Showing papers by "Harvard University published in 1994"

A short physical performance battery assessing lower extremity function: association with self-reported disability and prediction of mortality and nursing home admission.

Abstract: Background A short battery of physical performance tests was used to assess lower extremity function in more than 5,000 persons age 71 years and older in three communities. Methods Balance, gait, strength, and endurance were evaluated by examining ability to stand with the feet together in the side-by-side, semi-tandem, and tandem positions, time to walk 8 feet, and time to rise from a chair and return to the seated position 5 times. Results A wide distribution of performance was observed for each test. Each test and a summary performance scale, created by summing categorical rankings of performance on each test, were strongly associated with self-report of disability. Both self-report items and performance tests were independent predictors of short-term mortality and nursing home admission in multivariate analyses. However, evidence is presented that the performance tests provide information not available from self-report items. Of particular importance is the finding that in those at the high end of the functional spectrum, who reported almost no disability, the performance test scores distinguished a gradient of risk for mortality and nursing home admission. Additionally, within subgroups with identical self-report profiles, there were systematic differences in physical performance related to age and sex. Conclusion This study provides evidence that performance measures can validly characterize older persons across a broad spectrum of lower extremity function. Performance and self-report measures may complement each other in providing useful information about functional status.

A Randomized Comparison of Coronary-Stent Placement and Balloon Angioplasty in the Treatment of Coronary Artery Disease

Abstract: Background Coronary-stent placement is a new technique in which a balloon-expandable, stainless-steel, slotted tube is implanted at the site of a coronary stenosis. The purpose of this study was to compare the effects of stent placement and standard balloon angioplasty on angiographically detected restenosis and clinical outcomes. Methods We randomly assigned 410 patients with symptomatic coronary disease to elective placement of a Palmaz-Schatz stent or to standard balloon angioplasty. Coronary angiography was performed at base line, immediately after the procedure, and six months later. Results The patients who underwent stenting had a higher rate of procedural success than those who underwent standard balloon angioplasty (96.1 percent vs. 89.6 percent, P = 0.011), a larger immediate increase in the diameter of the lumen (1.72 ±0.46 vs. 1.23 ±0.48 mm, P<0.001), and a larger luminal diameter immediately after the procedure (2.49 ±0.43 vs. 1.99 ±0.47 mm, P<0.001). At six months, the patients with stented ...

Vascular Endothelial Growth Factor in Ocular Fluid of Patients with Diabetic Retinopathy and Other Retinal Disorders

Abstract: Background Retinal ischemia induces intraocular neovascularization, which often leads to glaucoma, vitreous hemorrhage, and retinal detachment, presumably by stimulating the release of angiogenic molecules. Vascular endothelial growth factor (VEGF) is an endothelial-cell-specific angiogenic factor whose production is increased by hypoxia. Methods We measured the concentration of VEGF in 210 specimens of ocular fluid obtained from 164 patients undergoing intraocular surgery, using both radioimmunoassays and radioreceptor assays. Vitreous proliferative potential was measured with in vitro assays of the growth of retinal endothelial cells and with VEGF-neutralizing antibody. Results VEGF was detected in 69 of 136 ocular-fluid samples from patients with diabetic retinopathy, 29 of 38 samples from patients with neovascularization of the iris, and 3 of 4 samples from patients with ischemic occlusion of the central retinal vein, as compared with 2 of 31 samples from patients with no neovascular disorders (P<0.00...

The Dynamic Capabilities of Firms: an Introduction

Abstract: An expanded paradigm is needed to explain how competitive advantage is gained and held. Firms resorting to 'resource-bas ed strategy' attempt to accumulate valuable technology assets and employ an aggressive intellectual property stance. However, winners in the global marketplace have been firms demonstrating timely responsiveness and rapid and flexible product innovation, along with the management capability to effectively coordinate and redeploy internal and external competences. This source of competitive advantage, 'dynamic capabilities', emphasizes two aspects. First, it refers to the shifting character of the environment; second, it emphasizes the key role of strategic management in appropriately adapting, integrating, and re-configuring internal and external organizational skills, resources, and functional competences toward changing environment.3 Only recently have researchers begun to focus on the specifics of developing firm-specific capabilities and the manner in which competences are renewed to respond to shifts in the business environment. The dynamic capabilities \ approach provides a coherent framework to integrate existing conceptual and empirical ^ knowledge, and facilitate prescription. This paper argues that the competitive advanis tage of firms stems from dynamic capabilities rooted in high performance routines z operating inside the firm, embedded in the firm's processes, and conditioned by its •*> history. It offers dynamic capabilities as an emerging paradigm of the modern business J firm that draws on multiple disciplines and advances, with the help of industry studies > in the USA and elsewhere.

Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group.

Abstract: Background and Methods Maternal-infant transmission is the primary means by which young children become infected with human immunodeficiency virus type 1 (HIV). We conducted a randomized, double-blind, placebo-controlled trial of the efficacy and safety of zidovudine in reducing the risk of maternal-infant HIV transmission. HIV-infected pregnant women (14 to 34 weeks' gestation) with CD4+ T-lymphocyte counts above 200 cells per cubic millimeter who had not received antiretroviral therapy during the current pregnancy were enrolled. The zidovudine regimen included antepartum zidovudine (100 mg orally five times daily), intrapartum zidovudine (2 mg per kilogram of body weight given intravenously over a one-hour period, then 1 mg per kilogram per hour until delivery), and zidovudine for the newborn (2 mg per kilogram orally every six hours for six weeks). Infants with at least one positive HIV culture of peripheral-blood mononuclear cells were classified as HIV-infected. Results From April 1991 through Decemb...

Guided Search 2.0 A revised model of visual search

Abstract: An important component of routine visual behavior is the ability to find one item in a visual world filled with other, distracting items. This ability to performvisual search has been the subject of a large body of research in the past 15 years. This paper reviews the visual search literature and presents a model of human search behavior. Built upon the work of Neisser, Treisman, Julesz, and others, the model distinguishes between a preattentive, massively parallel stage that processes information about basic visual features (color, motion, various depth cues, etc.) across large portions of the visual field and a subsequent limited-capacity stage that performs other, more complex operations (e.g., face recognition, reading, object identification) over a limited portion of the visual field. The spatial deployment of the limited-capacity process is under attentional control. The heart of the guided search model is the idea that attentional deployment of limited resources isguided by the output of the earlier parallel processes. Guided Search 2.0 (GS2) is a revision of the model in which virtually all aspects of the model have been made more explicit and/or revised in light of new data. The paper is organized into four parts: Part 1 presents the model and the details of its computer simulation. Part 2 reviews the visual search literature on preattentive processing of basic features and shows how the GS2 simulation reproduces those results. Part 3 reviews the literature on the attentional deployment of limited-capacity processes in conjunction and serial searches and shows how the simulation handles those conditions. Finally, Part 4 deals with shortcomings of the model and unresolved issues.

Strain gradient plasticity: Theory and experiment

Abstract: Dislocation theory is used to invoke a strain gradient theory of rate independent plasticity. Hardening is assumed to result from the accumulation of both randomly stored and geometrically necessary dislocation. The density of the geometrically necessary dislocations scales with the gradient of plastic strain. A deformation theory of plasticity is introduced to represent in a phenomenological manner the relative roles of strain hardening and strain gradient hardening. The theory is a non-linear generalization of Cosserat couple stress theory. Tension and torsion experiments on thin copper wires confirm the presence of strain gradient hardening. The experiments are interpreted in the light of the new theory.

Politicians and Firms

Abstract: We present a model of bargaining between politicians and managers that explains many stylized facts about the behavior of state firms, their commercialization, and privatization. Subsidies to public enterprises and bribes from managers to politicians emerge naturally in the model. We use the model and several extensions to understand why commercialization and privatization might work, and what forces contribute to effective restructuring of public enterprises. We illustrate the model using examples from several countries.

Excitatory amino acids as a final common pathway for neurologic disorders.

Abstract: In many neurologic disorders, injury to neurons may be caused at least in part by overstimulation of receptors for excitatory amino acids, including glutamate and aspartate. These neurologic conditions range from acute insults such as stroke, hypoglycemia, trauma, and epilepsy (Table 1) to chronic neurodegenerative states such as Huntington's disease, the acquired immunodeficiency syndrome (AIDS) dementia complex, amyotrophic lateral sclerosis, and perhaps Alzheimer's disease (Table 2)1–3. Glutamate is the principal excitatory neurotransmitter in the brain, and its interactions with specific membrane receptors are responsible for many neurologic functions, including cognition, memory, movement, and sensation4. In addition, excitatory . . .

Estimation of Regression Coefficients When Some Regressors are not Always Observed

Abstract: In applied problems it is common to specify a model for the conditional mean of a response given a set of regressors. A subset of the regressors may be missing for some study subjects either by design or happenstance. In this article we propose a new class of semiparametric estimators, based on inverse probability weighted estimating equations, that are consistent for parameter vector α0 of the conditional mean model when the data are missing at random in the sense of Rubin and the missingness probabilities are either known or can be parametrically modeled. We show that the asymptotic variance of the optimal estimator in our class attains the semiparametric variance bound for the model by first showing that our estimation problem is a special case of the general problem of parameter estimation in an arbitrary semiparametric model in which the data are missing at random and the probability of observing complete data is bounded away from 0, and then deriving a representation for the efficient score...

The stress-activated protein kinase subfamily of c-Jun kinases.

Abstract: The mitogen-activated protein (MAP) kinases Erk-1 and Erk-2 are proline-directed kinases that are themselves activated through concomitant phosphorylation of tyrosine and threonine residues. The kinase p54 (M(r) 54,000), which was first isolated from cycloheximide-treated rats, is proline-directed like Erks-1/2, and requires both Tyr and Ser/Thr phosphorylation for activity. p54 is, however, distinct from Erks-1/2 in its substrate specificity, being unable to phosphorylate pp90rsk but more active in phosphorylating the c-Jun transactivation domain. Molecular cloning of p54 reveals a unique subfamily of extracellularly regulated kinases. Although they are 40-45% identical in sequence to Erks-1/2, unlike Erks-1/2 the p54s are only poorly activated in most cells by mitogens or phorbol esters. However, p54s are the principal c-Jun N-terminal kinases activated by cellular stress and tumour necrosis factor (TNF)-alpha, hence they are designated stress-activated protein kinases, or SAPKs. SAPKs are also activated by sphingomyelinase, which elicits a subset of cellular responses to TNF-alpha (ref. 9). SAPKs therefore define a new TNF-alpha and stress-activated signalling pathway, possibly initiated by sphingomyelin-based second messengers, which regulates the activity of c-Jun.

Thalidomide is an inhibitor of angiogenesis.

Abstract: Thalidomide is a potent teratogen causing dysmelia (stunted limb growth) in humans. We have demonstrated that orally administered thalidomide is an inhibitor of angiogenesis induced by basic fibroblast growth factor in a rabbit cornea micropocket assay. Experiments including the analysis of thalidomide analogs revealed that the antiangiogenic activity correlated with the teratogenicity but not with the sedative or the mild immunosuppressive properties of thalidomide. Electron microscopic examination of the corneal neovascularization of thalidomide-treated rabbits revealed specific ultrastructural changes similar to those seen in the deformed limb bud vasculature of thalidomide-treated embryos. These experiments shed light on the mechanism of thalidomide's teratogenicity and hold promise for the potential use of thalidomide as an orally administered drug for the treatment of many diverse diseases dependent on angiogenesis.

mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer.

Abstract: Previously, we have isolated and characterized an enhancer from the 5'-flanking region of the adipocyte P2 (aP2) gene that directs high-level adipocyte-specific gene expression in both cultured cells and transgenic mice. The key regulator of this enhancer is a cell type-restricted nuclear factor termed ARF6. Target sequences for ARF6 in the aP2 enhancer exhibit homology to a direct repeat of hormone response elements (HREs) spaced by one nucleotide; this motif (DR-1) has been demonstrated previously to be the preferred binding site for heterodimers of the retinoid X receptor (RXR) and the peroxisome proliferator-activated receptor (PPAR). We have cloned a novel member of the peroxisome proliferator-activated receptor family designated mPPAR gamma 2, and we demonstrate that a heterodimeric complex of mPPAR gamma 2 and RXR alpha constitute a functional ARF6 complex. Expression of mPPAR gamma 2 is induced very early during the differentiation of several cultured adipocyte cell lines and is strikingly adipose-specific in vivo. mPPAR gamma 2 and RXR alpha form heterodimers on ARF6-binding sites in vitro, and antiserum to RXR alpha specifically inhibits ARF6 activity in adipocyte nuclear extracts. Moreover, forced expression of mPPAR gamma 2 and RXR alpha activates the adipocyte-specific aP2 enhancer in cultured fibroblasts, and this activation is potentiated by peroxisome proliferators, fatty acids, and 9-cis retinoic acid. These results identify mPPAR gamma 2 as the first adipocyte-specific transcription factor and suggest mechanisms whereby fatty acids, peroxisome proliferators, 9-cis retinoic acid, and other lipids may regulate adipocyte gene expression and differentiation.

Acute respiratory effects of particulate air pollution

Abstract: In the 1930s, 40s, and 50s, several episodes of extreme air pollution focused attention on the potential for adverse health effects of air pollution. These included an episode in the Meuse Valley, Belgium, in December 1930 ( 15), an episode in Donora, Pennsylvania in 1948 (36), and several episodes in London, England (23, 44). The sudden large increases in sickness and death that accompanied such episodes demonstrated that air pollution can adversely affect human health. The increased mortality associated with such episodes provided the first quantitative measure of the adverse effects of air pollution. By the 1970s, a link had been well established between respiratory disease and particulate and/or sulfur-oxide air pollution, but still there remained disagreement as to the level of pollution that would significantly affect human health. In reviewing research published between 1968 and 1977, Holland and several other prominent British scientists ( 19) concluded that particulate and related air pollution at high levels pose hazards to human health, but that health effects of particulate pollution at lower concentrations could not be "disentangled" from health effects of other factors. Shy (45) responded by asserting that the review by Holland et al systematically discounted evidence of pollution-related health effects at contemporary pollution levels. Shy, and other reviewers ( 1, 12, 45, 54), contended that the cumulative weight of evidence provided sound reasons to believe that

The weighted majority algorithm

Abstract: We study the construction of prediction algorithms in a situation in which a learner faces a sequence of trials, with a prediction to be made in each, and the goal of the learner is to make few mistakes. We are interested in the case where the learner has reason to believe that one of some pool of known algorithms will perform well, but the learner does not know which one. A simple and effective method, based on weighted voting, is introduced for constructing a compound algorithm in such a circumstance. We call this method the Weighted Majority Algorithm. We show that this algorithm is robust in the presence of errors in the data. We discuss various versions of the Weighted Majority Algorithm and prove mistake bounds for them that are closely related to the mistake bounds of the best algorithms of the pool. For example, given a sequence of trials, if there is an algorithm in the pool A that makes at most m mistakes then the Weighted Majority Algorithm will make at most c(log |A| + m) mistakes on that sequence, where c is fixed constant.

Mutation in the DNA mismatch repair gene homologue hMLH 1 is associated with hereditary non-polyposis colon cancer

Abstract: The human DNA mismatch repair gene homologue hMSH2, on chromosome 2p is involved in hereditary non-polyposis colon cancer (HNPCC) On the basis of linkage data, a second HNPCC locus was assigned to chromosome 3p21-23 (ref 3) Here we report that a human gene encoding a protein, hMLH1 (human MutL homologue), homologous to the bacterial DNA mismatch repair protein MutL, is located on human chromosome 3p213-23 We propose that hMLH1 is the HNPCC gene located on 3p because of the similarity of the hMLH1 gene product to the yeast DNA mismatch repair protein, MLH1, the coincident location of the hMLH1 gene and the HNPCC locus on chromosome 3, and hMLH1 missense mutations in affected individuals from a chromosome 3-linked HNPCC family

In Over Our Heads: The Mental Demands of Modern Life

Abstract: Prologue I. The Mental Demand of Adolescence 1. The Hidden Curriculum of Youth: "Whaddaya Want from Me?" 2. Coaching the Curriculum: A Bridge Must Be Well Anchored on Either Side II. The Mental Demand of Private Life: Parenting and Partnering 3. Parenting: Minding Our Children 4. Partnering: Love and Consciousness III. The Mental Demand of Public Life: Work and Self-Expansion 5. Working: On Seeking to Hire the Self-Employed 6. Dealing with Difference: Communication between the Sexes/Communication between the Theories 7. Healing: The Undiscussed Demands of Psychotherapy 8. Learning: "The Teacher Wants Us to Be Self-Directing" IV. The Mental Demand of Postmodern Life 9. Conflict, Leadership, and Knowledge Creation 10. On Being Good Company for the Wrong Journey Epilogue Notes Index

Error in Medicine

Abstract: FOR YEARS, medical and nursing students have been taught Florence Nightingale's dictum—first, do no harm. 1 Yet evidence from a number of sources, reported over several decades, indicates that a substantial number of patients suffer treatment-caused injuries while in the hospital. 2-6 In 1964 Schimmel 2 reported that 20% of patients admitted to a university hospital medical service suffered iatrogenic injury and that 20% of those injuries were serious or fatal. Steel et al 3 found that 36% of patients admitted to a university medical service in a teaching hospital suffered an iatrogenic event, of which 25% were serious or life threatening. More than half of the injuries were related to use of medication. 3 In 1991 Bedell et al 4 reported the results of an analysis of cardiac arrests at a teaching hospital. They found that 64% were preventable. Again, inappropriate use of drugs was the leading cause of

Pain and its treatment in outpatients with metastatic cancer.

Abstract: Background and Methods Pain is often inadequately treated in patients with cancer. A total of 1308 outpatients with metastatic cancer from 54 treatment locations affiliated with the Eastern Cooperative Oncology Group rated the severity of their pain during the preceding week, as well as the degree of pain-related functional impairment and the degree of relief provided by analgesic drugs. Their physicians attributed the pain to various factors, described its treatment, and estimated the impact of pain on the patients' ability to function. We assessed the adequacy of prescribed analgesic drugs using guidelines developed by the World Health Organization, studied the factors that influenced whether analgesia was adequate, and determined the effects of inadequate analgesia on the patients' perception of pain relief and functional status. Results Sixty-seven percent of the patients (871 of 1308) reported that they had had pain or had taken analgesic drugs daily during the week preceding the study, and 36 percen...

A mammalian protein targeted by G1-arresting rapamycin–receptor complex

Abstract: THE structurally related natural products rapamycin and FK506 bind to the same intracellular receptor, FKBP12, yet the resulting complexes interfere with distinct signalling pathways1,2. FKBP12–rapamycin inhibits progression through the Gl phase of the cell cycle in osteosarcoma3, liver4, 5 and T cells6, 7 as well as in yeast8 and interferes with mitogenic signalling pathways that are involved in Gl progression9, 10 namely with activation of the protein p70S6k (refs 5,11–13) and cyclin-dependent kinases3, 14–16. Here we isolate a mammalian FKBP–rapamycin-associated protein (FRAP) whose binding to structural variants of rapamycin complexed to FKBP12 correlates with the ability of these ligands to inhibit cell-cycle progression. Peptide sequences from purified bovine FRAP were used to isolate a human cDNA clone that is highly related to the DRR1/TOR1 and DRR2/TOR2 gene products from Saccharomyces cerevisiae8, 17, 18. Although it has not been previously demonstrated that either of the DRR/TOR gene products can bind the FKBP–rapamycin complex directly17, 19 these yeast genes have been genetically linked to a rapamycin-sensitive pathway and are thought to encode lipid kinases17–20.