J Marc Simard

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

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Publications (161)811.29 Total impact

  • K.N. Sheth · J.M. Simard · J. Elm · G. Kronenberg · H. Kunte · W.T. Kimberly ·

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    ABSTRACT: Ischemic stroke, a major cause of mortality, is frequently accompanied by life-threatening cerebral edema. Aquaporin-4 (Aqp4), an astrocytic transmembrane water channel, is an important molecular contributor to cerebral edema formation. Past studies of Aqp4 expression and localization after ischemia examined grey matter exclusively. However, as white matter astrocytes differ developmentally, physiologically, and molecularly from grey matter astrocytes, we hypothesized that functionally important regional heterogeneity exists in Aqp4 expression and subcellular localization following cerebral ischemia. Subcellular localization of Aqp4 was compared between cortical and white matter astrocytes in postmortem specimens of patients with focal ischemic stroke versus controls. Subcellular localization and expression of Aqp4 was examined in rats subjected to experimental stroke. Volumetric analysis was performed on the cortex and white matter of rats subjected to experimental stroke. Following cerebral ischemia, cortical astrocytes exhibited reduced perivascular Aqp4 and unchanged Aqp4 protein abundance. In contrast, white matter astrocytes exhibited increased perivascular and plasmalemmal Aqp4 and a 2.2- to 6.2-fold increase in Aqp4 isoform abundance. Ischemic white matter swelled by approximately 40 %, while cortex swelled by approximately 9 %. The findings reported here raise the possibility that cerebral white matter may play a heretofore underappreciated role in the formation of cerebral edema following ischemia.
    12/2015; 3(1). DOI:10.1186/s40478-015-0239-6
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    ABSTRACT: Background: In experimental autoimmune encephalomyelitis (EAE), deletion of transient receptor potential melastatin 4 (Trpm4) and administration of glibenclamide were found to ameliorate disease progression, prompting speculation that glibenclamide acts by directly inhibiting Trpm4. We hypothesized that in EAE, Trpm4 upregulation is accompanied by upregulation of sulfonylurea receptor 1 (Sur1) to form Sur1-Trpm4 channels, which are highly sensitive to glibenclamide, and that Sur1-Trpm4 channels are required for EAE progression. Methods: EAE was induced in wild-type (WT) and Abcc8-/- mice using myelin oligodendrocyte glycoprotein 35-55 (MOG35-55). Lumbar spinal cords were examined by immunohistochemistry, immuno-Förster resonance energy transfer (immunoFRET), and co-immunoprecipitation for Sur1-Trpm4. WT/EAE mice were administered with the Sur1 inhibitor, glibenclamide, beginning on post-induction day 10. Mice were evaluated for clinical function, inflammatory cells and cytokines, axonal preservation, and white matter damage. Results: Sur1-Trpm4 channels were upregulated in EAE, predominantly in astrocytes. The clinical course and severity of EAE were significantly ameliorated in glibenclamide-treated WT/EAE and in Abcc8-/-/EAE mice. At 30 days, the lumbar spinal cords of glibenclamide-treated WT/EAE and Abcc8-/-/EAE mice showed significantly fewer invading immune cells, including leukocytes (CD45), T cells (CD3), B cells (CD20) and macrophages/microglia (CD11b), and fewer cells expressing pro-inflammatory cytokines (TNF-α, IFN-γ, IL-17). In both glibenclamide-treated WT/EAE and Abcc8-/-/EAE mice, the reduced inflammatory burden correlated with better preservation of myelin, better preservation of axons, and more numerous mature and precursor oligodendrocytes. Conclusions: Sur-Trpm4 channels are newly upregulated in EAE and may represent a novel target for disease-modifying therapy in multiple sclerosis.
    Journal of Neuroinflammation 11/2015; 12(1):210. DOI:10.1186/s12974-015-0432-3 · 5.41 Impact Factor
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    ABSTRACT: Aims: Stem cell therapy is under active investigation for traumatic brain injury (TBI). Non-invasive stem cell delivery is the preferred method. But retention of stem cells at the site of injury in TBI has proven challenging and impacts effectiveness. To investigate the effects of applying a magnetic field on cell homing and retention, we delivered human neuroprogenitor cells labeled with a superparamagnetic nanoparticle into post-TBI animals in the presence of a static magnetic field. Methods and results: We have previously devised a method of loading human neuroprogenitor cells (hNPCs) with ultrasmall superparamagnetic iron-oxide nanoparticles (USPIO). Molday ION Rhodamine B (MIRB™). Labeling of hNPCs (MIRB-hNPCs) does not affect hNPCs viability, proliferation or differentiation (47). The 0.6 Tesla (T) permeant magnet was placed ~4 mm above the injured parietal cortex prior to intracarotid injection of 4 x 105 MIRB-hNPCs. Fluorescence imaging, Perl's Prussian blue histochemistry, immunocytochemistry with SC121, a human-specific antibody, and T2-weighted magnetic resonance imaging ex vivo, revealed there was increased homing and retention of MIRB-hNPCs in the injured cortex as compared to the 0 T group. Fluoro-Jade C staining, immunolabeling with the macrophage/microglial antibody Iba-1 and SC121 antibody confirmed the viability status of MIRB-hNPCs cells post-transplantation. Conclusions: These results show that increased homing and retention of MIRB-hNPCs post-TBI by applying a static magnetic field is a promising technique to deliver cells in the CNS in neurological injuries and neurodegenerative diseases.
    Cell Transplantation 09/2015; DOI:10.3727/096368915X689550 · 3.13 Impact Factor
  • J Marc Simard · Kevin N Sheth ·

    Critical care medicine 09/2015; 43(9):2040-1. DOI:10.1097/CCM.0000000000001112 · 6.31 Impact Factor
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    ABSTRACT: Explosive blast-related injuries are one of the hallmark injuries of veterans returning from recent wars, but the effects of a blast overpressure on the brain are poorly understood. In this study, we used in vivo diffusion kurtosis imaging (DKI) and proton magnetic resonance spectroscopy (MRS) to investigate tissue microstructure and metabolic changes in a novel, direct cranial blast traumatic brain injury (dc-bTBI) rat model. Imaging was performed on rats before injury and 1, 7, 14 and 28 days after blast exposure (~517 kPa peak overpressure to the dorsum of the head). No brain parenchyma abnormalities were visible on conventional T2-weighted MRI, but microstructural and metabolic changes were observed with DKI and proton MRS, respectively. Increased mean kurtosis, which peaked at 21 days post injury, was observed in the hippocampus and the internal capsule. Concomitant increases in myo-Inositol (Ins) and Taurine (Tau) were also observed in the hippocampus, while early changes at 1 day in the Glutamine (Gln) were observed in the internal capsule, all indicating glial abnormality in these regions. Neurofunctional testing on a separate but similarly treated group of rats showed early disturbances in vestibulomotor functions (days 1–14), which were associated with imaging changes in the internal capsule. Delayed impairments in spatial memory and in rapid learning, as assessed by Morris Water Maze paradigms (days 14– 19), were associated with delayed changes in the hippocampus. Significant microglial activation and neurodegeneration were observed at 28 days in the hippocampus. Overall, our findings indicate delayed neurofunctional and pathological abnormalities following dc-bTBI that are silent on conventional T2-weighted imaging, but are detectable using DKI and proton MRS.
    PLoS ONE 08/2015; 10(8). DOI:10.1371/journal.pone.0136151 · 3.23 Impact Factor
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    ABSTRACT: Microglia, the resident immune cells of the central nervous system, play a critical role in health and disease. Following injury, microglia upregulate inducible nitric oxide synthase (iNOS), and can exert neurotoxic effects by releasing large quantities of nitric oxide (NO). Expression of iNOS, and many other proinflammatory genes, is regulated in part by Ca influx and Ca-dependent transcription factors. The expression of the nonselective cation channel Sur1-Trpm4 may be 1 molecular mechanism by which microglia dynamically modulate Ca influx. We hypothesized that microglial Sur1-Trpm4 plays a role in microglial-mediated neuroinflammation by regulating the calcium-sensitive induction of iNOS. The Toll-like receptor 4 (TLR4) agonist lipopolysaccharide (LPS) was used as a stimulus to activate microglia. Protein expression was evaluated by immunohistochemistry, Western blot, and coimmunoprecipitation (Co-IP). Quantitative PCR (qPCR) was used to evaluate gene expression. Functional Sur1-Trpm4 activity was evaluated electrophysiologically. Confocal microscopy and the calcium-sensitive fluorescent dye, Fluo-4, was used to dynamically measure intracellular calcium. Extracellular nitrite, a by-product of NO formation, was measured to evaluate iNOS activity. Microglia express functional Sur1-Trpm4 channels, whose activity modulated Ca oscillations induced by TLR4 ligation. Inhibition of Ca, Sur1-Trpm4 or NFAT all significantly abrogated the induction of iNOS. The activation of NFAT induced by TLR4 ligation was modulated by inhibition of Sur1. Our results strongly support our hypothesis that Sur1-Trpm4 regulates the calcium-sensitive induction of iNOS by controlling NFAT activity. These observations have impactful therapeutic implications. Inhibition of Sur1-Trpm4 using the well-tolerated sulfonylurea glibenclamide (a.k.a. glyburide) may be a promising approach to limit the deleterious effects of microglial-mediated neuroinflammation.
    Neurosurgery 08/2015; 62 Suppl 1, CLINICAL NEUROSURGERY:217-218. DOI:10.1227/01.neu.0000467122.92580.13 · 3.62 Impact Factor
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    ABSTRACT: The nonselective monovalent cation channel transient receptor potential melastatin 4 (Trpm4) is transcriptionally upregulated in neural and vascular cells in animal models of brain infarction. It associates with sulfonylurea receptor 1 (Sur1) to form Sur1-Trpm4 channels, which have critical roles in cytotoxic edema, cell death, blood-brain barrier breakdown, and vasogenic edema. We examined Trpm4 expression in postmortem brain specimens from 15 patients who died within the first 31 days of the onset of focal cerebral ischemia. We found increased Trpm4 protein expression in all cases using immunohistochemistry; transcriptional upregulation was confirmed using in situ hybridization of Trpm4 messenger RNA. Transient receptor potential melastatin 4 colocalized and coassociated with Sur1 within ischemic endothelial cells and neurons. Coexpression of Sur1 and Trpm4 in necrotic endothelial cells was also associated with vasogenic edema indicated by upregulated perivascular tumor necrosis factor, extravasation of serum immunoglobulin G, and associated inflammation. Upregulated Trpm4 protein was present up to 1 month after the onset of cerebral ischemia. In a rat model of middle cerebral artery occlusion stroke, pharmacologic channel blockade by glibenclamide, a selective inhibitor of sulfonylurea receptor, mitigated perivascular tumor necrosis factor labeling. Thus, upregulated Sur1-Trpm4 channels and associated blood-brain barrier disruption and cerebral edema suggest that pharmacologic targeting of this channel may represent a promising therapeutic strategy for the clinical management of patients with cerebral ischemia.
    08/2015; 74(8):835-849. DOI:10.1097/NEN.0000000000000223
  • J Marc Simard ·

    Neurology 06/2015; 85(3). DOI:10.1212/WNL.0000000000001769 · 8.29 Impact Factor
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    ABSTRACT: Post-traumatic brain contusions (PTBCs) are traditionally considered primary injuries and can increase in size, generate perilesional edema, cause mass effect, induce neurological deterioration, and cause death. Most patients experience a progressive increase in pericontusional edema, and nearly half, an increase in the hemorrhagic component itself. The underlying molecular pathophysiology of contusion-induced brain edema and hemorrhagic progression remains poorly understood. The aim of this study was to investigate sulfonylurea 1/transient receptor potential melastatin 4 (SUR1-TRPM4) ion channel SUR1 expression in various cell types (neurons, astrocytes, endothelial cells, microglia, macrophages, and neutrophils) of human brain contusions and whether SUR1 up-regulation was related to time postinjury. Double immunolabeling of SUR1 and cell-type- specific proteins was performed in 26 specimens from traumatic brain injury patients whose lesions were surgically evacuated. Three samples from limited brain resections performed for accessing extra-axial skull-base tumors or intraventricular lesions were controls. We found SUR1 was significantly overexpresed in all cell types and was especially prominent in neurons and endothelial cells (ECs). The temporal pattern depended on cell type: 1) In neurons, SUR1 increased within 48 h of injury and stabilized thereafter; 2) in ECs, there was no trend; 3) in glial cells and microglia/macrophages, a moderate increase was observed over time; and 4) in neutrophils, it decreased with time. Our results suggest that up-regulation of SUR1 in humans point to this channel as one of the important molecular players in the pathophysiology of PTBCs. Our findings reveal opportunities to act therapeutically on the mechanisms of growth of traumatic contusions and therefore reduce the number of patients with neurological deterioration and poor neurological outcomes.
    Journal of Neurotrauma 06/2015; 32(19):150603133210003. DOI:10.1089/neu.2014.3706 · 3.71 Impact Factor
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    ABSTRACT: Decompressive craniectomy (DC) has been used for many years in the management of patients with elevated intracranial pressure and cerebral edema. Ongoing clinical trials are investigating the clinical and cost effectiveness of DC in trauma and stroke. While DC has demonstrable efficacy in saving life, it is accompanied by a myriad of non-trivial complications that have been inadequately highlighted in prospective clinical trials. Missing from our current understanding is a comprehensive analysis of all potential complications associated with DC. Here, we review the available literature, we tabulate all reported complications, and we calculate their frequency for specific indications. Of over 1500 records initially identified, a final total of 142 eligible records were included in our comprehensive analysis. We identified numerous complications related to DC that have not been systematically reviewed. Complications were of three major types: (1) Hemorrhagic (2) Infectious/Inflammatory, and (3) Disturbances of the CSF compartment. Complications associated with cranioplasty fell under similar major types, with additional complications relating to the bone flap. Overall, one of every ten patients undergoing DC may suffer a complication necessitating additional medical and/or neurosurgical intervention. While DC has received increased attention as a potential therapeutic option in a variety of situations, like any surgical procedure, DC is not without risk. Neurologists and neurosurgeons must be aware of all the potential complications of DC in order to properly advise their patients.
    Neurocritical Care 06/2015; 23(2). DOI:10.1007/s12028-015-0144-7 · 2.44 Impact Factor
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    ABSTRACT: Recent preclinical studies have identified three treatments that are especially promising for reducing acute lesion expansion following traumatic spinal cord injury (SCI): riluzole, systemic hypothermia, and glibenclamide. Each has demonstrated efficacy in multiple studies with independent replication, but there is no way to compare them in terms of efficacy or safety, since different models were used, different laboratories were involved, and different outcomes were evaluated. Here, using a model of lower cervical hemicord contusion, we compared safety and efficacy for the three treatments, administered beginning 4 hours after trauma. Treatment-associated mortality was 30% (3/10), 30% (3/10), 12.5% (1/8) and 0% (0/7), in control, riluzole, hypothermia and glibenclamide groups, respectively. For survivors, all three treatments showed overall favorable efficacy compared to controls. On open-field locomotor scores (modified Basso, Beattie and Bresnahan scores), hypothermia- and glibenclamide-treated animals were largely indistinguishable throughout the study, whereas riluzole-treated rats underperformed for the first 2 weeks; during the last 4 weeks, scores for the three treatments were similar, and significantly different from controls. On beam balance, hypothermia and glibenclamide treatments showed significant advantages over riluzole. After trauma, rats in the glibenclamide group rapidly regained a normal pattern of weight gain that differed markedly and significantly from that in all other groups. Lesion volumes at 6 weeks were: 4.80.7, 3.50.4, 3.10.3 and 2.50.3 mm3 in the control, riluzole, hypothermia and glibenclamide groups, respectively; measurements of spared spinal cord tissue confirmed these results. Overall, in terms of safety and efficacy, systemic hypothermia and glibenclamide were superior to riluzole.
    Journal of Neurotrauma 05/2015; 32(21):150528105059001. DOI:10.1089/neu.2015.3892 · 3.71 Impact Factor

  • The Lancet Neurology 04/2015; 14(4). DOI:10.1016/S1474-4422(15)70013-X · 21.90 Impact Factor
  • Arjun Khanna · J Marc Simard · Kristopher T Kahle ·

    New England Journal of Medicine 04/2015; 372(18):1765-6. DOI:10.1056/NEJMc1503138#SA2 · 55.87 Impact Factor
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    ABSTRACT: Ischemic and hemorrhagic strokes are associated with severe functional disability and high mortality. Except for recombinant tissue plasminogen activator, therapies targeting the underlying pathophysiology of central nervous system (CNS) ischemia and hemorrhage are strikingly lacking. Sur1-regulated channels play essential roles in necrotic cell death and cerebral edema following ischemic insults, and in neuroinflammation after hemorrhagic injuries. Inhibiting endothelial, neuronal, astrocytic and oligodendroglial sulfonylurea receptor 1-transient receptor potential melastatin 4 (Sur1-Trpm4) channels and, in some cases, microglial KATP (Sur1-Kir6.2) channels, with glibenclamide is protective in a variety of contexts. Robust preclinical studies have shown that glibenclamide and other sulfonylurea agents reduce infarct volumes, edema and hemorrhagic conversion, and improve outcomes in rodent models of ischemic stroke. Retrospective studies suggest that diabetic patients on sulfonylurea drugs at stroke presentation fare better if they continue on drug. Additional laboratory investigations have implicated Sur1 in the pathophysiology of hemorrhagic CNS insults. In clinically relevant models of subarachnoid hemorrhage, glibenclamide reduces adverse neuroinflammatory and behavioral outcomes. Here, we provide an overview of the preclinical studies of glibenclamide therapy for CNS ischemia and hemorrhage, discuss the available data from clinical investigations, and conclude with promising preclinical results that suggest glibenclamide may be an effective therapeutic option for ischemic and hemorrhagic stroke.
    International Journal of Molecular Sciences 03/2015; 16(3):4973-4984. DOI:10.3390/ijms16034973 · 2.86 Impact Factor
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    ABSTRACT: Neuroinflammation is a well-recognized consequence of subarachnoid hemorrhage (SAH), and may be responsible for important complications of SAH. Signaling by Toll-like receptor 4 (TLR4)-mediated nuclear factor κB (NFκB) in microglia plays a critical role in neuronal damage after SAH. Three molecules derived from erythrocyte breakdown have been postulated to be endogenous TLR4 ligands: methemoglobin (metHgb), heme and hemin. However, poor water solubility of heme and hemin, and lipopolysaccharide (LPS) contamination have confounded our understanding of these molecules as endogenous TLR4 ligands. We used a 5-step process to obtain highly purified LPS-free metHgb, as confirmed by Fourier Transform Ion Cyclotron Resonance mass spectrometry and by the Limulus amebocyte lysate assay. Using this preparation, we show that metHgb is a TLR4 ligand at physiologically relevant concentrations. metHgb caused time- and dose-dependent secretion of the proinflammatory cytokine, tumor necrosis factor α (TNFα), from microglial and macrophage cell lines, with secretion inhibited by siRNA directed against TLR4, by the TLR4-specific inhibitors, Rs-LPS and TAK-242, and by anti-CD14 antibodies. Injection of purified LPS-free metHgb into the rat subarachnoid space induced microglial activation and TNFα upregulation. Together, our findings support the hypothesis that, following SAH, metHgb in the subarachnoid space can promote widespread TLR4-mediated neuroinflammation.
    International Journal of Molecular Sciences 03/2015; 16(3):5028-5046. DOI:10.3390/ijms16035028 · 2.86 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; 77(5). DOI:10.1038/pr.2015.34 · 2.31 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; 11(2). DOI:10.1038/nrneurol.2014.264 · 15.36 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 · 2.05 Impact Factor

  • International journal of radiation oncology, biology, physics 09/2014; 90(1):S911. DOI:10.1016/j.ijrobp.2014.05.2587 · 4.26 Impact Factor

Publication Stats

3k Citations
811.29 Total Impact Points


  • 1994-2015
    • University of Maryland, Baltimore
      • • Department of Neurosurgery
      • • Department of Medicine
      • • Greenebaum Cancer Center
      • • Department of Neurology
      Baltimore, Maryland, United States
  • 2014
    • University of Maryland Medical Center
      Baltimore, Maryland, United States
  • 2013
    • Duke University
      Durham, North Carolina, United States
  • 2004
    • University of Miami Miller School of Medicine
      • Department of Pathology
      Miami, Florida, United States
  • 1992-2003
    • Texas A&M University - Galveston
      Galveston, Texas, United States
  • 1995
    • University Center Rochester
      • Department of Diagnostic Radiology
      Рочестер, Minnesota, United States
  • 1989-1993
    • University of Texas Medical Branch at Galveston
      • • Division of Neurosurgery
      • • Department of Surgery
      Galveston, Texas, United States