Showing papers by "Emory University published in 1999"

Perceptual symbol systems.

Abstract: Prior to the twentieth century, theories of knowledge were inherently perceptual. Since then, developments in logic, statis- tics, and programming languages have inspired amodal theories that rest on principles fundamentally different from those underlying perception. In addition, perceptual approaches have become widely viewed as untenable because they are assumed to implement record- ing systems, not conceptual systems. A perceptual theory of knowledge is developed here in the context of current cognitive science and neuroscience. During perceptual experience, association areas in the brain capture bottom-up patterns of activation in sensory-motor areas. Later, in a top-down manner, association areas partially reactivate sensory-motor areas to implement perceptual symbols. The stor- age and reactivation of perceptual symbols operates at the level of perceptual components - not at the level of holistic perceptual expe- riences. Through the use of selective attention, schematic representations of perceptual components are extracted from experience and stored in memory (e.g., individual memories of green, purr, hot). As memories of the same component become organized around a com- mon frame, they implement a simulator that produces limitless simulations of the component (e.g., simulations of purr). Not only do such simulators develop for aspects of sensory experience, they also develop for aspects of proprioception (e.g., lift, run) and introspec- tion (e.g., compare, memory, happy, hungry). Once established, these simulators implement a basic conceptual system that represents types, supports categorization, and produces categorical inferences. These simulators further support productivity, propositions, and ab- stract concepts, thereby implementing a fully functional conceptual system. Productivity results from integrating simulators combinato- rially and recursively to produce complex simulations. Propositions result from binding simulators to perceived individuals to represent type-token relations. Abstract concepts are grounded in complex simulations of combined physical and introspective events. Thus, a per- ceptual theory of knowledge can implement a fully functional conceptual system while avoiding problems associated with amodal sym- bol systems. Implications for cognition, neuroscience, evolution, development, and artificial intelligence are explored.

The glutamate receptor ion channels

Abstract: The ionotropic glutamate receptors are ligand-gated ion channels that mediate the vast majority of excitatory neurotransmission in the brain. The cloning of cDNAs encoding glutamate receptor subunits, which occurred mainly between 1989 and 1992 ([Hollmann and Heinemann, 1994][1]), stimulated this

Mitochondrial diseases in man and mouse.

Abstract: Over the past 10 years, mitochondrial defects have been implicated in a wide variety of degenerative diseases, aging, and cancer. Studies on patients with these diseases have revealed much about the complexities of mitochondrial genetics, which involves an interplay between mutations in the mitochondrial and nuclear genomes. However, the pathophysiology of mitochondrial diseases has remained perplexing. The essential role of mitochondrial oxidative phosphorylation in cellular energy production, the generation of reactive oxygen species, and the initiation of apoptosis has suggested a number of novel mechanisms for mitochondrial pathology. The importance and interrelationship of these functions are now being studied in mouse models of mitochondrial disease.

Effects of Risedronate Treatment on Vertebral and Nonvertebral Fractures in Women With Postmenopausal Osteoporosis: A Randomized Controlled Trial

Abstract: Context Risedronate, a potent bisphosphonate, has been shown to be effective in the treatment of Paget disease of bone and other metabolic bone diseases but, to our knowledge, it has not been evaluated in the treatment of established postmenopausal osteoporosis.

Risk for psychopathology in the children of depressed mothers: a developmental model for understanding mechanisms of transmission.

Abstract: A large body of literature documents the adverse effects of maternal depression on the functioning and development of offspring. Although investigators have identified factors associated with risk for abnormal development and psychopathology in the children, little attention has been paid to the mechanisms explaining the transmission of risk from the mothers to the children. Moreover, no existing model both guides understanding of the various processes' interrelatedness and considers the role of development in explicating the manifestation of risk in the children. This article proposes a developmentally sensitive, integrative model for understanding children's risk in relation to maternal depression. Four mechanisms through which risk might be transmitted are evaluated: (a) heritability of depression; (b) innate dysfunctional neuroregulatory mechanisms; (c) exposure to negative maternal cognitions, behaviors, and affect; and (d) the stressful context of the children's lives. Three factors that might moderate this risk are considered: (a) the father's health and involvement with the child, (b) the course and timing of the mother's depression, and (c) characteristics of the child. Relevant issues are discussed, and promising directions for future research are suggested.

A new oniom implementation in gaussian98. part i. the calculation of energies, gradients, vibrational frequencies and electric field derivatives

Abstract: The IMOMM, IMOMO, and ONIOM methods have been proven to be powerful tools for the theoretical treatment of large molecular systems where different levels of theory are applied to different parts of a molecule. Within this framework we present a modified handling of the link atoms which are introduced to terminate the dangling bonds of the model system. Using this new scheme the definition of the combined energy gradient, the Hessian matrix, and the integration of higher derivatives of the energy with respect to nuclear coordinates and the electric field vector becomes straightforward. This allows for the first time the consistent combination of vibrational frequencies and the calculation of other molecular properties such as IR intensities, Raman intensities as well as dipole moments, polarizabilities, and hyperpolarizabilities. Test calculations for some typical as well as unusual examples and partitioning schemes are presented to demonstrate the power and limitations of the method and to provide guidelines for its applicability. Users of the method are strongly advised to test, calibrate and confirm for themselves the validity of the method combination and the model subsystem for the properties they want to calculate.

Cell transformation by the superoxide-generating oxidase Mox1

Abstract: Reactive oxygen species (ROS) generated in some non-phagocytic cells are implicated in mitogenic signalling and cancer. Many cancer cells show increased production of ROS, and normal cells exposed to hydrogen peroxide or superoxide show increased proliferation and express growth-related genes. ROS are generated in response to growth factors, and may affect cell growth, for example in vascular smooth-muscle cells. Increased ROS in Ras-transformed fibroblasts correlates with increased mitogenic rate. Here we describe the cloning of mox1, which encodes a homologue of the catalytic subunit of the superoxide-generating NADPH oxidase of phagocytes, gp91phox. mox1 messenger RNA is expressed in colon, prostate, uterus and vascular smooth muscle, but not in peripheral blood leukocytes. In smooth-muscle cells, platelet-derived growth factor induces mox1 mRNA production, while antisense mox1 mRNA decreases superoxide generation and serum-stimulated growth. Overexpression of mox1 in NIH3T3 cells increases superoxide generation and cell growth. Cells expressing mox1 have a transformed appearance, show anchorage-independent growth and produce tumours in athymic mice. These data link ROS production by Mox1 to growth control in non-phagocytic cells.

Dramatic rise in plasma viremia after CD8+ T cell depletion in simian immunodeficiency virus-infected macaques

Abstract: To determine the role of CD8(+) T cells in controlling simian immunodeficiency virus (SIV) replication in vivo, we examined the effect of depleting this cell population using an anti-CD8 monoclonal antibody, OKT8F. There was on average a 99.9% reduction of CD8 cells in peripheral blood in six infected Macaca mulatta treated with OKT8F. The apparent CD8 depletion started 1 h after antibody administration, and low CD8 levels were maintained until day 8. An increase in plasma viremia of one to three orders of magnitude was observed in five of the six macaques. The injection of a control antibody to an infected macaque did not induce a sustained viral load increase, nor did it significantly reduce the number of CD8(+) T cells. These results demonstrate that CD8 cells play a crucial role in suppressing SIV replication in vivo.

Commonality in Liquidity

Abstract: Traditionally and understandably, the microscope of market microstructure has focused on attributes of single assets. Little theoretical attention and virtually no empirical work has been devoted to common determinants of liquidity nor to their empirical manifestation, correlated movements in liquidity. But a wider-angle lens exposes an imposing image of commonality. Quoted spreads, quoted depth, and effective spreads co-move with market- and industry-wide liquidity. After controlling for well-known individual liquidity determinants such as volatility, volume, and price, common influences remain significant and material. Recognizing the existence of commonality is a key to uncovering some suggestive evidence that inventory risks and asymmetric information both affect intertemporal changes in liquidity.

The role of corticotropin-releasing factor in depression and anxiety disorders

Abstract: Corticotropin-releasing factor (CRF), a 41 amino acid-containing peptide, appears to mediate not only the endocrine but also the autonomic and behavioral responses to stress. Stress, in particular early-life stress such as childhood abuse and neglect, has been associated with a higher prevalence rate of affective and anxiety disorders in adulthood. In the present review, we describe the evidence suggesting that CRF is hypersecreted from hypothalamic as well as from extrahypothalamic neurons in depression, resulting in hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and elevations of cerebrospinal fluid (CSF) concentrations of CRF. This increase in CRF neuronal activity is also believed to mediate certain of the behavioral symptoms of depression involving sleep and appetite disturbances, reduced libido, and psychomotor changes. The hyperactivity of CRF neuronal systems appears to be a state marker for depression because HPA axis hyperactivity normalizes following successful antidepressant treatment. Similar biochemical and behavioral findings have been observed in adult rats and monkeys that have been subjected to early-life stress. In contrast, clinical studies have not revealed any consistent changes in CSF CRF concentrations in patients with anxiety disorders; however, preclinical findings strongly implicate a role for CRF in the pathophysiology of certain anxiety disorders, probably through its effects on central noradrenergic systems. The findings reviewed here support the hypothesis that CRF receptor antagonists may represent a novel class of antidepressants and/or anxiolytics.

Information Technology Effects on Firm Performance as Measured by Tobin's q

Abstract: Despite increasing anecdotal evidence that information technology (IT) assets contribute to firm performance and future growth potential of firms, the empirical results relating IT investments to firm performance measures have been equivocal. However, the bulk of the studies have relied exclusively on accounting-based measures of firm performance, which largely tend to ignore IT's contribution to performance dimensions such as strategic flexibility and intangible value. In this paper, we use Tobin's q, a financial market-based measure of firm performance and examine the association between IT investments and firm q values, after controlling for a variety of industry factors and firm-specific variables. The results based on data from 1988-1993 indicate that, in all of the five years, the inclusion of the IT expenditure variable in the model increased the variance explained in q significantly. The results also showed that, for all five years, IT investments had a significantly positive association with Tobin's q value. Our results are consistent with the notion that IT contributes to a firm's future performance potential, which a forward-looking measure such as the q is better able to capture.

Multilevel Theorizing about Creativity in Organizations: A Sensemaking Perspective

Abstract: In this article we explore assumptions about the levels of analysis embedded in the extant literature on creativity in organizations. Uncovering and then relaxing these assumptions allow us to extend the literature with an alternative but complementary model of how creativity unfolds in complex, large-scale, and long-duration organizational projects. We build on the paradigm of sensemaking and propose a multilevel model of creativity that, as its defining feature, examines how periodic organizational crises reframe the negotiated order of belief structures about creativity.

Marketing, Business Processes, and Shareholder Value: An Organizationally Embedded View of Marketing Activities and the Discipline of Marketing

Abstract: The authors develop a framework for understanding the integration of marketing with business processes and shareholder value. The framework redefines marketing phenomena as embedded in three core b...

Cultural sensitivity in public health: defined and demystified.

Abstract: There is consensus that health promotion programs should be culturally sensitive (CS). Yet, despite the ubiquitous nature of CS within public health research and practice, there has been surprisingly little attention given to defining CS or delineating a framework for developing culturally sensitive programs and practitioners. This paper describes a model for understanding CS from a public health perspective; describes a process for applying this model in the development of health promotion and disease prevention interventions; and highlights research priorities. Cultural sensitivity is defined by two dimensions: surface and deep structures. Surface structure involves matching intervention materials and messages to observable, "superficial" characteristics of a target population. This may involve using people, places, language, music, food, locations, and clothing familiar to, and preferred by, the target audience. Surface structure refers to how well interventions fit within a specific culture. Deep structure involves incorporating the cultural, social, historical, environmental and psychological forces that influence the target health behavior in the proposed target population. Whereas surface structure generally increases the "receptivity" or "acceptance" of messages, deep structure conveys salience. Techniques, borrowed from social marketing and health communication theory, for developing culturally sensitive interventions are described. Research is needed to determine the effectiveness of culturally sensitive programs.

Attitudes and Beliefs of African Americans Toward Participation in Medical Research

Abstract: OBJECTIVE: To describe barriers to participation of African Americans in research. DESIGN: Focus group interviews conducted in 1997. PATIENTS: Thirty-three African-American adults presenting to an urban public hospital for outpatient medical care participated in one of five focus groups. MEASUREMENTS AND MAIN RESULTS: African-American patients' attitudes toward medical research were measured. Mistrust of doctors, scientists, and the government was reported consistently by the participants. Many participants described concerns about the ethical conduct of clinicians and investigators when poor or minority patients are involved and cited examples of exploitation as supporting evidence for their mistrust of the medical establishment. While participants were clear about the violation of human rights in the Tuskegee Syphilis Study, all were misinformed of the historical facts of the study. Few participants understood the concept of informed consent. Participants saw signing the document as relinquishing their autonomy and as a legal protection for physicians. Despite these concerns, participants gave recommendations to improve minority participation in research. CONCLUSIONS: African-American participants in this study described distrust of the medical community as a prominent barrier to participation in clinical research. Participants described real and perceived examples of exploitation to support their distrust of researchers. The goal of the consent process, to inform patients of risks and benefits so as to facilitate self-determination, was misinterpreted by these participants. Understanding the importance of interpersonal trust within the clinical relationship may prove to be a significant factor in enhancing participation in clinical trials.

Amygdala activity related to enhanced memory for pleasant and aversive stimuli.

Abstract: Pleasant or aversive events are better remembered than neutral events. Emotional enhancement of episodic memory has been linked to the amygdala in animal and neuropsychological studies. Using positron emission tomography, we show that bilateral amygdala activity during memory encoding is correlated with enhanced episodic recognition memory for both pleasant and aversive visual stimuli relative to neutral stimuli, and that this relationship is specific to emotional stimuli. Furthermore, data suggest that the amygdala enhances episodic memory in part through modulation of hippocampal activity. The human amygdala seems to modulate the strength of conscious memory for events according to emotional importance, regardless of whether the emotion is pleasant or aversive.

First Impressions Matter: A Model of Confirmatory Bias

Abstract: UNIVERSITY OF C A L I F O R N I A A T B E R K E L E Y Department of Economics Berkeley, California 94720-3880 Working Paper No. 97-250 First Impressions Matter: A Model of Confirmatory Bias Matthew Rabin University of California, Berkeley and Joel Schrag Emory University January 1997 Key words: confirmatory bias, overconfidence, bounded rationality JEL Classification: A12, B49, D83 We thank Jimmy Chan, Erik Eyster, Bruce Hsu, Clara Wang, and especially Steven Blatt for research assistance. We thank Steven Blatt, George Loewenstein, and seminar participants at Berkeley and Camegie-Mellon for helpful comments. For financial support, Rabin thanks the Alfred P. Sloan and Russell Sage Foundations and Schrag thanks the University Research Committee of Emory University.

Nuclear and Neuropil Aggregates in Huntington’s Disease: Relationship to Neuropathology

Abstract: The data we report in this study concern the types, location, numbers, forms, and composition of microscopic huntingtin aggregates in brain tissues from humans with different grades of Huntington’s disease (HD). We have developed a fusion protein antibody against the first 256 amino acids that preferentially recognizes aggregated huntingtin and labels many more aggregates in neuronal nuclei, perikarya, and processes in human brain than have been described previously. Using this antibody and human brain tissue ranging from presymptomatic to grade 4, we have compared the numbers and locations of nuclear and neuropil aggregates with the known patterns of neuronal death in HD. We show that neuropil aggregates are much more common than nuclear aggregates and can be present in large numbers before the onset of clinical symptoms. There are also many more aggregates in cortex than in striatum, where they are actually uncommon. Although the striatum is the most affected region in HD, only 1–4% of striatal neurons in all grades of HD have nuclear aggregates. Neuropil aggregates, which we have identified by electron microscopy to occur in dendrites and dendritic spines, could play a role in the known dendritic pathology that occurs in HD. Aggregates increase in size in advanced grades, suggesting that they may persist in neurons that are more likely to survive. Ubiquitination is apparent in only a subset of aggregates, suggesting that ubiquitin-mediated proteolysis of aggregates may be late or variable.

Simulation Technology for Health Care Professional Skills Training and Assessment

Abstract: Changes in medical practice that limit instruction time and patient availability, the expanding options for diagnosis and management, and advances in technology are contributing to greater use of simulation technology in medical education. Four areas of high-technology simulations currently being used are laparoscopic techniques, which provide surgeons with an opportunity to enhance their motor skills without risk to patients; a cardiovascular disease simulator, which can be used to simulate cardiac conditions; multimedia computer systems, which includes patient-centered, casebased programs that constitute a generalist curriculum in cardiology; and anesthesia simulators, which have controlled responses that vary according to numerous possible scenarios. Some benefits of simulation technology include improvements in certain surgical technical skills, in cardiovascular examination skills, and in acquisition and retention of knowledge compared with traditional lectures. These systems help to address the problem of poor skills training and proficiency and may provide a method for physicians to become self-directed lifelong learners.

Role of the posterior parietal cortex in updating reaching movements to a visual target.

Abstract: The exact role of posterior parietal cortex (PPC) in visually directed reaching is unknown. We propose that, by building an internal representation of instantaneous hand location, PPC computes a dynamic motor error used by motor centers to correct the ongoing trajectory. With unseen right hands, five subjects pointed to visual targets that either remained stationary or moved during saccadic eye movements. Transcranial magnetic stimulation (TMS) was applied over the left PPC during target presentation. Stimulation disrupted path corrections that normally occur in response to target jumps, but had no effect on those directed at stationary targets. Furthermore, left-hand movement corrections were not blocked, ruling out visual or oculomotor effects of stimulation.

Longitudinal Growth of Hospitalized Very Low Birth Weight Infants

Abstract: Background. The interpretation of growth rates for very low birth weight infants is obscured by limited data, recent changes in perinatal care, and the uncertain effects of multiple therapies. Objectives. To develop contemporary postnatal growth curves for very low birth weight preterm infants and to relate growth velocity to birth weight, nutritional practices, fetal growth status (small- or appropriate-for-gestational-age), and major neonatal morbidities (chronic lung disease, nosocomial infection or late-onset infection, severe intraventricular hemorrhage, and necrotizing enterocolitis). Design. Large, multicenter, prospective cohort study. Methods. Growth was prospectively assessed for 1660 infants with birth weights between 501 to 1500 g admitted by 24 hours of age to 1 of the 12 National Institute of Child Health and Human Development Neonatal Research Network centers between August 31, 1994 and August 9, 1995. Infants were included if they survived >7 days (168 hours) and were free of major congenital anomalies. Anthropometric measures (body weight, length, head circumference, and midarm circumference) were performed from birth until discharge, transfer, death, age 120 days, or a body weight of 2000 g. To obtain representative data, nutritional practices were not altered by the study protocol. Results. Postnatal growth curves suitable for clinical and research use were constructed for body weight, length, head circumference, and midarm circumference. Once birth weight was regained, weight gain (14.4–16.1 g/kg/d) approximated intrauterine rates. However, at hospital discharge, most infants born between 24 and 29 weeks of gestation had not achieved the median birth weight of the reference fetus at the same postmenstrual age. Gestational age, race, and gender had no effect on growth within 100-g birth weight strata. Appropriate-for-gestational age infants who survived to hospital discharge without developing chronic lung disease, severe intraventricular hemorrhage, necrotizing enterocolitis, or late onset-sepsis gained weight faster than comparable infants with those morbidities. More rapid weight gain was also associated with a shorter duration of parenteral nutrition providing at least 75% of the total daily fluid volume, an earlier age at the initiation of enteral feedings, and an earlier age at achievement of full enteral feedings. Conclusions. These growth curves may be used to better understand postnatal growth, to help identify infants developing illnesses affecting growth, and to aid in the design of future research. They should not be taken as optimal. Randomized clinical trials should be performed to evaluate whether different nutritional management practices will permit birth weight to be regained earlier and result in more rapid growth, more appropriate body composition, and improved short- and long-term outcomes.

Oxidative Stress as a Regulator of Gene Expression in the Vasculature

Abstract: Oxidative stress and the production of intracellular reactive oxygen species (ROS) have been implicated in the pathogenesis of a variety of diseases. In excess, ROS and their byproducts that are capable of causing oxidative damage may be cytotoxic to cells. However, it is now well established that moderate amounts of ROS play a role in signal transduction processes such as cell growth and posttranslational modification of proteins. Oxidants, antioxidants, and other determinants of the intracellular reduction-oxidation (redox) state play an important role in the regulation of gene expression. Recent insights into the etiology and pathogenesis of atherosclerosis suggest that this disease may be viewed as an inflammatory disease linked to an abnormality in oxidation-mediated signals in the vasculature. In this review, we summarize the evidence supporting the notion that oxidative stress and the production of ROS function as physiological regulators of vascular gene expression mediated via specific redox-sensitive signal transduction pathways and transcriptional regulatory networks. Elucidating, at the molecular level, the regulatory processes involved in redox-sensitive vascular gene expression represents a foundation not only for understanding the pathogenesis of atherosclerosis and other inflammatory diseases but also for the development of novel therapeutic treatment strategies.

Interactions between NO and reactive oxygen species: pathophysiological importance in atherosclerosis, hypertension, diabetes and heart failure

Abstract: Time for primary review 26 days. Soon after the discovery of EDRF (endothelium derived relaxins factor) it became apparent that certain diseases are associated with an impairment of endothelium dependent vasorelaxation. In hypercholesterolemic rabbits and monkeys, vasorelaxation to acetylcholine is almost absent (Fig. 1) or changed into vasoconstriction [1,2]. Similar observations have been made in patients with coronary artery disease [3,4] or risk factors predisposing to atherosclerosis [5]. Likewise, endothelium-dependent vasorelaxation is abnormal in disease states such as heart failure, diabetes and hypertension [6]. In almost all of these disorders, there is a loss of endothelial production and/or bioavailability of NO (nitric oxide, nitrogen monoxide). This alteration of vascular function has been termed ‘endothelial dysfunction’ in the scientific literature. Although this term is widely used, it is quite imprecise. ‘Endothelial dysfunction’ may refer to impairments of important endothelial functions other than vasodilation, including anticoagulant and anti-inflammatory properties of the endothelium [7,8]. Nevertheless, ‘endothelial dysfunction’ has become widely used, and in fact, loss of nitric oxide in these conditions may contribute to alterations of other aspects of vascular function. The mechanisms underlying altered endothelium-dependent vascular relaxation in various disease states are almost certainly multifactorial, and seem to be dependent on the specific pathological condition, its duration, and the vascular bed being studied. Treatment with l-arginine or tetrahydrobiopterin has improved NO-mediated vasodilation in some instances, suggesting that there may be a deficiency of either the substrate for the enzyme NO synthase or one of its critical co-factors. Alterations of endothelial cell signaling may impair appropriate activation of the NO synthase in response to neurohumoral or mechanical stimuli. In very advanced atherosclerosis, expression of NO synthase in the endothelium declines, almost certainly reducing endothelium-dependent vascular relaxation. Finally, there is substantial evidence that in certain disease conditions, NO production … * Corresponding author. Tel.: +1-404-727-3710; fax: +1-404-727-3585 dharr02{at}emory.edu

Persistence of Memory CD8 T Cells in MHC Class I-Deficient Mice

Abstract: An understanding of how T cell memory is maintained is crucial for the rational design of vaccines. Memory T cells were shown to persist indefinitely in major histocompatibility complex (MHC) class I-deficient mice and retained the ability to make rapid cytokine responses upon reencounter with antigen. In addition, memory CD8 T cells, unlike naive cells, divided without MHC-T cell receptor interactions. This "homeostatic" proliferation is likely to be important in maintaining memory T cell numbers in the periphery. Thus, after naive CD8 T cells differentiate into memory cells, they evolve an MHC class I-independent "life-style" and do not require further stimulation with specific or cross-reactive antigen for their maintenance.

Treatment of Active Rheumatoid Arthritis With Leflunomide Compared With Placebo and Methotrexate

Abstract: rheumatic drugs had failed. The ACR response and success rates for patients receiving leflunomide treatment (52% and 41%, respectively) and methotrexate treatment (46% and 35%, respectively) were significantly higher than those for patients receiving placebo (26% and 19%, respectively) (P,.001), and they were statistically equivalent, with mean time to initial response at 8.4 weeks for patients receiving leflunomide vs 9.5 weeks for patients receiving methotrexate therapy. X-ray analyses demonstrated less disease progression with leflunomide (P#.001) and methotrexate (P = .02) therapy than with placebo. Leflunomide and methotrexate treatment improved measures of physical function and health-related quality of life significantly more than placebo (P,.001 and P,.05, respectively). Common adverse events for patients receiving leflunomide treatment included gastrointestinal complaints, skin rash, and reversible alopecia. Asymptomatic transaminase elevations resulted in treatment discontinuations for 7.1% of patients receiving leflunomide therapy, 1.7% of patients receiving placebo, and 3.3% of patients receiving methotrexate therapy. Conclusions: Clinical responses following administration of leflunomide, a new therapeutic agent for the treatment of RA, were statistically superior to those with placebo and equivalent to those with methotrexate treatment. Both active treatments improved signs and symptoms of active RA, delayed disease progression as demonstrated by x-ray films, and improved function and health-related quality of life. Arch Intern Med. 1999;159:2542-2550