bluuebunny/crossref_metadata_2025 huggingface dataset:
Fatty Acids and Immune Responses—A New Perspective in Searching for Clues to Mechanism
Authors: Hwang Daniel
Published: July 2002

Dietary essential fatty acids are the precursors for eicosanoids. Among the eicosanoids derived from arachidonic acid, prostaglandin (PG) E2is known to possess immunosuppressive actions. Thus, it has been a prevailing hypothesis that the immuno-modulatory roles of dietary fatty acids are mediated at least in part through the alteration of PG biosynthesis. PGs exert their biological effects through their cognate receptors. There are four subtypes of PGE receptors (EP1, EP2, EP3, and EP4) so far identified. Although the association of EP receptors with G proteins coupled to adenylate cyclase and the mobilization of intracellular calcium are well documented, downstream signaling pathways for these receptors are virtually unknown. Identification of downstream signaling pathways for each subtype of EP receptors and target genes regulated by the activation of the receptor will help with our understanding of the mechanism by which dietary fatty acids affect immune responses through the modulation of PGE2biosynthesis. Emerging evidence suggests that fatty acids can additionally act as second messengers, regulators of signal transducing molecules or transcription factors. Acylation with long-chain fatty acids can occur on a variety of signaling molecules and can affect their membrane translocation and functions. Dietary fatty acids can alter functional properties of lipid mediators by changing the composition of acyl moieties of these molecules. Evidence accumulated recently indicates that long-chain unsaturated fatty acids and their metabolites bind and activate peroxisome proliferator–activated receptors (PPARs). PPARs are nuclear hormone receptors and transcription factors that regulate the expression of broad arrays of genes involved not only in lipid and glucose metabolism, but also in immune and inflammatory responses. PPARs may therefore be important cellular targets that mediate modulation of immune responses by dietary fatty acids. Together, it becomes clear now that multiple steps in various receptor-mediated signaling pathways can be modulated by dietary fatty acids. It will be a challenging task to quantitatively determine how different fatty acids alter functional properties of multitude of signaling components and final cellular responses. Elucidating the mechanism of actions of fatty acids on receptor-mediated signaling pathways in immuno-competent cells will provide a new insight for understanding the immuno-modulatory roles of dietary fatty acids.
THE EXTRACELLULAR Ca2+-SENSING RECEPTOR: Central Mediator of Systemic Calcium Homeostasis
Authors: Brown Edward M.
Published: July 2002

▪ Abstract  The cloning of the G protein-coupled, extracellular calcium (Ca2+o)-sensing receptor (CaR) has identified a central mediator of the mechanism governing systemic Ca2+o homeostasis. This system enables organisms to adapt successfully to wide variations in dietary Ca2+o intake while maintaining near constancy of Ca2+o. Whereas discussions of Ca2+o homeostasis have generally focused on the key role of Ca2+o-elicited changes in parathyroid hormone secretion, the presence of the CaRs in effector tissues of this system enables direct regulation of processes (e.g. renal tubular Ca2+ reabsorption and possibly bone formation and resorption) that add additional layers of homeostatic control. As we understand more about how the CaR regulates these tissues, we may find that it participates in other processes relevant to mineral ion homeostasis, including the control of the 1-hydroxylation and activation of vitamin D3 or reabsorption of phosphate in the renal proximal tubule. Regardless, the remarkable sensitivity of the CaR to small changes in Ca2+o allows adjustments in the response of the Ca2+o homeostatic system to increases or decreases in the intake of dietary Ca2+, for instance, that cause barely detectable alterations in Ca2+o. Furthermore, the CaR likely participates in coordinating interactions among several different homeostatic control systems (including those for water, Mg2+o, Na+, extracellular volume, and/or blood pressure), despite the fact that these systems are often considered to function largely independently of mineral ion metabolism.
MAMMALIAN SELENIUM-CONTAINING PROTEINS
Authors: Behne Dietrich , Kyriakopoulos Antonios
Published: July 2002

▪ Abstract  Mammalian selenium-containing proteins can be divided into three groups: proteins containing nonspecifically incorporated selenium, specific selenium-binding proteins, and specific selenocysteine-containing selenoproteins. Selenoproteins with known functions identified so far include five glutathione peroxidases, two deiodinases, several thioredoxin reductases, and selenophosphate synthetase 2. Alternative splicing leads to a greater variety of selenoproteins, as was shown in the cases of a specific sperm nuclei glutathione peroxidase and some thioredoxin reductases. Selenoprotein P, selenoprotein W, a 15-kDa selenoprotein, an 18-kDa selenoprotein, and several selenoproteins identified in silico from nucleotide sequence databases were found to contain selenocysteine but their functions are not known. Gel electrophoretic separation of tissue samples from rats labeled in vivo with 75Se showed the existence of further selenium-containing proteins.
GENETICEFFECTS OFMETHYLATIONDIETS
Authors: Van den Veyver Ignatia B.
Published: July 2002

▪ Abstract  DNA methylation at cytosines in CpG dinucleotides can lead to changes in gene expression and function without altering the primary sequence of the DNA. Methylation can be affected by dietary levels of methyl-donor components, such as folic acid. This may be an important mechanism for environmentally induced changes in gene expression. Recent literature supports a role for DNA-methylation changes in a number of adult-onset disorders and during development. These changes may be significant for better understanding certain birth defects (e.g., neural tube defects) and the long-term consequences of early environmental influences on gene expression (metabolic programming). Optimal “methylation diets” should be investigated as part of the prevention and treatment of all these conditions, as well as in disorders such as Rett syndrome, whose primary defects may lie in DNA methylation-dependent gene regulation.
The Impact of Genomics on Drug Discovery
Authors: Debouck C. , Metcalf B.
Published: July 2002

High-throughput gene sequencing has revolutionized the process used to identify novel molecular targets for drug discovery. Thousands of new gene sequences have been generated but only a limited number of these can be converted into validated targets likely to be involved in disease. We describe here some of the approaches used at SmithKline Beecham to select and validate novel targets. These include the identification of selective tissue gene product expression, such as for cathepsin K, a novel osteoclast-specific cysteine protease. We also describe the discovery and functional characterization of novel members of the G-protein coupled receptor superfamily and their pairing with natural ligands. Lastly, we discuss the promises of gene microarrays and proteomics, developing technologies that allow the parallel analyses of tissue expression patterns of thousands of genes or proteins, respectively.
Nicotinic Receptors at the Amino Acid Level
Authors: Corringer Pierre-Jean , Novère Nicolas Le , Changeux Jean-Pierre
Published: July 2002

nAChRs are pentameric transmembrane proteins into the superfamily of ligand-gated ion channels that includes the 5HT3, glycine, GABAA, and GABAC receptors. Electron microscopy, affinity labeling, and mutagenesis experiments, together with secondary structure predictions and measurements, suggest an all-β folding of the N-terminal extracellular domain, with the connecting loops contributing to the ACh binding pocket and to the subunit interfaces that mediate the allosteric transitions between conformational states. The ion channel consists of two distinct elements symmetrically organized along the fivefold axis of the molecule: a barrel of five M2 helices, and on the cytoplasmic side five loops contributing to the selectivity filter. The allosteric transitions of the protein underlying the physiological ACh-evoked activation and desensitization possibly involve rigid body motion of the extracellular domain of each subunit, linked to a global reorganization of the transmembrane domain responsible for channel gating.
Cytokine Modulators as Novel Therapies for Asthma
Authors: Barnes Peter J.
Published: July 2002

Cytokines play a critical role in orchestrating and perpetuating inflammation in asthmatic airways and several specific cytokine and chemokine inhibitors are now in development for the treatment of asthma. Inhibition of IL-4 with soluble IL-4 receptors has shown promising early results in asthma. Anti-IL-5 antibody is very effective at inhibiting peripheral blood and airway eosinophils but does not appear to be effective in symptomatic asthma. Inhibitory cytokines, such as IL-10, interferons, and IL-12 are less promising because systemic delivery produces intolerable side effects. Inhibition of TNF-α may be useful in severe asthma. Many chemokines are involved in the inflammatory response of asthma, and small-molecule inhibitors of chemokine receptors are in development. CCR3 antagonists are now in clinical development for the treatment of asthma. Because so many cytokines are involved in asthma, drugs that inhibit the synthesis of multiple cytokines may prove to be more useful. Several such classes of drug are now in clinical development, and the risk of side effects with these nonspecific inhibitors may be reduced by the inhaled route of delivery.
CYTOPLASMIC ATP-DEPENDENT REGULATION OF ION TRANSPORTERS AND CHANNELS: Mechanisms and Messengers
Authors: Hilgemann Donald W.
Published: July 2002

▪ Abstract  Many ion transporters and channels appear to be regulated by ATP-dependent mechanisms when studied in planar bilayers, excised membrane patches, or with whole-cell patch clamp.Protein kinases are obvious candidates to mediate ATP effects, but other mechanisms are also implicated. They include lipid kinases with the generation of phosphatidylinositol phosphates as second messengers, allosteric effects of ATP binding, changes of actin cytoskeleton, and ATP-dependent phospholipases. Phosphatidylinositol-4,5-bisphosphate (PIP2) is a possible membrane-delimited messenger that activates cardiac sodium-calcium exchange, KATP potassium channels, and other inward rectifier potassium channels. Regulation of PIP2 by phospholipase C, lipid phosphatases, and lipid kinases would thus tie surface membrane transport to phosphatidylinositol signaling. Sodium-hydrogen exchange is activated by ATP through a phosphorylation-independent mechanism, whereas ion cotransporters are activated by several protein kinase mechanisms. Ion transport in epithelium may be particularly sensitive to changes of cytoskeleton that are regulated by ATP-dependent cell signaling mechanisms.
CONTROL OF M-CURRENT
Authors: Marrion Neil V.
Published: July 2002

▪ Abstract  M-current is a non-inactivating potassium current found in many neuronal cell types. In each cell type, it is dominant in controlling membrane excitability by being the only sustained current in the range of action potential initiation. It can be modulated by a large array of receptor types, and the modulation can occur either by suppression or enhancement. Modulation of M-current has dramatic effects on neuronal excitability. This review discusses the numerous second messenger pathways that converge on regulation of this current: in particular, two forms of regulation of the M-current, receptor-mediated modulation and the control of macroscopic current amplitude by intracellular calcium. Both types of regulation are discussed with reference to the modulation of single-channel gating properties.
THE SYNAPTIC VESICLE CYCLE
Authors: Betz W. J. , Angleson J. K.
Published: July 2002

▪ Abstract  The ins and outs of the synaptic vesicle cycle are being examined in increasing detail with diverse investigative tools in a variety of cell types, particularly those with large granules. The cycle begins with the opening of a fusion pore that connects the vesicle lumen to the extracellular fluid. Sensitive electrophysiological techniques reveal the often-stuttering behavior of single pores in non-neuronal cells, through which small molecules trickle until the fusion pore expands and the remaining contents erupt from the vesicle. The granule membranes are then retrieved by multiple processes that appear to act in parallel and that are distinguished from each other kinetically and ultrastructurally. Following endocytosis, synaptic vesicles are then shuttled back into the vesicle pool, where they briefly mix with other vesicles, become immobilized, and remain gelled with their neighbors, even while moving en masse again to the presynaptic membrane as a prelude for another round of exocytosis.
SODIUM CHANNELS IN ALVEOLAR EPITHELIAL CELLS: Molecular Characterization, Biophysical Properties, and Physiological Significance
Authors: Matalon Sadis , O'Brodovich Hugh
Published: July 2002

▪ Abstract  At birth, fetal distal lung epithelial (FDLE) cells switch from active chloride secretion to active sodium (Na+) reabsorption. Sodium ions Senter the FDLE and alveolar type II (ATII) cells mainly through apical nonselective cation and Na+-selective channels, with conductances of 4–26 pS (picoSiemens) in FDLE and 20–25 pS in ATII cells. All these channels are inhibited by amiloride with a 50% inhibitory concentration of <1 μM, and some are also inhibited by [N-ethyl-N-isopropyl]-2′-4′-amiloride (50% inhibitory concentration of <1 μM). Both FDLE and ATII cells contain the α-, β-, and γ-rENaC (rat epithelial Na+ channels) mRNAs; reconstitution of an ATII cell Na+-channel protein into lipid bilayers revealed the presence of 25-pS Na+ single channels, inhibited by amiloride and [N-ethyl-N-isopropyl]-2′-4′-amiloride. A variety of agents, including cAMP, oxygen, glucocorticoids, and in some cases Ca2+, increased the activity and/or rENaC mRNA levels. The phenotypic properties of these channels differ from those observed in other Na+-absorbing epithelia. Pharmacological blockade of alveolar Na+ transport in vivo, as well as experiments with newborn α-rENaC knock-out mice, demonstrate the importance of active Na+ transport in the reabsorption of fluid from the fetal lung and in reabsorbing alveolar fluid in the injured adult lung. Indeed, in a number of inflammatory diseases, increased production of reactive oxygen-nitrogen intermediates, such as peroxynitrite (ONOO−), may damage ATII and FDLE Na+ channels, decrease Na+ reabsorption in vivo, and thus contribute to the formation of alveolar edema.
FUNCTIONS OF THE 3′-UNTRANSLATED REGIONS OF POSITIVE STRAND RNA VIRAL GENOMES
Authors: Dreher Theo W.
Published: July 2002

▪ Abstract  Positive strand RNA viral genomes are unique in the viral world in serving a dual role as mRNA and replicon. Since the origin of the minus-strand RNA replication intermediate is at the 3′-end of the genome, the 3′-untranslated region (UTR) clearly plays a role in viral RNA replication. The messenger role of this same RNA likely places functional demands on the 3′-UTR to serve roles typical of cellular mRNAs, including the regulation of RNA stability and translation. Current understanding indicates varied roles for positive strand RNA viral 3′-UTRs, with the dominant roles differing between viruses. Three case studies are discussed: turnip yellow mosaic virus RNA, whose 3′ tRNA mimicry is thought to negatively regulate minus strand synthesis; brome mosaic virus, whose 3′-UTR contains a unique promoter element directing minus strand synthesis; and tobacco mosaic virus, whose 3′-UTR contains an enhancer of translational expression.
Epidemiology: A Science of Patterns
Authors: Waggoner Paul E. , Aylor Donald E.
Published: July 2002

During the twentieth century disease detectives progressed by jagged leaps in understanding patterns of plant disease. With ladders, airplanes, and automatic traps they observed airborne spores, and with meteorological theory they explained takeoff, flight, and landing. They analyzed the grand, logistic rise of epidemics and the roles of horizontal versus vertical resistance. From early experiments on the details of life cycles and weather, they simulated epidemics with new computers. Early in the century they revealed genetic diversity with differential varieties and late in the century with differential fungicides and DNA. They learned the interplay of pest, photosynthesis, and supply and demand to reckon loss. Integrating observations of pest, host, losses, and weather, they placed winning short-term bets for farmer and environment on whether to spray. In the twenty-first century, their goal can be analyses so sound that the world can securely place winning long-term bets.
AMERICAN DEMOCRACY FROM A EUROPEAN PERSPECTIVE
Authors: Fabbrini Sergio
Published: July 2002

▪ Abstract  This article analyzes American democracy from a European perspective. It argues that American democracy (like European democracies) is based on antinomies, two societal and two institutional, deeply rooted in American constitutional development. Thus, each time American democracy has been used as a model and exported, the attempt has ended in failure. An antinomic model can be studied but not imitated. The article concludes that what is interesting for non-Americans is the way American democracy has historically dealt with these antinomies, more than the American model per se. The American method has to do with a peculiar constitutional structure that, having had the chance to institutionalize liberal principles, has tended to promote a positive-sum solution to those antinomies, in accord with individualistic values. Here resides the great divide between American and European constitutional structures; for opposite reasons, the European constitutional structure tends to promote a zero-sum solution to similar antinomies, in agreement with collectivistic values. In both structures, something important may be lost—private freedom in the latter and public good in the former. Could a reciprocal constitutional learning process allow both sides to learn the missing side of the story?
Success and Failure in Foreign Policy
Authors: Baldwin David A.
Published: July 2002

The field of foreign policy analysis needs a common set of concepts and analytical frameworks to facilitate comparison of alternative policy options. Not only is general agreement lacking, there is not even a common understanding of what is meant by success. In order to build policy-relevant knowledge concerning success and failure in foreign policy, the following questions must be addressed: How effective is a policy instrument likely to be, with respect to which goals and targets, at what cost, and in comparison with what other policy instruments? Failure to address each question may lead to serious policy mistakes.
Sentence and Text Comprehension: Roles of Linguistic Structure
Authors: Clifton Charles , Duffy Susan A.
Published: July 2002

▪ Abstract  Readers and listeners use linguistic structure in comprehending sentences and texts. We review research, mostly published in the past five years, that addresses the question of how they use it. We consider effects of syntactic, lexical, prosodic, morphological, semantic, and discourse structure, as well as reviewing research on how discourse context and frequency of experience, the contents of long-term memory, and the mental models being constructed by a reader or listener affect sentence and text comprehension. We point out areas of theoretical debate including depth-first versus breadth-first models of parsing and memory-based versus constructionist models of discourse comprehension, attempt to show how the empirical effects we review bear on such theoretical questions, and discuss how new lines of research, including research on languages other than English, may enrich the discussion of these questions.
Genetic Contributions to Addiction
Authors: Crabbe John C.
Published: July 2002

▪ Abstract  Even the most extreme environmentalists along the nature-nurture continuum in psychology now acknowledge that genes often contribute to individual differences in behavior. Behavioral traits are complex, reflecting the aggregate effects of many genes. These genetic effects are interactive, inter se and with the environments in which they are expressed. Human studies of addictive behaviors have clearly implicated both environmental and genetic influences. This review selects drug dependence as a paradigmatic addiction, and further, concentrates on the extensive literature with genetic animal models. Both traditional studies with inbred strains and selected lines and studies exploiting the new molecularly based technologies of the genomics era are discussed. Future directions for further contribution of animal models studies to our understanding of the brain dysregulations characteristic of addictions are identified.
ENVIRONMENTAL ECOLOGY OF CRYPTOSPORIDIUM AND PUBLIC HEALTH IMPLICATIONS
Authors: Rose Joan B.
Published: July 2002

▪ Abstract  Cryptosporidium has become the most important contaminant found in drinking water and is associated with a high risk of waterborne disease particularly for the immunocompromised.

There have been 12 documented waterborne outbreaks in North America since 1985; in two of these (Milwaukee and Las Vegas) mortality rates in the immunocompromised ranged from 52% to 68%.

The immunofluorescence antibody assay (IFA) using epifluorescence microscopy has been used to examine the occurrence of Cryptosporidium in sewage (1 to 120 oocysts/liter), filtered secondary treated wastewater (0.01 to 0.13 oocysts/liter), surface waters (0.001 to 107 oocysts/liter), groundwater (0.004 to 0.922 oocysts/liter) and treated drinking water (0.001 to 0.72 oocysts/liter).

New rules are being developed (Information Collection Rule and Enhanced Surface Water Treatment Rule) to obtain more occurrence data for drinking water systems for use with new risk assessment models. Public health officials should consider a communication program to physicians treating the immunocompromised, nursing homes, develop a plan to evaluate cases of cryptosporidiosis in the community, and contribute to the development of public policies that limit contamination of source waters, improve water treatment, and protect public health.
A NATIONAL STRATEGY FOR RESEARCH AND DEVELOPMENT:Lessons from England
Authors: Black Nick
Published: July 2002

▪ Abstract  Increasing concern about the state of basic and clinical research in England during the 1980s led to an influential parliamentary review. Surprisingly, the review recommended the strengthening of public health and health services research through the establishment of a research and development (R&D) program for the National Health Service (NHS). The program that started in 1991 was unique in that it was fully integrated into the management structure of the NHS. No country had ever attempted such an ambitious approach.

While a review of the first five years of the program reveals many achievements, it also raises several concerns: Debate about the philosophy and aims of the program continues; the need to maintain political support requires constant attention; policy changes in other areas need to be accommodated; central control of a national, coordinated R&D program has to be guarded; methods of priority setting need to be enhanced; insufficient human resources to run the program have to be contended with; and the program needs to be rigorously evaluated.

Other countries with a unified health system could learn much from the English experience. Countries with pluralist systems might benefit from specific parts of the experience.
School-Based Health Clinics: Remaining Viable in a Changing Health Care Delivery System
Authors: Brindis Claire D. , Sanghvi Rupal V.
Published: July 2002

▪ Abstract  Adolescents are often vulnerable to particular health risks and face multiple barriers to accessing health care. School-based clinics and school-linked services represent an alternative model of care that has responded to the unique health issues of adolescents by offering preventive, comprehensive services, including mental health and other sensitive services. The current restructuring of the American health care delivery system presents a serious challenge to the continued existence of these services, which must link successfully with managed care organizations and adapt to significant changes in federal and state funding streams to remain viable. The continued success of school-based health services in improving adolescent health will largely depend on how well they can capitalize on their strategic position to reach adolescents, respond to their health needs, and reduce barriers to care, and how effectively they can integrate themselves into a rapidly evolving US health care delivery system.
Teen Pregnancy Prevention: Do Any Programs Work?
Authors: Card Josefina J.
Published: July 2002

▪ Abstract  This paper begins with a review of the problem of teen pregnancy in the United States. Domestic trends are compared with those of other developed countries. Antecedents of the problem are discussed. New developments in addressing the problem are then described, including the following: (a) a renewed emphasis on abstinence on the one hand; (b) a move toward a more positive view of teen sexuality on the other; (c) the development of new prevention initiatives such as STD/HIV/AIDS prevention programs, community-wide teen pregnancy prevention collaboratives, broad-based youth development programs, and state and local government initiatives; and (d) the lauching of the National Campaign to Prevent Teen Pregnancy. An analysis of the different ways in which the problem can be framed and the implications for solutions of the problem follow. Examples of promising teen pregnancy and STD/HIV/AIDS prevention programs are provided. The paper ends with a recommendation for an eclectic approach to framing the problem and possible solutions.
The Burden of Illness of Cancer: Economic Cost and Quality of Life
Authors: Brown Martin L , Lipscomb Joseph , Snyder Claire
Published: July 2002

▪ Abstract  Cancer is a major public health issue and represents a significant burden of disease. In this chapter, we analyze the main measures of burden of disease as relate to cancer. Specifically, we review incidence and mortality, years of life lost from cancer, and cancer prevalence. We also discuss the economic burden of cancer, including cost of illness, phase-specific and long-term costs, and indirect costs. We then examine the impact of cancer on health-related quality of life as measured in global terms (disability-adjusted life years and quality-adjusted life years) and using evaluation-oriented applications of health-related quality of life scales. Throughout, we note the relative strengths and weaknesses of the various approaches to measuring the burden of cancer as well as the methodologic challenges that persist in burden-of-illness research. We conclude with a discussion of the research agenda to improve our understanding of the burden of cancer and of illness more generally.
States and Markets in an Era of Globalization
Authors: Riain Seán Ó
Published: July 2002

The paper considers how states and markets shape one another at the national and world-system levels and how globalization is transforming that relationship. This process is illustrated through a review of research on liberal, social rights, developmental, and socialist states in the postwar capitalist economy. These state models were reconciled with expanding international markets through a series of controls on trade and capital flows. Globalization has undermined many of these controls so that states must increasingly integrate themselves into local and global networks. States are experimenting with organizational and strategic changes nationally and internationally in order to respond to a networked economy and polity. Neoliberal institutions are the dominant force shaping the relation between states and markets in the contemporary era, but alternative state-society alliances are emerging to contest the hegemony of neoliberalism in shaping globalization.
Angiotensin-Converting Enzyme Inhibitors Improve Coronary Flow Reserve in Dilated Cardiomyopathy by a Bradykinin-Mediated, Nitric Oxide-Dependent Mechanism
Authors: Nikolaidis Lazaros A. , Doverspike Aaron , Huerbin Rhonda , Hentosz Teresa , Shannon Richard P.
Published: July 2002

Background

—

ACE inhibitors have been used extensively in heart failure, where they induce systemic vasodilatation. ACE inhibitors have also been shown to reduce ischemic events after myocardial infarction, although their mechanisms of action on the coronary circulation are less well understood. The purpose of the present study was to determine the effects and the mechanism of action of the ACE inhibitor enalaprilat and the AT
1
antagonist losartan on regional myocardial perfusion and coronary flow and vasodilator reserve in conscious dogs with pacing-induced dilated cardiomyopathy (DCM).

Methods and Results

—

Twenty-seven conscious, chronically instrumented dogs were studied during advanced stages of dilated cardiomyopathy, which was induced by rapid pacing. Enalaprilat (1.25 mg IV) improved transmural distribution (endocardial/epicardial ratio) at rest (baseline, 0.91±0.11; enalaprilat, 1.02±0.07 mL/min per g;
P
<0.05) and during atrial pacing (baseline, 0.82±0.11; enalaprilat, 0.98±0.07;
P
<0.05). Enalaprilat also restored subendocardial coronary flow reserve (CFR) (baseline CFR, 1.89±0.11; enalaprilat CFR, 2.74±0.33;
P
<0.05) in DCM. These effects were abolished by pretreatment with the NO synthase inhibitor nitro-
l
-arginine. The effects were recapitulated by the bradykinin
2
receptor agonist cereport but not by the AT
1
antagonist losartan.

Conclusions

—

The ACE inhibitor enalaprilat improves transmural myocardial perfusion at rest and after chronotropic stress and restores impaired subendocardial coronary flow and vasodilator reserve in DCM. The effects of enalaprilat were bradykinin mediated and NO dependent and were not recapitulated by losartan. These data suggest beneficial effects of ACE inhibitors on the coronary circulation in DCM that are not shared by AT
1
receptor antagonists.
Factor Xa Releases Matrix Metalloproteinase-2 (MMP-2) From Human Vascular Smooth Muscle Cells and Stimulates the Conversion of Pro–MMP-2 to MMP-2
Authors: Rauch Bernhard H. , Bretschneider Ellen , Braun Marina , Schrör Karsten
Published: July 2002

Pro–matrix metalloproteinase-2 (pro–MMP-2) is expressed in vascular smooth muscle cells (SMCs). We report that activated coagulation factor X (FXa) induces the release of MMP-2 (65 kDa) from human SMCs. In addition, FXa cleaves pro–MMP-2 (72 kDa) into MMP-2. Pro–MMP-2 and MMP-2 were determined by gelatin zymography. MMP-2 was generated in conditioned medium containing pro–MMP-2 in a concentration-dependent fashion by FXa (3 to 100 nmol/L). FX at concentrations up to 300 nmol/L was ineffective. The conversion of pro–MMP-2 to MMP-2 was inhibited by a selective FXa inhibitor (DX-9065a) at 3 to 10 μmol/L. There was a concentration-dependent induction of an intermediate MMP-2 form (68 kDa) in lysates of FXa-treated cells. This indicates that cellular mechanisms are involved in FXa-induced conversion of pro–MMP-2. As a possible biological consequence of MMP-2 activation by FXa, DNA synthesis and matrix invasion of SMCs were determined. Both were stimulated by FXa and inhibited by the selective FXa inhibitor DX-9065a and the MMP inhibitor GM 6001 but not by hirudin or aprotinin. It is concluded that stimulation of SMCs by FXa increases the levels of MMP-2 in the extracellular space and that two different mechanisms are involved: release of active MMP-2 and cleavage of secreted pro–MMP-2. Both might contribute to the mitogenic potency of FXa and FXa-stimulated matrix invasion of SMCs.
Small Amounts of α-Myosin Heavy Chain Isoform Expression Significantly Increase Power Output of Rat Cardiac Myocyte Fragments
Authors: Herron Todd J. , McDonald Kerry S.
Published: July 2002

Myocardial performance is likely affected by the relative expression of the two myosin heavy chain (MyHC) isoforms, namely α-MyHC and β-MyHC. The relative expression of each isoform is regulated developmentally and in pathophysiological states. Many pathophysiological states are associated with small shifts in the relative expression of each MyHC isoform, yet the functional consequence of these shifts remains unclear. The purpose of this study was to determine the functional effect of a small shift in the relative expression of α-MyHC. To this end, power output was measured in rat cardiac myocyte fragments that expressed ≈12% α-MyHC and in myocyte fragments that expressed ≈0% α-MyHC, as determined in the same cells by SDS-PAGE analysis after mechanical experiments. Myocyte fragments expressing ≈12% α-MyHC developed ≈52% greater peak normalized power output than myocyte fragments expressing ≈0% α-MyHC. These results indicate that small amounts of α-MyHC expression significantly augment myocyte power output.
Chasing Phantoms: The Political Economy of USTR
Authors: Noland Marcus
Published: July 2002

Trade barriers, though usually considered welfare-reducing, are globally ubiquitous. In light of the enormous clash between what is and what ought to be, researchers have begun addressing the question of why countries so consistently pursue such apparently counterproductive policies.
Cuba and the Latin American Terms of Trade: Old Theories, New Evidence
Authors: Salvucci Linda K. , Salvucci Richard J.
Published: July 2002

There is little historical evidence to support the thesis that deteriorating terms of trade hindered Cuban and Latin American economic growth, at precisely the time when large international disparities in income began to emerge (1820s to 1870s). For Cuba at least, it was resurgent Spanish imperialism in the form of new tariffs, taxes, and outright prohibitions that distorted patterns of trade, particularly with the United States. Likewise for Mexico, Brazil, Argentina, and Peru, the terms of trade do not appear to have contributed significantly, if at all, to underdevelopment.
A Corpus-Based Evaluation of Centering and Pronoun Resolution
Authors: Tetreault Joel R.
Published: July 2002

In this paper we compare pronoun resolution algorithms and introduce a centering algorithm(Left-Right Centering) that adheres to the constraints and rules of centering theory and is an alternative to Brennan, Friedman, and Pollard's (1987) algorithm. We then use the Left-Right Centering algorithm to see if two psycholinguistic claims on Cf-list ranking will actually improve pronoun resolution accuracy. Our results from this investigation lead to the development of a new syntax-based ranking of the Cf-list and corpus-based evidence that contradicts the psycholinguistic claims.
No Right to Speak? The Relationship between Object Naming and Semantic Impairment:Neuropsychological Evidence and a Computational Model
Authors: Ralph M. A. Lambon , McClelland J. L. , Patterson K. , Galton C. J. , Hodges J. R.
Published: July 2002

The processes required for object naming were addressed in a study of patients with semantic dementia (a selective decline of semantic memory resulting from progressive temporal lobe atrophy) and in a computational model of single-word production. Although all patients with semantic dementia are impaired in both single-word production and comprehension, previous reports had indicated two different patterns: (a) a parallel decline in accuracy of naming and comprehension, with frequent semantic naming errors, suggesting a purely semantic basis for the anomia and (b) a dramatic progressive anomia. Longitudinal data for 16 patients with semantic dementia reflected these two profiles, but with the following additional important specifications: (1)despite a few relatively extreme versions of one or other profile, the full set of cases formed a continuum in the extent of anomia for a given degree of degraded comprehension; (2) the degree of disparity between these two abilities was associated with relative asymmetry in laterality of atrophy: a parallel decline in the two measures characterized patients with greater right-than left-temporal atrophy, while disproportionate anomia occurred with a predominance of atrophy in the left-temporal lobe. In an implemented computational model of naming, semantic representations were distributed across simulated left-and right-temporal regions, but the semantic units on the left were more strongly connected to left-lateralized phonological representations. Asymmetric damage to semantic units reproduced the longitudinal patient profiles of naming relative to comprehension, plus additional characteristics of the patients' naming performance. On the basis of both the neuropsychological and computational evidence, we propose that semantic impairment alone can account for the full range of word production deficits described here.
An Electrophysiological Analysis of the Time Course of Conceptual and Syntactic Encoding during Tacit Picture Naming
Authors: Schmitt Bernadette M. , Schiltz Kolja , Zaake Wanda , Kutas Marta , Münte Thomas F.
Published: July 2002

A central question in psycholinguistic research is when various types of information involved in speaking (conceptual/ semantic, syntactic, and phonological information) become available during the speech planning process. Competing theories attempt to distinguish between parallel and serial models. Here, we investigated the relative time courses of conceptual and syntactic encoding in a tacit picture-naming task via event-related brain potential (ERP) recordings. Participants viewed pictures and made dual-choice go/no-go decisions based on conceptual features (whether the depicted item was heavier or lighter than 500 g) and syntactic features (whether the picture's German name had feminine or masculine syntactic gender). In support of serial models of speech production, both the lateralized readiness potential, or LRP (related to response preparation), and the N200 (related to response inhibition) measures indicated that conceptual processing began approximately 80 msec earlier than syntactic processing.
Automatic and Controlled Processing of Melodic Contour and Interval Information Measured by Electrical Brain Activity
Authors: Trainor Laurel J. , McDonald Kelly L. , Alain Claude
Published: July 2002

Most work on how pitch is encoded in the auditory cortex has focused on tonotopic (absolute) pitch maps. However, melodic information is thought to be encoded in the brain in two different “relative pitch” forms, a domain-general contour code (up/down pattern of pitch changes) and a music-specific interval code (exact pitch distances between notes). Event-related potentials were analyzed in nonmusicians from both passive and active oddball tasks where either the contour or the interval of melody—final notes was occasionally altered. The occasional deviant notes generated a right frontal positivity peaking around 350 msec and a central parietal P3b peaking around 580 msec that were present only when participants focused their attention on the auditory stimuli. Both types of melodic information were encoded automatically in the absence of absolute pitch cues, as indexed by a mismatch negativity wave recorded during the passive conditions. The results indicate that even in the absence of musical training, the brain is set up to automatically encode music-specific melodic information, even when absolute pitch information is not available.
Cortical-Hippocampal Auditory Processing Identified by Magnetoencephalography
Authors: Nishitani Nobuyuki , Nagamine Takashi , Fujiwara Naohito , Yazawa Shogo , Shibasaki Hiroshi
Published: July 2002

We recorded magnetic and electrical responses simultaneously in an auditory detection task to elucidate the brain areas involved in auditory processing. Target stimuli evoked magnetic fields peaking at approximately the same latency of around about 400 msec (M400) over the anterior temporal, superior temporal, and parietal regions on each hemisphere. Equivalent current dipoles (ECDs) were analyzed with a time-varying multidipole model and superimposed on each subject's magnetic resonance image (MRI). Multiple independent dipoles located in the superior temporal plane, inferior parietal lobe, and mesial temporal region best accounted for the recorded M400 fields. These findings suggest that distributed activity in multiple structures including the mesial temporal, superior temporal, and inferior parietal regions on both hemispheres is engaged during auditory attention and memory updating.
Neural Correlates of Levels of Emotional Awareness: Evidence of an Interaction between Emotion and Attention in the Anterior Cingulate Cortex
Authors: Lane Richard D. , Reiman Eric M. , Axelrod Beatrice , Yun Lang-Sheng , Holmes Andrew , Schwartz Gary E.
Published: July 2002

Recent functional imaging studies have begun to identify the neural correlates of emotion in healthy volunteers. However, studies to date have not differentially addressed the brain areas associated with the perception, experience, or expression of emotion during emotional arousal. To explore the neural correlates of emotional experience, we used positron emission tomography (PET) and 15O-water to measure cerebral blood flow (CBF) in 12 healthy women during film- and recall-induced emotion and correlated CBF changes attributable to emotion with subjects' scores on the Levels of Emotional Awareness Scale (LEAS), a measure of individual differences in the capacity to experience emotion in a differentiated and complex way. A conjunction analysis revealed that the correla-tions between LEAS and CBF during film- and recall-induced emotion overlapped significantly (z = 3.74, p < 0.001) in Brod-mann's area 24 of the anterior cingulate cortex (ACC). This finding suggests that individual differences in the ability to accurately detect emotional signals interoceptively or exteroceptively may at least in part be a function of the degree to which the ACC participates in the experiential processing and response to emotion cues. To the extent that this finding is consistent with the functions of the ACC involving attention and response selection, it suggests that this neural correlate of conscious emotional experience is not exclusive to emotion.
Asymptotic Bias in Information Estimates and the Exponential (Bell) Polynomials
Authors: Victor Jonathan D.
Published: July 2002

We present a new derivation of the asymptotic correction for bias in the estimate of information from a finite sample. The new derivation reveals a relationship between information estimates and a sequence of polynomials with combinatorial significance, the exponential (Bell) polynomials, and helps to provide an understanding of the form and behavior of the asymptotic correction for bias.
Analysis of Pointing Errors Reveals Properties of Data Representations and Coordinate Transformations Within the Central Nervous System
Authors: McIntyre J. , Stratta F. , Droulez J. , Lacquaniti F.
Published: July 2002

The execution of a simple pointing task invokes a chain of processing that includes visual acquisition of the target, coordination of multimodal proprioceptive signals, and ultimately the generation of a motor command that will drive the finger to the desired target location. These processes in the sensorimotor chain can be described in terms of internal representations of the target or limb positions and coordinate transformations between different internal reference frames. In this article we first describe how different types of error analysis can be used to identify properties of the internal representations and coordinate transformations within the central nervous system. We then describe a series of experiments in which subjects pointed to remembered 3D visual targets under two lighting conditions (dim light and total darkness) and after two different memory delays (0.5 and 5.0 s) and report results in terms of variable error, constant error, and local distortion. Finally, we present a set of simulations to help explain the patterns of errors produced in this pointing task. These analyses and experiments provide insight into the structure of the underlying sensorimotor processes employed by the central nervous system.
Efficient Event-Driven Simulation of Large Networks of Spiking Neurons and Dynamical Synapses
Authors: Mattia Maurizio , Giudice Paolo Del
Published: July 2002

A simulation procedure is described for making feasible large-scale simulations of recurrent neural networks of spiking neurons and plastic synapses. The procedure is applicable if the dynamic variables of both neurons and synapses evolve deterministically between any two successive spikes. Spikes introduce jumps in these variables, and since spike trains are typically noisy, spikes introduce stochasticity into both dynamics. Since all events in the simulation are guided by the arrival of spikes, at neurons or synapses, we name this procedure event-driven.

The procedure is described in detail, and its logic and performance are compared with conventional (synchronous) simulations. The main impact of the new approach is a drastic reduction of the computational load incurred upon introduction of dynamic synaptic efficacies, which vary organically as a function of the activities of the pre- and postsynaptic neurons. In fact, the computational load per neuron in the presence of the synaptic dynamics grows linearly with the number of neurons and is only about 6% more than the load with fixed synapses. Even the latter is handled quite efficiently by the algorithm.

We illustrate the operation of the algorithm in a specific case with integrate-and-fire neurons and specific spike-driven synaptic dynamics. Both dynamical elements have been found to be naturally implementable in VLSI. This network is simulated to show the effects on the synaptic structure of the presentation of stimuli, as well as the stability of the generated matrix to the neural activity it induces.
A Population Density Approach That Facilitates Large-Scale Modeling of Neural Networks: Extension to Slow Inhibitory Synapses
Authors: Nykamp Duane Q. , Tranchina Daniel
Published: July 2002

A previously developed method for efficiently simulating complex networks of integrate-and-fire neurons was specialized to the case in which the neurons have fast unitary postsynaptic conductances. However, inhibitory synaptic conductances are often slower than excitatory ones for cortical neurons, and this difference can have a profound effect on network dynamics that cannot be captured with neurons that have only fast synapses. We thus extend the model to include slow inhibitory synapses. In this model, neurons are grouped into large populations of similar neurons. For each population, we calculate the evolution of a probability density function (PDF), which describes the distribution of neurons over state-space. The population firing rate is given by the flux of probability across the threshold voltage for firing an action potential. In the case of fast synaptic conductances, the PDF was one-dimensional, as the state of a neuron was completely determined by its transmembrane voltage. An exact extension to slow inhibitory synapses increases the dimension of the PDF to two or three, as the state of a neuron now includes the state of its inhibitory synaptic conductance. However, by assuming that the expected value of a neuron's inhibitory conductance is independent of its voltage, we derive a reduction to a one-dimensional PDF and avoid increasing the computational complexity of the problem. We demonstrate that although this assumption is not strictly valid, the results of the reduced model are surprisingly accurate.