37 results on '"Theil D"'
Search Results
2. Mid-Infrared Imaging Polarimetry of NGC 7027
- Author
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Jurgenson, C. A., primary, Stencel, R. E., additional, Theil, D. S., additional, Klebe, D. I., additional, and Ueta, T., additional
- Published
- 2002
- Full Text
- View/download PDF
3. A low-IF RX two-point ΣΔ-modulation TX CMOS single-chip Bluetooth solution
- Author
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Durdodt, C., primary, Friedrich, M., additional, Grewing, C., additional, Hammes, M., additional, Hanke, A., additional, Heinen, S., additional, Oehm, J., additional, Pham-Stabner, D., additional, Seippel, D., additional, Theil, D., additional, Van Waasen, S., additional, and Wagner, E., additional
- Published
- 2001
- Full Text
- View/download PDF
4. THE EFFECT OF PHENOXYBENZAMINE ON VA/Q DISTRIBUTION DURING HYPOXIA
- Author
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Moon, R E., primary, Stauffer, J. L., additional, Theil, D. R., additional, Miyazawa, N., additional, Camporesi, E. M., additional, and Swanson, C. R., additional
- Published
- 1988
- Full Text
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5. ACUTE EFFECTS OF IV ACETAZOLAMIDE ON HYPOXIC AND HYPERCAPNIC VENTILATORY RESPONSES
- Author
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Theil, D. R., primary, Afifi, M. S., additional, Moon, R. E., additional, and Camporesi, E. M., additional
- Published
- 1989
- Full Text
- View/download PDF
6. VA/Q MISMATCHING BY MULTIPLE INERT GAS TECHNIQUE
- Author
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Inge, W., primary, Theil, D., additional, Fracica, P. J., additional, Exposilo, A., additional, Wong, A., additional, and Moon, R. E., additional
- Published
- 1989
- Full Text
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7. THE ROLE OF THROMBOXANE IN THE ACUTE LUNG INJURY INDUCED BY MICROBUBBLE INFUSION
- Author
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Miyazawa, N., primary, Theil, D. R., additional, Su, Y. F., additional, Malo, P. E., additional, Camporesi, E. M., additional, Watkins, W. D., additional, and Moon, R. E, additional
- Published
- 1988
- Full Text
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8. Neurofilament Light Chain: A Translational Safety Biomarker for Drug-Induced Peripheral Neurotoxicity.
- Author
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Theil D, Kuhle J, Brees D, Tritto E, Pognan F, Frieauff W, Penraat K, Meseck E, Valdez R, and Hartmann A
- Subjects
- Animals, Dogs, Pyridoxine, Biomarkers, Nerve Degeneration, Intermediate Filaments, Neurotoxicity Syndromes etiology
- Abstract
Branaplam is a splicing modulator previously under development as a therapeutic agent for Spinal Muscular Atrophy Type 1 and Huntington's disease. Branaplam increased the levels of survival motor neuron protein in preclinical studies and was well tolerated in early clinical studies; however, peripheral neurotoxicity was observed in a preclinical safety study in juvenile dogs. The aim of this study was to determine whether serum neurofilament light chain (NfL) concentrations in dogs could serve as a monitoring biomarker for branaplam-induced peripheral neurotoxicity. A 30-week time-course investigative study in dogs treated with vehicle control (negative control), neurotoxic pyridoxine (positive control), or branaplam was conducted to assess neuropathology, nerve morphometry, electrophysiological measurements, gene expression profiles, and correlation to NfL serum concentrations. In branaplam-treated animals, a mild to moderate nerve fiber degeneration was observed in peripheral nerves correlating with increased serum NfL concentrations, but there were no observed signs or changes in electrophysiological parameters. Dogs with pyridoxine-induced peripheral axonal degeneration displayed clinical signs and electrophysiological changes in addition to elevated serum NfL. This study suggests that NfL may be useful as an exploratory biomarker to assist in detecting and monitoring treatment-related peripheral nerve injury, with or without clinical signs, associated with administration of branaplam and other compounds bearing a neurotoxic risk.
- Published
- 2023
- Full Text
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9. An orally available, brain penetrant, small molecule lowers huntingtin levels by enhancing pseudoexon inclusion.
- Author
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Keller CG, Shin Y, Monteys AM, Renaud N, Beibel M, Teider N, Peters T, Faller T, St-Cyr S, Knehr J, Roma G, Reyes A, Hild M, Lukashev D, Theil D, Dales N, Cha JH, Borowsky B, Dolmetsch R, Davidson BL, and Sivasankaran R
- Subjects
- Animals, Brain metabolism, Disease Models, Animal, Humans, Huntingtin Protein genetics, Huntingtin Protein metabolism, Mice, Oligonucleotides, Antisense metabolism, Trinucleotide Repeat Expansion, Huntington Disease drug therapy, Huntington Disease genetics, Huntington Disease metabolism
- Abstract
Huntington's Disease (HD) is a progressive neurodegenerative disorder caused by CAG trinucleotide repeat expansions in exon 1 of the huntingtin (HTT) gene. The mutant HTT (mHTT) protein causes neuronal dysfunction, causing progressive motor, cognitive and behavioral abnormalities. Current treatments for HD only alleviate symptoms, but cerebral spinal fluid (CSF) or central nervous system (CNS) delivery of antisense oligonucleotides (ASOs) or virus vectors expressing RNA-induced silencing (RNAi) moieties designed to induce mHTT mRNA lowering have progressed to clinical trials. Here, we present an alternative disease modifying therapy the orally available, brain penetrant small molecule branaplam. By promoting inclusion of a pseudoexon in the primary transcript, branaplam lowers mHTT protein levels in HD patient cells, in an HD mouse model and in blood samples from Spinal Muscular Atrophy (SMA) Type I patients dosed orally for SMA (NCT02268552). Our work paves the way for evaluating branaplam's utility as an HD therapy, leveraging small molecule splicing modulators to reduce expression of dominant disease genes by driving pseudoexon inclusion., (© 2022. The Author(s).)
- Published
- 2022
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10. Orally administered branaplam does not impact neurogenesis in juvenile mice, rats, and dogs.
- Author
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Theil D, Valdez R, Darribat K, Doelemeyer A, Sivasankaran R, and Hartmann A
- Subjects
- Administration, Oral, Animals, Apoptosis drug effects, Brain drug effects, Cell Proliferation drug effects, Cerebellum drug effects, Disease Models, Animal, Dogs, Drug Evaluation, Preclinical, Mice, Neurons drug effects, RNA Splicing drug effects, Rats, Rats, Wistar, Survival of Motor Neuron 2 Protein drug effects, Neurogenesis drug effects, Pyridazines pharmacology
- Abstract
Branaplam is a therapeutic agent currently in clinical development for the treatment of infants with type 1 spinal muscular atrophy (SMA). Since preclinical studies showed that branaplam had cell-cycle arrest effects, we sought to determine whether branaplam may affect postnatal cerebellar development and brain neurogenesis. Here, we describe a novel approach for developmental neurotoxicity testing (DNT) of a central nervous system (CNS) active drug. The effects of orally administered branaplam were evaluated in the SMA neonatal mouse model (SMNΔ7), and in juvenile Wistar Hannover rats and Beagle dogs. Histopathological examination and complementary immunohistochemical studies focused on areas of neurogenesis in the cerebellum (mice, rats, and dogs), and the subventricular zone of the striatum and dentate gyrus (rats and dogs) using antibodies directed against Ki67, phosphorylated histone H3, cleaved caspase-3, and glial fibrillary acidic protein. Additionally, image-analysis based quantification of calbindin-D28k and Ki67 was performed in rats and dogs. The patterns of cell proliferation and apoptosis, and neural migration and innervation in the cerebellum and other brain regions of active adult neurogenesis did not differ between branaplam- and control-treated animals. Quantitative image analysis did not reveal any changes in calbindin-D28k and Ki67 expression in rats and dogs. The data show that orally administered branaplam has no impact on neurogenesis in juvenile animals. Application of selected immunohistochemical stainings in combination with quantitative image analysis on a few critical areas of postnatal CNS development offer a reliable approach to assess DNT of CNS-active drug candidates in juvenile animal toxicity studies., Competing Interests: Competing interests D.T., K.D., A.D., R.S., A.H. are current employees of Novartis. R.V. is a former employee of Novartis. R.V. declares no competing interests., (© 2021. Published by The Company of Biologists Ltd.)
- Published
- 2021
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11. Recent Advances and the Potential for Clinical Use of Autofluorescence Detection of Extra-Ophthalmic Tissues.
- Author
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Wizenty J, Schumann T, Theil D, Stockmann M, Pratschke J, Tacke F, Aigner F, and Wuensch T
- Subjects
- Clinical Decision-Making, Disease Management, Humans, Optical Imaging standards, Optical Imaging trends, Diagnostic Techniques and Procedures, Optical Imaging methods
- Abstract
The autofluorescence (AF) characteristics of endogenous fluorophores allow the label-free assessment and visualization of cells and tissues of the human body. While AF imaging (AFI) is well-established in ophthalmology, its clinical applications are steadily expanding to other disciplines. This review summarizes clinical advances of AF techniques published during the past decade. A systematic search of the MEDLINE database and Cochrane Library databases was performed to identify clinical AF studies in extra-ophthalmic tissues. In total, 1097 articles were identified, of which 113 from internal medicine, surgery, oral medicine, and dermatology were reviewed. While comparable technological standards exist in diabetology and cardiology, in all other disciplines, comparability between studies is limited due to the number of differing AF techniques and non-standardized imaging and data analysis. Clear evidence was found for skin AF as a surrogate for blood glucose homeostasis or cardiovascular risk grading. In thyroid surgery, foremost, less experienced surgeons may benefit from the AF-guided intraoperative separation of parathyroid from thyroid tissue. There is a growing interest in AF techniques in clinical disciplines, and promising advances have been made during the past decade. However, further research and development are mandatory to overcome the existing limitations and to maximize the clinical benefits.
- Published
- 2020
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12. Imaging Mass Cytometry and Single-Cell Genomics Reveal Differential Depletion and Repletion of B-Cell Populations Following Ofatumumab Treatment in Cynomolgus Monkeys.
- Author
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Theil D, Smith P, Huck C, Gilbart Y, Kakarieka A, Leppert D, Rauld C, Schmid C, Baumgartner R, Stuber N, Cordoba F, Dubost V, Darribat K, Jivkov M, Frieauff W, Kneuer R, Stoeckli M, Reinker S, Mansfield K, Carballido JM, Couttet P, and Weckbecker G
- Subjects
- Animals, Gene Expression Profiling, In Situ Hybridization, Macaca fascicularis, Antibodies, Monoclonal, Humanized pharmacology, B-Lymphocytes cytology, B-Lymphocytes immunology, Genomics, Lymph Nodes cytology, Lymph Nodes immunology, Lymphocyte Depletion, Mass Spectrometry, Single-Cell Analysis
- Abstract
Ofatumumab is the first, fully human, anti-CD20 monoclonal antibody in Phase 3 development for multiple sclerosis (MS). The study focused on changes in lymphocyte subsets in blood and lymphoid tissues and on potential novel biomarkers as a result of anti-CD20 antibody action in Cynomolgus monkeys treated with human equivalent doses of subcutaneous (s.c.) ofatumumab on Days 0, 7, and 14. Axillary lymph nodes (LNs) and blood samples were collected at various time points until Day 90. Lymphocyte subsets were quantified by flow cytometry, while morphological and immune cell changes were assessed by imaging mass cytometry (IMC), immunohistochemistry (IHC), in situ hybridization (ISH), and transcriptome analyses using single-cell methodology. Ofatumumab treatment resulted in a potent and rapid reduction of B cells along with a simultaneous drop in CD20
+ T cell counts. At Day 21, IHC revealed B-cell depletion in the perifollicular and interfollicular area of axillary LNs, while only the core of the germinal center was depleted of CD20+ CD21+ cells. By Day 62, the perifollicular and interfollicular areas were abundantly infiltrated by CD21+ B cells and this distribution returned to the baseline cytoarchitecture by Day 90. By IMC CD20+ CD3+ CD8+ cells could be identified at the margin of the follicles, with a similar pattern of distribution at Day 21 and 90. Single-cell transcriptomics analysis showed that ofatumumab induced reversible changes in t-distributed stochastic neighbor embedding (t-SNE) defined B-cell subsets that may serve as biomarkers for drug action. In summary, low dose s.c. ofatumumab potently depletes both B cells and CD20+ T cells but apparently spares marginal zone (MZ) B cells in the spleen and LN. These findings add to our molecular and tissue-architectural understanding of ofatumumab treatment effects on B-cell subsets.- Published
- 2019
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13. Retinoic-acid-orphan-receptor-C inhibition suppresses Th17 cells and induces thymic aberrations.
- Author
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Guntermann C, Piaia A, Hamel ML, Theil D, Rubic-Schneider T, Del Rio-Espinola A, Dong L, Billich A, Kaupmann K, Dawson J, Hoegenauer K, Orain D, Hintermann S, Stringer R, Patel DD, Doelemeyer A, Deurinck M, and Schümann J
- Subjects
- Animals, Down-Regulation, Female, Gene Expression, Humans, Jurkat Cells, Male, Mice, Mice, Inbred C57BL, Rats, Rats, Inbred Lew, Rats, Sprague-Dawley, Receptors, Retinoic Acid genetics, Th17 Cells metabolism, Receptors, Retinoic Acid antagonists & inhibitors, Th17 Cells cytology, Thymus Gland pathology
- Abstract
Retinoic-acid-orphan-receptor-C (RORC) is a master regulator of Th17 cells, which are pathogenic in several autoimmune diseases. Genetic Rorc deficiency in mice, while preventing autoimmunity, causes early lethality due to metastatic thymic T cell lymphomas. We sought to determine whether pharmacological RORC inhibition could be an effective and safe therapy for autoimmune diseases by evaluating its effects on Th17 cell functions and intrathymic T cell development. RORC inhibitors effectively inhibited Th17 differentiation and IL-17A production, and delayed-type hypersensitivity reactions. In vitro, RORC inhibitors induced apoptosis, as well as Bcl2l1 and BCL2L1 mRNA downregulation, in mouse and nonhuman primate thymocytes, respectively. Chronic, 13-week RORC inhibitor treatment in rats caused progressive thymic alterations in all analyzed rats similar to those in Rorc -deficient mice prior to T cell lymphoma development. One rat developed thymic cortical hyperplasia with preneoplastic features, including increased mitosis and reduced IKAROS expression, albeit without skewed T cell clonality. In summary, pharmacological inhibition of RORC not only blocks Th17 cell development and related cytokine production, but also recapitulates thymic aberrations seen in Rorc -deficient mice. While RORC inhibition may offer an effective therapeutic principle for Th17-mediated diseases, T cell lymphoma with chronic therapy remains an apparent risk., Competing Interests: Conflict of interest: MLH works for CiToxLAB performing studies by order of Novartis. ADRE works for Novartis. All other authors work for and own shares or options of Novartis.
- Published
- 2017
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14. Pharmacological BACE1 and BACE2 inhibition induces hair depigmentation by inhibiting PMEL17 processing in mice.
- Author
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Shimshek DR, Jacobson LH, Kolly C, Zamurovic N, Balavenkatraman KK, Morawiec L, Kreutzer R, Schelle J, Jucker M, Bertschi B, Theil D, Heier A, Bigot K, Beltz K, Machauer R, Brzak I, Perrot L, and Neumann U
- Subjects
- Amyloid Precursor Protein Secretases antagonists & inhibitors, Amyloid Precursor Protein Secretases genetics, Amyloid beta-Peptides metabolism, Animals, Aspartic Acid Endopeptidases antagonists & inhibitors, Aspartic Acid Endopeptidases genetics, Blotting, Western, Cell Line, Tumor, Female, Hair drug effects, Hair pathology, Humans, Male, Melanins metabolism, Melanocytes cytology, Melanocytes metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Microscopy, Fluorescence, Peptide Fragments metabolism, Picolinic Acids pharmacology, Pigmentation drug effects, Prosencephalon metabolism, Prosencephalon pathology, Protease Inhibitors pharmacology, RNA, Messenger metabolism, Real-Time Polymerase Chain Reaction, Thiazines pharmacology, Uvea drug effects, Uvea metabolism, Uvea pathology, gp100 Melanoma Antigen antagonists & inhibitors, Amyloid Precursor Protein Secretases metabolism, Aspartic Acid Endopeptidases metabolism, Hair metabolism, gp100 Melanoma Antigen metabolism
- Abstract
Melanocytes of the hair follicle produce melanin and are essential in determining the differences in hair color. Pigment cell-specific MELanocyte Protein (PMEL17) plays a crucial role in melanogenesis. One of the critical steps is the amyloid-like functional oligomerization of PMEL17. Beta Site APP Cleaving Enzyme-2 (BACE2) and γ-secretase have been shown to be key players in generating the proteolytic fragments of PMEL17. The β-secretase (BACE1) is responsible for the generation of amyloid-β (Aβ) fragments in the brain and is therefore proposed as a therapeutic target for Alzheimer's disease (AD). Currently BACE1 inhibitors, most of which lack selectivity over BACE2, have demonstrated efficacious reduction of amyloid-β peptides in animals and the CSF of humans. BACE2 knock-out mice have a deficiency in PMEL17 proteolytic processing leading to impaired melanin storage and hair depigmentation. Here, we confirm BACE2-mediated inhibition of PMEL17 proteolytic processing in vitro in mouse and human melanocytes. Furthermore, we show that wildtype as well as bace2(+/-) and bace2(-/-) mice treated with a potent dual BACE1/BACE2 inhibitor NB-360 display dose-dependent appearance of irreversibly depigmented hair. Retinal pigmented epithelium showed no morphological changes. Our data demonstrates that BACE2 as well as additional BACE1 inhibition affects melanosome maturation and induces hair depigmentation in mice.
- Published
- 2016
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15. Interferon beta and vitamin D synergize to induce immunoregulatory receptors on peripheral blood monocytes of multiple sclerosis patients.
- Author
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Waschbisch A, Sanderson N, Krumbholz M, Vlad G, Theil D, Schwab S, Mäurer M, and Derfuss T
- Subjects
- Antigen-Presenting Cells drug effects, Antigen-Presenting Cells metabolism, B7 Antigens genetics, B7 Antigens metabolism, Drug Synergism, Humans, Interferon-beta therapeutic use, Membrane Glycoproteins genetics, Multiple Sclerosis cerebrospinal fluid, Multiple Sclerosis drug therapy, Multiple Sclerosis genetics, Receptors, Cell Surface genetics, Receptors, Immunologic genetics, Up-Regulation drug effects, Vitamin D pharmacology, Vitamin D therapeutic use, Interferon-beta pharmacology, Membrane Glycoproteins metabolism, Monocytes drug effects, Monocytes metabolism, Multiple Sclerosis immunology, Receptors, Cell Surface metabolism, Receptors, Immunologic metabolism, Vitamin D analogs & derivatives
- Abstract
Immunoglobulin-like transcript (ILT) 3 and 4 are inhibitory receptors that modulate immune responses. Their expression has been reported to be affected by interferon, offering a possible mechanism by which this cytokine exerts its therapeutic effect in multiple sclerosis, a condition thought to involve excessive immune activity. To investigate this possibility, we measured expression of ILT3 and ILT4 on immune cells from multiple sclerosis patients, and in post-mortem brain tissue. We also studied the ability of interferon beta, alone or in combination with vitamin D, to induce upregulation of these receptors in vitro, and compared expression levels between interferon-treated and untreated multiple sclerosis patients. In vitro interferon beta treatment led to a robust upregulation of ILT3 and ILT4 on monocytes, and dihydroxyvitamin D3 increased expression of ILT3 but not ILT4. ILT3 was abundant in demyelinating lesions in postmortem brain, and expression on monocytes in the cerebrospinal fluid was higher than in peripheral blood, suggesting that the central nervous system milieu induces ILT3, or that ILT3 positive monocytes preferentially enter the brain. Our data are consistent with involvement of ILT3 and ILT4 in the modulation of immune responsiveness in multiple sclerosis by both interferon and vitamin D.
- Published
- 2014
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16. Functional roles of Lgr4 and Lgr5 in embryonic gut, kidney and skin development in mice.
- Author
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Kinzel B, Pikiolek M, Orsini V, Sprunger J, Isken A, Zietzling S, Desplanches M, Dubost V, Breustedt D, Valdez R, Liu D, Theil D, Müller M, Dietrich B, Bouwmeester T, Ruffner H, and Tchorz JS
- Subjects
- Animals, Blotting, Southern, DNA Primers genetics, Gene Components, Genotype, Green Fluorescent Proteins, Immunohistochemistry, Mice, Mice, Inbred BALB C, Mice, Knockout, Polymerase Chain Reaction, Receptors, G-Protein-Coupled genetics, Reverse Transcriptase Polymerase Chain Reaction, Stem Cells physiology, Wnt Signaling Pathway genetics, Intestines embryology, Kidney embryology, Receptors, G-Protein-Coupled physiology, Skin embryology, Wnt Signaling Pathway physiology
- Abstract
Lgr4 and Lgr5 are known markers of adult and embryonic tissue stem cells in various organs. However, whether Lgr4 and Lgr5 are important for embryonic development remains unclear. To study their functions during intestinal crypt, skin and kidney development we now generated mice lacking either Lgr4 (Lgr4KO), Lgr5 (Lgr5KO) or both receptors (Lgr4/5dKO). E16.5 Lgr4KO mice displayed complete loss of Lgr5+/Olfm4+intestinal stem cells, compromised Wnt signaling and impaired proliferation and differentiation of gut epithelium. Similarly, E16.5 Lgr4KO mice showed reduced basal cell proliferation and hair follicle numbers in the developing skin, as well as dilated kidney tubules and ectatic Bowman׳s spaces. Although Lgr4KO and Lgr5KO mice both died perinatally, Lgr5 deletion did not compromise embryonic development of gut, kidney or skin. Concomitant deletion of Lgr4 and Lgr5 did not prevent perinatal lethality, in contrast to a previous report that suggested rescue of Lgr5 KO perinatal lethality by a hypomorphic Lgr4 mutant. While the double deletion did not further promote the phenotypes observed in Lgr4KO intestines, impaired kidney cell proliferation, reduced epidermal thickness, loss of Lgr5+follicular epithelium and impaired hair follicle development were only observed in Lgr4/5dKO mice. This supports complementary functions of both receptors. Our findings clearly establish the importance of Lgr4 and Lgr5 during embryonic gut, skin and kidney development, with a dominant role of Lgr4., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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17. Calcineurin regulates coordinated outgrowth of zebrafish regenerating fins.
- Author
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Kujawski S, Lin W, Kitte F, Börmel M, Fuchs S, Arulmozhivarman G, Vogt S, Theil D, Zhang Y, and Antos CL
- Subjects
- Animal Fins anatomy & histology, Animal Fins metabolism, Animals, Blotting, Western, Immunoenzyme Techniques, Immunosuppressive Agents pharmacology, In Situ Hybridization, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction, Regeneration drug effects, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction drug effects, Tacrolimus pharmacology, Zebrafish anatomy & histology, Zebrafish metabolism, Animal Fins growth & development, Calcineurin metabolism, Regeneration physiology, Tretinoin metabolism, Zebrafish growth & development
- Abstract
Vertebrates develop organs and appendages in a proportionally coordinated manner, and animals that regenerate them do so to the same dimensions as the original structures. Coordinated proportional growth involves controlled regulation between allometric and isometric growth programs, but it is unclear what executes this control. We show that calcineurin inhibition results in continued allometric outgrowth of regenerating fins beyond their original dimensions. Calcineurin inhibition also maintains allometric growth of juvenile fins and induces it in adult fins. Furthermore, calcineurin activity is low when the regeneration rate is highest, and its activity increases as the rate decreases. Growth measurements and morphometric analysis of proximodistal asymmetry indicate that calcineurin inhibition shifts fin regeneration from a distal growth program to a proximal program. This shift is associated with the promotion of retinoic acid signaling. Thus, we identified a calcineurin-mediated mechanism that operates as a molecular switch between position-associated isometric and allometric growth programs., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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18. Characterization of neuronal populations in the human trigeminal ganglion and their association with latent herpes simplex virus-1 infection.
- Author
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Flowerdew SE, Wick D, Himmelein S, Horn AK, Sinicina I, Strupp M, Brandt T, Theil D, and Hüfner K
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- Adult, Aged, Animals, Biomarkers metabolism, Cell Size, Female, Gene Expression Regulation, Herpesvirus 1, Human metabolism, Humans, Male, Middle Aged, Protein Transport, Viral Proteins genetics, Viral Proteins metabolism, Young Adult, Herpesvirus 1, Human physiology, Neurons cytology, Neurons virology, Trigeminal Ganglion cytology
- Abstract
Following primary infection Herpes simplex virus-1 (HSV-1) establishes lifelong latency in the neurons of human sensory ganglia. Upon reactivation HSV-1 can cause neurological diseases such as facial palsy, vestibular neuritis or encephalitis. Certain populations of sensory neurons have been shown to be more susceptible to latent infection in the animal model, but this has not been addressed in human tissue. In the present study, trigeminal ganglion (TG) neurons expressing six neuronal marker proteins were characterized, based on staining with antibodies against the GDNF family ligand receptor Ret, the high-affinity nerve growth factor receptor TrkA, neuronal nitric oxide synthase (nNOS), the antibody RT97 against 200 kDa neurofilament, calcitonin gene-related peptide and peripherin. The frequencies of marker-positive neurons and their average neuronal sizes were assessed, with TrkA-positive (61.82%) neurons being the most abundant, and Ret-positive (26.93%) the least prevalent. Neurons positive with the antibody RT97 (1253 µm(2)) were the largest, and those stained against peripherin (884 µm(2)) were the smallest. Dual immunofluorescence revealed at least a 4.5% overlap for every tested marker combination, with overlap for the combinations TrkA/Ret, TrkA/RT97 and Ret/nNOS lower, and the overlap between Ret/CGRP being higher than would be expected by chance. With respect to latent HSV-1 infection, latency associated transcripts (LAT) were detected using in situ hybridization (ISH) in neurons expressing each of the marker proteins. In contrast to the mouse model, co-localization with neuronal markers Ret or CGRP mirrored the magnitude of these neuron populations, whereas for the other four neuronal markers fewer marker-positive cells were also LAT-ISH+. Ret and CGRP are both known to label neurons related to pain signaling.
- Published
- 2013
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19. Heart structure-specific transcriptomic atlas reveals conserved microRNA-mRNA interactions.
- Author
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Vacchi-Suzzi C, Hahne F, Scheubel P, Marcellin M, Dubost V, Westphal M, Boeglen C, Büchmann-Møller S, Cheung MS, Cordier A, De Benedetto C, Deurinck M, Frei M, Moulin P, Oakeley E, Grenet O, Grevot A, Stull R, Theil D, Moggs JG, Marrer E, and Couttet P
- Subjects
- Animals, Cell Line, Chromosome Mapping methods, Dogs, Female, Heart Valves metabolism, Humans, In Situ Hybridization, Macaca fascicularis, Male, Myocardium pathology, RNA Processing, Post-Transcriptional, Rats, Rats, Wistar, Species Specificity, Gene Expression Regulation, Heart physiology, MicroRNAs metabolism, RNA, Messenger metabolism, Transcriptome
- Abstract
MicroRNAs are short non-coding RNAs that regulate gene expression at the post-transcriptional level and play key roles in heart development and cardiovascular diseases. Here, we have characterized the expression and distribution of microRNAs across eight cardiac structures (left and right ventricles, apex, papillary muscle, septum, left and right atrium and valves) in rat, Beagle dog and cynomolgus monkey using microRNA sequencing. Conserved microRNA signatures enriched in specific heart structures across these species were identified for cardiac valve (miR-let-7c, miR-125b, miR-127, miR-199a-3p, miR-204, miR-320, miR-99b, miR-328 and miR-744) and myocardium (miR-1, miR-133b, miR-133a, miR-208b, miR-30e, miR-499-5p, miR-30e*). The relative abundance of myocardium-enriched (miR-1) and valve-enriched (miR-125b-5p and miR-204) microRNAs was confirmed using in situ hybridization. MicroRNA-mRNA interactions potentially relevant for cardiac functions were explored using anti-correlation expression analysis and microRNA target prediction algorithms. Interactions between miR-1/Timp3, miR-125b/Rbm24, miR-204/Tgfbr2 and miR-208b/Csnk2a2 were identified and experimentally investigated in human pulmonary smooth muscle cells and luciferase reporter assays. In conclusion, we have generated a high-resolution heart structure-specific mRNA/microRNA expression atlas for three mammalian species that provides a novel resource for investigating novel microRNA regulatory circuits involved in cardiac molecular physiopathology.
- Published
- 2013
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20. Contextual social cognition impairments in schizophrenia and bipolar disorder.
- Author
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Baez S, Herrera E, Villarin L, Theil D, Gonzalez-Gadea ML, Gomez P, Mosquera M, Huepe D, Strejilevich S, Vigliecca NS, Matthäus F, Decety J, Manes F, and Ibañez AM
- Subjects
- Adult, Female, Humans, Male, Task Performance and Analysis, Bipolar Disorder physiopathology, Bipolar Disorder psychology, Cognition Disorders physiopathology, Cognition Disorders psychology, Empathy, Schizophrenia physiopathology, Social Behavior Disorders physiopathology, Social Behavior Disorders psychology
- Abstract
Background: The ability to integrate contextual information with social cues to generate social meaning is a key aspect of social cognition. It is widely accepted that patients with schizophrenia and bipolar disorders have deficits in social cognition; however, previous studies on these disorders did not use tasks that replicate everyday situations., Methodology/principal Findings: This study evaluates the performance of patients with schizophrenia and bipolar disorders on social cognition tasks (emotional processing, empathy, and social norms knowledge) that incorporate different levels of contextual dependence and involvement of real-life scenarios. Furthermore, we explored the association between social cognition measures, clinical symptoms and executive functions. Using a logistic regression analysis, we explored whether the involvement of more basic skills in emotional processing predicted performance on empathy tasks. The results showed that both patient groups exhibited deficits in social cognition tasks with greater context sensitivity and involvement of real-life scenarios. These deficits were more severe in schizophrenic than in bipolar patients. Patients did not differ from controls in tasks involving explicit knowledge. Moreover, schizophrenic patients' depression levels were negatively correlated with performance on empathy tasks., Conclusions/significance: Overall performance on emotion recognition predicted performance on intentionality attribution during the more ambiguous situations of the empathy task. These results suggest that social cognition deficits could be related to a general impairment in the capacity to implicitly integrate contextual cues. Important implications for the assessment and treatment of individuals with schizophrenia and bipolar disorders, as well as for neurocognitive models of these pathologies are discussed.
- Published
- 2013
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21. Clonal expansions of CD8⁺ T cells in latently HSV-1-infected human trigeminal ganglia.
- Author
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Held K, Eiglmeier I, Himmelein S, Sinicina I, Brandt T, Theil D, Dornmair K, and Derfuss T
- Subjects
- Adolescent, Adult, Aged, Amino Acid Sequence, Autopsy, CD8-Positive T-Lymphocytes immunology, Cell Movement immunology, Cell Proliferation, Clone Cells immunology, Clone Cells virology, Complementarity Determining Regions genetics, Complementarity Determining Regions immunology, Female, Herpes Simplex immunology, Humans, Immunophenotyping, Male, Middle Aged, Molecular Sequence Data, Receptors, Antigen, T-Cell, alpha-beta biosynthesis, Receptors, Antigen, T-Cell, alpha-beta immunology, Trigeminal Ganglion immunology, CD8-Positive T-Lymphocytes virology, Herpes Simplex virology, Herpesvirus 1, Human physiology, Trigeminal Ganglion virology, Virus Latency immunology
- Abstract
Herpes simplex virus type 1 latency in trigeminal ganglia (TG) is accompanied by a chronic immune cell infiltration. The aim of this study was to analyse the T-cell receptor β-chain repertoire in latently HSV-1 infected human TG. Using complementarity-determining region 3 spectratyping, 74 expanded β-chain sequences were identified in five TG. No clone appeared in more than one subject. Similar clones were present in the right and the left TG of two subjects. This indicates that these T cells are primed in the periphery and recognise the same antigen in the TG of both sides.
- Published
- 2012
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22. HSV-1 genome subnuclear positioning and associations with host-cell PML-NBs and centromeres regulate LAT locus transcription during latency in neurons.
- Author
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Catez F, Picard C, Held K, Gross S, Rousseau A, Theil D, Sawtell N, Labetoulle M, and Lomonte P
- Subjects
- Animals, Carrier Proteins genetics, Carrier Proteins metabolism, Cells, Cultured, Centromere genetics, Co-Repressor Proteins, DNA Helicases genetics, DNA Helicases metabolism, Gene Expression Regulation, Viral physiology, Herpes Simplex genetics, Humans, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins metabolism, Mice, Mice, Inbred BALB C, Mice, Knockout, Molecular Chaperones, Nuclear Proteins genetics, Promyelocytic Leukemia Protein, Rabbits, Transcription Factors genetics, Tumor Suppressor Proteins genetics, X-linked Nuclear Protein, Centromere metabolism, Genetic Loci physiology, Genome, Viral physiology, Herpes Simplex metabolism, Herpesvirus 1, Human physiology, Nuclear Proteins metabolism, Transcription Factors metabolism, Transcription, Genetic physiology, Tumor Suppressor Proteins metabolism, Virus Latency physiology
- Abstract
Major human pathologies are caused by nuclear replicative viruses establishing life-long latent infection in their host. During latency the genomes of these viruses are intimately interacting with the cell nucleus environment. A hallmark of herpes simplex virus type 1 (HSV-1) latency establishment is the shutdown of lytic genes expression and the concomitant induction of the latency associated (LAT) transcripts. Although the setting up and the maintenance of the latent genetic program is most likely dependent on a subtle interplay between viral and nuclear factors, this remains uninvestigated. Combining the use of in situ fluorescent-based approaches and high-resolution microscopic analysis, we show that HSV-1 genomes adopt specific nuclear patterns in sensory neurons of latently infected mice (28 days post-inoculation, d.p.i.). Latent HSV-1 genomes display two major patterns, called "Single" and "Multiple", which associate with centromeres, and with promyelocytic leukemia nuclear bodies (PML-NBs) as viral DNA-containing PML-NBs (DCP-NBs). 3D-image reconstruction of DCP-NBs shows that PML forms a shell around viral genomes and associated Daxx and ATRX, two PML partners within PML-NBs. During latency establishment (6 d.p.i.), infected mouse TGs display, at the level of the whole TG and in individual cells, a substantial increase of PML amount consistent with the interferon-mediated antiviral role of PML. "Single" and "Multiple" patterns are reminiscent of low and high-viral genome copy-containing neurons. We show that LAT expression is significantly favored within the "Multiple" pattern, which underlines a heterogeneity of LAT expression dependent on the viral genome copy number, pattern acquisition, and association with nuclear domains. Infection of PML-knockout mice demonstrates that PML/PML-NBs are involved in virus nuclear pattern acquisition, and negatively regulate the expression of the LAT. This study demonstrates that nuclear domains including PML-NBs and centromeres are functionally involved in the control of HSV-1 latency, and represent a key level of host/virus interaction.
- Published
- 2012
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23. LRRK2 protein levels are determined by kinase function and are crucial for kidney and lung homeostasis in mice.
- Author
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Herzig MC, Kolly C, Persohn E, Theil D, Schweizer T, Hafner T, Stemmelen C, Troxler TJ, Schmid P, Danner S, Schnell CR, Mueller M, Kinzel B, Grevot A, Bolognani F, Stirn M, Kuhn RR, Kaupmann K, van der Putten PH, Rovelli G, and Shimshek DR
- Subjects
- Alveolar Epithelial Cells metabolism, Alveolar Epithelial Cells pathology, Alveolar Epithelial Cells ultrastructure, Animals, Blood Pressure drug effects, Dopamine metabolism, Dopamine Agonists pharmacology, Dopamine Antagonists pharmacology, Enzyme Stability drug effects, Kidney pathology, Kidney physiopathology, Kidney ultrastructure, Kidney Tubules, Proximal enzymology, Kidney Tubules, Proximal pathology, Kidney Tubules, Proximal physiopathology, Kidney Tubules, Proximal ultrastructure, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Lung drug effects, Lung pathology, Lysosomes drug effects, Lysosomes metabolism, Lysosomes ultrastructure, Mice, Mice, Inbred BALB C, Mice, Knockout, Mice, Mutant Strains, Motor Activity, Signal Transduction drug effects, Homeostasis drug effects, Kidney enzymology, Lung enzymology, Protein Serine-Threonine Kinases metabolism
- Abstract
Mutations in leucine-rich repeat kinase 2 (LRRK2) cause late-onset Parkinson's disease (PD), but the underlying pathophysiological mechanisms and the normal function of this large multidomain protein remain speculative. To address the role of this protein in vivo, we generated three different LRRK2 mutant mouse lines. Mice completely lacking the LRRK2 protein (knock-out, KO) showed an early-onset (age 6 weeks) marked increase in number and size of secondary lysosomes in kidney proximal tubule cells and lamellar bodies in lung type II cells. Mice expressing a LRRK2 kinase-dead (KD) mutant from the endogenous locus displayed similar early-onset pathophysiological changes in kidney but not lung. KD mutants had dramatically reduced full-length LRRK2 protein levels in the kidney and this genetic effect was mimicked pharmacologically in wild-type mice treated with a LRRK2-selective kinase inhibitor. Knock-in (KI) mice expressing the G2019S PD-associated mutation that increases LRRK2 kinase activity showed none of the LRRK2 protein level and histopathological changes observed in KD and KO mice. The autophagy marker LC3 remained unchanged but kidney mTOR and TCS2 protein levels decreased in KD and increased in KO and KI mice. Unexpectedly, KO and KI mice suffered from diastolic hypertension opposed to normal blood pressure in KD mice. Our findings demonstrate a role for LRRK2 in kidney and lung physiology and further show that LRRK2 kinase function affects LRRK2 protein steady-state levels thereby altering putative scaffold/GTPase activity. These novel aspects of peripheral LRRK2 biology critically impact ongoing attempts to develop LRRK2 selective kinase inhibitors as therapeutics for PD.
- Published
- 2011
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24. Expression of herpes simplex virus 1-encoded microRNAs in human trigeminal ganglia and their relation to local T-cell infiltrates.
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Held K, Junker A, Dornmair K, Meinl E, Sinicina I, Brandt T, Theil D, and Derfuss T
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- Adolescent, Adult, Aged, Aged, 80 and over, Child, Female, Herpesvirus 1, Human growth & development, Humans, Immunohistochemistry, Infant, Male, Middle Aged, RNA, Viral biosynthesis, Reverse Transcriptase Polymerase Chain Reaction, Trigeminal Ganglion pathology, Gene Expression Profiling, Gene Expression Regulation, Viral, Herpesvirus 1, Human pathogenicity, MicroRNAs biosynthesis, T-Lymphocytes immunology, Trigeminal Ganglion virology, Virus Latency
- Abstract
Herpes simplex type 1 (HSV-1) is a neurotropic virus which establishes lifelong latency in human trigeminal ganglia (TG). Currently, two nonexclusive control mechanisms of HSV-1 latency are discussed: antiviral CD8(+) T cells and viral microRNAs (miRNAs) encoded by the latency associated transcript (LAT). We investigate here to what extent these mechanisms may contribute to the maintenance of HSV-1 latency. We show that only a small proportion of LAT(+) neurons is surrounded by T cells in human TG. This indicates that viral latency in human TG might be controlled by other mechanisms such as viral miRNAs. Therefore, we assessed TG sections for the presence of HSV-1 miRNA, DNA, and mRNA by combining LAT in situ hybridization, T-cell immunohistochemistry, and single cell analysis of laser-microdissected sensory neurons. Quantitative reverse transcription-PCR (RT-PCR) revealed that LAT(+) neurons with or without surrounding T cells were always positive for HSV-1 miRNAs and DNA. Furthermore, ICP0 mRNA could rarely be detected only in LAT(+) neurons, as analyzed by single-cell RT-PCR. In contrast, in LAT(-) neurons that were surrounded by T cells, neither miRNAs nor the DNA of HSV-1, HSV-2, or varicella-zoster virus could be detected. These data indicate that the majority of LAT(+) neurons is not directly controlled by T cells. However, miRNA expression in every latently infected neuron would provide an additional checkpoint before viral replication is initiated.
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- 2011
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25. Fewer latent herpes simplex virus type 1 and cytotoxic T cells occur in the ophthalmic division than in the maxillary and mandibular divisions of the human trigeminal ganglion and nerve.
- Author
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Hüfner K, Horn A, Derfuss T, Glon C, Sinicina I, Arbusow V, Strupp M, Brandt T, and Theil D
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Female, Herpesvirus 1, Human genetics, Humans, Immunohistochemistry, In Situ Hybridization, Male, MicroRNAs genetics, Middle Aged, Young Adult, Herpesvirus 1, Human isolation & purification, T-Lymphocytes, Cytotoxic immunology, Trigeminal Ganglion immunology, Trigeminal Ganglion virology, Trigeminal Nerve immunology, Trigeminal Nerve virology
- Abstract
Following primary infection of the mouth, herpes simplex virus type 1 (HSV-1) travels retrogradely along the maxillary (V2) or mandibular (V3) nerve to the trigeminal ganglion (TG), where it establishes lifelong latency. Symptomatic HSV-1 reactivations frequently manifest as herpes labialis, while ocular HSV-1 disease is rare. We investigated whether these clinical observations are mirrored by the distribution of latent HSV-1 as well as cytotoxic T-cell infiltration around the nerve cell bodies and in the nerve fibers. The three divisions of the TG were separated by using neurofilament staining and carbocyanine dye Di-I tracing and then screened by in situ hybridization for the presence of HSV-1 latency-associated transcript (LAT). The T-cell distribution and the pattern of cytolytic molecule expression were evaluated by immunohistochemistry. The Di-I-labeled neurons were largely confined to the nerve entry zone of the traced nerve branches. Very few Di-I-labeled neurons were found in adjacent divisions due to traversing fiber bundles. LAT was abundant in the V2 and V3 divisions of all TG but was scarce or totally absent in the ophthalmic (V1) division. CD8(+) T cells were found in all three divisions of the TG and in the respective nerves, clearly clustering in V2 and V3, which is indicative of a chronic inflammation. Only T cells surrounding neurons in the V2 and V3 ganglionic divisions expressed granzyme B. In conclusion, the large accumulation of LAT and cytotoxic T cells in the V2 and V3 but not in the V1 division of the TG reflects the sites supplied by the sensory fibers and the clinical reactivation patterns.
- Published
- 2009
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26. Presence of HSV-1 immediate early genes and clonally expanded T-cells with a memory effector phenotype in human trigeminal ganglia.
- Author
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Derfuss T, Segerer S, Herberger S, Sinicina I, Hüfner K, Ebelt K, Knaus HG, Steiner I, Meinl E, Dornmair K, Arbusow V, Strupp M, Brandt T, and Theil D
- Subjects
- Adult, Aged, Aged, 80 and over, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes virology, Chemokines immunology, Chemokines metabolism, Chemotaxis, Leukocyte genetics, Chemotaxis, Leukocyte immunology, Clone Cells immunology, Clone Cells virology, Female, Gene Expression Regulation, Viral genetics, Genes, Viral genetics, Herpes Simplex physiopathology, Herpesvirus 1, Human immunology, Humans, Immunologic Memory genetics, Immunologic Memory immunology, Kv1.3 Potassium Channel metabolism, Male, Middle Aged, Neurons, Afferent immunology, Neurons, Afferent virology, Phenotype, Receptors, Chemokine immunology, Receptors, Chemokine metabolism, T-Lymphocytes immunology, Trigeminal Ganglion cytology, Trigeminal Ganglion immunology, Virus Latency genetics, Virus Latency immunology, Genes, Immediate-Early genetics, Herpes Simplex genetics, Herpes Simplex virology, Herpesvirus 1, Human genetics, T-Lymphocytes virology, Trigeminal Ganglion virology
- Abstract
The latent persistence of herpes simplex virus type 1 (HSV-1) in human trigeminal ganglia (TG) is accompanied by a chronic CD8 T-cell infiltrate. The focus of the current work was to look for HSV-1 transcription activity as a potential trigger of the immune response and to characterize the immune cell infiltrates by this feature. We combined in situ hybridization, laser cutting microscopy, and single cell RT-PCR to demonstrate the expression of the HSV-1 immediate early (IE) genes ICP0 and ICP4 in human trigeminal neurons. Using CDR3 spectratyping, we showed that the infiltrating T-cells are clonally expanded, indicating an antigen-driven immune response. Moreover, the persisting CD8+ T-cells had features of the memory effector phenotype. The voltage-gated potassium channel Kv1.3, a marker of chronic activated memory effector cells, and the chemokines CCL5 and CXCL10 were expressed by a subpopulation of infiltrating cells. The corresponding chemokine receptors CCR5 and CXCR3 were co-expressed on virtually all CD8 T-cells. In addition, T-cells expressed granzymes and perforin. In contrast to animal models of HSV-1 latency, hardly any FoxP3-positive regulatory T-cells were detected in human TG. Thus, HSV-1 IE genes are expressed in human TG and the infiltrating T-cells bear several characteristics that suggest viral antigenic stimulation.
- Published
- 2007
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27. The prevalence of human herpesvirus 6 in human sensory ganglia and its co-occurrence with alpha-herpesviruses.
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Hüfner K, Arbusow V, Himmelein S, Derfuss T, Sinicina I, Strupp M, Brandt T, and Theil D
- Subjects
- Autopsy, Ganglia, Sensory pathology, Ganglia, Spinal pathology, Herpesviridae genetics, Herpesvirus 6, Human genetics, Humans, Polymerase Chain Reaction, Trigeminal Ganglion pathology, Ganglia, Sensory virology, Ganglia, Spinal virology, Herpesviridae isolation & purification, Herpesvirus 6, Human isolation & purification, Trigeminal Ganglion virology
- Abstract
Human herpesvirus 6 (HHV-6) persists in the central nervous system, but its prevalence in the peripheral nervous system, a preferred latency site for herpesviruses, has not been studied. Using nested polymerase chain reaction (PCR), the authors determined the distribution of HHV-6 in human sensory ganglia. HHV-6 was present in 30% of trigeminal, 40% of geniculate, 25% of vestibular, and 55% of dorsal root ganglia. It co-occurred with alpha-herpesviruses (herpes simplex virus type 1 or varicella-zoster virus) in 91% of the ganglia. As HHV-6 positivity did not depend on the presence of inflammatory cells, known to harbor the virus, HHV-6 probably resides in the ganglia themselves.
- Published
- 2007
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28. The fiberoptic Intubating LMA-CTrach: an initial device evaluation.
- Author
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Goldman AJ, Wender R, Rosenblatt W, and Theil D
- Subjects
- Fiber Optic Technology, Humans, Prospective Studies, Intubation, Intratracheal instrumentation, Laryngeal Masks
- Published
- 2006
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29. Chemokines in multiple sclerosis: CXCL12 and CXCL13 up-regulation is differentially linked to CNS immune cell recruitment.
- Author
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Krumbholz M, Theil D, Cepok S, Hemmer B, Kivisäkk P, Ransohoff RM, Hofbauer M, Farina C, Derfuss T, Hartle C, Newcombe J, Hohlfeld R, and Meinl E
- Subjects
- Acute Disease, Adult, B-Lymphocytes immunology, Case-Control Studies, Cells, Cultured, Chemokine CXCL12, Chemokine CXCL13, Chemokines blood, Chemokines, CXC cerebrospinal fluid, Chemotaxis, Leukocyte, Enzyme-Linked Immunosorbent Assay methods, Female, Flow Cytometry, Humans, Immunoglobulins immunology, Immunohistochemistry methods, Interferon-gamma immunology, Interleukin-1 immunology, Interleukin-4 immunology, Lymphocyte Activation, Male, Middle Aged, Polymerase Chain Reaction methods, T-Lymphocytes immunology, Tumor Necrosis Factor-alpha immunology, Central Nervous System immunology, Chemokines cerebrospinal fluid, Multiple Sclerosis immunology, Up-Regulation
- Abstract
Understanding the mechanisms of immune cell migration to multiple sclerosis lesions offers significant therapeutic potential. This study focused on the chemokines CXCL12 (SDF-1) and CXCL13 (BCA-1), both of which regulate B cell migration in lymphoid tissues. We report that immunohistologically CXCL12 was constitutively expressed in CNS parenchyma on blood vessel walls. In both active and chronic inactive multiple sclerosis lesions CXCL12 protein was elevated and detected on astrocytes and blood vessels. Quantitative PCR demonstrated that CXCL13 was produced in actively demyelinating multiple sclerosis lesions, but not in chronic inactive lesions or in the CNS of subjects who had no neurological disease. CXCL13 protein was localized in perivascular infiltrates and scattered infiltrating cells in lesion parenchyma. In the CSF of relapsing-remitting multiple sclerosis patients, both CXCL12 and CXCL13 were elevated. CXCL13, but not CXCL12, levels correlated strongly with intrathecal immunoglobulin production as well as the presence of B cells, plasma blasts and T cells. About 20% of CSF CD4+ cells and almost all B cells expressed the CXCL13 receptor CXCR5. In vitro, CXCL13 was produced by monocytes and at much higher levels by macrophages. CXCL13 mRNA and protein expression was induced by TNFalpha and IL-1beta but inhibited by IL-4 and IFNgamma. Together, CXCL12 and CXCL13 are elevated in active multiple sclerosis lesions and CXCL12 also in inactive lesions. The consequences of CXCL12 up-regulation could be manifold. CXCL12 localization on blood vessels indicates a possible role in leucocyte extravasation, and CXCL12 may contribute to plasma cell persistence since its receptor CXCR4 is retained during plasma cell differentiation. CXCL12 may contribute to axonal damage as it can become a neurotoxic mediator of cleavage by metalloproteases, which are present in multiple sclerosis lesions. The strong linkage of CXCL13 to immune cells and immunoglobulin levels in CSF suggests that this is one of the factors that attract and maintain B and T cells in inflamed CNS lesions. Therefore, both CXCL13 and CXCR5 may be promising therapeutic targets in multiple sclerosis.
- Published
- 2006
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30. BAFF is produced by astrocytes and up-regulated in multiple sclerosis lesions and primary central nervous system lymphoma.
- Author
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Krumbholz M, Theil D, Derfuss T, Rosenwald A, Schrader F, Monoranu CM, Kalled SL, Hess DM, Serafini B, Aloisi F, Wekerle H, Hohlfeld R, and Meinl E
- Subjects
- B-Cell Activating Factor, B-Cell Activation Factor Receptor, B-Lymphocytes, Brain metabolism, Humans, Membrane Proteins genetics, Organ Specificity, RNA, Messenger metabolism, Receptors, Tumor Necrosis Factor metabolism, Tumor Necrosis Factor-alpha genetics, Up-Regulation, Astrocytes metabolism, Central Nervous System Neoplasms metabolism, Lymphoma metabolism, Membrane Proteins metabolism, Multiple Sclerosis metabolism, Tumor Necrosis Factor-alpha metabolism
- Abstract
We report that B cell-activating factor of the tumor necrosis factor (TNF) family (BAFF) is expressed in the normal human brain at approximately 10% of that in lymphatic tissues (tonsils and adenoids) and is produced by astrocytes. BAFF was regularly detected by enzyme-linked immunosorbent assay in brain tissue lysates and in normal spinal fluid, and in astrocytes by double fluorescence microscopy. Cultured human astrocytes secreted functionally active BAFF after stimulation with interferon-gamma and TNF-alpha via a furin-like protease-dependent pathway. BAFF secretion per cell was manifold higher in activated astrocytes than in monocytes and macrophages. We studied brain lesions with B cell components, and found that in multiple sclerosis plaques, BAFF expression was strongly up-regulated to levels observed in lymphatic tissues. BAFF was localized in astrocytes close to BAFF-R-expressing immune cells. BAFF receptors were strongly expressed in situ in primary central nervous system (CNS) lymphomas. This paper identifies astrocytes as a nonimmune source of BAFF. CNS-produced BAFF may support B cell survival in inflammatory diseases and primary B cell lymphoma.
- Published
- 2005
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31. Distinct responses of monocytes to Toll-like receptor ligands and inflammatory cytokines.
- Author
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Farina C, Theil D, Semlinger B, Hohlfeld R, and Meinl E
- Subjects
- Antigens, CD analysis, Antigens, CD immunology, Glycoproteins analysis, Humans, Immunity, Innate, Immunoglobulins analysis, Ligands, NF-kappa B metabolism, Palatine Tonsil cytology, Signal Transduction, Signaling Lymphocytic Activation Molecule Family Member 1, Spleen cytology, Toll-Like Receptor 2, Toll-Like Receptors, p38 Mitogen-Activated Protein Kinases metabolism, Cytokines pharmacology, Glycoproteins metabolism, Immunoglobulins metabolism, Membrane Glycoproteins metabolism, Monocytes immunology, Receptors, Cell Surface metabolism
- Abstract
In this study we compared the activation of monocytes by different bacterial products via Toll-like receptors (TLR), and by different proinflammatory mediators. In response to TLR-2, -4 and -5 engagement, approximately 50% of monocytes produced TNF-alpha, compared to only 5% after induction with IFN-gamma or GM-CSF. Furthermore, a small proportion of monocytes produced IL-10 after stimulation via TLR, but not after stimulation with cytokines. Both TLR-ligands and inflammatory cytokines induced the expression of CD25, CD69, CD80 and, surprisingly, also of CD83, commonly regarded as an activation marker for mature dendritic cells (DC). Conversely, TLR-ligands downregulated CD38, CD86 and ICOS-L. Importantly, signaling lymphocytic activation molecule (SLAM; CD150) was identified as a monocyte activation marker that could be induced ex novo via TLR-2, -4 and -5, but not by single stimulation with monocyte activators like IL-1, TNF-alpha, IFN-beta, IFN-gamma, GM-CSF or CD40-L. SLAM expression was transient and required mitogen activated protein kinase (MAPK) p38, but not ERK or JNK, and was surprisingly independent of NF-kappaB. SLAM+ monocytes, which are absent in blood, were detected in spleen and tonsils, where they could be localized to T-cell areas and germinal centers. Together, by comparing the response of monocytes to TLR-ligands and inflammatory cytokines, we have identified a monocyte activation marker, SLAM, which differs in its inducibility from other monocyte activation markers. SLAM+ monocytes and macrophages were identified for the first time in vivo. Their presence might be a sign of innate immune activation., (Copyright 2004 The Japanese Society for Immunology)
- Published
- 2004
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32. Latent herpesvirus infection in human trigeminal ganglia causes chronic immune response.
- Author
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Theil D, Derfuss T, Paripovic I, Herberger S, Meinl E, Schueler O, Strupp M, Arbusow V, and Brandt T
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Antibody Formation, Child, Child, Preschool, Computer Systems, Female, Herpesviridae Infections physiopathology, Humans, Immediate-Early Proteins metabolism, Immunohistochemistry, In Situ Hybridization, Infant, Male, MicroRNAs, Middle Aged, Reverse Transcriptase Polymerase Chain Reaction, Time Factors, Trans-Activators metabolism, Viral Envelope Proteins metabolism, Viral Proteins metabolism, Herpesviridae Infections immunology, Herpesvirus 1, Human physiology, Herpesvirus 3, Human physiology, Trigeminal Ganglion virology, Virus Latency
- Abstract
The majority of trigeminal ganglia (TGs) are latently infected with alpha-herpesviruses [herpes simplex virus type-1 (HSV-1) and varicella-zoster virus (VZV)]. Whereas HSV-1 periodically reactivates in the TGs, VZV reactivates very rarely. The goal of this study was to determine whether herpesvirus latency is linked to a local immune cell infiltration in human TGs. T cells positive for the CD3 and CD8 markers, and CD68-positive macrophages were found in 30 of 42 examined TGs from 21 healthy individuals. The presence of immune cells correlated constantly with the occurrence of the HSV-1 latency-associated transcript (LAT) and only irregularly with the presence of latent VZV protein. In contrast, uninfected TGs showed no immune cell infiltration. Quantitative RT-PCR revealed that CD8, interferon-gamma, tumor necrosis factor-alpha, IP-10, and RANTES transcripts were significantly induced in TGs latently infected with HSV-1 but not in uninfected TGs. The persisting lymphocytic cell infiltration and the elevated CD8 and cytokine/chemokine expression in the TGs demonstrate for the first time that latent herpesviral infection in humans is accompanied by a chronic inflammatory process at an immunoprivileged site but without any neuronal destruction. The chronic immune response seems to maintain viral latency and influence viral reactivation.
- Published
- 2003
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33. Prevalence of HSV-1 LAT in human trigeminal, geniculate, and vestibular ganglia and its implication for cranial nerve syndromes.
- Author
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Theil D, Arbusow V, Derfuss T, Strupp M, Pfeiffer M, Mascolo A, and Brandt T
- Subjects
- Adult, Aged, Aged, 80 and over, Cranial Nerve Diseases pathology, Cranial Nerve Diseases physiopathology, Gene Expression Regulation, Viral physiology, Geniculate Ganglion pathology, Geniculate Ganglion physiopathology, Herpes Simplex metabolism, Herpes Simplex pathology, Herpesvirus 1, Human metabolism, Herpesvirus 1, Human pathogenicity, Humans, Immediate-Early Proteins metabolism, In Situ Hybridization, Middle Aged, Reverse Transcriptase Polymerase Chain Reaction, Transcription, Genetic genetics, Trigeminal Ganglion pathology, Trigeminal Ganglion physiopathology, Vestibular Nerve pathology, Vestibular Nerve physiopathology, Virus Latency genetics, Cranial Nerve Diseases virology, Geniculate Ganglion virology, Herpes Simplex genetics, Herpesvirus 1, Human genetics, RNA, Viral metabolism, Trigeminal Ganglion virology, Vestibular Nerve virology
- Abstract
Herpes simplex virus type 1 (HSV-1) enters sensory neurons and can remain latent there until reactivation. During latency restricted HSV-1 gene expression takes place in the form of latency-associated transcripts (LAT). LAT has been demonstrated to be important not only for latency but also for reactivation, which may cause cranial nerve disorders. Tissue sections of the trigeminal ganglia (TG), geniculate ganglia (GG), and the vestibular ganglia (VG) from seven subjects were examined for the presence of LAT using the in situ hybridization technique. LAT was found on both sides in allTG (100%), on both sides of five subjects (70%) in the GG, and in none of the VG. Using a second more sensitive detection method (RT-PCR), we found LAT in the VG of seven of ten other persons (70%). This is the first study to demonstrate viral latency in the VG, a finding that supports the hypothesis that vestibular neuritis is caused by HSV-1 reactivation. The distribution of LAT in the cranial nerve ganglia indicates that primary infection occurs in the TG and GG and subsequently spreads along the faciovestibular anastomosis to the VG.
- Published
- 2001
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34. Viruses can silently prime for and trigger central nervous system autoimmune disease.
- Author
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Theil DJ, Tsunoda I, Rodriguez F, Whitton JL, and Fujinami RS
- Subjects
- Animals, Cell Division immunology, Demyelinating Diseases immunology, Demyelinating Diseases pathology, Encephalomyelitis, Autoimmune, Experimental immunology, Encephalomyelitis, Autoimmune, Experimental pathology, Female, Lymphocytes cytology, Lymphocytes virology, Mice, Mice, Inbred Strains, Molecular Mimicry immunology, Multiple Sclerosis immunology, Multiple Sclerosis pathology, Multiple Sclerosis virology, Myelin Proteolipid Protein genetics, Myelin Proteolipid Protein immunology, Plasmids, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins immunology, Ubiquitins genetics, Ubiquitins immunology, Vaccinia pathology, Vaccinia virus genetics, Demyelinating Diseases virology, Encephalomyelitis, Autoimmune, Experimental virology, Vaccinia immunology, Vaccinia virus immunology
- Abstract
Although many viruses have been isolated from patients with multiple sclerosis (MS), as yet, no one agent has been demonstrated to cause MS. In contrast, epidemiological data indicate that viral infections are associated with exacerbations of MS. Here, we present data showing that virus infections can subclinically prime animals for central nervous system (CNS) autoimmune disease; long after the original infection has been eradicated, a nonspecific challenge/infection can trigger an exacerbation. The priming infectious agent must show molecular mimicry with self-CNS antigens such as glial fibrillary acidic protein (GFAP), myelin associated glycoprotein (MAG) or myelin proteolipid protein (PLP). The subsequent challenge, however, may be nonspecific; complete Freund's adjuvant (CFA), or infection with a recombinant vaccinia virus encoding an irrelevant protein, could trigger CNS disease. In the CNS, we could detect a mononuclear cell infiltration, but no demyelination was found. However, if the pathogenesis of MS is similar to that of this novel animal model for CNS autoimmune disease, our findings could help explain why exacerbations of MS are often associated with a variety of different viral infections.
- Published
- 2001
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35. Antibody association with a novel model for primary progressive multiple sclerosis: induction of relapsing-remitting and progressive forms of EAE in H2s mouse strains.
- Author
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Tsunoda I, Kuang LQ, Theil DJ, and Fujinami RS
- Subjects
- Animals, Central Nervous System pathology, DNA, Bacterial physiology, Disease Models, Animal, Encephalomyelitis, Autoimmune, Experimental pathology, Encephalomyelitis, Autoimmune, Experimental physiopathology, Female, Immunoglobulins metabolism, In Situ Nick-End Labeling, Lymphocytes pathology, Mice, Mice, Mutant Strains, Myelin Proteins, Myelin-Associated Glycoprotein immunology, Myelin-Oligodendrocyte Glycoprotein, Nervous System pathology, Peptide Fragments immunology, Plasmids genetics, Antibodies analysis, Encephalomyelitis, Autoimmune, Experimental immunology, Multiple Sclerosis, Chronic Progressive immunology, Multiple Sclerosis, Relapsing-Remitting immunology
- Abstract
Multiple sclerosis (MS) can be divided into 4 clinical forms: relapsing-remitting (RR), primary progressive (PP), secondary progressive (SP), and progressive relapsing (PR). Since PP-MS is notably different from the other forms of MS, both clinically and pathologically, the question arises whether PP-MS is immunologically similar to the other forms. The pathogenesis of the PP-MS remains unclear, partly due to a lack of highly relevant animal models. Using an encephalitogenic peptide from myelin oligodendrocyte glycoprotein (MOG)92-106, we have established animal models that mimic different forms of MS in 2 strains of H-2s mice, SJL/J and A.SW. We induced experimental allergic encephalomyelitis (EAE) using MOG92-106 in the presence or absence of supplemental Bordetella pertussis (BP). Although, SJL/J mice developed RR-EAE whether BP was given or not, A.SW mice developed PP-EAE without BP and SP-EAE with BP. Histologically, SJL/J mice developed mild demyelinating disease with T cell infiltration, while A.SW mice developed large areas of plaque-like demyelination with immunoglobulin deposition and neutrophil infiltration, but with minimal T cell infiltration. In A.SW mice without BP, high titer serum anti-MOG antibody was detected and the anti-MOG IgG2a/IgG1 ratio correlated with survival times of mice. We hypothesized that, in A.SW mice, a Th2 response favors production of myelinotoxic antibodies, leading to progressive forms with early death. Our new models indicate that a single encephalitogen could induce either RR-, PP-, or SP- forms of demyelinating disease in hosts with immunologically different humoral immune responses.
- Published
- 2000
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36. Exacerbation of viral and autoimmune animal models for multiple sclerosis by bacterial DNA.
- Author
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Tsunoda I, Tolley ND, Theil DJ, Whitton JL, Kobayashi H, and Fujinami RS
- Subjects
- Animals, Antibodies, Viral blood, CpG Islands immunology, Cytokines biosynthesis, Cytomegalovirus immunology, DNA, Bacterial immunology, Disease Models, Animal, Dose-Response Relationship, Drug, Encephalomyelitis, Autoimmune, Experimental genetics, Encephalomyelitis, Autoimmune, Experimental immunology, Encephalomyelitis, Autoimmune, Experimental pathology, Female, Genetic Vectors adverse effects, Genetic Vectors immunology, Immunoglobulin G blood, Killer Cells, Natural immunology, Mice, Mice, Inbred Strains, Multiple Sclerosis pathology, Myelin Proteolipid Protein immunology, Spinal Cord pathology, Th1 Cells immunology, Theilovirus immunology, Vaccines, DNA adverse effects, Vaccines, DNA immunology, DNA, Bacterial adverse effects, Multiple Sclerosis immunology, Multiple Sclerosis microbiology
- Abstract
Theiler's murine encephalomyelitis virus (TMEV) infection and relapsing-remitting experimental allergic encephalomyelitis (R-EAE) have been used to investigate the viral and autoimmune etiology of multiple sclerosis (MS), a possible Th1-type mediated disease. DNA immunization is a novel vaccination strategy in which few harmful effects have been reported. Bacterial DNA and oligodeoxynucleotides, which contain CpG motifs, have been reported to enhance immunostimulation. Our objectives were two-fold: first, to ascertain whether plasmid DNA, pCMV, which is widely used as a vector in DNA immunization studies, could exert immunostimulation in vitro; and second, to test if pCMV injection could modulate animal models for MS in vivo. We demonstrated that this bacterially derived DNA could induce interleukin (IL)-12, interferon (IFN)gamma, (Th1-promoting cytokines), and IL-6 production as well as activate NK cells. Following pCMV injections, SJL/J mice were infected with TMEV or challenged with encephalitogenic myelin proteolipid protein (PLP) peptides. pCMV injection exacerbated TMEV-induced demyelinating disease in a dose-dependent manner. Exacerbation of the disease did not correlate with the number of TMEV-antigen positive cells but did with an increase in anti-TMEV antibody. pCMV injection also enhanced R-EAE with increased IFNgamma and IL-6 responses. These results caution the use of DNA vaccination in MS patients and other possible Th1-mediated diseases.
- Published
- 1999
- Full Text
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37. Recurrent hepatitis B in liver allograft recipients. Differentiation between viral hepatitis B and rejection.
- Author
-
Demetris AJ, Jaffe R, Sheahan DG, Burnham J, Spero J, Iwatsuki S, Van Theil DH, and Starzl TE
- Subjects
- Diagnosis, Differential, Hepatitis B diagnosis, Hepatitis B pathology, Hepatitis B therapy, Humans, Immunotherapy, Recurrence, Graft Rejection, Hepatitis B surgery, Liver Transplantation
- Abstract
The histologic findings in the original liver obtained from 9 liver allograft patients with active B virus hepatitis were compared with 28 posttransplant pathology specimens. All specimens were studied with the use of light and immunohistochemical microscopy in conjunction with pertinent clinical data. Eight of the 9 patients had chronic active hepatitis B (HB) with cirrhosis, prior to transplant, one of which had coexistent hepatocellular carcinoma. The ninth patient had fulminant hepatic necrosis secondary to acute HB prior to transplantation. In all of the patients with chronic HB prior to transplantation who survived more than 2 months after transplantation recurrent infection of the graft developed despite perioperative HB immunoglobulin therapy. The patient with acute fulminant hepatitis B pretransplant has done well postoperatively and has evidence of HB virus immunity (positive anti-HBs) 15 months after transplantation. Examination of tissue specimens obtained during episodes of allograft dysfunction in these 9 patients indicate that pathologic alterations of active HB infection of the allograft are associated with a preferential lobular insult, whereas those occurring in rejection preferentially involve portal tract structures. Serologic data combined with biopsy histopathologic data are essential in distinguishing between the two quite different events.
- Published
- 1986
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