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Background: Isocitrate dehydrogenase wild-type (WT) glioblastoma (GBM) accounts for 90% of all GBMs, yet only 27% of isocitrate dehydrogenase WT-GBMs have p53 mutations. However, the tumor surveillance function of WT-p53 in GBM is subverted by mechanisms that are not fully understood.Methods: We investigated the proteolytic inactivation of WT-p53 by asparaginyl endopeptidase (AEP) and its effects on GBM progression in cancer cells, murine models, and patients' specimens using biochemical and functional assays. The sera of healthy donors (n = 48) and GBM patients (n = 20) were examined by enzyme-linked immunosorbent assay. Furthermore, effects of AEP inhibitors on GBM progression were evaluated in murine models (n = 6-8 per group). The statistical significance between groups was determined using two-tailed Student t tests.Results: We demonstrate that AEP binds to and directly cleaves WT-p53, resulting in the inhibition of WT-p53-mediated tumor suppressor function in both tumor cells and stromal cells via extracellular vesicle communication. High expression of uncleavable p53-N311A-mutant rescue AEP-induced tumorigenesis, proliferation, and anti-apoptotic abilities. Knock down or pharmacological inhibition of AEP reduced tumorigenesis and prolonged survival in murine models. However, overexpression of AEP promoted tumorigenesis and shortened the survival time. Moreover, high AEP levels in GBM tissues were associated with a poor prognosis of GBM patients (n = 83; hazard ratio = 3.94, 95% confidence interval = 1.87 to 8.28; P < .001). A correlation was found between high plasma AEP levels and a larger tumor size in GBM patients (r = 0.6, P = .03), which decreased dramatically after surgery.Conclusions: Our results indicate that AEP promotes GBM progression via inactivation of WT-p53 and may serve as a prognostic and therapeutic target for GBM. [ABSTRACT FROM AUTHOR]

Byline: Liemei. Guo, Chunlong. Zhong, Jiyao. Jiang, Yongming. Qiu Sir, A 74-year-old man presented with a 2-week history of decreased sensation and weakness of bilateral lower extremities along with urinary [...]

Background: Traumatic brain injury (TBI) has become the most common cause of death and disability in persons between 15 and 30 years of age, and about 10-15% of patients affected by TBI will end up in a coma. Coma caused by TBI presents a significant challenge to neuroscientists. Right median nerve electrical stimulation has been reported as a simple, inexpensive, non-invasive technique to speed recovery and improve outcomes for traumatic comatose patients.Methods/design: This multicentre, prospective, randomised (1:1) controlled trial aims to demonstrate the efficacy and safety of electrical right median nerve stimulation (RMNS) in both accelerating emergence from coma and promoting long-term outcomes. This trial aims to enrol 380 TBI comatose patients to partake in either an electrical stimulation group or a non-stimulation group. Patients assigned to the stimulation group will receive RMNS in addition to standard treatment at an amplitude of 15-20 mA with a pulse width of 300 μs at 40 Hz ON for 20 s and OFF for 40 s. The electrical treatment will last for 8 h per day for 2 weeks. The primary endpoint will be the percentage of patients regaining consciousness 6 months after injury. The secondary endpoints will be Extended Glasgow Outcome Scale, Coma Recovery Scale-Revised and Disability Rating Scale scores at 28 days, 3 months and 6 months after injury; Glasgow Coma Scale, Glasgow Coma Scale Motor Part and Full Outline of Unresponsiveness scale scores on day 1 and day 7 after enrolment and 28 days, 3 months and 6 months after injury; duration of unconsciousness and mechanical ventilation; length of intensive care unit and hospital stays; and incidence of adverse events.Discussion: Right median nerve electrical stimulation has been used as a safe, inexpensive, non-invasive therapy for neuroresuscitation of coma patients for more than two decades, yet no trial has robustly proven the efficacy and safety of this treatment. The Asia Coma Electrical Stimulation (ACES) trial has the following novel features compared with other major RMNS trials: (1) the ACES trial is an Asian multicentre randomised controlled trial; (2) RMNS therapy starts at an early stage 7-14 days after the injury; and (3) various assessment scales are used to evaluate the condition of patients. We hope the ACES trial will lead to optimal use of right median nerve electrical treatment.Trial Registration: ClinicalTrials.gov, NCT02645578 . Registered on 23 December 2015. [ABSTRACT FROM AUTHOR]

Background: Glutamate carboxypeptidase II (GCPII) inactivates the peptide co-transmitter N-acetylaspartylglutamate following synaptic release. Inhibition of GCPII elevates extracellular levels of the peptide, inhibits glutamate release and is neuroprotective in an animal model of traumatic brain injury. GCPII gene knockout mice were used to examine the cellular mechanisms underlying the neuroprotective efficacy of this transmitter system.Results: Following controlled cortical impact injury, GCPII knockout (KO) mice exhibited reduced TUNEL-positive nuclei in the contusion margin of the cerebral cortex relative to wild type mice. Impact injury reduced glutathione levels and superoxide dismutase and glutathione peroxidase activities and increased malondialdehyde. Each of these effects was moderated in KO mice relative to wild type. Similarly, the injury-induced increases in cleaved caspase-3, cytosolic cytochrome c levels and Bcl-2/Bax ratio observed in wild type mice were attenuated in the knockout mice.Conclusions: These data support the hypothesis that the neuroprotective efficacy of GCPII KO in traumatic brain injury is mediated via a reduction in oxidative stress. [ABSTRACT FROM AUTHOR]

Introduction: Glial fibrillary acidic protein (GFAP) may serve as a serum marker of traumatic brain injury (TBI) that can be used to monitor biochemical changes in patients and gauge the response to treatment. However, the temporal profile of serum GFAP in the acute period of brain injury and the associated utility for outcome prediction has not been elucidated.Methods: We conducted a prospective longitudinal cohort study of consecutive severe TBI patients in a local tertiary neurotrauma center in Shanghai, China, between March 2011 and September 2014. All patients were monitored and managed with a standardized protocol with inclusion of hypothermia and other intensive care treatments. Serum specimens were collected on admission and then daily for the first 5 days. GFAP levels were measured using enzyme-linked immunosorbent assay techniques. Patient outcome was assessed at 6 months post injury with the Glasgow Outcome Scale and further grouped into death versus survival and unfavorable versus favorable.Results: A total of 67 patients were enrolled in the study. The mean time from injury to admission was 2.6 hours, and the median admission Glasgow Coma Scale score was 6. Compared with healthy subjects, patients with severe TBI had increased GFAP levels on admission and over the subsequent 5 days post injury. Serum GFAP levels showed a gradual reduction from admission to day 3, and then rebounded on day 4 when hypothermia was discontinued with slow rewarming. GFAP levels were significantly higher in patients who died or had an unfavorable outcome across all time points than in those who were alive or had a favorable outcome. Results of receiver operating characteristic curve analysis indicated that serum GFAP at each time point could predict neurological outcome at 6 months. The areas under the curve for GFAP on admission were 0.761 for death and 0.823 for unfavorable outcome, which were higher than those for clinical variables such as age, Glasgow Coma Scale score, and pupil reactions.Conclusions: Serum GFAP levels on admission and during the first 5 days of injury were increased in patients with severe TBI and were predictive of neurological outcome at 6 months. [ABSTRACT FROM AUTHOR]

Background: Cerebral hemorrhage is a critical medical condition that necessitates a rapid and precise diagnosis for timely medical intervention, including emergency operation. Computed tomography (CT) is essential for identifying cerebral hemorrhage, but its effectiveness is limited by the availability of experienced radiologists, especially in resource-constrained regions or when shorthanded during holidays or at night. Despite advancements in artificial intelligence-driven diagnostic tools, most require technical expertise. This poses a challenge for widespread adoption in radiological imaging. The introduction of advanced natural language processing (NLP) models such as GPT-4, which can annotate and analyze images without extensive algorithmic training, offers a potential solution., Objective: This study investigates GPT-4's capability to identify and annotate cerebral hemorrhages in cranial CT scans. It represents a novel application of NLP models in radiological imaging., Methods: In this retrospective analysis, we collected 208 CT scans with 6 types of cerebral hemorrhages at Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, between January and September 2023. All CT images were mixed together and sequentially numbered, so each CT image had its own corresponding number. A random sequence from 1 to 208 was generated, and all CT images were inputted into GPT-4 for analysis in the order of the random sequence. The outputs were subsequently examined using Photoshop and evaluated by experienced radiologists on a 4-point scale to assess identification completeness, accuracy, and success., Results: The overall identification completeness percentage for the 6 types of cerebral hemorrhages was 72.6% (SD 18.6%). Specifically, GPT-4 achieved higher identification completeness in epidural and intraparenchymal hemorrhages (89.0%, SD 19.1% and 86.9%, SD 17.7%, respectively), yet its identification completeness percentage in chronic subdural hemorrhages was very low (37.3%, SD 37.5%). The misidentification percentages for complex hemorrhages (54.0%, SD 28.0%), epidural hemorrhages (50.2%, SD 22.7%), and subarachnoid hemorrhages (50.5%, SD 29.2%) were relatively high, whereas they were relatively low for acute subdural hemorrhages (32.6%, SD 26.3%), chronic subdural hemorrhages (40.3%, SD 27.2%), and intraparenchymal hemorrhages (26.2%, SD 23.8%). The identification completeness percentages in both massive and minor bleeding showed no significant difference (P=.06). However, the misidentification percentage in recognizing massive bleeding was significantly lower than that for minor bleeding (P=.04). The identification completeness percentages and misidentification percentages for cerebral hemorrhages at different locations showed no significant differences (all P>.05). Lastly, radiologists showed relative acceptance regarding identification completeness (3.60, SD 0.54), accuracy (3.30, SD 0.65), and success (3.38, SD 0.64)., Conclusions: GPT-4, a standout among NLP models, exhibits both promising capabilities and certain limitations in the realm of radiological imaging, particularly when it comes to identifying cerebral hemorrhages in CT scans. This opens up new directions and insights for the future development of NLP models in radiology., Trial Registration: ClinicalTrials.gov NCT06230419; https://clinicaltrials.gov/study/NCT06230419., (©Daiwen Zhang, Zixuan Ma, Ru Gong, Liangliang Lian, Yanzhuo Li, Zhenghui He, Yuhan Han, Jiyuan Hui, Jialin Huang, Jiyao Jiang, Weiji Weng, Junfeng Feng. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 26.09.2024.)

Traumatic brain injury (TBI) poses a huge public health and societal problem worldwide. Uncertainty exists on how care system and treatment approaches for TBI worked in China may differ from those in Europe. Better knowledge on this is important to facilitate interpretation of findings reported by Chinese researchers and to inform opportunities for collaborative studies. We aimed to investigate concordance and variations in TBI care between Chinese and European neurotrauma centers. Investigators from 52 centers in China and 68 in Europe involved in the Collaborative European Neuro Trauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study were invited to complete provider profiling (PP) questionnaires, which covered the main aspects of care system and treatment approaches of TBI care. Participating Chinese and European centers were mainly publicly funded and academic. More centers in China indicated available dedicated neuro-intensive care than those in Europe (98% vs. 60%), and treatment decisions in the ICU were mainly determined by neurosurgeons (58%) in China while in Europe, (neuro)intensivists often took the lead (61%). The ambulance dispatching system was automatic in half of Chinese centers (49%), whereas selective dispatching was more common in European centers (74%). For treatment of refractory intracranial hypertension, a decompressive craniectomy was more frequently regarded as general policy in China compared with in Europe (89% vs. 45%). We observed both concordance and substantial variations with regard to the various aspects of TBI care between Chinese and European centers. These findings are fundamental to guide future research and offer opportunities for collaborative comparative effectiveness research to identify best practices.

Background: Isocitrate dehydrogenase wild-type (WT) glioblastoma (GBM) accounts for 90% of all GBMs, yet only 27% of isocitrate dehydrogenase WT-GBMs have p53 mutations. However, the tumor surveillance function of WT-p53 in GBM is subverted by mechanisms that are not fully understood., Methods: We investigated the proteolytic inactivation of WT-p53 by asparaginyl endopeptidase (AEP) and its effects on GBM progression in cancer cells, murine models, and patients' specimens using biochemical and functional assays. The sera of healthy donors (n = 48) and GBM patients (n = 20) were examined by enzyme-linked immunosorbent assay. Furthermore, effects of AEP inhibitors on GBM progression were evaluated in murine models (n = 6-8 per group). The statistical significance between groups was determined using two-tailed Student t tests., Results: We demonstrate that AEP binds to and directly cleaves WT-p53, resulting in the inhibition of WT-p53-mediated tumor suppressor function in both tumor cells and stromal cells via extracellular vesicle communication. High expression of uncleavable p53-N311A-mutant rescue AEP-induced tumorigenesis, proliferation, and anti-apoptotic abilities. Knock down or pharmacological inhibition of AEP reduced tumorigenesis and prolonged survival in murine models. However, overexpression of AEP promoted tumorigenesis and shortened the survival time. Moreover, high AEP levels in GBM tissues were associated with a poor prognosis of GBM patients (n = 83; hazard ratio = 3.94, 95% confidence interval = 1.87 to 8.28; P < .001). A correlation was found between high plasma AEP levels and a larger tumor size in GBM patients (r = 0.6, P = .03), which decreased dramatically after surgery., Conclusions: Our results indicate that AEP promotes GBM progression via inactivation of WT-p53 and may serve as a prognostic and therapeutic target for GBM., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Intracranial pressure (ICP) monitoring is widely used in the management of patients with severe traumatic brain injury (TBI). However, there is limited evidence about the efficacy of ICP monitoring in older subjects (aged ≥65 years). This study evaluated the effect of intraventricular ICP monitoring on the outcome of older adults suffering from a severe TBI., Methods: This prospective, observational study included 166 older TBI patients (aged ≥65 years) with Glasgow Coma scale (GCS) scores lower than 9 at admission. The study cohort was divided into two groups, intraventricular ICP monitoring and non-ICP monitoring. The primary outcome was in-hospital mortality. The secondary outcomes included the Glasgow Outcome Scale (GOS) score 6 months after injury, the ICU and total hospital lengths of stay, and mechanical ventilation days., Results: There were 80 patients in the intraventricular ICP monitoring group and 86 patients in non-ICP monitoring group. There was no statistical difference between groups in demographics and severity of head injury. Patients treated with intraventricular ICP monitoring had lower in-hospital mortality (33.8 % vs 51.2 %, P < 0.05), a higher 6-month GOS score (3.0 ± 1.4 vs 2.5 ± 1.2 P < 0.05), and a lower dosage (514 ± 246 g vs 840 ± 323 g, P < 0.0001) and shorter duration (7.2 ± 3.6 days vs 8.4 ± 4.3 days, P < 0.01) of mannitol use. However, the ICU length of stay (14.3 ± 6.4 days vs 11.6 ± 5.8 days, P < 0.01) and mechanical ventilation days (6.7 ± 3.5 days vs 5.6 ± 2.4 days, P < 0.05) were longer in the ICP monitoring group. The total length of hospital stay did not differ between the two groups (28.5 ± 12.1 days vs 26.1 ± 13.5 days, P = 0.23)., Conclusions: Intraventricular ICP monitoring may have beneficial effects on the decreased in-hospital mortality and improved 6-month outcome of older patients with severe TBI. However, given that this was an observational study conducted in a single institution, further well-designed randomized control trials are needed to evaluate the effect of intraventricular ICP monitoring on the outcome of older severe TBI patients.