bluuebunny/crossref_metadata_2025 huggingface dataset:
STRUCTURE-BASED DRUG DESIGN:Computational Advances
Authors: Marrone Tami J. , Briggs, and James M. , McCammon J. Andrew
Published: July 2002

▪ Abstract  Structure-based computational methods continue to enhance progress in the discovery and refinement of therapeutic agents. Several such methods and their applications are described. These include molecular visualization and molecular modeling, docking, fragment methods, 3-D database techniques, and free-energy perturbation. Related issues that are discussed include the use of simplified potential energy functions and the determination of the positions of tightly bound waters. Strengths and weaknesses of the various methods are described.
INSIGHTS FROM IN VIVO MODIFICATION OF ADRENERGIC RECEPTOR GENE EXPRESSION
Authors: Rohrer Daniel K. , Kobilka Brian K.
Published: July 2002

▪ Abstract  Adrenergic receptors are key targets within the autonomic nervous system, regulating a wide variety of physiological processes. The ability to modify adrenergic receptor expression patterns in vivo has added a powerful new tool to the functional analysis of these receptors. Modification of adrenergic receptor gene expression by overexpression, genetic ablation, or site-specific mutation has added new insight to models of receptor coupling behavior, pharmacology, and subtype-specific physiological function. This review highlights some of the recent advances resulting from such genetic approaches to the study of adrenergic receptors.
INHIBITION OF NITRIC OXIDE SYNTHASE AS A POTENTIAL THERAPEUTIC TARGET
Authors: Hobbs Adrian J. , Higgs Annie , Moncada Salvador
Published: July 2002

▪ Abstract  Nitric oxide (NO) regulates numerous physiological processes, including neurotransmission, smooth muscle contractility, platelet reactivity, and the cytotoxic activity of immune cells. Because of the ubiquitous nature of NO, inappropriate release of this mediator has been linked to the pathogenesis of a number of disease states. This provides the rationale for the design of therapies that modulate NO concentrations selectively. A well-characterized family of compounds are the inhibitors of NO synthase, the enzyme responsible for the generation of NO; such agents are potentially beneficial in the treatment of conditions associated with an overproduction of NO, including septic shock, neurodegenerative disorders, and inflammation. This article provides an overview of NO synthase inhibitors, focusing on agents that prevent binding of substrate l-arginine.
Properties and Biological Activities of Thioredoxins
Authors: Powis Garth , Montfort William R
Published: July 2002

The mammalian thioredoxins are a family of small (approximately 12 kDa) redox proteins that undergo NADPH-dependent reduction by thioredoxin reductase and in turn reduce oxidized cysteine groups on proteins. The two main thioredoxins are thioredoxin-1, a cytosolic and nuclear form, and thioredoxin-2, a mitochondrial form. Thioredoxin-1 has been studied more. It performs many biological actions including the supply of reducing equivalents to thioredoxin peroxidases and ribonucleotide reductase, the regulation of transcription factor activity, and the regulation of enzyme activity by heterodimer formation. Thioredoxin-1 stimulates cell growth and is an inhibitor of apoptosis. Thioredoxins may play a role in a variety of human diseases including cancer. An increased level of thioredoxin-1 is found in many human tumors, where it is associated with aggressive tumor growth. Drugs are being developed that inhibit thioredoxin and that have antitumor activity.
Drug Efficacy at G Protein–Coupled Receptors
Authors: Kenakin Terry
Published: July 2002

Efficacy has been defined in receptor pharmacology as a proportionality factor denoting the amount of physiological response a given ligand imparts to a biological system for a given amount of receptor occupancy. While first defined in terms of response, the concept can be expanded to a wide variety of G protein–coupled receptor (GPCR) behaviors, which includes pleiotropic interaction with multiple G proteins, internalization, oligomerization, desensitization, and interaction with membrane auxilliary proteins. Thus, there can be numerous types of efficacy, and different ligands can have a range of efficacies for different receptor behaviors. This review discusses the use of the efficacy concept in GPCR models based on the thermodynamic linkage theory and also in terms of the protein ensemble theory, in which macroaffinity of ligands for an ensemble of receptor microstates produces a new ligand-bound ensemble. The pharmacological characteristics of the ligand emerge from the intersection of the ligand-bound ensemble with the various ensembles defining pharmacological receptor behaviors. Receptor behaviors discussed are activation of G proteins; ability to be phosphorylated, desensitized, and internalized; formation of dimers and oligomers; and the interaction with auxiliary membrane and cytosolic proteins. The concepts of ligand-specific receptor conformation and conditional efficacy are also discussed in the context of ligand control of physiological response.
THEORETICAL STUDIES OF CHEMICAL DYNAMICS: Overview of Some Fundamental Mechanisms
Authors: Nakamura Hiroki
Published: July 2002

▪ Abstract  Recent remarkable progress in theoretical studies of (a) quantum dynamics of chemical reactions, (b) characteristics and dynamics of superexcited states of molecules, (c) nonadiabatic transitions at potential curve crossings, and (d) multidimensional tunneling is reviewed briefly. Underlying common basic concepts and fundamental mechanisms such as adiabaticity and nonadiabatic transition are extracted and discussed in order to facilitate a comprehensive understanding of chemical dynamics. Not only the basic theoretical methodologies but also the intriguing dynamical aspects of each subject are explained as simply as possible.
NANOCRYSTAL SUPERLATTICES
Authors: Collier C. P. , Vossmeyer T. , Heath J. R.
Published: July 2002

▪ Abstract  Ordered arrays, or superlattices, of metallic, insulating, or semiconducting quantum dots, represent an exciting new class of materials. These superlattices are often referred to as artificial solids, in which the nanocrystals take the place of atoms in traditional solids, and the packing arrangement of the nanocrystals determines the unit cell parameters of the superstructure. In this review, we discuss various approaches toward assembling nanocrystal superlattices and we discuss their physical properties.
CROSSED-BEAM STUDIES OF NEUTRAL REACTIONS: State-Specific Differential Cross Sections
Authors: Liu Kopin
Published: July 2002

▪ Abstract  Crossed-molecular-beam and laser techniques have enabled experimentalists to measure the state-resolved differential cross sections of elementary chemical reactions. This article reviews recent progress in this area. Particular emphasis is placed on some intriguing physical phenomena associated with a few benchmark reactions and how these measurements help in answering fundamental questions about reaction dynamics. We examine specifically the geometric phase effects in the reaction H + D2, the dynamical resonance phenomenon in F + HD, the unusually large spin-orbit reactivity in Cl(2P) + H2, the insertion reaction O(1D) + H2, and the mode-specific reactivity in Cl + CH4(ν). The give-and-take between experiment and theory in unraveling the physical picture of the dynamics is illustrated throughout this review.
ENDOTHELIAL CELL REGULATION OF CONTRACTILITY OF THE HEART
Authors: Winegrad Saul
Published: July 2002

▪ Abstract  Endocardial and coronary vascular endothelial cells release substances that modify the contraction of cardiac myocytes. The major and possibly the sole up-regulating substance is endothelin. Several down-regulating substances are secreted, but none has yet been specifically identified. The relative amounts of up- and down-regulating substances are related to tissue oxygen tension. As pO2 rises, the concentration of up- and down-regulating substances, respectively, increases and decreases. Endothelin increases isometric force and decreases actomyosin ATPase activity thus increasing the economy of conversion of chemical to hydrodynamic energy. Beta-adrenergic agonists increase ATPase activity through an endothelial cell-dependent mechanism, leading to decreased economy. Therefore, two endothelial cell-dependent systems exist for regulating contractile efficiency: One involving endothelin appears to optimize the contraction for efficiency; the other, the beta-adrenergic-mediated system, optimizes for power.
MOUSE MODELS OF AIRWAY RESPONSIVENESS: Physiological Basis of Observed Outcomes and Analysis of Selected Examples Using These Outcome Indicators
Authors: Drazen J. M. , Finn P. W. , De Sanctis G. T.
Published: July 2002

▪ Abstract  The mouse is an ideal species for investigation at the interface of lung biology and lung function. As detailed in this review, there are well-developed methods for the quantitative study of lung function in mice. These methods can be applied to mice in both terminal and nonterminal experiments. Terminal experimental approaches provide more detailed physiological information, but nonterminal measurements provide adequate data for certain experiments. In this review, we provide two examples of how these models can be used to further understanding of the primary pathobiology of airway responsiveness in both the absence and the presence of induced airway inflammation. The first model is a dissection of chromosomal loci linked to the variance in airway responsiveness observed in the absence of any manipulation to induce airway inflammation. The second model explores the role of T-cell costimulatory signals in the induction of airway hyperresponsiveness. As the number of mice with targeted deletions of effector genes or insertion of informative transgenes grows, additional examples are likely to accrue.
Ventricular Fibrillation: Mechanisms of Initiation and Maintenance
Authors: Jalife José
Published: July 2002

▪ Abstract  Ventricular fibrillation (VF) is the major immediate cause of sudden cardiac death. Traditionally, VF has been defined as turbulent cardiac electrical activity, which implies a large amount of irregularity in the electrical waves that underlie ventricular excitation. During VF, the heart rate is too high (> 550 excitations/minute) to allow adequate pumping of blood. In the electrocardiogram (ECG), ventricular complexes that are ever-changing in frequency, contour, and amplitude characterize VF. This article reviews prevailing theories for the initiation and maintenance of VF, as well as its spatio-temporal organization. Particular attention is given to recent experiments and computer simulations suggesting that VF may be explained in terms of highly periodic three-dimensional rotors that activate the ventricles at exceedingly high frequency. Such rotors may show at least two different behaviors: (a) At one extreme, they may drift throughout the heart at high speeds producing beat-to-beat changes in the activation sequence. (b) At the other extreme, rotors may be relatively stationary, activating the ventricles at such high frequencies that the wave fronts emanating from them breakup at varying distances, resulting in complex spatio-temporal patterns of fibrillatory conduction. In either case, the recorded ECG patterns are indistinguishable from VF. The data discussed have paved the way for a better understanding of the mechanisms of VF in the normal, as well as the diseased, human heart.

When the heart is diseased, its work is imperfectly performed: the vessels proceeding from the heart become inactive, so that you cannot feel them … If the heart trembles, has little power and sinks, the disease is advancing and death is near. Ebers Papyrus ∼3500 BC
Multiple Endocrine Neoplasias
Authors: Hoff A. O. , Cote G. J. , Gagel R. F.
Published: July 2002

▪ Abstract  The multiple endocrine neoplasia syndromes form a distinct group of genetic tumor syndromes. They include multiple endocrine neoplasia types 1 and 2, von Hippel Lindau syndrome, neurofibromatosis, and Carney complex. Research over the past decade has identified a molecular basis for each of these syndromes. This knowledge has revolutionized not only the clinical management but also has illuminated the field of human cancer research by the identification of new and important genes critical for regulation of cell growth, differentiation, and death. This review focuses on the structure, physiologic function, and molecular abnormalities of the genes involved in these syndromes.
Role of Transcription Factors in Fetal Lung Development and Surfactant Protein Gene Expression
Authors: Mendelson Carole R.
Published: July 2002

▪ Abstract  Branching morphogenesis of the lung and differentiation of specialized cell populations is dependent upon reciprocal interactions between epithelial cells derived from endoderm of embryonic foregut and surrounding mesenchymal cells. These interactions are mediated by elaboration and concerted actions of a variety of growth and differentiation factors binding to specific receptors. Such factors include members of the fibroblast growth factor family, sonic hedgehog, members of the transforming growth factor-β family, epidermal growth factor, and members of the platelet-derived growth factor family. Hormones that increase cyclic AMP formation, glucocorticoids, and retinoids also play important roles in branching morphogenesis, alveolar development, and cellular differentiation. Expression of the genes encoding these morphogens and their receptors is controlled by a variety of transcription factors that also are highly regulated. Several of these transcription factors serve dual roles as regulators of genes involved in early lung development and in specialized functions of differentiated cells. Targeted null mutations of genes encoding many of these morphogens and transcription factors have provided important insight into their function during lung development. In this chapter, the cellular and molecular mechanisms that control lung development are considered, as well as those that regulate expression of the genes encoding the surfactant proteins.
HOMOSERINE LACTONE-MEDIATED GENE REGULATION IN PLANT-ASSOCIATED BACTERIA
Authors: Pierson III Leland S. , Wood Derek W. , Pierson Elizabeth A.
Published: July 2002

▪ Abstract  Many plant-associated bacteria produce and utilize diffusible N-acyl-homoserine lactones (AHLs) to regulate the expression of specific bacterial genes and operons. AHL-mediated regulation utilizes two genes that encode proteins similar to the LuxI/LuxR system originally studied in the marine symbiont Vibrio fischeri. The LuxI-type proteins are AHL synthases that assemble the diffusible AHL signal. The LuxR-type proteins are AHL-responsive transcriptional regulatory proteins. LuxR proteins control the transcription of specific bacterial genes in response to the levels of AHL signal. To date, AHL-mediated gene regulation has been identified in a broad range of gram-negative bacteria, most of which are host-associated. However, it seems unlikely that such a widely conserved regulatory mechanism would be limited only to host-microbe interactions. These signals probably play central roles in ecological interactions among organisms in microbial communities by affecting communication among bacterial populations as well as between bacterial populations and their eukaryotic hosts.
HOST VARIATION FOR INTERACTIONS WITH BENEFICIAL PLANT-ASSOCIATED MICROBES
Authors: Smith Kevin P , Goodman Robert M
Published: July 2002

▪ Abstract  Beneficial plant-associated microbes can profoundly influence plant health by suppressing disease, enhancing nutrient uptake, fixing atmospheric nitrogen, and promoting plant growth. Host variation, among cultivars or plant genotypes, for response to beneficial microorganisms suggests that plant genes play a role in supporting these interactions. Such host variation can be found among diverse groups of microorganisms including rhizobia, mycorrhizal fungi, and microbial biocontrol agents. Discrete variation among plant genotypes for interaction with beneficial microbes has led to the discovery of single genes that specify compatible interactions. Continuous variation for interaction phenotypes such as disease suppression, plant growth, or nutrient uptake have led to hypotheses, and in some cases genetic descriptions, of multigenic control of these interactions. Future research into the role of plant genes involved in hosting beneficial plant-associated microbes will provide greater insight into this relatively unexplored area of biology and should provide new tools to improve plant health in agriculture.
CROWNGALLOFGRAPE: Biology and Disease Management
Authors: Burr Thomas J. , Otten Leon
Published: July 2002

▪ Abstract  Not until 1973 was it reported that strains of Agrobacterium that cause crown gall disease of grape form a specific group (later characterized as Agrobacterium vitis). Tumorigenic and nontumorigenic A. vitis have since been isolated from infected and symptomless grapes worldwide. Research on the genetic makeup of A. vitis has led to an improved understanding of pathogen biology and bacterial evolution. In addition, the identification of significant gene sequences has facilitated the development of PCR and RFLP-based identification procedures that continue to improve the detection of A. vitis in plants and soil. Current control practices rely on the use of disease-resistant cultivars, cultural practices that minimize plant injury, and the production of pathogen-free vines. Promising future controls include employment of biological control agents and development of crown gall–resistant transgenic grapevines.
Advances in Imaging the Cell Biology of Plant-Microbe Interactions
Authors: Heath Michèle C.
Published: July 2002

All plant-microbe interactions are initiated at the level of the cell. Recently, the light microscope has increased in popularity as an investigative tool in plant cell biology, in part because of the parallel developments of confocal laser scanning and video microscopy, computerized image processing, and an ever-increasing array of fluorescent probes that can be applied to living cells. In addition, transgenic plants and cells can be generated in which specific components are fluorescently labeled without any invasive experimental manipulation. The application of such techniques to plant-microbe interactions has revealed microbe-induced changes in cytosolic calcium levels, the visualization of reactive oxygen species generation, cytoskeleton rearrangements, DNA cleavage, and the detailed resolution of intercellular and intracellular trafficking of viral components. These techniques, integrated with electron microscopy, molecular genetics, and other types of investigations, are likely to play an increasingly important role in future studies of plant responses to microbial pathogens or mutualists.
RESISTANCEGENECOMPLEXES: Evolution and Utilization
Authors: Hulbert Scot H. , Webb Craig A. , Smith Shavannor M. , Sun Qing
Published: July 2002

▪ Abstract  More than 30 genes have been characterized from different plant species that provide resistance to a variety of different pathogen and pest species. The structures of most are consistent with a role in pathogen recognition and defense response signaling. Resistance genes are very abundant in plant genomes and most belong to tightly linked gene families. Evolution of R genes is driven by selection on allelic variation created by mutation and re-assorted by recombination between alleles and sometimes between different gene family members. Selection favors genes that can recognize pathogen avr gene products that are present in pathogen populations. Selection at linked gene families favors haplotypes with useful combinations of genes but a limited physiological cost to the plant. Future utilization of R genes will include transfer between related genera and identification or construction of genes that condition durable resistance to variable pathogens. Genes with durable resistance may interact with conserved pathogen elicitors or condition resistance responses that are independent of specific Avr gene interactions.
TAKINGSTOCK: The Constructivist Research Program in International Relations and Comparative Politics
Authors: Finnemore Martha , Sikkink Kathryn
Published: July 2002

▪ Abstract  Constructivism is an approach to social analysis that deals with the role of human consciousness in social life. It asserts that human interaction is shaped primarily by ideational factors, not simply material ones; that the most important ideational factors are widely shared or “intersubjective” beliefs, which are not reducible to individuals; and that these shared beliefs construct the interests of purposive actors. In international relations, research in a constructivist mode has exploded over the past decade, creating new and potentially fruitful connections with long-standing interest in these issues in comparative politics. In this essay, we evaluate the empirical research program of constructivism in these two fields. We first lay out the basic tenets of constructivism and examine their implications for research methodology, concluding that constructivism's distinctiveness lies in its theoretical arguments, not in its empirical research strategies. The bulk of the essay explores specific constructivist literatures and debates in international relations and comparative politics.
THENEWSMEDIA ASPOLITICALINSTITUTIONS
Authors: Schudson Michael
Published: July 2002

▪ Abstract  Political science has tended to neglect the study of the news media as political institutions, despite a long history of party-subsidized newspapers and despite a growing chorus of scholars who point to an increasing “mediatization” of politics. Still, investigators in sociology, communication, and political science have taken up the close study of news institutions. Three general approaches predominate. Political economy perspectives focus on patterns of media ownership and the behavior of news institutions in relatively liberal versus relatively repressive states; a second set of approaches looks at the social organization of newswork and relates news content to the daily patterns of interaction of reporters and their sources; a third style of research examines news as a form of culture that often unconsciously incorporates general belief systems, assumptions, and values into news writing.
COVARIANCE STRUCTURE ANALYSIS: Statistical Practice, Theory, and Directions
Authors: Bentler Peter M. , Dudgeon Paul
Published: July 2002

▪ Abstract  Although covariance structure analysis is used increasingly to analyze nonexperimental data, important statistical requirements for its proper use are frequently ignored. Valid conclusions about the adequacy of a model as an acceptable representation of data, which are based on goodness-of-fit test statistics and standard errors of parameter estimates, rely on the model estimation procedure being appropriate for the data. Using analogies to linear regression and anova, this review examines conditions under which conclusions drawn from various estimation methods will be correct and the consequences of ignoring these conditions. A distinction is made between estimation methods that are either correctly or incorrectly specified for the distribution of data being analyzed, and it is shown that valid conclusions are possible even under misspecification. A brief example illustrates the ideas. Internet access is given to a computer code for several methods that are not available in programs such as EQS or LISREL.
INDIVIDUAL PSYCHOTHERAPY OUTCOME AND PROCESS RESEARCH: Challenges Leading to Greater Turmoil or a Positive Transition?
Authors: Kopta S. Mark , Lueger Robert J. , Saunders Stephen M. , Howard Kenneth I.
Published: July 2002

▪ Abstract  Psychotherapy is facing challenges that relate to the emergence of managed health care, the possibility of a national health care system, and advances in biological psychiatry. These situations have created pressure to achieve a more accurate assessment of psychotherapeutic effectiveness. Psychotherapy has been proven to be generally effective; however, there is uncertainty as to why. The field is currently experiencing apparent turmoil in three areas: (a) theory development for psychotherapeutic effectiveness, (b) research design, and (c) treatment technique. This chapter reviews the dynamics within each of the areas and highlights the progress made in treating mental disorders. We conclude that recent advances in research design may provide a transition that will bring psychotherapy closer to becoming a unified paradigm with an acceptable theory of effectiveness.
REINVENTING PUBLIC HEALTH
Authors: Lee P. , Paxman D.
Published: July 2002

▪ Abstract  This chapter is a review of the current state of public health in light of the social, political, economic, scientific, and technological changes buffeting the United States. As an assessment of progress in current public health efforts, we address the five major issues in public health for the 1990s raised by Breslow ( 8 ): reconstruction of public health; setting objectives for public health; from disease control to health promotion; determinants of health and health policy; continuing social inequities and their impacts on health; and the health implications of accelerating developments in technology. Finally, we look to the twenty-first century and provide five clear paths necessary to strengthen the capacity of public health agencies to protect and improve the health status of the population.
PREVENTING YOUTH VIOLENCE: What Works?
Authors: Kellermann Arthur L. , Fuqua-Whitley Dawna S. , Rivara Frederick P. , Mercy James
Published: July 2002

▪ Abstract  Between 1985 and 1992, serious youth violence in the United States surged to unprecedented levels. The growing use of firearms to settle disputes has contributed to this phenomenon. Youth are most often victimized by one of their peers. In response to this problem, a wide variety of programs have been implemented in an attempt to prevent youth violence or reduce its severity. Few have been adequately evaluated. In general, interventions applied between the prenatal period and age 6 appear to be more effective than interventions initiated in later childhood or adolescence. Community-based programs that target certain high-risk behaviors may be beneficial as well. A sustained commitment to evaluation research is needed to identify the most effective approaches to youth violence prevention.
Managed Care: A View from Europe
Authors: Erdmann Yvonne , Wilson Renate
Published: July 2002

▪ Abstract  This article summarizes recent developments in the United Kingdom, the Netherlands, Switzerland, and the new Baltic states that reflect the influence of US managed care concepts and practices. We emphasize (a) developments in restructuring traditional health insurance mechanisms by shifting premium and out-of-pocket burdens to consumers so as to constrain demand and costs and (b) reliance on prospective hospital budgets and case management by primary physicians. Social insurance mechanisms and universal coverage remain national tasks as well as basic components of the social structure of most European countries. Full open-market competition between traditional sick funds and private insurance companies and the introduction of for-profit MCOs beholden to their shareholders appears unlikely on other than an experimental basis. Increased competition between providers may well result from the new right of insurers and payers to contract with medical care providers of their choice. It remains to be shown how far these experiments, which differ substantially between the countries examined, will succeed in their objectives and become permanent features of their national systems.
Cascade Effects of Medical Technology
Authors: Deyo Richard A.
Published: July 2002

▪ Abstract  Cascade effect refers to a process that proceeds in stepwise fashion from an initiating event to a seemingly inevitable conclusion. With regard to medical technology, the term refers to a chain of events initiated by an unnecessary test, an unexpected result, or patient or physician anxiety, which results in ill-advised tests or treatments that may cause avoidable adverse effects and/or morbidity. Examples include discovery of endocrine incidentalomas on head and body scans; irrelevant abnormalities on spinal imaging; tampering with random fluctuations in clinical measures; and unwanted aggressive care at the end of life. Common triggers include failing to understand the likelihood of false-positive results; errors in data interpretation; overestimating benefits or underestimating risks; and low tolerance of ambiguity. Excess capacity and perverse financial incentives may contribute to cascade effects as well. Preventing cascade effects may require better education of physicians and patients; research on the natural history of mild diagnostic abnormalities; achieving optimal capacity in health care systems; and awareness that more is not the same as better.
Growing Up American: The Challenge Confronting Immigrant Children and Children of Immigrants
Authors: Zhou Min
Published: July 2002

Since the 1980s, immigrant children and children of immigrant parentage have become the fastest growing and the most extraordinarily diverse segment of America's child population. Until the recent past, however, scholarly attention has focused on adult immigrants to the neglect of their offspring, creating a profound gap between the strategic importance of the new second generation and the knowledge about its socioeconomic circumstances. The purpose of this article is to pull together existing studies that bear directly or indirectly on children's immigrant experiences and adaptational outcomes and to place these studies into a general framework that can facilitate a better understanding of the new second generation. The article first describes the changing trends in the contexts of the reception the new second generation has encountered. The article then discusses the ways in which conventional theoretical perspectives about immigrant adaptation are being challenged and alternative frameworks are being developed. Thirdly, it examines empirical findings from recent research and evaluates their contribution to the sociology of immigration. Finally, it highlights the main conclusions from prior research and their theoretical and practical implications for future studies.
Myocardial Regeneration Therapy for Heart Failure
Authors: Miyagawa Shigeru , Sawa Yoshiki , Taketani Satoshi , Kawaguchi Naomasa , Nakamura Toshikazu , Matsuura Nariaki , Matsuda Hikaru
Published: July 2002

Background

—

We hypothesized that transfection of the gene for human hepatocyte growth factor (hHGF) combined with cellular cardiomyoplasty might regenerate the impaired myocardium.

Methods and Results

—

We used a ligation model of proximal left anterior descending coronary artery (LAD) of Lewis rats. Two weeks after LAD ligation, 3 different treatments were conducted: (1) neonatal rat cardiomyocytes group (10
6
cells, T group, n=11), (2) HVJ-liposomes bearing the hHGF gene group (H group, n=10), and (3) combined (T-H group, n=10). The injection site was the scar area of myocardial infarction. For control, culture medium was injected (C group, n=13). Echocardiography demonstrated that cardiac performance was significantly ameliorated in the T-H group 4 and 8 weeks after injection. Contrast echocardiography also showed a marked increase in myocardial perfusion in the T-H group but not in the other groups. In the T-H group, neovascularization and a marked reduction of fibrosis were observed histologically. In an immunohistochemical study, strong staining for β
1
-integrin, α-, and β-dystroglycan were found principally in the basement membrane of myocytes in the T-H group 8 weeks after transplantation, although there was weak immunoreactivity in the T group.

Conclusions

—

hHGF gene transfection enhanced the cellular cardiomyoplasty possibly by stimulating angiogenesis, restoring the impaired ECM, and promoting the integration of the dissociated grafted myocytes. The combined effects might have lead to the improved cardiac performance. Thus, combined therapy may be a promising strategy for the treatment of heart failure caused by myocardial infarction.
Expansive Arterial Remodeling Is Associated With Increased Neointimal Macrophage Foam Cell Content
Authors: Ivan Eugen , Khatri Jaikirshan J. , Johnson Chad , Magid Richard , Godin Denis , Nandi Sudeshna , Lessner Susan , Galis Zorina S.
Published: July 2002

Background
—

Recent observations associate plaque instability with expansive arterial remodeling, suggesting a common driving mechanism.

Methods and Results
—

To demonstrate that macrophages, a characteristic of vulnerable plaques, also assist in expansive remodeling, we compared carotid artery remodeling due to formation of experimental macrophage-rich and macrophage-poor lesions in the flow cessation model in hypercholesterolemic apolipoprotein E knockout (ApoE KO) and wild type (WT) mice. After ligation, macrophages started to rapidly accumulate in ApoE KO but not in WT carotid artery lesions. Macrophage-rich ApoE KO intimal lesions grew fast, typically occluding within 14 days, despite a tripling of the vessel area. Outward remodeling of macrophage-rich ApoE KO arteries positively correlated with macrophage area (
r
2
=0.600,
P
<0.001). To investigate potential mechanisms of macrophage-enabled expansive remodeling, we compared levels of matrix metalloproteinases in homogenates of macrophage-rich and macrophage-poor carotid arteries. Gelatinolytic activity of macrophage-rich lesions increased faster and reached maximal levels several fold higher than in the macrophage-poor WT lesions.

Conclusions
—

Our results suggest that macrophages facilitate expansive arterial remodeling through increased matrix degradation by matrix metalloproteinases. This initially favorable remodeling action may eventually increase the vulnerability of macrophage-rich atherosclerotic plaques.
Specific β
2
AR Blocker ICI 118,551 Actively Decreases Contraction Through a G
i
-Coupled Form of the β
2
AR in Myocytes From Failing Human Heart
Authors: Gong Haibin , Sun Hong , Koch Walter J. , Rau Thomas , Eschenhagen Thomas , Ravens Ursula , Heubach Jürgen F. , Adamson Dawn L. , Harding Sian E.
Published: July 2002

Background

—

We have observed direct (noncatecholamine-blocking) negative inotropic effects of the selective β
2
-adrenoceptor (AR) antagonist ICI 118,551 in myocytes from failing human ventricle. In this study we characterize the effect in parallel in human myocytes and in myocytes from animal models where β
2
ARs or G
i
proteins are overexpressed.

Methods and Results

—

Enzymatically isolated, superfused ventricular myocytes were exposed to βAR agonists and antagonists/inverse agonists, and contraction amplitude was measured. ICI 118,551 decreased contraction in ventricular myocytes from failing human hearts by 45.3±4.1% (n=20 hearts/31 myocytes,
P
<0.001) but had little effect in nonfailing hearts (4.9±4%, n=5 myocytes/3 hearts). Effects were significantly larger in patients classified as end-stage. Transgenic mice with high β
2
AR number and increased G
i
levels had normal basal contractility but showed a similar negative inotropic response to ICI 118,551. Overexpression of human β
2
AR in rabbit myocytes using adenovirus potentiated the negative inotropic effect of ICI 118,551. In human, rabbit, and mouse myocytes, the negative inotropic effects were blocked after treatment of cells with pertussis toxin to inactivate G
i
, and overexpression of G
i
α
2
induced the effect de novo in normal rat myocytes.

Conclusions

—

We hypothesize that ICI 118,551 binding directs the β
2
AR to a G
i
-coupled form and away from the G
s
-coupled form (ligand-directed trafficking). ICI 118,551 effectively acts as an agonist at the G
i
-coupled β
2
AR, producing a direct negative inotropic effect. Conditions where β
2
ARs are present and G
i
is raised (failing human heart, TGβ
2
mouse heart) predispose to the appearance of the negative inotropic effect.
Association of Plasma Homocysteine Concentration With Atherosclerotic Carotid Plaques and Lacunar Infarction
Authors: Sasaki Tsutomu , Watanabe Manabu , Nagai Yoji , Hoshi Taku , Takasawa Masashi , Nukata Masaru , Taguchi Akihiko , Kitagawa Kazuo , Kinoshita Naokazu , Matsumoto Masayasu
Published: July 2002

Background and Purpose

—

Higher plasma total homocysteine (tHcy) levels have been associated with carotid atherosclerosis and cerebral infarction in whites. However, data regarding such associations are limited for Asians. This study examined associations between tHcy levels and severity of carotid atherosclerosis in Japanese subjects. Additionally, because lacunar infarction is the most prevalent type of ischemic stroke in Japan, we also investigated its associations with tHcy levels.

Methods

—

The subjects were 152 Japanese patients (age, 66.2±11.0 years) at our hospital. Using ultrasound, we evaluated severity of carotid atherosclerosis by plaque score, which is defined by the sum of all plaque (intima-media thickness ≥1.1 mm) height in bilateral carotid arteries. In 112 of 152 patients, the existence of lacunar infarction was evaluated on brain MRI scans.

Results

—

A moderate linear association was found between tHcy levels and plaque score (
r
=0.48,
P
<0.0001). Moreover, tHcy level was associated with plaque score (β=0.26,
P
<0.001) independently of traditional atherosclerotic risk factors. In logistic regression analyses, each 1-μmol/L-higher tHcy level was associated with a 1.37-fold-higher [95% confidence interval (CI), 1.19 to 1.58] likelihood for lacunar infarction, increasing the likelihood by 1.22-fold (95% CI, 1.04 to 1.43) independently of traditional atherosclerotic risk factors.

Conclusions

—

Higher tHcy levels appear to have associations with increased severity of carotid atherosclerotic plaques and prevalent lacunar infarction in the Japanese. Larger prospective studies are necessary to establish whether higher tHcy levels serve as a harbinger for insidious carotid and cerebrovascular diseases.
Longitudinal Study of Motor Recovery After Stroke
Authors: Feydy A. , Carlier R. , Roby-Brami A. , Bussel B. , Cazalis F. , Pierot L. , Burnod Y. , Maier M.A.
Published: July 2002

Background and Purpose

—

The goal of this study was to characterize cortical reorganization after stroke and its relation with the site of the stroke-induced lesion and degree of motor recovery using functional MRI (fMRI).

Methods

—

Fourteen stroke patients with an affected upper limb were studied longitudinally. Three fMRI sessions were performed over a period of 1 to 6 months after stroke. Upper limb recovery, Wallerian degeneration of the pyramidal tract, and responses to transcranial magnetic stimulation were assessed.

Results

—

Two main patterns of cortical reorganization were found. Pattern 1 was focusing, in which, after initial recruitment of additional ipsilateral and contralateral areas, activation gradually developed toward a pattern of activation restricted to the contralateral sensorimotor cortex in 9 patients. Five patients were found to have pattern 2, persistent recruitment, in which there was an initial and sustained recruitment of ipsilateral activity. Occurrence of recruitment or focusing seemed to depend mainly on whether the primary motor cortex (M1) was lesioned; persistent recruitment was observed in 3 of 4 patients with M1 injury, and focusing was seen in 8 of 10 patients with spared M1. These patterns had no relation to the degree of recovery; in particular, focusing did not imply recovery. However, there was a clear relation between the degree of recovery and the degree of Wallerian degeneration.

Conclusions

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These results suggest that ipsilateral recruitment after stroke corresponds to a compensatory corticocortical process related to the lesion of the contralateral M1 and that the process of compensatory recruitment will persist if M1 is lesioned; otherwise, it will be transient.
Increased Risk for Postoperative Hemorrhage After Intracranial Surgery in Patients With Decreased Factor XIII Activity
Authors: Gerlach Rüdiger , Tölle Fabian , Raabe Andreas , Zimmermann Michael , Siegemund Annelie , Seifert Volker
Published: July 2002

Background and Purpose

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The functional integrity of the hemostatic system is a prerequisite for the safe performance of neurosurgical procedures. To monitor the individual coagulation capacity of each patient, standard tests are effective to detect deficiencies involving the generation of fibrin. However, fibrin clot strength depends primarily on coagulation factor XIII, which cross-links fibrin monomers and enhances clot resistance against fibrinolysis. Therefore, factor XIII is functionally involved in both the hemostatic and fibrinolytic systems. The objective of this prospective study was to determine the incidence and clinical relevance of perioperative decreased factor XIII with respect to standard coagulation parameters and the occurrence of postoperative hematoma.

Methods

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In 876 patients, 910 neurosurgical procedures were performed. Prothrombin time (PT), partial thromboplastin time (PTT), platelet count, fibrinogen, and factor XIII were tested in each patient preoperatively and postoperatively.

Results

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Postoperative intracranial hematoma (defined as requiring surgical evacuation) occurred after 39 (4.3%) of 910 surgical procedures. Patients with postoperative hematoma had significantly lower factor XIII and fibrinogen levels preoperatively and postoperatively than patients without hematoma. In patients with postoperative hematoma, PT and platelets differed significantly only postoperatively, whereas PTT was different neither preoperatively nor postoperatively. Of the 39 patients with a postoperative hematoma, 13 (33.3%) had a postoperative factor XIII <60% compared with 61 (7%) of 867 patients without hematoma (
P
<0.01, Fisher’s exact test). The relative risk of developing a postoperative hematoma is therefore increased 6.4-fold in patients with postoperative factor XIII <60%. The risk is increased 12-fold in patients who additionally have postoperative decreased fibrinogen levels (<1.5 g/L) and 9-fold in patients with platelet count <150×10
9
/L and factor XIII <60%.

Conclusions

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This is the first prospective study that demonstrates the association of decreased perioperative factor XIII with an increased risk of postoperative hematoma in neurosurgical patients. The risk is further increased in those patients with low factor XIII and additional abnormalities of fibrinogen, PT, platelets, and PTT. Factor XIII testing and specific replacement, as accepted for other clotting factors, may reduce the risk of postoperative hematoma.
Agricultural policy reform in the European Community: a three-level game analysis
Authors: Patterson Lee Ann
Published: July 2002

Since the beginning of the General Agreement on Tariffs and Trade (GATT) Uruguay Round the European Community (EC) has twice attempted to reform the Common Agricultural Policy (CAP), resulting in the February 1988 stabilizers reform package and the May 1992 MacSharry reform package. Curiously, these two attempts at reform resulted in vastly different outcomes. The 1988 reform was incremental in nature and functioned mainly as a stopgap measure. The 1992 reform, however, called for a shift from nontransparent consumer subsidies to transparent taxpayer subsidies. This shift represented a fundamental change in the philosophy underlying the CAP and laid the groundwork for an agreement in the Uruguay Round. This article examines the conditions under which this important policy shift occurred. It employs an interpretative case study method that demonstrates the empirical value of Robert Putnam's two-level game model when it is expanded to consider the simultaneous interaction of negotiations at three levels: the domestic level, the EC level, and the international level. The study concludes that the power and heterogeneity of interest groups at various levels of the game matter, that the real and perceived costs of no agreement affect the degree of substantive reform, and, finally, that a three-level interactive strategy is important in achieving an acceptable agreement at each level of the game.
U.S. politics and greater regulation of inward foreign direct investment
Authors: Kang C. S. Eliot
Published: July 2002

An analyst of U.S. foreign economic policy observes that each wave of antiforeign sentiment associated with the surge of foreign direct investment (FDI) coming into the United States washes ashore a flotsam of restrictive and exclusionary laws that recedes slightly or becomes buried and forgotten in the sand only to advance again with a new wave. During the late 1980s, the controversy generated by the sharp rise of Japanese acquisitions in the United States washed ashore the latest flotsam of regulatory measures and further advanced the tangle of rules and regulations targeting inward foreign direct investment (IFDI). Of the various types of FDI, the present study is concerned mainly with the policy change toward foreign investment in an already established domestic business. This type of investment often involves merger or acquisition and is distinct from a “greenfield” investment where the foreign investor establishes “from scratch” a new business in the host economy.
The Magic Bullet? The RTAA, Institutional Reform, and Trade Liberalization
Authors: Hiscox Michael J.
Published: July 2002

The Reciprocal Trade Agreements Act (RTAA) of 1934 has long been heralded as a simple institutional reform with revolutionary consequences: namely, by changing the trade policymaking process in the United States, the RTAA is held responsible for the dramatic liberalization in U.S. policy beginning in the 1930s and 1940s. This article takes issue with this conventional wisdom. I argue that the standard accounts—which emphasize the importance of delegation for overcoming logrolling in Congress or for facilitating reciprocity in international trade negotiations—fail to provide an adequate explanation for just how the institutional innovation was achieved and sustained in the face of protectionist opposition. I suggest instead that trade liberalization was driven by exogenous changes in party constituencies and societal preferences that had crucial effects on congressional votes to extend the RTAA authority and liberalize trade after 1945. The preservation of the RTAA program was symptomatic rather than causal; as a consequence, it may well be abandoned in the future. The evolution of U.S. trade policy has been, and will continue to be, powerfully shaped by changes in the preferences of societal groups and in the positions taken by parties on the trade issue.
Research Project Number 33: Investigating the Creative Process in a Microgravity Environment
Authors: Pietronigro Frank
Published: July 2002

The author, an interdiscipli-nary artist, discusses his creation of art in a microgravity environ-ment as part of the 1998 NASA Student Reduced Gravity Flight Program. He discusses his three-dimensional “drift paintings” which floated in the air along with his body in microgravity. The au-thor posits that the transcendent quality of the creative process can help keep the human spirit alive during long-term space missions.
Electronic Art and the Law: Intellectual Property Rights in Cyberspace
Authors: Search Patricia
Published: July 2002

The dematerialization of art that began in the 1960s has reached new heights with the use of electronic media. We are at an important crossroads in defining intellectual property rights that will have a direct impact on the way we create and disseminate electronic art in the future. This paper examines the historical evolution of the definition of “author” in copyright law. The paper shows how current copyright legislation and recent court decisions do not address the plasticity of the medium and the new forms of authorship that are defined by the artistic use of techniques such as virtual reality, artificial intelligence, hypermedia links and collaborative networking.