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.

Ultrasound-accelerated thrombolysis (USAT) versus standard catheter-directed thrombolysis (CDT) for treatment of pulmonary embolism: A retrospective analysis.

Ultrasound-accelerated thrombolysis (USAT) is advocated in pulmonary embolism (PE) based on the hypothesis that adjunctive ultrasound provides superior clinical efficacy compared to standard catheter-directed thrombolysis (CDT). This retrospective study was designed to compare outcomes between the two modalities. We analyzed patients with computed tomography-diagnosed PE at our institution treated with either USAT or standard CDT. Efficacy parameters assessed included invasive pulmonary artery systolic pressure (PASP; pre- and 24 hours post-treatment), non-invasive right-to-left ventricle (RV/LV) ratio (pre- and post-treatment), and general clinical outcomes (length-of-stay, significant bleeding, and mortality). We analyzed 98 cases (62 USAT and 36 CDT), in whom massive PE was diagnosed in 7%, intermediate/high risk in 81%, and intermediate/low risk in 12%. Overall, 92% had bilateral clot and 40% saddle embolus. At 24 hours, PASP decreased similarly in both groups (CDT Δ14.7 mmHg, USAT Δ10.8 mmHg; p = 0.14). Post-treatment, CDT showed similar improvement in the RV/LV ratio (CDT Δ0.58 vs USAT Δ0.45; p = 0.07), despite the baseline ratio being greater in the CDT group, indicating more severe RV strain (1.56 ± 0.36 vs 1.40 ± 0.29; p = 0.01). Intensive care unit and hospital length-of-stays were similar in both groups. A trend toward lesser significant bleeding rates in the CDT group (8.3% vs 12.9%, p = 0.74) as well as improved survival-to-discharge (97.2% vs 91.9%, p = 0.66) was observed. Compared to USAT, standard CDT achieves similar beneficial effects on hemodynamics, RV/LV ratios, and clinical outcomes. These observations suggest that salutary clinical results may be achieved without the need for very expensive devices.

Immunosuppressive mechanisms for stem cell transplant survival in spinal cord injury.

Spinal cord injury (SCI) has been associated with a dismal prognosis-recovery is not expected, and the most standard interventions have been temporizing measures that do little to mitigate the extent of damage. While advances in surgical and medical techniques have certainly improved this outlook, limitations in functional recovery continue to impede clinically significant improvements. These limitations are dependent on evolving immunological mechanisms that shape the cellular environment at the site of SCI. In this review, we examine these mechanisms, identify relevant cellular components, and discuss emerging treatments in stem cell grafts and adjuvant immunosuppressants that target these pathways. As the field advances, we expect that stem cell grafts and these adjuvant treatments will significantly shift therapeutic approaches to acute SCI with the potential for more promising outcomes.

Direct pressure on a pseudomeningocele resulting in intraoperative cerebral ischemia.

PURPOSE: When positioning patients with meningocele and meningomyelocele, it is standard practice to avoid direct pressure on the lesions. That caution is intended to prevent injury to neural elements within the lesion and violation of the cerebrospinal fluid space. We herein report an additional hazard of direct intraoperative pressure on such lesions. An adult patient with a lumbosacral pseudomeningocele sustained a cerebral ischemic injury as a consequence of direct pressure on the lesion during general anesthesia. CLINICAL FEATURES: A 32-yr-old male with spina bifida and a pseudomeningocele related to recent lumbar surgery underwent a urologic procedure in the lithotomy position. Because the lesion was recognized to lie to the left of the midline, cushioning was placed under the patient's left hip and buttock. The patient was slow to awaken and has sustained significant long-term cognitive deficits. Imaging is consistent with a diffuse cerebral ischemic insult. CONCLUSION: In retrospect, the size and leftward extent of the pseudomeningocele were not appreciated preoperatively, and in spite of the care taken, intraoperative pressure was placed on the lesion. This report cautions that intraoperative pressure related to positioning patients with extra-axial lesions containing cerebrospinal fluid (CSF), e.g., meningoceles and pseudomeningoceles, can result in increases in CSF pressure and thereby a reduction in cerebral perfusion pressure sufficient to result in cerebral ischemia.

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.

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.

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.

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.

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.

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.

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.

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.

Malignancies of the spinal cord.

The management of intramedullary spinal cord tumors (IMSCT) is primarily concerned with the preservation of existing neurologic function. To this end, clinical scientists are continually seeking tools and techniques to improve the safety and efficacy of tumor resection and control. Further advances in safety and efficacy can be proposed at each phase of management, from pre-operative screening to post-treatment monitoring. Innovations within the areas of molecular biology and genetics, intraoperative imaging and stereotactic radiosurgery offer exciting new options to explore in the management of IMSCT. This section will review the pathophysiology and epidemiology of IMSCT and the state-of-the-art management before delving into the promising new tools and techniques for each phase of management.

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.

A single institution's 1-year experience with uterine fibroid embolization marketing.

PURPOSE: To assess the impact of various marketing techniques on the referral pattern for uterine fibroid embolization (UFE) at an academic interventional radiology practice over a 1-year period. MATERIALS AND METHODS: All referrals to the interventional radiology clinic for UFE from January 1, 2009, to December 31, 2009, were retrospectively reviewed. A standard intake sheet was completed by the interventional clinic secretary at the time of initial patient contact that included the source of the referral (radio, television, newspaper, mailing, Internet, physician, friend, other). All patients who proceeded to consultation were seen in the interventional radiology clinic by attending interventional radiologists in a university-based academic center. The referral pattern was analyzed with respect to the number of patients who contacted the clinic, the number of actual clinic visits, the number of magnetic resonance (MR) imaging examinations performed before and after the procedure, the total number of embolization cases performed, and the subsequent downstream revenue. RESULTS: During the 1-year period, 344 patients contacted the interventional radiology clinic regarding UFE resulting in 171 consultations and 100 pelvic MR imaging examinations performed before the procedure. Sixty-two patients proceeded to UFE, and 32 patients underwent follow-up pelvic MR imaging. These results show a significant increase from eight cases the previous year and are presumably attributable almost entirely to the directed marketing campaign. The marketing initiative consisted primarily of print and radio advertisements, with the latter being the most effective. The total advertising cost for the year was approximately $24,706, of which $20,520 was for radio advertisements. The radio advertisements generated 69% (237 of 344) of the referrals and 69% (43 of 62) of the UFE procedures. Using Medicare reimbursement rates, the radio advertisements generated $281,994 in UFE technical fees and $50,329 in MR imaging technical fees. CONCLUSIONS: Direct patient marketing techniques can promote significant growth for a fibroid embolization practice. In our market, radio advertisements proved to be the most cost-effective strategy.

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.