Showing papers by "University of North Carolina at Chapel Hill published in 2002"

Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.

Abstract: Background Treatment with peginterferon alfa-2a alone produces significantly higher sustained virologic responses than treatment with interferon alfa-2a alone in patients with chronic hepatitis C virus (HCV) infection. We compared the efficacy and safety of peginterferon alfa-2a plus ribavirin, interferon alfa-2b plus ribavirin, and peginterferon alfa-2a alone in the initial treatment of chronic hepatitis C. Methods A total of 1121 patients were randomly assigned to treatment and received at least one dose of study medication, consisting of 180 μg of peginterferon alfa-2a once weekly plus daily ribavirin (1000 or 1200 mg, depending on body weight), weekly peginterferon alfa-2a plus daily placebo, or 3 million units of interferon alfa-2b thrice weekly plus daily ribavirin for 48 weeks. Results A significantly higher proportion of patients who received peginterferon alfa-2a plus ribavirin had a sustained virologic response (defined as the absence of detectable HCV RNA 24 weeks after cessation of therapy) th...

Role of Histone H3 Lysine 27 Methylation in Polycomb-Group Silencing

Abstract: Polycomb group (PcG) proteins play important roles in maintaining the silent state of HOX genes. Recent studies have implicated histone methylation in long-term gene silencing. However, a connection between PcG-mediated gene silencing and histone methylation has not been established. Here we report the purification and characterization of an EED-EZH2 complex, the human counterpart of the Drosophila ESC-E(Z) complex. We demonstrate that the complex specifically methylates nucleosomal histone H3 at lysine 27 (H3-K27). Using chromatin immunoprecipitation assays, we show that H3-K27 methylation colocalizes with, and is dependent on, E(Z) binding at an Ultrabithorax (Ubx) Polycomb response element (PRE), and that this methylation correlates with Ubx repression. Methylation on H3-K27 facilitates binding of Polycomb (PC), a component of the PRC1 complex, to histone H3 amino-terminal tail. Thus, these studies establish a link between histone methylation and PcG-mediated gene silencing.

Beware of q2

Abstract: Validation is a crucial aspect of any quantitative structure-activity relationship (QSAR) modeling. This paper examines one of the most popular validation criteria, leave-one-out cross-validated R2 (LOO q2). Often, a high value of this statistical characteristic (q2 > 0.5) is considered as a proof of the high predictive ability of the model. In this paper, we show that this assumption is generally incorrect. In the case of 3D QSAR, the lack of the correlation between the high LOO q2 and the high predictive ability of a QSAR model has been established earlier [Pharm. Acta Helv. 70 (1995) 149; J. Chemomet. 10(1996)95; J. Med. Chem. 41 (1998) 2553]. In this paper, we use two-dimensional (2D) molecular descriptors and k nearest neighbors (kNN) QSAR method for the analysis of several datasets. No correlation between the values of q2 for the training set and predictive ability for the test set was found for any of the datasets. Thus, the high value of LOO q2 appears to be the necessary but not the sufficient condition for the model to have a high predictive power. We argue that this is the general property of QSAR models developed using LOO cross-validation. We emphasize that the external validation is the only way to establish a reliable QSAR model. We formulate a set of criteria for evaluation of predictive ability of QSAR models.

Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial.

Abstract: ContextFollowing percutaneous coronary intervention (PCI), short-term clopidogrel therapy in addition to aspirin leads to greater protection from thrombotic complications than aspirin alone. However, the optimal duration of combination oral antiplatelet therapy is unknown. Also, although current clinical data suggest a benefit for beginning therapy with a clopidogrel loading dose prior to PCI, the practical application of this therapy has not been prospectively studied.ObjectivesTo evaluate the benefit of long-term (12-month) treatment with clopidogrel after PCI and to determine the benefit of initiating clopidogrel with a preprocedure loading dose, both in addition to aspirin therapy.Design, Setting, and ParticipantsThe Clopidogrel for the Reduction of Events During Observation (CREDO) trial, a randomized, double-blind, placebo-controlled trial conducted among 2116 patients who were to undergo elective PCI or were deemed at high likelihood of undergoing PCI, enrolled at 99 centers in North America from June 1999 through April 2001.InterventionsPatients were randomly assigned to receive a 300-mg clopidogrel loading dose (n = 1053) or placebo (n = 1063) 3 to 24 hours before PCI. Thereafter, all patients received clopidogrel, 75 mg/d, through day 28. From day 29 through 12 months, patients in the loading-dose group received clopidogrel, 75 mg/d, and those in the control group received placebo. Both groups received aspirin throughout the study.Main Outcome MeasuresOne-year incidence of the composite of death, myocardial infarction (MI), or stroke in the intent-to-treat population; 28-day incidence of the composite of death, MI, or urgent target vessel revascularization in the per-protocol population.ResultsAt 1 year, long-term clopidogrel therapy was associated with a 26.9% relative reduction in the combined risk of death, MI, or stroke (95% confidence interval [CI], 3.9%-44.4%; P = .02; absolute reduction, 3%). Clopidogrel pretreatment did not significantly reduce the combined risk of death, MI, or urgent target vessel revascularization at 28 days (reduction, 18.5%; 95% CI, −14.2% to 41.8%; P = .23). However, in a prespecified subgroup analysis, patients who received clopidogrel at least 6 hours before PCI experienced a relative risk reduction of 38.6% (95% CI, −1.6% to 62.9%; P = .051) for this end point compared with no reduction with treatment less than 6 hours before PCI. Risk of major bleeding at 1 year increased, but not significantly (8.8% with clopidogrel vs 6.7% with placebo; P = .07).ConclusionsFollowing PCI, long-term (1-year) clopidogrel therapy significantly reduced the risk of adverse ischemic events. A loading dose of clopidogrel given at least 3 hours before the procedure did not reduce events at 28 days, but subgroup analyses suggest that longer intervals between the loading dose and PCI may reduce events.

Service Quality Delivery Through Web Sites: A Critical Review of Extant Knowledge

Abstract: Evidence exists that service quality delivery through Web sites is an essential strategy to success, possibly more important than low price and Web presence. To deliver superior service quality, managers of companies with Web presences must first understand how customers perceive and evaluate online customer service. Information on this topic is beginning to emerge from both academic and practitioner sources, but this information has not yet been examined as a whole. The goals of this article are to review and synthesize the literature about service quality delivery through Web sites, describe what is known about the topic, and develop an agenda for needed research.

Crystal engineering of NLO materials based on metal-organic coordination networks

Abstract: Crystal engineering, the ability to predict and control the packing of molecular building units in the solid state, has attracted much attention over the past three decades owing to its potential exploitation for the synthesis of technologically important materials. We present here the development of crystal-engineering strategies toward the synthesis of noncentrosymmetric infinite coordination networks for use as second-order nonlinear optical (NLO) materials. Work performed mainly in our laboratory has demonstrated that noncentrosymmetric solids based on infinite networks can be rationally synthesized by combining unsymmetrical bridging ligands and metal centers with well-defined coordination geometries. Specifically, coordination networks based on 3D diamondoid and 2D grid structures can be successfully engineered with a high degree of probability and predictability to crystallize in noncentrosymmetric space groups. We have also included noncentrosymmetric solids based on 1D chains and related helical structures for comparison.

The convergent and discriminant validity of subjective fit perceptions.

Abstract: This study examined whether employees develop perceptions about 3 different types of fit: person-organization fit, needs-supplies fit, and demands-abilities fit. Confirmatory factor analyses of data from 2 different samples strongly suggested that employees differentiate between these 3 types of fit. Furthermore, results from a longitudinal design of 187 managers supported both the convergent and discriminant validity of the different types of fit perceptions. Specifically, person-organization fit perceptions were related to organization-focused outcomes (e.g., organizational identification, citizenship behaviors, turnover decisions), whereas needs-supplies fit perceptions were related to job- and career-focused outcomes (e.g., job satisfaction, career satisfaction, occupational commitment). Although demands-abilities fit perceptions emerged as a distinct construct, they were not related to hypothesized outcomes (e.g., job performance, raises).

Network Ties, Reputation, and the Financing of New Ventures

Abstract: Explaining how entrepreneurs overcome information asymmetry between themselves and potential investors to obtain financing is an important issue for entrepreneurship research. Our premise is that economic explanations for venture finance, which do not consider how social ties influence this process, are undersocialized and incomplete. However, we also argue that organization theoretic arguments, which draw on the concept of social obligation, are oversocialized. Drawing on the organizational theory literature, and in-depth fieldwork with 50 high-technology ventures, we examine the effects of direct and indirect ties between entrepreneurs and 202 seed-stage investors on venture finance decisions. We show that these ties influence the selection of ventures to fund through a process of information transfer.

Identification of Genes Periodically Expressed in the Human Cell Cycle and Their Expression in Tumors

Abstract: The genome-wide program of gene expression during the cell division cycle in a human cancer cell line (HeLa) was characterized using cDNA microarrays. Transcripts of >850 genes showed periodic variation during the cell cycle. Hierarchical clustering of the expression patterns revealed coexpressed groups of previously well-characterized genes involved in essential cell cycle processes such as DNA replication, chromosome segregation, and cell adhesion along with genes of uncharacterized function. Most of the genes whose expression had previously been reported to correlate with the proliferative state of tumors were found herein also to be periodically expressed during the HeLa cell cycle. However, some of the genes periodically expressed in the HeLa cell cycle do not have a consistent correlation with tumor proliferation. Cell cycle-regulated transcripts of genes involved in fundamental processes such as DNA replication and chromosome segregation seem to be more highly expressed in proliferative tumors simply because they contain more cycling cells. The data in this report provide a comprehensive catalog of cell cycle regulated genes that can serve as a starting point for functional discovery. The full dataset is available at http://genome-www.stanford.edu/Human-CellCycle/HeLa/.

Molecular pathogenesis of human hepatocellular carcinoma

Abstract: Hepatocarcinogenesis is a slow process during which genomic changes progressively alter the hepatocellular phenotype to produce cellular intermediates that evolve into hepatocellular carcinoma. During the long preneoplastic stage, in which the liver is often the site of chronic hepatitis, cirrhosis, or both, hepatocyte cycling is accelerated by upregulation of mitogenic pathways, in part through epigenetic mechanisms. This leads to the production of monoclonal populations of aberrant and dysplastic hepatocytes that have telomere erosion and telomerase re-expression, sometimes microsatellite instability, and occasionally structural aberrations in genes and chromosomes. Development of dysplastic hepatocytes in foci and nodules and emergence of hepatocellular carcinoma are associated with the accumulation of irreversible structural alterations in genes and chromosomes, but the genomic basis of the malignant phenotype is heterogeneous. The malignant hepatocyte phenotype may be produced by the disruption of a number of genes that function in different regulatory pathways, producing several molecular variants of hepatocellular carcinoma. New strategies should enable these variants to be characterized.

Arabidopsis gp91phox homologues AtrbohD and AtrbohF are required for accumulation of reactive oxygen intermediates in the plant defense response

Abstract: Reactive oxygen intermediates (ROI) are strongly associated with plant defense responses. The origin of these ROI has been controversial. Arabidopsis respiratory burst oxidase homologues (rboh genes) have been proposed to play a role in ROI generation. We analyzed lines carrying dSpm insertions in the highly expressed AtrbohD and AtrbohF genes. Both are required for full ROI production observed during incompatible interactions with the bacterial pathogen Pseudomonas syringae pv. tomato DC3000(avrRpm1) and the oomycete parasite Peronospora parasitica. We also observed reduced cell death, visualized by trypan blue stain and reduced electrolyte leakage, in the Atrboh mutants after DC3000(avrRpm1) inoculation. However, enhanced cell death is observed after infection of mutant lines with P. parasitica. Paradoxically, although atrbohD mutation eliminated the majority of total ROI production, atrbohF mutation exhibited the strongest effect on cell death.

Modeling Multilevel Data Structures

Abstract: data are becoming quite common in political science and provide numerous opportunities for theory testing and development. Unfortunately this type of data typically generates a number of statistical problems, of which clustering is particularly impor? tant. To exploit the opportunities of? fered by multilevel data, and to solve the statistical problems inherent in them, special statistical techniques are required. In this article, we focus on a technique that has become popular in educational statistics and sociology?multilevel analysis. In multilevel analysis, researchers build models that capture the layered structure of multilevel data, and determine how layers interact and impact a dependent variable of interest. Our objective in this article is to introduce the logic and statistical theory behind multilevel models, to illustrate how such models can be applied fruitfully in political science, and to call atten? tion to some of the pitfalls in multilevel analysis.

Qualitative Analysis on Stage: Making the Research Process More Public:

Abstract: Discussions regarding standards for assessing qualitative research have not sufficiently addressed questions concerning the privatization of this type of analysis. In response to this dilemma, the authors of this article address some of the strategies that they have employed in working with doctoral students and offer suggestions for assessing and publicly disclosing the methodological rigor and analytical defensibility of qualitative research. Specifically, tabular strategies are introduced for use in documenting the relationship between data sources and a study’s research questions, the development of themes and categories, and the triangulation of findings. Examples from three dissertations are provided.

The contextual effect of the local food environment on residents' diets: The atherosclerosis risk in communities study

Abstract: Objectives. We studied the association between the local food environment and residents’ report of recommended dietary intake. Methods. Recommended intakes of foods and nutrients for 10 623 Atherosclerosis Risk in Communities participants were estimated from food frequency questionnaires. Supermarkets, grocery stores, and full-service and fast-food restaurants were geocoded to census tracts. Results. Black Americans’ fruit and vegetable intake increased by 32% for each additional supermarket in the census tract (relative risk [RR] = 1.32; 95% confidence interval [CI] = 1.08, 1.60). White Americans’ fruit and vegetable intake increased by 11% with the presence of 1 or more supermarket (RR = 1.11; 95% CI = 0.93, 1.32). Conclusions. These findings suggest the local food environment is associated with residents’ recommended diets.

Microarray analysis reveals a major direct role of DNA copy number alteration in the transcriptional program of human breast tumors

Abstract: Genomic DNA copy number alterations are key genetic events in the development and progression of human cancers. Here we report a genome-wide microarray comparative genomic hybridization (array CGH) analysis of DNA copy number variation in a series of primary human breast tumors. We have profiled DNA copy number alteration across 6,691 mapped human genes, in 44 predominantly advanced, primary breast tumors and 10 breast cancer cell lines. While the overall patterns of DNA amplification and deletion corroborate previous cytogenetic studies, the high-resolution (gene-by-gene) mapping of amplicon boundaries and the quantitative analysis of amplicon shape provide significant improvement in the localization of candidate oncogenes. Parallel microarray measurements of mRNA levels reveal the remarkable degree to which variation in gene copy number contributes to variation in gene expression in tumor cells. Specifically, we find that 62% of highly amplified genes show moderately or highly elevated expression, that DNA copy number influences gene expression across a wide range of DNA copy number alterations (deletion, low-, mid- and high-level amplification), that on average, a 2-fold change in DNA copy number is associated with a corresponding 1.5-fold change in mRNA levels, and that overall, at least 12% of all the variation in gene expression among the breast tumors is directly attributable to underlying variation in gene copy number. These findings provide evidence that widespread DNA copy number alteration can lead directly to global deregulation of gene expression, which may contribute to the development or progression of cancer.

Effects of reduced mucus oxygen concentration in airway Pseudomonas infections of cystic fibrosis patients

Abstract: Current theories of CF pathogenesis predict different predisposing “local environmental” conditions and sites of bacterial infection within CF airways. Here we show that, in CF patients with established lung disease, Psuedomonas aeruginosa was located within hypoxic mucopurulent masses in airway lumens. In vitro studies revealed that CF-specific increases in epithelial O2 consumption, linked to increased airway surface liquid (ASL) volume absorption and mucus stasis, generated steep hypoxic gradients within thickened mucus on CF epithelial surfaces prior to infection. Motile P. aeruginosa deposited on CF airway surfaces penetrated into hypoxic mucus zones and responded to this environment with increased alginate production. With P. aeruginosa growth in oxygen restricted environments, local hypoxia was exacerbated and frank anaerobiosis, as detected in vivo, resulted. These studies indicate that novel therapies for CF include removal of hypoxic mucus plaques and antibiotics effective against P. aeruginosa adapted to anaerobic environments.

Mucus clearance as a primary innate defense mechanism for mammalian airways

Abstract: The conducting airways branch 20–25 times between the trachea and the alveoli as inhaled air passes from the relatively constricted nasal/tracheal passages to the large surface area of alveoli (70 m2), where gas exchange occurs. This branching anatomy leads to a surface area that expands greatly from proximal airways (e.g., third generation; ∼50 cm2) to distal airways (20th to 25th generation; ∼2 m2). The regional differences in airway surface area (or airway perimeters; ref. 1), which is often depicted by showing the airways as an inverted funnel (Figure ​(Figure1),1), pose interesting challenges for lung defense. Because many of the particles that settle on airway surfaces are infectious, airways have evolved innate defense mechanisms that constantly protect airways against bacterial and other types of infection. Figure 1 Pulmonary defense mechanisms preventing chronic bacterial infection. The lung is depicted as an inverted funnel, reflecting the relative surface area of distal versus proximal airways. The mechanical-clearance-of-mucus hypothesis is shown on the left. ... There is still little agreement on the nature of these innate airway defense mechanisms (2, 3) (Figure ​(Figure1).1). In the more traditional view, mechanical clearance of mucus is considered the primary innate airway defense mechanism (4–6). In this view, the role of the epithelia lining airway surfaces is to provide the integrated activities required for mucus transport, including ciliary activity and regulation of the proper quantity of salt and water on airway surfaces via transepithelial ion transport. More recently, a second view of innate airway defense has emerged as a result of studies of the pathogenesis of cystic fibrosis (CF) (7). This view emphasizes a role for a “chemical shield” in protecting the lung against inhaled bacteria (8). In this hypothesis, the two important functions for epithelia are the production of salt-sensitive defensins that are secreted into airway lumens, and the production of a low-salt (<50 mM NaCl) liquid on airway surfaces that renders defensins active (9). The predictions of each of these models and the relevant data have been extensively reviewed (2, 3, 10, 11). Here, we will focus on the role of mucus clearance in the lung as the more important innate defense mechanism in health and disease, including CF. We will attempt to fill in the gaps in our knowledge regarding important aspects of the mucus clearance system, and, where relevant, point out differences between the two views of innate airway defense.

Early Childhood Education: Young Adult Outcomes From the Abecedarian Project

Abstract: The high-risk infants who initially enrolled in the Abecedarian Project, a longitudinal prospective study of the benefits of early childhood educational intervention within a child care setting, were followed up as young adults (age 21 years). One hundred-eleven infants were in the original sample; 104 took part in the follow up. Treatment was provided in 2 phases: during preschool and in the primary grades. Participants received either both phases, 1, but not both, or neither. Assignment to groups was random. Those in the preschool treatment group earned significantly higher scores on intellectual and academic measures as young adults, attained significantly more years of total education, were more likely to attend a 4-year college, and showed a reduction in teenaged pregnancy compared with preschool controls. Preschool treatment was associated with educationally meaningful effect sizes on reading and math skills that persisted into adulthood. School-age treatment served to maintain preschool benefits fo...

A role for lipid shells in targeting proteins to caveolae, rafts, and other lipid domains.

Abstract: The surface membrane of cells is studded with morphologically distinct regions, or domains, like microvilli, cell-cell junctions, and coated pits. Each of these domains is specialized for a particular function, such as nutrient absorption, cell-cell communication, and endocytosis. Lipid domains, which include caveolae and rafts, are one of the least understood membrane domains. These domains are high in cholesterol and sphingolipids, have a light buoyant density, and function in both endocytosis and cell signaling. A major mystery, however, is how resident molecules are targeted to lipid domains. Here, we propose that the molecular address for proteins targeted to lipid domains is a lipid shell.

Visual Scanning of Faces in Autism

Abstract: The visual scanpaths of five high-functioning adult autistic males and five adult male controls were recorded using an infrared corneal reflection technique as they viewed photographs of human faces. Analyses of the scanpath data revealed marked differences in the scanpaths of the two groups. The autistic participants viewed nonfeature areas of the faces significantly more often and core feature areas of the faces (i.e., eyes, nose, and mouth) significantly less often than did control participants. Across both groups of participants, scanpaths generally did not differ as a function of the instructions given to the participants (i.e., “Please look at the faces in any manner you wish.” vs. “Please identify the emotions portrayed in these faces.”). Autistic participants showed a deficit in emotion recognition, but this effect was driven primarily by deficits in the recognition of fear. Collectively, these results indicate disorganized processing of face stimuli in autistic individuals and suggest a mechanism that may subserve the social information processing deficits that characterize autism spectrum disorders.

Gas molecule adsorption in carbon nanotubes and nanotube bundles

Abstract: We studied various gas molecules (NO2, O2, NH3, N2, CO2, CH4, H2O, H2, Ar) on single-walled carbon nanotubes (SWNTs) and bundles using first principles methods. The equilibrium position, adsorption energy, charge transfer, and electronic band structures are obtained for different kinds of SWNTs. Most molecules adsorb weakly on SWNTs and can be either charge donors or acceptors to the nanotubes. We find that the gas adsorption on the bundle interstitial and groove sites is stronger than that on individual nanotubes. The electronic properties of SWNTs are sensitive to the adsorption of certain gases such as NO2 and O2. Charge transfer and gas-induced charge fluctuation might significantly affect the transport properties of SWNTs. Our theoretical results are consistent with recent experiments.

Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial.

Abstract: Context Little randomized evidence is available to guide the in-hospital management of patients with an acute exacerbation of chronic heart failure. Although intravenous inotropic therapy usually produces beneficial hemodynamic effects and is labeled for use in the care of such patients, the effect of such therapy on intermediate-term clinical outcomes is uncertain. Objective To prospectively test whether a strategy that includes short-term use of milrinone in addition to standard therapy can improve clinical outcomes of patients hospitalized with an exacerbation of chronic heart failure. Design Prospective, randomized, double-blind, placebo-controlled trial conducted from July 1997 through November 1999. Setting Seventy-eight community and tertiary care hospitals in the United States. Participants A total of 951 patients admitted with an exacerbation of systolic heart failure not requiring intravenous inotropic support (mean age, 65 years; 92% with baseline New York Heart Association class III or IV; mean left ventricular ejection fraction, 23%). Intervention Patients were randomly assigned to receive a 48-hour infusion of either milrinone, 0.5 microg/kg per minute initially (n = 477), or saline placebo (n = 472). Main outcome measure Cumulative days of hospitalization for cardiovascular cause within 60 days following randomization. Results The median number of days hospitalized for cardiovascular causes within 60 days after randomization did not differ significantly between patients given milrinone (6 days) compared with placebo (7 days; P =.71). Sustained hypotension requiring intervention (10.7% vs 3.2%; P Conclusion These results do not support the routine use of intravenous milrinone as an adjunct to standard therapy in the treatment of patients hospitalized for an exacerbation of chronic heart failure.