Profound Neurological Deficits Research Articles

LOX-mediated ECM mechanical stress induces Piezo1 activation in hypoxic-ischemic brain damage and identification of novel inhibitor of LOX

Hypoxic-ischemic encephalopathy (HIE) poses a significant challenge in neonatal medicine, often resulting in profound and lasting neurological deficits. Current therapeutic strategies for hypoxia-ischemia brain damage (HIBD) remain limited. Ferroptosis has been reported to play a crucial role in HIE and serves as a potential therapeutic target. However, the mechanisms underlying ferroptosis in HIBD remain largely unclear. In this study, we found that elevated lysyl oxidase (LOX) expression correlates closely with the severity of HIE, suggesting LOX as a potential biomarker for HIE. LOX expression levels and enzymatic activity were significantly increased in HI-induced neuronal models both in vitro and in vivo. Notably, we discovered that HI-induced brain tissue injury results in increased stiffness and observed a selective upregulation of the mechanosensitive ion channel Piezo1 in both brain tissue of HIBD and primary cortex neurons. Mechanistically, LOX increases its catalytic substrates, the Collagen I/III components, promoting extracellular matrix (ECM) remodeling and possibly mediating ECM cross-linking, which leads to increased stiffness at the site of injury and subsequent activation of the Piezo1 channel. Piezo1 senses these stiffness stimuli and then induces neuronal ferroptosis in a GPX4-dependent manner. Pharmacological inhibition of LOX or Piezo1 ameliorated brain neuronal ferroptosis and improved learning and memory impairments. Furthermore, we identified traumatic acid (TA) as a novel LOX inhibitor that effectively suppresses LOX enzymatic activity, mitigating neuronal ferroptosis and promoting synaptic plasticity. In conclusion, our findings elucidate a critical role for LOX-mediated ECM mechanical stress-induced Piezo1 activation in regulating ferroptotic cell death in HIBD. This mechanistic insight provides a basis for developing targeted therapies aimed at ameliorating neurological outcomes in neonates affected by HIBD.

Stereotactic radiosurgery and radiotherapy for brainstem metastases: An international multicenter analysis.

Brainstem metastases (BSM) present a significant neuro-oncological challenge, resulting in profound neurological deficits and poor survival outcomes. Stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (FSRT) offer promising therapeutic avenues for BSM despite their precarious location. This international multicenter study investigates the efficacy and safety of SRS and FSRT in 136 patients with 144 BSM treated at nine institutions from 2005 to 2022. The median radiographic and clinical follow-up periods were 6.8 and 9.4 months, respectively. Predominantly, patients with BSM were managed with SRS (69.4%). The median prescription dose and isodose line for SRS were 18 Gy and 65%, respectively, while for FSRT, the median prescription dose was 21 Gy with a median isodose line of 70%. The 12-, 24-, and 36-month local control (LC) rates were 82.9%, 71.4%, and 61.2%, respectively. Corresponding overall survival rates at these time points were 61.1%, 34.7%, and 19.3%. In the multivariable Cox regression analysis for LC, only the minimum biologically effective dose was significantly associated with LC, favoring higher doses for improved control (in Gy, hazard ratio [HR]: 0.86, p < .01). Regarding overall survival, good performance status (Karnofsky performance status, ≥90%; HR: 0.43, p < .01) and prior whole brain radiotherapy (HR: 2.52, p < .01) emerged as associated factors. In 14 BSM (9.7%), treatment-related adverse events were noted, with a total of five (3.4%) radiation necrosis. SRS and FSRT for BSM exhibit efficacy and safety, making them suitable treatment options for affected patients.

Synergistic promotion of angiogenesis after intracerebral hemorrhage by ginsenoside Rh2 and chrysophanol in rats

BackgroundIntracerebral hemorrhage (ICH) is a debilitating condition characterized by the rupture of cerebral blood vessels, resulting in profound neurological deficits. A significant challenge in the treatment of ICH lies in the brain's limited capacity to regenerate damaged blood vessels. This study explores the potential synergistic effects of Ginsenoside Rh2 and Chrysophanol in promoting angiogenesis following ICH in a rat model. MethodsNetwork pharmacology was employed to predict the potential targets and pathways of Ginsenoside Rh2 and Chrysophanol for ICH treatment. Molecular docking was utilized to assess the binding affinity between these compounds and their respective targets. Experimental ICH was induced in male Sprague-Dawley rats through stereotactic injection of type VII collagenase into the right caudate putamen (CPu). The study encompassed various methodologies, including administration protocols, assessments of neurological function, magnetic resonance imaging, histological examination, observation of brain tissue ultrastructure, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), immunofluorescence staining, Western blot analysis, and statistical analyses. ResultsNetwork pharmacology analysis indicated that Ginsenoside Rh2 and Chrysophanol may exert their therapeutic effects in ICH by promoting angiogenesis. Results from animal experiments revealed that rats treated with Ginsenoside Rh2 and Chrysophanol exhibited significantly improved neurological function, reduced hematoma volume, and diminished pathological injury compared to the Model group. Immunofluorescence analysis demonstrated enhanced expression of vascular endothelial growth factor receptor 2 (VEGFR2) and CD31, signifying augmented angiogenesis in the peri-hematomal region following combination therapy. Importantly, the addition of a VEGFR2 inhibitor reversed the increased expression of VEGFR2 and CD31. Furthermore, Western blot analysis revealed upregulated expression of angiogenesis-related factors, including VEGFR2, SRC, AKT1, MAPK1, and MAPK14, in the combination therapy group, but this effect was abrogated upon VEGFR2 inhibitor administration. ConclusionThe synergistic effect of Ginsenoside Rh2 and Chrysophanol demonstrated a notable protective impact on ICH injury in rats, specifically attributed to their facilitation of angiogenesis. Consequently, this research offers a foundation for the utilization of Ginsenosides Rh2 and Chrysophanol in medical settings and offers direction for the advancement of novel pharmaceuticals for the clinical management of ICH.

Double Level Non-Contiguous Traumatic Lumbar Disc Herniation Presenting With Cauda Equina Syndrome: A Case Report and Literature Review.

A 52-year-old man presented with cauda equina syndrome after a motorcycle accident. Magnetic resonance imaging revealed traumatic disc herniation, at L2-L3 and L5-S1 levels without bony injury. He was managed successfully by wide laminectomy and microdiscectomy at both levels with complete neurological recovery at 2-month follow-up. With a reported incidence of 0.4%, traumatic disc herniation in the lumbar region is an uncommon occurrence that may resemble a spinal epidural hematoma in acute trauma. Although MRI may not reliably differentiate spinal epidural hematoma from disc herniation, urgent surgical intervention may be required in profound neurological deficits.

The Cell Permeant Phosphopetpidemimetic of VASP Alleviates Motor Function Deficits After Experimental Subarachnoid Hemorrhage.

Subarachnoid hemorrhage (SAH) due to the rupture of an intracranial aneurysm leads to delayed vasospasm and neuroischemia, which can result in profound neurologic deficit and death. Therapeutic options after SAH are currently limited to hemodynamic optimization and nimodipine, which have limited clinical efficacy. Experimental SAH results in cerebral vasospasm have demonstrated the downregulation of nitric oxide (NO)-protein kinase G (PKG) signaling elements. VP3 is a novel cell permeant phosphopeptide mimetic of VASP, a substrate of PKG and an actin-associated protein that modulates vasorelaxation in vascular smooth muscle cells. In this study, we determined that intravenous administration of high doses of VP3 did not induce systemic hypotension in rats except at the maximal soluble dose, implying that VP3 is well-tolerated and has a wide therapeutic window. Using a single cisterna magna injection rat model of SAH, we demonstrated that intravenous administration of low-dose VP3 after SAH improved neurologic deficits for up to 14days as determined by the rotarod test. These findings suggest that strategies aimed at targeting the cerebral vasculature with VP3 may improve neurologic deficits associated with SAH.

Effect of transcranial direct current stimulation on the level of arousal in hypoglycemic ischemic encephalopathy: A case study

Abstract: The current study presents the use of transcranial direct current stimulation (tDCS) as a novel intervention for improving the level of arousal in a patient with hypoglycemic ischemic encephalopathy (HIE). HIE is a rare but potentially devastating condition that can lead to impaired consciousness, coma, and profound neurological deficits. The Coma Recovery Scale was utilized as the primary outcome measure for arousal, along with the Oral Motor Assessment Scale for the assessment of oromotor functions as a secondary outcome to assess the effectiveness of tDCS in promoting neurological recovery.

Pediatric neuroblastoma with intraspinal extension: the role of surgical management.

Neuroblastoma with spinal involvement accounts for up to 30% of pediatric spinal tumors and can cause profound neurological deficits. Chemotherapy is the preferred treatment option, but in select patients resection may be indicated. The goal of this study was to identify preoperative factors that led to early surgical intervention, with a specific emphasis on identifying differences on long-term neurological function and spinal deformity in the recent treatment era. A retrospective chart review was performed on all children diagnosed with neuroblastoma at a single institution from 2007 to 2020. Patient demographics, symptoms (motor deficit and sphincter dysfunction), and tumor characteristics (e.g., 123I metaiodobenzylguanidine [MIBG] avidity, MYCN amplification, chromosomal abnormality, pathology, catecholamine secretion, and stage) were recorded. Spine involvement included neural or vertebral extension, spinal cord compression, and/or T2 signal change on MRI. Survival, neurological status (motor deficit, sphincter dysfunction), and spine deformity at last follow-up were compared using univariate and multivariate analyses. The variables that contributed to neurological and deformity outcome were assessed with binomial logistic and linear regression models using R software. Seventy-seven of the 160 patients with neuroblastoma had spinal neuroblastoma, meaning either bone metastases alone (n = 43) or intraspinal extension with or without neurological deficit (n= 34). Most patients with spinal neuroblastoma were treated with chemotherapy and/or radiation therapy (97% and 57%, respectively). Resection of the spinal tumor was performed in 14 (18%) patients, all of whom also received chemotherapy. Between the surgical and nonsurgical patients, no baseline demographic differences were found. However, surgical patients were more likely to present with either motor deficits (50% vs 5%, p = 0.0011) or bladder/bowel dysfunction (14% vs 0%, p 0.035), and a shorter median time to onset of neurological symptoms (33 vs 80 days, p = 0.0096). Surgical patients also had a significantly shorter median overall survival (33.0 vs 54 months, p = 0.014). Of the 14 patients who underwent spine surgery, 2 patients underwent surgery at the time of diagnosis while the remaining 12 underwent initial chemotherapy followed later by resection. The 2 patients who underwent initial surgery had excellent outcomes, with neither long-term motor or bowel/bladder deficits nor spinal deformity. Surgical patients had shorter overall survival. However, the 2 patients with radiographic evidence of cord compression and acute neurological symptom onset who underwent initial, immediate surgery within 3 days of diagnosis had fewer long-term neurological deficits than surgical patients who underwent initial trials of chemotherapy. Thus, acute decompression may provide benefit in carefully selected patients with acute neurological deficits and cord compression on imaging.

Iridium metal complex targeting oxidation resistance 1 protein attenuates spinal cord injury by inhibiting oxidative stress-associated reactive oxygen species

Oxidative stress is a key factor leading to profound neurological deficits following spinal cord injury (SCI). In this study, we present the development and potential application of an iridium (iii) complex, (CpxbiPh) Ir (N^N) Cl, where CpxbiPh represents 1-biphenyl-2,3,4,5-tetramethyl cyclopentadienyl, and N^N denotes 2-(3-(4-nitrophenyl)-1H-1,2,4-triazol-5-yl) pyridine chelating agents, to address this challenge through a mechanism governed by the regulation of an antioxidant protein. This iridium complex, IrPHtz, can modulate the Oxidation Resistance 1 (OXR1) protein levels within spinal cord tissues, thus showcasing its antioxidative potential. By eliminating reactive oxygen species (ROS) and preventing apoptosis, the IrPHtz demonstrated neuroprotective and neural healing characteristics on injured neurons. Our molecular docking analysis unveiled the presence of π stacking within the IrPHtz-OXR1 complex, an interaction that enhanced OXR1 expression, subsequently diminishing oxidative stress, thwarting neuroinflammation, and averting neuronal apoptosis. Furthermore, in in vivo experimentation with SCI-afflicted mice, IrPHtz was efficacious in shielding spinal cord neurons, promoting their regrowth, restoring electrical signaling, and improving motor performance. Collectively, these findings underscore the potential of employing the iridium metal complex in a novel, protein-regulated antioxidant strategy, presenting a promising avenue for therapeutic intervention in SCI.

Femoral Structure and Biomechanical Characteristics in Sanfilippo Syndrome Type-B Mice.

Sanfilippo syndrome Type-B, also known as mucopolysaccharidosis IIIB (MPS IIIB), accounts for approximately one-third of all Sanfilippo syndrome patients and is characterized by a similar natural history as Type-A. Patients suffer from developmental regression, bone malformation, organomegaly, GI distress, and profound neurological deficits. Despite human trials of enzyme replacement therapy (ERT) (SBC-103, AX250) in MPS IIIB, there is currently no FDA approved treatment and a few palliative options. The major concerns of ERT and gene therapy for the treatment of bone malformation are the inadequate biodistribution of the missing enzyme, N-acetyl-α-glucosaminidase (NAGLU), and that the skeleton is a poorly hit target tissue in ERT and gene therapy. Each of the four known human types of MPS III (A, B, C, and D) is usually regarded as having mild bone manifestations, yet it remains poorly characterized. This study aimed to determine bone mineral content (BMC), volumetric bone mineral density (vBMD), and biomechanical properties in femurs MPS IIIB C57BL/6 mice compared to phenotypic control C57BL/6 mice. Significant differences were observed in MPS IIIB mice within various cortical and cancellous bone parameters for both males and females (p < 0.05). Here, we establish some osteogenic manifestations of MPS IIIB within the mouse model by radiographic and biomechanical tests, which are also differentially affected by age and sex. This suggests that some skeletal features of the MPS IIIB mouse model may be used as biomarkers of peripheral disease correction for preclinical treatment of MPS IIIB.

Carrier-Free Nanodrug Based on Co-Assembly of Methylprednisolone Dimer and Rutin for Combined Treatment of Spinal Cord Injury.

Spinal cord injury (SCI), which is characterized by excessive inflammatory cell infiltration and accumulation of oxidative substance, would severely impede neurological functional recovery and lead to permanent and profound neurologic deficits and even disability. Methylprednisolone (MP) is the most commonly used clinical anti-inflammatory drug for SCI treatment, but high doses are typically required that can cause severe side effects. Here, we developed a carrier-free thioketal linked MP dimer@rutin nanoparticles (MP2-TK@RU NPs) which can achieve combined SCI treatment by coassembling reactive oxygen species (ROS) cleavable MP dimers and rutin. This proposed nanodrug possesses the following favorable advantages: (1) the carrier-free system is easily accessible and has a high drug-loading capacity, which is preferred by the pharmaceutical industry; (2) The ROS-cleavable linker increases the efficiency of targeted drug delivery to the injury site; (3) Rutin, a type of plant-derived natural flavonoid with good biocompatibility, anti-inflammatory, and antioxidant properties, is codelivered to enhance the therapy outcomes. The obtained MP2-TK@RU NPs exhibited potent anti-inflammatory and antioxidative properties both in vitro and in vivo, demonstrating superior locomotor function recovery and neuroprotective efficacy in rats with SCI. This carrier-free nanodrug is anticipated to provide a promising therapeutic strategy for clinical SCI treatment.

Case Series of Nitrous Oxide Related Subacute Combined Degeneration from 2016 to 2022 (P9-4.002)

<h3>Objective:</h3> To report laboratory, radiologic, and clinical findings in a case series of patients hospitalized with subacute combined degeneration (SCD) caused by nitrous oxide (NO) abuse. <h3>Background:</h3> NO is legal and widely available as a food additive, making it an easily accessible recreational drug. NO inhibits methionine synthase and inactivates vitamin B12. Prolonged use can lead to B12 deficiency and SCD. <h3>Design/Methods:</h3> We reviewed hospital records from March 2016 until August 2022 and found three cases of SCD associated with NO abuse. <h3>Results:</h3> One 43-year-old male and two females, 27 and 44 years old, had SCD in the setting of NO abuse. All had numbness, weakness, and ataxia. Cognitive and behavioral changes with loss of vibratory sensation and proprioception were not universal. MRI of the cervical cord in all patients demonstrated T2 hyperintensity of the posterior columns in the classic “inverted V” shape consistent with SCD. B12 levels in two patients were 0.54 and 0.73X lower limit of normal (LLN), while in the third patient it was 2.3X the LLN. Methylmalonic acid (MMA) and homocysteine levels were elevated in all patients up to 34X the upper limit of normal. All patients were treated with high-dose B12 repletion, physical therapy, and counseled on nitrous oxide cessation. Two patients were discharged home, while one was discharged to a skilled facility for further rehabilitation. <h3>Conclusions:</h3> NO abuse can induce SCD. Patients may have a normal B12 level but still be functionally B12 deficient because NO inactivates the B12 molecule. Elevated MMA and homocysteine levels are consistent with B12 inactivation as well as deficiency, illustrating the utility of these additional diagnostic tests when B12 deficiency is suspected. Profound neurological deficits can persist at the time of hospital discharge in NO-related SCD. <b>Disclosure:</b> Dr. Warren has nothing to disclose. Dr. Taylor has nothing to disclose. Dr. Savage has nothing to disclose.

Surgical decompression for malignant cerebral oedema after ischaemic stroke.

Large territory middle cerebral artery (MCA) ischaemic strokes account for around 10% of all ischaemic strokes and have a particularly devastating prognosis when associated with malignant oedema. Progressive cerebral oedema starts developing in the first 24 to 48 hours of stroke ictus with an associated rise in intracranial pressure. The rise in intracranial pressure may eventually overwhelm compensatory mechanisms leading to a cascading secondary damage to surrounding unaffected parenchyma. This downward spiral can rapidly progress to death or severe neurological disability. Early decompressive craniectomy to relieve intracranial pressure and associated tissue shift can help ameliorate this secondary damage and improve outcomes. Evidence has been accumulating of the benefit of early surgical decompression in stroke patients. Earlier studies have excluded people above the age of 60 due to associated poor outcomes; however, newer trials have included this patient subgroup. This review follows a Cochrane Review published in 2012. To assess the effectiveness of surgical decompression in people with malignant oedema after ischaemic stroke with regard to reduction in mortality and improved functional outcome. We also aimed to examine the adverse effects of surgical decompression in this patient cohort. We searched the Cochrane Stroke Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL; 2022, Issue 7 of 12), MEDLINE Ovid, Embase Ovid, Web of Science Core Collection, Scopus databases, ClinicalTrials.gov, and the WHO ICTRP to July 2022. We also reviewed the reference lists of relevant articles. We included randomised controlled trials (RCTs) comparing decompressive craniectomy with medical management to best medical management alone for people with malignant cerebral oedema after MCA ischaemic stroke. Two review authors independently screened the search results, assessed study eligibility, performed risk of bias assessment, and extracted the data. The primary outcomes were death and death or severe disability (modified Rankin Scale (mRS) &gt; 4) at 6 to 12 months follow-up. Other outcomes included death or moderate disability (mRS &gt; 3), severe disability (mRS = 5), and adverse events. We assessed the certainty of the evidence using the GRADE approach, categorising it as high, moderate, low, or very low. We included nine RCTs with a total of 513 participants included in the final analysis. Three studies included patients younger than 60 years of age; two trials accepted patients up to 80 years of age; and one trial only included patients 60 years or older. The majority of included trials (six) mandated a time from stroke ictus to treatment of &lt; 48 hours, whilst in two of them this was &lt; 96 hours. Surgical decompression was associated with a reduction in death (odds ratio (OR) 0.18, 95% confidence interval (CI) 0.12 to 0.27, 9 trials, 513 participants, P &lt; 0.001; high-certainty evidence); death or severe disability (mRS &gt; 4, OR 0.22, 95% CI 0.15 to 0.32, 9 trials, 513 participants, P &lt; 0.001; high-certainty evidence); and death or moderate disability (mRS &gt; 3, OR 0.34, 95% CI 0.22 to 0.52, 9 trials, 513 participants, P &lt; 0.001; moderate-certainty evidence). Subgroup analysis did not reveal any significant effect on treatment outcomes when analysing age (&lt; 60 years versus ≥ 60 years); time from stroke ictus to intervention (&lt; 48 hours versus ≥ 48 hours); or dysphasia. There was a significant subgroup effect of time at follow-up (6 versus 12 months, P = 0.02) on death as well as death or severe disability (mRS &gt; 4); however, the validity of this finding was affected by fewer participant numbers in the six-month follow-up subgroup. There was no consistent reporting of per-participant adverse event rates in any of the included studies, which prevented further analysis. Surgical decompression improves outcomes in the management of malignant oedema after acute ischaemic stroke, including a considerable reduction in death or severe disability (mRS &gt; 4) and a reduction in death or moderate disability (mRS &gt; 3). Whilst there is evidence that this positive treatment effect is present in patients &gt; 60 years old, it is important to take into account that these patients have a poorer prospect of functional survival independent of this treatment effect. In interpreting these results it must also be considered that the data demonstrating benefit are drawn from a unique patient subset with profound neurological deficit, reduced level of consciousness, and no pre-morbid disability or severe comorbidity.

Correlation between neurologic status and spinal injury at the Cervicothoracic Junction.

With limited studies on spinal injuries occurring at the cervicothoracic junction, there is currently a knowledge gap regarding the correlation between morphology of injury and neurology and whether surgery provides a favorable neurological outcome. The primary objective was to determine whether the neurological deficit correlated with the severity of injury at this region of the spine. All patients with injuries at the cervicothoracic junction from December 2015 to December 2020 in a government trauma hospital were included. Patient demographics, characteristics of the injury, neurological score, imaging findings, surgery details and neurological outcomes were analyzed. All patients had a minimum follow up of 2 years. Of the total 30 patients, 23 were male and 7 female with mean age 42.4 years. 90% had fall injuries with 76.7% sustaining AO type C injury and 10% with AO B2 injury.73.4% had injury at C6-C7 level followed by 13.3% , C7-T1. Only 16.7% patients presented with intact neurology. Plain x-rays failed to detect cervicothoracic junction, injuries in 63.3% patients. Posterior stabilization was performed in 56.7%. Neurological improvement was observed in 9 patients. Though cervicothoracic junction injuries are uncommon, they are highly unstable injuries and difficult to diagnose by plain x-rays. These injuries also result in profound neurological deficit. Surgical stabilization of these injuries should be considered for a favorable neurological and functional outcome.

HUC-MSC-mediated recovery of subacute spinal cord injury through enhancing the pivotal subunits β3 and γ2 of the GABAA receptor.

Rationale: Spinal cord injury (SCI) remains an incurable neurological disorder leading to permanent and profound neurologic deficits and disabilities. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) are particularly appealing in SCI treatment to curtail damage, restore homeostasis and possible neural relay. However, the detailed mechanisms underlying hUC-MSC-mediated functional recovery of SCI have not been fully elucidated. The purpose of our current study is to identify novel therapeutic targets and depict the molecular mechanisms underlying the hUC-MSC-mediated recovery of subacute SCI.Methods: Adult female rats suffering from subacute incomplete thoracic SCI were treated with intrathecal transplantation of hUC-MSCs. The beneficial effects of hUC-MSCs on SCI repair were evaluated by a series of behavioral analyses, motor evoked potentials (MEPs) recording of hindlimb and immunohistochemistry. We carried out extensive transcriptome comparative analyses of spinal cord tissues at the lesion site from the subacute phase of SCI (sub-SCI) either treated without (+PBS) or with hUC-MSCs (+MSC) at 0 (sub-SCI), 1, 2, and 4 weeks post-transplantation (wpt), as well as normal spinal cord segments of intact/sham rats (Intact). Adeno-associated virus (AAV)-mediated neuron-specific expression system was employed to functionally screen specific γ-aminobutyric acid type A receptor (GABAAR) subunits promoting the functional recovery of SCI in vivo. The mature cortical axon scrape assay and transplantation of genetically modified MSCs with either overexpression or knockdown of brain-derived neurotrophic factor (BDNF) were employed to demonstrate that hUC-MSCs ameliorated the reduction of GABAAR subunits in the injured spinal cord via BDNF secretion in vitro and in vivo, respectively.Results: Comparative transcriptome analysis revealed the GABAergic synapse pathway is significantly enriched as a main target of hUC-MSC-activated genes in the injured spinal cord. Functional screening of the primary GABAAR subunits uncovered that Gabrb3 and Garbg2 harbored the motor and electrophysiological recovery-promoting competence. Moreover, targeting either of the two pivotal subunits β3 or γ2 in combination with/without the K+/Cl- cotransporter 2 (KCC2) reinforced the therapeutic effects. Mechanistically, BDNF secreted by hUC-MSCs contributed to the upregulation of GABAAR subunits (β3 & γ2) and KCC2 in the injured neurons.Conclusions: Our study identifies a novel mode for hUC-MSC-mediated locomotor recovery of SCI through synergistic upregulation of GABAAR β3 and γ2 along with KCC2 by BDNF secretion, indicating the significance of restoring the excitation/inhibition balance in the injured neurons for the reestablishment of neuronal circuits. This study also provides a potential combinatorial approach by targeting the pivotal subunit β3 or γ2 and KCC2, opening up possibilities for efficacious drug design.

Clinico-Radiological assesment of lumbar spinal canal stenosis and evaluation of its surgical treatment

Objective: This study aimed to predict the absolute criteria for surgical intervention and study the outcome of surgical intervention. Materials and Methods: A prospective study was conducted from June 2002 to July 2003. A total of 35 patients were included in the study. Pre- and postoperative Oswestry Disability Index (ODI) scores were evaluated for all the patients. All patients underwent magnetic resonance imaging (MRI). The surgical indications were disabling backache with radicular pain, limited walking capacity, and neurological deficits leading to a poor ODI score. Surgical procedures done were discectomy and laminectomy with or without fixation with pedicle screws on a case-to-case basis. Follow-up was done for up to 1 year at three-monthly intervals. The final ODI score was taken at the last follow-up and was compared with preoperative scores. Results: A 50 ± 10 years was the average age of patients included in the study. The average walking capacity was 40 m; the average duration of symptoms was 41 months. ODI improved from average score of 71% ± 4% preoperatively to 22% ± 6% postoperatively. L4–L5 was the level most severely narrowed, with a mean cross-sectional area of 75 mm2. The most common surgical interventions done were discectomy and laminectomy, which were performed in 54% of the cases. We had good-to-excellent results in all our cases. None of the cases deteriorated after surgery. Conclusion: The findings in this study have important implications in clinical practice. The radiological findings in the MRI correlated well with the clinical signs and symptoms of the patients, i.e., patients with significant findings in the MRI had profound clinical symptoms and neurological deficits. Clinical Significance: Lumbar canal stenosis is a clinicoradiological diagnosis. ODI score is related to canal narrowing on MRI. Clinical improvement is related to preoperative disability and canal narrowing on MRI.

In Reply to the Letter to the Editor Regarding ‘Transtentorial Brain Herniation After Lumbar Drainage in Patient Planned for Cranioplastic Reconstruction: Catastrophic Play Between Atmospheric and Intracranial Pressure’

Cerebral vasospasm and delayed ischemic neurologic deficits are well-known clinical aftereffects of subarachnoid hemorrhage due to rupture of an intracranial aneurysm. However, vasospasm with consequential ischemia after clipping of an unruptured aneurysm is an exceedingly rare sequela encountered in the reported neurosurgical literature.A 53-year-old woman had presented for elective craniotomy with microsurgical clipping of an unruptured left middle cerebral artery bifurcation saccular aneurysm, which was successfully treated without complications. Despite an initially benign clinical course, she experienced diffuse vasospasm with profound ischemic neurologic deficits on postoperative day 13 with a left middle cerebral artery distribution ischemic infarct. Moreover, she developed recurrent delayed spasm of the right posterior cerebral artery on postoperative day 26 and, consequentially, a left homonymous hemianopsia despite treatment with intra-arterial verapamil infusion.To the best of our knowledge, we have reported the first case of recurrent cerebral vasospasm and delayed ischemia neurologic deficits weeks subsequent to clipping of an unruptured aneurysm. The findings from the present case highlight the importance of considering delayed vasospasm as a cause of acute onset neurologic symptoms for patients who have recently undergone elective aneurysm surgery. We also reviewed the current data regarding the epidemiology, surgical factors, and proposed pathophysiologic mechanisms related to vasospasm after elective cases.

Resection of anterolateral midbrain cavernous malformation via orbitozygomatic transsylvian pretemporal approach with uncal resection.

Brainstem cavernomas are benign, angiographically occult, low-flow lesions and constitute 18%–35% of intracranial cavernomas.4,6 They are known to have an annual rupture risk of 2%–6%,2,5 and once symptomatic, they frequently cause progressive neurological morbidity. A 22-year-old lady presented with progressive profound neurologic deficits from three distinct hemorrhages over 2 months. Surgery was indicated given the aggressive natural history, and the lesion now presented to the surface with displacement of corticospinal tracts noted on diffusion tensor imaging.1,7 We describe a surgical technique via an orbitozygomatic transsylvian pretemporal approach with uncal resection to open the oculomotor-tentorial window and resect the lesion.3The video can be found here: https://youtu.be/j5yYp4OsaRc.

Increased Cortical Interleukin‐1 Receptor Signaling Following Blast‐Induced Traumatic Brain Injury

Traumatic Brain Injury (TBI) is a leading cause of disability in the United States resulting in an estimated annual economic cost of over $75 billion. Furthermore, there is a lack of any FDA approved medications aimed at ameliorating the effects of acute injury or the chronic comorbidities of TBI. Those affected are often left with profound chronic neurologic deficits such as major depressive disorder (MDD), anxiety, sleep disturbances, and/or post‐traumatic epilepsy. Neuroinflammation is a hallmark of TBI, although whether neuroinflammatory signaling contributes to the etiology of neuropsychiatric complications following various forms of neurotrauma is not well characterized. We hypothesize that following TBI, interleukin‐1 alpha (IL‐1α) and interleukin‐1 beta (IL‐1β) signaling through functional type 1 interleukin‐1 receptors (IL‐1R1) acts to orchestrate molecular signaling that contributes to the generation of neuropsychiatric sequelae. To test this hypothesis, the current study aimed to characterize alterations in interleukin‐1 (IL‐1) signaling elicited by blast‐induced TBI in murine subjects. Moderate blast‐induced TBI (≈ 20 psi) resulted in an acute increase in righting reflex time (RRT) and a transient decrease in total locomotor activity 3 hrs post‐injury. Rapid increases in il‐1β, il‐1α and tnf‐α mRNA expression occurred in cortical and hippocampal samples ipsilateral to injury in TBI subjects as compared to their sham counterparts, indicating increased CNS production of proinflammatory cytokines. Elevated levels of il‐1r1 mRNA were found in the ipsilateral cortex following injury, however no changes were found in interleukin‐1 receptor associated kinase‐4 (irak‐4) mRNA expression, providing evidence of increased cortical IL‐1R1‐mediated signaling in TBI subjects. Further, TBI resulted in increased mRNA expression and immunoreactivity of the astrocytic marker glial fibrillary acidic protein (GFAP) in the ipsilateral cortex as compared to sham subjects 24 and 72 hrs post‐injury, respectively, indicative of significant reactive astrogliosis. One‐week post‐injury, TBI increased despair‐like behavior as compared to sham treatments as determined by the Porsolt forced swim test (FST). Importantly, no concomitant alterations in general locomotor activity were found in TBI subjects one‐week post‐injury. Future studies will utilize murine models, affording the conditional elimination and restoration of IL‐1R1 in conjunction with blast‐induced TBI to ascertain the cell‐specific contributions of IL‐1R1‐mediated signaling to injury‐induced neuroinflammation and functional outcomes post‐injury. Systematic characterization of IL‐1R1 signaling post‐injury will lead to a better understanding of how neuroinflammatory signaling contributes to the acute and chronic neurologic sequelae of TBI and may lead to viable pharmacotherapeutic targets aimed at ameliorating these deficits.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

DPM-1001 decreased copper levels and ameliorated deficits in a mouse model of Wilson's disease.

The levels of copper, which is an essential element in living organisms, are under tight homeostatic control. Inactivating mutations in ATP7B, a P-type Cu-ATPase that functions in copper excretion, promote aberrant accumulation of the metal, primarily the in liver and brain. This condition underlies Wilson's disease, a severe autosomal recessive disorder characterized by profound hepatic and neurological deficits. Current treatment regimens rely on the use of broad specificity metal chelators as "decoppering" agents; however, there are side effects that limit their effectiveness. Here, we present the characterization of DPM-1001 {methyl 4-[7-hydroxy-10,13-dimethyl-3-({4-[(pyridin-2-ylmethyl)amino]butyl}amino)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl] pentanoate} as a potent and highly selective chelator of copper that is orally bioavailable. Treatment of cell models, including fibroblasts derived from Wilson's disease patients, eliminated adverse effects associated with copper accumulation. Furthermore, treatment of the toxic milk mouse model of Wilson's disease with DPM-1001 lowered the levels of copper in the liver and brain, removing excess copper by excretion in the feces while ameliorating symptoms associated with the disease. These data suggest that it may be worthwhile to investigate DPM-1001 further as a new therapeutic agent for the treatment of Wilson's disease, with potential for application in other indications associated with elevated copper, including cancer and neurodegenerative diseases.

Diagnostic and Prognostic Capability of Newer Magnetic Resonance Imaging Brain Sequences in Diffuse Axonal Injury Patient.

Objectives:Diffuse axonal injury is one of the major causes of unconsciousness, profound neurologic deficits and persistent vegetative state after head trauma. In recent years, MR imaging has been gaining popularity as an adjunctive imaging method in patients with DAI. Our study aims to assess the relative diagnostic and prognostic capability of various MRI sequences.Patients and Methods:Retrospective observational study done in 1 year duration on 30 DAI patients. Clinical assessment done with GCS at admission and GOS at 6 month. MRI Brain FLAIR, DWI, T2*GRE AND SWI sequences taken. DAI grade were evaluated for different MRI sequences. Prognosis was correlated to total number of lesion/locations and DAI grade of patients. Statistical analysis was done using SPSS Statistical software (ver.20.0.0) and XL-Stat and ANOVA one way test, post hoc test (Turkey test) and Chi square test.Result:We studied 30 male patients, mean age 32.57±8.72 ranges. The commonest mode of injury is RTA-80%, fall-16% followed by assault-3.33%. Out of 30 patients, 17 patients (56.67%) had GCS <=8, 13 patients (43.33%) had GCS between 9 and 12 and no patient had a GCS score between 13 and 15. The mean GCS score was 8.47±1.50. At a 6 month follow up, out of a total of 30 patients, 2 patients (6.66%) expired (GOS-1), 3 patients (10%) remained in persistent vegetative state (GOS-2), 11 patients (36.67%) and 10 patients (33.33%) were found to be severely (GOS-3) and moderately (GOS-4) disabled respectively and 4 patients (13.33%) showed good recovery (GOS-5). Mean GOS is 3.37+/-1.06. Newer imaging -SWI able to detects lesion better (diagnosis of DAI) as compared to other older sequences like FLAIR,DWI,T2*GRE. But no statistically significant found between total number of lesion/locations to the outcome and also newer imaging do not change the grade of DAI patients.Conclusion:Although advanced imaging in head injury, SWI helps in diagnosing the diffuse axonal injury more efficiently than other imaging sequences, but it is the grade of patients at admission that predicts the outcome best.