ABSTRACT
BACKGROUND AND PURPOSE: Distal embolism and acute thrombosis due to rupture of a vulnerable atherosclerotic plaque are the common mechanisms of stroke in patients with carotid disease. The purpose of this study was to develop the first animal model of vulnerable carotid atherosclerotic plaque. MATERIALS AND METHODS: Carotid atherosclerotic models were created in 12 Yucatan minipigs by using a combination of partial ligation and high cholesterol diet. Retia mirabilia from these animals were examined histopathologically to identify distal embolism. The association of distal embolism with advanced atherosclerosis and a thin fibrous cap was analyzed by using the Fisher exact test. RESULTS: Typical features of vulnerable plaques, including a thin fibrous cap, necrotic core, and intraplaque hemorrhage, were observed in this swine model of carotid atherosclerosis. Distal embolism was detected in retia mirabilia supplied by 7 of 10 carotid arteries with advanced atherosclerotic plaques, compared with 3 of 14 carotid arteries without advanced plaque (P < .05). CONCLUSIONS: This swine model of carotid atherosclerosis contains the salient features of vulnerable plaques, including plaque rupture and distal embolism.
Subject(s)
Carotid Artery Diseases/complications , Carotid Stenosis/etiology , Disease Models, Animal , Stroke/etiology , Swine, Miniature , Animals , Carotid Arteries/pathology , Carotid Artery Diseases/pathology , Carotid Stenosis/pathology , Intracranial Embolism/etiology , Intracranial Embolism/pathology , Male , Rupture , Stroke/pathology , SwineABSTRACT
Rett syndrome (RTT) is an X-linked, dominant neurodevelopmental disorder caused by mutations in MECP2, encoding the methyl-CpG-binding protein 2 (MeCP2). A major paradox in the pathogenesis of RTT is how mutations in ubiquitously transcribed MECP2 result in a phenotype specific to the central nervous system (CNS) during postnatal development. To address this question, we have used a novel approach for quantitating the level and distribution of wild-type and mutant MeCP2 in situ by immunofluorescence and laser scanning cytometry. Surprisingly, cellular heterogeneity in MeCP2 expression level was observed in normal brain with a subpopulation of cells exhibiting high expression (MeCP2(hi)) and the remainder exhibiting low expression (MeCP2(lo)). MeCP2 expression was significantly higher in CNS compared with non-CNS tissues of human and mouse by automated quantitation of MeCP2 on multiple tissue arrays. Quantitative localization of MeCP2 expression phenotypes in normal human brain showed a mosaic, but distinct, distribution pattern, with MeCP2(hi) neurons highest in layer IV of the cerebrum and MeCP2(lo )neurons highest in the granular layer of the cerebellum. In female RTT brains, MECP2 mutant-expressing cells were identified as cells negative for the MeCP2 C-terminal epitope. MECP2 mutant-expressing cells were randomly localized in Rett cerebrum and cerebellum and showed normal MeCP2 expression with N-terminal-specific anti-MeCP2. These results demonstrate a CNS-specific cellular phenotype of MeCP2 high expression and suggest that MECP2 mutations in RTT are only manifested in MeCP2(hi) cells. In addition, our results demonstrate the power of laser scanning cytometry in examining complex cellular phenotypes in disease pathogenesis.
Subject(s)
Chromosomal Proteins, Non-Histone , DNA-Binding Proteins/genetics , Repressor Proteins/genetics , Rett Syndrome/genetics , Animals , Brain/cytology , Central Nervous System/metabolism , CpG Islands , DNA-Binding Proteins/biosynthesis , Female , Gene Expression Regulation , Genotype , Humans , Methyl-CpG-Binding Protein 2 , Mice , Microscopy, Confocal , Mutation , Oligonucleotide Array Sequence Analysis , Phenotype , Rett Syndrome/diagnosis , Rett Syndrome/metabolismABSTRACT
Although gold is one of the few therapeutic agents that has been proven effective in producing remission in patients with rheumatoid arthritis, its mechanism of action is unknown. Since nociceptive afferent and sympathetic efferent fibers of the peripheral nervous system contribute to the pathophysiology of inflammation, and since a known side effect of gold therapy is a polyneuropathy, we tested the hypothesis that gold is toxic to small-diameter peripheral nerve fibers in the rat. We found that prolonged treatment with gold, at the same dosage reported to be effective against adjuvant-induced arthritis in the rat, produced a significant decrease in the numbers of unmyelinated, but not of myelinated, axons. Gold treatment also elevated nociceptive thresholds in both articular and nonarticular structures. These results suggest that gold produces an antiinflammatory effect on arthritis by a neurotoxic effect on the peripheral nerves involved in neurogenic inflammation.
