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An in vitro model yields ‘importin’ new insights into chronic traumatic encephalopathy: damaged astrocytes stop ‘thrombospondin’ to the injury An Editorial Highlight for ‘Defective synthesis and release of astrocytic thrombospondin‐1 mediates the neuronal TDP‐43 proteinopathy, resulting in defects in neuronal integrity associated with chronic traumatic encephalopathy: in vitro studies’This Editorial highlights a study by Jayakumar and colleagues (2016) in the current issue of Journal of Neurochemistry. The authors introduce an in vitro model of chronic traumatic encephalopathy (CTE) to explore the mechanistic underpinnings of CTE pathogenesis, including investigation of how traumatized astrocytes affect traumatized neurons through the release of secreted factors. The model recapitulates two key features of the human post-mortem CTE brain: neuronal tauopathy and TDP-43 proteinopathy—the respective accretion of hyperphosphorylated tau and cytoplasmic hyperphosphorylated and ubiquitinated TDP-43. Oxidative stress and casein kinase 1 episilon (CK1ε) are identified as key upstream regulators of cytoplasmic TDP-43 phosphorylation, and this phosphorylation is found to correlate with decreased importin-β protein level and a decline in synaptic integrity. RNA silencing of importin-β is sufficient to mimic both the phospho-TDP-43 accumulation and synaptic injury observed after mild in vitro trauma. Strikingly, Jayakumar et al. find that thrombospondin-1 (TSP-1), a protein secreted by traumatized astrocytes at elevated levels during the initial 5 days after damage, can attenuate CK1ε phosphorylation of TDP-43 and synaptic injury. However, TSP-1 secretion by astrocytes is lost at 10–15 days post-injury, and neurons succumb to unchecked TDP-43 pathogenesis.
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Chronic Sensory and Affective Craniofacial Pain After Blast-Induced Traumatic Brain Injury and Peripheral Nerve Injury in RatsThousands of military members suffer long-term consequences of blast-induced traumatic brain injury (Blast-TBI), including chronic head and face pain. Pain after blast-TBI usually manifests as post-traumatic headaches with a high degree of comorbid mood disorders, suggesting that the affective dimension of pain may burden survivors of blast-TBI. Here, we tested the hypothesis that an innovative model of the unique aspect of blast-TBI over blunt-force TBI, the primary blast injury, directed over the cranium sufficiently modeled long-term conditions of human blast exposure in rats. Rats exposed to cranium-directed primary blast-TBI demonstrated behavioral manifestations of ongoing pain, mechanical hyperalgesia, and cold allodynia three weeks after injury, recapitulating chronic facial pain in patients after blast-TBI. We predicted that maladaptive changes to pain-signaling and -processing nuclei in CNS would induce and maintain pain behavior after blast-TBI. We recorded single units in sensory pain-associated nuclei, the posterior nucleus of the thalamus (PO) and spinal trigeminal nucleus caudalis (SpVc), which have previously been causally associated with pain after spinal cord injury. We observed hyperexcitability at baseline of PO neurons after blast injury in absence of changes to evoked response to cutaneous noxious stimuli. Neuronal hyperexcitability in PO is not associated with persistent gliosis. Affective pain processing through the parabrachial complex (PB) occurs in parallel to information coding the sensory dimension of pain through PO. We assessed central changes to PB neuronal activity in a robust model of post-traumatic pain using the chronic constriction injury of the infraorbital nerve (CCI-ION). PB neurons, weeks to months after injury, are hyper-excitable in chronic pain, as shown by prolonged response after presentation of noxious cutaneous stimulation ("after-discharges"), previously observed to be causally-related to pain due to CCI-ION in SpVc. Further study of PB hyperexcitability in blast-TBI rodent models may elucidate the mechanism underlying blast-TBI-associated affective pain.
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Extent of Spinal Cord Decompression in Motor Complete (American Spinal Injury Association Impairment Scale Grades A and B) Traumatic Spinal Cord Injury Patients: Post-Operative Magnetic Resonance Imaging Analysis of Standard Operative ApproachesAlthough decompressive surgery following traumatic spinal cord injury (TSCI) is recommended, adequate surgical decompression is rarely verified via imaging. We utilized magnetic resonance imaging (MRI) to analyze the rate of spinal cord decompression after surgery. Pre-operative (within 8 h of injury) and post-operative (within 48 h of injury) MRI images of 184 motor complete patients (American Spinal Injury Association Impairment Scale [AIS] grade A = 119, AIS grade B = 65) were reviewed to verify spinal cord decompression. Decompression was defined as the presence of a patent subarachnoid space around a swollen spinal cord. Of the 184 patients, 100 (54.3%) underwent anterior cervical discectomy and fusion (ACDF), and 53 of them also underwent laminectomy. Of the 184 patients, 55 (29.9%) underwent anterior cervical corpectomy and fusion (ACCF), with (26 patients) or without (29 patients) laminectomy. Twenty-nine patients (16%) underwent stand-alone laminectomy. Decompression was verified in 121 patients (66%). The rates of decompression in patients who underwent ACDF and ACCF without laminectomy were 46.8% and 58.6%, respectively. Among these patients, performing a laminectomy increased the rate of decompression (72% and 73.1% of patients, respectively). Twenty-five of 29 (86.2%) patients who underwent a stand-alone laminectomy were found to be successfully decompressed. The rates of decompression among patients who underwent laminectomy at one, two, three, four, or five levels were 58.3%, 68%, 78%, 80%, and 100%, respectively (p < 0.001). In multi-variate logistic regression analysis, only laminectomy was significantly associated with successful decompression (odds ratio 4.85; 95% confidence interval 2.2-10.6; p < 0.001). In motor complete TSCI patients, performing a laminectomy significantly increased the rate of successful spinal cord decompression, independent of whether anterior surgery was performed. ©2018 Bizhan Aarabi et al.
