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Evelyne Emery, Philipp Aldana, Mary Bartlett Bunge, William Puckett, Anu Srinivasan, Robert W. Keane, John Bethea and Allan D. O. Levi

patients without SCI and 15 patients who died at different time points after an SCI. Fifteen specimens were obtained from the Miami Project's Human Spinal Cord Injury Bank, which contains more than 100 injured human spinal cords. The cases were selected based on the short interval between SCI and death (0–2 months) and the availability of tissue above and below the lesion site. Preparation of Specimens The spinal cords had been removed at autopsy, usually within 16 hours after death. They were then fixed in 10% neutral buffered formalin for a minimum of 15 days

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Evelyne Emery, Philipp Aldana, Mary Bartlett Bunge, William Puckett, Anu Srinivasan, Robert W. Keane, John Bethea and Allan D. O. Levi

Apoptosis is a form of programmed cell death seen in a variety of developmental and disease states, including traumatic injuries. The main objective of this study was to determine whether apoptosis is observed after human spinal cord injury (SCI). The spatial and temporal expression of apoptotic cells as well as the nature of the cells involved in programmed cell death were also investigated.

The authors examined the spinal cords of 15 patients who died between 3 hours and 2 months after a traumatic SCI. Apoptotic cells were found at the edges of the lesion epicenter and in the adjacent white matter, particularly in the ascending tracts, by using histological (cresyl violet, hematoxylin and eosin) and nuclear staining (Hoechst 33342). The presence of apoptotic cells was supported by staining with the terminal deoxynucleotidyl transferase-mediated deoxyuridinetriphosphate nick-end labeling technique and confirmed by immunostaining for the processed form of caspase-3 (CPP-32), a member of the interleukin-1-beta-converting enzyme/Caenorhabditis elegans D 3 (ICE/CED-3) family of proteases that plays an essential role in programmed cell death. Apoptosis in this series of human SCIs was a prominent pathological finding in 14 of the 15 spinal cords examined when compared with five uninjured control spinal cords. To determine the type of cells undergoing apoptosis, the authors immunostained specimens with a variety of antibodies, including glial fibrillary acidic protein, 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNPase), and CD45/68. Oligodendrocytes stained with CNPase and a number of apoptotic nuclei colocalized with positive staining for this antibody.

These results support the hypothesis that apoptosis occurs in human SCIs and is accompanied by the activation of caspase-3 of the cysteine protease family. This mechanism of cell death contributes to the secondary injury processes seen after human SCI and may have important clinical implications for the further development of protease inhibitors to prevent programmed cell death.

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Evelyne Emery, Philipp Aldana, Mary Bartlett Bunge, William Puckett, Anu Srinivasan, Robert W. Keane, John Bethea and Allan D. O. Levi

Object

Apoptosis is a form of programmed cell death seen in a variety of developmental and disease states, including traumatic injuries. The main objective of this study was to determine whether apoptosis is observed after human spinal cord injury (SCI). The spatial and temporal expression of apoptotic cells as well as the nature of the cells involved in programmed cell death were also investigated.

Methods

The authors examined the spinal cords of 15 patients who died between 3 hours and 2 months after a traumatic SCI. Apoptotic cells were found at the edges of the lesion epicenter and in the adjacent white matter, particularly in the ascending tracts, by using histological (cresyl violet, hematoxylin and eosin) and nuclear staining (Hoechst 33342). The suspected presence of apoptotic cells was supported by staining with the terminal deoxynucleotidyl transferase-mediated biotinylated-deoxyuridinetriphosphate nick-end labeling technique and confirmed by immunostaining for the processed form of caspase-3 (CPP-32), a member of the interleukin-1-beta-converting enzyme/Caenorhabditis elegans D 3 family of proteases that plays an essential role in programmed cell death. Apoptosis in this series of human SCIs was a prominent pathological finding in 14 of the 15 spinal cords examined when compared with five uninjured control spinal cords. To determine the type of cells undergoing apoptosis, the authors immunostained specimens with a variety of antibodies, including glial fibrillary acidic protein, 2,′3′-cyclic nucleotide 3′-phosphohydrolase (CNPase), and CD45/68. Oligodendrocytes stained with CNPase and a number of apoptotic nuclei colocalized with positive staining for this antibody.

Conclusions

These results support the hypothesis that apoptosis occurs in human SCIs and is accompanied by the activation of CPP-32 of the cysteine protease family. This mechanism of cell death contributes to the secondary injury processes seen after human SCI and may have important clinical implications for the further development of protease inhibitors to prevent programmed cell death.

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Charles H. Tator and Izumi Koyanagi

to visualize the vascular system in the human spinal cord. It was believed that this technique would provide useful information for interpreting vascular damage in acute spinal cord injury, especially the phenomena of secondary injury and remote infarction. In addition, we analyzed histological findings in nine traumatized human spinal cords obtained at autopsy. The purpose of these studies was to determine the role of vascular injuries in the pathophysiology of human spinal cord injury. Materials and Methods Silicone Rubber Angiography in the Uninjured Human

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Charles H. Tator and Izumi Koyanagi

Vascular injury plays an important role in the primary and secondary injury mechanisms that cause damage to the acutely traumatized spinal cord. To understand the pathophysiology of human spinal cord injury, the authors investigated the vascular system in three uninjured human spinal cords using silicone rubber microangiography and analyzed the histological findings related to vascular injury in nine acutely traumatized human spinal cords obtained at autopsy. The interval from spinal cord injury to death ranged from 20 minutes to 9 months. The microangiograms of the uninjured human cervical cords demonstrated new information about the sulcal arterial system and the pial arteries. The centrifugal sulcal arterial system was found to supply all of the anterior gray matter, the anterior half of the posterior gray matter, approximately the inner half of the anterior and lateral white columns, and the anterior half of the posterior white columns. Traumatized spinal cord specimens in the acute stage (3-5 days postinjury) showed severe hemorrhages predominantly in the gray matter, but also in the white matter. The white matter surrounding the hemorrhagic gray matter showed a variety of lesions, including decreased staining, disrupted myelin, and axonal and periaxonal swelling. The white matter lesions extended far from the injury site, especially in the posterior columns. There was no evidence of complete occlusion of any of the larger arteries, including the anterior and posterior spinal arteries and the sulcal arteries. However, occluded intramedullary veins were identified in the degenerated posterior white columns. In the chronic stage (3-9 months postinjury), the injured segments showed major tissue loss with large cavitations, whereas both rostral and caudal remote sites showed well-demarcated necrotic areas indicative of infarction mainly in the posterior white columns. Obstruction of small intramedullary arteries and veins by the initial mechanical stress or secondary injury mechanisms most likely produced these extensive white matter lesions. Our studies implicate damage to the anterior sulcal arteries in causing the hemorrhagic necrosis and subsequent central myelomalacia at the injury site in acute spinal cord injury in humans.

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Kun Li, Darryn Atkinson, Maxwell Boakye, Carie Z. Tolfo, Sevda Aslan, Matthew Green, Barry McKay, Alex Ovechkin and Susan J. Harkema

and voluntary motor control in motor-incomplete human spinal cord injury . Exp Brain Res 163 : 379 – 387 , 2005 10 McKay WB , Lim HK , Priebe MM , Stokic DS , Sherwood AM : Clinical neurophysiological assessment of residual motor control in post-spinal cord injury paralysis . Neurorehabil Neural Repair 18 : 144 – 153 , 2004 11 McKay WB , Ovechkin AV , Vitaz TW , Terson de Paleville DG , Harkema SJ : Long-lasting involuntary motor activity after spinal cord injury . Spinal Cord 49 : 87 – 93 , 2011 12 McKay WB

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Jau-Ching Wu, Wen-Cheng Huang, Yu-Chun Chen, Tsung-Hsi Tu, Yun-An Tsai, Shih-Fong Huang, Hsueh-Chen Huang and Henrich Cheng

regeneration in the adult CNS by modulation of the PTEN/mTOR pathway . Science 322 : 963 – 966 , 2008 25 Rihn JA , Anderson DT , Sasso RC , Zdeblick TA , Lenke LG , Harris MB , : Emergency evaluation, imaging, and classification of thoracolumbar injuries . Instr Course Lect 58 : 619 – 628 , 2009 26 Tator CH : Review of treatment trials in human spinal cord injury: issues, difficulties, and recommendations . Neurosurgery 59 : 957 – 987 , 2006 27 Tsai EC , Krassioukov AV , Tator CH : Corticospinal regeneration into lumbar grey

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Shlomo Constantini and Wise Young

T wo recent clinical trials have tested treatments that improve neurological recovery in human spinal cord injury. In the first trial, the second National Acute Spinal Cord Injury Study (NASCIS 2) showed that methylprednisolone sodium succinate (MP) improves neurological recovery when given in high doses and within 8 hours after injury. 14, 15, 131 Patients receiving MP more than 8 hours after injury may have a worse recovery than placebo-treated patients. 15 Because the doses of MP required for neuroprotection greatly exceed that needed to activate

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Sukhvinder Kalsi-Ryan, Armin Curt, Mary C. Verrier and Michael G. Fehlings

Object

Primary outcome measures for the upper limb in trials concerning human spinal cord injury (SCI) need to distinguish between functional and neurological changes and require satisfying psychometric properties for clinical application.

Methods

The Graded Redefined Assessment of Strength, Sensibility and Prehension (GRASSP) was developed by the International GRASSP Research and Design Team as a clinical outcome measure specific to the upper limbs for individuals with complete and incomplete tetraplegia (that is, paralysis or paresis). It can be administered across the continuum of recovery after acute cervical SCI. An international multicenter study (involving centers in North America and Europe) was conducted to apply the measure internationally and examine its applicability.

Results

The GRASSP is a multimodal test comprising 5 subtests for each upper limb: dorsal sensation, palmar sensation (tested with Semmes-Weinstein monofilaments), strength (tested with motor grading of 10 muscles), and prehension (distinguishes scores for qualitative and quantitative grasping). Thus, administration of the GRASSP results in 5 numerical scores that provide a comprehensive profile of upper-limb function. The established interrater and test-retest reliability for all subtests within the GRASSP range from 0.84 to 0.96 and from 0.86 to 0.98, respectively. The GRASSP is approximately 50% more sensitive (construct validity) than the International Standards of Neurological Classification of SCI (ISNCSCI) in defining sensory and motor integrity of the upper limb. The subtests show concurrence with the Spinal Cord Independence Measure (SCIM), SCIM self-care subscales, and Capabilities of Upper Extremity Questionnaire (CUE) (the strongest concurrence to impairment is with self-perception of function [CUE], 0.57–0.83, p < 0.0001).

Conclusions

The GRASSP was found to demonstrate reliability, construct validity, and concurrent validity for use as a standardized upper-limb impairment measure for individuals with complete or incomplete tetraplegia. Responsiveness (follow-up from onset to 1 year postinjury) is currently being tested in international studies (in North America and Europe). The GRASSP can be administered early after injury, thus making it a tool that can be administered in acute care (in the ICU), rehabilitation, and outpatient clinics.

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Scott A. Shapiro

actually have no effect on the mean motor recovery. It would reduce the mean light touch recovery by 1.6 points to 23.9 points, and also reduce the mean pinprick recovery by 1.4 points to 19 points. The conclusion of the study would not change. The device appears to be feasible and safe in humans and a suggestion of efficacy is still made for improving neurological outcome following compete human spinal cord injury. We have since placed 3 more devices and continue to see similar results. The device still warrants further study.