Bio

Clinical Focus


  • Pathology

Academic Appointments


Professional Education


  • Residency:University of Washington Medical Center (1993) WA
  • Medical Education:University of Virgina School of Medicine (1987) VA
  • Board Certification: Pathology, American Board of Pathology (1995)
  • Board Certification: Neuropathology, American Board of Pathology (1995)

Publications

Journal Articles


  • Two patients with primary sellar leiomyomas, a rare entity JOURNAL OF CLINICAL NEUROSCIENCE Ko, A., Su, D. K., Born, D., DeSantis, A., Failor, R. A., Ferreira, M. 2013; 20 (6): 897-901
  • Contractility and kinetics of human fetal and human adult skeletal muscle JOURNAL OF PHYSIOLOGY-LONDON Racca, A. W., Beck, A. E., Rao, V. S., Flint, G. V., Lundy, S. D., Born, D. E., Bamshad, M. J., Regnier, M. 2013; 591 (12): 3049-3061

    Abstract

    Little is known about the contraction and relaxation properties of fetal skeletal muscle, and measurements thus far have been made with non-human mammalian muscle. Data on human fetal skeletal muscle contraction are lacking, and there are no published reports on the kinetics of either fetal or adult human skeletal muscle myofibrils. Understanding the contractile properties of human fetal muscle would be valuable in understanding muscle development and a variety of muscle diseases that are associated with mutations in fetal muscle sarcomere proteins. Therefore, we characterised the contractile properties of developing human fetal skeletal muscle and compared them to adult human skeletal muscle and rabbit psoas muscle. Electron micrographs showed human fetal muscle sarcomeres are not fully formed but myofibril formation is visible. Isolated myofibril mechanical measurements revealed much lower specific force, and slower rates of isometric force development, slow phase relaxation, and fast phase relaxation in human fetal when compared to human adult skeletal muscle. The duration of slow phase relaxation was also significantly longer compared to both adult groups, but was similarly affected by elevated ADP. F-actin sliding on human fetal skeletal myosin coated surfaces in in vitro motility (IVM) assays was much slower compared with adult rabbit skeletal myosin, though the Km(app) (apparent (fitted) Michaelis-Menten constant) of F-actin speed with ATP titration suggests a greater affinity of human fetal myosin for nucleotide binding. Replacing ATP with 2 deoxy-ATP (dATP) increased F-actin speed for both groups by a similar amount. Titrations of ADP into IVM assays produced a similar inhibitory affect for both groups, suggesting ADP binding may be similar, at least under low load. Together, our results suggest slower but similar mechanisms of myosin chemomechanical transduction for human fetal muscle that may also be limited by immature myofilament structure.

    View details for DOI 10.1113/jphysiol.2013.252650

    View details for Web of Science ID 000320398000008

    View details for PubMedID 23629510

  • Novel deletion of lysine 7 expands the clinical, histopathological and genetic spectrum of TPM2-related myopathies BRAIN Davidson, A. E., Siddiqui, F. M., Lopez, M. A., Lunt, P., Carlson, H. A., Moore, B. E., Love, S., Born, D. E., Roper, H., Majumdar, A., Jayadev, S., Underhill, H. R., Smith, C. O., von der Hagen, M., Hubner, A., Jardine, P., Merrison, A., Curtis, E., Cullup, T., Jungbluth, H., Cox, M. O., Winder, T. L., Salam, H. A., Li, J. Z., Moore, S. A., Dowling, J. J. 2013; 136: 508-521
  • Increased age of transformed mouse neural progenitor/stem cells recapitulates age-dependent clinical features of human glioma malignancy AGING CELL Mikheev, A. M., Ramakrishna, R., Stoll, E. A., Mikheeva, S. A., Beyer, R. P., Plotnik, D. A., Schwartz, J. L., Rockhill, J. K., Silber, J. R., Born, D. E., Kosai, Y., Horner, P. J., Rostomily, R. C. 2012; 11 (6): 1027-1035

    Abstract

    Increasing age is the most robust predictor of greater malignancy and treatment resistance in human gliomas. However, the adverse association of clinical course with aging is rarely considered in animal glioma models, impeding delineation of the relative importance of organismal versus progenitor cell aging in the genesis of glioma malignancy. To address this limitation, we implanted transformed neural stem/progenitor cells (NSPCs), the presumed cells of glioma origin, from 3- and 18-month-old mice into 3- and 20-month host animals. Transplantation with progenitors from older animals resulted in significantly shorter (P ≤ 0.0001) median survival in both 3-month (37.5 vs. 83 days) and 20-month (38 vs. 67 days) hosts, indicating that age-dependent changes intrinsic to NSPCs rather than host animal age accounted for greater malignancy. Subsequent analyses revealed that increased invasiveness, genomic instability, resistance to therapeutic agents, and tolerance to hypoxic stress accompanied aging in transformed NSPCs. Greater tolerance to hypoxia in older progenitor cells, as evidenced by elevated HIF-1 promoter reporter activity and hypoxia response gene (HRG) expression, mirrors the upregulation of HRGs in cohorts of older vs. younger glioma patients revealed by analysis of gene expression databases, suggesting that differential response to hypoxic stress may underlie age-dependent differences in invasion, genomic instability, and treatment resistance. Our study provides strong evidence that progenitor cell aging is responsible for promoting the hallmarks of age-dependent glioma malignancy and that consideration of progenitor aging will facilitate development of physiologically and clinically relevant animal models of human gliomas.

    View details for DOI 10.1111/acel.12004

    View details for Web of Science ID 000311113500012

    View details for PubMedID 22958206

  • INVASION AND PROLIFERATION KINETICS PREDICT IDH-1 MUTATION IN CONTRAST-ENHANCING GLIOMAS NEURO-ONCOLOGY Baldock, A. L., Yagle, K., Anh, S., Born, D., Swanson, P., Rockne, R., Swanson, K. R. 2012; 14: 131-131
  • MODELING THE IMPACT OF CELL OF ORIGIN AND HOST AGING ON CLINICAL FEATURES OF GLIOMA MALIGNANCY NEURO-ONCOLOGY Mikheev, A. M., Ramakrishna, R., Stoll, E. A., Mikheeva, S. A., Beyer, R. P., Born, D., Rockhill, J. K., Silber, J. R., Horner, P. J., Rostomily, R. 2012; 14: 164-164
  • Radiation Necrosis: Relevance with Respect to Treatment of Primary and Secondary Brain Tumors CURRENT NEUROLOGY AND NEUROSCIENCE REPORTS Fink, J., Born, D., Chamberlain, M. C. 2012; 12 (3): 276-285

    Abstract

    Radiation injury to the central nervous system (CNS) manifests in multiple forms and is divided into three categories termed acute, early-delayed, and late-delayed injury patterns. Late-delayed radiation injury, primarily manifesting as leukoencephalopathy or radiation necrosis, is often progressive and may have a negative impact on quality of life. Radiation injury is believed to be a consequence of cell membrane and DNA injury with a pathological expression as vascular injury, depletion of oligodendroglial progenitor cells, and failure of cell-cell interactions that constitute the cellular network of the CNS. In addition, radiation injury results in activation of the inflammatory cascade with perturbation of cytokines, production of reactive oxygen species and vascular endothelial growth factor. Medical treatment of CNS radiation injury and in particular radiation necrosis remains problematic as there is a paucity of clinical trial data to inform treatment decisions, and aside from surgery and corticosteroids only bevacizumab appears to have a compelling therapeutic role.

    View details for DOI 10.1007/s11910-012-0258-7

    View details for Web of Science ID 000303515500007

    View details for PubMedID 22350279

  • Clinicopathologic Assay of 15 Tumor Resections in a Family with Neurofibromatosis Type 2 JOURNAL OF NEUROLOGICAL SURGERY PART B-SKULL BASE Di Maio, S., Mrak, G., Juric-Sekhar, G., Born, D., Mantovani, A., Sekhar, L. N. 2012; 73 (2): 90-103

    Abstract

    The objective of this study is the management of multiple family members with multiple neurofibromatosis type 2 (NF2) related tumors of the skull base that can be challenging, on purely technical, decision-making, and ethical levels. These issues are addressed in this manuscript based on an experience treating an unique large family with NF2. A retrospective chart review was performed, reviewing clinical, radiological, surgical, and pathological data. A unique family of 17 siblings, whose father was the proband as a sporadic mutation is reported. Over a 4-month period, five of eight affected siblings underwent 12 procedures for resection of 15 different NF2-related tumors. This single family experience of NF2-related skull base tumors underscores the importance of preservation of function and quality of life as the major determinants of treatment success.

    View details for DOI 10.1055/s-0032-1301394

    View details for Web of Science ID 000321267800002

    View details for PubMedID 23543817

  • Multiplex Immunoassays of Peptide Hormones Extracted from Formalin-Fixed, Paraffin-Embedded Tissue Accurately Subclassify Pituitary Adenomas CLINICAL CHEMISTRY Strathmann, F. G., Borlee, G., Born, D. E., Gonzalez-Cuyar, L. F., Huber, B. R., Baird, G. S. 2012; 58 (2): 366-374

    Abstract

    The current gold standard for diagnostic classification of many solid-tissue neoplasms is immunohistochemistry (IHC) performed on formalin-fixed, paraffin-embedded (FFPE) tissue. Although IHC is commonly used, there remain important issues related to preanalytic variability, nonstandard methods, and operator bias that may contribute to clinically significant error. To increase the quantitative accuracy and reliability of FFPE tissue-based diagnosis, we sought to develop a clinical proteomic method to characterize protein expression in pathologic tissue samples rapidly and quantitatively.We subclassified FFPE tissue from 136 clinical pituitary adenoma samples according to hormone translation with IHC and then extracted tissue proteins and quantified pituitary hormones with multiplex bead-based immunoassays. Hormone concentrations were normalized and compared across diagnostic groups. We developed a quantitative classification scheme for pituitary adenomas on archived samples and validated it on prospectively collected clinical samples.The most abundant relative hormone concentrations differentiated sensitively and specifically between IHC-classified hormone-expressing adenoma types, correctly predicting IHC-positive diagnoses in 85% of cases overall, with discrepancies found only in cases of clinically nonfunctioning adenomas. Several adenomas with clinically relevant hormone-expressing phenotypes were identified with this assay yet called "null" by IHC, suggesting that multiplex immunoassays may be more sensitive than IHC for detecting clinically meaningful protein expression.Multiplex immunoassays performed on FFPE tissue extracts can provide diagnostically relevant information and may exceed the performance of IHC in classifying some pituitary neoplasms. This technique is simple, largely amenable to automation, and likely applicable to other diagnostic problems in molecular pathology.

    View details for DOI 10.1373/clinchem.2011.170613

    View details for Web of Science ID 000300303700009

    View details for PubMedID 22205691

  • CYSTIC GLIOMAS ARE QUANTITATIVELY LESS BIOLOGICALLY AGGRESSIVE NEURO-ONCOLOGY Baldock, A. L., Rockne, R., Canoll, P., Born, D., Yagle, K., Swanson, K. R. 2011; 13: 65-65
  • Pseudoprogression: Relevance With Respect to Treatment of High-Grade Gliomas CURRENT TREATMENT OPTIONS IN ONCOLOGY Fink, J., Born, D., Chamberlain, M. C. 2011; 12 (3): 240-252

    Abstract

    The post-treatment imaging assessment of high-grade gliomas remains challenging notwithstanding the increased utilization of advanced MRI and PET imaging. Several post-treatment imaging entities are recognized including: late-delayed radiation injury, including radionecrosis mimicking tumor progression; early-delayed (within 6 months of temozolomide-based chemoradiation) post-treatment radiographic changes, herein referred to as pseudoprogression (the subject of this review); early post-treatment changes following local glioma therapy (i.e. biodegradable BCNU wafer implantation or stereotactic radiotherapy); and pseudoresponse, seen following treatment with angiogenic inhibition based therapy such as bevacizumab. A literature review searched specifically for "pseudoprogression" within the last 5 years (2005-2010). Approximately 24 recent papers were identified and reviewed in detail. Eight small population-based studies demonstrate 26-58% (median 49%) of glioblastoma patients treated with chemoradiotherapy manifest early disease progression at first post-radiotherapy imaging. Patients with early radiographic disease progression continued on planned therapy, and a median of 38% (range 28-66%) showed radiographic improvement or stabilization and were defined retrospectively as manifesting pseudoprogression. In conclusion, pseudoprogression is a frequent early post-treatment imaging change that at present is not easily differentiated from tumor progression by anatomic or physiologic brain imaging. Consequently, an operational definition of pseudoprogression has been adopted by the Response Assessment in Neuro-Oncology Working Group wherein either the index (i.e. target) lesion stabilizes or diminishes in size on continued post-radiation (temozolomide) therapy as determined by follow-up radiologic imaging.

    View details for DOI 10.1007/s11864-011-0157-1

    View details for Web of Science ID 000293407200003

    View details for PubMedID 21594589

  • HIF Induces Human Embryonic Stem Cell Markers in Cancer Cells CANCER RESEARCH Mathieu, J., Zhang, Z., Zhou, W., Wang, A. J., Heddleston, J. M., Pinna, C. M., Hubaud, A., Stadler, B., Choi, M., Bar, M., Tewari, M., Liu, A., Vessella, R., Rostomily, R., Born, D., Horwitz, M., Ware, C., Blau, C. A., Cleary, M. A., Rich, J. N., Ruohola-Baker, H. 2011; 71 (13): 4640-4652

    Abstract

    Low oxygen levels have been shown to promote self-renewal in many stem cells. In tumors, hypoxia is associated with aggressive disease course and poor clinical outcomes. Furthermore, many aggressive tumors have been shown to display gene expression signatures characteristic of human embryonic stem cells (hESC). We now tested whether hypoxia might be responsible for the hESC signature observed in aggressive tumors. We show that hypoxia, through hypoxia-inducible factor (HIF), can induce an hESC-like transcriptional program, including the induced pluripotent stem cell (iPSC) inducers, OCT4, NANOG, SOX2, KLF4, cMYC, and microRNA-302 in 11 cancer cell lines (from prostate, brain, kidney, cervix, lung, colon, liver, and breast tumors). Furthermore, nondegradable forms of HIFα, combined with the traditional iPSC inducers, are highly efficient in generating A549 iPSC-like colonies that have high tumorigenic capacity. To test potential correlation between iPSC inducers and HIF expression in primary tumors, we analyzed primary prostate tumors and found a significant correlation between NANOG-, OCT4-, and HIF1α-positive regions. Furthermore, NANOG and OCT4 expressions positively correlated with increased prostate tumor Gleason score. In primary glioma-derived CD133 negative cells, hypoxia was able to induce neurospheres and hESC markers. Together, these findings suggest that HIF targets may act as key inducers of a dynamic state of stemness in pathologic conditions.

    View details for DOI 10.1158/0008-5472.CAN-10-3320

    View details for Web of Science ID 000292287300033

    View details for PubMedID 21712410

  • Parahippocampal Corpora Amylacea: Case Report NEUROSURGERY Abel, T. J., Hebb, A. O., Keene, C. D., Born, D. E., Silbergeld, D. L. 2010; 66 (6): E1206-U340

    Abstract

    Corpora amylacea (CA) normally accumulate within perivascular, subpial, and subependymal astrocytic processes. CA are associated with a number of conditions including normal aging, hippocampal sclerosis associated with temporal lobe epilepsy, multiple sclerosis, Lafora-type progressive myoclonic epilepsy, and adult polyglucosan body disease. Reports of massive localized accumulation of CA in the brain outside of these conditions are rare.A 49-year-old woman, with a long-standing history of migraine headaches, presented to her primary care provider for increased headache duration. Brain magnetic resonance imaging (MRI) revealed a left parahippocampal lesion, suggestive of low-grade glioma.Given the MRI suggestive of left parahippocampal glioma, left-sided frontotemporal craniotomy was performed for resection of the lesion. Specimens obtained during the operation revealed focal high-density accumulation of CA with no evidence of neoplasm, ischemia, or hypoxic injury.This case illustrates the possibility that localized high-density CA accumulation can present as an intrinsic lesion on brain MRI. CA should be included in the differential diagnosis for patients presenting with brain MRI suggestive of nonenhancing space-occupying lesions.

    View details for DOI 10.1227/01.NEU.0000369196.94664.4E

    View details for Web of Science ID 000278006200057

    View details for PubMedID 20495392

  • A Case of High-Grade Undifferentiated Sarcoma after Surgical Resection and Stereotactic Radiosurgery of a Vestibular Schwannoma SKULL BASE-AN INTERDISCIPLINARY APPROACH Yang, T., Rockhill, J., Born, D. E., Sekhar, L. N. 2010; 20 (3): 179-183

    Abstract

    Stereotactic radiosurgery has become a more frequently used treatment modality for vestibular schwannomas; a few reports of malignant transformation and/or radiation-associated tumors have surfaced. The majority of these reported cases were in patients with underlying neurofibromatosis. The authors report a case of a 74-year-old man with rapid progression of a cerebellar-pontine angle tumor 14 years after surgical resection of a vestibular schwannoma (VS) from the same site, and 6 years after stereotactic radiosurgery. A pathological study of the recent tumor showed a high-grade spindle cell neoplasm that bore no resemblance to the initial schwannoma. The patient had no diagnosis of neurofibromatosis. Secondary malignancy occurred in a non-neurofibromatosis patient 6 years after stereotactic radiosurgery. It is our belief that documentation of such cases will provide important evidence that helps evaluate the long-term effect of radiosurgery for VS. Such observations can influence clinical decisions regarding the choice of treatment modalities.

    View details for DOI 10.1055/s-0029-1242195

    View details for Web of Science ID 000276538500007

    View details for PubMedID 21318035

  • Quantitative Proteomic Analysis of Oligodendrogliomas With and Without 1p/19q Deletion JOURNAL OF PROTEOME RESEARCH Rostomily, R. C., Born, D. E., Beyer, R. P., Jin, J., Alvord, E. C., Mikheev, A. M., Matthews, R. T., Pan, C., Khorasani, L., Sonnen, J. A., Montine, T. J., Shi, M., Zhang, J. 2010; 9 (5): 2610-2618

    Abstract

    Approximately 50-80% of oligodendrogliomas demonstrate a combined loss of chromosome 1p and 19q. Chromosome 1p/19q deletion, appearing early in tumorigenesis, is associated with improved clinical outcomes, including response to chemotherapy and radiation. Although many hypotheses have been proposed, the molecular mechanisms underlying improved clinical outcomes with 1p/19q deletion in oligodendrogliomas have not been characterized fully. To investigate the molecular differences between oligodendrogliomas, we employed an unbiased proteomic approach using microcapillary liquid chromatography mass spectrometry, along with a quantitative technique called isotope-coded affinity tags, on patient samples of grade II oligodendrogliomas. Following conventional biochemical separation of pooled tumor tissue from five samples of undeleted and 1p/19q deleted grade II oligodendrogliomas into nuclei-, mitochondria-, and cytosol-enriched fractions, relative changes in protein abundance were quantified. Among the 442 total proteins identified, 163 nonredundant proteins displayed significant changes in relative abundance in at least one of the three fractions between oligodendroglioma with and without 1p/19q deletion. Bioinformatic analyses of differentially regulated proteins supported the potential importance of metabolism and invasion/migration to the codeleted phenotype. A subset of altered proteins, including the pro-invasive extracellular matrix protein BCAN, was further validated by Western blotting as candidate markers for the more aggressive undeleted phenotype. These studies demonstrate the utility of proteomic analysis to identify candidate biological motifs and molecular mechanisms that drive differential malignancy related to 1p19q phenotypes. Future analysis of larger patient samples are warranted to further refine biomarker panels to predict biological behavior and assist in the identification of deleted gene products that define the 1p/19q phenotype.

    View details for DOI 10.1021/pr100054v

    View details for Web of Science ID 000277353200049

    View details for PubMedID 20337498

  • Histopathological changes in brain arteriovenous malformations after embolization using Onyx or N-butyl cyanoacrylate Laboratory investigation JOURNAL OF NEUROSURGERY Natarajan, S. K., Born, D., Ghodke, B., Britz, G. W., Sekhar, L. N. 2009; 111 (1): 105-113

    Abstract

    The aim of this study was to analyze the histopathological changes in a consecutive series of 32 patients with brain arteriovenous malformations that were resected after undergoing endovascular embolization (22 using Onyx and 10 using N-butyl cyanoacrylate [NBCA]).Selections from fixed paraffin-embedded specimens were stained for histological examination with H & E and Verhoeff-van Gieson stain. Lipid dye Oil Red O was used to stain vessel specimens that were embolized using NBCA. Specimens were evaluated for the presence of embolic agent, inflammation, angionecrosis, and evidence of recanalization. These results were correlated with the time interval between the bleeding, embolization, and resection.The smallest vessel occluded by the embolic agent was 5 microm in the Onyx group and 20 microm in the NBCA group. There was evidence of vascular or perivascular inflammation in 20 (90.9%) of 22 and 9 (90%) of 10 specimens after Onyx and NBCA embolization, respectively. Chronic foreign-body giant cells were observed in 12 (54.5%) of 22 specimens after Onyx embolization, but were absent in specimens after NBCA embolization. Angionecrosis of the embolized vessel was observed in 13 (59.1%) of 22 specimens and in 4 (40%) of 10 specimens after Onyx and NBCA embolization, respectively. There was evidence of recanalization in Onyx embolized vessels in 4 (18.2%) of 22 specimens, and there was no evidence of recanalization after NBCA embolization.Onyx penetrates much smaller vessels than NBCA. Inflammation occurs with both embolic agents at equal frequency. Evidence of chronic foreign-body giant cells and recanalization after Onyx embolization shows a long-standing reaction to Onyx and raises questions about the permanence of occlusion after Onyx embolization.

    View details for DOI 10.3171/2008.12.JNS08441

    View details for Web of Science ID 000267383900023

    View details for PubMedID 19326974

  • A patient with Huntington's disease and long-surviving fetal neural transplants that developed mass lesions ACTA NEUROPATHOLOGICA Keene, C. D., Chang, R. C., Leverenz, J. B., Kopyov, O., Perlman, S., Hevner, R. F., Born, D. E., Bird, T. D., Montine, T. J. 2009; 117 (3): 329-338

    Abstract

    Transplantation of human fetal neural tissue into adult neostriatum is an experimental therapy for Huntington's disease (HD). Here we describe a patient with HD who received ten intrastriatal human fetal neural transplants and, at one site, an autologous sural nerve co-graft. Although initially clinically stable, she developed worsening asymmetric upper motor neuron symptoms in addition to progression of HD, and ultimately died 121 months post transplantation. Eight neural transplants, up to 2.9 cm, and three ependymal cysts, up to 2.0 cm, were identified. The autologous sural nerve co-graft was found adjacent to the largest mass lesion, which, along with the ependymal cyst, exhibited pronounced mass effect on the internal capsules bilaterally. Grafts were composed of neurons and glia embedded in disorganized neuropil; robust Y chromosome labeling was present in a subset of grafts and cysts. The graft-host border was discrete, and there was no evidence of graft rejection or HD pathologic changes within donor neurons. This report, for the first time, highlights the potential for graft overgrowth in a patient receiving fetal neural transplantation.

    View details for DOI 10.1007/s00401-008-0465-0

    View details for Web of Science ID 000263540500010

    View details for PubMedID 19057918

  • The effects of binge alcohol exposure in the 2nd trimester on the estimated density of cerebral microvessels in near-term fetal sheep BRAIN RESEARCH Simon, K. E., Mondares, R. L., Born, D. E., Gleason, C. A. 2008; 1231: 75-80

    Abstract

    Heavy fetal alcohol exposure is associated with a spectrum of neurological abnormalities, although the mechanism of injury is largely unknown. We previously reported attenuated cerebral blood flow response to hypoxia in fetal and newborn sheep which were exposed to alcohol earlier in pregnancy. One possible mechanism for this effect of alcohol on the developing cerebral vasculature is a decrease in cerebral microvessel density, similar to its effect on developing neurons. Therefore, we tested the hypothesis that prenatal alcohol exposure decreases cerebral microvessel density. Pregnant ewes received intravenous infusions of ethanol or saline during days 60-84 of gestation (term=150 days) and at 125 days of gestation we obtained the fetal brains for study. We immunohistochemically labeled vessels of the left cerebral forebrain hemispheres with antibody to endothelial nitric oxide synthase and then obtained unbiased stereological estimates of cerebral microvessel density using a modified optical fractionator method. We studied 20 fetal brains of which 9 were alcohol-exposed, 11 were saline-controls, and all were products of a twin gestation. Although brain and body weights were not different between groups, the alcohol-exposed group had significantly lower brain weight as a percentage of body weight. Estimates of cerebral microvessel density were not significantly different between alcohol-exposed and saline-control groups: 12.7+/-8.7 and 9.1+/-2.8 microvessels per mm(3), respectively (mean+/-SD, p=0.32). Since there is no change in estimated cerebral microvessel density after prenatal alcohol exposure, we conclude that decreased cerebral microvessel density is not a likely explanation for attenuated cerebral blood flow in response to hypoxia.

    View details for DOI 10.1016/j.brainres.2008.06.125

    View details for Web of Science ID 000259887800008

    View details for PubMedID 18657528

  • Multimodality treatment of brain arteriovenous malformations with microsurgery after embolization with Onyx: Single-center experience and technical nuances NEUROSURGERY Natarajan, S. K., Ghodke, B., Britz, G. W., Born, D. E., Sekhar, L. N. 2008; 62 (6): 1213-1225

    Abstract

    To report our experience with the treatment of brain arteriovenous malformations (AVM) with microsurgical resection after embolization with Onyx liquid embolic agent (eV3, Irvine, CA).Between August 2005 and December 2006, 28 patients were treated by the same surgical-endovascular team. Twenty-eight AVMs were embolized preoperatively in 55 sessions (71 pedicles) with Onyx. We analyzed the AVM size, volume, number of embolization sessions, degree of preoperative obliteration, time to embolization and resection after the bleed, intraprocedural complications, intraoperative blood loss, other complications, and postoperative outcome at 6 months. Technical nuances of the embolization and surgical resection of the embolized AVMs are illustrated in illustrative cases.The average size and volume of AVMs treated with Onyx were 3.56 cm (largest, 7.6 cm), and 13.03 ml, respectively. The average Spetzler-Martin grade was 2.75. The average preoperative volumetric obliteration was 74.1%. The average blood loss during resection of embolized AVMs was 348 ml. Complications related to embolization were stuck microcatheter (two patients), proximal vessel perforation (one patient), and anterior choroidal territory stroke (one patient). Surgical complications included wound infection (one patient), residual AVM nidus (one patient), normal pressure perfusion breakthrough with worsening of neurological deficit caused by embolization (one patient), and new-onset motor deficits in five patients. At the time of the 6-month follow-up examination, four patients with new-onset motor deficits had recovered completely or nearly completely, and one patient was disabled. One patient died, never recovering from the initial poor condition due to the bleed. Pathological examination of resected AVMs showed angionecrosis in 42.9%, foreign body giant cells in 39.3%, and evidence of recanalization of Onyx-embolized vessels in 14.3% of specimens.Multimodality treatment with microsurgery is safe and effective after embolization with Onyx. High occlusion rates and low complication rates were observed after Onyx embolization and were comparable to those in previous reports. Superselective intranidal or perinidal catheter positions and slow, controlled injections that protect the draining veins make the therapy safe even in complex AVMs and critical locations. We recommend resection of the AVM despite apparently complete embolization with Onyx. Team work and coordination between the surgeon and the interventional neuroradiologist are important to achieve a good outcome.

    View details for Web of Science ID 000258226500011

    View details for PubMedID 18824988

  • Graft overgrowth and ependymal cyst formation despite initial clinical improvement in a Huntington's patient who received fetal neural transplants CELL TRANSPLANTATION Keene, C. D., Chang, R., Leverenz, J. B., Kopyov, O., Hevner, R., Born, D., Bird, T. D., Montine, T. J. 2008; 17 (4): 469-469
  • The effect of binge fetal alcohol exposure on the number of vasoactive intestinal peptide-producing neurons in fetal sheep brain DEVELOPMENTAL NEUROSCIENCE Anderson, D. J., Mondares, R. L., Born, D. E., Gleason, C. A. 2008; 30 (4): 276-284

    Abstract

    Previously we demonstrated that fetal alcohol exposure attenuates hypoxic cerebral vasodilation in fetal and neonatal sheep. One mechanism may be altered expression of brain vasoactive substances. We hypothesized that early fetal alcohol exposure alters the number of fetal neurons expressing vasoactive intestinal peptide (VIP), a potent cerebral vasodilator. Thirteen pregnant ewes received daily i.v. infusions of alcohol (1.5 g/kg) or saline on days 30-54 of gestation (term = 145 days). Fourteen fetal brains (6 alcohol-exposed, 8 saline control) were obtained on gestational day 126. Using unbiased stereology, we counted immunohistochemically-labeled VIP neurons in one half of each forebrain with an optical fractionator. The total NeuN-labeled neurons were similarly counted. Alcohol-exposed fetal sheep brains had fewer VIP-immunopositive neurons per hemisphere, 14.6 x 10(6), compared to saline controls, 19.8 x 10(6). The total neuron number was not different, 1.19 x 10(9) versus 1.23 x 10(9) respectively, indicating a selective decrease in VIP neurons as a result of alcohol exposure. In sheep, alcohol exposure early in gestation is associated with fewer VIP-producing neurons later in gestation compared to saline controls; therefore, alcohol-related changes in the number of VIP-expressing neurons may be responsible in part for the attenuated hypoxic cerebral vasodilation described in fetal and neonatal sheep exposed to alcohol earlier in gestation.

    View details for DOI 10.1159/000110349

    View details for Web of Science ID 000255586600007

    View details for PubMedID 17960055

  • Mycobacterium marinum infection of adult zebrafish causes caseating granulomatous tuberculosis and is moderated by adaptive immunity (vol 74, pg 6108, 2006) INFECTION AND IMMUNITY Swaim, L. E., Connolly, L. E., Volkman, H. E., Humbert, O., Born, D. E., Ramakrishnan, L. 2007; 75 (3): 1540-1540
  • Epidermal growth factor receptor and p53 expression in a large series of gliosarcomas: A tissue microarray study MODERN PATHOLOGY Reed, R. C., Born, D. E. 2007; 20: 300A-300A
  • Mycobacterium marinum infection of adult zebrafish causes caseating granulomatous tuberculosis and is moderated by adaptive immunity INFECTION AND IMMUNITY Swaim, L. E., Connolly, L. E., Volkman, H. E., Humbert, O., Born, D. E., Ramakrishnan, L. 2006; 74 (11): 6108-6117

    Abstract

    The zebrafish, a genetically tractable model vertebrate, is naturally susceptible to tuberculosis caused by Mycobacterium marinum, a close genetic relative of the causative agent of human tuberculosis, Mycobacterium tuberculosis. We previously developed a zebrafish embryo-M. marinum infection model to study host-pathogen interactions in the context of innate immunity. Here, we have constructed a flowthrough fish facility for the large-scale longitudinal study of M. marinum-induced tuberculosis in adult zebrafish where both innate and adaptive immunity are operant. We find that zebrafish are exquisitely susceptible to M. marinum strain M. Intraperitoneal injection of five organisms produces persistent granulomatous tuberculosis, while the injection of approximately 9,000 organisms leads to acute, fulminant disease. Bacterial burden, extent of disease, pathology, and host mortality progress in a time- and dose-dependent fashion. Zebrafish tuberculous granulomas undergo caseous necrosis, similar to human tuberculous granulomas. In contrast to mammalian tuberculous granulomas, zebrafish lesions contain few lymphocytes, calling into question the role of adaptive immunity in fish tuberculosis. However, like rag1 mutant mice infected with M. tuberculosis, we find that rag1 mutant zebrafish are hypersusceptible to M. marinum infection, demonstrating that the control of fish tuberculosis is dependent on adaptive immunity. We confirm the previous finding that M. marinum DeltaRD1 mutants are attenuated in adult zebrafish and extend this finding to show that DeltaRD1 predominantly produces nonnecrotizing, loose macrophage aggregates. This observation suggests that the macrophage aggregation defect associated with DeltaRD1 attenuation in zebrafish embryos is ongoing during adult infection.

    View details for DOI 10.1128/IAI.00887-06

    View details for Web of Science ID 000241600500010

    View details for PubMedID 17057088

  • Effects of first trimester binge alcohol exposure on developing white matter in fetal sheep PEDIATRIC RESEARCH Watari, H., Born, D. E., Gleason, C. A. 2006; 59 (4): 560-564

    Abstract

    Heavy prenatal alcohol exposure is associated with neurodevelopmental abnormalities. Neuropathologic and neuroimaging studies have shown a wide range of structural problems, including abnormal neuronal migration and volume reduction in specific brain regions, including white matter. We identified foci of significant fetal white matter microglia-macrophage immunoreactivity in a "binge" model of early prenatal alcohol exposure in sheep. Ewes of alcohol-exposed fetuses received daily 90 min alcohol (1.5 gm/kg i.v.) infusions at 30-60 d gestation (term = 147 d). Ewes of control fetuses received same volume infusions of normal saline intravenously. Near-term (125 d gestation) fetal brains were labeled with microglia-macrophages using HAM56 antibody. We quantified dense immunoreactive cellular regions across sections and anatomical locations using computer-assisted microscopy and quantitative morphometry. The proportional HAM56-positive area in cortical white matter was greater in the alcohol-exposed fetuses (1.6%) compared with the saline controls (0.7%). The areas were localized to the frontal gyral white matter, temporal gyral white matter, optic radiation, and others (corpus callosum, septum pellucidum, fasciculus subcallosus, and external capsule), with a greater distribution in the gyral white matter. The greater area of macrophage-rich regions in near-term fetal sheep brain suggests a vulnerability of developing white matter that is enhanced by early alcohol exposure.

    View details for DOI 10.1203/01.pdr.0000203102.01364.de

    View details for Web of Science ID 000236359200013

    View details for PubMedID 16549529

  • Clinical utility of somatiostatin receptor scintigraphic imaging (Octreoscan) in esthesioneuroblastoma: A case study and survey of somatostatin receptor subtype expression HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Rostomily, R. C., Elias, M., Deng, M., Elias, P., Born, D. E., Muballe, D., Silbergeld, D. L., Futran, N., Weymuller, E. A., Mankoff, D. A., Eary, J. 2006; 28 (4): 305-312

    Abstract

    For tumors that express somatostatin receptors (SSTR), radiolabeled somatostatin analogs, such as 111In-pentetreotide, can demonstrate the presence of tumor by radioligand uptake using somatostatin receptor scintigraphy (SRS). The use of 111In-pentetreotide for SRS depends on the specific high affinity of octreotide for SSTR subtypes 2, 3, and 5. Of these, SSTR2 has the greatest affinity for octreotide and the greatest relevance for tumor detection with Octreoscan imaging. Discriminating between postoperative changes and residual or recurrent tumor after extensive skull base surgery is often difficult, but in a case of recurrent esthesioneuroblastoma (ENB) we found the use of Octreoscan imaging clinically useful. To better define the general relevance of this imaging technique in this setting, we analyzed SSTR subtype expression in a panel of ENB tumors.The case history and correlations between MRI and 111In-pentetreotide SRS of a patient with recurrent ENB were reviewed. The expression pattern of the SSTR subtypes in a panel of ENB tumors was then analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR) to better define the potential of more general use of Octreoscan for imaging ENB. To correlate SSTR2 protein expression with 111In-pentetreotide uptake, immunohistochemistry to detect SSTR2 was performed on tumor samples from regions of increased uptake on Octreoscan.The SSTR2 message was expressed at high levels in all five ENB tumor samples, and either SSTR2 protein or histologic findings typical for ENB were found in all tumor tissue obtained from regions of increased 111In-pentetreotide uptake. Furthermore, Octreoscan imaging in this case proved useful in clinical decision making.The expression pattern of SSTR2 and the specificity of the Octreoscan for regions of active tumor growth support further investigation of the utility of Octreoscan imaging in the diagnosis and surveillance of ENB. Recent advances in novel therapies based on SSTR ligand binding also provide the rationale to consider such novel therapeutic approaches in patients with ENB.

    View details for DOI 10.1002/hed.20356

    View details for Web of Science ID 000236536300003

    View details for PubMedID 16470879

  • NeuN expression correlates with reduced mitotic index of neoplastic cells in central neurocytomas NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY Englund, C., Alvord, E. C., Folkerth, R. D., Silbergeld, D., Born, D. E., Small, R., Hevner, R. F. 2005; 31 (4): 429-438

    Abstract

    In the developing brain, neuronal differentiation is associated with permanent exit from the mitotic cycle. This raises the possibility that neuronal differentiation may suppress proliferative activity, even in neoplastic cells. As a first step towards understanding the relation between neuronal differentiation and mitotic cycling in brain tumours, we studied the expression of NeuN (a neuronal marker) and Ki-67 (a mitotic marker) by double-labelling immuno-fluorescence in 16 brain tumours with neuronal differentiation. The tumours included a series of 11 central neurocytomas, and five single cases of other tumour types. In the central neurocytomas, NeuN(+) cells had a 15-fold lower Ki-67 labelling index, on average, than did NeuN(-) cells (P < 0.01). In the other tumours (one extraventricular neurocytoma, one desmoplastic medulloblastoma, one olfactory neuroblastoma, one ganglioglioma and one anaplastic ganglioglioma), the Ki-67 labelling index was always at least fourfold lower in NeuN(+) cells than in NeuN(-) cells. These results indicate that neuronal differentiation is associated with a substantial decrease of proliferative activity in neoplastic cells of central neurocytomas, and suggest that the same may be true across diverse types of brain tumours. However, tumours with extensive neuronal differentiation may nevertheless have a high overall Ki-67 labelling index, if the mitotic activity of NeuN(-) cells is high. The correlation between NeuN expression and reduced mitotic activity in neurocytoma cells is consistent with the hypothesis that neuronal differentiation suppresses proliferation, but further studies will be necessary to determine causality and investigate underlying mechanisms.

    View details for DOI 10.1111/j.1365-2990.2005.00665.x

    View details for Web of Science ID 000231015400010

    View details for PubMedID 16008827

  • Quantitative proteomic analysis of oligodendrogliomas with and without ip/19q deletion. JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY Rostomily, R., Born, D., Alvord, E., Pan, C., Jin, J. H., Montine, T., Zhang, J. 2005; 64 (5): 438-438
  • Aberrant neuronal-glial differentiation in Taylor-type focal cortical dysplasia (type IIA/B) ACTA NEUROPATHOLOGICA Englund, C., Folkerth, R. D., Born, D., Lacy, J. M., Hevner, R. F. 2005; 109 (5): 519-533

    Abstract

    Focal cortical dysplasia (FCD) type IIA/B (Taylor type) is a malformation of cortical development characterized by laminar disorganization and dysplastic neurons. FCD IIA and FCD IIB denote subtypes in which balloon cells are absent or present, respectively. The etiology of FCD IIA/B is unknown, but previous studies suggest that its pathogenesis may involve aberrant, mixed neuronal-glial differentiation. To investigate whether aberrant differentiation is a consistent phenotype in FCD IIA/B, we studied a panel of neuronal and glial marker antigens in a series of 15 FCD IIB cases, and 2 FCD IIA cases. Double-labeling immunofluorescence and confocal imaging revealed that different combinations of neuronal and glial antigens were co-expressed by individual cells in all cases of FCD IIA/B, but not in control cases of epilepsy due to other causes. Co-expression of neuronal and glial markers was most common in balloon cells, but was also observed in dysplastic neurons. The relative expression of neuronal and glial antigens varied over a broad range. Microtubule-associated protein 1B, an immature neuronal marker, was more frequently co-expressed with glial antigens than were mature neuronal markers, such as neuronal nuclear antigen. Our results indicate that aberrant neuronal-glial differentiation is a consistent and robust phenotype in FCD IIA/B, and support the hypothesis that developmental defects of neuronal and glial fate specification play an important role in its pathogenesis.

    View details for DOI 10.1007/s00401-005-1005-9

    View details for Web of Science ID 000229803200009

    View details for PubMedID 15877232

  • Progression from frontal-parietal to mesial-temporal epilepsy after fluid percussion injury in the rat BRAIN D'Ambrosio, R., Fender, J. S., Fairbanks, J. P., Simon, E. A., Born, D. E., Doyle, D. L., Miller, J. W. 2005; 128: 174-188

    Abstract

    We recently described an in vivo model of post-traumatic epilepsy (PTE) in the rat where chronic spontaneous recurrent seizures appear following a single episode of fluid percussion injury (FPI). PTE, studied during the first 2 months post-injury, was focal and seizures originated predominantly from the frontal-parietal neocortex at or around the injury site. However, rarer bilateral seizures originating from a different and undefined focus were also observed. To shed light on the Posttraumatic Epileptogenic mechanisms and on the generation of bilateral seizures, we studied rats up to 7 months post-injury. In vivo paired epidural and depth-electrode recordings indicated that the anterior hippocampus evolves into an epileptic focus which initiates bilateral seizures. The rate of frontal-parietal seizures remained constant over time after 2 weeks post-injury, while the rate of hippocampal seizures greatly increased over time, suggesting that different mechanisms mediate neocortical and hippocampal post-traumatic epileptogenesis. Because of different temporal evolution of these foci, the epileptic syndrome was characterized by predominant frontal-parietal seizures early after injury, but by predominant mesio-temporal seizures at later time points. Pathological analysis demonstrated progressive hippocampal and temporal cortex pathology that paralleled the increase in frequency and duration of bilateral seizures. These results demonstrate that FPI-induced frontal-parietal epilepsy (FPE) progresses to mesial-temporal lobe epilepsy (MTLE) with dual pathology. These observations establish numerous similarities between FPI-induced and human PTE and further validate it as a clinically relevant model of PTE.

    View details for DOI 10.1093/brain/awh337

    View details for Web of Science ID 000226187800019

    View details for PubMedID 15563512

  • Progression from frontal-parietal to mesial-temporal epilepsy after fluid percussion injury in the rat JOURNAL OF NEUROTRAUMA Fender, J. S., Fairbanks, J. P., Simon, E., Born, D. E., Doyle, D., Miller, J. W., D'Ambrosio, R. 2004; 21 (9): 1317-1317
  • Post-traumatic epilepsy following fluid percussion injury in the rat BRAIN D'Ambrosio, R., Fairbanks, J. P., Fender, J. S., Born, D. E., Doyle, D. L., Miller, J. W. 2004; 127: 304-314

    Abstract

    The lack of an adequate model of post-traumatic epilepsy (PTE), in which, similarly to the human condition, chronic spontaneous focal seizures follow a single episode of traumatic brain injury, has hampered the identification of clinically relevant epileptogenic mechanisms and the development of effective therapies. We studied the electrophysiological, behavioural and structural consequences of a clinically relevant model of closed head injury, the lateral fluid percussion injury (FPI), in the rat. We found that a single episode of severe FPI is sufficient to cause PTE. Chronic electrocorticography (ECoG) demonstrated spontaneous chronic seizures that were partial, originated from the neocortex at the site of injury, and progressively worsened and spread over time. The cases of epilepsy in the post-traumatic population increased over time following injury. Post-FPI epileptic rats exhibited pauses in their behaviour, facial automatisms and myoclonus at the time of epileptiform ECoG events. In vitro local field potential recordings demonstrated persistent hyperexcitability of the neocortex at and around the site of injury that was associated with intense glial reactivity. These results for the first time demonstrate persistent hyperexcitability of the injured neocortex and define a useful model for pathophysiological studies of basic mechanisms of spontaneous epileptogenesis and for preclinical screening of effective antiepileptogenic drugs.

    View details for DOI 10.1093/brain/awh038

    View details for Web of Science ID 000188389900007

    View details for PubMedID 14607786

  • Progression from frontal-parietal to mesial-temporal epilepsy after fluid percussion injury in the rat EPILEPSIA D'Ambrosio, R., Born, D., Simons, E., Miller, J. 2004; 45: 358-358
  • Posttraumatic epilepsy following fluid percussion injury in the rat. JOURNAL OF NEUROTRAUMA D'Ambrosio, R., Fairbanks, J. P., Fender, J. S., Born, D. E., Doyle, D., Miller, J. W. 2003; 20 (10): 1059-1059
  • Factors predicting outcome of surgery for intractable epilepsy with pathologically verified mesial temporal sclerosis EPILEPSIA Hardy, S. G., Miller, J. W., Holmes, M. D., Born, D. E., OJEMANN, G. A., Dodrill, C. B., Hallam, D. K. 2003; 44 (4): 565-568

    Abstract

    To examine the subgroup of patients with medically intractable epilepsy receiving temporal lobectomies who have pathologically verified mesial temporal sclerosis (MTS) and to determine the relation of demographic and clinical factors, results of diagnostic testing, and details of the surgical procedure with prognosis for achieving control of seizures.All patients receiving surgical treatment for intractable epilepsy between 1991 and 1998 at the University of Washington were reviewed. There were 118 patients who met inclusion criteria of adequate pathological analysis showing MTS without a progressive process and a minimum of 1-year follow-up.Only personal history of status epilepticus demonstrated significant (p = 0.0276) prediction of outcome, increasing the risk of surgical failure. No other factors were significant predictors of outcome, including history of febrile seizures, possible etiologic factors, EEG, magnetic resonance imaging (MRI) or neuropsychological testing results, or extent of resection.Many factors that have been previously described to predict favorable outcome in the overall group of patients receiving temporal lobe resections for intractable epilepsy are, in fact, predictors of MTS and lose their predictive value when the subgroup of patients with confirmed MTS is examined. Neurosurgical treatment of MTS can be very effective even in the presence of significant etiologic factors, or of bilateral or extratemporal abnormalities on EEG or MRI.

    View details for Web of Science ID 000182253100011

    View details for PubMedID 12681006

  • Atypical speech is rare in individuals with normal developmental histories NEUROLOGY Miller, J. W., Dodrill, C. B., Born, D. E., OJEMANN, G. A. 2003; 60 (6): 1042-1044

    Abstract

    The prevalence of atypical (right, bilateral) speech lateralization is unknown in normal populations. The authors investigated this by studying people with normal developmental histories but a later, specific adult neurologic event leading to intractable epilepsy. Fifty of 836 people receiving intracarotid amobarbital procedures (IAPs) met criteria of normal neurologic histories through age 15 years, with later head trauma or cerebral infection as probable cause of subsequent epilepsy. All 50 patients had left hemispheric speech on IAP. Atypical speech lateralization is rare unless there is also a positive neurologic history.

    View details for Web of Science ID 000182948600035

    View details for PubMedID 12654981

  • The effect of fetal alcohol exposure on the number of vasoactive intestinal peptide producing neurons in fetal sheep brain. JOURNAL OF INVESTIGATIVE MEDICINE ANDERSON, D. J., Born, D. E., Gleason, C. A. 2003; 51: S140-S140
  • The application of direct immunofluorescence to intraoperative neurosurgical diagnosis BIOMOLECULAR ENGINEERING Iwamoto, S., Burrows, R. C., Born, D. E., PIEPKORN, M., Bothwell, M. 2000; 17 (1): 17-22

    Abstract

    A diagnostic problem can occur at the time of intraoperative consultation of neurosurgical tumors as to whether the tumor is of neuroectodermal origin or whether it represents an epithelial metastasis from another site. Intraoperative diagnoses based on hematoxylin and eosin stained frozen sections are often later confirmed by immunocytochemical analysis of formalin-fixed, paraffin-embedded tissue sections that are not available at the time of surgery. The objective of the current study was to demonstrate that the application of direct immunofluorescence to the intraoperative diagnosis of neurosurgical tumors would provide unequivocal, and nearly immediate results. This report describes a new application of an existing technique for an optimized, rapid procedure utilizing direct immunocytochemistry with fluorescence-labeled primary antibodies to analyze surgical biopsies intraoperatively. The examination of five neurosurgical biopsies established a neuroectodermal origin of three tumors via immunolabeling for glial fibrillary acidic protein (GFAP) and lack of labeling with keratin markers, whereas several metastatic lung carcinomas were identified by immunostaining for keratin, but not GFAP, markers. The results of the direct immunolabeling method were unequivocal and required only minutes. The same diagnoses were confirmed by standard immunocytochemical labeling of formalin-fixed, paraffin-embedded sections, though it required several days to obtain the results. Direct immunofluorescence using fluorescently conjugated primary antibodies is a practical and rapid method for deciding whether a neurosurgical tumor is a primary glial or an epithelial metastatic tumor in origin. It is the first reported application of the technique for this aspect of rapid neurosurgical diagnosis.

    View details for Web of Science ID 000089919900003

    View details for PubMedID 11042473

  • Outcome after surgery in patients with refractory temporal lobe epilepsy and normal MRI SEIZURE-EUROPEAN JOURNAL OF EPILEPSY Holmes, M. D., Born, D. E., Kutsy, R. L., Wilensky, A. J., OJEMANN, G. A., Ojemann, L. M. 2000; 9 (6): 407-411

    Abstract

    Our purpose is to determine predictors of outcome in patients with refractory temporal lobe epilepsy and normal high resolution magnetic resonance imaging (MRI) who undergo surgical therapy. We identified 23 patients who underwent temporal lobectomy and had normal pre-operative MRI, including surface coil phased array temporal lobe imaging. All were followed at least 2 years after surgery. We graded outcome as seizure-free, > 75% reduction in seizures, or < 75% reduction in seizures. We examined pre-operative interictal and ictal electroencephalographic (EEG) findings, age of onset, gender, duration of epilepsy, risk factors, family history, physical findings, age at operation, side of operation, and pathology of resected tissue in order to determine if any of these factors were associated with outcome. Overall, 48% (11/23) of patients were seizure-free, 39% (9/23) had > 75% reduction in seizures, while 13% (3/23) had < 75% reduction in seizures. Only the EEG findings were useful in predicting outcome. When ictal onsets arose from basal-temporal regions, 61% (11/18) of patients were seizure-free, while none (0/5) were seizure-free when seizures arose from mid-posterior temporal regions (P = 0.04). Interictally, if all epileptiform patterns were localized exclusively to one basal-temporal region, a finding that invariably correlated with ictal onsets, 78% (7/9) of patients were seizure-free, while only 29% (4/14) were seizure-free if discharges were bilateral or multifocal (P = 0.04). We conclude that surgery may be a reasonable treatment for some patients with intractable temporal lobe seizures and normal MRI. The best outcomes occur when seizure onsets and interictal epileptiform patterns are exclusive to one basal-temporal region. Unfavorable outcomes are most likely to occur when ictal origins are from mid-posterior temporal regions and when interictal discharges are bitemporal or multifocal in distribution.

    View details for Web of Science ID 000089609300007

    View details for PubMedID 10985997

  • Intraoperative hippocampal electrocorticography to predict the extent of hippocampal resection in temporal lobe epilepsy surgery JOURNAL OF NEUROSURGERY McKhann, G. M., Schoenfeld-McNeill, J., Born, D. E., Haglund, M. M., OJEMANN, G. A. 2000; 93 (1): 44-52

    Abstract

    Among the variety of surgical procedures that are performed for the treatment of medically refractory mesial temporal lobe epilepsy (TLE), no consensus exists as to how much of the hippocampus should be removed. Whether all patients require a maximal hippocampal resection has not yet been determined.At the University of Washington, all TLE operations are performed in a tailored fashion, guided by electrocorticography (ECoG). The amount of hippocampal resection is determined intraoperatively by the extent of interictal epileptiform abnormalities on ECoG recorded from that structure, resulting in a hippocampal resection that is individualized for each patient. Using this approach, the authors prospectively observed 140 consecutive patients who underwent surgery for mesial TLE with pathological diagnoses of either mesial temporal sclerosis with neuronal loss (MTS group) or mild gliosis without neuronal loss (non-MTS group) to determine whether the extent of hippocampal resection correlates with outcome when a tailored approach is used. Additionally, the authors analyzed whether the presence of residual interictal epileptiform activity on ECoG following mesial temporal resection predicts poorer seizure control. With at least 18 months of clinical follow up, 67% of the 140 patients were seizure free or had only a single postoperative seizure. There was no correlation between the size of the hippocampal resection and seizure control in the group as a whole or when stratified by pathological subtype. Using an intraoperatively tailored strategy, individuals with a larger hippocampal resection (> 2.5 cm) were not more likely to have seizure-free outcomes than patients with smaller resections (p = 0.9). Additionally, both MTS and non-MTS patients, in whom postoperative ECoG detected residual epileptiform hippocampal (but not cortical or parahippocampal) interictal activity following surgical resection, had significantly worse seizure outcomes (p = 0.01 in the MTS group; p = 0.002 in the non-MTS group).Intraoperative hippocampal ECoG can predict how much hippocampus should be removed to maximize seizure-free outcome, allowing for sparing of possibly functionally important hippocampus.

    View details for Web of Science ID 000087813100007

    View details for PubMedID 10883904

  • Diffusion-weighted magnetic resonance imaging in boys with neural cell adhesion molecule L1 mutations and congenital hydrocephalus ANNALS OF NEUROLOGY Graf, R. D., Born, D. E., Shaw, D. W., Thomas, J. R., Holloway, B. W., Michaelis, R. C. 2000; 47 (1): 113-117

    Abstract

    The phenotype of severe congenital hydrocephalus secondary to neural cell adhesion molecule L1 (L1CAM) gene mutations includes the distinct finding of brainstem corticospinal tract hypoplasia. Using diffusion-weighted imaging (DWI), we failed to demonstrate anisotropy in the corticospinal tracts of the basis pontis in 4 affected boys with L1CAM mutations. The DWI findings correlated with the neuropathological findings in a fifth patient. DWI may be a useful technique to screen for boys with L1CAM mutations.

    View details for Web of Science ID 000084636800018

    View details for PubMedID 10632110

  • Morphological plasticity in an infant monkey model of temporal lobe epilepsy EPILEPSIA Wenzel, H. J., Born, D. E., Dubach, M. F., GUNDERSON, V. M., Maravilla, K. R., Robbins, C. A., Szot, P., Zierath, D., Schwartzkroin, P. A. 2000; 41: S70-S75

    Abstract

    Seizures in early life are thought to contribute to the development of human temporal lobe epilepsy. To examine the consequences of early seizures, we elicited status epilepticus in immature, 5.5- to 7.0-month-old pigtailed macaques by unilateral microinfusion of bicuculline methiodide into the entorhinal cortex.This report focuses on neuropathological changes in the hippocampus. Bicuculline infusion consistently elicited limbic-like seizures with prolonged, relatively localized electrographic activity. Magnetic resonance imaging revealed enhanced signal intensity in the ipsilateral hippocampus after seizures; in some cases, there was also progressive hippocampal atrophy. Histological changes were variable; in two of five monkeys, there was significant hippocampal neuron loss, gliosis, granule cell dispersion, and mossy fiber reorganization.The histopathological findings and associated magnetic resonance imaging abnormalities after bicuculline-induced status epilepticus in infant monkeys mimic common aspects of human temporal lobe epilepsy.

    View details for Web of Science ID 000089156500014

    View details for PubMedID 10999523

  • Brainstem diffusion-weighted MRI in boys with L1CAM mutations EUROPEAN JOURNAL OF PEDIATRIC SURGERY Graf, W. D., Born, D. E., Shaw, D. W., Thomas, J. R., Holloway, L. W., Michaelis, R. C. 1999; 9: 41-42

    View details for Web of Science ID 000084656200015

    View details for PubMedID 10661793

  • Hippocampal N-methyl-D-aspartate receptor subunit mRNA levels in temporal lobe epilepsy patients ANNALS OF NEUROLOGY Mathern, G. W., Pretorius, J. K., Mendoza, D., Leite, J. P., Chimelli, L., Born, D. E., Fried, I., Assirati, J. A., OJEMANN, G. A., Adelson, P. D., Cahan, L. D., Kornblum, H. I. 1999; 46 (3): 343-358

    Abstract

    Changes in the subunit stoichiometry of the N-methyl-D-aspartate (NMDA) receptor (NMDAR) alters its channel properties, and may enhance or reduce neuronal excitability in temporal lobe epilepsy patients. This study determined whether hippocampal NMDA receptor subunit mRNA levels were increased or decreased in temporal lobe epilepsy patients compared with nonseizure autopsy cases. Hippocampal sclerosis (HS; n = 16), non-HS (n = 10), and autopsy hippocampi (n = 9) were studied for NMDAR1 (NR1) and NR2A-D mRNA levels by using semiquantitative in situ hybridization techniques, along with neuron densities. Compared with autopsy hippocampi, non-HS and HS patients showed increased NR2A and NR2B hybridization densities per dentate granule cell. Furthermore, non-HS hippocampi showed increased NR1 and NR2B mRNA levels per CA2/3 pyramidal neuron compared with autopsy cases. HS patients, by contrast, showed decreased NR2A hybridization densities per CA2/3 pyramidal neuron compared with non-HS and autopsy cases. These findings indicate that chronic temporal lobe seizures are associated with differential changes in hippocampal NR1 and NR2A-D hybridization densities that vary by subfield and clinical-pathological category. In temporal lobe epilepsy patients, these findings support the hypothesis that in dentate granule cells NMDA receptors are increased, and excitatory postsynaptic potentials should be strongly NMDA mediated compared with nonseizure autopsies. HS patients, by comparison, showed decreased pyramidal neuron NR2A mRNA levels, and this suggests that NMDA-mediated pyramidal neuron responses should be reduced in HS patients compared with non-HS cases.

    View details for Web of Science ID 000082360000010

    View details for PubMedID 10482265

  • Seizures induced in young primates as a model of temporal lobe epilepsy. JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY Born, D. E., Wenzel, H. J., GUNDERSON, V. M., Szot, P., Dubach, M. F., Maravilla, K. R., Schwartzkroin, P. A. 1999; 58 (5): 545-545
  • Development of a model of status epilepticus in pigtailed macaque infant monkeys DEVELOPMENTAL NEUROSCIENCE Gunderson, V. M., Dubach, M., Szot, P., Born, D. E., Wenzel, H. J., Maravilla, K. R., Zierath, D. K., Robbins, C. A., Schwartzkroin, P. A. 1999; 21 (3-5): 352-364

    Abstract

    Seizures, particularly multiple episodes and/or status epilepticus (SE) are prevalent in pediatric patients. Pediatric SE is associated with brain changes that have been hypothesized to contribute to the onset of temporal lobe epilepsy (TLE). In order to gain insight into the effects of seizures on the immature brain and the risk for later TLE, we have developed a model of limbic SE in the pigtailed macaque monkey. In separate studies, bicuculline methiodide or a bicuculline 'cocktail' was infused into three regions of the brain (area tempestas, hippocampus, entorhinal cortex) to induce seizures. Measures included MRI, electrophysiology, behavior and morphology. Our results suggest that monkey models of SE may provide useful tools for understanding the effects of prolonged seizures during infancy and the origins of TLE in humans.

    View details for Web of Science ID 000084057600022

    View details for PubMedID 10575259

  • Chromogranin-A in the human hippocampus in normal development and in perinatal hypoxic/ischemic encephalopathy EPILEPSIA Sarnat, H. B., Flores, L., Born, D. E. 1999; 40: 201-201
  • Hippocampal GAD 65 & 67 labeled cells and mRNA levels per cell in temporal lope epilepsy patients. EPILEPSIA Mathern, G. W., Pretorius, J. K., Mendoza, D., Born, D., Adelson, P. D., Leite, J. P., Cahan, L. D., Fried, I., Kornblum, H. I. 1999; 40: 155-156
  • Synaptophysin immunocytochemistry with thermal intensification: a marker of terminal axonal maturation in the human fetal nervous system BRAIN & DEVELOPMENT Sarnat, H. B., Born, D. E. 1999; 21 (1): 41-50

    Abstract

    Synaptophysin is a protein of synaptic vesicles and may be demonstrated in tissue sections of human brain and spinal cord by immunocytochemistry using a monoclonal antibody. Synaptophysin immunoreactivity was studied in paraffin-embedded sections of the central nervous system (CNS) in 14 normal human fetuses and neonates ranging in age from 8 to 41 weeks gestation, and in three brains with heterotopic neurons or malformations. A progressive expression of synaptophysin is seen in axonal terminals within grey matter in various parts of the CNS, beginning in the ventral horns of the spinal cord and brainstem tegmentum at 12-14 weeks. In the cerebellum, the molecular layer shows a band of reactivity from 18 weeks; by term two parallel bands of synaptophysin are seen in the molecular layer and reactivity also is demonstrated in the Purkinje and internal granular layers. In the cerebral neocortex, the molecular zone has weak synaptophysin reactivity as early as 10 weeks, though reactivity is not detected in the deep layers of the cortical plate until 19 weeks and in layers 2-4 until 25 weeks gestation. Synaptophysin reactivity is strong at the surface of neurons but not detected in their somatic cytoplasm; coarsely beaded reactivity within the neuropil probably corresponds to synaptic vesicles in terminal axons. Similar granular synaptophysin reactivity is seen around heterotopic neurons in the subcortical white matter, in dysgenesis of the cerebellar cortex and in the residual anencephalic forebrain. Thermal intensification by heating the incubating solution in a microwave oven often enhances immunoreactivity because of more complete antigen retrieval and is recommended for tissue stored in formalin or in paraffin for long periods. Synaptophysin provides a useful tissue marker of synaptogenesis during normal development and in cerebral dysgeneses, and may provide useful correlations with functional imaging of the brain in living patients. Used in conjunction with other neuronal markers, the expression of synaptophysin in terminal axons of distant neurons, in temporal relation to the maturation of the neurons they innervate, may provide clues to the pathogenesis of epilepsy in early infancy.

    View details for Web of Science ID 000078632800009

    View details for PubMedID 10082252

  • The pachygyria-polymicrogyria spectrum of cortical dysplasia in X-linked hydrocephalus EUROPEAN JOURNAL OF PEDIATRIC SURGERY Graf, W. D., Born, D. E., Sarnat, H. B. 1998; 8: 10-14

    Abstract

    Neural cell adhesion molecules (CAM) play important roles in neural development, neurite outgrowth, axonal guidance, fasciculation and synapse formation. Neuropathological studies of X-linked hydrocephalus (XLH) associated with L1 CAM mutations emphasize marked hypoplasia of the pyramidal tract, agenesis of the corpus callosum and septum pellucidum, and a thin cerebral mantle with hypoplastic white matter, but there are no detailed studies of the cerebral cortex in the literature. We report clinical, neuroimaging, and neuropathological findings in three boys with XLH. All had severe congenital hydrocephalus with marked thinning of the cerebral mantle and severe development disabilities. The brain specimens from the three boys showed both pachygyria and polymicrogyria, hypoplasia of the medullary pyramids, hypoplasia of the corpus callosum, small anterior commissure, hypoplasia and poorly differentiated hippocampi. A small but patent aqueduct was present in all three brains. Despite the extensive cerebral malformations, the cortex in all three brains showed normal-appearing laminar cortical neuronal architecture and absence of gliosis. In XLH, it is likely that the poor developmental outcome of spasticity, contractures and severe mental retardation results from a disturbance of neuronal connectivity, fasciculation, and synapse formation rather than aqueductal stenosis, increased intracranial pressure, or abnormal neuroblast migration.

    View details for Web of Science ID 000078237900004

    View details for PubMedID 9926316

  • Altered hippocampal kainate-receptor mRNA levels in temporal lobe epilepsy patients NEUROBIOLOGY OF DISEASE Mathern, G. W., Pretorius, J. K., Kornblum, H. I., Mendoza, D., Lozada, A., Leite, J. P., Chimelli, L., Born, D. E., Fried, I., Sakamoto, A. C., Assirati, J. A., Peacock, W. J., OJEMANN, G. A., Adelson, P. D. 1998; 5 (3): 151-176

    Abstract

    This study determined whether hippocampal kainate (KA) receptor mRNA levels were increased or decreased in temporal lobe epilepsy patients compared with nonseizure autopsies. Hippocampal sclerosis (HS; n = 17), nonsclerosis (non-HS; n = 11), and autopsy hippocampi (n = 9) were studied for KA1-2 and GluR5-7 mRNA levels using semiquantitative in situ hybridization techniques, along with neuron densities. Compared with autopsy hippocampi, HS and non-HS cases showed decreased GluR5 and GluR6 hybridization densities per CA2 and/or CA3 pyramid. Furthermore, HS patients demonstrated increased KA2 and GluR5 hybridization densities per granule cell compared with autopsy hippocampi. These findings indicate that chronic temporal lobe seizures were associated with differential changes in hippocampal KA1-2 and GluR5-7 hybridization densities that vary by subfield and pathology group. In temporal lobe epilepsy patients, these results support the hypothesis that pyramidal cell GluR5 and GluR6 mRNA levels are decreased as a consequence of seizures, and in HS patients granule cell KA2 and GluR5 mRNA levels are increased in association with aberrant fascia dentata mossy fiber sprouting and/or hippocampal neuronal loss.

    View details for Web of Science ID 000076770000003

    View details for PubMedID 9848088

  • Neuronal nuclear antigen (NeuN): a marker of neuronal maturation in the early human fetal nervous system BRAIN & DEVELOPMENT Sarnat, H. B., Nochlin, D., Born, D. E. 1998; 20 (2): 88-94

    Abstract

    Neuronal nuclear antigen (NeuN) immunocytochemistry was studied in 15 normal human fetal nervous systems of 8-24 weeks gestation and in four term neonates. Material was derived from products of conception or from autopsy. Antigen retrieval was enhanced for immunocytochemistry by microwave heating of formalin-fixed paraffin sections. NeuN appears highly specific as a marker of neuronal nuclei in human fetal brain. Only rare nuclei are recognized in the germinal matrix. Cerebellar external granule cells are more strongly immunoreactive than postmigratory internal granule cells until 24 weeks gestation; by term most internal and only a few external granule cells are recognized by NeuN antibody. In the cerebrum, some reactive nuclei are demonstrated along radial glial fibers, particularly near the cortical plate. Within the cortical plate, only deep neurons (future layers 4-6) are marked at 19-22 weeks, but by 24 weeks most neurons in the cortical plate exhibit immunoreactivity, though at term some in layer 2 are still non-reactive. Some neurons fail to be recognized by NeuN at all ages: Cajal-Retzius cells, Purkinje cells, inferior olivary and dentate nucleus neurons, and sympathetic ganglion cells are examples. Despite their common origin in the cerebellar tubercle, basal pontine neurons are strongly reactive even before midgestation, hence NeuN does not predict embryonic origin. Neurons of dorsal root and cranial nerve ganglia are reactive even at 8 weeks. This study of normal fetal central nervous system provides a basis for neuropathological evaluation and as a prelude to applications in cerebral dysgeneses.

    View details for Web of Science ID 000072610300005

    View details for PubMedID 9545178

  • Ultrastructral localization of zinc transporter-3 (ZnT-3) to synaptic vesicle membranes within mossy fiber boutons in the hippocampus of mouse and monkey PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Wenzel, H. J., Cole, T. B., Born, D. E., Schwartzkroin, P. A., Palmiter, R. D. 1997; 94 (23): 12676-12681

    Abstract

    Zinc transporter-3 (ZnT-3), a member of a growing family of mammalian zinc transporters, is expressed in regions of the brain that are rich in histochemically reactive zinc (as revealed by the Timm's stain), including entorhinal cortex, amygdala, and hippocampus. ZnT-3 protein is most abundant in the zinc-enriched mossy fibers that project from the dentate granule cells to hilar and CA3 pyramidal neurons. We show here by electron microscopy that ZnT-3 decorates the membranes of all clear, small, round synaptic vesicles (SVs) in the mossy fiber boutons of both mouse and monkey. Furthermore, up to 60-80% of these SVs contain Timm's-stainable zinc. The coincidence of ZnT-3 on the membranes of SVs that accumulate zinc, and its homology with known zinc transporters, suggest that ZnT-3 is responsible for the transport of zinc into SVs, and hence for the ability of these neurons to release zinc upon excitation.

    View details for Web of Science ID A1997YF39300078

    View details for PubMedID 9356509

  • NeuN: A marker of neuronal maturation in the human fetal CNS BRAIN PATHOLOGY Sarnat, H. B., Nochlin, D., Born, D. 1997; 7 (4): 1271-1271
  • Markers of neuronal maturation BRAIN PATHOLOGY Sarnat, H. B., Nochlin, D., Born, D. E. 1997; 7 (4): 1269-1270
  • CORRELATION OF PATHOLOGICAL-CHANGES IN THE MESIAL TEMPORAL-LOBE AND SURGICAL OUTCOME EPILEPSIA Haglund, M. M., Born, D. E., OJEMANN, G. A. 1995; 36: 370-370
  • UNILATERAL VESTIBULAR SCHWANNOMA IN A CHILD WITH PRIOR ORBITAL RHABDOMYOSARCOMA SURGICAL NEUROLOGY Kim, D. K., Born, D. E., Berger, M. S., Mayberg, M. R. 1994; 42 (2): 125-129

    Abstract

    In the absence of neurofibromatosis, vestibular schwannomas (acoustic neuromas) are rarely found in children. We report a case of a 13-year-old boy who presented with unilateral vestibular schwannoma 11 years after resection of an orbital rhabdomyosarcoma. The coincidence of these tumors has not been previously reported.

    View details for Web of Science ID A1994PJ02200007

    View details for PubMedID 8091288

  • PARAGANGLIOMAS OF THE SELLAR REGION - REPORT OF 2 CASES NEUROSURGERY Steel, T. R., Dailey, A. T., Born, D., Berger, M. S., Mayberg, M. R., Chandler, W. 1993; 32 (5): 844-847
  • Paragangliomas of the sellar region: report of two cases. Neurosurgery Steel, T. R., Dailey, A. T., Born, D., Berger, M. S., Mayberg, M. R. 1993; 32 (5): 844-847

    Abstract

    Two cases of paraganglioma arising from the parasellar region are presented. Both occurred in middle-aged women who sought treatment of headaches but who had no endocrinological dysfunction; one case was associated with ophthalmoplegia from cavernous sinus involvement. Diagnosis in both cases was confirmed by typical histological appearance and cytochemical demonstration of immunoreactive chromogranin in tumor cells. The pathological features and possible pathogenesis of parasellar paragangliomas are discussed.

    View details for PubMedID 8492863

  • PRENATAL SONOGRAPHIC DIAGNOSIS OF A PONTINE LIPOMA JOURNAL OF ULTRASOUND IN MEDICINE Winter, T. C., Laing, F. C., MACK, L. A., Born, D. E. 1992; 11 (10): 559-561

    View details for Web of Science ID A1992KY02600010

    View details for PubMedID 1404588

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