Faculty Research

 

James P. Bennett, Jr., M.D., Ph.D.

Dr. Bennett's laboratory is one of four labs that form The Center for the Study of Neurodegenerative Diseases. The major goal of the Center is to uncover the underlying molecular genetic, biochemical, and physiological abnormalities that cause neuronal death in neurodegenerative diseases such as Alzheimer's and Parkinson's. Dr. Bennett's efforts are directed at understanding the molecular cascades involved in programmed cell death, how mitochondrial dysfunction activates these cascades, and how the nucleus regulates scavenging and anti-apoptosis strategies of the cell. The research team makes use of human model neuronal cells and, where appropriate, animal models.

  • Swerdlow RH, Parks JK, Davis JN, Cassarino DS, Trimmer PA, Currie LJ, Doherty J, Bridges WS, Bennett JP,Jr., Wooten GF, and Parker WD. Matrilineal inheritance of complex I dysfunction in a multigenerational Parkinson's disease family. Annals of Neurology 44: 873-881, 1998.
  • Fall CP and Bennett JP, Jr. Characterization and timecourse of MPP+-induced apoptosis in human SH-SY5Y neuroblastoma cells. Journal of Neuroscience Research 55: 620-628, 1999.
  • Cassarino DS and Bennett JP, Jr. An evaluation of the role of mitochondria in neurodegenerative diseases: Mitochondrial mutations and oxidative pathology, protective nuclear responses, and cell death in neurodegeneration. Brain Research Reviews 29: 1-25, 1999.
  • Cassarino DS, Parks JP, Parker WD, Jr., and Bennett JP, Jr. The parkinsonian neurotoxin MPP+ opens the mitochondrial permeability transition pore and releases cytochrome c in isolated mitochondria via an oxidative mechanism. Biochimica et Biophysica Acta, 1453: 49-62, 1999.
  • Khan SM, Smith TS, and Bennett JP, Jr. Effects of single and multiple treatments with L-dihydroxyphenylalanine (L-DOPA) on dopamine receptor-G protein interactions and supersensitive immediate early gene responses in striata of rats after reserpine treatment or with unilateral nigrostriatal lesions. Journal of Neuroscience Research 55: 71-79, 1999.
  • Fall CP and Bennett, JP, Jr. Visualization of cyclosporin A- and Ca+2-sensitive spontaneous mitochondrial depolarizations in cell culture. Biochimica et Biophysica Acta 1410: 77-84, 1999.
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Edward H. Bertram, M.D.

This laboratory is using a new animal model of chronic limbic epilepsy to investigate the natural history of untreated epilepsy. This study will provide the basis for examining a variety of factors which may affect long-term outcome. In addition, the functional anatomy of limbic seizures is under investigation to determine which brain regions are critical to the generation of spontaneous seizures. These studies include the evaluation of physiologic and anatomic interactions among these areas to determine how normal function and connectivity may be altered to achieve this pathologic state.

Clinical investigation centers on the evaluation of patients for surgical treatment of intractable epilepsy, concentrating on improving monitoring and imaging techniques that will better localize the epileptogenic region. These studies involve investigators from neurosurgery, neuroradiology, neuropathology, neuropsychology, and biomedical engineering.

  • Bertram EH. The functional anatomy of spontaneous seizures in a rat model of chronic limbic epilepsy. Epilepsia 38:95-105, 1997.
  • Rempe DA, Bertram EH, Williamson JM, and Lothman EW. Area CA1 interneurons remain functionally connected to excitatory synaptic input in chronically epileptic animals. Journal of Neurophysiology 78:1504-1515, 1997.
  • Bertram EH, Williamson JM, Cornett JC, Spradlin S, and Chen ZF. Design and construction of a long-term continuous video-EEG monitoring unit for simultaneous recording of multiple small animals. Brain Research Protocols 2:85-97, 1997.
  • Mangan PS and Bertram EH. Ontogeny of altered synaptically mediated responses of CA1 pyramidal cells in a model of limbic epilepsy. Brain Research 799:183-196, 1998.
  • Bertram EH, Zhang DX, Mangan PS, Fountain N, and Rempe D. Functional anatomy of limbic epilepsy: A proposal for central synchronization of a diffusely hyperexcitable network. Epilepsy Research 32:194-205, 1998.
  • Bertram EH and Zhang DX. Thalamic excitation of hippocampal CA1 neurons: A comparison with the effects of CA3 stimulation. Neuroscience 92:15-26, 1999.
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Ted M. Burns, M.D.

ARTICLES:

  • Burns TM, Lawn NC, Low PA, Camilleri M, Wijdicks EFM. Adynamic ileus in severe Guillain-Barré syndrome. Muscle Nerve 2001; 24:963-965.
  • Burns TM, Shneker BF, Juel VC. Gasoline sniffing neuropathy mimicking mononeuropathy multiplex. Pediatric Neurology 2001; 25:419-421.
  • Apfel SC, Asbury AK, Bril V, Burns TM, Campbell JN, Chalk CH, et al. Neuropathic positive sensory symptoms as endpoints in diabetic neuropathy trials. J Neurol Sci 2001; 189:3-5.
  • Burns TM. Carpal tunnel sonography by the rheumatologist versus nerve conduction study by the neurolgist (letter). J Rheum 2001;28:2560.
  • Burns TM, Taly A, O’Brien PC.Dyck PJ. Clinical versus quantitative vibration assessment: improving clinical performance. J Periph Nerv System 2002; 7:112-117.
  • Klein CJ, Dyck PJB, Friedenberg SM, Burns TM, Windebank AJ, Dyck PJ. Inflammation and neuropathic attacks in hereditary brachial plexus neuropathy. J Neurol Neurosurg Psych 2002; 73:45-51.
  • Burns TM, Russell JA, LaChance DH, Jones HR. Oculobulbar involvement is typical with Lambert-Eaton myasthenic syndrome. Annals Neurol 2003 ;53 :270-273.
  • Burns TM, Jones HR. Oculobulbar involvement is typical with Lambert-Eaton myasthenic syndrome (reply to letter to editor). Annals Neurol 2003;54:136-137.
  • Burns TM, Quijano-Roy S, Jones HR. Benefit of IVIG for long-standing ataxic sensory   neuronopathy with Sjögren’s syndrome (letter). Neurology 2003;61:873.
  • Burns TM, Ryan M, Darras BT, Jones HR. Current therapeutic strategies for patients with polyneuropathy secondary to inherited metabolic disorders. Mayo Clinic Proceedings 2003;78:858-868.
  • Burns TM. Neurosarcoidosis. Arch Neurol 2003;60:1166-1168.
  • Burns TM, Jones HR, Phillips LH, Bugawan TL, Erlich HA, Lennon VA. Clinically Disparate Stiff-person syndrome with GAD65 Autoantibodies in a Father and Daughter. Neurology 2003; 61:1291-1293
  • Burns TM. Chronic Inflammatory Demyelinating Polyradiculoneuropathy. Arch Neurol 2003; in press.
  • Cameron CL, Kang PB, Burns TM, Darras BT, Jones HR. Multifocal Slowing of Nerve Conduction in Metachromatic Leukodystrophy. Muscle Nerve 2004; in press. Burns TM. Vasculitic Neuropathy. Continuum. Lifelong Learning in Neurology. 2003;9:146-159.

    CHAPTERS:

    • Burns TM, Dyck PJB. Treatment of Vasculitic Neuropathy, in Johnson RT, Griffin JW (eds): Current Therapy in Neurologic Diseases. 6th edition. Mosby-Year Book, Inc, 2001. p. 390-394.
    • Burns TM, Dyck PJ, Darras BT, Jones HR. Childhood Chronic Inflammatory Demyelinating Polyradiculoneuropathy, in Jones HR, Darras B, DeVivo DC (eds): Neuromuscular Disorders of Infancy, Childhood and Adolescence. Butterworth-Heinemann, 2002. p. 445-468.
    • Burns TM. Inherited Neuropathies with Known Metabolic Derangement, in Noseworthy JH (ed): Neurological Therapeutics: Principles and Practice, Martin Dunitz, 2003. p. 2166 – 2180.
    • Burns TM, Darras B, Jones HR. Pediatric Peripheral Neuropathy, in Dyck PJ, Thomas PK (eds): Peripheral Neuropathy. 4th edition. Saunders, 2004. in press.
    • Burns TM. Mechanisms of acute and chronic compression neuropathy, in Dyck PJ, Thomas PK (eds): Peripheral Neuropathy. 4th edition. Saunders, 2004. in press.
    • Burns TM, Jones HR. Lambert-Eaton Myasthenic Syndrome, in Jones HR. Netter’s Neurology; in press.
    • Burns TM, Srinivasin J, Russell JA. Disorders of the Autonomic Nervous System, in Jones HR: Netter’s Neurology; in press.
    • Burns TM, Bradshaw D, Kuntz N. Clinical Neurophysiology of Polyneuropathies of Infants, Children and Adolescents. In Holmes G, Moshe, Jones HR: Clinical Neurophysiology of Infants, Children and Adolescents. Butterworth-Heinemann, 2004. in press.
    • Ryan M, Burns TM, Kuntz N. Autonomic Dysfunction in Infants, Children and Adolescents. In Holmes G, Moshe, Jones HR: Clinical Neurophysiology of Infants, Children and Adolescents. Butterworth-Heinemann, 2004. in press.

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Nathan B. Fountain, M.D.

Clinical pharmacology of experimental antiepileptic drugs and development of novel therapies for refractory epilepsy are examined through the infrastructure of the Epilepsy Clinical Research Program. The natural history of epilepsy is studied through a large clinical relational database. Investigations of nonconvulsive status epilepticus are intended to define its pathophysiology, classification and natural history. Basic science research collaborations include examining the role of mitochondrial genetic abnormalities in human temporal lobe epilepsy.

SELECTED ARTICLES:

  • Fountain, N.B., Waldman, W.A. Effects of benzodiazepines on triphasic waves: Implications for nonconvulsive status epilepticus. Journal of Clinical Neurophysiology, 2001;18(4):345-352.
  • Pellock JM, Glauser TA, Bebin EM, Fountain NB, Ritter FJ, Coupez RM, Shields WD. Pharmacokinetic Study of Levetiracetam in Children. Epilepsia 2001;42(12):1574-1579.
  • Glauser TA, Pellock JM, Bebin EM, Fountain NB, Ritter FJ, Jensen CM, Sheilds WD. Efficacy and safety of levetiracetam in children with partial seizures: an open-label trial. Epilepsia 2002;43:518-524.
  • Quigg MS, Armstrong RF, Farace E, Fountain NB. Quality of life outcome is associated with cessation rather than reduction of psychogenic nonepileptic seizures. Epilepsy and Behavior 2002;3:455-459.
  • Gullapalli D, Fountain NB.  Clinical correlation of occipital intermittent rhythmic delta activity (OIRDA). Journal of Clinical Neurophysiology, 2003;20(1):35-41.
  • Fountain, N.B., May A.C. Epilepsy and Athletics. Clinics in Sports Medicine 2003;33(3):605-616.
  • Shneker BF, Fountain NB. Assessment of acute morbidity and mortality in nonconvulsive status epilepticus. Neurology 2003;61:1066-1073.
  • Kirby D, Fountain NB, Quigg MS. Standardized Mental Status Testing For Nonconvulsive Status Epilepticus. American Journal of Electroneurodiagnositc Technology 2004;44:198-201.
  • Huff JS, Fountain NB. Pathophysiology of seizures and status epilepticus. Annals of Emergency Medicine, 2004 submitted.
  • Miller, J.Q., Fountain, N.B., Editors, Neurology Recall, 2nd Edition. Philadelphia: Lippincott Williams and Wilkins, 2003.

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E. Clarke Haley, JR., M.D.

Major interests are in acute stroke intervention, management of cerebral vasospasm following subarachnoid hemorrhage, and noninvasive assessment of the cerebral circulation. Funded projects in progress include a randomized, controlled trial of a glycine antagonist in acute stroke.

  • The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. New England Journal of Medicine 333:1581-1587, 1995.
  • Findlay JM, Kassell NF, Weir BKA, Haley EC, Kongable G, Germanson T, Truskowski L, Alves WM, Holness RO, Knuckey NW, Yonas H, Steinberg GK, West M, Winn HR, and Ferguson G. A randomized trial of intraoperative, intracisternal tissue plasminogen activator for the prevention of vasospasm. Neurosurgery 37:168-178, 1995.
  • Kassell NF, Haley EC, Apperson-Hansen C, Alves WM, and the Participants. A randomized, double-blind, vehicle-controlled trial of tirilazad mesylate in patients with aneurysmal subarachnoid hemorrhage: A cooperative study in Europe/Australia/New Zealand. Journal of Neurosurgery 84:221-228, 1996.
  • The RANTTAS Investigators. A randomized trial of tirilazad mesylate in patients with acute stroke (RANTTAS). Stroke 27:1453-1458, 1996.
  • Haley EC, Kassell NF, Apperson-Hansen C, Maile MH, Alves WM, and the Participants. A randomized, double-blind, vehicle-controlled trial of tirilazad mesylate in patients with aneurysmal subarachnoid hemorrhage: A cooperative study in North America. Journal of Neurosurgery 86:467-474, 1997.
  • Haley EC, Jr., Lewandowski C, Tilley BC, and the NINDS rt-PA Stroke Study Group. Myths regarding the NINDS rt-PA stroke trial: Setting the record straight. Annals of Emergency Medicine 30:676-682, 1997.

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Madaline B. Harrison, M.D.

The principal focus in the laboratory is on the cellular mechanisms of neuropharmacologic actions in the striatum. The current emphasis is on interactions of dopamine and acetylcholine in regulating striatal output neurons because of the relevance of these transmitters to the pathophysiology and treatment of neurodegenerative disease. Dr. Harrison and colleagues have used retrogradely transported neurotoxins or "suicide transport" agents to produce selective lesions of striatonigral and striatopallidal neurons to examine localization and regulation of neurotransmitter receptors. With this technique, they have demonstrated selective localization of specific dopamine and muscarinic receptor subtypes to striatonigral neurons using receptor autoradiography and in situ hybridization. In a collaborative project, investigators have examined dopaminergic regulation of acetylcholine release in the striatum using striatal slices and acutely dissociated striatal neurons. With the same technique, they are now studying selective muscarinic receptor actions on striatal output neurons and their interactions with dopaminergic receptor effects. In addition, the laboratory has begun work to characterize effects of a selective immunotoxin lesion of cholinergic interneurons.
  • Harrison MB, Tissot M, and Wiley RG. Expression of m1 and m4 mRNA in the striatum following a selective lesion of striatonigral neurons. Brain Research 734:332-336, 1996.
  • Login IS and Harrison MB. A D1 dopamine agonist stimulates acetylcholine release through a direct action on striatal cholinergic neurons. Brain Research 727:162-168, 1996.
  • Wooten GF, Currie LJ, Bennett JP, Harrison MB, Trugman JM, and Parker DM. Maternal inheritance in Parkinson’s disease. Annals of Neurology 41:265-268, 1997.
  • Currie LJ, Bennett JP, Harrison MB, Trugman JM, and Wooten GF. Clinical correlates of sleep benefit in Parkinson’s disease. Neurology 48:1115-1117, 1997.
  • Garrett WT, Brashear HR, Cail WS, Lovell MA, Clayton M, and Harrison MB. Severe circumscribed cortical atrophy in Huntington’s disease. Neurology 51:638-639, 1998.
  • Currie LJ, HarrisonMB, Trugman JM, Bennett JP, and Wooten GF. Early morning dystonia in Parkinson’s disease. Neurology 51:283-285, 1998.
  • Swerdlow RH, Parks JK, Cassarino DS, Schilling AT, Bennett JP, Harrison MB, and Parker WD. Characterization of cybrid cell lines containing mtDNA from Huntington’s disease patients. Biochemical and Biophysical Research Communications, in press, 1999.

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J. Stephen Huff, M.D.

Research interests involve the overlap areas of neurology and emergency medicine. Current projects include studies in acute seizures and acute cerebrovascular disease. Computer-aided education of physicians in residency and fellowship training is another focus area.
  • Huff JS. New-onset sensory loss or alteration. Emergency Medicine Cl N Am 16:811-824, 1998.
  • Dziedzic L, Brady WJ, Lindsay R, and Huff JS. The use of the mini-mental status examination in the ED evaluation of the elderly. American Journal of Emergency Medicine 16:686-689, 1998.
  • Perron AD, Huff JS, Ullrich CG, Heafner MD, and Kline JA. A multicenter study to improve emergency medicine residents' recognition of intracranial emergencies on computed tomography. Annals of Emergency Medicine 32:554-562, 1998.
  • Huff JS. Status epilepticus. Emedicine: Emergency Medicine; an online medical reference. http://emedicine.com/emerg/; 1998.
  • Huff JS and Jackson JM. Web-based interactive case simulations: Promise, development, and examples. Academy of Emergency Medicine 5:484, 1999.
  • Huff JS, Bleck TP, and Buchman AS. Emergency evaluation of neurologic disorders. In: Principles and Practice of Emergency Medicine, Eds. GR Schwartz et al. pp. 1052-1056, 1999.

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Karen C. Johnston, M.D., M.Sc.

Clinical research interests focus on acute stroke care, clinical trials, and outcome. Acute therapy trials currently include thrombolytic, anti platelet and  glucose lowering compounds.

Clinical trials methodology research involves exploration of improved techniques for development and conduct of stroke trials. Specific areas of pursuit include development of risk adjustment methods and surrogate outcome measures for use in stroke clinical research.

  • Johnston KC, Connors AF, Wagner DP, and Haley EC. Predicting Outcome in Ischemic Stroke: External Validation of Predictive Risk Models.  Stroke . 2003; 200-202.
  • Juel, Vern C and Johnston, Karen C. Predict Resident Exam Performance (PREP) Study. Neurology . 2003; 60:1385-1388.
  • Johnston , Karen C. University of Virginia Competency Assessment and Evaluation Instruments: Self Assessment and Vital Evaluations (SAVE) Neurology. Academic Medicine . 2003; 78:1217-1220.
  • Johnston, Karen C and Mayer, Stephan A. Blood pressure reduction in ischemic stroke: two-edged sword?. Neurology . 2003; 61:1030-1031.
  • Johnston, Karen C. Introducing the Resident and Fellow Page. Neurology . 2004; 62:12.
  • Johnston KC, Connors AF, Wagner DP, Haley EC. Risk Adjustment Effect on Stroke Clinical Trials. Stroke . 2004; 35:e43-e45.
  • Brown Devin L, Johnston Karen C, Wagner Douglas P, Haley E. Clarke.  Predicting major neurological improvement with intravenous rt-PA treatment of stroke. Stroke. 2004;35:147-150
  • Johnston Karen C, Connors Alfred F Jr, Wagner Douglas P and Haley E. Clarke Jr.  Risk Adjustment Effect on Stroke Clinical Trials.  Stroke . 2004; 35:e43-e45.  
  • Rundek T, Nielsen K, Phillips S, Johnston KC, et.al.  Healthcare Resource Utilization after Acute Stroke in the Glycine Antagonist in Neuroprotection (GAIN) Americas Trial.  Stroke . 2004; 35:1368-1374.
  • Haley EC, Lyden PD, Johnston KC, et.al. A Pilot dose-escalation safety study of Tenecteplase (TNK) in acute ischemic stroke.  Stroke . 2005; 36:607-612.
  • Palesch, YY, Tilley BC , Sackett DL, Johnston KC, et.al. Applying a Phase II Futility Study Design to Therapeutic Stroke Trials.  Stroke . 2005; in press.

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Jaideep Kapur, M.D., PH.D.

There are three major areas of study in the laboratory all related to synaptic plasticity. First, we seek to understand the pathophysiological mechanisms underlying status epilepticus, which is a prolonged life threatening seizure. Our past studies initially established loss of GABA-mediated inhibition in the hippocampus and altered function of GABAA receptors in hippocampal neurons as key mechanisms initiating status epilepticus. Current studies focus on mechanisms underlying the plasticity of GABAA receptors during status epilepticus. They suggest that status epilepticus differentially alters the function of synaptic and extrasynaptic GABAA receptors and the GABA release from presynaptic terminal is diminished. Other studies in the lab focus on the role of excitatory neurotransmission in the pathogenesis of status epilepticus were prompted by the novel finding that N-methyl-D-Aspartate (NMDA) receptor antagonists could treat prolonged status epilepticus, refractory to currently used agents. Initial mechanistic studies suggest that there is increased presynaptic release of glutamate during status epilepticus.

Second area of research is to understand hormonal regulation of seizures. Although seizures appear unpredictable, biological rhythms and external stimuli can modulate seizure frequency, partly through circulating steroid hormones. Neurosteroids like allopregnanolone are synthesized in the brain from circulating steroids like progesterone and have powerful anticonvulsant effects. We observed that physiological concentrations of allopregnanolone potently enhance GABA mediated inhibition in hippocampal neurons of naïve rats, but fail to do so in hippocampal neurons of epileptic rats. Future studies test the hypothesis that decreased allopregnanolone modulation is due to altered expression of synaptic and extrasynaptic receptors. In collaboration with Dr Edward Bertram we study loss of GABAergic interneurons in the hippocampus and thalamus in a model of temporal lobe epilepsy.

Pregnenolone sulfate is one of the most abundant neurosteroids in the brain and plays an important role in age related memory decline. Our studies demonstrate that concentrations of pregnenolone sulfate commonly observed in the hippocampus inhibit GABAergic synaptic transmission by diminishing release of GABA from the presynaptic terminal. These findings for the first time demonstrate an effect of physiological concentration of this neurosteroid on synaptic transmission. Ongoing studies seek to understand the mechanism of action of pregnenolone sulfate.

Third area of interest is to understand normal and abnormal development of GABAergic synapses in vitro and in vivo. The in vitro studies combine electrophysiological characterization of synapse development with immunocytochemistry in low-density cultures of hippocampal neurons. We plan to investigate the role of neuronal activity and seizures on the development of GABAergic synapses. A direct application of these studies is to investigate the development of GABAergic synapses in cortical dysplasias, which can lead to seizures. In collaboration with Dr. Kevin Lee of the Department of Neuroscience, we seek to investigate the development of GABAergic synaptic transmission in a rat model of focal cortical dysplasia.

REFERENCE LIST:
  • Borris DJ, Bertram EH, and Kapur J. 2000. Ketamine controls prolonged status epilepticus. Epilepsy Res 42:117-122.
  • Kapur J. 2000. Hippocampal neurons express GABA A receptor insensitive to diazepam in hyperexcitable conditions. Epilepsia 41 Suppl 6:S86-S89.
  • Kapur J. 2002. Prehospital treatment of status epilepticus with benzodiazepines is effective and safe. Epilepsy Currents 2:121-124.
  • Kapur J. 2003a. Role of GABA(A) receptor-mediated inhibition in the pathogenesis of generalized seizures. Exp Neurol 184:1-2.
  • Mangan PS and Kapur J. 2004. Factors underlying bursting behavior in a network of cultured hippocampal neurons exposed to zero magnesium. J Neurophysiol 91:946-957.
  • Mtchedlishvili Z and Kapur J. 2003. A presynaptic action of the neurosteroid pregnenolone sulfate on GABAergic synaptic transmission. Mol Pharmacol 64:857-864.
  • Mtchedlishvili Z, Sun CS, Harrison MB, and Kapur J. 2003. Increased neurosteroid sensitivity of hippocampal GABAA receptors during postnatal development. Neuroscience 118:655-666.
  • Williamson J, Mtchedlishvili Z, and Kapur J. 2004. Characterization of the convulsant action of pregnenolone sulfate. Neuropharmacology 46:856-864.

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Ivan S. Login, M.D.

With the recent advances in diagnosis and management of migraine and other headache disorders, Dr. Login has initiated a dedicated interest in this field. Patients are seen on referral with new or complex headache problems to help establish a diagnosis or to offer advice on therapeutic strategies. Selected patients may be enrolled in clinical research protocols to evaluate new agents or investigate new applications of established agents.
  • Login IS. Managing headaches. In: Multiple Small Feedings of the Mind, American College of Physicians 80th Annual Meeting, New Orleans, Louisiana, April 1999.
  • Login, I.S.: New approaches to diagnosing and managing migraine in women.  Women Health Primary Care 3: 569 - 583, 2000.
  • Login, I.S.: A miracle of Chanukah.  Neurology 57: 2146-2147,  2001.
  • Burns, J.M. and Login, I.S.: Confounding factors in diagnosing brain death: a case report.  BMC Neurology [serial online] 2:5, 2002. Available at:  http://www.biomedcentral.com/1471-2377/2/5 .
  •  Watson,L.A., Burns, J.M. and Login, I.S.: Exploring new ways of publishing: a library-faculty partnership.  J Med Lib Assoc 91: 245-247, 2003.
  • Goldman, M.D. and Login, I.S.: Misdiagnosis of migraine.  Letter to the Editor.  Headache 43: 85-86, 2003.

Sattin, J.A. and Login, I.S.: Buspirone, prolactin and the pathophysiology of migraine.  Letter to the Editor.  Cephalalgia, in press, 2004.

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Carol A. Manning, PH.D.

The major aim of Dr. Manning’s research is to investigate the interface between cognitive and neurobiologic conceptualizations of memory. Of particular interest are individuals with memory deficits resulting from a variety of conditions including old age, Alzheimer’s disease, and Parkinson’s disease. Extrapolating from work with rodents, glucose ingestion has been found to enhance performance on a variety of memory tasks in individuals with memory deficits. In addition, individual differences in glucose regulation are correlated with overall memory performance. Examination of the strategies affected by glucose provides insight into the accuracy of current mapping conceptualizations of both cognitive and neurobiologic understanding of memory processes.
  • Crews WD, Manning CA, and Skalabrin E. Neuropsychological impairments of executive functions and memory in a case of bilateral thalamic infarction. Neurocase 2:405-412, 1996.
  • Manning CA, Parsons MW, Cotter EM, and Gold PE. Glucose effects on declarative and nondeclarative memory in healthy elderly and young adults. Psychobiology 25:103-108, 1997.
  • Wilkniss SM, Jones MG, Korol DL, Gold PE, and Manning CA. Age-related differences in an ecologically based study of route learning. Psychology and Aging 12:372-375, 1997.
  • Manning CA, Stone WS, Korol DL, and Gold PE. Glucose enhancement of 24 hour memory retrieval in healthy elderly humans. Behavioural Brain Research 93:71-76, 1998.
  • Manning CA, Honn VJ, Jane JS, and Gold PE. Glucose facilitation of memory in adults with Down’s Syndrome. Neuropsychology 12:479-484, 1998.
  • Manning CA, Wilkniss SM, and Pinkerton JV. Cognitive functioning in older women. The Gerontologist, in press, 1999.

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Barnett R. Nathan, M.D.

Laboratory research is directed toward the investigation of the pathophysiology of central nervous system infection. Experimental models include brain abscess and meningitis. New antimicrobials are tested for their efficacy in treating brain abscess and bacterial meningitis. The MRI changes in bacterial meningitis are also investigated. On a more cellular level investigations into the relative rolls of substance P, nitric oxide, and microgolia in models of CNS infection are investigated with tissue culture as well as molecular genetics techniques.

Clinical investigation involves fever in the intensive care unit, particularly the role of neurogenic, non-infectious fever.

  • Nathan B. Neurologic infectious disease and neurologic manifestations of HIV. In: Neurologic Recall, Eds. J Miller and N Fountain. Williams and Wilkins, Baltimore, 1997.
  • Nathan B. Neuroinfectious disease. In: Medicine Recall, Ed. DJ Bergin. Williams and Wilkins, Baltimore, 1997.
  • Nathan B. Cerebrospinal fluid and intracranial pressure. In: Textbook of Clinical Neurology, Eds. CG Goetz and EJ Pappert. W. B. Saunders Co., Philadelphia, 1998.
  • Nathan B. Nervous system infections and parainfectious disorders. Current Opinion in Critical Care 4(2):76-82, 1998.
  • Nathan B and Bleck T. Neurologic complications of critical medical illness. In: Critical Care Neurology, Eds. D Miller and E Raps. Butterworth-Heinemann, 1999.

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W. Davis Parker, JR., M.D.
Janice K. Parks, B.A.

This laboratory (which is one of four laboratories that form The Center for the Study of Neuro-degenerative Diseases) carries out molecular and genetic analysis of mitochondrial electron transport chain defects in the pathogenesis of human neurologic disorders. Dr. Parker and colleagues are particularly interested in the role of mitochondrial genes in the pathogenesis of apparently sporadic disorders including Parkinson’s disease, Alzheimer’s disease, and ALS. Using mitochondrial gene transfer techniques, they have demonstrated specific mitochondrial genetic abnormalities in these disorders. The team also investigates the impact of these gene defects on normal cellular functioning, oxygen radical production, and in activation of cell death programs.
  • Swerdlow RH, Parks JK, Miller SW, Tuttle JB, Trimmer PA, Sheehan JP, Bennett JP, Davis RE, and Parker WD. Origin and functional consequences of the complex I defect in Parkinson’s disease. Annals of Neurology 40:663-671,1996.
  • Parker WD and Swerdlow RH. Mitochondrial dysfunction in Parkinson’s disease. American Journal of Human Genetics 62:758-762, 1998.
  • Swerdlow RH, Parks JK, Cassarino DS, Trimmer PA, Miller SW, Maguire DJ, Sheehan JP, Maguire RS, Pattee G, Juel VC, Phillips LH, Tuttle JB, Bennett JP, Davis RE, and Parker WD. Mitochondria in sporadic amyotrophic lateral sclerosis. Experimental Neurology 153:135-142, 1998.
  • Swerdlow RH and Parker WD. Mitochondrial pathology in Parkinson’s disease and implications for therapeutic intervention. Drug Development Research 46:44-50, 1999.
  • Swerdlow RH, Binder D, and Parker WD. Maternal inheritance in schizophrenia. New England Journal of Medicine, in press, 1999.
  • Swerdlow RH, Parks JK, Cassarino DS, Schilling AT, Bennett JP, Harrison MB, and Parker WD. Characterization of cybrid cell lines containing mtDNA from Huntington’s disease patients. Biochemical and Biophysical Research Communications, in press, 1999.

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Lawrence H. Phillips, II, M.D.

Overview:  Dr. Phillips’ research is center in the Clinical Electromyography Laboratory.  It is clinically based in neuromuscular disease, and much of it is done in collaboration with other investigators at the University of Virginia and other institutions.

Amyotrophic Lateral Sclerosis:  The research involves multi-center treatment trials of various proposed therapies for ALS.  Past trials have included glutamate antagonists  such as riluzole and various neurotrophic factors, including insulin-like growth factor, brain-derived neurotrophic factor, and ciliary neurotrophic factor.  Current trials include creatine and pramipexole.

Myasthenia Gravis:  The research is devoted to multi-center treatment trials of new immunosuppressive drugs for myasthenia gravis.  Current trials are testing the effect of mycophenolate mofetil (CellCept) as an immunosuppressive drug in patients with myasthenia.  Trials in the planning stages include a study of the effect of low-dose Prednisone on the natural history of ocular myasthenia and a study of the efficacy of thymectomy on the course of generalized myasthenia.  Additional research is devoted to the development of clinical research standards in myasthenia gravis.

Epidemiology of Neuromuscular Diseases:  Investigations into the epidemiology of myasthenia gravis and other neuromuscular diseases utilize classical population-based studies and meta-analysis of the literature.

Axonal excitability testing:  Studies into the behavior of ion channels in peripheral motor nerve using axonal excitability measures are ongoing.  The purpose of this research is to expand the role of nerve conduction testing in various diseases of peripheral nerve and muscle.

  • Burns TM, Juel VC, Sanders DB, Phillips LH.  Neuroendocrine lung tumors and disorders of the neuromuscular junction.  Neurology 1999;52:1490-1491
  • The BDNF Study Group (Phase III) (Phillips LH included).  A controlled trial of recombinant methionyl human BDNF in ALS.  Neurology 1999;52:1427-1433
  • Phillips LH, Juel VC.  Myasthenia gravis in the tenth decade.  Muscle Nerve 1999;22:1297-1298
  • Simnad VI, Juel VC, Phillips LH.  Clinical and electrophysiological findings in the migrant sensory “neuritis” of Wartenberg.  J Clin Neuromusc Dis 1999;1:6-10
  • Juel VC, Kiely JM, Leone KV, Morgan RF, Smith T, Phillips LH.  Isolated musculocutaneous neuropathy due to a proximal humeral exostosis.  Neurology 2000;65:494-496
  • Phillips LH, Park TS, Shaffrey ME, Shaffrey CI.  Electrophysiological evidence for afferent nerve fibers in ventral roots.  Muscle Nerve 2000;23:410-415
  • Apfel SC, Schwart S, Adornato BT, Freeman R, Biton V, Rendell M, Vinik A, Giuliani M, Stevens JC, Barbano R, Dyck PJ, The rhNGF Clinical Investigator Group (LH Phillips included).  Efficacy and safety of recombinant human nerve growth factor in patients with diabetic polyneuropathy.  A randomized controlled trial.  JAMA 2000;284:2215-2221
  • Burns TM, Juel VC, Hess CE, Phillips LH.  Motor neuron disease and serum monoclonal proteins:  poor response to treatment of the paraproteinemia.  J Clin Neuromusc Dis 2000;2:70-72
  • Bryan WW, Hoagland RJ, Murphy J, Armon C, Barohn RJ, Goodpasture JC, Miller RG, Parry GJ, Petajan JH, Ross MA, Stromatt SC, the rhCNTF ALS Study Group (Phillips LH included).  Can we eliminate placebo in ALS clinical trials?  ALS and other Motor Neuron Dis 2003;4:11-15
  • Fiero PL, Galper DI, Cox DJ, Phillips LH, Fryburg DA.  Thermal biofeedback and lower extremity blood flow in adults with diabetes:  is neuropathy a limiting factor?  Appl Psychophysiol Biofeedback 2003;28:193-203
  • Jaretzki A, Aarli JAA, Kaminski HJ, Phillips LH, Sanders DB.  Thymectomy for myasthenia gravis:  evaluation requires controlled prospective studies (Editorial).  Ann Thorac Surg 2003;76:1-3
  • Phillips LH.  The epidemiology of myasthenia gravis.  Proc NY Acad Sci 2003;998:407-412
  • Burns TM, Phillips LH, Bugawan TL, Erlich HA Jones HR.  Clinical disparate stiff person syndrome with GAD65 autoantibody in a father and daughter.  Neurology 2003;1291-1293

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Mark S. Quigg, M.D.

Laboratory research centers on the interaction of circadian regulation and the temporal clustering of partial seizures with the goal of defining the anatomic and neuroendocrinological modulation of temporal lobe epilepsy. This research involves both an animal model of chronic limbic epilepsy and human subjects with medically-refractory partial seizures.

Clinical investigations center on the diagnosis and treatment of medically-refractory epilepsy, including epilepsy surgery. These studies involve development of electrographic and neuroimaging techniques that can better identify the epileptogenic zone. Participation in anticonvulsant drug trials is also ongoing.

  • Quigg M and Bleck T. Syncope. In: Epilepsy: A Comprehensive Textbook, Eds. Engel and Pedley. Raven Press, New York, 1996.
  • Quigg M, Bertram III EH, Jackson T, and Laws E. Volumetric MRI evidence of bilateral atrophy in unilateral mesial temporal lobe epilepsy. Epilepsia 38:588-594, 1997.
  • Quigg M, Bertram III EH, and Jackson T. Longitudinal distribution of atrophy in mesial temporal lobe epilepsy. Epilepsy Research 27:101-110, 1997.
  • Quigg M, Straume M, Menaker M, and Bertram EH. Temporal distribution of partial epilepsy: Comparison of an animal model with human partial epilepsy. Annals of Neurology 43:748-755, 1998.
  • Quigg M and Fountain NB. Conduction aphasia elicited by electrical cortical stimulation of the posterior superior temporal gyrus. Journal of Neurology, Neurosurgery, and Psychiatry 66:393-400, 1999.
  • Quigg M, Clayburn H, Straume M, Menaker M, and Bertram E. Hypothalamic neuronal loss and altered circadian rhythm of temperature in a rat model of temporal lobe epilepsy. Epilepsia, in press, 1999.

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Robert S. Rust, Jr., M.D.

Dr. Rust’s clinical and research interests encompass the areas of epilepsy, headache, neonatal neurology, degenerative disorders, and clinical pharmacology.

  • Gidal BE, Inglese CM, Meyer JF, and Rust RS. Effect of carnitine supplementation on valproate-mediate transient hyperammonemia in children. Pediatric Neurology 16:301-305, 1997.
  • Bushara KF and Rust RS. Facial palsy in mucocutaneous lymph node syndrome (Kawasaki Disease). Pediatric Neurology 17:362-364, 1997.
  • Bushara KF and Rust RS. Reversible MRI lesions due to pegaspargase treatment of non-Hodgkins lymphoma. Pediatric Neurology 17:180-184, 1997.
  • Rust RS, Thompson W, Beaty BJ, and Chun RWM. California (LaCrosse) Encephalitis. Journal of Child Neurology 14:1-14, 1999.
  • Rust RS and Schutta HS. Ophthalmoplegic migraine: Diagnostic criteria and clinical aspects. Pediatric Neurology, in press, 1999.
  • Rust RS and Hedley-White T. CPC: A five-year old with seizures and pseudobulbar palsy. Case records of the Massachusetts General Hospital, New England Journal of Medicine, in press, 1999.

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Virginia I. Simnad, M.D.

Dr. Simnad is the Clinical Director for the James Q. Miller Consultative Multiple Sclerosis Center. The MS Center provides second opinion and consultative services on management issues in multiple sclerosis. She is also involved in clinical trials in multiple sclerosis and treats general adult neurology patients.
  • Simnad VI. Acute onset of painful ophthalmoplegia following chiropractic manipulation of the neck: Initial sign of intracranial aneurysm. Western Journal of Medicine 166:207-210, 1997.
  • Simnad VI, Pisani DE, and Rose JW. Multiple sclerosis presenting as transverse myelopathy: Clinical and MRI features. Neurology 48:65-73, 1997.
  • Simnad VI, Juel VC, and Phillips LH. Clinical and electrophysiological findings in the migrant sensory "neuritis" of Wartenberg. Journal of Clinical Neuromuscular Disease, in press, 1999.

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Nina Solenski, M.D.

The aim of the research in this laboratory is to elucidate the role of oxygen free radicals during reversible focal ischemia by characterizing their temporal and spatial characteristics during and after ischemic conditions and by understanding their relationship to known excitatory amino acids and nitric oxide related mechanisms. Research focuses on elucidating specific targets of free radical species, including the role of neuronal mitochondria in acute ischemic damage. Specifically, these experiments couple the well-established technique, brain tissue microdialysis, to a reliable focal ischemia model in the rat. This experimental design allows for the in situ recovery of stable free radical adducts and the administration of pharmacological substances.
  • Zhang HE, Weir BKA, MacDonald RL, Marton LS, Solenski NJ, and Lee KS. Mechanisms of [Ca++]I elevation induced by erythrocyte components in endothelial cells. Journal of Pharmacology and Experimental Therapeutics 277:1501-1509, 1996.
  • Kwan AL, Solenski NJ, Kassell NF, and Lee KS. Hemolysate induces structural and functional injury to endothelial cells. Kaohsiung Journal of Medical Science 13:67-74, 1997.
  • Kwan AL, Solenski NJ, Kassell NF, and Lee KS. Inhibition of nitric oxide generation and lipid peroxidation attenuates hemolysate-induced injury to cerebrovascular endothelium. Acta Neurochirurgica 139:240-248, 1997.
  • Solenski NJ and Haley EC. Neurological complications of infective endocarditis. In: Central Nervous System Infectious Diseases and Therapy, Ed. K.L. Roos. Marcel Dekker, New York, pp. 331-363, 1997.
  • Solenski NJ, Yanamoto H, Kwan AL, Kassell NF, Bennett JP, and Lee KS. Differential elevation of hydroxyl radical in core and penumbra regions - during focal reversible cerebral ischemia. Stroke 28:2545-2551, 1997.

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Patricia A. Trimmer, Ph.D.

This laboratory investigates the role mitochondrial impairment plays in the neurodegeneration that characterizes Alzheimer’s and Parkinson’s diseases. The research focuses on how neuronal function is compromised by dysfunction of the mitochondrial electron transport chain. To address this issue

Dr. Trimmer and colleagues have concentrated on mitochondrial morphology at the light and electron microscope levels. The movement of mitochondria in axons and dendrites of neuronal cells is also addressed by making time-lapse recordings of mitochondrial movement in living neurons in culture. These studies are being carried out in collaboration with the labs of Drs. Bennett and Parker as part of The Center for the Study of Neurodegenerative Diseases. Techniques for these studies include neuronal cell culture, immunocytochemistry, confocal microscopy, electron microscopy, and time-lapse video recording of living neurons in culture.

A second area of interest for this lab is the role normal and reactive astrocytes play in development, synaptic plasticity, degeneration, and regeneration in the central nervous system. Recent studies have been designed to determine whether reactive astrocytes are involved in the pathogenesis of Alzheimer’s disease and Parkinson’s disease.

  • Trimmer PA, Smith TS, Jung AB, and Bennett JP, Jr. Dopamine neurons from transgenic mice with a knockout of the p53 gene resist MPTP neurotoxicity. Neurodegeneration 5:233-239, 1996.
  • Swerdlow RH, Parks JK, Miller S, Tuttle JB, Trimmer PA, Sheehan JP, Bennett JP, Jr, Davis RE, and Parker WD, Jr. Origin and functional consequences of the complex I defect in Parkinson’s disease. Annals of Neurology 40:663-671, 1996.
  • Miller SW, Davis RE, Trimmer PA, and Parker WD. Creation and characterization of mitochondrial DNA depleted cell lines with neuronal-like properties. Journal of Neurochemistry 67:1897-1907, 1996.
  • Steward O and Trimmer PA. Genetic influences on cellular reactions to CNS injury: The reactive response of astrocytes in denervated neuropil regions in mice carrying a mutation (Wld-s) that causes delayed Wallerian degeneration. Journal of Comparative Neurology 380:70-81, 1997.
  • Smith TS, Trimmer PA, Khan SM, Tinklepaugh DL, and Bennett JP, Jr. Mitochondrial toxins in models of neurodegenerative diseases II: Elevated zif268 transcription and independent temporal regulation of striatal D1 and D2 receptor mRNAs and D1 and D2 receptor-binding in C57BL/6 mice during MPTP treatment. Brain Research 765:189-197, 1997.
  • Swerdlow RH, Parks JK, Davis JN, Cassarino DS, Trimmer PA, Currie LJ, Dougherty J, Bridges WS, Bennett JP, Wooten GF, and Parker, WD. Matrilineal inheritance of complex I dysfunction in a multigenerational Parkinson’s disease family. Annals of Neurology 44:873-881, 1998.

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G. Frederick Wooten, M.D.

Dr. Wooten's principal research interests focus on the treatment of Parkinson's disease and other movement disorders. In addition, Dr. Wooten and colleagues in the Movement Disorders Program are utilizing an extensive clinical database to address prospectively several issues that are relevant to the pathogenesis of Parkinson's disease. The Movement Disorders Program also participates in numerous multicenter clinical trials of potential new drugs to treat Parkinson's disease.

  • Wooten, G.F.: Anatomy and functions of dopamine receptors: Understanding pathophysiology of fluctuations in Parkinson=s disease. Parkinsonism and Related Disorders 8:79-83, 2001.
  • Currie, L.J., Harrison, M.B., Trugman, J.M., Bennett, J.P., Swerdlow, R.H., and Wooten, G.F.: Maternal age is not a risk factor for Parkinson=s disease. Journal of Neurology, Neurosurgery, and Psychiatry 71:130-131, 2001.
  • Swerdlow, R.S. and Wooten, G.F.: A novel DFN-1 mutation that causes dystonia in female carriers of the Mohr-Tranebjaerg Syndrome. Annals of Neurology 50:537-540, 2001.
  • Nutt, J.G., Burchiel, K.J., Comella, C.L., Jankovic, J., Lang, A.E., Laws, E.R., Lozano, A.M., Penn, R.D., Simpson, R.K., Stacy, M., & Wooten, G.F.: Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD. Neurology 60:69-73, 2003.
  • Wooten, G.F.: Agonists vs levodopa in PD: the thrilla of whitha. Neurology 60:360-362, 2003.
  • Wooten, G.F., Currie, L.J., Bovbjerg, V.E., Lee, J.K., & Patrie,J.: Are men at greater risk for Parkinson's disease than women? Journal of Neurology, Neurosurgery, and Psychiatry 75:637-639, 2004.
  • Currie, L.J., Harrison,M.B., Trugman, J.M., Bennett,J.P., & Wooten,G.F.: Postmenopausal estrogen use affects risk for Parkinson's disease. Archives of Neurology 61:886-888, 2004.
  • Nutt, J.G. & Wooten, G.F.: Diagnosis and initial management of parkinson's disease.  The New England Journal of Medicine 353:1021-1027, 2005.

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Bradford B. Worrall, M.D., M.Sc.

Dr. Worrall’s research focuses on genetic and inflammatory issues in cerebrovascular disease approaching from several angles. He is currently funded by the NIH-NINDS to investigate a large animal model of atherosclerosis and runs a translational research laboratory.  Dr. Worrall also conducts stroke genetics clinical trials at the University of Virginia as a part of 4 multicentered studies.  He is a founding member of the International Stroke Genetics Consortium currently developing an effort to conduct a genome-wide scan in ischemic stroke.  He is a non-resident faculty member of the Center for Public Health Genomics.  He also works with other members of the UVA stroke group in ongoing clinical trials.

  • Worrall BB, Herman ST, Capellari S, Lynch T, Chin SS, Gambetti P, Parchi P. Type 1 PrPres and valine/valine at codon 129 of PRNP identify a variant of CJD. Journal of Neurology, Neurosurgery, & Psychiatry. 1999; 67:671-674.
  • Worrall BB, Chen DT, Meschia JF. Ethical and methodological issues in pedigree stroke research. Stroke 2001;32(6):1242-1249.
  • Worrall BB, Degraba TJ. The genetics of cerebrovascular atherosclerosis. J Stroke Cerebrovasc Dis. 2002;11:220-229.
  • Worrall BB, Azhar S, Nyquist PA, Ackerman RH, Hamm TL, DeGraba TJ. Interleukin-1 receptor antagonist gene polymorphisms in carotid atherosclerosis. Stroke 2003;34:790-793.
  • Worrall BB, Brott TG, Brown RD, Brown WB, Rich SS, Arepalli S, Wayrant-De Vrièze F, Duckworth J, Singleton AB, Hardy J, Meschia JF for the SWISS, ISGS and MSGD Investigators. IL1RN VNTR polymorphism in ischemic stroke analysis in 3 populations. Stroke 2007 Apr;38(4):1189-1196.
  • Matarin M, Scholz S, Simon-Sanchez J, Fung H-C, Hernandez D, Crews C, Britton A, Gibbs JR, Brown WM, Langefeld C, Wayrant-De Vrièze F, Brott TG, Brown RD, Worrall BB, Frankel M, Silliman S, Case LD, Singleton A, Hardy JA, Rich SS, Meschia JF.  Genome Wide SNP Association Study in Ischemic Stroke.  Lancet Neurology 2007 May;6(5):414-420
  • Chen DT, Case LD, Brott TG, Brown RD Jr, Silliman SL, Meschia JF, Worrall BB.  Impact of restricting enrollment in stroke genetics research to adults able to provide informed consent.  Stroke 2008 Mar;39(3):831-837.
  • Matarin M, Simon-Sanchez J, Crews C, Fung H-C, Scholz S, Gibbs R, Hernandez D, Britton A, Wayrant-De Vrièze F, Brott TG; Brown RD Jr, Worrall BB, Silliman SL, Case LD, Hardy JA, Rich SS, Meschia JF, Singleton AB. Structural genomic variation in ischemic stroke. Neurogenetics 2008 May;9(2):101-108.
  • Chen DT, Meschia JF, Brott TG, Brown RD, Worrall BB for the SWISS investigators. Stroke genetic research and adults with impaired decision-making capacity: a survey of IRB and investigator practices.  Stroke 2008 Oct;39(10):2732-2735.
  • Worrall BB, Foroud T, Brown RD Jr, Hornung RW, Houston J III, Kleindorfer D,  Koller DL, Lai D, Moomaw CJ, Sauerbeck L, Woo D, Broderick JP for the Familial Intracranial Aneurysm Study Investigators. Genome screen to detect linkage to common susceptibility genes for intracranial and aortic aneurysms. Stroke 2009 Jan;40(1):71-76.

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