The GAA triplet-repeat sequence in Friedreich ataxia shows a high level of somatic instability in vivo,with a significant predilection for large contractions

Friedreich ataxia is commonly caused by large expansions of a GAA triplet-repeat (GAA-TR) sequence in the first intron of the FRDA gene. We used small-pool PCR to analyze somatic variability among 7190 individual FRDA molecules from peripheral blood DNA of subjects carrying 12 different expanded alleles, ranging in size from 241 to 1105 triplets. Expanded alleles showed a length-dependent increase in somatic variability, with mutation loads ranging from 47% to 78%. We noted a strong contraction bias among long alleles (>500 triplets), which showed a 4-fold higher frequency of large contractions versus expansions. Some contractions were very large; of all somatic mutations scored, approximately 5% involved contractions of >50% of the original allele length, and 0.29% involved complete reversion to the normal/premutation length (< or =60 triplets). These observations contrast sharply with the strong expansion bias seen in expanded CTG triplet repeats in myotonic dystrophy. No somatic variability was detected in >6000 individual FRDA molecules analyzed from 15 normal alleles (8-25 triplets). A premutation allele with 44 uninterrupted GAA repeats was found to be unstable, ranging in size from 6 to 113 triplets, thus establishing the threshold for somatic instability between 26 and 44 GAA triplets. Analysis of an additional 7850 FRDA molecules from serially passaged lymphoblastoid cell lines carrying nine expanded alleles (132-933 triplets) showed very low mutation loads, ranging from 0% to 6.2%. Our data indicate that expanded GAA-TR alleles in Friedreich ataxia are highly mutable and have a natural tendency to contract in vivo, and that these properties depend on multiple factors, including DNA sequence, triplet-repeat length and unknown cell-type-specific factors.     

Gastrointestinal stromal tumors: an ultrastructural study

Gastrointestinal stromal tumors (GISTs) represent an enigmatic group of lesions of uncertain phenotype and biologic potential. Although earlier studies suggested smooth muscle cells, schwann cells, or neuronal differentiation, more recent evidence indicates that these tumors show phenotypic features that are similar to the interstitial cells of Cajal. Recently, investigators have begun to evaluate these lesions in a site-specific manner and have found that, in addition to morphologic differences between them, their biologic behavior also appears to be linked to their anatomic location. Many of these studies have emphasized the histologic and immunophenotypic features of GISTs in relation to their sites of origin, however, their site-specific ultrastructural characteristics have received little attention in the literature. In this study, we evaluated 34 GISTs (15 gastric, 12 small intestinal, 4 colonic, and 3 omental) for a variety of ultrastructural features in an effort to identify site-specific similarities and differences. Tumors predominantly composed of epithelioid cells were more commonly seen in gastric (60%) and omental (67%) tumors than in those of the small intestine (33%) and colon (0%). Cytoplasmic filaments and intercellular junctions were commonly seen in tumors from all locations, the filaments frequently forming paranuclear aggregates in the epithelioid cells. Tumors from all sites were composed of cells with surface filopodia and interdigitating cell processes, but in tumors of the stomach and omentum the filopodia were usually short and minimally intertwined, whereas those of small and large intestinal GISTs were characteristically long and complex. Basal lamina, though poorly formed, was present only in tumors of gastric and omental origin (13% and 67%, respectively). Pinocytotic vesicles were also seen in tumors from these sites (33% of gastric tumors and 67% of omental lesions) as well as those of the small intestine (17%) and the colon (25%). None of the gastric or omental tumors had microtubules; they were, however, seen in small intestinal (33%) and colonic (25%) stromal tumors. Skenoid fibers were seen in 33% of small intestinal GISTs and 1 metastatic gastric GIST. Overall, gastric and omental tumors have better developed features of myogenic differentiation and have blunt filopodia and minimally intertwined cell processes. Indeed, these 2 groups are indistinguishable ultrastructurally, raising the possibility that the genesis of omental GISTs is similar to that of gastric stromal tumors. Small intestinal stromal tumors have characteristic interdigitating cell processes and numerous elongate filopodia-like structures harboring intercellular junctions as well as microtubules and extracellular skenoid fibers. The constituent cells in colonic stromal tumors, while more reminiscent of small intestinal stromal, were frequently more primitive in appearance. In conclusion, GISTs from different anatomic locations share many overlapping ultrastructural characteristics; however, a few features are distinctive. It is hoped that these findings will aid in their recognition and contribute to the classification of this heterogeneous group of neoplasms.     

Impaired late suppression of Epstein-Barr virus (EBV)-induced immunoglobulin synthesis: A common feature of autoimmune disease

We examined regulation of Epstein-Barr virus-induced plaque-forming cell generation in peripheral blood mononuclear cells from several autoimmune and seronegative diseases and correlated these results with Epstein-Barr virus-induced proliferation. We confirmed the defective regulation of Epstein-Barr virus-induced plaque-forming cells in peripheral blood mononuclear cells of patients with rheumatoid arthritis and scleroderma. Peripheral blood mononuclear cells from patients with seronegative arthropathies and chronic infective inflammation (cystic fibrosis) had normal regulation of Epstein-Barr virus-induced plaque-forming cells. Peripheral blood mononuclear cells from rheumatoid arthritis had excessive plaque-forming cell generation in the face of a normally regulated decrease in Epstein-Barr virus-induced proliferation. In contrast, peripheral blood mononuclear cells from scleroderma had defective suppression of both Epstein-Barr virus-induced proliferation and plaque-forming cell generation. Thus, impaired regulation of Epstein-Barr virus-induced plaque-forming cell generation is a common feature of autoimmune disease and demonstrates some specificity for these disorders.     

Thoughts about encounters between nondisabled and disabled peers: Situational constraints,states-of-mind,valenced thought categories

This study explores three issues: thoughts and feelings of individuals with and without physical disabilities concerning encounters in different situations, ways of grouping self-statements into valenced categories, and use of states-of-mind (SOM) ratios as an alternative to positive and negative thought frequencies. Data from 127 able-bodied and 46 physically disabled college students indicate that, in everyday social encounters, nondisabled individuals' thoughts and feelings were more negative, while those of disabled individuals were more negative when helping was involved and when encounters centered on the impairment. Thus, problematic encounters between people with and without disabilities may be due to the reactions of individuals with disabilities in situations which involve help, and to reactions of able-bodied persons in everyday contexts. The data also confirm the utility of SOM ratios as an alternative to valenced frequencies in cognitive assessment: SOM scores discriminated groups when situational demands were manipulated and scores were linearly related to criterion measures. However, SOM ratios differed dramatically, depending on the attentional focus of thoughts. The findings illustrate types of thoughts which occur during interaction between people with and without disabilities, demonstrate a simple technique for grouping thoughts into valenced categories on an empirical basis, and highlight the relative contribution of cognitive and affective elements to overall valenced scores. Implications for research on assessment of self-statements are discussed and recommendations are made concerning programming to facilitate the social integration of people with disabilities.This research was supported by grants to the first author from the Social Sciences and Humanities Research Council of Canada and from Fonds F.C.A.R. pour l'aide et le soutien à la recherche. Thanks are due to Meribah Aikens, Maria Barile, Leo Bissonette, Bosco Daude, Jim Dubois, Lillian Fox, Evelyn Gold, Naomi Goodz, Darlene Judd, André Leblanc, John Martos, Sue McKenzie, Irwin Slopak, and Joan Wolforth for their assistance with various stages of this investigation.     

Usual Intake of Flavonoids Is Inversely Associated with Metabolic Syndrome in African American and White Males but Not Females in Baltimore City,Maryland, USA

Despite research that suggests flavonoids protect against metabolic syndrome (MetS) and evidence that intake of these compounds differs by race, knowledge about whether flavonoid–MetS associations vary among racial groups is limited. This study sought to estimate usual total flavonoid intake in African American and White adults and assess its sex- and sex/race-specific associations with MetS and its risk factors. Analysis of cross-sectional data from 1837 adults participating in the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study were analyzed. Usual total flavonoid intake was estimated using the NCI Method, and logistic regression measured its linkages with health outcomes. Among males overall and when stratified by race, odds of MetS and its risk factors low high-density lipoprotein cholesterol (HDL-C) and elevated glucose were lower at the 75th percentile of usual total flavonoid intake than at the 25th percentile (OR for MetS = 0.62; 95% CI = 0.53, 0.71). However, low HDL-C and elevated glucose were positively associated with usual flavonoid intake among females. The comparable associations by race within sex imply that the relationships between flavonoid and health outcomes may be evident across an array of intakes.