J Marc Simard

University of Maryland, Baltimore, Baltimore, Maryland, United States

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Publications (143)681.28 Total impact

  • The Lancet Neurology 04/2015; 14(4). DOI:10.1016/S1474-4422(15)70013-X · 21.82 Impact Factor
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    ABSTRACT: Background Three risk factors are associated with hemorrhagic forms of encephalopathy of prematurity (EP): (i) prematurity, (ii) in utero ischemia (IUI) or perinatal ischemia, and (iii) mechanical ventilation. We hypothesized that IUI would induce an angiogenic response marked by activation of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9), the latter degrading vascular basement membrane and increasing vulnerability to raised intravenous pressure during positive pressure mechanical ventilation.Methods We studied a rat model of hemorrhagic-EP characterized by periventricular hemorrhages in which a 20-min episode of IUI is induced at E19, pups are born naturally at E21-22, and on P0, are subjected to a 20-min episode of positive pressure mechanical ventilation. Tissues were studied by H&E staining, immunolabeling, immunoblot and zymography.ResultsMechanical ventilation of rat pups 2-3 days after 20-min IUI caused widespread hemorrhages in periventricular tissues. IUI resulted in upregulation of VEGF and MMP-9. Zymography confirmed significantly elevated gelatinase activity. MMP-9 activation was accompanied by severe loss of MMP-9 substrates, collagen IV and laminin, in microvessels in periventricular areas.Conclusions Our findings are consistent with the hypothesis that positive pressure mechanical ventilation of the newborn in the context of recent prenatal ischemia/hypoxia can predispose to periventricular hemorrhages.Pediatric Research (2015); doi:10.1038/pr.2015.34.
    Pediatric Research 02/2015; DOI:10.1038/pr.2015.34 · 2.84 Impact Factor
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    ABSTRACT: Perihaematomal oedema (PHO) is an important pathophysiological marker of secondary injury in intracerebral haemorrhage (ICH). In this Review, we describe a novel method to conceptualize PHO formation within the framework of Starling's principle of movement of fluid across a capillary wall. We consider progression of PHO through three stages, characterized by ionic oedema (stage 1) and progressive vasogenic oedema (stages 2 and 3). In this context, possible modifiers of PHO volume and their value in identifying patients who would benefit from therapies that target secondary injury are discussed; the practicalities of using neuroimaging to measure PHO volume are also considered. We examine whether PHO can be used as a predictor of neurological outcome following ICH, and we provide an overview of emerging therapies. Our discussion emphasizes that PHO has clinical relevance both as a therapeutic target, owing to its augmentation of the mass effect of a haemorrhage, and as a surrogate marker for novel interventions that target secondary injury.
    Nature Reviews Neurology 01/2015; DOI:10.1038/nrneurol.2014.264 · 14.10 Impact Factor
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    ABSTRACT: Cerebrospinal fluid (CSF) flow dynamics play critical roles in both the immature and adult brain, with implications for neurodevelopment and disease processes such as hydrocephalus and neurodegeneration. Remarkably, the only reported method to date for measuring CSF formation in laboratory rats is the indirect tracer dilution method (a.k.a., ventriculocisternal perfusion), which has limitations. Anesthetized rats were mounted in a stereotaxic apparatus, both lateral ventricles were cannulated, and the Sylvian aqueduct was occluded. Fluid exited one ventricle at a rate equal to the rate of CSF formation plus the rate of infusion (if any) into the contralateral ventricle. Pharmacological agents infused at a constant known rate into the contralateral ventricle were tested for their effect on CSF formation in real-time. The measured rate of CSF formation was increased by blockade of the Sylvian aqueduct but was not changed by increasing the outflow pressure (0-3cm of H2O). In male Wistar rats, CSF formation was age-dependent: 0.39±0.06, 0.74±0.05, 1.02±0.04 and 1.40±0.06μL/min at 8, 9, 10 and 12 weeks, respectively. CSF formation was reduced 57% by intraventricular infusion of the carbonic anhydrase inhibitor, acetazolamide. Tracer dilution methods do not permit ongoing real-time determination of the rate of CSF formation, are not readily amenable to pharmacological manipulations, and require critical assumptions. Direct measurement of CSF formation overcomes these limitations. Direct measurement of CSF formation in rats is feasible. Our method should prove useful for studying CSF dynamics in normal physiology and disease models. Copyright © 2014. Published by Elsevier B.V.
    Journal of Neuroscience Methods 12/2014; 241. DOI:10.1016/j.jneumeth.2014.12.015 · 1.96 Impact Factor
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    ABSTRACT: Cerebral edema formation stems from disruption of blood brain barrier (BBB) integrity and occurs after injury to the CNS. Due to the restrictive skull, relatively small increases in brain volume can translate into impaired tissue perfusion and brain herniation. In excess, cerebral edema can be gravely harmful. Astrocytes are key participants in cerebral edema by virtue of their relationship with the cerebral vasculature, their unique compliment of solute and water transport proteins, and their general role in brain volume homeostasis. Following the discovery of aquaporins, passive conduits of water flow, aquaporin 4 (AQP4) was identified as the predominant astrocyte water channel. Normally, AQP4 is highly enriched at perivascular endfeet, the outermost layer of the BBB, whereas after injury, AQP4 expression disseminates to the entire astrocytic plasmalemma, a phenomenon termed dysregulation. Arguably, the most important role of AQP4 is to rapidly neutralize osmotic gradients generated by ionic transporters. In pathological conditions, AQP4 is believed to be intimately involved in the formation and clearance of cerebral edema. In this review, we discuss aquaporin function and localization in the BBB during health and injury, and we examine post-injury ionic events that modulate AQP4-dependent edema formation.
    Neurochemical Research 07/2014; 40(2). DOI:10.1007/s11064-014-1374-3 · 2.55 Impact Factor
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    ABSTRACT: Traumatic brain injury due to an explosive blast (blast-TBI) is postulated to be due, in part, to transvascular transmission to the brain of a hydrodynamic pulse (a.k.a., volumetric blood surge, ballistic pressure wave, hydrostatic shock or hydraulic shock) induced in major intrathoracic blood vessels. To our knowledge, this mechanism of blast-TBI has not been demonstrated directly. Here, we tested the hypothesis that a blast wave impacting solely the thorax would induce pathological changes in the brain. We constructed and tested a "Thorax-Only Blast Injury Apparatus" (TOBIA) that delivered a collimated blast wave to the right lateral thorax of an anesthetized rat, precluding direct impact of the blast wave on the cranium. Adult male Long Evans rats were subjected to sublethal injury by TOBIA (peak overpressure, 45111 kPa). Pulse oximetry was monitored during the procedure. The lungs and brains were examined 24 hours after injury. Blast injury to the thorax induced by TOBIA was characterized by apnea and diffuse bilateral hemorrhagic injury to the lungs, and was associated with a reduction in pulse oximetry signals for 30 minutes. Gross and histological examination of the brains 24 hours after non-lethal blast exposure showed no subarachnoid or intraparenchymal brain hemorrhages. Immunolabeling 24 hours after non-lethal blast exposure showed upregulation of TNF, ED-1, Sur1 and GFAP in veins or perivenular tissues and microvessels throughout the brain. We conclude that blast injury to the thorax leads to widespread perivenular inflammation, Sur1 upregulation and reactive astrocytosis. The long-term consequences of these findings remain to be determined.
    Journal of neurotrauma 03/2014; DOI:10.1089/neu.2013.3016 · 3.97 Impact Factor
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    ABSTRACT: Malignant infarction is characterized by the formation of cerebral edema, and medical treatment is limited. Preclinical data suggest that glyburide, an inhibitor of SUR1-TRPM4, is effective in preventing edema. We previously reported feasibility of the GAMES-Pilot study, a two-center prospective, open label, phase IIa trial of 10 subjects at high risk for malignant infarction based on diffusion weighted imaging (DWI) threshold of 82 cm(3) treated with RP-1127 (glyburide for injection). In this secondary analysis, we tested the hypothesis that RP-1127 may be efficacious in preventing poor outcome when compared to controls. Controls suffering large hemispheric infarction were obtained from the EPITHET and MMI-MRI studies. We first screened subjects for controls with the same DWI threshold used for enrollment into GAMES-Pilot, 82 cm(3). Next, to address imbalances, we applied a weighted Euclidean matching. Ninety day mRS 0-4, rate of decompressive craniectomy, and mortality were the primary clinical outcomes of interest. The mean age of the GAMES cohort was 51 years and initial DWI volume was 102 ± 23 cm(3). After Euclidean matching, GAMES subjects showed similar NIHSS, higher DWI volume, younger age and had mRS 0-4-90 % versus 50 % in controls p = 0.049; with a similar trend in mRS 0-3 (40 vs. 25 %; p = 0.43) and trend toward lower mortality (10 vs. 35 %; p = 0.21). In this pilot study, RP-1127-treated subjects showed better clinical outcomes when compared to historical controls. An adequately powered and randomized phase II trial of patients at risk for malignant infarction is needed to evaluate the potential efficacy of RP-1127.
    Neurocritical Care 03/2014; 21(1). DOI:10.1007/s12028-014-9970-2 · 2.60 Impact Factor
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    ABSTRACT: Metastatic disease to the brain results in significant morbidity because of edema in the central nervous system. Current anti-edema therapies are either expensive or result in unwanted long-term side effects. Sulfonylurea receptor 1 (Sur1) is a transmembrane protein that, when activated in the central nervous system, allows for unregulated sodium influx into cells, a process that has been linked to cytotoxic edema formation in ischemic stroke, subarachnoid hemorrhage, spinal cord injury, traumatic brain injury, and, most recently, brain metastases. In this focused review, we explore preclinical data linking Sur1 channel formation to development of edema and reference evidence suggesting that the antidiabetic sulfonylurea drug glyburide (a Sur1 inhibitor) is an inexpensive and well-tolerated agent that can be clinically tested to reduce or prevent malignancy and/or treatment-associated edema.
    Expert Review of Neurotherapeutics 02/2014; DOI:10.1586/14737175.2014.890891 · 2.83 Impact Factor
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    ABSTRACT: Abstract Context: Subarachnoid hemorrhage (SAH) has a high fatality rate and many suffer from delayed neurological deficits. Biomarkers may aid in the identification of high-risk patients, guide treatment/management and improve outcome. Objective: The aim of this review was to summarize biomarkers of SAH associated with outcome. Methods: An electronic database query was completed, including an additional review of reference lists to include all potential human studies. Results: A total of 298 articles were identified; 112 were reviewed; 55 studies were included. Conclusion: This review details biomarkers of SAH that correlate with outcome. It provides the basis for research investigating their possible translation into the management of SAH patients.
    Biomarkers 02/2014; DOI:10.3109/1354750X.2014.881418 · 2.52 Impact Factor
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    ABSTRACT: Cerebral edema and hemorrhagic conversion are common, potentially devastating complications of ischemic stroke and are associated with high rates of mortality and poor functional outcomes. Recent work exploring the molecular pathophysiology of the neurogliovascular unit in ischemic stroke suggests that deranged cellular ion homeostasis due to altered function and regulation of ion pumps, channels, and secondary active transporters plays an integral role in the development of cytotoxic and vasogenic edema and hemorrhagic conversion. Among these proteins involved in ion homeostasis, the ischemia-induced, nonselective cation conductance formed by the SUR1-TRPM4 protein complex appears to play a prominent role and is potently inhibited by glibenclamide, an FDA-approved drug commonly used in patients with Type 2 diabetes. Several robust preclinical studies have demonstrated the efficacy of glibenclamide blockade of SUR1-TRPM4 activity in reducing edema and hemorrhagic conversion in rodent models of ischemic stroke, prompting the study of the potential protective effects of glibenclamide in humans in an ongoing prospective phase II clinical trial. Preliminary data suggest glibenclamide significantly reduces cerebral edema and lowers the rate of hemorrhagic conversion following ischemic stroke, suggesting the potential use of glibenclamide to improve outcomes in humans.
    Neurosurgical FOCUS 01/2014; 36(1):E11. DOI:10.3171/2013.10.FOCUS13404 · 2.14 Impact Factor
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    ABSTRACT: Cerebral edema is a major cause of morbidity and mortality following ischemic stroke, but its underlying molecular pathophysiology is incompletely understood. Recent data have revealed the importance of ion flux via channels and transporters expressed in the neurogliovascular unit in the development of ischemia-triggered cytotoxic edema, vasogenic edema, and hemorrhagic conversion. Disruption of homeostatic mechanisms governing cell volume regulation and epithelial/endothelial ion transport due to ischemia-associated energy failure results in the thermodynamically driven re-equilibration of solutes and water across the CSF-blood and blood-brain barriers that ultimately increases the brain's extravascular volume. Additionally, hypoxia, inflammation, and other stress-triggered increases in the functional expression of ion channels and transporters normally expressed at low levels in the neurogliovascular unit cause disruptions in ion homeostasis that contribute to ischemic cerebral edema. Here, we review the pathophysiological significance of several molecular mediators of ion transport expressed in the neurogliovascular unit, including targets of existing FDA-approved drugs, which might be potential nodes for therapeutic intervention.
    Translational Stroke Research 11/2013; 5(1). DOI:10.1007/s12975-013-0307-9 · 1.94 Impact Factor
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    ABSTRACT: N-glycosylation is important for the function and regulation of ion channels. We examined the role of N-glycosylation of transient receptor potential melastatin (Trpm) 4b, a membrane glycoprotein that regulates calcium influx. Trpm4b was expressed in vivo in all rat tissues examined. In each tissue, Trpm4b had a different molecular mass, between ~129 and ~141 kDa, but all reverted to ~120 kDa following treatment with peptide: N-glycosidase F, consistent with N-glycosylation being the principal form of post-translational modification of Trpm4b in vivo. In 6 stable isogenic cell lines that express different levels of Trpm4b, 2 forms were found, high mannose, core-glycosylated (CG) and complex, highly-glycosylated (HG), with HG-Trpm4b comprising 85% of the total Trpm4b expressed. For both forms, surface expression was directly proportional to the total Trpm4b expressed. Complex N-glycosylation doubled the percent of Trpm4b at the surface, compared to high mannose N-glycosylation. Mutation of the single N-glycosylation consensus sequence at Asn-988 (Trpm4b-N988Q), located near the pore-forming loop between transmembrane helices 5 and 6, prevented glycosylation, but did not prevent surface expression, impair formation of functional membrane channels, or alter channel conductance. In transfection experiments, the time courses for appearance of HG-Trpm4b and Trpm4b-N988Q on the surface were similar. In experiments with cycloheximide inhibition of protein synthesis, the time course for disappearance of HG-Trpm4b from the surface was much slower than that for Trpm4b-N988Q. We conclude that N-glycosylation is not required for surface expression or channel function, but that complex N-glycosylation plays a crucial role in stabilizing surface expression of Trpm4b.
    Journal of Biological Chemistry 11/2013; 288(51). DOI:10.1074/jbc.M113.530584 · 4.60 Impact Factor
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    ABSTRACT: Preclinical and retrospective clinical data indicate that glyburide, a selective inhibitor of sulfonylurea receptor 1-transient receptor potential melastatin 4, is effective in preventing edema and improving outcome after focal ischemia. We assessed the feasibility of recruiting and treating patients with severe stroke while obtaining preliminary information on the safety and tolerability of RP-1127 (glyburide for injection). We studied 10 patients with acute ischemic stroke, with baseline diffusion-weighted imaging lesion volumes of 82 to 210 cm(3), whether treated with intravenous recombinant tissue-type plasminogen activator, age 18 to 80 years, and time to RP-1127 ≤10 hours. Recruitment was completed within 10 months. The mean age was 50.5 years, and baseline diffusion-weighted image lesion volume was 102±23 cm(3). There were no serious adverse events related to drug and no symptomatic hypoglycemia. The increase in ipsilateral hemisphere volume was 50±33 cm(3). The proportion of 90-day modified Rankin Scale ≤4 was 90% (40% modified Rankin Scale, ≤3). RP-1127 at a dose of 3 mg/d was well tolerated and did not require any dose reductions. A clinical trial of RP-1127 is feasible. http://www.clinicaltrials.gov. Unique identifier: NCT01268683.
    Stroke 11/2013; 45(1). DOI:10.1161/STROKEAHA.113.003352 · 6.02 Impact Factor
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    ABSTRACT: Cerebral aneurysms represent common intracranial vascular lesions encountered in neurosurgical practice. The clinical presentation is varied, ranging from asymptomatic lesions to those presenting with catastrophic intracranial hemorrhage. Aneurysm treatment has been a rapidly evolving field with numerous technical innovations, especially in the last two decades. Selecting the appropriate treatment can be a complex process that involves integration of information regarding the patient's clinical presentation, associated comorbidities, the aneurysm's morphological characteristics, safety and efficacy of the treatment options and skill and experience of available practitioners, amongst others. In this article, we review each of these factors and appraise the available scientific evidence in an effort to facilitate decision making in the treatment of cerebral aneurysms. The treatment of intracranial aneurysms is best performed at high volume centers that utilize a multidisciplinary, team-based approach.
    Seminars in Neurology 11/2013; 33(5):476-87. DOI:10.1055/s-0033-1364217 · 1.78 Impact Factor
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    ABSTRACT: The sulfonylurea receptor 1 (Sur1)-transient receptor potential 4 (Trpm4) channel is an important molecular element in focal cerebral ischemia. The channel is upregulated in all cells of the neurovascular unit following ischemia, and is linked to microvascular dysfunction that manifests as edema formation and secondary hemorrhage, which cause brain swelling. Activation of the channel is a major molecular mechanism of cytotoxic edema and "accidental necrotic cell death." Blockade of Sur1 using glibenclamide has been studied in different types of rat models of stroke: (i) in conventional non-lethal models (thromboembolic, 1-2 h temporary, or permanent middle cerebral artery occlusion), glibenclamide reduces brain swelling and infarct volume and improves neurological function; (ii) in lethal models of malignant cerebral edema, glibenclamide reduces edema, brain swelling, and mortality; (iii) in models with rtPA, glibenclamide reduces swelling, hemorrhagic transformation, and death. Retrospective studies of diabetic patients who present with stroke have shown that those whose diabetes is managed with a sulfonylurea drug and who are maintained on the sulfonylurea drug during hospitalization for stroke have better outcomes at discharge and are less likely to suffer hemorrhagic transformation. Here, we provide a comprehensive review of the basic science, preclinical experiments, and retrospective clinical studies on glibenclamide in focal cerebral ischemia and stroke. We also compare the preclinical work in stroke models to the updated recommendations of the Stroke Therapy Academic Industry Roundtable (STAIR). The findings reviewed here provide a strong foundation for a translational research program to study glibenclamide in patients with ischemic stroke.
    Neurocritical Care 10/2013; 20(2). DOI:10.1007/s12028-013-9923-1 · 2.60 Impact Factor
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    ABSTRACT: Subarachnoid hemorrhage (SAH) can leave patients with memory impairments that may not recover fully. Molecular mechanisms are poorly understood, and no treatment is available. The sulfonylurea receptor 1-transient receptor potential melastatin 4 (Sur1-Trpm4) channel plays an important role in acute central nervous system injury. We evaluated upregulation of Sur1-Trpm4 in humans with SAH and, in rat models of SAH, we examined Sur1-Trpm4 upregulation, its role in barrier dysfunction and neuroinflammation, and its consequences on spatial learning. We used Förster resonance energy transfer to detect coassociated Sur1 and Trpm4 in human autopsy brains with SAH. We studied rat models of SAH involving filament puncture of the internal carotid artery or injection of blood into the subarachnoid space of the entorhinal cortex. In rats, we used Förster resonance energy transfer and coimmunoprecipitation to detect coassociated Sur1 and Trpm4, we measured immunoglobulin G extravasation and tumor necrosis α overexpression as measures of barrier dysfunction and neuroinflammation, and we assessed spatial learning and memory on days 7 to 19. Sur1-Trpm4 channels were upregulated in humans and rats with SAH. In rats, inhibiting Sur1 using antisense or the selective Sur1 inhibitor glibenclamide reduced SAH-induced immunoglobulin G extravasation and tumor necrosis α overexpression. In models with entorhinal SAH, rats treated with glibenclamide for 7 days after SAH exhibited better platform search strategies and better performance on incremental and rapid spatial learning than vehicle-treated controls. Sur1-Trpm4 channels are upregulated in humans and rats with SAH. Channel inhibition with glibenclamide may reduce neuroinflammation and the severity of cognitive deficits after SAH.
    Stroke 10/2013; 44(12). DOI:10.1161/STROKEAHA.113.002904 · 6.02 Impact Factor
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    ABSTRACT: First introduced into clinical practice in 1969, glibenclamide (US adopted name, glyburide) is known best for its use in the treatment of diabetes mellitus type 2, where it is used to promote the release of insulin by blocking pancreatic KATP [sulfonylurea receptor 1 (Sur1)-Kir6.2] channels. During the last decade, glibenclamide has received renewed attention due to its pleiotropic protective effects in acute CNS injury. Acting via inhibition of the recently characterized Sur1-Trpm4 channel (formerly, the Sur1-regulated NCCa-ATP channel) and, in some cases, via brain KATP channels, glibenclamide has been shown to be beneficial in several clinically relevant rodent models of ischemic and hemorrhagic stroke, traumatic brain injury, spinal cord injury, neonatal encephalopathy of prematurity, and metastatic brain tumor. Glibenclamide acts on microvessels to reduce edema formation and secondary hemorrhage, it inhibits necrotic cell death, it exerts potent anti-inflammatory effects and it promotes neurogenesis-all via inhibition of Sur1. Two clinical trials, one in TBI and one in stroke, currently are underway. These recent findings, which implicate Sur1 in a number of acute pathological conditions involving the CNS, present new opportunities to use glibenclamide, a well-known, safe pharmaceutical agent, for medical conditions that heretofore had few or no treatment options.
    Pharmaceuticals 10/2013; 6(10):1287-1303. DOI:10.3390/ph6101287
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    ABSTRACT: Study design:Experimental, controlled, animal study.Objectives:To use non-invasive magnetic resonance imaging (MRI) to corroborate invasive studies showing progressive expansion of a hemorrhagic lesion during the early hours after spinal cord trauma and to assess the effect of glibenclamide, which blocks Sur1-Trpm4 channels implicated in post-traumatic capillary fragmentation, on lesion expansion.Setting:Baltimore.Methods:Adult female Long-Evans rats underwent unilateral impact trauma to the spinal cord at C7, which produced ipsilateral but not contralateral primary hemorrhage. In series 1 (six control rats and six administered glibenclamide), hemorrhagic lesion expansion was characterized using MRI at 1 and 24 h after trauma. In series 2, hemorrhagic lesion size was characterized on coronal tissue sections at 15 min (eight rats) and at 24 h after trauma (eight control rats and eight administered glibenclamide).Results:MRI (T2 hypodensity) showed that lesions expanded 2.3±0.33-fold (P<0.001) during the first 24 h in control rats, but only 1.2±0.07-fold (P>0.05) in glibenclamide-treated rats. Measuring the areas of hemorrhagic contusion on tissue sections at the epicenter showed that lesions expanded 2.2±0.12-fold (P<0.001) during the first 24 h in control rats, but only 1.1±0.05-fold (P>0.05) in glibenclamide-treated rats. Glibenclamide treatment was associated with significantly better neurological function (unilateral BBB scores) at 24 h in both the ipsilateral (median scores, 9 vs 0; P<0.001) and contralateral (median scores, 12 vs 2; P<0.001) hindlimbs.Conclusion:MRI is an accurate non-invasive imaging biomarker of lesion expansion and is a sensitive measure of the ability of glibenclamide to reduce lesion expansion.Spinal Cord advance online publication, 17 September 2013; doi:10.1038/sc.2013.99.
    Spinal Cord 09/2013; 51(11). DOI:10.1038/sc.2013.99 · 1.70 Impact Factor
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    ABSTRACT: Object Aneurysmal subarachnoid hemorrhage (aSAH) predisposes to delayed neurological deficits, including stroke and cognitive and neuropsychological abnormalities. Heparin is a pleiotropic drug that antagonizes many of the pathophysiological mechanisms implicated in secondary brain injury after aSAH. Methods The authors performed a retrospective analysis in 86 consecutive patients with Fisher Grade 3 aSAH due to rupture of a supratentorial aneurysm who presented within 36 hours and were treated by surgical clipping within 48 hours of their ictus. Forty-three patients were managed postoperatively with a low-dose intravenous heparin infusion (Maryland low-dose intravenous heparin infusion protocol: 8 U/kg/hr progressing over 36 hours to 10 U/kg/hr) beginning 12 hours after surgery and continuing until Day 14 after the ictus. Forty-three control patients received conventional subcutaneous heparin twice daily as deep vein thrombosis prophylaxis. Results Patients in the 2 groups were balanced in terms of baseline characteristics. In the heparin group, activated partial thromboplastin times were normal to mildly elevated; no clinically significant hemorrhages or instances of heparin-induced thrombocytopenia or deep vein thrombosis were encountered. In the control group, the incidence of clinical vasospasm requiring rescue therapy (induced hypertension, selective intraarterial verapamil, and angioplasty) was 20 (47%) of 43 patients, and 9 (21%) of 43 patients experienced a delayed infarct on CT scanning. In the heparin group, the incidence of clinical vasospasm requiring rescue therapy was 9% (4 of 43, p = 0.0002), and no patient suffered a delayed infarct (p = 0.003). Conclusions In patients with Fisher Grade 3 aSAH whose aneurysm is secured, postprocedure use of a low-dose intravenous heparin infusion may be safe and beneficial.
    Journal of Neurosurgery 09/2013; 119(6). DOI:10.3171/2013.8.JNS1337 · 3.15 Impact Factor
  • Journal of Neurosurgery 09/2013; 119(3):821-2. · 3.15 Impact Factor

Publication Stats

3k Citations
681.28 Total Impact Points


  • 1994–2015
    • University of Maryland, Baltimore
      • • Department of Neurosurgery
      • • Department of Physiology
      • • Greenebaum Cancer Center
      • • Department of Neurology
      Baltimore, Maryland, United States
  • 2013
    • Duke University
      Durham, North Carolina, United States
  • 2009
    • Walter Reed National Military Medical Center
      • Department of Surgery
      Washington, D. C., DC, United States
  • 2003
    • Texas A&M University - Galveston
      Galveston, Texas, United States
  • 1989–1993
    • University of Texas Medical Branch at Galveston
      • • Division of Neurosurgery
      • • Department of Surgery
      Galveston, Texas, United States