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Moses Rodriguez - One of the best experts on this subject based on the ideXlab platform.
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distinct promoters regulate tissue specific and differential expression of kallikrein 6 in cns Demyelinating Disease
Journal of Neurochemistry, 2004Co-Authors: George P Christophi, Sachiko I Blaber, Michael Blaber, Moses Rodriguez, Paul J Isackson, Isobel A. ScarisbrickAbstract:Kallikrein 6 is a serine protease expressed abundantly in normal adult human and rodent CNS, and therein is regulated by injury. In the case of CNS Demyelinating Disease, K6 expression in CNS occurs additionally in perivascular and parenchymal inflammatory cells suggesting a role in pathogenesis. Herein we describe two unique transcripts that occur within the human and mouse K6 genes that differ in their 5'-untranslated regions. These transcripts have identical translation initiation sites in exon 3, are expressed in a tissue-specific fashion and are differentially regulated in response to CNS injury. While the human and mouse 5'-transcripts differ in sequence they are identical in genomic organization and tissue-specific expression. The most 5'-transcript, designated transcript 1, includes exon 1-7, and was detectable in all CNS regions, but not in any non-CNS tissues examined (spleen, thymus, liver, kidney, pancreas, submandibular gland and peripheral nerve). In contrast, transcript 2 lacks exon 1, but contains a unique sequence at the 5'-end of exon 2, designated exon 2A. Transcript 2 was expressed both in CNS and in each peripheral tissue. In a murine model of human CNS Demyelinating inflammatory Disease induced by Theiler's picornovirus, mouse K6 transcript 1 was up-regulated in brain and spinal cord at acute and more chronic phases of CNS inflammation and demyelination, while overall transcript 2 expression was not significantly altered. However, in isolated splenocyte cultures, transcript 2 was up-regulated two-fold by cellular activation. Tissue-specific expression patterns and differential regulation in CNS Disease indicates that each K6 5'-transcript is probably regulated by unique promoter elements and may serve as a molecular target to treat inflammatory Demyelinating Disease.
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experimental models of virus induced demyelination
Myelin Biology and Disorders, 2004Co-Authors: Allan J Bieber, Moses RodriguezAbstract:Publisher Summary This chapter reviews two of the most widely studied animal models of virus-induced Demyelinating Disease. These are Theiler's murine encephalomyelitis virus and murine hepatitis virus. Both viruses produce acute inflammatory encephalitis that is followed by chronic central-nervous-system (CNS) Demyelinating Disease. The clinical and pathologic correlates of virus-induced demyelination are largely immune mediated. Furthermore, several pathologic mechanisms have been proposed to explain the development of myelin damage and neurologic deficits, and each of the proposed mechanisms may play a role in Disease progression depending on the genetic constitution of the infected animal. The induction of Demyelinating Disease by virus may be directly relevant to human MS. Several viruses are known to cause demyelination in humans and viral infection is an epidemiologic factor that is consistently associated with clinical exacerbation of MS. It is suggested that viral infection may be a cause of MS, although no specific virus has been identified as a causative agent.
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a randomized trial of plasma exchange in acute central nervous system inflammatory Demyelinating Disease
Annals of Neurology, 1999Co-Authors: Brian G Weinshenker, Claudia F Lucchinetti, Peter C Obrien, Tanya M Petterson, John H Noseworthy, David W Dodick, Alvaro A Pineda, Lorna N Stevens, Moses RodriguezAbstract:There are no established treatments for patients with acute, severe neurological deficits caused by multiple sclerosis or other inflammatory Demyelinating Diseases of the central nervous system who fail to recover after treatment with high-dose corticosteroids. We conducted a randomized, sham-controlled, double-masked study of plasma exchange without concomitant immunosuppressive treatment in patients with recently acquired, severe neurological deficits resulting from attacks of inflammatory Demyelinating Disease, who failed to recover after treatment with intravenous corticosteroids. Patients who did not achieve moderate or greater improvement after the first treatment phase crossed over to the opposite treatment. Moderate or greater improvement in neurological disability occurred during 8 of 19 (42.1%) courses of active treatment compared with 1 of 17 (5.9%) courses of sham treatment. The primary analysis was positive. Improvement occurred early in the course of treatment, and was sustained on follow-up. However, 4 of the patients who responded to the active treatment experienced new attacks of Demyelinating Disease during 6 months of follow-up. Moderate or greater improvement occurred during follow-up in only 2 of 13 patients who failed to improve during the treatment phase. Plasma exchange leads to functionally important neurological recovery in an important proportion of severely disabled patients with acute attacks of idiopathic inflammatory Demyelinating Disease.
Thomas E Lane - One of the best experts on this subject based on the ideXlab platform.
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the pathogenesis of murine coronavirus infection of the central nervous system
Critical Reviews in Immunology, 2010Co-Authors: Martin P Hosking, Thomas E LaneAbstract:Mouse hepatitis virus (MHV) is a positive-strand RNA virus that causes an acute encephalomyelitis that later resolves into a chronic fulminating Demyelinating Disease. Cytokine production, chemokine secretion, and immune cell infiltration into the central nervous system are critical to control viral replication during acute infection. Despite potent antiviral T-lymphocyte activity, sterile immunity is not achieved, and MHV chronically persists within oligodendrocytes. Continued infiltration and activation of the immune system, a result of the lingering viral antigen and RNA within oligodendrocytes, lead directly to the development of an immune-mediated demyelination that bears remarkable similarities, both clinically and histologically, to the human Demyelinating Disease multiple sclerosis. MHV offers a unique model system for studying host defense during acute viral infection and immune-mediated demyelination during chronic infection.
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dynamic regulation of alpha and beta chemokine expression in the central nervous system during mouse hepatitis virus induced Demyelinating Disease
Journal of Immunology, 1998Co-Authors: Thomas E Lane, Valerie C Asensio, Alyssa D Paoletti, Iain L Campbell, Michael J BuchmeierAbstract:Infection of C57BL/6 mice with the V5A13.1 strain of mouse hepatitis virus (MHV-V5A13.1) results in an acute encephalomyelitis and chronic Demyelinating Disease with features similar to the human Demyelinating Disease multiple sclerosis. Chemokines are a family of proinflammatory cytokines associated with inflammatory pathology in various Diseases. The kinetics and histologic localization of chemokine production in the central nervous system of MHV-infected mice were examined to identify chemokines that contribute to inflammation and demyelination. Transcripts for the chemokines cytokine-response gene-2 (CRG-2), regulated on activation, normal T cell expressed and secreted (RANTES), macrophage-chemoattractant protein-1 and protein-3 (MCP-1, MCP-3), macrophage-inflammatory protein-1beta (MIP-1beta), and MIP-2 were detected in the brains of MHV-infected mice at 3 days postinfection (p.i.), and these transcripts were increased markedly in brains and spinal cords at day 7 p.i., which coincides with the occurrence of acute viral encephalomyelitis. By day 35 p.i., RANTES, CRG-2, and MIP-1beta were detected in brains and spinal cords of mice with chronic demyelination. CRG-2 mRNA expression colocalized with viral RNA and was associated with Demyelinating lesions. Astrocytes were the predominant cell type expressing CRG-2 mRNA. These observations suggest a role for chemokines, notably CRG-2, in the initiation and maintenance of an inflammatory response following infection with MHV, which is important in contributing to demyelination.
Claudia F Lucchinetti - One of the best experts on this subject based on the ideXlab platform.
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neuromyelitis optica igg serostatus in fulminant central nervous system inflammatory Demyelinating Disease
JAMA Neurology, 2009Co-Authors: Setty M Magana, Brian G Weinshenker, Sean J Pittock, Vanda A Lennon, Mark B Keegan, Claudia F LucchinettiAbstract:Background The aquaporin-4–specific serum autoantibody neuromyelitis optica (NMO) IgG is a validated biomarker distinguishing NMO spectrum disorders from multiple sclerosis (MS). Because fulminant attacks are more common in NMO spectrum disorders than in MS, some investigators suggest that NMO IgG may be a marker of destructive demyelination rather than a Disease-specific biomarker. To our knowledge, this study is the first to compare NMO IgG serostatus among patients with fulminant central nervous system inflammatory Demyelinating Disease (CNS IDD). Objective To determine whether NMO IgG distinguishes patients with NMO spectrum disorders from those with other fulminant corticosteroid-refractory CNS IDD. Design Descriptive historical cohort. Setting Neuroimmunology laboratory and neurology practice, Mayo Clinic College of Medicine, Rochester, Minnesota. Patients Serum samples from 74 patients who underwent plasmapheresis between February 24, 1993, and November 22, 2007, for a corticosteroid-refractory CNS IDD were tested for NMO IgG by indirect immunofluorescence assay. Main Outcome Measures Two blinded observers scored serum samples tested at 1:120 dilution. Clinical data were obtained by medical record review. Results Preplasmapheresis serum samples were available from 74 patients (ratio of women to men, 2:5); the mean interval between blood draw and plasmapheresis was 13 days. At the time of plasmapheresis, the mean age of patients was 46 years (age range, 7-80 years); the mean Expanded Disability Status Scale score was 7.0 (score range, 3.5-9.5 [10.0 is death]). Diagnoses included MS (18 patients with definite and 11 patients with probable), longitudinally extensive transverse myelitis involving at least 3 vertebral segments (20 patients), NMO (14 patients), transverse myelitis involving fewer than 3 vertebral segments (8 patients), optic neuritis (2 patients), and acute disseminated encephalomyelitis (1 patient). Neuromyelitis optica IgG was detected in 20 patients (27%) (10 with longitudinally extensive transverse myelitis, 9 with NMO, and 1 with recurrent optic neuritis) and was not detected in any patient with MS, short transverse myelitis, monophasic optic neuritis, or acute disseminated encephalomyelitis. Conclusion Neuromyelitis optica IgG is a specific biomarker for NMO spectrum disorders and is not simply a marker of destructive CNS IDD.
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acute disseminated encephalomyelitis current understanding and controversies
Seminars in Neurology, 2008Co-Authors: Nathan P Young, Brian G Weinshenker, Claudia F LucchinettiAbstract:Acute disseminated encephalomyelitis (ADEM) is an uncommon monophasic idiopathic inflammatory Demyelinating Disease. Available diagnostic criteria do not reliably distinguish it from first presentations of relapsing Diseases such as multiple sclerosis (MS) and neuromyelitis optica (NMO). In this article, we review current concepts about ADEM and what distinguishes it from other idiopathic inflammatory Demyelinating Disease, and we highlight controversial aspects and diagnostic problems. We review pathological differences between ADEM and MS in terms of their utility in the diagnosis of ADEM. Finally, we present a practical approach for management of patients suspected of having ADEM when the diagnosis is uncertain.
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a randomized trial of plasma exchange in acute central nervous system inflammatory Demyelinating Disease
Annals of Neurology, 1999Co-Authors: Brian G Weinshenker, Claudia F Lucchinetti, Peter C Obrien, Tanya M Petterson, John H Noseworthy, David W Dodick, Alvaro A Pineda, Lorna N Stevens, Moses RodriguezAbstract:There are no established treatments for patients with acute, severe neurological deficits caused by multiple sclerosis or other inflammatory Demyelinating Diseases of the central nervous system who fail to recover after treatment with high-dose corticosteroids. We conducted a randomized, sham-controlled, double-masked study of plasma exchange without concomitant immunosuppressive treatment in patients with recently acquired, severe neurological deficits resulting from attacks of inflammatory Demyelinating Disease, who failed to recover after treatment with intravenous corticosteroids. Patients who did not achieve moderate or greater improvement after the first treatment phase crossed over to the opposite treatment. Moderate or greater improvement in neurological disability occurred during 8 of 19 (42.1%) courses of active treatment compared with 1 of 17 (5.9%) courses of sham treatment. The primary analysis was positive. Improvement occurred early in the course of treatment, and was sustained on follow-up. However, 4 of the patients who responded to the active treatment experienced new attacks of Demyelinating Disease during 6 months of follow-up. Moderate or greater improvement occurred during follow-up in only 2 of 13 patients who failed to improve during the treatment phase. Plasma exchange leads to functionally important neurological recovery in an important proportion of severely disabled patients with acute attacks of idiopathic inflammatory Demyelinating Disease.
Brian G Weinshenker - One of the best experts on this subject based on the ideXlab platform.
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neuromyelitis optica igg serostatus in fulminant central nervous system inflammatory Demyelinating Disease
JAMA Neurology, 2009Co-Authors: Setty M Magana, Brian G Weinshenker, Sean J Pittock, Vanda A Lennon, Mark B Keegan, Claudia F LucchinettiAbstract:Background The aquaporin-4–specific serum autoantibody neuromyelitis optica (NMO) IgG is a validated biomarker distinguishing NMO spectrum disorders from multiple sclerosis (MS). Because fulminant attacks are more common in NMO spectrum disorders than in MS, some investigators suggest that NMO IgG may be a marker of destructive demyelination rather than a Disease-specific biomarker. To our knowledge, this study is the first to compare NMO IgG serostatus among patients with fulminant central nervous system inflammatory Demyelinating Disease (CNS IDD). Objective To determine whether NMO IgG distinguishes patients with NMO spectrum disorders from those with other fulminant corticosteroid-refractory CNS IDD. Design Descriptive historical cohort. Setting Neuroimmunology laboratory and neurology practice, Mayo Clinic College of Medicine, Rochester, Minnesota. Patients Serum samples from 74 patients who underwent plasmapheresis between February 24, 1993, and November 22, 2007, for a corticosteroid-refractory CNS IDD were tested for NMO IgG by indirect immunofluorescence assay. Main Outcome Measures Two blinded observers scored serum samples tested at 1:120 dilution. Clinical data were obtained by medical record review. Results Preplasmapheresis serum samples were available from 74 patients (ratio of women to men, 2:5); the mean interval between blood draw and plasmapheresis was 13 days. At the time of plasmapheresis, the mean age of patients was 46 years (age range, 7-80 years); the mean Expanded Disability Status Scale score was 7.0 (score range, 3.5-9.5 [10.0 is death]). Diagnoses included MS (18 patients with definite and 11 patients with probable), longitudinally extensive transverse myelitis involving at least 3 vertebral segments (20 patients), NMO (14 patients), transverse myelitis involving fewer than 3 vertebral segments (8 patients), optic neuritis (2 patients), and acute disseminated encephalomyelitis (1 patient). Neuromyelitis optica IgG was detected in 20 patients (27%) (10 with longitudinally extensive transverse myelitis, 9 with NMO, and 1 with recurrent optic neuritis) and was not detected in any patient with MS, short transverse myelitis, monophasic optic neuritis, or acute disseminated encephalomyelitis. Conclusion Neuromyelitis optica IgG is a specific biomarker for NMO spectrum disorders and is not simply a marker of destructive CNS IDD.
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acute disseminated encephalomyelitis current understanding and controversies
Seminars in Neurology, 2008Co-Authors: Nathan P Young, Brian G Weinshenker, Claudia F LucchinettiAbstract:Acute disseminated encephalomyelitis (ADEM) is an uncommon monophasic idiopathic inflammatory Demyelinating Disease. Available diagnostic criteria do not reliably distinguish it from first presentations of relapsing Diseases such as multiple sclerosis (MS) and neuromyelitis optica (NMO). In this article, we review current concepts about ADEM and what distinguishes it from other idiopathic inflammatory Demyelinating Disease, and we highlight controversial aspects and diagnostic problems. We review pathological differences between ADEM and MS in terms of their utility in the diagnosis of ADEM. Finally, we present a practical approach for management of patients suspected of having ADEM when the diagnosis is uncertain.
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a randomized trial of plasma exchange in acute central nervous system inflammatory Demyelinating Disease
Annals of Neurology, 1999Co-Authors: Brian G Weinshenker, Claudia F Lucchinetti, Peter C Obrien, Tanya M Petterson, John H Noseworthy, David W Dodick, Alvaro A Pineda, Lorna N Stevens, Moses RodriguezAbstract:There are no established treatments for patients with acute, severe neurological deficits caused by multiple sclerosis or other inflammatory Demyelinating Diseases of the central nervous system who fail to recover after treatment with high-dose corticosteroids. We conducted a randomized, sham-controlled, double-masked study of plasma exchange without concomitant immunosuppressive treatment in patients with recently acquired, severe neurological deficits resulting from attacks of inflammatory Demyelinating Disease, who failed to recover after treatment with intravenous corticosteroids. Patients who did not achieve moderate or greater improvement after the first treatment phase crossed over to the opposite treatment. Moderate or greater improvement in neurological disability occurred during 8 of 19 (42.1%) courses of active treatment compared with 1 of 17 (5.9%) courses of sham treatment. The primary analysis was positive. Improvement occurred early in the course of treatment, and was sustained on follow-up. However, 4 of the patients who responded to the active treatment experienced new attacks of Demyelinating Disease during 6 months of follow-up. Moderate or greater improvement occurred during follow-up in only 2 of 13 patients who failed to improve during the treatment phase. Plasma exchange leads to functionally important neurological recovery in an important proportion of severely disabled patients with acute attacks of idiopathic inflammatory Demyelinating Disease.
Andrew R Pachner - One of the best experts on this subject based on the ideXlab platform.
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treatment of theiler s virus induced Demyelinating Disease with teriflunomide
Journal of NeuroVirology, 2017Co-Authors: Francesca Gilli, Darlene B Royce, Krista D Disano, Andrew R PachnerAbstract:Teriflunomide is an oral therapy approved for the treatment of relapsing remitting multiple sclerosis (MS), showing both anti-inflammatory and antiviral properties. Currently, it is uncertain whether one or both of these properties may explain teriflunomide's beneficial effect in MS. Thus, to learn more about its mechanisms of action, we evaluated the effect of teriflunomide in the Theiler's encephalomyelitis virus-induced Demyelinating Disease (TMEV-IDD) model, which is both a viral infection and an excellent model of the progressive disability of MS. We assessed the effects of the treatment on central nervous system (CNS) viral load, intrathecal immune response, and progressive neurological disability in mice intracranially infected with TMEV. In the TMEV-IDD model, we showed that teriflunomide has both anti-inflammatory and antiviral properties, but there seemed to be no impact on disability progression and intrathecal antibody production. Notably, benefits in TMEV-IDD were mostly mediated by effects on various cytokines produced in the CNS. Perhaps the most interesting result of the study has been teriflunomide's antiviral activity in the CNS, indicating it may have a role as an antiviral prophylactic and therapeutic compound for CNS viral infections.