Systemic inflammation alters the neuroinflammatory response: a prospective clinical trial in traumatic brain injury.

BACKGROUND: Neuroinflammation following traumatic brain injury (TBI) has been shown to be associated with secondary injury development; however, how systemic inflammatory mediators affect this is not fully understood. The aim of this study was to see how systemic inflammation affects markers of neuroinflammation, if this inflammatory response had a temporal correlation between compartments and how different compartments differ in cytokine composition. METHODS: TBI patients recruited to a previous randomised controlled trial studying the effects of the drug anakinra (Kineret®), a human recombinant interleukin-1 receptor antagonist (rhIL1ra), were used (n = 10 treatment arm, n = 10 control arm). Cytokine concentrations were measured in arterial and jugular venous samples twice a day, as well as in microdialysis-extracted brain extracellular fluid (ECF) following pooling every 6 h. C-reactive protein level (CRP), white blood cell count (WBC), temperature and confirmed systemic clinical infection were used as systemic markers of inflammation. Principal component analyses, linear mixed-effect models, cross-correlations and multiple factor analyses were used. RESULTS: Jugular and arterial blood held similar cytokine information content, but brain-ECF was markedly different. No clear arterial to jugular gradient could be seen. No substantial delayed temporal associations between blood and brain compartments were detected. The development of a systemic clinical infection resulted in a significant decrease of IL1-ra, G-CSF, PDGF-ABBB, MIP-1b and RANTES (p < 0.05, respectively) in brain-ECF, even if adjusting for injury severity and demographic factors, while an increase in several cytokines could be seen in arterial blood. CONCLUSIONS: Systemic inflammation, and infection in particular, alters cytokine levels with different patterns seen in brain and in blood. Cerebral inflammatory monitoring provides independent information from arterial and jugular samples, which both demonstrate similar information content. These findings could present potential new treatment options in severe TBI patients, but novel prospective trials are warranted to confirm these associations.

Improved cephalic index following early cranial vault remodeling in patients with isolated nonsyndromic sagittal synostosis.

OBJECTIVE: Isolated nonsyndromic sagittal synostosis (SS) is the most common form of craniosynostosis in children, accounting for approximately 60% of all craniosynostoses. The typical cranial measurement used to define and follow SS is the cephalic index (CI). Several surgical techniques have been suggested, but agreement on type and timing of surgery is lacking. This study aimed to evaluate the authors' institutional experience of surgically treating SS using a modified subtotal cranial vault remodeling technique in a population-based cohort. Special attention was directed toward the effect of patient age at time of surgery on long-term CI outcome. METHODS: A retrospective analysis was conducted on all patients with isolated nonsyndromic SS who were surgically treated from 2003 to 2011. Data from electronic medical records were gathered. Eighty-two patients with SS were identified, 77 fulfilled inclusion criteria, and 72 had sufficient follow-up data and were included. CI during follow-up after surgery was investigated with ANOVA and a linear mixed model. RESULTS: In total, 72 patients were analyzed, consisting of 16 females (22%) and 56 males (78%). The mean ± SD age at surgery was 4.1 ± 3.1 months. Blood transfusions were received by 81% of patients (26% intraoperatively, 64% postoperatively, 9% both). The mean ± SD time in the pediatric ICU was 1.1 ± 0.25 days, and the mean ± SD total hospital length of stay was 4.6 ± 2.0 days. No patient required reoperation. The mean ± SD CI increased from 69 ± 3 to 87 ± 5 for patients who underwent surgery before 45 days of age. Surgery resulted in a larger increase in CI for patients who underwent surgery at a younger age compared with older patients (p < 0.05, Tukey's HSD test). In the comparison of patients who underwent surgery before 45 days of age with patients who underwent surgery at 45-90, 90-180, and more than 180 days of age, the linear mixed model estimated a long-term loss of CI of 3.0, 5.5, and 7.4 points, respectively. CONCLUSIONS: The modified subtotal cranial vault remodeling technique used in this study significantly improved CI in patients with SS. The best results were achieved when surgery was performed early in life.

Utility of neuron-specific enolase in traumatic brain injury; relations to S100B levels, outcome, and extracranial injury severity.

BACKGROUND: In order to improve assessment and outcome prediction in patients suffering from traumatic brain injury (TBI), cerebral protein levels in serum have been suggested as biomarkers of injury. However, despite much investigation, biomarkers have yet to reach broad clinical utility in TBI. This study is a 9-year follow-up and clinical experience of the two most studied proteins, neuron-specific enolase (NSE) and S100B, in a neuro-intensive care TBI population. Our aims were to investigate to what extent NSE and S100B, independently and in combination, could predict outcome, assess injury severity, and to investigate if the biomarker levels were influenced by extracranial factors. METHODS: All patients treated at the neuro-intensive care unit at Karolinska University Hospital, Stockholm, Sweden between 2005 and 2013 with at least three measurements of serum S100B and NSE (sampled twice daily) were retrospectively included. In total, 417 patients fulfilled the criteria. Parameters were extracted from the computerized hospital charts. Glasgow Outcome Score (GOS) was used to assess long-term functional outcome. Univariate, and multivariate, regression models toward outcome and what explained the high levels of the biomarkers were performed. Nagelkerke's pseudo-R(2) was used to illustrate the explained variance of the different models. A sliding window assessed biomarker correlation to outcome and multitrauma over time. RESULTS: S100B was found a better predictor of outcome as compared to NSE (area under the curve (AUC) samples, the first 48 hours had Nagelkerke's pseudo-R(2) values of 0.132 and 0.038, respectively), where the information content of S100B peaks at approximately 1 day after trauma. In contrast, although both biomarkers were independently correlated to outcome, NSE had limited additional predictive capabilities in the presence of S100B in multivariate models, due to covariance between the two biomarkers (correlation coefficient 0.673 for AUC 48 hours). Moreover, NSE was to a greater extent correlated to multitrauma the first 48 hours following injury, whereas the effect of extracerebral trauma on S100B levels appears limited to the first 12 hours. CONCLUSIONS: While both biomarkers are independently correlated to long-term functional outcome, S100B is found a more accurate outcome predictor and possibly a more clinically useful biomarker than NSE for TBI patients.

Revision and Infection Rate in 728 Shunt-Treated Adult Hydrocephalus Patients-a Single-Center Retrospective Study.

BACKGROUND: Hydrocephalus is a common diagnosis worldwide that is treated with shunts and is associated with potential life-threatening risks of shunt dysfunction and infection. We investigated differences in rates of shunt revisions and infections including various factors in patients with different causes of hydrocephalus. We also studied causes of infections and efficacy of perioperative antibiotic regimens. Our objective was to identify patients at risk of higher revision and infection rates after shunt treatment. METHODS: We conducted a retrospective single-center cohort study including 728 adult patients who underwent shunt surgery between 2013 and 2019 at our center. RESULTS: Overall revision rate was 20.1%, and infection rate was 4.8%. Infection was detected in 24% of all revisions. The main location for a positive culture was cerebrospinal fluid (67.5%), frequently caused by Cutibacterium acnes (60%). Younger age and prior shunts were the only predictors confirmed in multivariate Cox regression as significantly increasing the risk of revision surgery. Multivariate Cox regression analysis of infection risk factors showed that obstructive hydrocephalus, prior shunt, and cloxacillin significantly increased risk of shunt infection. CONCLUSIONS: We found revision and infection rates in accordance with other studies. We showed a significantly increased risk in younger patients. Previous shunts also increased the risk of revisions and infections. We showed a small but significant effect of perioperative prophylaxis with broader-spectrum antibiotics compared with cloxacillin. Our study identified a group of younger patients with congenital hydrocephalus and prior implants with an increased risk of shunt infection in whom additional preventive measures should be employed.

Diffuse reflectance spectroscopy sensor to differentiate between glial tumor and healthy brain tissue: a proof-of-concept study.

Glial tumors grow diffusely in the brain. Survival is correlated to the extent of tumor removal, but tumor borders are often invisible. Resection beyond the borders as defined by conventional methods may further improve prognosis. In this proof-of-concept study, we evaluate diffuse reflectance spectroscopy (DRS) for discrimination between glial tumors and normal brain ex vivo. DRS spectra and histology were acquired from 22 tumor samples and nine brain tissue samples retrieved from 30 patients. The content of biological chromophores and scattering features were estimated by fitting a model derived from diffusion theory to the DRS spectra. DRS parameters differed significantly between tumor and normal brain tissue. Classification using random forest yielded a sensitivity and specificity for the detection of low-grade gliomas of 82.0% and 82.7%, respectively, and the area under curve (AUC) was 0.91. Applied in a hand-held probe or biopsy needle, DRS has the potential to provide intra-operative tissue analysis.

Delineating Astrocytic Cytokine Responses in a Human Stem Cell Model of Neural Trauma.

Neuroinflammation has been shown to mediate the pathophysiological response following traumatic brain injury (TBI). Accumulating evidence implicates astrocytes as key immune cells within the central nervous system (CNS), displaying both pro- and anti-inflammatory properties. The aim of this study was to investigate how in vitro human astrocyte cultures respond to cytokines across a concentration range that approximates the aftermath of human TBI. To this end, enriched cultures of human induced pluripotent stem cell (iPSC)-derived astrocytes were exposed to interleukin-1ß (IL-1ß) (1-10,000 pg/mL), IL-4 (1-10,000 pg/mL), IL-6 (100-1,000,000 pg/mL), IL-10 (1-10,000 pg/mL) and tumor necrosis factor (TNF)-α (1-10,000 pg/mL). After 1, 24, 48 and 72 h, cultures were fixed and immunolabeled, and the secretome/supernatant was analyzed at 24, 48, and 72 h using a human cytokine/chemokine 39-plex Luminex assay. Data were compared to previous in vitro studies of neuronal cultures and clinical TBI studies. The secretome revealed concentration-, time- and/or both concentration- and time-dependent production of downstream cytokines (29, 21, and 17 cytokines, respectively, p<0.05). IL-1ß exposure generated the most profound downstream response (27 cytokines), IL-6 and TNF had intermediate responses (13 and 11 cytokines, respectively), whereas IL-4 and IL-10 only led to weak responses over time or in escalating concentration (8 and 8 cytokines, respectively). Notably, expression of IL-1ß, IL-6, and TNF cytokine receptor mRNA was higher in astrocyte cultures than in neuronal cultures. Several secreted cytokines had temporal trajectories, which corresponded to those seen in the aftermath of human TBI. In summary, iPSC-derived astrocyte cultures exposed to cytokine concentrations reflecting those in TBI generated an increased downstream cytokine production, particularly IL-1ß. Although more work is needed to better understand how different cells in the CNS respond to the neuroinflammatory milieu after TBI, our data shows that iPSC-derived astrocytes represent a tractable model to study cytokine stimulation in a cell type-specific manner.

Syngeneic, in contrast to allogeneic, mesenchymal stem cells have superior therapeutic potential following spinal cord injury.

We evaluated the importance of histocompatibility of transplanted MSCs in terms of therapeutic potential. Mouse syngeneic MSCs or allogeneic MSCs were transplanted following SCI in mouse. In this study we found that syngeneic, but not allogeneic, MSCs alternatively activated macrophages resulting in a down-regulation of pro-inflammation. Syngeneic MSCs also had a general suppressive effect on the immune response as compared to allogeneic MSCs. Additionally, syngeneic, but not allogeneic, MSCs significantly enhanced the recovery of hind limb function. In this study we show that the histocompatibility of transplanted MSCs is of importance for their therapeutic potential.

Mesenchymal stem cells transplanted into spinal cord injury adopt immune cell-like characteristics.

BACKGROUND: Mesenchymal stem cells (MSCs) and their cellular response to various stimuli have been characterized in great detail in culture conditions. In contrast, the cellular response of MSCs in an in vivo setting is still uncharted territory. In this study, we investigated the cellular response of MSCs following transplantation into spinal cord injury (SCI). METHODS: Mouse bone marrow-derived MSCs were transplanted 24 h following severe contusion SCI in mice. As controls, MSCs transplanted to the uninjured spinal cord and non-transplanted MSCs were used. At 7 days post transplantation, the MSCs were isolated from the SCI, and their global transcriptional changes, survival, differentiation, proliferation, apoptosis, and phenotypes were investigated using RNA sequencing, immunohistochemistry, and flow cytometry. RESULTS: MSCs transplanted into SCI downregulated genes related to cell-cycle regulation/progression, DNA metabolic/biosynthetic process, and DNA repair and upregulated genes related to immune system response, cytokine production/response, response to stress/stimuli, signal transduction and signaling pathways, apoptosis, and phagocytosis/endocytosis. MSCs maintained their surface expression of Sca1 and CD29 but upregulated expression of CD45 following transplantation. Transplanted MSCs maintained their surface expression of MHC-I but upregulated surface expression of MHC-II. Transplanted MSCs survived and proliferated to a low extent, did not express Caspase-3, and did not differentiate into neurons or astrocytes. CONCLUSION: MSCs transplanted into SCI upregulate expression of CD45 and MHC-II and expression of genes related to cytokine production, phagocytosis/endocytosis, and immune cells/response and thereby adopt immune cell-like characteristics within the recipient.

Adult Neural Progenitor Cells Transplanted into Spinal Cord Injury Differentiate into Oligodendrocytes, Enhance Myelination, and Contribute to Recovery.

Long-term survival and integration of neural progenitor cells (NPCs) transplanted following spinal cord injury (SCI) have been observed. However, questions concerning the differentiation choice, the mechanism of action, and the contribution of NPCs to functional recovery remains unanswered. Therefore, we investigated the differentiation of NPCs, global transcriptomal changes in transplanted NPCs, the effect of NPCs on neuroinflammation, and the causality between NPC transplantation and functional recovery. We found that NPCs transplanted following SCI differentiate mainly into oligodendrocytes and enhance myelination, upregulate genes related to synaptic signaling and mitochondrial activity, and downregulate genes related to cytokine production and immune system response. NPCs suppress the expression of pro-inflammatory cytokines/chemokines; moreover, NPC ablation confirm that NPCs were responsible for enhanced recovery in hindlimb locomotor function. Understanding the reaction of transplanted NPCs is important for exploiting their full potential. Existence of causality implies that NPCs are useful in the treatment of SCI.

A Serum Protein Biomarker Panel Improves Outcome Prediction in Human Traumatic Brain Injury.

Brain-enriched protein biomarkers of tissue fate are being introduced clinically to aid in traumatic brain injury (TBI) management. The aim of this study was to determine how concentrations of six different protein biomarkers, measured in samples collected during the first weeks after TBI, relate to injury severity and outcome. We included neurocritical care TBI patients that were prospectively enrolled from 2007 to 2013, all having one to three blood samples drawn during the first 2 weeks. The biomarkers analyzed were S100 calcium-binding protein B (S100B), neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase-L1 (UCH-L1), tau, and neurofilament-light (NF-L). Glasgow Outcome Score (GOS) was assessed at 12 months. In total, 172 patients were included. All serum markers were associated with injury severity as classified on computed tomography scans at admission. Almost all biomarkers outperformed other known outcome predictors with higher levels the first 5 days, correlating with unfavorable outcomes, and UCH-L1 (0.260, pseduo-R2) displaying the best discrimination in univariate analyses. After adjusting for acknowledged TBI outcome predictors, GFAP and NF-L added most independent information to predict favorable/unfavorable GOS, improving the model from 0.38 to 0.51 pseudo-R2. A correlation matrix indicated substantial covariance, with the strongest correlation between UCH-L1, GFAP, and tau (r = 0.827-0.880). Additionally, the principal component analysis exhibited clustering of UCH-L1 and tau, as well as GFAP, S100B, and NSE, which was separate from NF-L. In summary, a panel of several different protein biomarkers, all associated with injury severity, with different cellular origin and temporal trajectories, improve outcome prediction models.

Guiding Device for Precision Grafting of Peripheral Nerves in Complete Thoracic Spinal Cord Injury: Design and Sizing for Clinical Trial.

BACKGROUND: In an effort to translate preclinical success in achieving spinal cord regeneration through peripheral nerve grafts, this study details the design and sizing of a guiding device for precision grafting of peripheral nerves for use in a clinical trial in complete (AIS-A) thoracic spinal cord injury (SCI). The device's design and sizing are compared to a simulation of human spinal cord sizes based on the best available data. METHODS: Spinal cord segmental sizes were generated by computer simulation based on data from a meta-analysis recently published by our group. Thoracic segments T2-T12 were plotted, and seven elliptical shapes were positioned across the center of the distribution of sizes. Geometrical measures of error-of-fit were calculated. CAD modeling was used to create cranial and caudal interfaces for the human spinal cord, aiming to guide descending white matter tracts to gray matter at the caudal end of the device and ascending white matter tracts to gray matter at the cranial end of the device. The interfaces were compared qualitatively to the simulated spinal cord sizes and gray-to-white matter delineations. RESULTS: The mean error-of-fit comparing simulated spinal cord segments T2-T12 to the best elliptical shape was 0.41 and 0.36 mm, and the 95th percentile was found at 1.3 and 0.98 mm for transverse and anteroposterior diameter, respectively. A guiding device design was reached for capturing the majority of corticospinal axons at the cranial end of the device and guiding them obliquely to gray matter at the caudal end of the device. Based on qualitative comparison, the vast majority of spinal cord sizes generated indicate an excellent fit to the device's interfaces. CONCLUSION: A set of SCI guiding devices of seven sizes can cover the variability of human thoracic spinal cord segments T2-T12 with an acceptable error-of-fit for the elliptical shape as well as guiding channels. The computational framework developed can be used with other medical technologies involving the human spinal cord where exact sizes and positioning are of importance.

Assessment of Platelet Function in Traumatic Brain Injury-A Retrospective Observational Study in the Neuro-Critical Care Setting.

BACKGROUND: Despite seemingly functional coagulation, hemorrhagic lesion progression is a common and devastating condition following traumatic brain injury (TBI), stressing the need for new diagnostic techniques. Multiple electrode aggregometry (MEA) measures platelet function and could aid in coagulopathy assessment following TBI. The aims of this study were to evaluate MEA temporal dynamics, influence of concomitant therapy, and its capabilities to predict lesion progression and clinical outcome in a TBI cohort. MATERIAL AND METHODS: Adult TBI patients in a neurointensive care unit that underwent MEA sampling were retrospectively included. MEA was sampled if the patient was treated with antiplatelet therapy, bled heavily during surgery, or had abnormal baseline coagulation values. We assessed platelet activation pathways involving the arachidonic acid receptor (ASPI), P2Y12 receptor, and thrombin receptor (TRAP). ASPI was the primary focus of analysis. If several samples were obtained, they were included. Retrospective data were extracted from hospital charts. Outcome variables were radiologic hemorrhagic progression and Glasgow Outcome Scale assessed prospectively at 12 months posttrauma. MEA levels were compared between patients on antiplatelet therapy. Linear mixed effect models and uni-/multivariable regression models were used to study longitudinal dynamics, hemorrhagic progression and outcome, respectively. RESULTS: In total, 178 patients were included (48% unfavorable outcome). ASPI levels increased from initially low values in a time-dependent fashion (p < 0.001). Patients on cyclooxygenase inhibitors demonstrated low ASPI levels (p < 0.001), while platelet transfusion increased them (p < 0.001). The first ASPI (p = 0.039) and TRAP (p = 0.009) were significant predictors of outcome, but not lesion progression, in univariate analyses. In multivariable analysis, MEA values were not independently correlated with outcome. CONCLUSION: A general longitudinal trend of MEA is identified in this TBI cohort, even in patients without known antiplatelet therapies. Values appear also affected by platelet inhibitory treatment and by platelet transfusions. While significant in univariate models to predict outcome, MEA values did not independently correlate to outcome or lesion progression in multivariable analyses. Further prospective studies to monitor coagulation in TBI patients are warranted, in particular the interpretation of pathological MEA values in patients without antiplatelet therapies.

Protein profiling in serum after traumatic brain injury in rats reveals potential injury markers.

INTRODUCTION: The serum proteome following traumatic brain injury (TBI) could provide information for outcome prediction and injury monitoring. The aim with this affinity proteomic study was to identify serum proteins over time and between normoxic and hypoxic conditions in focal TBI. MATERIAL AND METHODS: Sprague Dawley rats (n=73) received a 3mm deep controlled cortical impact ("severe injury"). Following injury, the rats inhaled either a normoxic (22% O2) or hypoxic (11% O2) air mixture for 30min before resuscitation. The rats were sacrificed at day 1, 3, 7, 14 and 28 after trauma. A total of 204 antibodies targeting 143 unique proteins of interest in TBI research, were selected. The sample proteome was analyzed in a suspension bead array set-up. Comparative statistics and factor analysis were used to detect differences as well as variance in the data. RESULTS: We found that complement factor 9 (C9), complement factor B (CFB) and aldolase c (ALDOC) were detected at higher levels the first days after trauma. In contrast, hypoxia inducing factor (HIF)1α, amyloid precursor protein (APP) and WBSCR17 increased over the subsequent weeks. S100A9 levels were higher in hypoxic-compared to normoxic rats, together with a majority of the analyzed proteins, albeit few reached statistical significance. The principal component analysis revealed a variance in the data, highlighting clusters of proteins. CONCLUSIONS: Protein profiling of serum following TBI using an antibody based microarray revealed temporal changes of several proteins over an extended period of up to four weeks. Further studies are warranted to confirm our findings.

A Review of the Segmental Diameter of the Healthy Human Spinal Cord.

Knowledge of the average size and variability of the human spinal cord can be of importance when treating pathological conditions in the spinal cord. Data on healthy human spinal cord morphometrics have been published for more than a century using different techniques of measurements, but unfortunately, comparison of results from different studies is difficult because of the different anatomical landmarks used as reference points along the craniocaudal axis for the measurements. The aim of this review was to compute population estimates of the transverse and anteroposterior diameter of the human spinal cord by comparing and combining previously published data on a normalized craniocaudal axis. We included 11 studies presenting measurements of spinal cord cross-sectional diameters, with a combined sample size ranging from 15 to 488 subjects, depending on spinal cord level. Based on five published studies presenting data on the lengths of the segments of the spinal cord and vertebral column, we calculated the relative positions of all spinal cord neuronal segments and vertebral bony segments and mapped measurements of spinal cord size to a normalized craniocaudal axis. This mapping resulted in better alignment between studies and allowed the calculation of weighted averages and standard deviations (SDs) along the spinal cord. These weighted averages were smoothed using a generalized additive model to yield continuous population estimates for transverse and anteroposterior diameter and associated SDs. The spinal cord had the largest transverse diameter at spinal cord neuronal segment C5 (13.3 ± 2.2), decreased to segment T8 (8.3 ± 2.1), and increased slightly again to 9.4 ± 1.5 at L3. The anteroposterior diameter showed less variation in size along the spinal cord at C5 (7.4 ± 1.6), T8 (6.3 ± 2.0), and L3 (7.5 ± 1.6). All estimates are presented in millimeters ± 2 SDs. We conclude that segmental transverse and anteroposterior diameters of the healthy human spinal cord from different published sources can be combined on a normalized craniocaudal axis and yield meaningful population estimates. These estimates could be useful in routine management of patients with neurodegenerative diseases as well as for clinical research and experimental applications aimed at surgical spinal cord repair.

Adjuvant Stereotactic Radiosurgery Reduces Need for Retreatments in Patients with Meningioma Residuals.

BACKGROUND: Radical surgical resection of cerebral meningiomas involving the dura mater of venous sinuses is challenging, and tumor residuals are frequently left after surgery. This study sought to evaluate the effect of adjuvant stereotactic radiosurgery (aSRS) on the time to significant growth of meningioma residuals requiring retreatment. METHODS: A total of 119 consecutive patients (2004-2013) receiving primary surgical treatment for a meningioma in proximity to a venous structure were included. The patients were assessed retrospectively, with a focus on retreatments and mortality. Radicality of initial tumor surgery was scored using postoperative magnetic resonance imaging. Three subgroups were identified: 1) radical total resection (RTR); 2) near-total resection (NTR), followed by aSRS (NTR + aSRS); and 3) NTR but no aSRS (NTR - aSRS). In the NTR - aSRS group, intervention was initiated after radiologic (magnetic resonance imaging) findings verified growth of residual tumor, in contrast to the NTR + aSRS group, which received aSRS before regrowth. Time to first retreatment, progression-free survival (PFS), and overall survival were analyzed with the log-rank test and multiple-events Cox regression. RESULTS: RTR was associated with the best prognosis. The patients in the NTR + aSRS group had significantly longer time to first retreatment compared with NTR - aSRS patients (P < 0.001). There was also a significant difference in mortality (P < 0.05) and a tendency to prolonged PFS (P = 0.07) in the NTR + aSRS group. The Cox regressions confirmed the positive effects of NTR + aSRS on time to retreatment (hazard ratio, 7.3; P < 0.01) and PFS (hazard ratio, 3.69; P = 0.055). CONCLUSIONS: aSRS of meningioma residuals had a positive effect on tumor control and should be considered in patients with meningioma residuals.

Lesion Size Is Exacerbated in Hypoxic Rats Whereas Hypoxia-Inducible Factor-1 Alpha and Vascular Endothelial Growth Factor Increase in Injured Normoxic Rats: A Prospective Cohort Study of Secondary Hypoxia in Focal Traumatic Brain Injury.

BACKGROUND: Hypoxia following traumatic brain injury (TBI) is a severe insult shown to exacerbate the pathophysiology, resulting in worse outcome. The aim of this study was to investigate the effects of a hypoxic insult in a focal TBI model by monitoring brain edema, lesion volume, serum biomarker levels, immune cell infiltration, as well as the expression of hypoxia-inducible factor-1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF). MATERIALS AND METHODS: Female Sprague-Dawley rats (n = 73, including sham and naive) were used. The rats were intubated and mechanically ventilated. A controlled cortical impact device created a 3-mm deep lesion in the right parietal hemisphere. Post-injury, rats inhaled either normoxic (22% O2) or hypoxic (11% O2) mixtures for 30 min. The rats were sacrificed at 1, 3, 7, 14, and 28 days post-injury. Serum was collected for S100B measurements using ELISA. Ex vivo magnetic resonance imaging (MRI) was performed to determine lesion size and edema volume. Immunofluorescence was employed to analyze neuronal death, changes in cerebral macrophage- and neutrophil infiltration, microglia proliferation, apoptosis, complement activation (C5b9), IgG extravasation, HIF-1α, and VEGF. RESULTS: The hypoxic group had significantly increased blood levels of lactate and decreased pO2 (p < 0.0001). On MRI post-traumatic hypoxia resulted in larger lesion areas (p = 0.0173), and NeuN staining revealed greater neuronal loss (p = 0.0253). HIF-1α and VEGF expression was significantly increased in normoxic but not in hypoxic animals (p < 0.05). A trend was seen for serum levels of S100B to be higher in the hypoxic group at 1 day after trauma (p = 0.0868). No differences were observed between the groups in cytotoxic and vascular edema, IgG extravasation, neutrophils and macrophage aggregation, microglia proliferation, or C5b-9 expression. CONCLUSION: Hypoxia following focal TBI exacerbated the lesion size and neuronal loss. Moreover, there was a tendency to higher levels of S100B in the hypoxic group early after injury, indicating a potential validity as a biomarker of injury severity. In the normoxic group, the expression of HIF-1α and VEGF was found elevated, possibly indicative of neuro-protective responses occurring in this less severely injured group. Further studies are warranted to better define the pathophysiology of post-TBI hypoxia.

FGF1 containing biodegradable device with peripheral nerve grafts induces corticospinal tract regeneration and motor evoked potentials after spinal cord resection.

PURPOSE: Repairing the spinal cord with peripheral nerve grafts (PNG) and adjuvant acidic fibroblast growth factor (FGF1) has previously resulted in partial functional recovery. To aid microsurgical placement of PNGs, a graft holder device was previously developed by our group. In hope for a translational development we now investigate a new biodegradable graft holder device containing PNGs with or without FGF1. METHODS: Rats were subjected to a T11 spinal cord resection with subsequent repair using twelve white-to-grey matter oriented PNGs prepositioned in a biodegradable device with or without slow release of FGF1. Animals were evaluated with BBB-score, electrophysiology and immunohistochemistry including anterograde BDA tracing. RESULTS: Motor evoked potentials (MEP) in the lower limb reappeared at 20 weeks after grafting. MEP responses were further improved in the group treated with adjuvant FGF1. Reappearance of MEPs was paralleled by NF-positive fibers and anterogradely traced corticospinal fibers distal to the injury. BBB-scores improved in repaired animals. CONCLUSIONS: The results continue to support that the combination of PNGs and FGF1 may be a regeneration strategy to reinnervate the caudal spinal cord. The new device induced robust MEPs augmented by FGF1, and may be considered for translational research.