The inactive X chromosome drives sex differences in microglial inflammatory activity in human glioblastoma.

Biological sex is an important risk factor in cancer, but the underlying cell types and mechanisms remain obscure. Since tumor development is regulated by the immune system, we hypothesize that sex-biased immune interactions underpin sex differences in cancer. The male-biased glioblastoma multiforme (GBM) is an aggressive and treatment-refractory tumor in urgent need of more innovative approaches, such as considering sex differences, to improve outcomes. GBM arises in the specialized brain immune environment dominated by microglia, so we explored sex differences in this immune cell type. We isolated adult human TAM-MGs (tumor-associated macrophages enriched for microglia) and control microglia and found sex-biased inflammatory signatures in GBM and lower-grade tumors associated with pro-tumorigenic activity in males and anti-tumorigenic activity in females. We demonstrated that genes expressed or modulated by the inactive X chromosome facilitate this bias. Together, our results implicate TAM-MGs, specifically their sex chromosomes, as drivers of male bias in GBM.

Addressing challenges for repairing adult spinal cord with insights from neonates.

Stem cell therapy has emerged as a promising area of scientific investigation, sparking considerable interest, especially in spinal cord injury (SCI). Sun et al.1 discover that the extracellular matrix (ECM) from the neonatal spinal cord transmits biochemical signals to endogenous axons, thus promoting axonal regeneration.

Traumatic Brain Injuries After Falls From Height vs Falls at the US-Mexico Border Wall.

This cohort study examines the incidence, severity, and mortality of fall-related injuries among migrants at the US-Mexico border in San Diego, California.

Novel Association of Blunt Cerebrovascular Injuries with the San Diego-Mexico Border Wall Height Extension.

BACKGROUND: The San Diego-Mexico border wall height extension is associated with increased traumatic injuries and related costs after wall falls. We report previous trends and a neurological injury type not previously associated with border falls: blunt cerebrovascular injuries (BCVIs). METHODS: In this retrospective cohort study, patients who presented to the UC San Diego Health Trauma Center for injuries from border wall falls from 2016 to 2021 were considered. Patients were included if they were admitted before (January 2016 to May 2018) or after (January 2020 to December 2021) the height extension period. Patient demographics, clinical data, and hospital stay data were compared. RESULTS: We identified 383 patients, 51 (68.6% male; mean age, 33.5 years) in the pre-height extension cohort and 332 (77.1% male; mean age, 31.5 years) in the post-height extension cohort. There were 0 and 5 BCVIs in the pre- and post-height extension groups, respectively. BCVIs were associated with increased injury severity scores (9.16 vs. 31.33; P < 0.001), longer intensive care unit lengths of stay (median, 0 days; [interquartile range (IQR), 0-3 days]; vs. median, 5 days [IQR, 2-21 days]; P = 0.022), and increased total hospital charges (median, $163,490 [IQR, $86,578-$282,036]; vs. median, $835,260 [IQR, $171,049-$1,933,996]; P = 0.048). Poisson modeling found BCVI admissions were 0.21 (95% confidence interval, 0.07-0.41; P = 0.042) per month higher after the height extension. CONCLUSIONS: We review the injuries correlating with the border wall extension and reveal an association with rare, potentially devastating BCVIs that were not seen before the border wall modifications. These BCVIs and associated morbidity shed light on the trauma increasingly found at the southern U.S. border, which could be informative for future infrastructure policy decisions.

Case report: Neuronal intranuclear inclusion disease presenting with acute encephalopathy.

Neuronal intranuclear inclusion disease (NIID), a neurodegenerative disease previously thought to be rare, is increasingly recognized despite heterogeneous clinical presentations. NIID is pathologically characterized by ubiquitin and p-62 positive intranuclear eosinophilic inclusions that affect multiple organ systems, including the brain, skin, and other tissues. Although the diagnosis of NIID is challenging due to phenotypic heterogeneity, a greater understanding of the clinical and imaging presentations can improve accurate and early diagnosis. Here, we present three cases of pathologically proven adult-onset NIID, all presenting with episodes of acute encephalopathy with protracted workups and lengthy time between symptom onset and diagnosis. Case 1 highlights challenges in the diagnosis of NIID when MRI does not reveal classic abnormalities and provides a striking example of hyperperfusion in the setting of acute encephalopathy, as well as unique pathology with neuronal central chromatolysis, which has not been previously described. Case 2 highlights the progression of MRI findings associated with multiple NIID-related encephalopathic episodes over an extended time period, as well as the utility of skin biopsy for antemortem diagnosis.

Utilizing Neuromodulation in the Treatment of Spinal Cord Injury: An Assessment of Clinical Trials from the National ClinicalTrials.gov Database.

OBJECTIVE: Spinal cord injury (SCI) is responsible for approximately 18,000 trauma cases each year in the United States, often resulting in debilitating motor and autonomic disability. Neuromodulation is a rapidly growing field of interest in the neurosurgical field and has additionally shown promise in the treatment of SCI. This review characterizes all clinical trials to date studying neuromodulation for the treatment of SCI. METHODS: The ClinicalTrials.gov database was queried using the search terms "neuromodulation" and "spinal cord injury" on ClinicalTrials.gov. Trials were excluded if they were not yet recruiting, suspended, terminated early, or of unknown status. RESULTS: In total, 33 clinical trials were included in this study. Of the 33 trials, 8 were completed and 1 had published results. Most trials studied deficits of motor function (60%) and bladder control (37%). Fourteen studies (42.4%) utilized transcutaneous spinal stimulation, 7 (21.2%) utilized epidural electrical stimulation, and 6 (18.2%) utilized tibial nerve stimulation. There was an uptrend of clinical trials studying SCI indexed on PubMed, which was comparable to the increased number of publications indexed overall (Pearson correlation, P < 0.001). Of these, only 1 study regarding home tibial nerve stimulation for neurogenic bladder had published data, which was performed with no adverse events. CONCLUSIONS: Neuromodulation in SCI studies currently assess transcutaneous spinal stimulation, epidural electrical stimulation, and tibial nerve stimulation. There is currently 1 completed study suggesting feasibility of home neuromodulation techniques without adverse events. The results of trials that will be completed in the next few years will help dictate the potential of neuromodulation as a treatment for SCI.

Expandable Sendai-Virus-Reprogrammed Human iPSC-Neuronal Precursors: In Vivo Post-Grafting Safety Characterization in Rats and Adult Pig.

One of the challenges in clinical translation of cell-replacement therapies is the definition of optimal cell generation and storage/recovery protocols which would permit a rapid preparation of cell-treatment products for patient administration. Besides, the availability of injection devices that are simple to use is critical for potential future dissemination of any spinally targeted cell-replacement therapy into general medical practice. Here, we compared the engraftment properties of established human-induced pluripotent stem cells (hiPSCs)-derived neural precursor cell (NPCs) line once cells were harvested fresh from the cell culture or previously frozen and then grafted into striata or spinal cord of the immunodeficient rat. A newly developed human spinal injection device equipped with a spinal cord pulsation-cancelation magnetic needle was also tested for its safety in an adult immunosuppressed pig. Previously frozen NPCs showed similar post-grafting survival and differentiation profile as was seen for freshly harvested cells. Testing of human injection device showed acceptable safety with no detectable surgical procedure or spinal NPCs injection-related side effects.

Derivation of Sendai-Virus-Reprogrammed Human iPSCs-Neuronal Precursors: In Vitro and In Vivo Post-grafting Safety Characterization.

The critical requirements in developing clinical-grade human-induced pluripotent stem cells-derived neural precursors (hiPSCs-NPCs) are defined by expandability, genetic stability, predictable in vivo post-grafting differentiation, and acceptable safety profile. Here, we report on the use of manual-selection protocol for generating expandable and stable human NPCs from induced pluripotent stem cells. The hiPSCs were generated by the reprogramming of peripheral blood mononuclear cells with Sendai-virus (SeV) vector encoding Yamanaka factors. After induction of neural rosettes, morphologically defined NPC colonies were manually harvested, re-plated, and expanded for up to 20 passages. Established NPCs showed normal karyotype, expression of typical NPCs markers at the proliferative stage, and ability to generate functional, calcium oscillating GABAergic or glutamatergic neurons after in vitro differentiation. Grafted NPCs into the striatum or spinal cord of immunodeficient rats showed progressive maturation and expression of early and late human-specific neuronal and glial markers at 2 or 6 months post-grafting. No tumor formation was seen in NPCs-grafted brain or spinal cord samples. These data demonstrate the effective use of in vitro manual-selection protocol to generate safe and expandable NPCs from hiPSCs cells. This protocol has the potential to be used to generate GMP (Good Manufacturing Practice)-grade NPCs from hiPSCs for future clinical use.

Characterizing the frequency, morbidity, and types of traumatic brain injuries after the Mexico-San Diego border wall extension: a retrospective cohort review.

OBJECTIVE: The aim of this study was to investigate the impact of the US-Mexico border wall height extension on traumatic brain injuries (TBIs) and related costs. METHODS: In this retrospective cohort study, patients who presented to the UC San Diego Health Trauma Center for injuries from falling at the border wall between 2016 and 2021 were considered. Patients in the pre-height extension period (January 2016-May 2018) were compared with those in the post-height extension period (January 2020-December 2021). Demographic characteristics, clinical data, and hospital charges were analyzed. RESULTS: A total of 383 patients were identified: 51 (0 TBIs, 68.6% male) in the pre-height extension cohort and 332 (14 TBIs, 77.1% male) in the post-height extension cohort, with mean ages of 33.5 and 31.5 years, respectively. There was an increase in the average number of TBIs per month (0.0 to 0.34) and operative TBIs per month (0.0 to 0.12). TBIs were associated with increased Injury Severity Score (8.8 vs 24.2, p < 0.001), median (IQR) hospital length of stay (5.0 [2-11] vs 8.5 [4-45] days, p = 0.03), and median (IQR) hospital charges ($163,490 [$86,369-$277,918] vs $243,658 [$136,769-$1,127,920], p = 0.04). TBIs were normalized for changing migration rates on the basis of Customs and Border Protection apprehensions. CONCLUSIONS: This heightened risk of intracranial injury among vulnerable immigrant populations poses ethical and economic concerns to be addressed regarding border wall infrastructure.

Intradermal and Intramuscular Bupivacaine Reduces Opioid Use Following Noninstrumented Spine Surgery.

OBJECTIVE: To evaluate the efficacy of intraoperative bupivacaine hydrochloride wound infiltration as an adjunct means of pain relief following noninstrumented posterior spine surgery. METHODS: A retrospective cohort analysis was performed of all patients who underwent posterior spinal decompression surgery at the University of California, San Diego, and at the San Diego VA Medical Center between June 2020 and July 2021, following a change in practice to including bupivacaine infiltration at the end of the surgery. Patients were stratified into groups based on whether they received intrawound bupivacaine during surgery. Demographic and clinical data were extracted from the electronic health record. Postoperative opioid use, visual analog pain scores, heart rate, and blood pressure were compared. RESULTS: The analysis included 43 patients; 21 received bupivacaine infiltration, and 22 did not. No complications were encountered in the perioperative period. Patients who received bupivacaine consumed significantly less opioids over the 72 hours following surgery, had slightly lower pain scores, and experienced slightly lower heart rates. No significant difference was found between groups with respect to systolic blood pressure, operative time, or length of hospital stay. CONCLUSIONS: Intraoperative infiltration of the exposed paraspinous musculature and peri-incisional subdermal layer with bupivacaine significantly reduced postoperative opioid consumption for 72 hours after surgery and slightly reduced pain ratings and conferred superior heart rate control. This low-cost intervention produced significant patient benefit with minimal risk and no significant increase in surgical time or hospital stay.

The impact of the Mexico-San Diego border wall extension on spine injuries: a retrospective cohort review.

BACKGROUND: The recent San Diego-Mexico border wall height extension has resulted in an increased injury risk for unauthorized immigrants falling from greater heights. However, the effects of the border wall extension on frequency and morbidity of spinal injuries and related economic costs have yet to be highlighted. METHODS: We retrospectively compared two cohorts who presented to the UC San Diego Health Trauma Center for border wall falls: pre-height extension (12 patients; January 2016-May 2018), and post-height extension (102 patients; January 2020-December 2021). Patients presented during border wall construction (June 2018-December 2019) were excluded. Demographics, clinical data and hospital costs were collected. Spinal injuries were normalized using Customs and Border Protection apprehensions. Costs were adjusted for inflation using the 2021 medical care price index. RESULTS: The increase in spine injuries per month (0.8-4.25) and operative spine injuries per month (0.3- 1.7) was statistically significant (P < 0.001). Increase in median length of stay from 6 [interquartile range (IQR) 2-7] to 9 days (IQR 6-13) was statistically significant (P = 0.006). Median total hospital charges increased from $174 660 to $294 421 and was also significant (P < 0.001). CONCLUSION: The data support that the recent San Diego-Mexico border wall extension is correlated with more frequent, severe and costly spinal injuries. This current infrastructure should be re-evaluated as border-related injuries represent a humanitarian and public health crisis.

Constructing 2D maps of human spinal cord activity and isolating the functional midline with high-density microelectrode arrays.

Intraoperative neuromonitoring (IONM) is a widely used practice in spine surgery for early detection and minimization of neurological injury. IONM is most commonly conducted by indirectly recording motor and somatosensory evoked potentials from either muscles or the scalp, which requires large-amplitude electrical stimulation and provides limited spatiotemporal information. IONM may inform of inadvertent events during neurosurgery after they occur, but it does not guide safe surgical procedures when the anatomy of the diseased spinal cord is distorted. To overcome these limitations and to increase our understanding of human spinal cord neurophysiology, we applied a microelectrode array with hundreds of channels to the exposed spinal cord during surgery and resolved spatiotemporal dynamics with high definition. We used this method to construct two-dimensional maps of responsive channels and define with submillimeter precision the electrophysiological midline of the spinal cord. The high sensitivity of our microelectrode array allowed us to record both epidural and subdural responses at stimulation currents that are well below those used clinically and to resolve postoperative evoked potentials when IONM could not. Together, these advances highlight the potential of our microelectrode arrays to capture previously unexplored spinal cord neural activity and its spatiotemporal dynamics at high resolution, offering better electrophysiological markers that can transform IONM.

Precision spinal gene delivery-induced functional switch in nociceptive neurons reverses neuropathic pain.

Second-order spinal cord excitatory neurons play a key role in spinal processing and transmission of pain signals to the brain. Exogenously induced change in developmentally imprinted excitatory neurotransmitter phenotypes of these neurons to inhibitory has not yet been achieved. Here, we use a subpial dorsal horn-targeted delivery of AAV (adeno-associated virus) vector(s) encoding GABA (gamma-aminobutyric acid) synthesizing-releasing inhibitory machinery in mice with neuropathic pain. Treated animals showed a progressive and complete reversal of neuropathic pain (tactile and brush-evoked pain behavior) that persisted for a minimum of 2.5 months post-treatment. The mechanism of this treatment effect results from the switch of excitatory to preferential inhibitory neurotransmitter phenotype in dorsal horn nociceptive neurons and a resulting increase in inhibitory activity in regional spinal circuitry after peripheral nociceptive stimulation. No detectable side effects (e.g., sedation, motor weakness, loss of normal sensation) were seen between 2 and 13 months post-treatment in naive adult mice, pigs, and non-human primates. The use of this treatment approach may represent a potent and safe treatment modality in patients suffering from spinal cord or peripheral nerve injury-induced neuropathic pain.

Application of Antibiotic-Impregnated Polymethyl-Methacrylate Bone Cement for the Treatment of Infected Cranioplasties: Initial Experience.

BACKGROUND: Management of infected cranioplasty implants remains a surgical challenge. Surgical debridement, removal of the infected implant, and prolonged antibiotic therapy are part of the acute management. In addition, cranioplasty removal poses the risk of dural tear. Reconstruction of the cranial defect is usually delayed for several months to years, increasing the difficulty due to soft tissue contraction and scarring. OBJECTIVE: The aim of the study was to propose an alternative to delayed reconstruction in the face of infection with a dual purpose: treat the infection with a material which delivers antibiotic to the area (polymethyl-methacrylate antibiotic) and which functions as a temporary or permanent cranioplasty. METHODS: We reviewed the records of 3 consecutive patients who underwent single-stage polymethyl-methacrylate antibiotic salvage cranioplasty. RESULTS: All patients underwent debridement of infected tissue. Titanium mesh was placed over the bony defect. Polymethyl methacrylate impregnated with vancomycin and tobramycin was then spread over the plate and defect before closure. Patients also received extended treatment with systemic antimicrobials. Early outcomes have been encouraging for both cosmesis and treatment of infection. CONCLUSIONS: Benefits of this treatment strategy include immediate reconstruction rather than staged procedures and delivery of high concentrations of antibiotics directly to the affected area in addition to systemic antibiotics.

Review of operative considerations in spinal cord stem cell therapy.

Spinal cord injury (SCI) can permanently impair motor and sensory function and has a devastating cost to patients and the United States healthcare system. Stem cell transplantation for treatment of SCI is a new technique aimed at creating biological functional recovery. Operative techniques in stem cell transplantation for SCI are varied. We review various clinical treatment paradigms, surgical techniques and technical considerations important in SCI treatment. The NCBI PubMed database was queried for "SCI" and "stem cell" with a filter placed for "clinical trials". Thirty-nine articles resulted from the search and 29 were included and evaluated by study authors. A total of 10 articles were excluded (9 not SCI focused or transplantation focused, 1 canine model). Key considerations for stem cell transplantation include method of delivery (intravenous, intrathecal, intramedullary, or excision and engraftment), time course of treatment, number of treatments and time from injury until treatment. There are no phase III clinical trials yet, but decreased time from injury to treatment and a greater number of stem cell injections both seem to increase the chance of functional recovery.

Traumatic rupture of thoracic epidural capillary hemangioma resulting in acute neurologic deficit: illustrative case.

BACKGROUND: Thoracic epidural capillary hemangioma is exceedingly rare, with only a few reported cases. The typical presentation usually includes chronic, progressive symptoms of spinal cord compression in middle-aged adults. To the authors' knowledge, this case is the first report in the literature of acute traumatic capillary hemangioma rupture. OBSERVATIONS: A 22-year-old male presented with worsening lower extremity weakness and paresthesias after a fall onto his spine. Imaging showed no evidence of spinal fracture but revealed an expanding hematoma over 24 hours. Removal of the lesion demonstrated a ruptured capillary hemangioma. LESSONS: This unique case highlights a rare occurrence of traumatic rupture of a previously unknown asymptomatic thoracic capillary hemangioma in a young adult.

Basal impulses: findings from the last twenty years on impulsivity and reward pathways using deep brain stimulation.

INTRODUCTION: Deep brain stimulation (DBS) is an important treatment modality for movement disorders. Its role in tasks and processes of higher cortical function continues to increase in importance and relevance. This systematic review investigates the impact of DBS on measures of impulsivity. EVIDENCE ACQUISITION: A total of 45 studies were collated from PubMed (30 prospective, 8 animal, 4 questionnaire-based, and 3 computational models), excluding case reports and review articles. Two areas extensively studied are the subthalamic nucleus (STN) and nucleus accumbens (NAc). EVIDENCE SYNTHESIS: While both are part of the basal ganglia, the STN and NAc have extensive connections to the prefrontal cortex, cingulate cortex, and limbic system. Therefore, understanding cause and treatment of impulsivity requires understanding motor pathways, learning, memory, and emotional processing. DBS of the STN and NAc shell can increase objective measures of impulsivity, as measured by reaction times or reward-based learning, independent from patient insight. The ability for DBS to treat impulse control disorders, and also cause and/or worsen impulsivity in Parkinson's disease, may be explained by the affected closely-related neuroanatomical areas with discrete and sometimes opposing functions. CONCLUSIONS: As newer, more refined DBS technology emerges, large-scale prospective studies specifically aimed at treatment of impulsivity disorders are needed.

Spinal subpial delivery of AAV9 enables widespread gene silencing and blocks motoneuron degeneration in ALS.

Gene silencing with virally delivered shRNA represents a promising approach for treatment of inherited neurodegenerative disorders. In the present study we develop a subpial technique, which we show in adult animals successfully delivers adeno-associated virus (AAV) throughout the cervical, thoracic and lumbar spinal cord, as well as brain motor centers. One-time injection at cervical and lumbar levels just before disease onset in mice expressing a familial amyotrophic lateral sclerosis (ALS)-causing mutant SOD1 produces long-term suppression of motoneuron disease, including near-complete preservation of spinal α-motoneurons and muscle innervation. Treatment after disease onset potently blocks progression of disease and further α-motoneuron degeneration. A single subpial AAV9 injection in adult pigs or non-human primates using a newly designed device produces homogeneous delivery throughout the cervical spinal cord white and gray matter and brain motor centers. Thus, spinal subpial delivery in adult animals is highly effective for AAV-mediated gene delivery throughout the spinal cord and supraspinal motor centers.

Spinal parenchymal occupation by neural stem cells after subpial delivery in adult immunodeficient rats.

Neural precursor cells (NSCs) hold great potential to treat a variety of neurodegenerative diseases and injuries to the spinal cord. However, current delivery techniques require an invasive approach in which an injection needle is advanced into the spinal parenchyma to deliver cells of interest. As such, this approach is associated with an inherent risk of spinal injury, as well as a limited delivery of cells into multiple spinal segments. Here, we characterize the use of a novel cell delivery technique that employs single bolus cell injections into the spinal subpial space. In immunodeficient rats, two subpial injections of human NSCs were performed in the cervical and lumbar spinal cord, respectively. The survival, distribution, and phenotype of transplanted cells were assessed 6-8 months after injection. Immunofluorescence staining and mRNA sequencing analysis demonstrated a near-complete occupation of the spinal cord by injected cells, in which transplanted human NSCs (hNSCs) preferentially acquired glial phenotypes, expressing oligodendrocyte (Olig2, APC) or astrocyte (GFAP) markers. In the outermost layer of the spinal cord, injected hNSCs differentiated into glia limitans-forming astrocytes and expressed human-specific superoxide dismutase and laminin. All animals showed normal neurological function for the duration of the analysis. These data show that the subpial cell delivery technique is highly effective in populating the entire spinal cord with injected NSCs, and has a potential for clinical use in cell replacement therapies for the treatment of ALS, multiple sclerosis, or spinal cord injury.

Neurosurgical Management of a Thoracic Dorsal Arachnoid Web: Case Illustration.

Dorsal thoracic arachnoid webs are rare clinical entities caused by a thickened intradural extramedullary band of arachnoid tissue that compresses the spinal cord, and often present with progressive back pain, paresthesias, and lower extremity weakness. In this report, we review the radiographic features of the "Scalpel Sign" and describe the case of a 47-year-old male that failed conservative therapy and was found to have dorsal thoracic arachnoid web. The patient underwent laminectomy and microsurgical release of the compressing arachnoid band. Postoperatively, the patient had complete resolution of his pain. Intraoperatively, the somatosensory evoked potentials were improved once the band was released. The prompt diagnosis of dorsal arachnoid webs remains critical because surgical treatment arrests and potentially reverses the pathology.