Neuroimmunopathology in a murine model of neuropsychiatric lupus.
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Animal models are extremely useful tools in defining pathogenesis and treatment of human disease. For many years researchers believed that structural damage to the brain of neuropsychiatric (NP) patients lead to abnormal mental function, but this possibility was not extensively explored until recently. Imaging studies of NP-systemic lupus erythematosus (SLE) support the notion that brain cell death accounts for the emergence of neurologic and psychiatric symptoms, and evidence suggests that it is an autoimmunity-induced brain disorder characterized by profound metabolic alterations and progressive neuronal loss. While there are a number of murine models of SLE, this article reviews recent literature on the immunological connections to neurodegeneration and behavioral dysfunction in the Fas-deficient MRL model of NP-SLE. Probable links between spontaneous peripheral immune activation, the subsequent central autoimmune/inflammatory responses in MRL/MpJ-Tnfrsf6(lpr) (MRL-lpr) mice and the sequential mode of events leading to Fas-independent neurodegenerative autoimmune-induced encephalitis will be reviewed. The role of hormones, alternative mechanisms of cell death, the impact of central dopaminergic degeneration on behavior, and germinal layer lesions on developmental/regenerative capacity of MRL-lpr brains will also be explored. This model can provide direction for future therapeutic interventions in patients with this complex neuroimmunological syndrome. (+info)
Identification of a mutation in the CHAT gene of Old Danish Pointing Dogs affected with congenital myasthenic syndrome.
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The presence of a recessive inherited muscle disease in Old Danish Pointing Dogs has been well known for years. Comparisons of this disease with myasthenic diseases of other dog breeds and humans have pointed toward a defect in the synthesis of the neurotransmitter acetylcholine possibly due to decreased activity of the enzyme choline acetyltransferase. We sequenced exons 5-18 of the gene encoding choline acetyltransferase (CHAT) in 2 affected and 2 unaffected dogs and identified a G to A missense mutation in exon 6. The mutation causes a valine to methionine substitution and segregates in agreement with the inheritance of the disease. The mutation was not detected in 50 dogs representing 25 other dog breeds. A DNA test has been developed and is now available to the breeders of Old Danish Pointing Dogs. (+info)
Sequential polymicrobial infections lead to CNS inflammatory disease: possible involvement of bystander activation in heterologous immunity.
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VV(PLP) is a recombinant vaccinia virus (VV) encoding myelin proteolipid protein (PLP) that has been used to investigate molecular mimicry and autoimmunity. Since virus infections can cause bystander activation, mice were first infected with VV(PLP), and later challenged with wild-type VV, lymphocytic choriomeningitis virus (LCMV), or murine cytomegalovirus (MCMV). Among the VV(PLP)-primed mice, only MCMV challenge induced significant Ki-67(+), CD3(+)T cell infiltration into the central nervous system (CNS) with a mild PLP antibody response. While MCMV alone caused no CNS disease, control VV-infected mice followed with MCMV developed mild CNS inflammation. Thus, heterologous virus infections can induce CNS pathology. (+info)
The anesthetic management of children with neonatal-onset multi-system inflammatory disease.
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BACKGROUND: Neonatal-onset multi-system inflammatory disease (NOMID), a rare autosomal dominantly inherited disease, belongs to a growing spectrum of autoinflammatory diseases, is characterized by urticarial rash, arthropathy, and chronic aseptic meningitis, and is associated with mutations in the cold-induced autoinflammatory gene, CIAS1, the gene that encodes the protein, cryopyrin. As little is known about the anesthetic considerations of the disease, we sought to identify the main features and respective anesthetic and perioperative implications of NOMID. METHODS: We examined perianesthetic records of children with NOMID who were anesthetized for invasive diagnostic and therapeutic interventions between 2003 and 2006. In addition, we conducted an extensive literature review of the genetic, clinical, and biochemical abnormalities of the disease. RESULTS: Seventeen children with NOMID (median age 8 yr, range 9 mo to 11 yr) were anesthetized for diagnostic and therapeutic procedures. All patients had neurological involvement, including increased intracranial pressure, chronic aseptic meningitis, and developmental delay; 7 had bony overgrowth, 15 ocular, and 14 otological manifestations of NOMID. Despite the complexity of the disease, the perioperative course was uncomplicated, and no serious adverse events were observed. CONCLUSIONS: This study is the first to investigate the anesthetic implications of NOMID, an autoinflammatory disease associated with arthropathy, recurrent fevers, urticarial rash, and chronic aseptic meningitis. While for the pediatric anesthesiologist, the presence of fever and aseptic meningitis might make the conduct of anesthetics for elective procedures less desirable, our findings suggest that without evidence of active infection, even in the presence of fever and chronic aseptic meningitis, general and regional anesthesia may be conducted in patients with NOMID without untoward complications. (+info)
Induction of immunologic tolerance to myelin basic protein prevents central nervous system autoimmunity and improves outcome after stroke.
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