edema in clinical practice.

Failed back surgery syndrome (FBSS) is a major, worldwide health problem that generates considerable expense for healthcare systems. A number of controversial issues concerning the management of FBSS are regularly debated, but no clear consensus has been reached. This pitfall is the result of lack of a standardized care pathway due to insufficient characterization of underlying pathophysiological mechanisms, which are essential to identify in order to offer appropriate treatment, and the paucity of evidence of treatment outcomes. In an attempt to address the challenges and barriers in the clinical management of FBSS, an international panel of physicians with a special interest in FBSS established the Chronic Back and Leg Pain (CBLP) Network with the primary intention to provide recommendations through consensus on how to optimize outcomes. In the first of a series of two papers, a definition of FBSS was delineated with specification of criteria for patient assessment and identification of appropriate evaluation tools in order to choose the right treatment options. In this second paper, we present a proposal of a standardized care pathway aiming to guide clinicians in their decision-making on how to optimize their management of FBSS patients. The utilization of a multidisciplinary approach is emphasized to ensure that care is provided in a uniform manner to reduce variation in practice and improve patient outcomes.

Objective: To evaluate the effectiveness and safety of percutaneous octapolar (8-contact) leads in spinal cord stimulation (SCS) treatment of failed back surgery syndrome (FBSS) patients who have not reached their therapy goals with other treatment interventions., Methods: Our prospective, multicenter, open-label, nonrandomized study included 93 patients ≥ 18 years of age suffering from chronic (≥ 6 months), intractable pain predominantly in the legs. Patients implanted with octapolar lead(s) and a neurostimulator after a successful test trial were followed for 12 months. Patients provided self-reported data on change in visual analog scale (VAS) score for leg pain (primary outcome) and low back pain, quality of life (EuroQol 5 dimensions [EQ-5D] index), sleep, medication use, and paresthesia coverage (secondary outcomes). Adverse events and preferred stimulation settings were documented., Results: Eighty-one (87%) patients had a successful SCS trial. Patients reported significantly improved leg pain relief; average VAS score was 72 ± 17 prior to SCS treatment and 32 ± 24 at 12 months (P < 0.001). Significant decrease in back pain (P < 0.001), improvement in quality of life (P < 0.001), and improvement in sleep (P < 0.05) was observed. Sixty-three percent and 40% of patients were responders (≥ 50% pain reduction) on leg and back pain, respectively, after 12 months. A decrease in medication use was seen for antidepressants and anticonvulsants. Eighty-eight percent of the patients managed with 1 or 2 programs for optimal effect and paresthesia coverage. Twenty-five SCS-related adverse events were registered in 22 patients (24%). Surgical revision due to lead displacement or dysfunction was needed in 6 (6%) of the patients., Conclusions: Use of percutaneous octapolar SCS leads gives significant long-term pain relief and improvement in quality of life and sleep in FBSS patients. The outcomes are better than reported on 4-contact leads and indicate that the progress in SCS technology that has taken place during the past decade correlates with therapy improvements., (© 2016 World Institute of Pain.)

Background: AF-16 is a 16-amino-acid-long peptide derived from the amino-terminal part of the endogenous protein, antisecretory factor (AF). AF-16 in vivo has been shown to regulate dysfunctions in the water and ion transport system under various pathological conditions and also to counteract experimentally increased tissue pressure., Methods: Rats were subjected to a cryogenic brain injury in order to increase the intracranial pressure (ICP). The distribution of AF-16 in blood and CSF after intravenous or intranasal administration was determined in injured and control rats. ICP was monitored in freely moving, awake rats, by means of an epidural pressure transducer catheter connected to a wireless device placed subcutaneously on the skull. The continuous ICP registrations were achieved by means of telemetry., Results: Intranasal administration of AF-16 resulted in a significantly higher CSF concentrations of AF-16 in injured than in control rats, 1.3 versus 0.6 ng/ml, whereas no difference between injured and control rats was seen when AF-16 was given intravenously. Rats subjected to cryogenic brain injury developed gradually increasing ICP levels. Intranasal administration of AF-16 suppressed the increased ICP to normal values within 30 min., Conclusion: Optimal AF-16 concentrations in CSF are achieved after intranasal administration in rats subjected to a cryogenic brain injury. The ability of AF-16 to suppress an increased ICP was manifested.

Introduction: The Neuromodulation Appropriateness Consensus Committee (NACC) of the International Neuromodulation Society (INS) evaluated evidence regarding the safety and efficacy of neurostimulation to treat chronic pain, chronic critical limb ischemia, and refractory angina and recommended appropriate clinical applications., Methods: The NACC used literature reviews, expert opinion, clinical experience, and individual research. Authors consulted the Practice Parameters for the Use of Spinal Cord Stimulation in the Treatment of Neuropathic Pain (2006), systematic reviews (1984 to 2013), and prospective and randomized controlled trials (2005 to 2013) identified through PubMed, EMBASE, and Google Scholar., Results: Neurostimulation is relatively safe because of its minimally invasive and reversible characteristics. Comparison with medical management is difficult, as patients considered for neurostimulation have failed conservative management. Unlike alternative therapies, neurostimulation is not associated with medication-related side effects and has enduring effect. Device-related complications are not uncommon; however, the incidence is becoming less frequent as technology progresses and surgical skills improve. Randomized controlled studies support the efficacy of spinal cord stimulation in treating failed back surgery syndrome and complex regional pain syndrome. Similar studies of neurostimulation for peripheral neuropathic pain, postamputation pain, postherpetic neuralgia, and other causes of nerve injury are needed. International guidelines recommend spinal cord stimulation to treat refractory angina; other indications, such as congestive heart failure, are being investigated., Conclusions: Appropriate neurostimulation is safe and effective in some chronic pain conditions. Technological refinements and clinical evidence will continue to expand its use. The NACC seeks to facilitate the efficacy and safety of neurostimulation., (© 2014 International Neuromodulation Society.)

Intracranial hypertension develops after, for example, trauma, stroke and brain inflammation, and contributes to increased morbidity, mortality, and persistent neuropsychiatric sequelae. Nonsurgical therapy offers limited relief. We investigated whether the peptide AF-16 and the endogenous protein Antisecretory Factor (AF) counteracted abnormal fluid transfer by cells, and lowered raised intracranial pressure (ICP). Adult rats, infected with an encephalitogenic Herpes simplex virus (HSV-1), developed after 5 days' sickness of increasing severity. AF-16 rescued all rats while vehicle treatment only saved 20%. AF-16 from day 4 reduced the ICP in HSV-1-infected rats from 30.7 to 14.6 mmHg and all survived without sequelae. A standardised closed head brain injury in rats raised the ICP. Continuous and intermittent AF-16 kept ICP at an almost normal level. A single dose of AF-16 maintained the raised ICP after a TBI lowered during 3-9 h. The AF protein, enriched in egg yolk, similarly lowered the post-traumatically raised ICP in rats. AF-16 also lowered the ICP in rabbits with diffuse brain injury. We conclude that the peptide AF-16 and the AF protein offer new approaches to treat raised ICP with no side effects.

Background: The high interstitial fluid pressure (IFP) in solid tumors restricts the access to nutrients, oxygen and drugs., Material and Methods: We investigated the ability of the peptide AF-16, involved in water and ion transfer through cell membranes, to lower the IFP in two different solid rat mammary tumors, one chemically induced, slowly growing, and the other transplantable, and rapidly progressing having high cellularity. AF-16 was administered either in the tumor capsule, intranasally or intravenously. The IFP was measured by a miniature fiber optic device., Results: AF-16 significantly lowered the IFP in both the slowly and the rapidly progressing tumors, whether administrated locally or systemically. The AF-16 induced IFP reduction was maximal after 90 min, lasted at least 3 h, and returned to pretreatment levels in less than 24 h. Topical AF-16 transiently reduced the IFP in the DMBA tumors from 17.7 ± 4.2 mmHg to 8.6 ± 2.1 mmHg., Conclusion: We conclude that AF-16 transiently and reversibly lowered the high IFP in solid tumors during a few hours, which might translate into improved therapeutic efficacy.

Apoptosis-related mechanisms are important in the pathophysiology of hypoxic-ischemic injury in the neonatal brain. Caspases are the major executioners of apoptosis, but there are a number of upstream players that influence the cell death pathways. The Bcl-2 family proteins are important modulators of mitochondrial permeability, working either to promote or prevent apoptosis. In this study we focused on the anti-apoptotic Bcl-2 protein after neonatal cerebral hypoxia-ischemia (HI) in 8-day-old rats. Bcl-2 translocated to nuclei and accumulated there over the first 24h of reperfusion after HI, as judged by immunohistochemistry and immuno-electron microscopy. We also found that the total level of Bcl-2 decreased after HI in vivo and after ionophore challenge in cultured human neuroblastoma (IMR-32) cells in vitro. Furthermore, the Bcl-2 reduction was calpain-dependent, because it could be prevented by the calpain inhibitor CX295 both in vivo and in vitro, suggesting cross-talk between excitotoxic and apoptotic mechanisms., (Copyright 2009 Elsevier Inc. All rights reserved.)

The aim of this study was to investigate the potential ability of Schwann cells to sequester axonally transported material via so called axon-Schwann cell networks (ASNs). These are entities consisting of sheets of Schwann cell adaxonal plasma membrane that invade the axon and segregate portions of axoplasm in paranodes of large myelinated mammalian nerve fibres. Rat hindlimb alpha-motor axons were examined in the L4-S1 ventral roots using light/fluorescence, confocal laser, and electron microscopy for detection of retrogradely transported red-fluorescent latex nanospheres taken up at a sciatic nerve crush, and intramuscularly injected horseradish peroxidase endocytosed by intact synaptic terminals. Survival times after tracer administration ranged from 27 hours to 4 weeks. During their retrograde transport toward the motor neuron perikarya, organelles carrying nanospheres/peroxidase accumulated at nodes of Ranvier, where they often appeared in close association with the paranodal myelin sheath. Serial section electron microscopy showed that many of the tracer-containing bodies were situated within ASN complexes, thereby being segregated from the main axon. Four weeks after nanosphere administration, several node-paranode regions still showed ASN-associated aggregations of spheres, some of which were situated in the adaxonal Schwann cell cytoplasm. The data establish the ability of Schwann cells to segregate material from motor axons with intact myelin sheaths, using the ASN as mediator. Taken together with our earlier observations that ASNs in alpha-motor axons are also rich in lysosomes, this process would allow a local elimination and secluded degradation of retrogradely transported foreign substances and degenerate organelles before reaching the motor neuron perikarya. In addition, ASNs may serve as sites for disposal of indigestable material.

Lysosomes play an important role for the maintenance of a normal internal milieu in the cell. In neurons lysosomes are abundant in the perikaryon and dendrites, but have been observed to a much lesser degree in the axon. A general opinion has therefore formed among biologists interested in the nervous system that axonal material destined for degradation has to be transported to the neuronal perikaryon. The lysosomal occurrence and distribution at the level of the axon have, however, not been investigated systematically. This review summarizes recent morphological data based on light, fluorescence, and electron microscopic observations in peripheral nerve fibres of cats and rats providing evidence that node-paranode regions mainly along the peripheral parts of alpha motor axons, where the axon cross-section area decreases to 10-25% of internodal values, can control the passage and participate in a lysosome-mediated degradation of axonally transported materials directed towards the neuronal perikaryon. An important role is played by the paranodal axon-Schwann cell networks, which are lysosome-rich entities whereby the Schwann cells can sequester material from the axoplasm of large myelinated peripheral nerve fibres. The networks also seem to serve as depots for axonal waste products. The degradative ability of node-paranode regions in alpha-motor axons could be of some significance for the protection of the motor neuron perikarya from being flooded with and perhaps injured by indigestible materials as well as potentially deleterious, exogenous substances imbibed by the axon terminals in the muscle. A similar degradative capacity may not be needed in nerve fibres with synaptic terminals in the CNS where the local environment is regulated by the blood-brain barrier.

Horseradish peroxidase (HRP) was injected into the left dorsal column nuclei of adult cats. Large dorsal funiculi axons of the C3, C5, C8 and L7 segments were searched for HRP-activity after 12, 24, 36 and 48h using light and electron microscopy. Accumulations of intra-axonal HRP-positive bodies occurred at nodes of Ranvier in the C3-C8 segments at 12, 24 and 36h and in the L7 segments at 24, 36, and 48h. The accumulations of HRP in three spatio-temporally different consecutive patterns, noted earlier at nodes of Ranvier in the peripheral nervous system (PNS) portion of feline alpha motor axons for more than 70h after an intramuscular injection of the enzyme, were not observed in the present material. We suggest that the differences in the modes in which large PNS and CNS axons interact with retrogradely transported HRP are due to differences in the organization of the respective nodal regions. We also emphasize that endocytosis via axon terminals in the CNS normally represents uptake of material from an extracellular space which is controlled and protected by the blood-brain barrier. This is in contrast to endocytosis via axon terminals in a muscle, which represents uptake of material from an extracellular space openly exposed to influx of different substances from the blood stream.

The occurrence of acid phosphatase (AcPase)-positive bodies, i.e. lysosomes, in dorsal column and dorsal root axons of the spinal cord segments C8 and L7 in adult cats was analyzed by light and electron cytochemical methods after injection of horseradish peroxidase (HRP) in the dorsal column nuclei. Axonal lysosomes were, with few exceptions, concentrated at the nodes of Ranvier. We found no changes in nodal occurrence and distribution of lysosomes in axons of the HRP-injected sides, as compared to axons of the uninjected sides or of animals not exposed to HRP. Axonal lysosomes were very rare in the dorsal columns, where the frequency of nodes containing light microscopically detectable AcPase-positive bodies was 0-5% at the HRP-injected sides, 0-6% at the contralateral sides, and 0-3% in control animals. The corresponding values in the cervical and lumbar dorsal roots were 6-23%, 9-20%, 10-12% and 19-37%, 21-40%, 26-43%, respectively. In view of our recent observations in alpha-motor neurons, the results point at a noteworthy difference in local degradative ability between dorsal column axons and alpha-motor axons, the latter being able to accumulate intramuscularly injected and retrogradely transported HRP at their PNS nodes of Ranvier for 48-60 h, during which period the axoplasmic AcPase activity/concentration increases at some nodes. Such a degradative activity, which could protect the motor neurons by restricting axoplasmic transport of exogenous materials imbibed by their axon terminals outside the CNS, may not be of the same significance for neurons, e.g. dorsal root ganglion neurons, the axon terminals of which are located within the CNS.

The occurrence of acid phosphatase (AcPase)-positive bodies, i.e., lysosomes, in lumbosacral alpha-motor axons of kittens, 0-16 weeks of age, was analyzed by light and electron cytochemical methods under normal conditions and after intramuscular injection of horseradish peroxidase (HRP). Axonal lysosomes were rare early postnatally. In 3-week-old animals, a few AcPase-positive bodies appeared in the axoplasm at some nodes of Ranvier in the peripheral nervous system (PNS) and internodally in the intrafunicular motor axon parts within the central nervous system (CNS). From 6 weeks postnatally, a nodal concentration of AcPase-positive bodies was also noted in the CNS. The number of AcPase-positive bodies continued to increase gradually in the course of neuronal maturation. In 16-week-old animals, axonal AcPase activity was still at considerably lower levels than at adult stages. At all ages, acid hydrolase-containing organelles were most commonly found at ventral root nodes. After injection of HRP in the medial gastrocnemius muscle, accumulations of AcPase-positive bodies were seen in the axoplasm at some PNS nodes of the HRP-injected sides of kittens aged 8, 12, and 16 weeks. Incubation for demonstration of both HRP and AcPase activity showed that some organelles at HRP-transporting nodes contained both types of reaction product. The nodal AcPase activity in the intrafunicular, CNS parts of alpha-motor axons of the HRP-exposed sides did not differ from that of the contralateral, uninjected sides. In view of our previous observations in alpha-motor neurons of adult cats in which a lysosome-mediated degradation of axonally transported materials may take place at PNS nodes of Ranvier, the present study illuminates possible differences in the ability to interfere with axonal transport between developing and mature neurons. The infrequent presence of lysosomes in developing alpha-motor axons and the implied disability of their nodal regions to interfere with axonally transported constituents in a way similar to that seen in adult animals may be of significance in that trophic and chemical signals can pass unhindered between the periphery and perikaryon. However, this could also have negative consequences for the vulnerable immature neuron in that various materials retrieved at the axon terminals outside the CNS are permitted a more-or-less free access to the perikaryon.

The paranodal occurrence of axon-Schwann cell networks (ASNs), which are entities assumed to take part in the removal of degenerate axonal material, was examined quantitatively by electron microscopical serial section analysis in normal cat ventral and dorsal spinal roots. In nerve fibres greater than or equal to 10 microns in diameter 88% of the nodal regions in the ventral roots and 97% in the dorsal roots showed ASN complexes, which especially in the ventral roots often consisted of many segregated axoplasmic portions. The corresponding frequencies in fibres less than 10 microns were 28% and 62% in the ventral and the dorsal roots, respectively. ASN complexes were rare in fibres less than 5 microns. The results show that the ASN is a part of the normal paranodal architecture in large myelinated nerve fibres. The ASN occurrence seems to differ with neurone type.

The CNS-PNS (central nervous system-peripheral nervous system) transitional region of cranial and spinal nerve roots in some vertebrate species was analysed with respect to the occurrence and the distribution of myelinoid Marchi-positive bodies. Both cranial and spinal nerve roots contained more Marchi-positive bodies in their CNS than in their PNS segments. An accumulation of Marchi-positive bodies was usually noted just central to the CNS-PNS borderline. Comparisons between calibre spectra and Marchi index in the cat revealed a particularly high number of Marchi-positive bodies in nerve roots with a high content of myelinated fibres with diameters greater than or equal to 5 microns. Marchi-positive bodies were absent in CNS tissue lacking myelinated nerve fibres. CNS borderline internodes measuring between 200 and 300 microns in length were noted in fibres as thick as 15 microns in feline S1 ventral and dorsal roots. The general picture was similar in all analysed species. Noteworthy however, was the small difference in number of Marchi-positive bodies between CNS and PNS tissue in Xenopus. The chicken contained many myelinoid bodies of similar size and texture as the Marchi-positive bodies but without the Marchi-positive staining properties. The results show that normally occurring Marchi-positive bodies in the CNS are more numerous along paranodal segments than along mid-internodal segments of myelinated nerve fibres and thus support the hypothesis that Marchi-positive bodies are preferentially derived from paranodal myelin.