Use of global sagittal flexibility to predict proximal junctional kyphosis after spinal deformity surgery.

OBJECTIVE: Sagittal alignment is an important predictor of functional outcomes after surgery for adult spinal deformity (ASD). A rigid spinal column may create a large lever arm that may impact the rate of proximal junctional kyphosis (PJK) after ASD surgery. In this study, the authors sought to determine whether relatively low preoperative global spinal flexibility (i.e., rigid spine) predicts increased incidence of PJK at 1 year after ASD surgery. METHODS: The authors retrospectively reviewed long-segment thoracolumbar fusions with pelvic fixation performed at a single tertiary care center between October 2015 and September 2020 in patients with a minimum of 1-year radiographic and clinical follow-up. Two cohorts were established on the basis of the optimal value for spinal flexibility, as defined by the absolute difference between the preoperative standing and supine C7 sagittal vertical axes, which the authors termed global sagittal flexibility (GSF). Demographic information, radiographs, various associated complications, and patient-reported outcome measures (PROMs) were analyzed. RESULTS: Eighty-five patients met the inclusion criteria. Receiver operating characteristic (ROC) analysis using GSF to predict an increase in the proximal junctional sagittal Cobb angle (PJCA) greater than or equal to 10° at 1-year follow-up provided an area under the curve of 0.64 and identified an optimal GSF threshold value of 3.7 cm. Patients with GSF > 3.7 cm were considered globally flexible (48 patients), and those with GSF ≤ 3.7 cm were classified as rigid (37 patients). Rigid patients were noted to have a significantly higher risk of ΔPJCA ≥ 10° at 1-year follow-up (51.4% vs 29.3%, p = 0.049). No changes in the reoperation rates or PROMs based on GSF were observed in the 1- or 2-year postoperative window. CONCLUSIONS: Based on these retrospective data, preoperative global spinal rigidity portends an independently elevated risk for the development of PJK after ASD surgery. No differences in other complication rates or PROMs data were observed between groups. Data collection was limited to a 2-year postoperative window; therefore, longer follow-up is required to further elucidate the relationship between rigidity and reoperation rates. Based on these retrospective data, flexibility may influence the outcomes of patients with ASD.

Comparison of Transforaminal Lumbar Interbody Fusion in the Ambulatory Surgery Center and Traditional Hospital Settings, Part 2: Assessment of Surgical Safety in Medicare Beneficiaries.

(1) Background: The clinical benefits and procedural efficiencies of performing minimally invasive fusion procedures, such as transforaminal lumbar interbody fusion (TLIF), in the ambulatory surgery center (ASC) are becoming increasingly well established. Currently, Medicare does not provide reimbursement for its beneficiaries eligible for TLIF in the ASC due to a lack of evidence regarding procedural safety. However, the initiation of the Hospital Without Walls program allowed for traditional hospital procedures to be relocated to other facilities such as ASCs, providing a unique opportunity to evaluate the utility of TLIF in the ASC in Medicare-age patients. (2) Methods: This single-center, retrospective study compared baseline characteristics, intraoperative variables, and 30-day postoperative safety outcomes between 48 Medicare-age patients undergoing TLIF in the ASC and 48 patients having the same procedure as hospital in-patients. All patients had a one-level TLIF using the VariLift®-LX expandable lumbar interbody fusion device. (3) Results: There were similar patient characteristics, procedural efficiency, and occurrence of clinical 30-day safety events between the two study groups. However, there was a marked and statistically significant difference in the median length of stay favoring TLIF patients treated in the ASC (23.9 h vs. 1.6 h, p = 0.001). All ASC-treated patients were discharged on the day of surgery. Postoperative visits to address adverse events were rare in either group. (4) Conclusions: These findings provide evidence that minimally invasive TLIF can be performed safely and efficiently in the ASC in Medicare-age patients. With same-day discharge, fusion procedures performed in the ASC offer a similar safety and more attractive cost-benefit profile for older patients than the same surgery undertaken in the traditional hospital setting. The Centers for Medicare and Medicaid Services should strongly consider extending the appropriate reimbursement codes (CPT ® 22630, 22633) for minimally invasive TLIF and PLIF to the ASC Covered Procedure List so that Medicare-age patients can realize the clinical benefits of surgeries performed in this setting.

Spinal deformity correction in ankylosing spondylitis.

Background: Ankylosing spondylitis (AS) is a complex, debilitating disease with few available medical therapies in its later stages. Methods: We reviewed current clinical approaches for caring for AS patients with an emphasis on the risks and outcomes associated with surgical intervention. Results: It is critical to understand the natural history and surgical outcomes of patient with AS. Surgery is not without risks, as a vertebral body osteotomy is often required to re-establish spinopelvic equilibrium. However, surgery can lead to clinical improvements in pain, disability, cardiac function, respiration, digestion, and sexual activity. Conclusion: Deformity correction for AS should be carefully considered in symptomatic patients.

Static Cage Morphology in Short-Segment Transforaminal Lumbar Interbody Fusions Is Associated With Alterations in Foraminal Height But Not Clinical Outcomes.

INTRODUCTION: Steerable "banana" cages have been posited to increase segmental lordosis in short-segment transforaminal lumbar interbody fusions (TLIF). The same is not necessarily true for straight "bullet" cages. Although increased lordosis is generally thought to be advantageous, a potential complication is decreased foraminal height. Here we evaluate for any association between cage type and change in foraminal height and clinical outcomes following short-segment TLIFs. METHODS: We retrospectively reviewed consecutive 1- and 2-level TLIFs with bilateral facetectomies with minimum 1-year clinical and radiographic follow-up. Two cohorts were based on cage morphology: steerable "banana" cage or straight "bullet" cage. Patient reported outcome measures (PROMs), radiographic measurements, and revision rates were compared. RESULTS: A total of 46 patients with 53 straight and 95 patients with 131 steerable cage levels were included. Steerable cages showed increased segmental lordosis (9.1° vs. 13.5°, P < 0.001) and decreased foraminal height (20.3 vs. 18.5 mm, P < 0.001) after surgery. Straight cages demonstrated similar segmental lordosis (8.7° vs 8.1°, P = 0.30) and foraminal height (19.4 vs 20.0 mm, P < 0.065). Both cohorts showed improved PROMs at last follow-up (P ≤ 0.005). Subanalysis comparing patients who had increased or decreased foraminal height revealed similarly improved PROMs between cohorts. Revision rates at 1 year were similar between cohorts (4.3% for straight and 3.2% for steerable group, P = 0.72). CONCLUSIONS: Although the increased segmental lordosis afforded by placement of steerable cages may decrease foraminal height after short segment TLIF, clinical outcomes are not negatively affected by this association.

Radiographic and clinical outcomes in one- and two-level transforaminal lumbar interbody fusions: a comparison of bullet versus banana cages.

OBJECTIVE: The aim of this study was to determine whether cage morphology influences clinical and radiographic outcomes following short-segment transforaminal lumbar interbody fusion (TLIF) procedures. METHODS: The authors retrospectively reviewed one- and two-level TLIFs at a single tertiary care center between August 2012 and November 2019 with a minimum 1-year radiographic and clinical follow-up. Two cohorts were compared based on interbody cage morphology: steerable "banana" cage or straight "bullet" cage. Patient-reported outcome measures (PROMs), radiographs, and complications were analyzed. RESULTS: A total of 135 patients with 177 interbody levels were identified; 45 patients had 52 straight cages and 90 patients had 125 steerable cages. Segmental lordosis increased with steerable cages, while it decreased with straight cages (+3.8 ± 4.6 vs -1.9 ± 4.3, p < 0.001). Conversely, the mean segmental lordosis of adjacent lumbar levels decreased in the former group, while it increased in the latter group (-0.52 ± 1.9 vs +0.52 ± 2.1, p = 0.004). This reciprocal relationship results in global sagittal parameters, including pelvic incidence minus lumbar lordosis and lumbar distribution index, which did not change after surgery with either cage morphology. Multivariate analysis confirmed that steerable cage morphology, anterior cage positioning, and less preoperative index-level segmental lordosis were associated with greater improvement in index-level segmental lordosis. PROMs were improved after surgery with both cage types, and the degree of improvement did not differ between cohorts (p > 0.05). Perioperative and radiographic complications were similar between cohorts (p > 0.05). Overall reoperation rates, as well as reoperation rates for adjacent-segment disease within 2 years of surgery, were not significantly different between cohorts. CONCLUSIONS: Steerable cages are more likely to lie within the anterior disc space, thus increasing index-level segmental lordosis, which is accompanied by a reciprocal change in segmental alignment at the adjacent lumbar levels. The converse relationship occurs for straight cages, with a kyphotic change at the index levels and reciprocal lordosis occurring at adjacent levels.

FGFR1-TACC1 fusion associated with malignant transformation in a primary spinal cord glioma: a case report.

Molecular mechanisms of malignant transformation in spinal cord gliomas are not well-understood. Our objective was to investigate genetic causes of malignant transformation in a primary spinal cord glioma. A 32-year-old female patient presented with bilateral lower extremity weakness and was diagnosed with a primary spinal cord glioma from T9 to T12, with a syrinx extending from the craniocervical junction to the conus. She underwent resection in 2006. Pathology showed an abundance of Rosenthal fibers, calcification and degenerative features consistent with a low-grade pilocytic astrocytoma. She presented in 2020 with tumor recurrence and underwent re-resection. Whole exome sequencing, DNA methylation profiling and immunohistochemistry were performed on her initial and recurrent tumor samples. Immunohistochemical profiling of her recurrent tumor showed pleomorphic cells with extensive necrosis consistent with a high-grade glioma. DNA methylation profiling showed that the initial tumor clustered with pilocytic astrocytomas, whereas the recurrent lesion clustered with anaplastic astrocytomas, confirming malignant transformation. Whole-exome sequencing showed interim acquisition of a rare fibroblast growth factor receptor-transforming acidic coiled-coil (FGFR1-TACC1) gene fusion. We report an FGFR1-TACC1 fusion associated with malignant transformation in a primary spinal cord glioma. Our study adds to growing reports of FGFR-TACC fusions, which are amenable to receptor tyrosine kinase inhibition.

Compressive epidural collection as an unusual complication of FESS for a pediatric mycetoma.

Functional endoscopic sinus surgery (FESS) is a treatment of choice for fungal sinus ball (mycetoma), which is considered safe with a very low major complication rate. We present an unusual case of a 12-year-old female, who underwent FESS for a sphenoid sinus mycetoma and which was complicated by an acute, compressive epidural fluid collection. This presumably resulted from sinus irrigation in the setting of an under-appreciated skull base and mucosal defects causing a ball-valve effect. Our patient had a temporary neurologic deficit with complete recovery, however, similar complications can have fatal consequences.

Inhibition of protein phosphatase-2A with LB-100 enhances antitumor immunity against glioblastoma.

PURPOSE: Glioblastoma (GBM) carries a dismal prognosis despite standard multimodal treatment with surgery, chemotherapy and radiation. Immune checkpoint inhibitors, such as PD1 blockade, for treatment of GBM failed to show clinical benefit. Rational combination strategies to overcome resistance of GBM to checkpoint monotherapy are needed to extend the promise of immunotherapy to GBM management. Emerging evidence suggests that protein phosphatase 2A (PP2A) plays a critical role in the signal transduction pathways of both adaptive and innate immune cells and that inhibition of PP2A could enhance cancer immunity. We investigated the use of a PP2A inhibitor, LB-100, to enhance antitumor efficacy of PD1 blockade in a syngeneic glioma model. METHODS: C57BL/6 mice were implanted with murine glioma cell line GL261-luc or GL261-WT and randomized into 4 treatment arms: (i) control, (ii) LB-100, (iii) PD1 blockade and (iv) combination. Survival was assessed and detailed profiling of tumor infiltrating leukocytes was performed. RESULTS: Dual PP2A and PD1 blockade significantly improved survival compared with monotherapy alone. Combination therapy resulted in complete regression of tumors in about 25% of mice. This effect was dependent on CD4 and CD8 T cells and cured mice established antigen-specific secondary protective immunity. Analysis of tumor lymphocytes demonstrated enhanced CD8 infiltration and effector function. CONCLUSION: This is the first preclinical investigation of the effect of combining PP2A inhibition with PD1 blockade for GBM. This novel combination provided effective tumor immunotherapy and long-term survival in our animal GBM model.

Adult revision surgery of prior hook-and-rod wire instrumentation for idiopathic scoliosis.

Adolescent idiopathic scoliosis patients treated with spinal fusion may develop adjacent segment disease and curve progression into adulthood. Revision operations can be challenging, especially for adult patients treated with outdated instrumentation such as sublaminar hooks and/or wires. The authors demonstrate revision lumbar spine surgery in a 38-year-old female with scoliosis progression from junctional degeneration below a prior T5-L3 posterior instrumented arthrodesis with a hook-and-rod wire system. They also demonstrate safe application of an ultrasonic bone scalpel for completion of a Smith-Petersen osteotomy. The patient provided written, informed consent for all material presented in this case demonstration. The video can be found here: https://youtu.be/3PmaFtNcqKc.

Resection of Myxopapillary Ependymoma of the Filum Terminale: 2-Dimensional Operative Video.

We present the case of a 48-yr-old female who presented with persistent thigh pain and was found to have a heterogeneous mass caudal to the conus most consistent with a myxopapillary ependymoma. We performed L2-3 laminectomies for tumor resection. For this procedure, we used intraoperative ultrasound as well as neuromonitoring. This video illustrates the gross pathology of a myxopapillary ependymoma, effective circumferential blunt and sharp dissection of the cauda equina from the tumor, and identification, preparation, and sectioning of the filum terminale. This case also underlines the challenges of removing a large myxopapillary ependymoma when motor nerve rootlets are encapsulated in the tumor. In this case, we were obligated to enter the tumor capsule ventrally in order to dissect away cauda equina nerves passing through the tumor. The patient consented to be part of our research study.

Resection of von Hippel Lindau Related Brainstem Hemangioblastoma.

Patients with von Hippel Lindau (VHL) disease develop multiple central nervous system hemangioblastomas (HB). The surgical resection of VHL-HBs is the standard of clinical care when these HBs become symptomatic due to tumor growth, edema, or cyst formation. VHL-HBs frequently present at the obex of the brainstem, making this a challenging surgical problem. Here, we present a case of a large symptomatic brainstem VHL-HB that was resected using a dorsal midline approach and midline myelotomy. This 35-year-old man with VHL disease and multiple prior resections of cerebellar hemangioblastomas presented with progressive bilateral upper extremity weakness, ataxia, and dysphagia. The accompanying two-dimensional (2D) video demonstrates the key techniques for resection of this brainstem hemangioblastoma, including recognizing the pial presentation, sharp pial/subpial dissection, and en bloc removal. Subsequently, we discuss circumferential dissection, identification, and division of feeding vessels. We also demonstrate key maneuvers to recognize and divide the main arterial pedicle while preserving the anterior spinal artery. The patient tolerated the resection without complication and the patient was discharged home after 6 days at his baseline neurologic function. This work was supported by the Intramural Research Program of the National Institutes of Health. The link to the video can be found at: https://youtu.be/mb2VqcLpxDQ .

Chiari Malformation Type 1 in EPAS1-Associated Syndrome.

A syndrome of multiple paragangliomas/pheochromocytomas, somatostatinoma, and polycythemia due to somatic mosaic gain-of-function mutation of EPAS1, encoding HIF-2α, was previously described. HIF-2α has been implicated in endochondral and intramembranous ossification. Abnormal bone growth of the skull base may lead to Chiari malformation type I. We report two cases of EPAS1 gain-of-function mutation syndrome with Chiari malformation and developmental skull base anomalies. Patients were referred to the Section on Medical Endocrinology, Eunice Kennedy Shriver NICHD, NIH for evaluation of recurrent and metastatic paragangliomas or pheochromocytoma. The syndrome was confirmed genetically by identification of the functional EPAS1 gain-of-function mutation in the resected tumors and circulating leukocytes. Both patients were confirmed for characteristics of EPAS1 gain-of-function mutation syndrome by complete blood count (CBC), plasma biochemistry, and computed tomography (CT) of the abdomen and pelvis. Chiari malformation type I and abnormal bony development of the posterior fossa was found on MRI and CT of the head. The present study implicates EPAS1 mutations in abnormal posterior fossa development resulting in Chiari malformation type I.

Pharmacologic inhibition of protein phosphatase-2A achieves durable immune-mediated antitumor activity when combined with PD-1 blockade.

Mounting evidence suggests that inhibition of protein phosphatase-2A (PP2A), a serine/threonine phosphatase, could enhance anticancer immunity. However, drugs targeting PP2A are not currently available. Here, we report that a PP2A inhibitor, LB-100, when combined with anti-PD-1 (aPD-1) blockade can synergistically elicit a durable immune-mediated antitumor response in a murine CT26 colon cancer model. This effect is T-cell dependent, leading to regression of a significant proportion of tumors. Analysis of tumor lymphocytes demonstrates enhanced effector T-cell and reduced suppressive regulatory T-cell infiltration. Clearance of tumor establishes antigen-specific secondary protective immunity. A synergistic effect of LB-100 and aPD-1 blockade is also observed in B16 melanoma model. In addition, LB-100 activates the mTORC1 signaling pathway resulting in decreased differentiation of naive CD4 cells into regulatory T cells. There is also increased expression of Th1 and decreased expression of Th2 cytokines. These data highlight the translational potential of PP2A inhibition in combination with checkpoint inhibition.

Isocitrate dehydrogenase 2 mutations correlate with leukemic transformation and are predicted by 2-hydroxyglutarate in myelodysplastic syndromes.

PURPOSE: The myelodysplastic syndromes (MDS) are a group of hematologic disorders characterized by the presence of somatically mutated hematopoietic stem cells (HSCs) that increase the risk of progression to secondary acute myeloid leukemia (sAML). Mutations in isocitrate dehydrogenase (IDHmut) are thought to correlate with the increased production of the oncogenic protein 2-hydroxyglutarate (2-HG) in AML. The aim of this study was to examine whether serum 2-HG has utility as a prognostic biomarker, and whether elevated 2-HG levels are predictive of IDH mutations in patients with MDS. METHODS: Genetic profiling was utilized to determine the genetic composition of a large cohort of MDS patients, including the presence or absence of IDH1 or IDH2 mutations (n = 281). Serum 2-HG levels were detected by liquid chromatography-tandem mass spectrometry. RESULTS: In the current study of MDS patients, elevated serum 2-HG levels were predictive of inferior overall- and leukemia-free survival irrespective of IPSS risk grouping. Higher serum 2-HG levels predicted the presence of IDH mutations. IDH2mut patients had a higher risk of leukemic transformation. The co-occurrence of DNMT3A or SRSF2 mutations was found to be increased in IDH2mut patients. IDH2 mutations were associated with significantly worse OS and LFS amongst patients with low-risk MDS by IPSS grouping. CONCLUSIONS: The noted predictive value of serum 2-HG levels and IDH2 mutations on OS and LFS support the use of biomarkers and/or underlying cytogenetics in novel prognostic scoring systems for MDS.

Publisher Correction: PP2A inhibition from LB100 therapy enhances daunorubicin cytotoxicity in secondary acute myeloid leukemia via miR-181b-1 upregulation.

A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper.

Vorinostat suppresses hypoxia signaling by modulating nuclear translocation of hypoxia inducible factor 1 alpha.

Histone deacetylase inhibitors (HDACis) are a potent class of tumor-suppressive agents traditionally believed to exert their effects through loosening tightly-wound chromatin resulting in de-inhibition of various tumor suppressive genes. Recent literature however has shown altered intratumoral hypoxia signaling with HDACi administration not attributable to changes in chromatin structure. We sought to determine the precise mechanism of HDACi-mediated hypoxia signaling attenuation using vorinostat (SAHA), an FDA-approved class I/IIb/IV HDACi. Through an in-vitro and in-vivo approach utilizing cell lines for hepatocellular carcinoma (HCC), osteosarcoma (OS), and glioblastoma (GBM), we demonstrate that SAHA potently inhibits HIF-a nuclear translocation via direct acetylation of its associated chaperone, heat shock protein 90 (Hsp90). In the presence of SAHA we found elevated levels of acetyl-Hsp90, decreased interaction between acetyl-Hsp90 and HIF-a, decreased nuclear/cytoplasmic HIF-α expression, absent HIF-α association with its nuclear karyopharyin Importin, and markedly decreased HIF-a transcriptional activity. These changes were associated with downregulation of downstream hypoxia molecules such as endothelin 1, erythropoietin, glucose transporter 1, and vascular endothelial growth factor. Findings were replicated in an in-vivo Hep3B HRE-Luc expressing xenograft, and were associated with significant decreases in xenograft tumor size. Altogether, this study highlights a novel mechanism of action of an important class of chemotherapeutic.

Functional Outcome After Resection of Von Hippel-Lindau Disease-Associated Cauda Equina Hemangioblastomas: An Observational Cohort Study.

BACKGROUND: Cauda equina hemangioblastomas in von Hippel-Lindau (VHL) disease can cause significant neurological signs and symptoms. Despite their associated morbidity, the management of these tumors remains incompletely defined. OBJECTIVE: To determine optimal management, we analyzed the functional outcomes after resection of these tumors. METHODS: VHL patients who underwent surgical resection of cauda equina hemangioblastomas at the National Institutes of Health and the University of Virginia were included. Clinical and radiological follow-up was performed at 6- to 12-month intervals after surgery. RESULTS: Fifteen patients underwent 18 operations for 21 cauda equina hemangioblastomas (median follow-up 5.9 years). Patients often presented with multiple symptoms, including pain (67%), numbness (50%), urinary complaints (33%), and weakness (11%). Median preoperative tumor volume was 1.2 cm 3 . Four tumors at 3 operations were not resected due to a motor nerve root origin. Gross total resection was achieved in 14 surgeries (93% of operations when resection was attempted). New mild (non-function limiting) neurological symptoms were noted after 11 operations (61%), which most often (64%) resolved within 2 weeks of surgery. At 6-month follow-up, 15 patients (83%) were stable, 2 (11%) were improved, and 1 (6%) was worse. Histological analysis revealed that all tumors originated from within the involved nerve fascicle. CONCLUSIONS: VHL-associated cauda equina hemangioblastomas have an intrafascicular origin and require interruption of the rootlet of origin for complete resection. Motor nerve root involvement may preclude complete resection but strategies including bony decompression and/or interruption of vascular supply may provide a therapeutic option. Nevertheless, most VHL patients with symptom-producing lesions improve with resection.

PP2A inhibition from LB100 therapy enhances daunorubicin cytotoxicity in secondary acute myeloid leukemia via miR-181b-1 upregulation.

Patients with secondary acute myeloid leukemia (sAML) arising from myelodysplastic syndromes have a poor prognosis marked by an increased resistance to chemotherapy. An urgent need exists for adjuvant treatments that can enhance or replace current therapeutic options. Here we show the potential of LB100, a small-molecule protein phosphatase 2 A (PP2A) inhibitor, as a monotherapy and chemosensitizing agent for sAML using an in-vitro and in-vivo approach. We demonstrate that LB100 decreases cell viability through caspase activation and G2/M cell-cycle arrest. LB100 enhances daunorubicin (DNR) cytotoxicity resulting in decreased xenograft volumes and improved overall survival. LB100 profoundly upregulates miR-181b-1, which we show directly binds to the 3' untranslated region of Bcl-2 mRNA leading to its translational inhibition. MiR-181b-1 ectopic overexpression further diminishes Bcl-2 expression leading to suppression of sAML cell growth, and enhancement of DNR cytotoxicity. Our research highlights the therapeutic potential of LB100, and provides new insights into the mechanism of LB100 chemosensitization.

Identifying the Long-Term Role of Inducible Nitric Oxide Synthase after Contusive Spinal Cord Injury Using a Transgenic Mouse Model.

Inducible nitric oxide synthase (iNOS) is a potent mediator of oxidative stress during neuroinflammation triggered by neurotrauma or neurodegeneration. We previously demonstrated that acute iNOS inhibition attenuated iNOS levels and promoted neuroprotection and functional recovery after spinal cord injury (SCI). The present study investigated the effects of chronic iNOS ablation after SCI using inos-null mice. iNOS-/- knockout and wild-type (WT) control mice underwent a moderate thoracic (T8) contusive SCI. Locomotor function was assessed weekly, using the Basso Mouse Scale (BMS), and at the endpoint (six weeks), by footprint analysis. At the endpoint, the volume of preserved white and gray matter, as well as the number of dorsal column axons and perilesional blood vessels rostral to the injury, were quantified. At weeks two and three after SCI, iNOS-/- mice exhibited a significant locomotor improvement compared to WT controls, although a sustained improvement was not observed during later weeks. At the endpoint, iNOS-/- mice showed significantly less preserved white and gray matter, as well as fewer dorsal column axons and perilesional blood vessels, compared to WT controls. While short-term antagonism of iNOS provides histological and functional benefits, its long-term ablation after SCI may be deleterious, blocking protective or reparative processes important for angiogenesis and tissue preservation.