Showing papers by "Brown University published in 1997"

Antiretroviral Therapy for HIV Infection in 1997: Updated Recommendations of the International AIDS Society—USA Panel

Abstract: Objective. —To provide current recommendations for antiretroviral therapy for human immunodeficiency virus (HIV) disease. Participants. —The original International AIDS Society—USA 13-member panel representing international expertise in antiretroviral research and care of patients with HIV infection. Evidence. —The following were considered: Newly available clinical and basic science study results, including phase 3 controlled trials; clinical, virological, and immunologic end-point data; interim analyses of studies presented at national and international research conferences; studies of HIV pathophysiology; and expert opinions of panel members. Recommendations were limited to the drugs available in mid 1997. Process. —The full panel met on a regular basis (July 1996, September 1996, November 1996, January 1997, and April 1997) since the publication of its initial recommendations in mid 1996 to review new research reports and interim results. The panel discussed whether and how new information changed its initial recommendations. The recommendations contained herein were determined by group consensus. Conclusions. —New data have provided a stronger rationale for earlier initiation of more aggressive therapy than previously recommended and reinforce the importance of careful selection of initial drug regimen for each patient for optimal long-term clinical benefit and adherence. The plasma viral load is a crucial element of clinical management for assessing prognosis and the effectiveness of therapy, and such testing must be done properly. Treatment failure is most readily indicated by a rising plasma HIV RNA level and should be confirmed prior to a change of treatment. Therapeutic approaches must be updated as new data, particularly on the long-term clinical effect of aggressive antiretroviral treatment, continue to emerge.

Biologically erodable microspheres as potential oral drug delivery systems

Abstract: Biologically adhesive delivery systems offer important advantages over conventional drug delivery systems. Here we show that engineered polymer microspheres made of biologically erodable polymers, which display strong adhesive interactions with gastrointestinal mucus and cellular linings, can traverse both the mucosal absorptive epithelium and the follicle-associated epithelium covering the lymphoid tissue of Peyer's patches. The polymers maintain contact with intestinal epithelium for extended periods of time and actually penetrate it, through and between cells. Thus, once loaded with compounds of pharmacological interest, the microspheres could be developed as delivery systems to transfer biologically active molecules to the circulation. We show that these microspheres increase the absorption of three model substances of widely different molecular size: dicumarol, insulin and plasmid DNA.

Bypass of Senescence After Disruption of p21CIP1/WAF1 Gene in Normal Diploid Human Fibroblasts

Abstract: Most somatic cells die after a finite number of cell divisions, a phenomenon described as senescence. The p21 CIP1/WAF1 gene encodes an inhibitor of cyclin-dependent kinases. Inactivation of p21 by two sequential rounds of targeted homologous recombination was sufficient to bypass senescence in normal diploid human fibroblasts. At the checkpoint between the prereplicative phase of growth and the phase of chromosome replication, cells lacking p21 failed to arrest the cell cycle in response to DNA damage, but their apoptotic response and genomic stability were unaltered. These results establish the feasibility of using gene targeting for genetic studies of normal human cells.

Environmental contamination due to methicillin-resistant Staphylococcus aureus: possible infection control implications.

Abstract: Objective:To study the possible role of contaminated environmental surfaces as a reservoir of methicillin-resistant Staphylococcus aureus (MRSA) in hospitals.Design:A prospective culture survey of inanimate objects in the rooms of patients with MRSA.Setting:A 200-bed university-affiliated teaching hospital.Patients:Thirty-eight consecutive patients colonized or infected with MRSA. Patients represented endemic MRSA cases.Results:Ninety-six (27%) of 350 surfaces sampled in the rooms of affected patients were contaminated with MRSA. When patients had MRSA in a wound or urine, 36% of surfaces were contaminated. In contrast, when MRSA was isolated from other body sites, only 6% of surfaces were contaminated (odds ratio, 8.8; 95% confidence interval, 3.725.5; Pく.0001). Environmental contamination occurred in the rooms of 73% of infected patients and 69% of colonized patients. Frequently contaminated objects included the floor, bed linens, the patient's gown, overbed tables, and blood pressure cuffs. Sixty-five percent of nurses who had performed morning patient-care activities on patients with MRSA in a wound or urine contaminated their nursing uniforms or gowns with MRSA. Forty-two percent of personnel who had no direct contact with such patients, but had touched contaminated surfaces, contaminated their gloves with MRSA.Conclusions:We concluded that inanimate surfaces near affected patients commonly become contaminated with MRSA and that the frequency of contamination is affected by the body site at which patients are colonized or infected. That personnel may contaminate their gloves (or possibly their hands) by touching such surfaces suggests that contaminated environmental surfaces may serve as a reservoir of MRSA in hospitals.

On the Gibbs Phenomenon and Its Resolution

Abstract: The nonuniform convergence of the Fourier series for discontinuous functions, and in particular the oscillatory behavior of the finite sum, was already analyzed by Wilbraham in 1848. This was later named the Gibbs phenomenon. This article is a review of the Gibbs phenomenon from a different perspective. The Gibbs phenomenon, as we view it, deals with the issue of recovering point values of a function from its expansion coefficients. Alternatively it can be viewed as the possibility of the recovery of local information from global information. The main theme here is not the structure of the Gibbs oscillations but the understanding and resolution of the phenomenon in a general setting. The purpose of this article is to review the Gibbs phenomenon and to show that the knowledge of the expansion coefficients is sufficient for obtaining the point values of a piecewise smooth function, with the same order of accuracy as in the smooth case. This is done by using the finite expansion series to construct a different, rapidly convergent, approximation.

What We Know About Engendering Civic Identity

Abstract: Taking the position that there is a developmental process in the formation of citizenship, the authors reviewed studies that reported a link between youth's participation in organized activities and civic behaviors 15 or more years later in adulthood. Data uniformly showed that students who participated in high school government or community service projects, meant in the broad sense, are more likely to vote and to join community organizations than are adults who were nonparticipants during high school. Results support the authors' view that participation during the youth era can be seminal in the construction of civic identity that includes a sense of agency and social responsibility in sustaining the community's well-being.

Learning policies for partially observable environments: scaling up

Abstract: Partially observable Markov decision processes (POMDP's) model decision problems in which an agent tries to maximize its reward in the face of limited and/or noisy sensor feedback. While the study of POMDP's is motivated by a need to address realistic problems, existing techniques for finding optimal behavior do not appear to scale well and have been unable to find satisfactory policies for problems with more than a dozen states. After a brief review of POMDP's, this paper discusses several simple solution methods and shows that all are capable of finding near- optimal policies for a selection of extremely small POMDP'S taken from the learning literature. In contrast, we show that none are able to solve a slightly larger and noisier problem based on robot navigation. We find that a combination of two novel approaches performs well on these problems and suggest methods for scaling to even larger and more complicated domains.

A Quantitative Description of Short-Term Plasticity at Excitatory Synapses in Layer 2/3 of Rat Primary Visual Cortex

Abstract: Cortical synapses exhibit several forms of short-term plasticity, but the contribution of this plasticity to visual response dynamics is unknown. In part, this is because the simple patterns of stimulation used to probe plasticity in vitro do not correspond to patterns of activity that occur in vivo. We have developed a method of quantitatively characterizing short-term plasticity at cortical synapses that permits prediction of responses to arbitrary patterns of stimulation. Synaptic responses were recorded intracellularly as EPSCs and extracellularly as local field potentials in layer 2/3 of rat primary visual cortical slices during stimulation of layer 4 with trains of electrical stimuli containing random mixtures of frequencies. Responses exhibited complex dynamics that were well described by a simple three-component model consisting of facilitation and two forms of depression, a stronger form that decayed exponentially with a time constant of several hundred milliseconds and a weaker, but more persistent, form that decayed with a time constant of several seconds. Parameters obtained from fits to one train were used to predict accurately responses to other random and constant frequency trains. Control experiments revealed that depression was not caused by a decrease in the effectiveness of extracellular stimulation or by a buildup of inhibition. Pharmacological manipulations of transmitter release and postsynaptic sensitivity suggested that both forms of depression are mediated presynaptically. These results indicate that firing evoked by visual stimuli is likely to cause significant depression at cortical synapses. Hence synaptic depression may be an important determinant of the temporal features of visual cortical responses.

Evolution and dissemination of β-lactamases accelerated by generations of β-lactam antibiotics

Abstract: beta-Lactamases are the principal mechanism of bacterial resistance to beta-lactam antibiotics. In recent years the number and variety of new beta-lactamases detected has risen at an alarming rate, apparently in response to the clinical use of novel classes of beta-lactam antibiotics. This paper reviews the structure and evolution of beta-lactamases in an attempt to understand the pressures that have contributed to their emergence.

Statistical parsing with a context-free grammar and word statistics

Abstract: We describe a parsing system based upon a language model for English that is, in turn, based upon assigning probabilities to possible parses for a sentence. This model is used in a parsing system by finding the parse for the sentence with the highest probability. This system outperforms previous schemes. As this is the third in a series of parsers by different authors that are similar enough to invite detailed comparisons but different enough to give rise to different levels of performance, we also report on some experiments designed to identify what aspects of these systems best explain their relative performance.

A severity rating scale for body dysmorphic disorder: development, reliability, and validity of a modified version of the Yale-Brown Obsessive Compulsive Scale.

Abstract: The authors developed the Yale Brown Obsessive Compulsive Scale Modified for Body Dysmorphic Disorder (BDD-YBOCS), a 12-item semistructured clinician-rated instrument designed to rate severity of body dysmorphic disorder (BDD). The scale was administered to 125 subjects with BDD, and interviews with 15 subjects were rated by 3 other raters. Test-retest reliability was assessed in 30 subjects. Other scales were administered to assess convergent and discriminant validity, and sensitivity to change was evaluated in a study of fluvoxamine. Each item was frequently endorsed across a range of severity. Good interrater reliability, test-retest reliability, and internal consistency were obtained. BDD-YBOCS scores correlated with global severity scores but not with a measure of general psychopathology; they were modestly positively correlated with depression severity scores. Three factors accounted for 59.6 percent of the variance. The scale was sensitive to change in BDD severity. The BDD-YBOCS appears to be a reliable and valid measure of BDD severity and is a suitable outcome measure in treatment studies of BDD.

The Distribution of Human Capital and Economic Growth

Abstract: This paper analyzes the interaction between the distribution of human capital, technological progress, and economic growth. It argues that the composition of human capital is an important factor in the determination of the pattern of economic development. The study demonstrates that the evolutionary pattern of the human capital distribution, the income distribution, and economic growth are determined simultaneously by the interplay between a local home environment externality and a global technological externality. In early stages of development the local home environment externality is the dominating factor and hence the distribution of income becomes polarized; whereas in mature stages of development the global technological externality dominates and the distribution of income ultimately contracts. Polarization, in early stages of development may be a necessary ingredient for future economic growth. An economy that prematurely implements a policy designed to enhance equality may be trapped at a low stage of development. An underdeveloped economy, which values equality as well as prosperity, may confront a trade-off between equality in the short-run followed by equality and stagnation in the long-run, and inequality in the short-run followed by equality and prosperity in the long run.

The role of positive interactions in communities: lessons from intertidal habitats

Abstract: Positive interactions that result from neighbors buffering one another from stressful conditions are predictably important community forces in physically stressful habitats. Here, we examine the generality of this hypothesis in marine intertidal communities. Intertidal communities have historically played a large role in the development of community ecology since they occur across pronounced physical gradients and are easily manipulated. Positive interactions, however, have not been emphasized in studies of intertidal communities. We first review studies of intertidal marsh plant communities that suggest that positive interactions play a dominant role in the structure and dynamics of these common assemblages. We then present the results of an experimental manipulation on New England rocky shores that suggests that group benefits are as important in maintaining the upper intertidal limits of dominant spaceholders on rocky shores as the negative forces of competition and predation are in maintaining lower d...

Minimax Entropy Principle and Its Application to Texture Modeling

Abstract: This article proposes a general theory and methodology, called the minimax entropy principle, for building statistical models for images (or signals) in a variety of applications. This principle consists of two parts. The first is the maximum entropy principle for feature binding (or fusion): for a given set of observed feature statistics, a distribution can be built to bind these feature statistics together by maximizing the entropy over all distributions that reproduce them. The second part is the minimum entropy principle for feature selection: among all plausible sets of feature statistics, we choose the set whose maximum entropy distribution has the minimum entropy. Computational and inferential issues in both parts are addressed; in particular, a feature pursuit procedure is proposed for approximately selecting the optimal set of features. The minimax entropy principle is then corrected by considering the sample variation in the observed feature statistics, and an information criterion for feature pursuit is derived. The minimax entropy principle is applied to texture modeling, where a novel Markov random field (MRF) model, called FRAME (filter, random field, and minimax entropy), is derived, and encouraging results are obtained in experiments on a variety of texture images. The relationship between our theory and the mechanisms of neural computation is also discussed.

Phenotypes of c-Myc-deficient rat fibroblasts isolated by targeted homologous recombination

Abstract: Rat fibroblast cell lines with targeted disruptions of both c-myc gene copies were constructed. Although c-myc null cells are viable, their growth is significantly impaired. The absence of detectable N-myc or L-myc expression indicates that Myc function is not absolutely essential for cell viability. The c-myc null phenotype is stable and can be reverted by introduction of a c-myc transgene. Exponentially growing c-myc null cells have the same cell size, rRNA, and total protein content as their c-myc +1+ parents, but the rates of RNA and protein accumulation as well as protein degradation are reduced. Both the G1 and G2 phases of the cell cycle are significantly lengthened, whereas the duration of S phase is unaffected. This is the first direct demonstration of a requirement for c-myc in G2. The G0-+S transition is synchronous, but S-phase entry is significantly delayed. The c-myc null cell lines reported here are a new experimental system in which to investigate the importance of putative c-Myc target genes and to identify novel downstream genes involved in cell cycle progression and apoptosis.

The fas system is a key regulator of germ cell apoptosis in the testis

Abstract: Apoptosis occurs in the testis as an important physiological mechanism to limit the number of germ cells in the seminiferous epithelium. Sertoli cells, which tightly regulate germ cell proliferation and differentiation, are implicated in the control of germ cell apoptosis. Fas (APO-1, CD95), a transmembrane receptor protein, transmits an apoptotic signal within cells when bound by Fas ligand (FasL). The Fas system has been implicated in immune regulation, including cytotoxic T cell-mediated cytotoxicity, activation-induced suicide of T cells, and control of immune-privileged sites. Here we propose the Fas system as a key regulator of spermatogenesis. In this model, FasL expressed by Sertoli cells initiates the apoptotic death of germ cells expressing Fas. Using immunohistochemistry, we localized Fas to germ cells and FasL to Sertoli cells. The expression of these genes was dramatically up-regulated after exposure to mono-(2-ethylhexyl) phthalate and 2,5-hexanedione, two widely studied Sertoli cell toxicants known to induce germ cell apoptosis. Mouse germ cells in vitro were susceptible to anti-Fas antibody-induced death, and the survival of rat germ cells was increased after disruption of FasL by antisense oligonucleotide treatment. Unlike its expression in other tissues, testicular expression of Fas in the lpr mouse, a spontaneous mutant of the Fas gene, is similar to that in the normal mouse, arguing for the importance of the Fas system in maintaining testicular homeostasis. These data implicate the Sertoli cell in the paracrine control of germ cell output during spermatogenesis by a Fas-mediated pathway.

Statistical Methods for Profiling Providers of Medical Care: Issues and Applications

Abstract: Recent public debate on costs and effectiveness of health care in the United States has generated a growing emphasis on “profiling” of medical care providers. The process of profiling involves comparing resource use and quality of care among medical providers to a community or a normative standard. This is valuable for targeting quality improvement strategies. For example, hospital profiles may be used to determine whether institutions deviate in important ways in the process of care they deliver. In this article we propose a class of performance indices to profile providers. These indices are based on posterior tail probabilities of relevant model parameters that indicate the degree of poor performance by a provider. We apply our performance indices to profile hospitals on the basis of 30-day mortality rates for a cohort of elderly heart attack patients. The analysis used data from 96 acute care hospitals located in one state and accounted for patient and hospital characteristics using a hierarc...

Balancing push and pull for data broadcast

Abstract: The increasing ability to interconnect computers through internet-working, wireless networks, high-bandwidth satellite, and cable networks has spawned a new class of information-centered applications based on data dissemination. These applications employ broadcast to deliver data to very large client populations. We have proposed the Broadcast Disks paradigm [Zdon94, Acha95b] for organizing the contents of a data broadcast program and for managing client resources in response to such a program. Our previous work on Broadcast Disks focused exclusively on the “push-based” approach, where data is sent out on the broadcast channel according to a periodic schedule, in anticipation of client requests. In this paper, we study how to augment the push-only model with a “pull-based” approach of using a backchannel to allow clients to send explicit requests for data to the server. We analyze the scalability and performance of a broadcast-based system that integrates push and pull and study the impact of this integration on both the steady state and warm-up performance of clients. Our results show that a client backchannel can provide significant performance improvement in the broadcast environment, but that unconstrained use of the backchannel can result in scalability problems due to server saturation. We propose and investigate a set of three techniques that can delay the onset of saturation and thus, enhance the performance and scalability of the system.

Image plane interaction techniques in 3D immersive environments

Abstract: This paper presents a set of interaction techniques for use in headtracked immersive virtual environments. With these techniques, the user interacts with the 2D projections that 3D objects in the scene make on his image plane. The desktop analog is the use of a mouse to interact with objects in a 3D scene based on their projections on the monitor screen. Participants in an immersive environment can use the techniques we discuss for object selection, object manipulation, and user navigation in virtual environments. CR Categories and Subject Descriptors: 1.3.6 [Computer Graphics]: Methodology and Techniques - InteractionTechniques; 1.3.7 [Computer Graphics]: Three-Dimensional Graphics and Realism - VirtualReality. Additional Keywords: virtual worlds, virtual environments, navigation, selection, manipulation.

Incremental pruning: a simple, fast, exact method for partially observable Markov decision processes

Abstract: Most exact algorithms for general partially observable Markov decision processes (POMDPs) use a form of dynamic programming in which a piecewise-linear and convex representation of one value function is transformed into another. We examine variations of the "incremental pruning" method for solving this problem and compare them to earlier algorithms from theoretical and empirical perspectives. We find that incremental pruning is presently the most efficient exact method for solving POMDPS.

Some implications of direct positive interactions for community species diversity

Abstract: Direct positive interactions (mutualisms and commensalisms) are generally accepted as important processes in communities. They appear to be most common in environments with relatively high physical disturbance, stress, or predation, where associated species can increase the growth and survival of other species unable to survive in isolation. Although ecologists have documented direct positive interactions among species for decades, there is less known about how these interactions affect community species diversity patterns. In this paper, we present a qualitative theoretical model that considers how direct positive interactions affect community species diversity. The model uses, as its basis, familiar unimodel species diversity models (i.e., “compensatory mortality” and “intermediate disturbance” hypothesis) to understand where direct positive interactions are likely to be important. Initially, it predicts that direct positive interactions increase species diversity by facilitating species that might not normally survive under very high physical disturbance, stress, or predation. In addition, it suggests that, under intermediate physical disturbance, stress, or predation, facilitator species that might normally be competitively excluded are released from competition. We suggest that facilitator species may then create new interaction webs that would not be possible in their absence. To illustrate these ideas, we describe a case study taken from a New England salt marsh community where a gradient in physical conditions occurs. In this community, direct positive interactions, and their indirect effects, are predicted to increase the species diversity by at least 35%. This empirical case study and model show that by incorporating direct positive interactions into ecological experiments and theory, it is possible to expand our understanding of the mechanisms responsible for community species diversity patterns.