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The gastrointestinal (GI) tract redox environment, influenced by commensal microbiota and bacterial-derived metabolites, is crucial in shaping T-cell responses. Specifically, metabolites from gut microbiota (GM) exhibit robust anti-inflammatory effects, fostering the differentiation and regulation of CD8 + tissue-resident memory (TRM) cells, mucosal-associated invariant T (MAIT) cells, and stabilizing gut-resident Treg cells. Nitric oxide (NO), a pivotal redox mediator, emerges as a central regulator of T-cell functions and gut inflammation. NO impacts the composition of the gut microbiome, driving the differentiation of pro-inflammatory Th17 cells and exacerbating intestinal inflammation, and supports Treg expansion, showcasing its dual role in immune homeostasis. This review delves into the complex interplay between GI redox balance and GM metabolites, elucidating their profound impact on T-cell regulation. Additionally, it comprehensively emphasizes the critical role of GI redox, particularly reactive oxygen species (ROS) and NO, in shaping T-cell phenotype and functions. These insights offer valuable perspectives on disease mechanisms and potential therapeutic strategies for conditions associated with oxidative stress. Understanding the complex cross-talk between GI redox, GM metabolites, and T-cell responses provides valuable insights into potential therapeutic avenues for immune-mediated diseases, underscoring the significance of maintaining GI redox balance for optimal immune health., Competing Interests: Author SP is an employee of MLM Medical Labs, LLC. The remaining authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Prasad, Singh, Menge, Mohapatra, Kim, Helland, Singh and Singh.)

Background: While directionally rotating tumor-treating fields (TTF) therapy has garnered considerable clinical interest in recent years, there has been comparatively less focus on directionally non-rotating electric field therapy (dnEFT)., Methods: We explored dnEFT generated through customized electrodes as a glioblastoma therapy in in vitro and in vivo preclinical models. The effects of dnEFT on tumor apoptosis and microglia/macrophages in the tumor microenvironment were tested using flow-cytometric and qPCR assays., Results: In vitro, dnEFT generated using a clinical-grade spinal cord stimulator showed antineoplastic activity against independent glioblastoma cell lines. In support of the results obtained using the clinical-grade electrode, dnEFT delivered through a customized, 2-electrode array induced glioblastoma apoptosis. To characterize this effect in vivo, a custom-designed 4-electrode array was fabricated such that tumor cells can be implanted into murine cerebrum through a center channel equidistant from the electrodes. After implantation with this array and luciferase-expressing murine GL261 glioblastoma cells, mice were randomized to dnEFT or placebo. Relative to placebo-treated mice, dnEFT reduced tumor growth (measured by bioluminescence) and prolonged survival (median survival gain of 6.5 days). Analysis of brain sections following dnEFT showed a notable increase in the accumulation of peritumoral macrophage/microglia with increased expression of M1 genes (IFNγ, TNFα, and IL-6) and decreased expression of M2 genes (CD206, Arg, and IL-10) relative to placebo-treated tumors., Conclusions: Our results suggest therapeutic potential in glioblastoma for dnEFT delivered through implanted electrodes, supporting the development of a proof-of-principle clinical trial using commercially available deep brain stimulator electrodes., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Introduction: The introduction of successful neuromodulation strategies for managing chronic visceral pain lag behind what is now treatment of choice in refractory chronic back and extremity pain for many providers in the United States and Europe. Changes in public policy and monetary support to identify nonopioid treatments for chronic pain have sparked interest in alternative options. In this review, we discuss the scope of spinal cord stimulation (SCS) for visceral pain, its limitations, and the potential role for new intradural devices of the type that we are developing in our laboratories, which may be able to overcome existing challenges., Methods: A review of the available literature relevant to this topic was performed, with particular focus on the pertinent neuroanatomy and uses of spinal cord stimulation systems in the treatment of malignant and nonmalignant gastrointestinal, genitourinary, and chronic pelvic pain., Results: To date, there have been multiple off-label reports testing SCS for refractory gastrointestinal and genitourinary conditions. Though some findings have been favorable for these organs and systems, there is insufficient evidence to make this practice routine. The unique configuration and layout of the pelvic pain pathways may not be ideally treated using traditional SCS implantation techniques, and intradural stimulation may be a viable alternative., Conclusions: Despite the prevalence of visceral pain, the application of neuromodulation therapies, a standard approach for other painful conditions, has received far too little attention, despite promising outcomes from uncontrolled trials. Detailed descriptions of visceral pain pathways may offer several clues that could be used to implement devices tailored to this unique anatomy., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Study Design: Retrospective cohort study., Objective: To determine the impact of including C2 in posterior fusions on radiographic parameters of cervical alignment in cervical spondylotic myelopathy., Summary of Background Data: Despite the use of posterior instrumentation and arthrodesis after cervical laminectomy, loss of lordosis and the development of kyphosis are prevalent. Inadequate cervical lordosis and other measures of sagittal cervical alignment have been shown to correlate with disability, general health scores, and severity of myelopathy. The role of C2 in the posterior tension band, which maintains sagittal alignment, differs from the subaxial spine, as it is the insertion point for erector spinae muscles that play a critical role in maintaining posture., Patients and Methods: This study compares the radiographic outcomes of sagittal balance between 2 cohorts of patients who underwent posterior cervical decompression and fusion for cervical myelopathy over a 12-year period at a single institution. Demographic and surgical characteristics were collected using the electronic medical record of patients undergoing posterior cervical fusions (PCF) which included the axis [axial fusion (AF)] and those that were subaxial fusions (SAF). Radiographic measurements included preopertaive and postoperative C2-C7 lordosis (CL), C2-C7 sagittal vertical axis (SVA), and T1 slope (T1S)., Results: After review of the electronic medical records, 229 patients were identified as having PCF and decompression for treatment of myelopathy. One hundred sixty-seven patients had AF, whereas 62 had SAF. PCF resulted in loss of CL in both cohorts. Although there was no statistical difference in postoperative CL, there was a significant increase in SVA (P<0.001) and T1S (P<0.001) with AF., Conclusions: PCF often result in loss of lordosis. When compared with SAF, inclusion of C2 into the fusion construct may result in worsened sagittal balance, increasing the SVA and T1S.

Introduction: We are developing a novel intradural spinal cord stimulator for treatment of neuropathic pain and spasticity. A key feature is the means by which it seals the dura mater to prevent leakage of cerebrospinal fluid (CSF). We have built and employed a test rig that enables evaluation of candidate seal materials., Methods: To guide the design of the test rig, we reviewed the literature on neurosurgical durotomies. The test rig has a mock durotomy slot with a dural substitute serving as the surrogate dura mater and water as the CSF. The primary experimental goal was to evaluate the effectiveness of candidate gasket materials as seals against CSF leakage in an implanted prototype device, at both normal and super-physiologic pressures. A secondary goal was to measure the transmembrane flows in a representative dural substitute material, to establish its baseline aqueous transport properties., Results: The seals prevented leakage of water at the implantation site over periods of ≈ ten days, long enough for the scar tissue to form in the clinical situation. The seals also held at water pressure transients approaching 250 mm Hg. The residual volumetric flux of water through the dura substitute membrane (Durepair®) was δV T /A ≈ 0.24 mm 3 /min/cm 2 , consistent with expectations for transport through the porous membrane prior to closure and equalization of internal/external pressures., Conclusions: We have demonstrated the workability of obtaining robust seal against leakage at the implantation site of a novel intradural stimulator using a custom-designed test rig. Extension of the method to in vivo testing in a large animal model will be the next step., (© 2019 International Neuromodulation Society.)

Introduction: Contemporary approaches to surgical site infections have evolved significantly over the last several decades in response to the economic pressures of soaring health care costs and increasing patient expectations of safety. Neurosurgeons face multiple unique challenges when striving to avoid as well as manage surgical implant infections. The tissue compartment, organ system, or joint is characterized by biological factors and physical forces that may not be universally relevant. Such implants, once rare, are now routine. Although the prevention, diagnosis, and treatment of surgical site infections involving neural implants has advanced, guidelines are ever changing, and the incidence still exceeds acceptable levels. We assess the impact of these factors on a new class of implantable neuromodulation devices., Methods: The available evidence along with practice patterns were examined and organized to establish relevant groupings for continuing evaluation and to propose justifiable recommendations for the treatment of infections that might arise in the case of intradural spinal cord stimulators., Results: Few studies in the modern era have systematically evaluated preventive behaviors that were applied to intradural neural implants alone. We anticipate that future efforts will focus even more on the investigation of modifiable factors along a continuum from bacterially repellant implants to weight management. Early diagnosis could offer the best hope for device salvage but to date has been largely understudied., Conclusions: Historically, prevention is the cornerstone to infection mitigation. However, immediate diagnosis and hardware salvage have not received the attention deserved, and that approach may be especially important for intradural devices., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Study Design: A retrospective cohort study., Objective: The aim of this study was to identify advantages and disadvantages of the anterior and posterior approaches in the treatment of cervical stenosis and myelopathy., Summary of Background Data: Both anterior and posterior surgical approaches for cervical stenosis and myelopathy have been shown to result in improvement in health-related outcomes. Despite the evidence, controversy remains regarding the best approach to achieve decompression and correct deformity., Methods: We retrospectively reviewed patients with cervical stenosis and myelopathy who had undergone anterior cervical fusion and instrumentation (n = 38) or posterior cervical laminectomy and instrumentation (n = 51) with at least 6 months of follow-up. Plain radiographs, magnetic resonance imaging, and computed tomography scans, as well as health-related outcomes, including Visual Analog Scale for neck pain, Japanese Orthopedic Association score for myelopathy, Neck Disability Index, and Short Form-36 Health Survey, were collated before surgery and at follow-up (median 12.0 and 12.1 months for anterior and posterior group, respectively)., Results: Both anterior and posterior approaches were associated with significant improvements in all studied quality of life parameters with the exception of general health in the anterior group and energy and fatigue in the posterior group. In the anterior group, follow-up assessment revealed a significant increase in C2-7 lordosis. Both approaches were accompanied by significant increases in C2-7 sagittal balance [sagittal vertical axis (SVA)]. There were two complications in the anterior group and nine complications in the posterior group; the incidence of complications between the two groups was not significantly different., Conclusion: When the benefits of one approach over the other are not self-evident, the anterior approach is recommended, as it was associated with a shorter hospital stay and more successful restoration of cervical lordosis than posterior surgery., Level of Evidence: 3.

OBJECTIVEAdult spinal arachnoid cysts (SACs) are rare entities of indistinct etiology that present with pain or myelopathy. Diagnosis is made on imaging studies with varying degrees of specificity. In symptomatic cases, the standard treatment involves surgical exploration and relief of neural tissue compression. The aim of this study was to illustrate features of SACs in adults, surgical management, and outcomes.METHODSThe authors searched medical records for all SACs in adults in the 10-year period ending in December 2016. Radiology and pathology reports were reviewed to exclude other spine cystic disorders. Recurrent or previously treated patients were excluded. Demographic variables (age, sex) and clinical presentation (symptoms, duration, history of infection or trauma, and examination findings) were extracted. Radiological features were collected from radiology reports and direct interpretation of imaging studies. Operative reports and media were reviewed to accurately describe the surgical technique. Finally, patient-reported outcomes were collected at every clinic visit using the SF-36.RESULTSThe authors' search identified 22 patients with SACs (mean age at presentation 53.5 years). Seventeen patients were women, representing an almost 3:1 sex distribution. Symptoms comprised back pain (n = 16, 73%), weakness (n = 10, 45%), gait ataxia (n = 11, 50%), and sphincter dysfunction (n = 4, 18%). The mean duration of symptoms was 15 months. Seven patients (32%) exhibited signs of myelopathy. All patients underwent preoperative MRI; in addition, 6 underwent CT myelography. SACs were located in the thoracic spine (n = 17, 77%), and less commonly in the lumbar spine (n = 3, 14%) and cervical/cervicothoracolumbar region (n = 2, 9%). Based on imaging findings, the cysts were interpreted as intradural SACs (n = 11, 50%), extradural SACs (n = 6, 27%), or ventral spinal cord herniation (n = 2, 9%); findings in 3 patients (14%) were inconclusive. Nineteen patients underwent surgical treatment consisting of laminoplasty in addition to cyst resection (n = 13, 68%), ligation of the connecting pedicle (n = 4, 21%), or fenestration/marsupialization (n = 2, 11%). Postoperatively, patients were followed up for an average of 8.2 months (range 2-30 months). Postoperative MRI showed complete resolution of the SAC in 14 of 16 patients. Patient-reported outcomes showed improvement in SF-36 parameters. One patient suffered a delayed wound infection.CONCLUSIONSIn symptomatic patients with imaging findings suggestive of spinal arachnoid cyst, surgical exploration and complete resection is the treatment of choice. Treatment is usually well tolerated, carries low risks, and provides the best chances for optimal recovery.

We have studied the retrograde axonal transport of dopamine-beta-hydroxylase (DBH) with the aid of a new stop-flow technique. Rabbit sciatic nerves in vitro were incubated in chambers which exposed different regions to oxygenated physiological saline solution at different temperatures. These chambers contained no mechanical barriers that could generate local compression or anoxia. When the proximal halves of nerves were cooled to 2 degrees C while the distal halves were kept at 37 degrees C, a peak of DBH activity began to accumulate in the middle. Accumulation was detectable after 1.5 h of proximal cooling, and the amount of activity in the peak increased linearly with time for up to 4.5 h. The rate of this accumulation was only about 20% of the rate at which DBH activity accumulates proximal to locally cooled regions. Retrograde accumulation of DBH activity is not an artifact that depends upon the simple juxtaposition of cooled and warmed regions; it does not occur when nerves are locally warmed to 37 degrees C while being kept elsewhere at 2 degrees C. When nerves that had been proximally cooled for 3h were rewarmed, the accumulated DBH activity was asymmetrically displaced toward the proximal end. The migrating wave lacked a definite peak, but appeared as a shoulder with a well-defined front that moved steadily at about 12mm/h. We take this as direct evidence for retrograde axonal transport of DBH. The maximum velocity of this transport is very similar to the velocity of orthograde transport previously determined by stop-flow techniques.