Brain Swelling versus Infarct Size: A Problematizing Review.

In human stroke, brain swelling is an important predictor of neurological outcome and mortality, yet treatments to reduce or prevent brain swelling are extremely limited, due in part to an inadequate understanding of mechanisms. In preclinical studies on cerebroprotection in animal models of stroke, historically, the focus has been on reducing infarct size, and in most studies, a reduction in infarct size has been associated with a corresponding reduction in brain swelling. Unfortunately, such findings on brain swelling have little translational value for treating brain swelling in patients with stroke. This is because, in humans, brain swelling usually becomes evident, either symptomatically or radiologically, days after the infarct size has stabilized, requiring that the prevention or treatment of brain swelling target mechanism(s) that are independent of a reduction in infarct size. In this problematizing review, we highlight the often-neglected concept that brain edema and brain swelling are not simply secondary, correlative phenomena of stroke but distinct pathological entities with unique molecular and cellular mechanisms that are worthy of direct targeting. We outline the advances in approaches for the study of brain swelling that are independent of a reduction in infarct size. Although straightforward, the approaches reviewed in this study have important translational relevance for identifying novel treatment targets for post-ischemic brain swelling.

Acute Development of Traumatic Intracranial Aneurysms After Civilian Gunshot Wounds to the Head.

In previous studies, the incidence of traumatic intracranial aneurysms (TICAs) after civilian gunshot wound to the head (cGSWH) was ∼3%. Given the use of delayed vessel imaging, we hypothesize that a significant fraction of TICAs is missed on initial non-contrasted scans. This study was designed to characterize acute TICAs using admission computed tomographic angiography (aCTA) in cGSWH. Over the period from 2017 to 2022, 341 patients were admitted to R. Adams Cowley Shock Trauma Center with cGSWH; 136 subjects had aCTA ∼3 (standard deviation [SD] 3.5) h post-injury. Demographics, clinical findings, imaging techniques, endovascular/surgical interventions, and outcomes were analyzed. Mean age was 34.7 (SD 13.1), male:female ratio was 120:16. Average admission Glasgow Coma Scale (GCS) score was 6 (SD 3.9). Entry site was frontal in 41, temporal in 55, parietal in 18, occipital in 6, suboccipital in 9, temporo-parietal in 1, and frontobasal-temporal in 6. Projectiles crossed multiple dural compartments in 76 (55%) patients. 35 TICAs were diagnosed in 28 subject: 24 were located along the middle cerebral artery (MCA), 6 in the anterior cerebral artery (ACA), 3 in the internal carotid artery (ICA), 1 in the posterior cerebral artery (PCA), and 1 in the middle meningeal artery (MMA). Eleven TICAs resolved spontaneously in nine patients. Eight aneurysms were treated by endovascular means, two via combined endovascular/open approaches. Forty-nine patients died, 10 of whom had 15 TICAs. Eighty patients developed intracerebral hematoma s (ICHs). Regression models showed that the presence of an ICH was the main predictor of TICA in cGSWH. Larger ICHs (average 22.3 cc vs. 9.4 cc in patients with and without aneurysms, respectively) in patients with cGSWH suggest hidden TICAs. Nearly 30% of patients had spontaneous resolution within 1 week. When CTA was performed acutely, TICAs were 10 times more frequent in cGSWH than in previous literature, and those patients were more likely to proceed to surgery. Almost one third of patients in this series died from the devastating effects of cGSWH.

Nerve Transfer Surgery in Acute Flaccid Myelitis: Prognostic Factors, Long-Term Outcomes, Comparison With Natural History.

BACKGROUND: Nerve transfer surgery is sometimes offered to patients with acute flaccid myelitis (AFM). The objectives of this study were to evaluate surgical efficacy, assess which clinical and neurophysiological data are valuable for preoperative planning, and report long-term outcomes. METHODS: This is a single-center, retrospective case series of patients with AFM who received nerve transfer surgery. All patients had preoperative electromyography and nerve conduction studies (EMG/NCS). Matched control muscles that did not receive nerve transfer surgery were defined in the same cohort. RESULTS: Ten patients meeting inclusion criteria received a total of 23 nerve transfers (19 upper extremity, four lower extremity). The mean age at symptom onset was 3.8 years, surgery was 0.5 to 1.25 years after diagnosis, and mean follow-up was 2.3 years (range 1.3 to 4.5 years). Among muscles with preoperative strength Medical Research Council (MRC) grade 0, muscles receiving nerve transfers performed significantly better than those that did not (MRC grade 2.17 ± 0.42 vs 0 ± 0, respectively, P = 0.0001). Preoperative EMG/NCS predicted worse outcomes in recipient muscles with more abundant acute denervation potentials (P = 0.0098). Donor nerves found to be partially denervated performed equally well as unaffected nerves. Limited data suggested functional improvement accompanying strength recovery. CONCLUSIONS: Nerve transfer surgery is an effective strategy to restore strength for patients with AFM with persistent, severe motor deficits. Postoperative outcomes in patients with complete paralysis are better than the natural history of disease. This study demonstrates the utility of preoperative clinical and electrophysiological data in guiding patient selection for nerve transfer surgery.

Canagliflozin, an Inhibitor of the Na+-Coupled D-Glucose Cotransporter, SGLT2, Inhibits Astrocyte Swelling and Brain Swelling in Cerebral Ischemia.

Brain swelling is a major cause of death and disability in ischemic stroke. Drugs of the gliflozin class, which target the Na+-coupled D-glucose cotransporter, SGLT2, are approved for type 2 diabetes mellitus (T2DM) and may be beneficial in other conditions, but data in cerebral ischemia are limited. We studied murine models of cerebral ischemia with middle cerebral artery occlusion/reperfusion (MCAo/R). Slc5a2/SGLT2 mRNA and protein were upregulated de novo in astrocytes. Live cell imaging of brain slices from mice following MCAo/R showed that astrocytes responded to modest increases in D-glucose by increasing intracellular Na+ and cell volume (cytotoxic edema), both of which were inhibited by the SGLT2 inhibitor, canagliflozin. The effect of canagliflozin was studied in three mouse models of stroke: non-diabetic and T2DM mice with a moderate ischemic insult (MCAo/R, 1/24 h) and non-diabetic mice with a severe ischemic insult (MCAo/R, 2/24 h). Canagliflozin reduced infarct volumes in models with moderate but not severe ischemic insults. However, canagliflozin significantly reduced hemispheric swelling and improved neurological function in all models tested. The ability of canagliflozin to reduce brain swelling regardless of an effect on infarct size has important translational implications, especially in large ischemic strokes.

Cation flux through SUR1-TRPM4 and NCX1 in astrocyte endfeet induces water influx through AQP4 and brain swelling after ischemic stroke.

Brain swelling causes morbidity and mortality in various brain injuries and diseases but lacks effective treatments. Brain swelling is linked to the influx of water into perivascular astrocytes through channels called aquaporins. Water accumulation in astrocytes increases their volume, which contributes to brain swelling. Using a mouse model of severe ischemic stroke, we identified a potentially targetable mechanism that promoted the cell surface localization of aquaporin 4 (AQP4) in perivascular astrocytic endfeet, which completely ensheathe the brain's capillaries. Cerebral ischemia increased the abundance of the heteromeric cation channel SUR1-TRPM4 and of the Na+/Ca2+ exchanger NCX1 in the endfeet of perivascular astrocytes. The influx of Na+ through SUR1-TRPM4 induced Ca2+ transport into cells through NCX1 operating in reverse mode, thus raising the intra-endfoot concentration of Ca2+. This increase in Ca2+ stimulated calmodulin-dependent translocation of AQP4 to the plasma membrane and water influx, which led to cellular edema and brain swelling. Pharmacological inhibition or astrocyte-specific deletion of SUR1-TRPM4 or NCX1 reduced brain swelling and improved neurological function in mice to a similar extent as an AQP4 inhibitor and was independent of infarct size. Thus, channels in astrocyte endfeet could be targeted to reduce postischemic brain swelling in stroke patients.

Intracranial and Blood Pressure Variability and In-Hospital Outcomes in Intracranial Device-Monitored Patients with Spontaneous Intracerebral Hemorrhage.

BACKGROUND: Spontaneous intracerebral hemorrhage (sICH) is a major health concern and has high mortality rates up to 52%. Despite a decrease in its incidence, fatality rates remain unchanged; understanding and preventing of factors associated with mortality and treatments for these are needed. Blood pressure variability (BPV) has been shown to be a potential modifiable factor associated with clinical outcomes in patients with traumatic intracerebral hemorrhage and sICH. Few data are available on the effect of intracranial pressure (ICP) variability (ICPV) and outcomes in patients with sICH. The goal of our study was to investigate the association between ICPV and BPV during the first 24 h of intensive care unit (ICU) admission and external ventricular drain (EVD) placement, and mortality in patients with sICH who were monitored with an EVD. METHODS: We conducted a single-center retrospective study of adult patients admitted to an ICU with a diagnosis of sICH who required EVD placement during hospitalization. We excluded patients with ICH secondary to other pathological conditions such as trauma, underlying malignancy, or arteriovenous malformation. Blood pressure and ICP measurements were collected and recorded hourly during the first 24 h of ICU admission and EVD placement, respectively. Measures of variability used were standard deviation (SD) and successive variation (SV). Primary outcome of interest was in-hospital mortality, and secondary outcomes were hematoma expansion and discharge home (a surrogate for good functional outcome at discharge). Descriptive statistics and multivariable logistic regressions were performed. RESULTS: We identified 179 patients with sICH who required EVD placement. Of these, 52 (29%) patients died, 121 (68%) patients had hematoma expansion, and 12 (7%) patients were discharged home. Patient's mean age (± SD) was 56 (± 14), and 87 (49%) were women. The mean opening ICP (± SD) was 21 (± 8) and median ICH score (interquartile range) was 2 (2-3). Multivariable logistic regression found an association between ICP-SV and ICP-SD and hematoma expansion (odds ratio 1.6 [1.03-2.30], p = 0.035 and odds ratio 0.77 [0.63-0.93] p = 0.009, respectively). CONCLUSIONS: Our study found an association between ICPV and hematoma expansion in patients with sICH monitored with an EVD. Measures of ICPV relating to rapid changes in ICP (ICP-SV) were associated with a higher odds of hematoma expansion, whereas measures relating to tight control of ICP (ICP-SD) were associated with a lower odds of hematoma expansion. One measure of BPV, sytolic blood pressure maximum-minimum (SBP max-min), was found to be weakly associated with discharge home (a surrogate for good functional outcome at hospital discharge). More research is needed to support these findings.

Surgical Decompression of Traumatic Cervical Spinal Cord Injury: A Pilot Study Comparing Real-Time Intraoperative Ultrasound After Laminectomy With Postoperative MRI and CT Myelography.

BACKGROUND: Decompression of the injured spinal cord confers neuroprotection. Compared with timing of surgery, verification of surgical decompression is understudied. OBJECTIVE: To compare the judgment of cervical spinal cord decompression using real-time intraoperative ultrasound (IOUS) following laminectomy with postoperative MRI and CT myelography. METHODS: Fifty-one patients were retrospectively reviewed. Completeness of decompression was evaluated by real-time IOUS and compared with postoperative MRI (47 cases) and CT myelography (4 cases). RESULTS: Five cases (9.8%) underwent additional laminectomy after initial IOUS evaluation to yield a final judgment of adequate decompression using IOUS in all 51 cases (100%). Postoperative MRI/CT myelography showed adequate decompression in 43 cases (84.31%). Six cases had insufficient bony decompression, of which 3 (50%) had cerebrospinal fluid effacement at >1 level. Two cases had severe circumferential intradural swelling despite adequate bony decompression. Between groups with and without adequate decompression on postoperative MRI/CT myelography, there were significant differences for American Spinal Injury Association motor score, American Spinal Injury Association Impairment Scale grade, AO Spine injury morphology, and intramedullary lesion length (IMLL). Multivariate analysis using stepwise variable selection and logistic regression showed that preoperative IMLL was the most significant predictor of inadequate decompression on postoperative imaging (P = .024). CONCLUSION: Patients with severe clinical injury and large IMLL were more likely to have inadequate decompression on postoperative MRI/CT myelography. IOUS can serve as a supplement to postoperative MRI/CT myelography for the assessment of spinal cord decompression. However, further investigation, additional surgeon experience, and anticipation of prolonged swelling after surgery are required.

Proposal of a Management Algorithm to Predict the Need for Expansion Duraplasty in American Spinal Injury Association Impairment Scale Grades A-C Traumatic Cervical Spinal Cord Injury Patients.

Expansion duraplasty to reopen effaced subarachnoid space and improve spinal cord perfusion, autoregulation, and spinal pressure reactivity index (sPRX) has been advocated in patients with traumatic cervical spinal cord injury (tCSCI). We designed this study to identify candidates for expansion duraplasty, based on the absence of cerebrospinal fluid (CSF) interface around the spinal cord on magnetic resonance imaging (MRI), in the setting of otherwise adequate bony decompression. Over a 61-month period, 104 consecutive American Spinal Injury Association Impairment Scale (AIS) grades A-C patients with tCSCI had post-operative MRI to assess the adequacy of surgical decompression. Their mean age was 53.4 years, and 89% were male. Sixty-one patients had falls, 31 motor vehicle collisions, 11 sport injuries, and one an assault. The AIS grade was A in 56, B in 18, and C in 30 patients. Fifty-four patients had fracture dislocations; there was no evidence of skeletal injury in 50 patients. Mean intramedullary lesion length (IMLL) was 46.9 (standard deviation = 19.4) mm. Median time from injury to decompression was 17 h (interquartile range 15.2 h). After surgery, 94 patients had adequate decompression as judged by the presence of CSF anterior and posterior to the spinal cord, whereas 10 patients had effacement of the subarachnoid space at the injury epicenter. In two patients whose decompression was not definitive and post-operative MRI indicated inadequate decompression, expansion duraplasty was performed. Candidates for expansion duraplasty (i.e., those with inadequate decompression) were significantly younger (p < 0.0001), were AIS grade A (p < 0.0016), had either sport injuries (six patients) or motor vehicle collisions (three patients) (p < 0.0001), had fracture dislocation (p = 0.00016), and had longer IMLL (p = 0.0097). In regression models, patients with sport injuries and inadequate decompression were suitable candidates for expansion duraplasty (p = 0.03). Further, 9.6% of patients failed bony decompression alone and either did (2) or would have (8) benefited from expansion duraplasty.

Comparative Therapeutic Effectiveness of Anticoagulation and Conservative Management in Traumatic Cerebral Venous Sinus Thrombosis.

BACKGROUND: Consensus is currently lacking in the optimal treatment for blunt traumatic cerebral venous sinus thrombosis (tCVST). Anticoagulation (AC) is used for treating spontaneous CVST, but its role in tCVST remains unclear. OBJECTIVE: To investigate the characteristics and outcomes of patients treated with AC compared with patients managed conservatively. METHODS: We retrospectively reviewed patients who presented to a Level 1 trauma center with acute skull fracture after blunt head trauma who underwent dedicated venous imaging. RESULTS: There were 137 of 424 patients (32.3%) presenting with skull fractures with tCVST on venous imaging. Among them, 82 (60%) were treated with AC while 55 (40%) were managed conservatively. Analysis of baseline characteristics demonstrated no significant difference in age, sex, admission Glasgow Coma Scale, admission Injury Severity Score, rates of associated intracranial hemorrhage, or neurosurgical interventions. New or worsening intracranial hemorrhage was seen in 7 patients treated with AC. Patients on AC had significantly lower mortality than non-AC (1% vs 15%; P = .003). There was no difference in the Glasgow Coma Scale or Glasgow Outcome Scale at last clinical follow-up. On follow-up venous imaging, patients treated with AC were more likely to experience full thrombus recanalization than non-AC (54% vs 32%; P = .012), and subsequent multiple regression analysis revealed that treatment with AC was a significant predictor of full thrombus recanalization (odds ratio, 5.18; CI, 1.60-16.81; P = .006). CONCLUSION: Treatment with AC for tCVST due to blunt head trauma may promote higher rates of complete thrombus recanalization when compared with conservative management.

Initial Stress Hyperglycemia Is Associated With Malignant Cerebral Edema, Hemorrhage, and Poor Functional Outcome After Mechanical Thrombectomy.

BACKGROUND: Malignant cerebral edema (MCE) and intracranial hemorrhage (ICH) are associated with poor neurological outcomes despite revascularization after mechanical thrombectomy (MT). The factors associated with the development of MCE and ICH after MT are not well understood. OBJECTIVE: To determine periprocedural factors associated with MCE, ICH, and poor functional outcome. METHODS: We retrospectively analyzed anterior cerebral circulation large vessel occlusion cases that underwent MT from 2012 to 2019 at a single Comprehensive Stroke Center. Multivariate logistic regression analyses were performed to determine significant predictors of MCE, ICH, and poor functional outcome (modified Rankin Scale, 3-6) at 90 d. RESULTS: Four hundred patients were included. Significant independent predictors of MCE after MT included initial stress glucose ratio (iSGR) (odds ratio [OR], 14.26; 95% CI, 3.82-53.26; P < .001), National Institutes of Health Stroke Scale (NIHSS) (OR, 1.10; 95% CI, 1.03-1.18; P = .008), internal carotid artery compared with M1 or M2 occlusion, and absence of successful revascularization (OR, 0.16; 95% CI, 0.06-0.44; P < .001). Significant independent predictors of poor functional outcome included MCE (OR, 7.47; 95% CI, 2.20-25.37; P = .001), iSGR (OR, 5.15; 95% CI, 1.82-14.53; P = .002), ICH (OR, 4.77; 95% CI, 1.20-18.69; P = .024), NIHSS (OR, 1.10; 95% CI, 1.05-1.16; P < .001), age (OR, 1.04; 95% CI, 1.03-1.07; P < .001), and thrombolysis in cerebral infarction 2C/3 recanalization (OR, 0.12; 95% CI, 0.05-0.29; P < .001). CONCLUSION: Elevated iSGR significantly increases the risk of MCE and ICH and is an independent predictor of poor functional outcome. Thrombolysis in cerebral infarction 2C/3 revascularization is associated with reduced risk of MCE, ICH, and poor functional outcome. Whether stress hyperglycemia represents a modifiable risk factor is uncertain, and further investigation is warranted.

When the Blood Hits Your Brain: The Neurotoxicity of Extravasated Blood.

Hemorrhage in the central nervous system (CNS), including intracerebral hemorrhage (ICH), intraventricular hemorrhage (IVH), and aneurysmal subarachnoid hemorrhage (aSAH), remains highly morbid. Trials of medical management for these conditions over recent decades have been largely unsuccessful in improving outcome and reducing mortality. Beyond its role in creating mass effect, the presence of extravasated blood in patients with CNS hemorrhage is generally overlooked. Since trials of surgical intervention to remove CNS hemorrhage have been generally unsuccessful, the potent neurotoxicity of blood is generally viewed as a basic scientific curiosity rather than a clinically meaningful factor. In this review, we evaluate the direct role of blood as a neurotoxin and its subsequent clinical relevance. We first describe the molecular mechanisms of blood neurotoxicity. We then evaluate the clinical literature that directly relates to the evacuation of CNS hemorrhage. We posit that the efficacy of clot removal is a critical factor in outcome following surgical intervention. Future interventions for CNS hemorrhage should be guided by the principle that blood is exquisitely toxic to the brain.

A large portion of the astrocyte proteome is dedicated to perivascular endfeet, including critical components of the electron transport chain.

The perivascular astrocyte endfoot is a specialized and diffusion-limited subcellular compartment that fully ensheathes the cerebral vasculature. Despite their ubiquitous presence, a detailed understanding of endfoot physiology remains elusive, in part due to a limited understanding of the proteins that distinguish the endfoot from the greater astrocyte body. Here, we developed a technique to isolate astrocyte endfeet from brain tissue, which was used to study the endfoot proteome in comparison to the astrocyte somata. In our approach, brain microvessels, which retain their endfoot processes, were isolated from mouse brain and dissociated, whereupon endfeet were recovered using an antibody-based column astrocyte isolation kit. Our findings expand the known set of proteins enriched at the endfoot from 10 to 516, which comprised more than 1/5th of the entire detected astrocyte proteome. Numerous critical electron transport chain proteins were expressed only at the endfeet, while enzymes involved in glycogen storage were distributed to the somata, indicating subcellular metabolic compartmentalization. The endfoot proteome also included numerous proteins that, while known to have important contributions to blood-brain barrier function, were not previously known to localize to the endfoot. Our findings highlight the importance of the endfoot and suggest new routes of investigation into endfoot function.

Low-Dose Intravenous Heparin Infusion After Aneurysmal Subarachnoid Hemorrhage is Associated With Decreased Risk of Delayed Neurological Deficit and Cerebral Infarction.

BACKGROUND: Patients who survive aneurysmal subarachnoid hemorrhage (aSAH) are at risk for delayed neurological deficits (DND) and cerebral infarction. In this exploratory cohort comparison analysis, we compared in-hospital outcomes of aSAH patients administered a low-dose intravenous heparin (LDIVH) infusion (12 U/kg/h) vs those administered standard subcutaneous heparin (SQH) prophylaxis for deep vein thrombosis (DVT; 5000 U, 3 × daily). OBJECTIVE: To assess the safety and efficacy of LDIVH in aSAH patients. METHODS: We retrospectively analyzed 556 consecutive cases of aSAH patients whose aneurysm was secured by clipping or coiling at a single institution over a 10-yr period, including 233 administered the LDIVH protocol and 323 administered the SQH protocol. Radiological and outcome data were compared between the 2 cohorts using multivariable logistic regression and propensity score-based inverse probability of treatment weighting (IPTW). RESULTS: The unadjusted rate of cerebral infarction in the LDIVH cohort was half that in SQH cohort (9 vs 18%; P = .004). Multivariable logistic regression showed that patients in the LDIVH cohort were significantly less likely than those in the SQH cohort to have DND (odds ratio (OR) 0.53 [95% CI: 0.33, 0.85]) or cerebral infarction (OR 0.40 [95% CI: 0.23, 0.71]). Analysis following IPTW showed similar results. Rates of hemorrhagic complications, heparin-induced thrombocytopenia and DVT were not different between cohorts. CONCLUSION: This cohort comparison analysis suggests that LDIVH infusion may favorably influence the outcome of patients after aSAH. Prospective studies are required to further assess the benefit of LDIVH infusion in patients with aSAH.

Emerging Pharmacological Treatments for Cerebral Edema: Evidence from Clinical Studies.

Cerebral edema, a common and often fatal companion to most forms of acute central nervous system disease, has been recognized since the time of ancient Egypt. Unfortunately, our therapeutic armamentarium remains limited, in part due to historic limitations in our understanding of cerebral edema pathophysiology. Recent advancements have led to a number of clinical trials for novel therapeutics that could fundamentally alter the treatment of cerebral edema. In this review, we discuss these agents, their targets, and the data supporting their use, with a focus on agents that have progressed to clinical trials.

Sulfonylurea Receptor 1, Transient Receptor Potential Cation Channel Subfamily M Member 4, and KIR6.2:Role in Hemorrhagic Progression of Contusion.

In severe traumatic brain injury (TBI), contusions often are worsened by contusion expansion or hemorrhagic progression of contusion (HPC), which may double the original contusion volume and worsen outcome. In humans and rodents with contusion-TBI, sulfonylurea receptor 1 (SUR1) is upregulated in microvessels and astrocytes, and in rodent models, blockade of SUR1 with glibenclamide reduces HPC. SUR1 does not function by itself, but must co-assemble with either KIR6.2 or transient receptor potential cation channel subfamily M member 4 (TRPM4) to form KATP (SUR1-KIR6.2) or SUR1-TRPM4 channels, with the two having opposite effects on membrane potential. Both KIR6.2 and TRPM4 are reportedly upregulated in TBI, especially in astrocytes, but the identity and function of SUR1-regulated channels post-TBI is unknown. Here, we analyzed human and rat brain tissues after contusion-TBI to characterize SUR1, TRPM4, and KIR6.2 expression, and in the rat model, to examine the effects on HPC of inhibiting expression of the three subunits using intravenous antisense oligodeoxynucleotides (AS-ODN). Glial fibrillary acidic protein (GFAP) immunoreactivity was used to operationally define core versus penumbral tissues. In humans and rats, GFAP-negative core tissues contained microvessels that expressed SUR1 and TRPM4, whereas GFAP-positive penumbral tissues contained astrocytes that expressed all three subunits. Förster resonance energy transfer imaging demonstrated SUR1-TRPM4 heteromers in endothelium, and SUR1-TRPM4 and SUR1-KIR6.2 heteromers in astrocytes. In rats, glibenclamide as well as AS-ODN targeting SUR1 and TRPM4, but not KIR6.2, reduced HPC at 24 h post-TBI. Our findings demonstrate upregulation of SUR1-TRPM4 and KATP after contusion-TBI, identify SUR1-TRPM4 as the primary molecular mechanism that accounts for HPC, and indicate that SUR1-TRPM4 is a crucial target of glibenclamide.

Correction: Cerebral microbleeds in a neonatal rat model.

[This corrects the article DOI: 10.1371/journal.pone.0171163.].

Selective Vulnerability of the Foramen Magnum in a Rat Blast Traumatic Brain Injury Model.

Primary blast traumatic brain injury (bTBI) accounts for a significant proportion of wartime trauma. Previous studies have demonstrated direct brain injury by blast waves, but the effect of the location of the blast epicenter on the skull with regard to brain injury remains poorly characterized. In order to investigate the role of the blast epicenter location, we modified a previously established rodent model of cranium-only bTBI to evaluate two specific blast foci: a rostrally focused blast centered on bregma (B-bTBI), which excluded the foramen magnum region, and a caudally focused blast centered on the occipital crest, which included the foramen magnum region (FM-bTBI). At all blast overpressures studied (668-1880 kPa), rats subjected to FM-bTBI demonstrated strikingly higher mortality, increased durations of both apnea and hypoxia, and increased severity of convexity subdural hematomas, than rats subjected to B-bTBI. Together, these data suggest a unique role for the foramen magnum region in mortality and brain injury following blast exposure, and emphasize the importance of the choice of blast focus location in experimental models of bTBI.

Cross-species transcriptional analysis reveals conserved and host-specific neoplastic processes in mammalian glioma.

Glioma is a unique neoplastic disease that develops exclusively in the central nervous system (CNS) and rarely metastasizes to other tissues. This feature strongly implicates the tumor-host CNS microenvironment in gliomagenesis and tumor progression. We investigated the differences and similarities in glioma biology as conveyed by transcriptomic patterns across four mammalian hosts: rats, mice, dogs, and humans. Given the inherent intra-tumoral molecular heterogeneity of human glioma, we focused this study on tumors with upregulation of the platelet-derived growth factor signaling axis, a common and early alteration in human gliomagenesis. The results reveal core neoplastic alterations in mammalian glioma, as well as unique contributions of the tumor host to neoplastic processes. Notable differences were observed in gene expression patterns as well as related biological pathways and cell populations known to mediate key elements of glioma biology, including angiogenesis, immune evasion, and brain invasion. These data provide new insights regarding mammalian models of human glioma, and how these insights and models relate to our current understanding of the human disease.

SUR1-TRPM4 and AQP4 form a heteromultimeric complex that amplifies ion/water osmotic coupling and drives astrocyte swelling.

Astrocyte swelling occurs after central nervous system injury and contributes to brain swelling, which can increase mortality. Mechanisms proffered to explain astrocyte swelling emphasize the importance of either aquaporin-4 (AQP4), an astrocyte water channel, or of Na+ -permeable channels, which mediate cellular osmolyte influx. However, the spatio-temporal functional interactions between AQP4 and Na+ -permeable channels that drive swelling are poorly understood. We hypothesized that astrocyte swelling after injury is linked to an interaction between AQP4 and Na+ -permeable channels that are newly upregulated. Here, using co-immunoprecipitation and Förster resonance energy transfer, we report that AQP4 physically co-assembles with the sulfonylurea receptor 1-transient receptor potential melastatin 4 (SUR1-TRPM4) monovalent cation channel to form a novel heteromultimeric water/ion channel complex. In vitro cell-swelling studies using calcein fluorescence imaging of COS-7 cells expressing various combinations of AQP4, SUR1, and TRPM4 showed that the full tripartite complex, comprised of SUR1-TRPM4-AQP4, was required for fast, high-capacity transmembrane water transport that drives cell swelling, with these findings corroborated in cultured primary astrocytes. In a murine model of brain edema involving cold-injury to the cerebellum, we found that astrocytes newly upregulate SUR1-TRPM4, that AQP4 co-associates with SUR1-TRPM4, and that genetic inactivation of the solute pore of the SUR1-TRPM4-AQP4 complex blocked in vivo astrocyte swelling measured by diolistic labeling, thereby corroborating our in vitro functional studies. Together, these findings demonstrate a novel molecular mechanism involving the SUR1-TRPM4-AQP4 complex to account for bulk water influx during astrocyte swelling. These findings have broad implications for the understanding and treatment of AQP4-mediated pathological conditions.