Publications by authors named "James W Mandell"

48 Publications

Lichen sclerosus of the eyelid.

Cutis 2020 Sep;106(3):E16-E17

Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, USA.

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http://dx.doi.org/10.12788/cutis.0097DOI Listing
September 2020

Rosai-Dorfman Disease: A Less Common Cause of Leptomeningeal and Nerve Root Enhancement.

Neurohospitalist 2020 Oct 4;10(4):309-313. Epub 2020 Jun 4.

Department of Neurology, University of Virginia Health System, VA, USA.

A 46-year-old male experienced progressive neurocognitive decline, weight loss, intermittent headaches, and weakness over 6 months. Magnetic resonance imaging of the brain revealed hydrocephalus and the spinal cord imaging showed diffuse leptomeningeal enhancement with prominent nerve root involvement. Intradural biopsy of lumbar arachnoid tissue found mixed inflammatory infiltrate consisting predominantly of histiocytes, S100 and CD68 positivity, and lymphocytophagocytosis (emperipolesis) consistent with extranodal Rosai-Dorfman disease. Rosai-Dorfman disease, a non-Langerhans cell histocytic disorder, can mimic the appearance of neurosarcoidosis and leptomeningeal carcinomatosis and should remain on the differential of a patient presenting with diffuse leptomeningeal enhancement, a common occurrence on a neurohospitalist service.
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http://dx.doi.org/10.1177/1941874420929187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7495699PMC
October 2020

A cytoskeleton regulator AVIL drives tumorigenesis in glioblastoma.

Nat Commun 2020 07 10;11(1):3457. Epub 2020 Jul 10.

Department of Pathology, School of Medicine, University of Virginia, Charlottesville, VA, 22908, USA.

Glioblastoma is a deadly cancer, with no effective therapies. Better understanding and identification of selective targets are urgently needed. We found that advillin (AVIL) is overexpressed in all the glioblastomas we tested including glioblastoma stem/initiating cells, but hardly detectable in non-neoplastic astrocytes, neural stem cells or normal brain. Glioma patients with increased AVIL expression have a worse prognosis. Silencing AVIL nearly eradicated glioblastoma cells in culture, and dramatically inhibited in vivo xenografts in mice, but had no effect on normal control cells. Conversely, overexpressing AVIL promoted cell proliferation and migration, enabled fibroblasts to escape contact inhibition, and transformed immortalized astrocytes, supporting AVIL being a bona fide oncogene. We provide evidence that the tumorigenic effect of AVIL is partly mediated by FOXM1, which regulates LIN28B, whose expression also correlates with clinical prognosis. AVIL regulates the cytoskeleton through modulating F-actin, while mutants disrupting F-actin binding are defective in its tumorigenic capabilities.
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http://dx.doi.org/10.1038/s41467-020-17279-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351761PMC
July 2020

A Rare Case of Pancreatoblastoma with Intracranial Seeding.

World Neurosurg 2020 10 1;142:334-338. Epub 2020 Jul 1.

Department of Neurological Surgery, University of Virginia Health System, Charlottesville, Virginia, USA.

Background: Pancreatoblastoma is an extremely rare neoplasm that accounts for 0.5% of all pancreatic exocrine tumors. These rare entities typically manifest in the pediatric population but can rarely occur in adults. Systemic seeding has been described before but intracranial metastasis in adults has yet to be described.

Case Description: A 28-year-old woman with a history of pancreatoblastoma that had been in remission for 51 months after treatment with cisplatin, doxorubicin (Adriamycin), and etoposide had presented to the emergency room with chronic recurrent headaches. Conservative management of the headaches failed, which led to a diagnostic workup with magnetic resonance imaging of the brain. Magnetic resonance imaging demonstrated a well-circumscribed solitary cerebellar lesion. Metastatic disease was suspected, and the patient underwent suboccipital craniotomy for tumor resection with adjuvant gamma knife radiosurgery.

Conclusions: Central nervous system seeding of pancreatoblastoma is rare, and the available evidence suggests that the strategy we used could be adequate for treating such occurrences.
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http://dx.doi.org/10.1016/j.wneu.2020.06.210DOI Listing
October 2020

Focused Ultrasound Preconditioning for Augmented Nanoparticle Penetration and Efficacy in the Central Nervous System.

Small 2019 12 22;15(49):e1903460. Epub 2019 Oct 22.

Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, 22908, USA.

Microbubble activation with focused ultrasound (FUS) facilitates the noninvasive and spatially-targeted delivery of systemically administered therapeutics across the blood-brain barrier (BBB). FUS also augments the penetration of nanoscale therapeutics through brain tissue; however, this secondary effect has not been leveraged. Here, 1 MHz FUS sequences that increase the volume of transfected brain tissue after convection-enhanced delivery of gene-vector "brain-penetrating" nanoparticles were first identified. Next, FUS preconditioning is applied prior to trans-BBB nanoparticle delivery, yielding up to a fivefold increase in subsequent transgene expression. Magnetic resonance imaging (MRI) analyses of tissue temperature and K confirm that augmented transfection occurs through modulation of parenchymal tissue with FUS. FUS preconditioning represents a simple and effective strategy for markedly improving the efficacy of gene vector nanoparticles in the central nervous system.
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http://dx.doi.org/10.1002/smll.201903460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084172PMC
December 2019

Segmental arterial mediolysis: A rare cause of rapidly progressive arterial dissections.

Neurol Clin Pract 2017 Dec;7(6):e43-e46

Departments of Neurology (DAL, JJP, BBW, AMS), Medicine (MSA, AMS), Pathology (JJD, JWM, MBSL), and Public Health Sciences (BBW, AMS), University of Virginia Health System, Charlottesville.

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http://dx.doi.org/10.1212/CPJ.0000000000000403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5800711PMC
December 2017

Whole Slide Imaging Versus Microscopy for Primary Diagnosis in Surgical Pathology: A Multicenter Blinded Randomized Noninferiority Study of 1992 Cases (Pivotal Study).

Am J Surg Pathol 2018 Jan;42(1):39-52

Department of Pathology, Keck School of Medicine University of Southern California, Los Angeles, CA.

Most prior studies of primary diagnosis in surgical pathology using whole slide imaging (WSI) versus microscopy have focused on specific organ systems or included relatively few cases. The objective of this study was to demonstrate that WSI is noninferior to microscopy for primary diagnosis in surgical pathology. A blinded randomized noninferiority study was conducted across the entire range of surgical pathology cases (biopsies and resections, including hematoxylin and eosin, immunohistochemistry, and special stains) from 4 institutions using the original sign-out diagnosis (baseline diagnosis) as the reference standard. Cases were scanned, converted to WSI and randomized. Sixteen pathologists interpreted cases by microscopy or WSI, followed by a wash-out period of ≥4 weeks, after which cases were read by the same observers using the other modality. Major discordances were identified by an adjudication panel, and the differences between major discordance rates for both microscopy (against the reference standard) and WSI (against the reference standard) were calculated. A total of 1992 cases were included, resulting in 15,925 reads. The major discordance rate with the reference standard diagnosis was 4.9% for WSI and 4.6% for microscopy. The difference between major discordance rates for microscopy and WSI was 0.4% (95% confidence interval, -0.30% to 1.01%). The difference in major discordance rates for WSI and microscopy was highest in endocrine pathology (1.8%), neoplastic kidney pathology (1.5%), urinary bladder pathology (1.3%), and gynecologic pathology (1.2%). Detailed analysis of these cases revealed no instances where interpretation by WSI was consistently inaccurate compared with microscopy for multiple observers. We conclude that WSI is noninferior to microscopy for primary diagnosis in surgical pathology, including biopsies and resections stained with hematoxylin and eosin, immunohistochemistry and special stains. This conclusion is valid across a wide variety of organ systems and specimen types.
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http://dx.doi.org/10.1097/PAS.0000000000000948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5737464PMC
January 2018

Proteomic identification of synaptic caspase substrates.

Synapse 2018 01 9;72(1). Epub 2017 Oct 9.

Department of Pathology, University of Virginia School of Medicine, Charlottesville, Virginia.

The dismantling and elimination of excess neurons and their connections (pruning) is essential for brain development and may be aberrantly reactivated in some neurodegenerative diseases. Growing evidence implicates caspase-mediated apoptotic and nonapoptotic cascades in the dysfunction and death of neurons in neurodegenerative disorders such as Alzheimer's, Parkinson, and Huntington's diseases. It is the cleaved caspase substrates that are the effectors of synapse elimination. However, their identities, specific cleavage sites, and functional consequences of cleavage are largely unknown. An important gap in our knowledge is a comprehensive catalog of synapse-specific or synapse-enriched caspase targets. Traditional biochemical approaches have revealed only a small number of neuronal caspase targets. Instead, we utilized a gel-based proteomics approach to enable the first global analysis of caspase-mediated cleavage events in mammalian brain synapses, employing both an in vitro system with recombinant activated caspases and an in vivo model of ethanol-induced neuronal apoptosis. Of the more than 70 putative cleavage substrates that were identified, 22 were previously known caspase substrates. Among the novel targets identified and validated by Western blot were the proton pump ATPase subunit ATP6V1B2 and the N-ethylmaleimide-sensitive fusion protein (NSF). Our work represents the first comprehensive, proteome-wide screen for proteolytic targets of caspases in neuronal synapses. Our discoveries will have significance for both furthering basic understanding of roles of caspases in synaptic plasticity and synaptic loss in neurodegeneration, and on a more immediately practical level, may provide candidate biomarkers for measuring synapse loss in human disease states.
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http://dx.doi.org/10.1002/syn.22014DOI Listing
January 2018

Diagnostic Efficiency in Digital Pathology: A Comparison of Optical Versus Digital Assessment in 510 Surgical Pathology Cases.

Am J Surg Pathol 2018 Jan;42(1):53-59

Department of Pathology.

Prior work has shown that digital images and microscopic slides can be interpreted with comparable diagnostic accuracy. Although accuracy has been well-validated, the interpretative time for digital images has scarcely been studied and concerns about efficiency remain a major barrier to adoption. We investigated the efficiency of digital pathology when compared with glass slide interpretation in the diagnosis of surgical pathology biopsy and resection specimens. Slides were pulled from 510 surgical pathology cases from 5 organ systems (gastrointestinal, gynecologic, liver, bladder, and brain). Original diagnoses were independently confirmed by 2 validating pathologists. Diagnostic slides were scanned using the Philips IntelliSite Pathology Solution. Each case was assessed independently on digital and optical by 3 reading pathologists, with a ≥6 week washout period between modalities. Reading pathologists recorded assessment times for each modality; digital times included time to load the case. Diagnostic accuracy was determined based on whether a rendered diagnosis differed significantly from the original diagnosis. Statistical analysis was performed to assess for differences in interpretative times across modalities. All 3 reading pathologists showed comparable diagnostic accuracy across optical and digital modalities (mean major discordance rates with original diagnosis: 4.8% vs. 4.4%, respectively). Mean assessment times ranged from 1.2 to 9.1 seconds slower on digital versus optical. The slowest reader showed a significant learning effect during the course of the study so that digital assessment times decreased over time and were comparable with optical times by the end of the series. Organ site and specimen type did not significantly influence differences in interpretative times. In summary, digital image reading times compare favorably relative to glass slides across a variety of organ systems and specimen types. Mean increase in assessment time is 4 seconds/case. This time can be minimized with experience and may be further balanced by the improved ease of electronic chart access allowed by digital slide viewing, as well as quantitative assessments which can be expedited on digital images.
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http://dx.doi.org/10.1097/PAS.0000000000000930DOI Listing
January 2018

Novel Focused Ultrasound Gene Therapy Approach Noninvasively Restores Dopaminergic Neuron Function in a Rat Parkinson's Disease Model.

Nano Lett 2017 06 18;17(6):3533-3542. Epub 2017 May 18.

Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia 22908, United States

Therapies capable of decelerating, or perhaps even halting, neurodegeneration in Parkinson's disease (PD) remain elusive. Clinical trials of PD gene therapy testing the delivery of neurotrophic factors, such as the glial cell-line derived neurotrophic factor (GDNF), have been largely ineffective due to poor vector distribution throughout the diseased regions in the brain. In addition, current delivery strategies involve invasive procedures that obviate the inclusion of early stage patients who are most likely to benefit from GDNF-based gene therapy. Here, we introduce a two-pronged treatment strategy, composed of MR image-guided focused ultrasound (FUS) and brain-penetrating nanoparticles (BPN), that provides widespread but targeted GDNF transgene expression in the brain following systemic administration. MR image-guided FUS allows circulating gene vectors to partition into the brain tissue by noninvasive and transient opening of the blood-brain barrier (BBB) within the areas where FUS is applied. Once beyond the BBB, BPN provide widespread and uniform GDNF expression throughout the targeted brain tissue. After only a single treatment, our strategy led to therapeutically relevant levels of GDNF protein content in the FUS-targeted regions in the striatum of the 6-OHDA-induced rat model of PD, which lasted at least up to 10 weeks. Importantly, our strategy restored both dopamine levels and dopaminergic neuron density and reversed behavioral indicators of PD-associated motor dysfunction with no evidence of local or systemic toxicity. Our combinatorial approach overcomes limitations of current delivery strategies, thereby potentially providing a novel means to treat PD.
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http://dx.doi.org/10.1021/acs.nanolett.7b00616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5539956PMC
June 2017

Quantitative Analysis of the Cellular Microenvironment of Glioblastoma to Develop Predictive Statistical Models of Overall Survival.

J Neuropathol Exp Neurol 2016 12;75(12):1110-1123

From the University of Virginia School of Medicine (JXY, FFB, JWM, BJH, JMM), Department of Biomedical Engineering, University (JXY, JMM), Department of Pathology (FFB, JWM), and Department of Public Health Sciences (BJH), Division of Translational Research and Applied Statistics, University of Virginia, Charlottesville, Virginia.

Glioblastomas, the most common primary malignant brain tumors, have a distinct tissue microenvironment. Although non-neoplastic cells contribute to glioblastoma progression, very few quantitative studies have shown the effect of tumor microenvironmental influences on patient survival. We examined relationships of the cellular microenvironment, including astrocytes, microglia, oligodendrocytes, and blood vessels, to survival in glioblastoma patients. Using histological staining and quantitative image analyses, we examined the tumor-associated parenchyma of 33 patients and developed statistical models to predict patient outcomes based on the cellular picture of the tumor parenchyma. We found that blood vessel density correlated with poorer prognosis. To examine the role of adjacent parenchymal versus higher tumor cell density bulk parenchymal tissue, we examined the glial components in these highly variable regions. Comparison of bulk and adjacent astrocytes and microglia in tissue yielded the strongest prediction of survival, with high levels of adjacent astrocytes predicted poor prognosis and high levels of microglia correlated with a better prognosis. These results indicate that parenchymal components predict survival in glioblastoma patients and in particular that the balance between reactive glial populations is important for patient prognosis.
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http://dx.doi.org/10.1093/jnen/nlw090DOI Listing
December 2016

mTOR and neuronal cell cycle reentry: How impaired brain insulin signaling promotes Alzheimer's disease.

Alzheimers Dement 2017 02 29;13(2):152-167. Epub 2016 Sep 29.

Department of Biology, University of Virginia, Charlottesville, VA, USA; Department of Cell Biology, University of Virginia, Charlottesville, VA, USA; Department of Neuroscience, University of Virginia, Charlottesville, VA, USA. Electronic address:

A major obstacle to presymptomatic diagnosis and disease-modifying therapy for Alzheimer's disease (AD) is inadequate understanding of molecular mechanisms of AD pathogenesis. For example, impaired brain insulin signaling is an AD hallmark, but whether and how it might contribute to the synaptic dysfunction and neuron death that underlie memory and cognitive impairment has been mysterious. Neuron death in AD is often caused by cell cycle reentry (CCR) mediated by amyloid-β oligomers (AβOs) and tau, the precursors of plaques and tangles. We now report that CCR results from AβO-induced activation of the protein kinase complex, mTORC1, at the plasma membrane and mTORC1-dependent tau phosphorylation, and that CCR can be prevented by insulin-stimulated activation of lysosomal mTORC1. AβOs were also shown previously to reduce neuronal insulin signaling. Our data therefore indicate that the decreased insulin signaling provoked by AβOs unleashes their toxic potential to cause neuronal CCR, and by extension, neuron death.
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http://dx.doi.org/10.1016/j.jalz.2016.08.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5318248PMC
February 2017

LRP1 expression in microglia is protective during CNS autoimmunity.

Acta Neuropathol Commun 2016 07 11;4(1):68. Epub 2016 Jul 11.

Center for Brain Immunology and Glia, Department of Neuroscience, University of Virginia, Charlottesville, VA, USA.

Multiple sclerosis is a devastating neurological disorder characterized by the autoimmune destruction of the central nervous system myelin. While T cells are known orchestrators of the immune response leading to MS pathology, the precise contribution of CNS resident and peripheral infiltrating myeloid cells is less well described. Here, we explore the myeloid cell function of Low-density lipoprotein receptor-related protein-1 (LRP1), a scavenger receptor involved in myelin clearance and the inflammatory response, in the context of Multiple sclerosis. Supporting its central role in Multiple sclerosis pathology, we find that LRP1 expression is increased in Multiple sclerosis lesions in comparison to the surrounding healthy tissue. Using two genetic mouse models, we show that deletion of LRP1 in microglia, but not in peripheral macrophages, negatively impacts the progression of experimental autoimmune encephalomyelitis, an animal model of Multiple sclerosis. We further show that the increased disease severity in experimental autoimmune encephalomyelitis is not due to haplodeficiency of the Cx3cr1 locus. At the cellular level, microglia lacking LRP1 adopt a pro-inflammatory phenotype characterized by amoeboid morphology and increased production of the inflammatory mediator TNF-α. We also show that LRP1 functions as a robust inhibitor of NF-kB activation in myeloid cells via a MyD88 dependent pathway, potentially explaining the increase in disease severity observed in mice lacking LRP1 expression in microglia. Taken together, our data suggest that the function of LRP1 in microglia is to keep these cells in an anti-inflammatory and neuroprotective status during inflammatory insult, including experimental autoimmune encephalomyelitis and potentially in Multiple sclerosis.
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http://dx.doi.org/10.1186/s40478-016-0343-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4940960PMC
July 2016

Culture conditions tailored to the cell of origin are critical for maintaining native properties and tumorigenicity of glioma cells.

Neuro Oncol 2016 10 21;18(10):1413-24. Epub 2016 Apr 21.

Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia (P.F.L., C.L., A.R.H., H.Z.); Department of Neurological Surgery, University of Virginia, Charlottesville, Virginia (M.E.S., A.A., D.S.); Division of Neuropathology, Department of Pathology, Charlottesville, Virginia (M.B.S.L., J.W.M.); Department of Neurology, School of Medicine, University of Virginia, Charlottesville, Virginia (D.S.); Department of Pathology and Pathological Physiology, Center for Cancer Research, Zhejiang University School of Medicine, Zhejiang Diseases Proteomics Key Laboratory, Hangzhou, China (C.L.); Department of Biophysics and Center of Biotechnology, Federal University of Rio Grande do Sul, Porto Alegre, Brazil (P.F.L., D.C.M., G.L.); Department of Neurosurgery, Changzheng Hospital, Second Affiliated Hospital of Second Military Medical University, Shanghai, China (H.H., Y.-C.L.); Department of Pathology, Xiang-ya Hospital, Central South University, Changsha, Hunan, China (H.-Y.Z.).

Background: Cell culture plays a pivotal role in cancer research. However, culture-induced changes in biological properties of tumor cells profoundly affect research reproducibility and translational potential. Establishing culture conditions tailored to the cancer cell of origin could resolve this problem. For glioma research, it has been previously shown that replacing serum with defined growth factors for neural stem cells (NSCs) greatly improved the retention of gene expression profile and tumorigenicity. However, among all molecular subtypes of glioma, our laboratory and others have previously shown that the oligodendrocyte precursor cell (OPC) rather than the NSC serves as the cell of origin for the proneural subtype, raising questions regarding the suitability of NSC-tailored media for culturing proneural glioma cells.

Methods: OPC-originated mouse glioma cells were cultured in conditions for normal OPCs or NSCs, respectively, for multiple passages. Gene expression profiles, morphologies, tumorigenicity, and drug responsiveness of cultured cells were examined in comparison with freshly isolated tumor cells.

Results: OPC media-cultured glioma cells maintained tumorigenicity, gene expression profiles, and morphologies similar to freshly isolated tumor cells. In contrast, NSC-media cultured glioma cells gradually lost their OPC features and most tumor-initiating ability and acquired heightened sensitivity to temozolomide.

Conclusions: To improve experimental reproducibility and translational potential of glioma research, it is important to identify the cell of origin, and subsequently apply this knowledge to establish culture conditions that allow the retention of native properties of tumor cells.
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http://dx.doi.org/10.1093/neuonc/now062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5035523PMC
October 2016

Redefining the Prevalence of Dural Involvement in Rosai-Dorfman Disease of the Central Nervous System.

World Neurosurg 2016 Jun 9;90:702.e13-702.e20. Epub 2016 Mar 9.

Department of Neurological Surgery, University of Virginia, Charlottesville, Virginia, USA.

Background: Sinus histiocytosis with massive lymphadenopathy, also known as Rosai-Dorfman disease, is a rare condition, classically characterized by painless, massive cervical lymphadenopathy. Histologically, the pathognomonic findings include a dense, mixed inflammatory infiltrate with areas of emperipolesis. Albeit infrequent, when Rosai-Dorfman disease affects the central nervous system, it typically manifests as an isolated dural lesion, often mimicking a meningioma. A purely intraparenchymal manifestation of Rosai-Dorfman disease of the brain and spine with absent dural involvement is exceedingly rare.

Case Description: In this report, we describe a 59-year-old woman who underwent surgical excision of an intraparenchymal cerebellar lesion. Histologic analysis of the resected specimen diagnosed isolated Rosai-Dorfman disease with absent systemic involvement. We also provide an updated review of the literature of nondural-based Rosai-Dorfman disease in the central nervous system.

Conclusions: With the recent increase of such reported cases, it becomes imperative that Rosai-Dorfman be considered more than as a dural lesion that may mimic meningioma. Diagnostic and therapeutic challenges surrounding this disease entity are also discussed.
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http://dx.doi.org/10.1016/j.wneu.2016.02.121DOI Listing
June 2016

Disseminated Balamuthia mandrillaris Infection.

J Clin Microbiol 2015 Sep 1;53(9):3072-6. Epub 2015 Jul 1.

Centers for Disease Control and Prevention, Atlanta, Georgia, USA.

Balamuthia mandrillaris is a rare cause of human infection, but when infections do occur, they result in high rates of morbidity and mortality. A case of disseminated Balamuthia infection is presented. Early diagnosis and initiation of recommended therapy are essential for increased chances of successful outcomes.
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http://dx.doi.org/10.1128/JCM.01549-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4540941PMC
September 2015

Structural and functional features of central nervous system lymphatic vessels.

Nature 2015 Jul 1;523(7560):337-41. Epub 2015 Jun 1.

1] Center for Brain Immunology and Glia, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA [2] Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA [3] Medical Scientist Training Program, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA.

One of the characteristics of the central nervous system is the lack of a classical lymphatic drainage system. Although it is now accepted that the central nervous system undergoes constant immune surveillance that takes place within the meningeal compartment, the mechanisms governing the entrance and exit of immune cells from the central nervous system remain poorly understood. In searching for T-cell gateways into and out of the meninges, we discovered functional lymphatic vessels lining the dural sinuses. These structures express all of the molecular hallmarks of lymphatic endothelial cells, are able to carry both fluid and immune cells from the cerebrospinal fluid, and are connected to the deep cervical lymph nodes. The unique location of these vessels may have impeded their discovery to date, thereby contributing to the long-held concept of the absence of lymphatic vasculature in the central nervous system. The discovery of the central nervous system lymphatic system may call for a reassessment of basic assumptions in neuroimmunology and sheds new light on the aetiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction.
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http://dx.doi.org/10.1038/nature14432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4506234PMC
July 2015

Fractalkine is a "find-me" signal released by neurons undergoing ethanol-induced apoptosis.

Front Cell Neurosci 2014 7;8:360. Epub 2014 Nov 7.

Department of Pathology, School of Medicine, University of Virginia Charlottesville, VA, USA ; Center for Cell Clearance, University of Virginia Charlottesville, VA, USA.

Apoptotic neurons generated during normal brain development or secondary to pathologic insults are efficiently cleared from the central nervous system. Several soluble factors, including nucleotides, cytokines, and chemokines are released from injured neurons, signaling microglia to find and clear debris. One such chemokine that serves as a neuronal-microglial communication factor is fractalkine, with roles demonstrated in several models of adult neurological disorders. Lacking, however, are studies investigating roles for fractalkine in perinatal brain injury, an important clinical problem with no effective therapies. We used a well-characterized mouse model of ethanol-induced apoptosis to assess the role of fractalkine in neuronal-microglial signaling. Quantification of apoptotic debris in fractalkine-knockout (KO) and CX3CR1-KO mice following ethanol treatment revealed increased apoptotic bodies compared to wild type mice. Ethanol-induced injury led to release of soluble, extracellular fractalkine. The extracellular media harvested from apoptotic brains induces microglial migration in a fractalkine-dependent manner that is prevented by neutralization of fractalkine with a blocking antibody or by deficiency in the receptor, CX3CR1. This suggests fractalkine acts as a "find-me" signal, recruiting microglial processes toward apoptotic cells to promote their clearance. Next, we aimed to determine whether there are downstream alterations in cytokine gene expression due to fractalkine signaling. We examined mRNA expression in fractalkine-KO and CX3CR1-KO mice after alcohol-induced apoptosis and found differences in cytokine production in the brains of these KOs by 6 h after ethanol treatment. Collectively, this suggests that fractalkine acts as a "find me" signal released by apoptotic neurons, and subsequently plays a critical role in modulating both clearance and inflammatory cytokine gene expression after ethanol-induced apoptosis.
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http://dx.doi.org/10.3389/fncel.2014.00360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4224129PMC
November 2014

Histiocytic sarcoma of the cavernous sinus: case report and literature review.

Brain Tumor Pathol 2015 Jan 8;32(1):66-71. Epub 2014 May 8.

Department of Neurological Surgery, University of Virginia Health System, Charlottesville, VA, USA,

Histiocytic sarcoma is a rare malignant neoplasm of hematopoietic origin composed of cells showing morphologic and immunophenotypic evidence of histiocytic differentiation. We describe the 2nd case of primary histiocytic sarcoma of the cavernous sinus/Meckel's cave, and the 8th case involving the CNS. A 61-year-old Caucasian man presented with numbness on the entire left side of his face, shooting pain in the left frontal region, and headaches. Imaging revealed an enhancing extra axial soft tissue mass located in the left cavernous sinus and left Meckel's cave. Diagnosis was established through open biopsy, after failed attempts via CT-guided trans-foramen ovale fine-needle aspiration biopsy and keyhole biopsy. The tumor was composed of large non-cohesive epithelioid cells invading nerves and ganglion cells. Tumor cells were immunopositive for CD68, CD163, and immunonegative for the anaplastic large cell lymphoma marker ALK-1 as well as other lymphoid, myeloid, and dendritic cell markers. Histiocytic sarcoma has strong potential for systemic spread; early diagnosis and treatment are important. Our patient was initially treated with radiation therapy but subsequently developed metastases.
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http://dx.doi.org/10.1007/s10014-014-0191-3DOI Listing
January 2015

Caspase-mediated cleavage of actin and tubulin is a common feature and sensitive marker of axonal degeneration in neural development and injury.

Acta Neuropathol Commun 2014 Feb 7;2:16. Epub 2014 Feb 7.

Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.

Background: Axon degeneration is a characteristic feature of multiple neuropathologic states and is also a mechanism of physiological neurodevelopmental pruning. The vast majority of in vivo studies looking at axon degeneration have relied on the use of classical silver degeneration stains, which have many limitations including lack of molecular specificity and incompatibility with immunolabeling methods. Because Wallerian degeneration is well known to involve cytoskeletal disassembly and because caspases are recently implicated in aspects of this process, we asked whether antibodies directed at caspase-generated neoepitopes of beta-actin and alpha-tubulin would be useful immunohistochemical markers of pathological and developmental axon degeneration.

Results: Here we demonstrate that several forms of axon degeneration involve caspase-mediated cleavage of these cytoskeletal elements and are well-visualized using this approach. We demonstrate the generation of caspase-induced neoepitopes in a) an in vitro neuronal culture model using nerve growth factor-deprivation-induced degeneration and b) an in vivo model using ethanol-induced neuronal apoptosis, and c) during normal developmental pruning and physiological turnover of neurons.

Conclusions: Our findings support recent experimental data that suggests caspase-3 and caspase-6 have specific non-redundant roles in developmental pruning. Finally, these findings may have clinical utility, as these markers highlight degenerating neurites in human hypoxic-ischemic injury. Our work not only confirms a common downstream mechanism involved in axon degeneration, but also illuminates the potential utility of caspase-cleavage-neoepitope antibodies as markers of neurodegeneration.
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http://dx.doi.org/10.1186/2051-5960-2-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3996144PMC
February 2014

Phosphatidylserine receptor BAI1 and apoptotic cells as new promoters of myoblast fusion.

Nature 2013 May 24;497(7448):263-7. Epub 2013 Apr 24.

Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia 22908, USA.

Skeletal muscle arises from the fusion of precursor myoblasts into multinucleated myofibres. Although conserved transcription factors and signalling proteins involved in myogenesis have been identified, upstream regulators are less well understood. Here we report an unexpected discovery that the membrane protein BAI1, previously linked to recognition of apoptotic cells by phagocytes, promotes myoblast fusion. Endogenous BAI1 expression increased during myoblast fusion, and BAI1 overexpression enhanced myoblast fusion by means of signalling through ELMO/Dock180/Rac1 proteins. During myoblast fusion, a fraction of myoblasts within the population underwent apoptosis and exposed phosphatidylserine, an established ligand for BAI1 (ref. 3). Blocking apoptosis potently impaired myoblast fusion, and adding back apoptotic myoblasts restored fusion. Furthermore, primary human myoblasts could be induced to form myotubes by adding apoptotic myoblasts, even under normal growth conditions. Mechanistically, apoptotic cells did not directly fuse with the healthy myoblasts, rather the apoptotic cells induced a contact-dependent signalling with neighbours to promote fusion among the healthy myoblasts. In vivo, myofibres from Bai1(-/-) mice are smaller than those from wild-type littermates. Muscle regeneration after injury was also impaired in Bai1(-/-)mice, highlighting a role for BAI1 in mammalian myogenesis. Collectively, these data identify apoptotic cells as a new type of cue that induces signalling via the phosphatidylserine receptor BAI1 to promote fusion of healthy myoblasts, with important implications for muscle development and repair.
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http://dx.doi.org/10.1038/nature12135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3773542PMC
May 2013

A rare intraosseous arteriovenous malformation of the spine.

J Neurosurg Spine 2011 Sep 10;15(3):336-9. Epub 2011 Jun 10.

Department of Neurological Surgery, University of Virginia Health System, Charlottesville, Virginia 22903, USA.

The authors report the case of a patient with an intraosseous spinal arteriovenous malformation (AVM) presenting as an epidural mass lesion that was causing spinal cord compression. The 59-year-old woman had bilateral numbness, weakness, and hyperreflexia of both legs. Magnetic resonance imaging revealed intermediate T1 signal and hyperintense T2 signal involving the right transverse process, bilateral pedicles, and T-5 spinous process; the lesion's epidural extension was causing severe canal compromise and cord displacement. Coil embolization was performed, and the patient underwent resection, after which preoperative symptoms improved. Histopathological analysis revealed a benign vascular proliferation consistent with an intraosseous spinal AVM. On review of the literature, the authors found this case to be the second intraosseous spinal AVM, and the first in a patient whose clinical presentation was consistent with that of a mass lesion of the bone.
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http://dx.doi.org/10.3171/2011.5.SPINE10872DOI Listing
September 2011

Phagocytic clearance in neurodegeneration.

Am J Pathol 2011 Apr;178(4):1416-28

Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.

The cellular and molecular mechanisms of phagocytic clearance of apoptotic cells and debris have been intensely studied in invertebrate model organisms and in the mammalian immune system. This evolutionarily conserved process serves multiple purposes. Uncleared debris from dying cells or aggregated proteins can be toxic and may trigger exaggerated inflammatory responses. Even though apoptotic cell death and debris accumulation are key features of neurodegenerative diseases, relatively little attention has been paid to this important homeostatic function in the central nervous system (CNS). This review attempts to summarize our knowledge of phagocytic clearance in the CNS, with a focus on retinal degeneration, forms of which are caused by mutations in genes within known phagocytic pathways, and on Alzheimer's disease (AD). Interest in phagocytic clearance mechanisms in AD was stimulated by the discovery that immunization could promote phagocytic clearance of amyloid-β; however, much less is known about clearance of neuronal and synaptic corpses in AD and other neurodegenerative diseases. Because the regulation of phagocytic activity is intertwined with cytokine signaling, this review also addresses the relationships among CNS inflammation, glial responses, and phagocytic clearance.
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http://dx.doi.org/10.1016/j.ajpath.2010.12.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3078427PMC
April 2011

Brain-specific angiogenesis inhibitor-1 expression in astrocytes and neurons: implications for its dual function as an apoptotic engulfment receptor.

Brain Behav Immun 2011 Jul 1;25(5):915-21. Epub 2010 Oct 1.

Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.

Brain-specific angiogenesis inhibitor-1 (BAI1) is a transmembrane protein highly expressed in normal brain that has been ascribed two apparently distinct functions: inhibition of angiogenesis and recognition and engulfment of apoptotic cells by phagocytes. A previous localization study reported BAI1 expression only in neurons. Because a phagocytic function of BAI1 could be important for neuroglial antigen processing and presentation, we performed immunolocalization studies in adult mouse brain and cultured neural cells, using a pair of antibodies directed against N- and C-terminal epitopes. BAI1 immunoreactivity is enriched in gray matter structures and largely excluded from myelinated axon tracts. Neuronal BAI1 expression was readily detectable in the cerebellar molecular layer as well as in primary hippocampal cultures. In some brain regions, especially olfactory bulb glomeruli, BAI1 was expressed by GFAP-positive astrocytes. Cultured cortical astrocytes show small (∼0.4μm(2)) BAI1 immunoreactive membrane puncta as well as prominent focal adhesion localization in a subset of cells. In mixed neuronal-glial cultures, BAI1-expressing astrocytes frequently contained engulfed apoptotic debris. Cultured astrocytes engulfed apoptotic targets, and BAI1 showed accumulation within the phagocytic cup. We hypothesize that glial BAI1 may subserve an engulfment function in adult brain regions such as olfactory bulb with ongoing apoptotic turnover, whereas neuronal-derived BAI1 may serve primarily as an anti-angiogenic factor in the mature neuropil.
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http://dx.doi.org/10.1016/j.bbi.2010.09.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3033447PMC
July 2011

WT1 is not a reliable marker to distinguish reactive from neoplastic astrocyte populations in the central nervous system.

Brain Pathol 2010 Nov 22;20(6):1090-5. Epub 2010 Jun 22.

Department of Pathology (Neuropathology), University of Virginia School of Medicine, Charlottesville, VA 22908, USA.

A diagnostic difficulty in neuropathology practice is distinguishing reactive from neoplastic astrocyte populations. This is particularly true in small biopsy samples that lack evidence of increased cellularity or mitotic activity, microvascular proliferation, or necrosis. We performed the current study to validate the previously reported finding that in the central nervous system, the expression of WT1 is limited to neoplastic astrocytes. We retrospectively studied WT1 protein expression by immunohistochemistry (IHC) in 100 formalin-fixed, paraffin-embedded brain tissue samples consisting of 3 normal control tissues, 44 cases of reactive gliosis, 49 gliomas and 4 lesions suspicious for glioma. In normal human cortex, WT1 staining was restricted to vascular endothelium. Most cases of reactive gliosis (82%) showed at least focal WT1 positivity, and analysis of specimens with electrode monitoring lesions showed an inverse relationship between WT1 expression intensity and the number of days from electrode placement to tissue resection. All glioma samples (100%) and all cases suspicious for glioma (100%) showed at least focal WT1 positivity. Our results likely differ from those in the prior report because of differences in tissue fixation and IHC methodology. Thus, our findings indicate that WT1 expression alone is not a reliable feature to distinguish reactive from neoplastic astrocytes.
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http://dx.doi.org/10.1111/j.1750-3639.2010.00415.xDOI Listing
November 2010

Serotonergic dystrophy induced by excess serotonin.

Mol Cell Neurosci 2010 Jul 13;44(3):297-306. Epub 2010 Apr 13.

Neuroscience Graduate Program, University of Virginia, Charlottesville, VA 22908, USA.

Administration of certain serotonin-releasing amphetamine derivatives (fenfluramine and/or 3,4-methylenedioxymethamphetamine, MDMA, 'ecstasy') results in dystrophic serotonergic morphology in the mammalian brain. In addition to drug administration, dystrophic serotonergic neurites are also associated with neurodegenerative disorders. We demonstrate here that endogenously elevated serotonin in the Drosophila CNS induces aberrant enlarged varicosities, or spheroids, that are morphologically similar to dystrophic mammalian serotonergic fibers. In Drosophila these spheroids are specific to serotonergic neurons, distinct from typical varicosities, and form only after prolonged increases in cytoplasmic serotonin. Our results also suggest that serotonin levels during early development determine later sensitivity of spheroid formation to manipulations of the serotonin transporter (SERT). Elevated serotonin also interacts with canonical protein aggregation and autophagic pathways to form spheroids. The data presented here support a model in which excess cytoplasmic neurotransmitter triggers a cell-specific pathway inducing aberrant morphology in fly serotonergic neurons that may be shared in certain mammalian pathologies.
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http://dx.doi.org/10.1016/j.mcn.2010.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2878889PMC
July 2010

Intracranial plasmacytoma with apoplectic presentation and spontaneous intracerebral hemorrhage: Case report and review of the literature.

Clin Neurol Neurosurg 2010 Feb 23;112(2):172-5. Epub 2009 Dec 23.

Department of Neurological Surgery, University of Virginia School of Medicine, Charlottesville, 22908, United States.

Involvement of the nervous system is not uncommon in patients with multiple myeloma, with polyneuropathy and myelopathy predominating. Intracranial involvement producing neurological symptoms, however, is distinctly uncommon. Massive intraparenchymal hemorrhage from a previously unrecognized intracranial plasmacytoma is exceedingly rare. The authors report the case of a 57-year-old male who presented with sudden onset of severe headache, rapid onset of right-sided weakness and deterioration in level of consciousness while at work. Two years earlier the patient had completed treatment for multiple myeloma and was considered to be in remission, with a recent bone marrow biopsy that was negative, and complete normalization of serum protein electrophoresis. Imaging studies revealed a massive intracerebral hemorrhage with the possibility of an underlying lesion, and the patient was taken for emergent hematoma evacuation and tumor resection. The patient made an excellent recovery and was treated with intracranial radiation. Even in patients with multiple myeloma without evidence of systemic disease following successful treatment, the possibility of unrecognized lesions lingers. The onset of new symptoms referable to potential intracranial pathology in this setting should prompt consideration of intracranial plasmacytoma in the differential diagnosis.
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http://dx.doi.org/10.1016/j.clineuro.2009.11.003DOI Listing
February 2010

Brain-specific deletion of extracellular signal-regulated kinase 2 mitogen-activated protein kinase leads to aberrant cortical collagen deposition.

Am J Pathol 2009 Dec 5;175(6):2586-99. Epub 2009 Nov 5.

Department of Pathology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.

The mitogen-activated protein kinases extracellular signal-regulated kinase (ERK)1 and 2 are essential intracellular mediators of numerous transmembrane signals. To investigate neural-specific functions of ERK2 in the brain, we used a Cre/lox strategy using Nestin:Cre to drive recombination in neural precursor cells. Nestin:Cre;ERK2(fl/fl) conditional knockout (cKO) mice have architecturally normal brains and no gross behavioral deficits. However, all cKO mice developed early-onset (postnatal day 35 to 40) frontal cortical astrogliosis, without evidence of neuronal degeneration. Frontoparietal cortical gray matter, but not underlying white matter, was found to contain abundant pericapillary and parenchymal reticulin fibrils, which were shown by immunohistochemistry to contain fibrillar collagens, including type I collagen. ERK1 general KO mice showed neither fibrils nor astrogliosis, indicating a specific role for ERK2 in the regulation of brain collagen. Collagen fibrils were also observed to a lesser extent in GFAP:Cre;ERK2(fl/fl) mice but not in CamKII-Cre;ERK2(fl/fl) mice (pyramidal neuron specific), consistent with a possible astroglial origin. Primary astroglial cultures from cKO mice expressed elevated fibrillar collagen levels, providing further evidence that the phenotype may be cell autonomous for astroglia. Unlike most other tissues, brain and spinal cord parenchyma do not normally contain fibrillar collagens, except in disease states. Determining mechanisms of ERK2-mediated collagen regulation may enable targeted suppression of glial scar formation in diverse neurological disorders.
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http://dx.doi.org/10.2353/ajpath.2009.090130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2789603PMC
December 2009

Dephosphorylation of beta-arrestin 1 in glioblastomas.

J Neuropathol Exp Neurol 2009 May;68(5):535-41

Department of Pathology, University of Virginia Health System, Charlottesville, VA 22903, USA.

Beta-Arrestins act as signal terminators for G protein-coupled receptors; they have also been implicated as scaffolding proteins for Src and mitogen-activated protein kinase signaling pathways and transactivators of receptor tyrosine kinases, suggesting their possible role in development and oncogenic signaling. Dephosphorylation of serine 412 is necessary for Src and mitogen-activated protein kinase transactivation. We hypothesized that altered beta-arrestin 1 phosphorylation and activation status could play a role in gliomagenesis. Using monoclonal anti-phospho-(serine 412)- and total beta-arrestin 1 antibodies, we performed immunohistochemistry on 126 human glioma samples and 7 nonneoplastic controls and Western blot analysis on 5 glioblastomas and 5 nonneoplastic controls. We found high constitutive beta-arrestin 1 phosphorylation in nonneoplastic brain tissue, particularly in neurons and neuropil. Most Grade II and III gliomas retained high beta-arrestin 1 phosphorylation. By contrast, most of the glioblastoma samples (58/81) showed nearly complete beta-arrestin 1 dephosphorylation by immunohistochemistry and decreased relative phosphorylation by Western blot. Expression of constitutively activated epidermal growth factor receptor vIII in U251 cells caused decreased beta-arrestin 1 phosphorylation without altering total beta-arrestin 1 levels. These results suggest that beta-arrestin 1 dephosphorylation/inactivation is associated with aspects of the malignant behavior of glioblastomas.
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http://dx.doi.org/10.1097/NEN.0b013e3181a2b8F4-9DOI Listing
May 2009