bluuebunny/crossref_metadata_2025 huggingface dataset:
Polymicrobial candidaemia revealed by peripheral blood smear and chromogenic medium
Authors: Yera H , Poulain D , Lefebvre A , Camus D , Sendid B
Published: January 2004

Candidaspp are the fourth most common group of nosocomial pathogens isolated from patients on medical, surgical, and intensive care wards. Polymicrobial candidaemia has rarely been described. The diagnosis of candidaemia from peripheral blood smears has not been widely reported. This report describes the case of a young woman suffering from Ewing’s sarcoma who developed a syndrome of septic shock. Deep fungal infection was diagnosed from a systematic peripheral blood smear and yeasts were isolated within 24 hours. A subculture on CHROMagar® Candida allowed the differentiation and presumptive identification ofCandida tropicalisandCandida krusei. Species identification was confirmed by the ID 32C® system. This report underlines the usefulness of peripheral blood smears in the diagnosis of fulminant deep fungal infections, and of a differential isolation medium in the rapid presumptive identification of clinically important yeast species from clinical samples. This medium is particularly useful for the detection of mixed fungal infections, allowing early and better adapted antifungal treatment.
SIMPLICITY IN COMPACT ABSTRACT THEORIES
Authors: BEN-YAACOV ITAY
Published: January 2004

We continue [2], developing simplicity in the framework of compact abstract theories. Due to the generality of the context we need to introduce definitions which differ somewhat from the ones use in first order theories.

With these modified tools we obtain more or less classical behaviour: simplicity is characterized by the existence of a certain notion of independence, stability is characterized by simplicity and bounded multiplicity, and hyperimaginary canonical bases exist.
A TIME-DOMAIN APPROACH TO EXTRACTING POLARIZATION RESISTANCE FROM ELECTROCHEMICAL NOISE DATA
Authors: KLASSEN R. D. , ROBERGE P. R.
Published: January 2004

Measuring the corrosion rate of a corroding metal is of interest in many situations including monitoring industrial processes and fundamental research in laboratories. The corrosion rate of a metal can be measured electrochemically by determining its polarization resistance, which is inversely proportional to the corrosion rate. What is introduced in this letter is a novel technique for extracting polarization resistance from electrochemical noise (EN) data. An advantage of this approach is that very short time records, of the order of a few seconds, can be assessed to see if they reveal a polarization resistance. The theoretical framework for this approach is based on a time-domain analysis of an electrical circuit model of an EN experimental arrangement. The analysis indicates that polarization resistance can be interpreted only if one electrode, not both electrodes, is predomi-nately generating electrochemical transients during a given time record. An algorithm for extracting polarization resistance from EN measurements is described and examples of its implementation on EN data support the features of the theoretical framework.
THE BIRTH AND DEATH PROCESSES OF HYPERCYCLE SPIRALS
Authors: OIDA KAZUMASA
Published: January 2004

The behavior of hypercycle spirals in a two-dimensional cellular automaton model is analyzed. Each spiral can be approximated by an Archimedean spiral with center, width, and phase change according to Brownian motion. A barrier exists between two spirals if the phase synchronization hypothesis is taken into account, and the occurrence rate of pair decay (simultaneous disappearance of two spirals) can be explained through a random walk simulation with the barrier. Simulation experiments show that adjacent species violation is necessary to create new spirals. A hypercycle system can live for a long time if spirals in the system are somewhat unstable, since new spirals cannot emerge when existing spirals are too stable.
ASYMMETRY IN THE HIERARCHY MODEL OF BONABEAU ET AL.
Authors: STAUFFER D. , SÁ MARTINS J. S.
Published: January 2004

The 1995 model of Bonabeau et al. explains the emergence of social hierarchies through randomness, but gives as many leaders as followers. A simple modification allows a more realistic asymmetry with far fewer leaders.
ANALYSIS AND MODELING OF SCIENCE COLLABORATION NETWORKS
Authors: PÜTSCH FELIX
Published: January 2004

We analyze a science collaboration network, i.e. a network whose nodes are scientists with edges connecting them for each paper published together. Furthermore, we develop a model for the simulation of discontiguous small-world networks that shows good coherence with empirical data.
SYSTEMIC LUPUS ERYTHEMATOSUS IN AFRICAN-AMERICAN WOMEN: COGNITIVE PHYSIOLOGICAL MODULES, AUTOIMMUNE DISEASE, AND STRUCTURED PSYCHOSOCIAL STRESS
Authors: WALLACE RODRICK
Published: January 2004

Examining elevated rates of systemic lupus erythematosus in African-American women from perspectives of immune cognition suggests the disease constitutes an internalized physiological image of external patterns of structured psychosocial stress, a 'pathogenic social hierarchy' involving the synergism of racism and gender discrimination, in the context of policy-driven social disintegration which has particularly affected ethnic minorities in the USA. The disorder represents the punctuated resetting of 'normal' immune self-image to a self-attacking 'excited' state, a process formally analogous to models of punctuated equilibrium in evolutionary theory.

Thus disease onset takes place in the context of a particular immunological 'cognitive module' similar to what has been proposed by evolutionary psychologists for the human mind. Disease progression involves interaction of the hypothalamic-pituitary-adrenal axis, which we also treat as a cognitive physiological submodule, with both immune cognition and an embedding pathogenic social hierarchy, a structured psychosocial stress which literally writes an image of itself on the course of the disorder. Both onset and progression may be stratified by a relation to cyclic physiological responses which are long in comparison with heartbeat period: circadian, hormonal, and annual light/temperature cycles.

The high rate of lupus in African-American women suggests existence of a larger dynamic which entrains powerful as well as subordinate population subgroups, implying that the wide ranging programs of social and economic reform required to cause declines in disease among African-American women will bring significant benefit to all.
Insect Walking and Robotics
Authors: Delcomyn Fred
Published: January 2004

With the advent of significant collaborations between researchers who study insect walking and robotics engineers interested in constructing adaptive legged robots, insect walking is once again poised to make a more significant scientific contribution than the numbers of participants in the field might suggest. This review outlines current knowledge of the physiological basis of insect walking with an emphasis on recent new developments in biomechanics and genetic dissection of behavior, and the impact this knowledge is having on robotics. Engineers have begun to team with neurobiologists to build walking robots whose physical design and functional control are based on insect biology. Such an approach may have benefits for engineering, by leading to the construction of better-performing robots, and for biology, by allowing real-time and real-world tests of critical hypotheses about how locomotor control is effected. It is argued that in order for the new field of biorobotics to have significant influence it must adopt criteria for performance and an experimental approach to the development of walking robots.
THEBIOLOGY OFXYLEMFLUID–FEEDINGINSECTVECTORS OFXYLELLA FASTIDIOSAANDTHEIRRELATION TODISEASEEPIDEMIOLOGY
Authors: Redak Richard A. , Purcell Alexander H. , Lopes João R.S. , Blua Matthew J. , Mizell III Russell F. , Andersen Peter C.
Published: January 2004

▪ Abstract  Xylophagous leafhopppers are common and abundant insects of tropical and subtropical environments and play important ecological roles in these ecosystems. The feeding biology of these insects is unique in terms of their high feeding rates and a digestive physiology that allows them to assimilate amino acids, organic acids, and sugars at approximately 99% efficiency. For those species well studied, fluctuations in plant xylem chemistry and tension appear to determine the diurnal and seasonal use of their host plants. Relatively few species of xylem fluid–feeding leafhoppers are considered important pests in commercial agriculture, as they transmit the bacterial plant pathogen Xylella fastidiosa. X. fastidiosa induces diseases of grapevines, citrus, coffee, almond, alfalfa, stone fruits, landscape ornamentals, and native hardwoods for which there is no cure. Two Xylella diseases, citrus variegated chlorosis (CVC) and Pierce's disease (PD) of grapevines, have emerged as important issues within the past decade. In Brazil, CVC became important in the early 1990s and has now expanded throughout many citrus-growing areas of South America and threatens to spread to North America. The recent establishment of the exotic glassy-winged sharpshooter (Homalodisca coagulata) in California now threatens much of the United States' wine grape, table grape, and almond production. The spread of H. coagulata throughout southern California and the spread of CVC northward from Argentina through Brazil exemplifies the biological risks from exotic species. The occurrence and epidemiology of leafhopper-vectored Xylella diseases are discussed.
THE GUT BACTERIA OF INSECTS: Nonpathogenic Interactions
Authors: Dillon R.J. , Dillon V.M.
Published: January 2004

▪ Abstract  The diversity of the Insecta is reflected in the large and varied microbial communities inhabiting the gut. Studies, particularly with termites and cockroaches, have focused on the nutritional contributions of gut bacteria in insects living on suboptimal diets. The indigenous gut bacteria, however, also play a role in withstanding the colonization of the gut by non-indigenous species including pathogens. Gut bacterial consortia adapt by the transfer of plasmids and transconjugation between bacterial strains, and some insect species provide ideal conditions for bacterial conjugation, which suggests that the gut is a “hot spot” for gene transfer. Genomic analysis provides new avenues for the study of the gut microbial community and will reveal the molecular foundations of the relationships between the insect and its microbiome. In this review the intestinal bacteria is discussed in the context of developing our understanding of symbiotic relationships, of multitrophic interactions between insects and plant or animal host, and in developing new strategies for controlling insect pests.
Pseudogenes: Are They “Junk” or Functional DNA?
Authors: Balakirev Evgeniy S. , Ayala Francisco J.
Published: January 2004

▪ Abstract  Pseudogenes have been defined as nonfunctional sequences of genomic DNA originally derived from functional genes. It is therefore assumed that all pseudogene mutations are selectively neutral and have equal probability to become fixed in the population. Rather, pseudogenes that have been suitably investigated often exhibit functional roles, such as gene expression, gene regulation, generation of genetic (antibody, antigenic, and other) diversity. Pseudogenes are involved in gene conversion or recombination with functional genes. Pseudogenes exhibit evolutionary conservation of gene sequence, reduced nucleotide variability, excess synonymous over nonsynonymous nucleotide polymorphism, and other features that are expected in genes or DNA sequences that have functional roles. We first review the Drosophila literature and then extend the discussion to the various functional features identified in the pseudogenes of other organisms. A pseudogene that has arisen by duplication or retroposition may, at first, not be subject to natural selection if the source gene remains functional. Mutant alleles that incorporate new functions may, nevertheless, be favored by natural selection and will have enhanced probability of becoming fixed in the population. We agree with the proposal that pseudogenes be considered as potogenes, i.e., DNA sequences with a potentiality for becoming new genes.
Heparan Sulfate Core Proteins in Cell-Cell Signaling
Authors: Kramer Kenneth L. , Yost H. Joseph
Published: January 2004

▪ Abstract  Heparan sulfate (HS) binds numerous extracellular ligands, including cell-cell signaling molecules and their signal-transducing receptors. Ligand binding sites in HS have specific sulfation patterns; and several observations suggest that the HS sulfation pattern is the same for every HS chain that a cell synthesizes, regardless of the core protein to which it is attached. Nonetheless, virtually every Drosophila, zebrafish, Xenopus, and mouse that lacks a specific HS core protein has a mutant phenotype, even though other HS core proteins are expressed in the affected cells. Genetic manipulation of HS core protein genes is beginning to indicate that HS core proteins have functional specificities that are required during distinct stages of development.
Thiol-Based Regulatory Switches
Authors: Paget Mark S.B. , Buttner Mark J.
Published: January 2004

▪ Abstract  Thiol-based regulatory switches play central roles in cellular responses to oxidative stress, nitrosative stress, and changes in the overall thiol-disulfide redox balance. Protein sulfhydryls offer a great deal of flexibility in the different types of modification they can undergo and the range of chemical signals they can perceive. For example, recent work on OhrR and OxyR has clearly established that disulfide bonds are not the only cysteine oxidation products that are likely to be relevant to redox sensing in vivo. Furthermore, different stresses can result in distinct modifications to the same protein; in OxyR it seems that distinct modifications can occur at the same cysteine, and in Yap1 a partner protein ensures that the disulfide bond induced by peroxide stress is different from the disulfide bond induced by other stresses. These kinds of discoveries have also led to the intriguing suggestion that different modifications to the same protein can create multiple activation states and thus deliver discrete regulatory outcomes. In this review, we highlight these issues, focusing on seven well-characterized microbial proteins controlled by thiol-based switches, each of which exhibits unique regulatory features.
The Need for Winter in the Switch to Flowering
Authors: Henderson Ian R. , Shindo Chikako , Dean Caroline
Published: January 2004

▪ Abstract  Vernalization is the process whereby the floral transition is promoted through exposure of plants to long periods of cold temperature or winter. A requirement for vernalization aligns flowering with the seasons to ensure that their reproductive phase occurs in favorable conditions. The mitotic stability of vernalization, suggestive of an epigenetic mechanism, has intrigued researchers for many years. Genetic analysis of the vernalization requirement in Arabidopsis has identified key floral repressor genes, FRI and FLC. The action of these floral repressors is antagonized by vernalization and the activity of a set of genes grouped into the autonomous floral pathway. Analysis of the vernalization pathway has defined a series of epigenetic regulators crucial for “cellular-memory” of the cold signal, whereas the autonomous pathway appears to function in part through posttranscriptional mechanisms. The mechanism of the vernalization requirement, which is now being explored in a range of plant species, should uncover the evolutionary origins of this key agronomic trait.
Transposon-Based Strategies for Microbial Functional Genomics and Proteomics
Authors: Hayes Finbarr
Published: January 2004

▪ Abstract  Transposons are mobile genetic elements that can relocate from one genomic location to another. As well as modulating gene expression and contributing to genome plasticity and evolution, transposons are remarkably diverse molecular tools for both whole-genome and single-gene studies in bacteria, yeast, and other microorganisms. Efficient but simple in vitro transposition reactions now allow the mutational analysis of previously recalcitrant microorganisms. Transposon-based signature-tagged mutagenesis and genetic footprinting strategies have pinpointed essential genes and genes that are crucial for the infectivity of a variety of human and other pathogens. Individual proteins and protein complexes can be dissected by transposon-mediated scanning linker mutagenesis. These and other transposon-based approaches have reaffirmed the usefulness of these elements as simple yet highly effective mutagens for both functional genomic and proteomic studies of microorganisms.
Genetics of Hair and Skin Color
Authors: Rees Jonathan L.
Published: January 2004

▪ Abstract  Differences in skin and hair color are principally genetically determined and are due to variation in the amount, type, and packaging of melanin polymers produced by melanocytes secreted into keratinocytes. Pigmentary phenotype is genetically complex and at a physiological level complicated. Genes determining a number of rare Mendelian disorders of pigmentation such as albinism have been identified, but only one gene, the melanocortin 1 receptor (MCR1), has so far been identified to explain variation in the normal population such as that leading to red hair, freckling, and sun-sensitivity. Genotype-phenotype relations of the MC1R are reviewed, as well as methods to improve the phenotypic assessment of human pigmentary status. It is argued that given advances in model systems, increases in technical facility, and the lower cost of genotype assessment, the lack of standardized phenotype assessment is now a major limit on advance.
Genetics of Lactase Persistence and Lactose Intolerance
Authors: Swallow Dallas M.
Published: January 2004

▪ Abstract  The enzyme lactase that is located in the villus enterocytes of the small intestine is responsible for digestion of lactose in milk. Lactase activity is high and vital during infancy, but in most mammals, including most humans, lactase activity declines after the weaning phase. In other healthy humans, lactase activity persists at a high level throughout adult life, enabling them to digest lactose as adults. This dominantly inherited genetic trait is known as lactase persistence. The distribution of these different lactase phenotypes in human populations is highly variable and is controlled by a polymorphic element cis-acting to the lactase gene. A putative causal nucleotide change has been identified and occurs on the background of a very extended haplotype that is frequent in Northern Europeans, where lactase persistence is frequent. This single nucleotide polymorphism is located 14 kb upstream from the start of transcription of lactase in an intron of the adjacent gene MCM6. This change does not, however, explain all the variation in lactase expression.
Toward Alzheimer Therapies Based on Genetic Knowledge
Authors: Hardy John
Published: January 2004

Genetic analysis has allowed the dissection of the pathogenic pathway that leads to Alzheimer's disease. It has also been integral to the development of earlier and more accurate diagnostic practices. This analysis has identified many potential therapeutic targets, and clinical trials aimed at these targets are now under way. If these approaches are successful, it will be a spectacular validation of genetic-knowledge–based treatment strategies; if they are not, researchers will need to re-evaluate this approach toward understanding and developing strategies for treating complex diseases.
Systemic Mastocytosis
Authors: Akin Cem , Metcalfe Dean D.
Published: January 2004

Systemic mastocytosis is a clonal disorder of the mast cell and its progenitor. The symptoms of systemic mastocytosis are due to the pathologic accumulation and activation of mast cells in various tissues such as bone marrow, skin, gastrointestinal tract, liver, and spleen. Recent studies revealed striking differences between the molecular and cellular biology of mast cells in patients with mastocytosis and those of healthy individuals. These findings are being used in formulating diagnostic criteria as well as designing novel treatment approaches to the disease.
Basic Advances and New Avenues in Therapy of Spinal Cord Injury
Authors: Dobkin Bruce H. , Havton Leif A.
Published: January 2004

The prospects for successful clinical trials of neuroprotective and neurorestorative interventions for patients with acute and chronic myelopathies depend on preclinical animal models of injury and repair that reflect the human condition. Remarkable progress continues in the attempt to promote connections between the brain and the sensory and motor neurons below a spinal cord lesion. Recent experiments demonstrate the potential for biological therapies to regenerate or remyelinate axons and to incorporate new neural cells into the milieu of a traumatic spinal cord injury. The computational flexibility and plasticity of the sensorimotor systems of the brain, spinal cord, and motor unit make functional use of new circuitry feasible in patients. To incorporate residual and new pathways, neural repair strategies must be coupled to rehabilitation therapies that drive activity-dependent plasticity for walking, for reaching and grasping, and for bowel and bladder control. Prevention of pain and dysautonomia are also clinical targets. Research aims to define the temporal windows of opportunity for interventions, test the safety and efficacy of delivery systems of agents and cells, and provide a better understanding of the cascades of gene expression and cell interactions both acutely and chronically after injury. These bench-to-bedside studies are defining the neurobiology of spinal cord injury rehabilitation.
Recent Advances in the Development of HIV-1 Vaccines Using Replication-Incompetent Adenovirus Vectors
Authors: Shiver John W. , Emini Emilio A.
Published: January 2004

An increasing body of evidence suggests that a vaccine that elicits anti-HIV-1 cellular immunity could provide the basis for an effective AIDS vaccine. Comparative immunization experiments testing a variety of vaccine approaches have demonstrated that replication-incompetent adenovirus vectors are an effective means for eliciting cytotoxic T-lymphocyte (CTL) immune responses against HIV-1 antigens. These immune responses effectively control viremia in nonhuman primates following challenge with simian AIDS viruses. Such data, coupled with epidemiology studies that identify HIV-1 gag, pol, and nef as the best antigens for broadly directed cellular immune responses, provide guidance for the development of a potential AIDS vaccine.
The Scientific Basis for the Current Treatment of Parkinson's Disease
Authors: Olanow C. Warren
Published: January 2004

Parkinson's disease (PD) is an age-related neurodegenerative disease that affects approximately one million people in the United States. The introduction of levodopa revolutionized the treatment for this disorder, but the long-term utility of the drug is limited by motor complications, the development of features such as postural instability and dementia that do not respond to treatment, and continued disease progression. Insights into the organization of the basal ganglia in the normal and PD conditions has permitted the design of new treatment strategies that reduce the risk of developing motor complications. Additionally, increased knowledge of the mechanisms responsible for cell death in PD has permitted the development of putative neuroprotective drugs that might slow or stop disease progression. No drug has yet been established to alter the rate of disease progression, but the rapid pace of research offers reason for optimism.
The Impact of the Completed Human Genome Sequence on the Development of Novel Therapeutics for Human Disease
Authors: Austin Christopher P.
Published: January 2004

With the official completion of the Human Genome Project in April 2003, we have both the opportunity and the imperative to translate this unprecedented scientific accomplishment into tangible improvements in human health. Medical benefits from the genome will come in stages and can be conceptualized as occurring in three areas: improved understanding of disease causation at the molecular level, improved diagnosis and disease classification based on genetic profiles, and new therapeutics based on targets identified in the genome. These improvements will require increased physician understanding of genetic principles applied to common diseases.
Predicting Human Drug Glucuronidation Parameters: Application of In Vitro and In Silico Modeling Approaches
Authors: Miners John O. , Smith Paul A. , Sorich Michael J. , McKinnon Ross A. , Mackenzie Peter I.
Published: January 2004

Cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT), which both exist as enzyme “superfamilies,” are together responsible for the metabolism of most hepatically cleared drugs. There is currently intense interest in the development of techniques that permit identification of the CYP and UGT isoform(s) involved in the metabolism of a newly discovered drug, and hence prediction of factors likely to alter elimination in vivo. In addition, the quantitative scaling of kinetic parameters for a metabolic pathway assumes importance for identifying newly discovered drugs with undesirable in vivo pharmacokinetic properties. Although qualitative and quantitative in vitro–in vivo correlation based on data generated using human liver tissue or recombinant enzymes have been applied successfully to many drugs eliminated by CYP, these strategies have proved less definitive for glucuronidated compounds. Computational (in silico) modeling techniques that potentially provide a facile and economic alternative to the in vitro methods are now emerging. This review assesses the utility of in vitro and in silico approaches for the qualitative and quantitative prediction of drug glucuronidation parameters and the challenges facing the development of generalizable models.
Muscarinic Acetylcholine Receptor Knockout Mice: Novel Phenotypes and Clinical Implications
Authors: Wess Jürgen
Published: January 2004

Muscarinic acetylcholine receptors (mAChRs; M1–M5) play key roles in regulating the activity of many important functions of the central and peripheral nervous system. Because of the lack of ligands endowed with a high degree of receptor subtype selectivity and the fact that most tissues or cell types express two or more mAChR subtypes, identification of the physiological and pathophysiological roles of the individual mAChR subtypes has proven a difficult task. To circumvent these difficulties, several laboratories recently employed gene-targeting techniques to generate mutant mouse strains deficient in each of the five mAChR subtypes. Phenotyping studies showed that each mutant mouse line displayed characteristic physiological, pharmacological, behavioral, biochemical, or neurochemical deficits. The novel insights gained from these studies should prove instrumental for the development of novel classes of muscarinic drugs.
Human Research and Data Collection via the Internet
Authors: Birnbaum Michael H.
Published: January 2004

Advantages and disadvantages of Web and lab research are reviewed. Via the World Wide Web, one can efficiently recruit large, heterogeneous samples quickly, recruit specialized samples (people with rare characteristics), and standardize procedures, making studies easy to replicate. Alternative programming techniques (procedures for data collection) are compared, including client-side as opposed to server-side programming. Web studies have methodological problems; for example, higher rates of drop out and of repeated participation. Web studies must be thoroughly analyzed and tested before launching on-line. Many studies compared data obtained in Web versus lab. These two methods usually reach the same conclusions; however, there are significant differences between college students tested in the lab and people recruited and tested via the Internet. Reasons that Web researchers are enthusiastic about the potential of the new methods are discussed.
Motivational Influences on Cigarette Smoking
Authors: Baker Timothy B. , Brandon Thomas H. , Chassin Laurie
Published: January 2004

Cigarette smoking is a leading cause of mortality and morbidity and a particularly common and intractable addictive disorder. Research shows that nicotine is a sine qua non of tobacco addiction and that it produces the hallmark effects of addictive drugs: sensitization, tolerance, physical dependence, and euphoria/elation. Research on the development of smoking reveals that although smoking prevalence has declined from a peak in the mid-1990s, close to 30% of twelfth graders still smoke. Smoking in adolescents is related to development of physical dependence, ethnicity, impulsivity, affective disorder, and peer influences. However, which of these exerts the greatest causal effects is unknown, and their influence no doubt varies across individuals and across development. Once dependence on tobacco smoking is established, evidence suggests that tobacco motivation is strongly influenced by a reduction in withdrawal symptoms, an expectation of stress reduction, and conditioned reinforcement. Nicotine motivation may also be influenced by modulation in stimulus incentive value.
Changes in Dietary Fat Intake Alter Plasma Levels of Oxidized Low-Density Lipoprotein and Lipoprotein(a)
Authors: Silaste Marja-Leena , Rantala Maire , Alfthan Georg , Aro Antti , Witztum Joseph L. , Kesäniemi Y. Antero , Hörkkö Sohvi
Published: January 2004

Objective—

To assess the effects of dietary modifications on oxidized low-density lipoprotein (LDL).

Methods and Results—

Thirty-seven healthy women were fed two diets. Both diets contained a reduced amount of total and saturated fat. In addition, one diet was low in vegetables and the other was high in vegetables, berries, and fruit. The dietary intake of total fat was 70 g per day at baseline and decreased to 56 g (low-fat, low-vegetable diet) and to 59 g (low-fat, high-vegetable diet). The saturated fat intake decreased from 28 g to 20 g and to 19 g, and the amount of polyunsaturated fat intake increased from 11 g to 13 g and to 19 g (baseline; low-fat, low-vegetable; low-fat, high-vegetable; respectively). The amount of oxidized LDL in plasma was determined as the content of oxidized phospholipid per ApoB-100 using a monoclonal antibody EO6 (OxLDL-EO6). The median plasma OxLDL-EO6 increased by 27% (
P
<0.01) in response to the low-fat, low-vegetable diet and 19% (
P
<0.01) in response to the low-fat, high-vegetable diet. Also, the Lp(a) concentration was increased by 7% (
P
<0.01) and 9% (
P=
0.01), respectively.

Conclusion—

Alterations in the dietary fat intake resulted in increased plasma concentrations of lipoprotein(a) and OxLDL-EO6.
Overexpression of Glutathione Peroxidase Prevents Left Ventricular Remodeling and Failure After Myocardial Infarction in Mice
Authors: Shiomi Tetsuya , Tsutsui Hiroyuki , Matsusaka Hidenori , Murakami Kimiyo , Hayashidani Shunji , Ikeuchi Masaki , Wen Jing , Kubota Toru , Utsumi Hideo , Takeshita Akira
Published: January 2004

Background—

Oxidative stress plays an important role in the pathophysiology of heart failure. We determined whether the overexpression of glutathione peroxidase (GSHPx) could attenuate left ventricular (LV) remodeling and failure after myocardial infarction (MI).

Methods and Results—

We created MI in 12- to 16-week-old, male GSHPx transgenic mice (TG+MI) and nontransgenic wild-type littermates (WT+MI) by ligating the left coronary artery. GSHPx activity was increased in the hearts of TG mice, with no significant changes in other antioxidant enzymes. LV concentrations of thiobarbituric acid–reactive substances measured in TG+MI at 4 weeks were significantly lower than those in WT+MI. The survival rate during 4 weeks of MI was significantly higher in TG+MI than in WT+MI, although the infarct size was comparable. LV cavity dilatation and dysfunction were significantly attenuated in TG+MI. LV end-diastolic pressure was increased in WT+MI and reduced in TG+MI. Improvement of LV function in TG+MI was accompanied by a decrease in myocyte hypertrophy, apoptosis, and interstitial fibrosis in the noninfarcted LV. Myocardial matrix metalloproteinase-9 zymographic and protein levels were increased in WT+MI after 3 days but were attenuated in TG+MI.

Conclusions—

Overexpression of GSHPx inhibited LV remodeling and failure after MI. Therapies designed to interfere with oxidative stress might be beneficial to prevent cardiac failure.
Cardiovascular Risk Factors and Sequelae in Hypertensive Children Identified by Referral Versus School-Based Screening
Authors: Sorof Jonathan M. , Turner Jennifer , Martin David S. , Garcia Kathleen , Garami Zsolt , Alexandrov Andrei V. , Wan Fiona , Portman Ronald J.
Published: January 2004

To determine whether systematic differences exist between hypertensive children referred for evaluation by primary care providers and children identified through community-based screening, cardiovascular risk factors and surrogate markers of hypertensive injury were compared based on subject source (referral versus screening). Children referred to a hypertension clinic for persistently elevated blood pressure were compared with children identified as hypertensive during school screening of 5102 students in Houston public schools. M-mode echocardiography of the left ventricle was performed and subsequently reviewed by 2 independent sonographers blinded to identifying subject information. Subsets of subjects also underwent carotid artery ultrasound for measurement of intimal-medial thickness, overnight urine collections for microalbuminuria, and fasting serum cholesterol, triglycerides, and glucose. Ninety-seven total subjects (54 screening and 43 referral) met inclusion criteria and had technically adequate echocardiography performed. The prevalence of left ventricular hypertrophy (LVH) was 37%. Referral subjects demonstrated significantly greater left ventricular mass index (38.8 versus 34.2 g/m
2.7
;
P
<0.01) and a higher prevalence of LVH (49% versus 28%;
P
<0.05). Among subjects who underwent carotid ultrasound (n=75), carotid intimal-medial thickness was significantly higher in referral subjects (0.61 versus 0.57,
P
<0.05). When controlling for BMI
z
score, which was significantly higher in referral subjects, systematic differences by subject source did not persist. These findings suggest that hypertensive children who are predominantly overweight, independent of the manner in which patients come to medical attention, will manifest evidence of more severe cardiovascular disease assessed by surrogate markers such as left ventricular mass index or carotid artery intimal medial thickness.
Angiotensin II Stimulates Calcium and Nitric Oxide Release From Macula Densa Cells Through AT
1
Receptors
Authors: Liu Ruisheng , Persson A. Erik G.
Published: January 2004

A fluorescent nitric oxide (NO) indicator, 4,5-diaminofluorescein diacetate, and the calcium indicator, indo-1, with 488 nm and 364 nm UV confocal laser scanning microscopy were used to detect NO and calcium concentration in rabbit macula densa (MD) cells challenged by angiotensin II (Ang II). Glomeruli with attached thick ascending limbs with the MD plaque were isolated and perfused. Ang II concentration from 10
−9
to 10
−5
progressively increased MD cell calcium and NO to peak values at 10
−6
and 10
−7
, respectively. Ang II (10
−6
M) caused the cytosolic calcium concentration ([Ca
2+
]
i
) to increase by 125.8±16.3 nM (n=17) from the bath and by 52.3±11.5 nM (n=18) from the lumen. AT
1
antagonist CV-11974 (10
−6
M) blocked the Ang II-induced calcium responses from bath and lumen, but AT
2
antagonist PD-123319 (10
−6
M) did not. AT
2
agonist CGP-42112A (10
−6
M) did not affect [Ca
2+
]
i
in MD cells from either side. Ang II (10
−6
M) increased the NO production by 16%±3.4% (n=26) from the bath and by 18%±3.1% (n=24) from the lumen. CV-11974 (10
−6
M) blocked the NO responses from both sides, but PD-123319 (10
−6
M) did not on either side. CGP-42112A (10
−6
M) had no effect on NO in MD cells. In calcium-free experiments there was no difference from the result in normal calcium solutions. In conclusion, we found that Ang II increased [Ca
2+
]
i
and stimulated NO production in MD cells from the basolateral and luminal sides through AT
1
receptors.
Functional Variant in the α
2B
Adrenoceptor Gene, a Positional Candidate on Chromosome 2, Associates With Hypertension
Authors: von Wowern Fredrik , Bengtsson Kristina , Lindblad Ulf , Råstam Lennart , Melander Olle
Published: January 2004

In a genome-wide scan in Scandinavians, we found suggestive linkage between early-onset primary hypertension and a region on chromosome 2. The α
2B
-adrenoceptor gene, a candidate gene within this region, harbors a functional insertion/deletion (I/D) polymorphism of three glutamate residues. The aim of this study was to investigate if the DD genotype is associated with hypertension in Swedes. We performed an association study between the I/D polymorphism of the α
2B
-adrenoceptor and hypertension in the Skaraborg population. The material consists of all known patients with primary hypertension in Skara (n=772 nondiabetic subjects; n=171 normoalbuminuric type 2 diabetic subjects) and 817 population control subjects. We first compared genotype frequencies between patients with early-onset hypertension (aged 50 years or younger at onset) and subjects with normotension (blood pressure <120/80 mm Hg). Thereafter, the polymorphism was tested for association with hypertension at the population level. When comparing patients with early-onset hypertension and normotensive subjects, the DD versus II genotype was associated with early-onset hypertension when diabetic subjects were excluded from the analysis (OR=2.0; 95% CI=1.2 to 3.5) or when they were not excluded (OR=1.8; 95% CI=1.0 to 3.1). At the population level, the DD versus II genotype was weakly associated with nondiabetic hypertension (OR=1.4; 95% CI=1.0 to 1.8). Our data suggest that carriers of the DD versus II genotype of the α
2B
-adrenoceptor are at increased risk for hypertension. The genotypic effect is most evident when comparing groups corresponding to the upper and lower tails of the blood pressure distribution in the population; however, in nondiabetic hypertensive subjects it is weakly detectable even at the population level.
Enhanced
S
-Nitroso-Albumin Formation From Inhaled NO During Ischemia/Reperfusion
Authors: Ng Ella S.M. , Jourd’heuil David , McCord Joe M. , Hernandez Daniel , Yasui Mitsukuni , Knight Derrice , Kubes Paul
Published: January 2004

In the present study, we investigated whether inhaled nitric oxide (NO) was transported by plasma proteins, such as
S
-nitroso-albumin (SNO-Alb), in the feline circulation and whether this molecule delivers NO to the periphery under conditions of stress, specifically ischemia/reperfusion (I/R). A flow probe was interposed between the femoral and superior mesenteric artery for blood flow measurements, and a branch of the superior mesenteric vein was cannulated for arterial-venous sampling. In animals breathing room air, SNO-Alb was below detection level in arterial or venous blood. NO inhalation resulted in a significant arterial-venous gradient for SNO-Alb. Concomitant with this loss of SNO-Alb across the intestinal vasculature was an increase in nitrite (NO
2
−
). However, this release of NO was not sufficient to alter intestinal blood flow. I/R during NO inhalation caused a very large increase in arterial SNO-Alb that permitted a 5-fold increase in SNO-Alb consumption and significant generation of NO
2
−
within the postischemic intestinal vasculature. The increased SNO-Alb consumption was sufficient to dramatically improve intestinal blood flow. The very large burst of arterial SNO-Alb during I/R was completely blocked by the administration of superoxide dismutase, suggesting that oxidative stress contributed to the increased SNO-Alb formation. Our data suggest that inhaled NO can increase nitrosothiol production and these molecules may be a functional NO delivery system during cardiovascular disease.
Increased Intimal Hyperplasia and Smooth Muscle Cell Proliferation in Transgenic Mice With Heparan Sulfate–Deficient Perlecan
Authors: Tran Phan-Kiet , Tran-Lundmark Karin , Soininen Raija , Tryggvason Karl , Thyberg Johan , Hedin Ulf
Published: January 2004

Smooth muscle cell (SMC) proliferation is a critical process in vascular disease. Heparan sulfate (HS) proteoglycans inhibit SMC growth, but the role of endogenous counterparts in the vessel wall in control of SMC function is not known in detail. Perlecan is the major HS proteoglycans in SMC basement membranes and in vessel wall extracellular matrix (ECM). In this study, transgenic mice with HS-deficient perlecan were analyzed with respect to vascular phenotype and intimal lesion formation. Furthermore, SMC cultures were established and characterized with respect to morphology, immunocytochemical features, proteoglycan synthesis, proliferative capacity, and ECM binding of basic fibroblast growth factor (FGF-2). In vitro, mutant SMCs formed basement membranes with perlecan core protein, but with decreased levels of HS, they showed diminished secretion of HS-containing perlecan into the medium and a defective ECM-binding capacity of FGF-2. In vitro, mutant SMCs showed increased proliferation compared with wild-type cells, and in vivo, enhanced SMC proliferation and intimal hyperplasia were observed after flow cessation of the carotid artery in mutant mice. The results indicate that the endogenous HS side-chains of perlecan contribute to SMC growth control both in vitro and during intimal hyperplasia, possibly by sequestering heparin-binding mitogens such as FGF-2.
Calcineurin Promotes the Expression of Monocyte Chemoattractant Protein-1 in Vascular Myocytes and Mediates Vascular Inflammation
Authors: Satonaka Hiroshi , Suzuki Etsu , Nishimatsu Hiroaki , Oba Shigeyoshi , Takeda Ryo , Goto Atsuo , Omata Masao , Fujita Toshiro , Nagai Ryozo , Hirata Yasunobu
Published: January 2004

Although the role of the calcineurin-dependent pathway in the development of cardiac hypertrophy has been intensively studied, little is known of its role in vascular inflammatory diseases such as atherosclerosis and restenosis after angioplasty. To help elucidate the role of calcineurin in vascular inflammation, we infected cultured vascular smooth muscle cells (VSMCs) with an adenovirus construct expressing a constitutively active mutant of calcineurin, and examined its effect on the expression of monocyte chemoattractant protein-1 (MCP-1). We also examined the role of calcineurin in vivo using a transluminal wire injury model of the rat femoral artery. Forced activation of calcineurin significantly increased the expression of MCP-1 both at the transcriptional and protein levels. Angiotensin II (Ang II) also significantly stimulated MCP-1 expression, and this increase was significantly inhibited by cyclosporin A (CyA). Constitutive activation of calcineurin stabilized MCP-1 mRNA without enhancing MCP-1 promoter activity. In accordance with the results, Ang II–induced increase of MCP-1 promoter activity was not suppressed by CyA. Ang II stabilized MCP-1 mRNA, and this effect of Ang II was diminished by CyA. CyA suppressed MCP-1 expression in the femoral artery after the transluminal mechanical injury. CyA also inhibited macrophage infiltration and neointimal formation in the wire-injured femoral arteries. These results suggested that calcineurin mediates vascular inflammation via stimulation of MCP-1 expression in VSMCs and macrophage infiltration.
Comparative Evaluation of FGF-2–, VEGF-A–, and VEGF-C–Induced Angiogenesis, Lymphangiogenesis, Vascular Fenestrations, and Permeability
Authors: Cao Renhai , Eriksson Anna , Kubo Hajime , Alitalo Kari , Cao Yihai , Thyberg Johan
Published: January 2004

Several endothelial growth factors induce both blood and lymphatic angiogenesis. However, a systematic comparative study of the impact of these factors on vascular morphology and function has been lacking. In this study, we report a quantitative analysis of the structure and macromolecular permeability of FGF-2–, VEGF-A–, and VEGF-C–induced blood and lymphatic vessels. Our results show that VEGF-A stimulated formation of disorganized, nascent vasculatures as a result of fusion of blood capillaries into premature plexuses with only a few lymphatic vessels. Ultrastructural analysis revealed that VEGF-A–induced blood vessels contained high numbers of endothelial fenestrations that mediated high permeability to ferritin, whereas the FGF-2–induced blood vessels lacked vascular fenestrations and showed only little leakage of ferritin. VEGF-C induced approximately equal amounts of blood and lymphatic capillaries with endothelial fenestrations present only on blood capillaries, mediating a medium level of ferritin leakage into the perivascular space. No endothelial fenestrations were found in FGF-2–, VEGF-A–, or VEGF-C–induced lymphatic vessels. These findings highlight the structural and functional differences between blood and lymphatic vessels induced by FGF-2, VEGF-A, and VEGF-C. Such information is important to consider in development of novel therapeutic strategies using these angiogenic factors.
Eligibility for Recombinant Tissue Plasminogen Activator in Acute Ischemic Stroke
Authors: Kleindorfer Dawn , Kissela Brett , Schneider Alex , Woo Daniel , Khoury Jane , Miller Rosemary , Alwell Kathleen , Gebel James , Szaflarski Jerzy , Pancioli Arthur , Jauch Edward , Moomaw Charles , Shukla Rakesh , Broderick Joseph P.
Published: January 2004

Background and Purpose—

Acute ischemic stroke patients are infrequently treated with recombinant tissue plasminogen activator (rtPA). We present unique population-based data regarding the eligibility of ischemic stroke patients for rtPA treatment.

Methods—

All ischemic strokes presenting to an emergency department (ED) within a biracial population of 1.3 million were identified. The patient was considered eligible for rtPA on the basis of exclusion criteria from the National Institute of Neurological Disorders and Stroke rtPA trial.

Results—

Of 2308 ischemic strokes, 1849 presented to an ED. Only 22% of all ischemic strokes in the population arrived in the ED in <3 hours from symptom onset; of these, 209 (51%) were ineligible for rtPA on the basis of mild stroke severity, medical and surgical history, or blood tests.

Conclusions—

In our population in 1993 to 1994, 8% of all ischemic stroke patients presented to an ED within 3 hours and met other eligibility criteria for rtPA. Even if time were not an exclusion for rtPA, only 29% of all ischemic strokes in our population would have otherwise been eligible for rtPA.