Katherine E. Lewis

Increase in serum amyloid a evoked by dietary cholesterol is associated with increased atherosclerosis in mice.

Background—Elevated serum amyloid A (SAA) levels are associated with increased cardiovascular risk. SAA levels can be increased by dietary fat and cholesterol. Moreover, SAA can cause lipoproteins to bind extracellular vascular proteoglycans, a process that is critical in atherogenesis. Therefore, we hypothesized that diet-induced increases in SAA would increase atherosclerosis independent of their effect on plasma cholesterol levels. Methods and Results—Female LDL-receptor–null (LDLR−/−) mice were fed high–saturated fat diets (21%, wt/wt), with or without added cholesterol (0.15%, wt/wt), for 10 weeks. Compared with chow-fed controls, the high-fat diets increased plasma SAA levels. Addition of cholesterol further increased SAA levels 2-fold (P<0.05) without further increasing plasma cholesterol levels. Addition of dietary cholesterol also increased atherosclerosis (P<0.05). Four lines of evidence suggest that SAA actually might cause atherosclerosis: (1) SAA levels when mice were euthanized correlated with the extent of atherosclerosis (r=0.49; P<0.02); (2) SAA levels after 5 weeks of diet correlated with the extent of atherosclerosis at 10 weeks (r=0.66; P<0.01); (3) binding of HDL from these animals to proteoglycans in vitro was related to the HDL-SAA content (r=0.65; P<0.01); and (4) immunoreactive SAA was present in lesion areas enriched with both proteoglycans and apolipoprotein A-I, the major HDL apolipoprotein. Conclusions—Addition of cholesterol to a high-fat diet increased plasma SAA levels and atherosclerosis independent of an adverse effect on plasma lipoproteins, consistent with the hypothesis that SAA may promote atherosclerosis directly by mediating retention of SAA-enriched HDL to vascular proteoglycans.

Serum Amyloid A and Lipoprotein Retention in Murine Models of Atherosclerosis

Objective—Elevated serum amyloid A (SAA) levels are associated with increased cardiovascular risk in humans. Because SAA associates primarily with lipoproteins in plasma and has proteoglycan binding domains, we postulated that SAA might mediate lipoprotein retention on atherosclerotic extracellular matrix. Methods and Results—Immunohistochemistry was performed for SAA, apolipoprotein A-I (apoA-I), apolipoprotein B (apoB), and perlecan on proximal aortic lesions from chow-fed low-density lipoprotein receptor (LDLR)−/− and apoE−/− mice euthanized at 10, 50, and 70 weeks. SAA was detected on atherosclerotic lesion extracellular matrix at all time points in both strains. SAA area correlated highly with lesion areas (apoE−/−, r=0.76; LDLR−/−, r=0.86), apoA-I areas (apoE−/−, r=0.88; LDLR−/−, r=0.80), apoB areas (apoE−/−, r=0.74; LDLR−/−, r=0.89), and perlecan areas (apoE−/−, r=0.83; LDLR−/−, r=0.79) (all P<0.0001). In vitro, SAA enrichment increased high-density lipoprotein (HDL) binding to heparan sulfate proteoglycans, and immunoprecipitation experiments using plasma from apoE−/− and LDLR−/− mice demonstrated that SAA was present on both apoA-I–containing and apoB-containing lipoproteins. Conclusions—In chow-fed apoE−/− and LDLR−/− mice, SAA is deposited in murine atherosclerosis at all stages of lesion development, and SAA immunoreactive area correlates highly with lesion area, apoA-I area, apoB area, and perlecan area. These findings are consistent with a possible role for SAA-mediated lipoprotein retention in atherosclerosis.

Cell-Associated and Extracellular Phospholipid Transfer Protein in Human Coronary Atherosclerosis

Background Phospholipid transfer protein (PLTP) plays an important role in HDL particle metabolism and may modulate hepatic secretion of apolipoprotein B‐containing lipoproteins. However, whether PLTP might participate directly in human atherosclerotic lesion formation is unknown. Methods and Results The cellular and extracellular distributions of PLTP were determined in normal and atherosclerotic human coronary lesions with a monoclonal antibody to human PLTP. Cell types (smooth muscle cells [SMCs] or macrophages), apolipoproteins (apoA‐I, apoB, and apoE), and extracellular matrix proteoglycans (biglycan and versican) were identified on adjacent sections with monospecific antibodies. Minimal extracellular PLTP was detected in nonatherosclerotic coronary arteries, but extracellular and cellular PLTP immunostaining was widespread in atherosclerotic lesions. PLTP was detected in foam cell SMCs and in foam cell macrophages, which suggests that cellular cholesterol accumulation might increase PLTP expression in both cell types. This was confirmed by in vitro studies demonstrating that cholesterol loading of macrophages leads to 2‐ to 3‐fold increases in PLTP steady‐state mRNA levels, protein expression, and activity. PLTP also was detected in an extracellular distribution, colocalizing with apoA‐I, apoB, apoE, and the vascular proteoglycan biglycan. In gel mobility shift assays, both active and inactive recombinant PLTP markedly increased HDL binding to biglycan, which suggests that PLTP may mediate lipoprotein binding to proteoglycans independent of its phospholipid transfer activity. Conclusions PLTP is present in human atherosclerotic lesions, and its distribution suggests roles for PLTP in both cellular cholesterol metabolism and lipoprotein retention on extracellular matrix. (Circulation. 2003;108:270‐274.)

Supporting Generative Thinking About the Integer Number Line in Elementary Mathematics

This report provides evidence of the influence of a tutorial “communication game” on fifth graders’ generative understanding of the integer number line. Students matched for classroom and pretest score were randomly assigned to a tutorial (n = 19) and control group (n = 19). The tutorial group students played a 13-problem game in which student and tutor each were required to mark the same position on a number line but could not see one anothers activities. To resolve discrepant solutions, tutor and student constructed agreements about number line principles and conventions to guide subsequent placements. Pre-/posttest contrasts showed that (a) tutorial students gained more than controls and (b) agreement use predicted gain. Analyses of micro-constructions during play revealed properties of student learning trajectories.

An insider’s view of a mathematics learning disability: Compensating to gain access to fractions

ABSTRACT Research on mathematics learning disability (i.e., dyscalculia) tends to adopt a deficit model of the learner and quantify the ways in which these students are deficient. In this study we adopt a radically different approach. We understand disabilities to result from issues of access, and we explore mathematics learning disability (MLD) by leveraging the expertise of an individual with first-hand experience with this disability. Dylan (second author) has a unique perspective because, in addition to having an MLD, she also majored in statistics in college. Through videotaped interviews we documented the issues of access Dylan encountered and the ways in which she compensated to gain access. In this article we focus specifically on the topic of fractions, and identify Dylan’s issues of access with standard representations of fractions, including symbolic notation, area models, and fraction manipulatives. These issues of access mirrored the difficulties documented in other students with MLD, but were not similarly problematic for Dylan. This research provides novel insight into the difficulties experienced by students with MLD, reframes deficits in terms of issues of access, and demonstrates how an individual with an MLD may learn to compensate.

Clinical Interviews: Assessing and Designing Mathematics Instruction for Students With Disabilities:

Mathematics assessment is integral in enabling teachers to implement specially designed instruction for students with disabilities. This article presents an overview of an underutilized form of assessment, the clinical interview. A type of diagnostic assessment, clinical interviews are critically important when designing individualized instruction because the assessment provides information about how a student understands something or why a student is struggling. A rationale for its use is provided along with step-by-step instructions on how to implement a clinical interview to effectively document students’ strengths and weaknesses. The article concludes with an example of how a clinical interview can be used to directly inform instruction.

Access Through Compensation: Emancipatory View of a Mathematics Learning Disability

Abstract In this article, we provide a novel view of mathematics learning disability (MLD) by studying a student with an MLD (Dylan) who had compensated so effectively that she was able to major in statistics. We push back on the dominant deficit model used in studies of MLD, and consider issues of access and compensation from a Vygotskian theoretical frame. Through 8 videotaped interview sessions, we identified that Dylan’s primary difficulties were with mathematical notation and number sense, which resulted in issues accessing standard mathematical forms. Analysis revealed 8 compensatory strategies that Dylan used to address these issues of access. We frame our approach as emancipatory research. Dylan was involved in all phases of the study’s design, implementation, analysis, and dissemination, and is the second author. This work acknowledges that individuals with disabilities have research agendas of their own and have critical insight to share about the lived experience of their disability.

Designing a Bridging Discourse: Re-Mediation of a Mathematical Learning Disability

Students with disabilities present a unique instructional design challenge. These students often have qualitatively different ways of processing information, meaning that standard instructional approaches may not be effective. In this study I present a case study of a student with a mathematical learning disability for whom standard instruction on fractions had been ineffective. With regard to theory, I draw on Lev Vygotsky’s framing of disability and then use Anna Sfard’s conceptualization of mathematics as a discourse to design a fraction re-mediation that provided a bridge from the student’s discourse to the canonical mathematics discourse. This bridging discourse was used in 5 videotaped re-mediation sessions with the case study student. A fine-grained analysis of the re-mediation sessions traced the ways in which the student’s discourse shifted over time, which enabled her to solve problems she had previously been unable to solve. This study provides a proof of concept for reconceptualizing remediation and illustrates the potential utility of a bridging discourse to help students who have a history of failure gain access to the canonical mathematics discourse and content.

Beyond Error Patterns: A Sociocultural View of Fraction Comparison Errors in Students with Mathematical Learning Disabilities.

Although many students struggle with fractions, students with mathematical learning disabilities (MLDs) experience pervasive difficulties because of neurological differences in how they process numerical information. These students make errors that are qualitatively different than their typically achieving and low-achieving peers. This study builds upon a quantitative study of fraction comparison errors and a qualitative study of students’ understandings to explore why students with MLDs make errors on the easiest fraction comparison problems. A detailed analysis of videotaped individual tutoring sessions with two adult students with MLDs revealed that both students understood mathematical representations in atypical ways, which may help explain the unique and persistent error patterns identified in students with MLDs. This study illustrates how building upon both quantitative and qualitative studies can provide a more nuanced understanding of student errors, which in turn can directly connect to implications for instructional interventions.