Cells proliferating from human atherosclerotic lesions are resistant to the antiproliferative effect of TGF-␤ 1, a key factor in wound repair. DNA from human atherosclerotic and restenotic lesions was used to test the hypothesis that microsatellite instability leads to specific loss of the Type II receptor for TGF-␤ 1 (T ␤ R-II), causing acquired resistance to TGF-␤ 1. High fidelity PCR and restriction analysis was adapted to analyze deletions in an A 10 microsatellite within T ␤ R-II. DNA from lesions, and cells grown from lesions, showed acquired 1 and 2 bp deletions in T ␤ R-II, while microsatellites in the hMSH3 and hMSH6 genes, and hypermutable regions of p53 were unaffected. Sequencing confirmed that these deletions occurred principally in the replication error-prone A 10 microsatellite region, though nonmicrosatellite mutations were observed. The mutations could be identified within specific patches of the lesion, while the surrounding tissue, or unaffected arteries, exhibited the wild-type genotype. This microsatellite deletion causes frameshift loss of receptor function, and thus, resistance to the antiproliferative and apoptotic effects of TGF-␤ 1. We propose that microsatellite instability in T ␤ R-II disables growth inhibitory pathways, allowing monoclonal selection of a disease-prone cell type within some vascular lesions. ( J. Clin. Invest. 1997.

Glucocorticoid (GC) resistance can occur in a number of diseases. It can be either generalized (i.e., familial glucocorticoid resistance) or localized (i.e., asthma). In many cases, a reason for this resistance to steroids lies with mutations or polymorphisms present in the glucocorticoid receptor gene (GR/NR3C1) that belongs to a large family of nuclear receptors. A number of GC-resistant cell lines have been isolated in vitro, some of which arose or may have arisen in vivo. These and the mutations defined in them are included in this review as well as mutations engineered in plasmids and expressed in vitro. It also lists polymorphisms and the individual studies where association-related studies have been performed. NR3C1 is located on chromosome 5q31 and contains 10 exons that code for a 777 amino acid protein. There are two naturally occurring isoforms of the NR3C1, GRalpha (functional) and GRbeta (no hormone-binding ability). A total of 15 missense, three nonsense, three frameshift, one splice site, and two alternative spliced mutations have been reported in the NR3C1 gene associated with glucocorticoid resistance as well as 16 polymorphisms. Mutation and polymorphism data for NR3C1 will soon be found on the newly created locus-specific database.

This study investigated agreement between boys and their parents when reporting on health-related quality of life and the effects of steroid use, age, and physical functioning on self-reported health-related quality of life in boys with Duchenne muscular dystrophy. The Pediatric Quality of Life Inventory™ and brief functional measures were administered to 35 parent-son dyads. We found that agreement between parents and their sons was moderate (intraclass correlation coefficient [ICC](2,1) = 0.66; 95% confidence interval [CI], 0.40-0.80) to poor (ICC(2,1) = 0.64; 95% CI, 0.43-0.64). The boys' self-reports revealed a relationship between disease progression and physical functioning (r = -.75; P = .01); however, disease stage was not related to psychosocial functioning (r = -.27; NS). Parents and boys affected by Duchenne muscular dystrophy have a moderate to poor agreement on health-related quality of life measures, with parents reporting lower overall health-related quality of life when compared with their sons.

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The explosion of the toll-like receptors (TLRs) over the past decade has touched almost every field of mammalian biology and neuroscience is not an exception. The current advent of research papers examining the TLRs in the central nervous system (CNS) signifies that these receptors are not only involved in peripheral innate immunity but may also play a role in the development and regulation of CNS inflammation, neurodegeneration and brain trauma. This review addresses the potential role of TLRs in the brain and how they may be involved in various neuropathologies.

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Using the CMTPedS as an outcome measure of disease severity, children with CMT progress at a significant rate over 2 years. Understanding the rate at which children with CMT deteriorate is essential for adequately powering trials of disease-modifying interventions. Ann Neurol 2017;82:353-359.