bluuebunny/crossref_metadata_2025 huggingface dataset:
Selecting effective index terms
using a decision tree
Authors: TAKENOBU TOKUNAGA , KENJI KIMURA , HIRONORI OGIBAYASHI , HOZUMI TANAKA
Published: August 2002

This paper explores the effectiveness of index terms more complex than the single words used
in conventional information retrieval systems. Retrieval is done in two phases: in the first, a
conventional retrieval method (the Okapi system) is used; in the second, complex index terms
such as syntactic relations and single words with part-of-speech information are introduced
to rerank the results of the first phase. We evaluated the effectiveness of the different types
of index terms through experiments using the TREC-7 test collection and 50 queries. The
retrieval effectiveness was improved for 32 out of 50 queries. Based on this investigation,
we then introduce a method to select effective index terms by using a decision tree. Further
experiments with the same test collection showed that retrieval effectiveness was improved in
25 of the 50 queries.
A bootstrapping approach for
robust topic analysis
Authors: FERRET OLIVIER , GRAU BRIGITTE
Published: August 2002

Topic analysis is important for many applications dealing with texts, such as text summarization or information extraction. However, it can be done with great precision only if it relies
on structured knowledge, which is difficult to produce on a large scale. In this paper, we
propose using bootstrapping to solve this problem: a first topic analysis based on a weakly
structured source of knowledge, a collocation network, is used for learning explicit topic
representations that then support a more precise and reliable topic analysis.
Architectural elements of
language engineering robustness
Authors: MAYNARD DIANA , TABLAN VALENTIN , CUNNINGHAM HAMISH , URSU CRISTIAN , SAGGION HORACIO , BONTCHEVA KALINA , WILKS YORICK
Published: August 2002

We discuss robustness in LE systems from the perspective of engineering, and the predictability
of both outputs and construction process that this entails. We present an architectural system
that contributes to engineering robustness and low-overhead systems development (GATE, a
General Architecture for Text Engineering). To verify our ideas we present results from the
development of a multi-purpose cross-genre Named Entity recognition system. This system
aims be robust across diverse input types, and to reduce the need for costly and timeconsuming adaptation of systems to new applications, with its capability to process texts
from widely differing domains and genres.
Calcium-activated K+ Channels of Mouse β-cells are Controlled by Both Store and Cytoplasmic Ca2+
Authors: Goforth P.B. , Bertram R. , Khan F.A. , Zhang M. , Sherman A. , Satin L.S.
Published: August 2002

A novel calcium-dependent potassium current (Kslow) that slowly activates in response to a simulated islet burst was identified recently in mouse pancreatic β-cells (Göpel, S.O., T. Kanno, S. Barg, L. Eliasson, J. Galvanovskis, E. Renström, and P. Rorsman. 1999. J. Gen. Physiol. 114:759–769). Kslow activation may help terminate the cyclic bursts of Ca2+-dependent action potentials that drive Ca2+ influx and insulin secretion in β-cells. Here, we report that when [Ca2+]i handling was disrupted by blocking Ca2+ uptake into the ER with two separate agents reported to block the sarco/endoplasmic calcium ATPase (SERCA), thapsigargin (1–5 μM) or insulin (200 nM), Kslow was transiently potentiated and then inhibited. Kslow amplitude could also be inhibited by increasing extracellular glucose concentration from 5 to 10 mM. The biphasic modulation of Kslow by SERCA blockers could not be explained by a minimal mathematical model in which [Ca2+]i is divided between two compartments, the cytosol and the ER, and Kslow activation mirrors changes in cytosolic calcium induced by the burst protocol. However, the experimental findings were reproduced by a model in which Kslow activation is mediated by a localized pool of [Ca2+] in a subspace located between the ER and the plasma membrane. In this model, the subspace [Ca2+] follows changes in cytosolic [Ca2+] but with a gradient that reflects Ca2+ efflux from the ER. Slow modulation of this gradient as the ER empties and fills may enhance the role of Kslow and [Ca2+] handling in influencing β-cell electrical activity and insulin secretion.
Coupling between Voltage Sensor Activation, Ca2+ Binding and Channel Opening in Large Conductance (BK) Potassium Channels
Authors: Horrigan Frank T. , Aldrich Richard W.
Published: August 2002

To determine how intracellular Ca2+ and membrane voltage regulate the gating of large conductance Ca2+-activated K+ (BK) channels, we examined the steady-state and kinetic properties of mSlo1 ionic and gating currents in the presence and absence of Ca2+ over a wide range of voltage. The activation of unliganded mSlo1 channels can be accounted for by allosteric coupling between voltage sensor activation and the closed (C) to open (O) conformational change (Horrigan, F.T., and R.W. Aldrich. 1999. J. Gen. Physiol. 114:305–336; Horrigan, F.T., J. Cui, and R.W. Aldrich. 1999. J. Gen. Physiol. 114:277–304). In 0 Ca2+, the steady-state gating charge-voltage (QSS-V) relationship is shallower and shifted to more negative voltages than the conductance-voltage (GK-V) relationship. Calcium alters the relationship between Q-V and G-V, shifting both to more negative voltages such that they almost superimpose in 70 μM Ca2+. This change reflects a differential effect of Ca2+ on voltage sensor activation and channel opening. Ca2+ has only a small effect on the fast component of ON gating current, indicating that Ca2+ binding has little effect on voltage sensor activation when channels are closed. In contrast, open probability measured at very negative voltages (less than −80 mV) increases more than 1,000-fold in 70 μM Ca2+, demonstrating that Ca2+ increases the C-O equilibrium constant under conditions where voltage sensors are not activated. Thus, Ca2+ binding and voltage sensor activation act almost independently, to enhance channel opening. This dual-allosteric mechanism can reproduce the steady-state behavior of mSlo1 over a wide range of conditions, with the assumption that activation of individual Ca2+ sensors or voltage sensors additively affect the energy of the C-O transition and that a weak interaction between Ca2+ sensors and voltage sensors occurs independent of channel opening. By contrast, macroscopic IK kinetics indicate that Ca2+ and voltage dependencies of C-O transition rates are complex, leading us to propose that the C-O conformational change may be described by a complex energy landscape.
Na+ Block and Permeation in a K+ Channel of Known Structure
Authors: Nimigean Crina M. , Miller Christopher
Published: August 2002

The effects of intracellular Na+ were studied on K+ and Rb+ currents through single KcsA channels. At low voltage, Na+ produces voltage-dependent block, which becomes relieved at high voltage by a “punchthrough” mechanism representing Na+ escaping from its blocking site through the selectivity filter. The Na+ blocking site is located in the wide, hydrated vestibule, and it displays unexpected selectivity for K+ and Rb+ against Na+. The voltage dependence of Na+ block reflects coordinated movements of the blocker with permeant ions in the selectivity filter.
Calmodulin Binding to the 3614–3643 Region of RyR1 Is Not Essential for Excitation–Contraction Coupling in Skeletal Myotubes
Authors: O'Connell Kristen M.S. , Yamaguchi Naohiro , Meissner Gerhard , Dirksen Robert T.
Published: August 2002

Calmodulin is a ubiquitous Ca2+ binding protein that modulates the in vitro activity of the skeletal muscle ryanodine receptor (RyR1). Residues 3614–3643 of RyR1 comprise the CaM binding domain and mutations within this region result in a loss of both high-affinity Ca2+-bound calmodulin (CaCaM) and Ca2+-free CaM (apoCaM) binding (L3624D) or only CaCaM binding (W3620A). To investigate the functional role of CaM binding to this region of RyR1 in intact skeletal muscle, we compared the ability of RyR1, L3624D, and W3620A to restore excitation–contraction (EC) coupling after expression in RyR1-deficient (dyspedic) myotubes. W3620A-expressing cells responded normally to 10 mM caffeine and 500 μM 4-chloro-m-cresol (4-cmc). Interestingly, L3624D-expressing cells displayed a bimodal response to caffeine, with a large proportion of cells (∼44%) showing a greatly attenuated response to caffeine. However, high and low caffeine-responsive L3624D-expressing myotubes exhibited Ca2+ transients of similar magnitude after activation by 4-cmc (500 μM) and electrical stimulation. Expression of either L3624D or W3620A in dyspedic myotubes restored both L-type Ca2+ currents (retrograde coupling) and voltage-gated SR Ca2+ release (orthograde coupling) to a similar degree as that observed for wild-type RyR1, although L-current density was somewhat larger and activated at more hyperpolarized potentials in W3620A-expressing myotubes. The results indicate that CaM binding to the 3614–3643 region of RyR1 is not essential for voltage sensor activation of RyR1.
Comparison of Simulated and Measured Calcium Sparks in Intact Skeletal Muscle Fibers of the Frog
Authors: Baylor S.M. , Hollingworth S. , Chandler W.K.
Published: August 2002

Calcium sparks in frog intact skeletal muscle fibers were modeled as stereotypical events that arise from a constant efflux of Ca2+ from a point source for a fixed period of time (e.g., 2.5 pA of Ca2+ current for 4.6 ms; 18°C). The model calculates the local changes in the concentrations of free Ca2+ and of Ca2+ bound to the major intrinsic myoplasmic Ca2+ buffers (troponin, ATP, parvalbumin, and the SR Ca2+ pump) and to the Ca2+ indicator (fluo-3). A distinctive feature of the model is the inclusion of a binding reaction between fluo-3 and myoplasmic proteins, a process that strongly affects fluo-3′s Ca2+-reaction kinetics, its apparent diffusion constant, and hence the morphology of sparks. ΔF/F (the change in fluo-3′s fluorescence divided by its resting fluorescence) was estimated from the calculated changes in fluo-3 convolved with the microscope point-spread function. To facilitate comparisons with measured sparks, noise and other sources of variability were included in a random repetitive fashion to generate a large number of simulated sparks that could be analyzed in the same way as the measured sparks. In the initial simulations, the binding of Ca2+ to the two regulatory sites on troponin was assumed to follow identical and independent binding reactions. These simulations failed to accurately predict the falling phase of the measured sparks. A second set of simulations, which incorporated the idea of positive cooperativity in the binding of Ca2+ to troponin, produced reasonable agreement with the measurements. Under the assumption that the single channel Ca2+ current of a ryanodine receptor (RYR) is 0.5–2 pA, the results suggest that 1–5 active RYRs generate an average Ca2+ spark in a frog intact muscle fiber.
The Role of NH2-terminal Positive Charges in the Activity of Inward Rectifier KATP Channels
Authors: Cukras C.A. , Jeliazkova I. , Nichols C.G.
Published: August 2002

Approximately half of the NH2 terminus of inward rectifier (Kir) channels can be deleted without significant change in channel function, but activity is lost when more than ∼30 conserved residues before the first membrane spanning domain (M1) are removed. Systematic replacement of the positive charges in the NH2 terminus of Kir6.2 with alanine reveals several residues that affect channel function when neutralized. Certain mutations (R4A, R5A, R16A, R27A, R39A, K47A, R50A, R54A, K67A) change open probability, whereas an overlapping set of mutants (R16A, R27A, K39A, K47A, R50A, R54A, K67A) change ATP sensitivity. Further analysis of the latter set differentiates mutations that alter ATP sensitivity as a consequence of altered open state stability (R16A, K39A, K67A) from those that may affect ATP binding directly (K47A, R50A, R54A). The data help to define the structural determinants of Kir channel function, and suggest possible structural motifs within the NH2 terminus, as well as the relationship of the NH2 terminus with the extended cytoplasmic COOH terminus of the channel.
The Effects of Polarizing Current on Nerve Terminal Impulses Recorded from Polymodal and Cold Receptors in the Guinea-pig Cornea
Authors: Carr Richard W. , Pianova Svetlana , Brock James A.
Published: August 2002

It was reported recently that action potentials actively invade the sensory nerve terminals of corneal polymodal receptors, whereas corneal cold receptor nerve terminals are passively invaded (Brock, J.A., S. Pianova, and C. Belmonte. 2001. J. Physiol. 533:493–501). The present study investigated whether this functional difference between these two types of receptor was due to an absence of voltage-activated Na+ conductances in cold receptor nerve terminals. To address this question, the study examined the effects of polarizing current on the configuration of nerve terminal impulses recorded extracellularly from single polymodal and cold receptors in guinea-pig cornea isolated in vitro. Polarizing currents were applied through the recording electrode. In both receptor types, hyperpolarizing current (+ve) increased the negative amplitude of nerve terminal impulses. In contrast, depolarizing current (−ve) was without effect on polymodal receptor nerve terminal impulses but increased the positive amplitude of cold receptor nerve terminal impulses. The hyperpolarization-induced increase in the negative amplitude of nerve terminal impulses represents a net increase in inward current. In both types of receptor, this increase in inward current was reduced by local application of low Na+ solution and blocked by lidocaine (10 mM). In addition, tetrodotoxin (1 μM) slowed but did not reduce the hyperpolarization-induced increase in the negative amplitude of polymodal and cold nerve terminal impulses. The depolarization-induced increase in the positive amplitude of cold receptor nerve terminal impulses represents a net increase in outward current. This change was reduced both by lidocaine (10 mM) and the combined application of tetraethylammomium (20 mM) and 4-aminopyridine (1 mM). The interpretation is that both polymodal and cold receptor nerve terminals possess high densities of tetrodotoxin-resistant Na+ channels. This finding suggests that in cold receptors, under normal conditions, the Na+ conductances are rendered inactive because the nerve terminal region is relatively depolarized.
Movement and Crevices Around a Sodium Channel S3 Segment
Authors: Nguyen Thao P. , Horn Richard
Published: August 2002

Voltage sensing is due mainly to the movement of positively charged S4 segments through the membrane electric field during changes of membrane potential. The roles of other transmembrane segments are under study. The S3 segment of domain 4 (D4/S3) in the sodium channel Nav1.4 carries two negatively charged residues and has been implicated in voltage-dependent gating. We substituted cysteines into nine putative “high impact” sites along the complete length of D4/S3 and evaluated their accessibilities to extracellular sulfhydryl reagents. Only the four outermost substituted cysteines (L1433C, L1431C, G1430C, and S1427C) are accessible to extracellular sulfhydryl reagents. We measured the voltage-dependent modification rates of the two cysteines situated at the extreme ends of this accessible region, L1433C and S1427C. Independent of the charge on the sulfhydryl reagents, depolarization increases the reactivity of both of these residues. Thus, the direction of the voltage dependence is opposite to that expected for a negatively charged voltage sensor, namely an inward translational movement in response to depolarization. Intrinsic electrostatic potentials were probed by charged sulfhydryl reagents and were either negative or positive, respectively, near L1433C and S1427C. The magnitude of the electrostatic potential near S1427C decreases with depolarization, suggesting that the extracellular crevice next to it widens during depolarization. S1427C experiences 44% of the electric field, as probed by charged cysteine reagents. To further explore movements around D4/S3, we labeled cysteines with the photoactivatable cross-linking reagent benzophenone-4-carboxamidocysteine methanethiosulfonate and examined the effects of UV irradiation on channel gating. After labeling with this reagent, all accessible cysteine mutants show altered gating upon brief UV irradiation. In each case, the apparent insertion efficiency of the photoactivated benzophenone increases with depolarization, indicating voltage-dependent movement near the extracellular end of D4/S3.
Methylation-Spanning Linker Libraries Link Gene-Rich Regions and Identify Epigenetic Boundaries in Zea mays
Authors: Yuan Yinan , SanMiguel Phillip J. , Bennetzen Jeffrey L.
Published: September 2002

Complex cereal genomes are largely composed of small gene-rich regions intermixed with 5 kb to 200 kb blocks of repetitive DNA. The repetitive DNA blocks are usually 5-methylated at 5′-CG-3′ and 5′-CNG-3′ cytosines in most or all adult tissues, while the genes are generally unmethylated at these sites. We have developed methylation-spanning linker library (MSLL) technology as a tool to span large methylated DNA blocks and thereby link unmethylated genic regions. MSLL clones contain insertions of large fragments that are size fractionated over gels after complete digestion of total genomic DNA with restriction enzymes that are sensitive to the 5-methylation of cytosines in 5′-CG-3′ and 5′-CNG-3′ sequences. Our data indicate that the end sequences of maize MSLL clones are greatly depleted in repetitive DNAs and enriched in genes relative to total genomic DNA. Combined with other gene-enrichment approaches, MSLL technology can efficiently generate fully-linked contiguous sequences in complex genomes that are resistant to shotgun sequencing.
Deterministic Mutation Rate Variation in the Human Genome
Authors: Smith Nick G.C. , Webster Matthew T. , Ellegren Hans
Published: September 2002

Several studies of substitution rate variation have indicated that the local mutation rate varies over the mammalian genome. In the present study, we show significant variation in substitution rates within the noncoding part of the human genome using 4.7 Mb of human-chimpanzee pairwise comparisons. Moreover, we find a significant positive covariation of lineage-specific chimpanzee and human local substitution rates, and very similar mean substitution rates down the two lineages. The substitution rate variation is probably not caused by selection or biased gene conversion, and so we conclude that mutation rates vary deterministically across the noncoding nonrepetitive regions of the human genome. We also show that noncoding substitution rates are significantly affected by G+C base composition, partly because the base composition is not at equilibrium.
Impact of the Presence of Paralogs on Sequence Divergence in a Set of Mouse-Human Orthologs
Authors: Nembaware Victoria , Crum Karen , Kelso Janet , Seoighe Cathal
Published: September 2002

Using a large set of orthologous human and mouse gene pairs, we have characterized genes that have been retained in duplicate in human over timescales comparable to the time of speciation of human and mouse. Orthologous gene pairs for which a paralogous gene has been present for much or all of the time since speciation show an increased rate of nonsynonymous substitution. We have related rate of divergence to functional classification using the Gene Ontology terms. Protein function was found, in some cases, to have a larger impact on rate of evolution than the presence or absence of a paralog. No evidence was found that genes that have been retained in duplicate are weighted toward any functional categories. An increase in the ratio of nonsynonymous to synonymous changes following duplication has previously been reported. However, because amino acid sequences include conservative as well as more freely evolving sites, the ratio of nonsynonymous to synonymous changes tends to be higher for closely related pairs. By measuring the divergence of orthologs only and comparing between genes for which a paralogous gene is either present or absent, we have compared gene pairs that share a common divergence time. We have also found that shorter genes have a higher probability of being found duplicated in the human genome, possibly reflecting a mutational effect.
The Molecular Biology of West Nile Virus: A New Invader of the Western Hemisphere
Authors: Brinton Margo A.
Published: September 2002

▪ Abstract  West Nile virus (WNV) is a mosquito-borne flavivirus that primarily infects birds but occasionally also infects humans and horses. In recent years, the frequency of WNV outbreaks in humans has increased, and these outbreaks have been associated with a higher incidence of severe disease. In 1999, the geographical distribution of WNV expanded to the Western hemisphere. WNV has a positive strand RNA genome of about 11 kb that encodes a single polyprotein. WNV replicates in the cytoplasm of infected cells. Although there are still many questions to be answered, a large body of data on the molecular biology of WNV and other flaviviruses has already been obtained. Aspects of virion structure, the viral replication cycle, viral protein function, genome structure, conserved viral elements, host factors, virus-host interactions, and vaccines are discussed in this review.
Biofilms as Complex Differentiated Communities
Authors: Stoodley P. , Sauer K. , Davies D. G. , Costerton J. W.
Published: September 2002

▪ Abstract  Prokaryotic biofilms that predominate in a diverse range of ecosystems are often composed of highly structured multispecies communities. Within these communities metabolic activities are integrated, and developmental sequences, not unlike those of multicellular organisms, can be detected. These structural adaptations and interrelationships are made possible by the expression of sets of genes that result in phenotypes that differ profoundly from those of planktonically grown cells of the same species. Molecular and microscopic evidence suggest the existence of a succession of de facto biofilm phenotypes. We submit that complex cell-cell interactions within prokaryotic communities are an ancient characteristic, the development of which was facilitated by the localization of cells at surfaces. In addition to spatial localization, surfaces may have provided the protective niche in which attached cells could create a localized homeostatic environment. In a holistic sense both biofilm and planktonic phenotypes may be viewed as integrated components of prokaryote life.
Type IV Pili and Twitching Motility
Authors: Mattick John S.
Published: September 2002

▪ Abstract  Twitching motility is a flagella-independent form of bacterial translocation over moist surfaces. It occurs by the extension, tethering, and then retraction of polar type IV pili, which operate in a manner similar to a grappling hook. Twitching motility is equivalent to social gliding motility in Myxococcus xanthus and is important in host colonization by a wide range of plant and animal pathogens, as well as in the formation of biofilms and fruiting bodies. The biogenesis and function of type IV pili is controlled by a large number of genes, almost 40 of which have been identified in Pseudomonas aeruginosa. A number of genes required for pili assembly are homologous to genes involved in type II protein secretion and competence for DNA uptake, suggesting that these systems share a common architecture. Twitching motility is also controlled by a range of signal transduction systems, including two-component sensor-regulators and a complex chemosensory system.
Bacteriocins: Evolution, Ecology, and Application
Authors: Riley Margaret A. , Wertz John E.
Published: September 2002

▪ Abstract  Microbes produce an extraordinary array of microbial defense systems. These include classical antibiotics, metabolic by-products, lytic agents, numerous types of protein exotoxins, and bacteriocins. The abundance and diversity of this potent arsenal of weapons are clear. Less clear are their evolutionary origins and the role they play in mediating microbial interactions. The goal of this review is to explore what we know about the evolution and ecology of the most abundant and diverse family of microbial defense systems: the bacteriocins. We summarize current knowledge of how such extraordinary protein diversity arose and is maintained in microbial populations and what role these toxins play in mediating microbial population-level and community-level dynamics. In the latter half of this review we focus on the potential role bacteriocins may play in addressing human health concerns and the current role they serve in food preservation.
Control of Chromosome Replication inCaulobacter Crescentus
Authors: Marczynski Gregory T. , Shapiro Lucy
Published: September 2002

▪ Abstract  Caulobacter crescentus permits detailed analysis of chromosome replication control during a developmental cell cycle. Its chromosome replication origin (Cori) may be prototypical of the large and diverse class of alpha-proteobacteria. Cori has features that both affiliate and distinguish it from the Escherichia coli chromosome replication origin. For example, requirements for DnaA protein and RNA transcription affiliate both origins. However, Cori is distinguished by several features, and especially by five binding sites for the CtrA response regulator protein. To selectively repress and limit chromosome replication, CtrA receives both protein degradation and protein phosphorylation signals. The signal mediators, proteases, response regulators, and kinases, as well as Cori DNA and the replisome, all show distinct patterns of temporal and spatial organization during cell cycle progression. Future studies should integrate our knowledge of biochemical activities at Cori with our emerging understanding of cytological dynamics in C. crescentus and other bacteria.
Cross-Species Infections and Their Analysis
Authors: Tan Man-Wah
Published: September 2002

▪ Abstract  The ability of certain pathogens to infect multiple hosts has led to the development of genetically tractable nonvertebrate hosts to elucidate the molecular mechanisms of interactions between these pathogens and their hosts. The use of plant, insect, nematode, and protozoan hosts to study human pathogens has facilitated the elucidation of molecular nature of pathogenesis and host responses. Analyses of virulence of multihost pathogens on their respective hosts revealed that pathogens utilize many universal offensive strategies to overcome host defenses, irrespective of the evolutionary lineage of the host. Likewise, genetic dissections of the defense response of the nonvertebrate hosts have also shown that key features underlying host defense responses are highly conserved. This review summarizes how the information gained from the analysis of cross-species infections contributes to our understanding of host-pathogen interactions.
Prions as Protein-Based Genetic Elements
Authors: Uptain Susan M. , Lindquist Susan
Published: September 2002

▪ Abstract  Fungal prions are fascinating protein-based genetic elements. They alter cellular phenotypes through self-perpetuating changes in protein conformation and are cytoplasmically partitioned from mother cell to daughter. The four prions of Saccharomyces cerevisiae and Podospora anserina affect diverse biological processes: translational termination, nitrogen regulation, inducibility of other prions, and heterokaryon incompatibility. They share many attributes, including unusual genetic behaviors, that establish criteria to identify new prions. Indeed, other fungal traits that baffled microbiologists meet some of these criteria and might be caused by prions. Recent research has provided notable insight about how prions are induced and propagated and their many biological roles. The ability to become a prion appears to be evolutionarily conserved in two cases. [PSI+] provides a mechanism for genetic variation and phenotypic diversity in response to changing environments. All available evidence suggests that prions epigenetically modulate a wide variety of fundamental biological processes, and many await discovery.
Accumulation of Foam Cells in Liver X Receptor-Deficient Mice
Authors: Schuster Gertrud U. , Parini Paolo , Wang Ling , Alberti Siegfried , Steffensen Knut R. , Hansson Göran K. , Angelin Bo , Gustafsson Jan-Åke
Published: August 2002

Background—

The nature of some of the target genes for liver X receptors (LXRs)-α and -β, such as sterol regulatory element binding protein-1 and ATP-binding cassette transporter proteins, suggests a pivotal role of these nuclear receptors in the regulation of fatty acid and cholesterol homeostasis. The present study aimed to elucidate the physiological relevance of both LXRs with regard to lipid metabolism and macrophage cholesterol efflux.

Methods and Results—

Mice depleted for LXRα, LXRβ, or both were fed low-fat rodent chow for 18 months before investigations. The combined deficiency of LXRα and LXRβ was linked to impaired triglyceride metabolism, increased LDL and reduced HDL cholesterol levels, and cholesterol accumulation in macrophages (foam cells) of the spleen, lung, and arterial wall.

Conclusions—

Our data demonstrate the physiological importance of both LXRs in lipid metabolism and strongly indicate that both LXRs have a protective role against the development of atherosclerosis.
Hypercholesterolemia in Minipigs Impairs Left Ventricular Response to Stress
Authors: Theilmeier Gregor , Verhamme Peter , Dymarkowski Steven , Beck Heike , Bernar Hilde , Lox Marleen , Janssens Stefan , Herregods Marie-Christine , Verbeken Erik , Collen Désiré , Plate Karl , Flameng Willem , Holvoet Paul
Published: August 2002

Background—

Hypercholesterolemia induces functional and structural changes of the microvasculature and reduces coronary flow reserve in humans and experimental animals. The effect of hypercholesterolemia on left ventricular (LV) function in the absence of coronary stenosis is, however, unknown. Our objective was therefore to assess the effect of hypercholesterolemia and cholesterol withdrawal on LV function in the presence of advanced coronary plaques that do not cause stenosis.

Methods and Results—

Twenty-eight minipigs on cholesterol diet for 34 weeks and 16 control pigs were studied. Seven hypercholesterolemic pigs were withdrawn from the diet for 26 weeks. LV function was assessed with cine-MRI, myocardial blood flow with colored microspheres, and capillary density with immunohistochemistry, and microvascular endothelial cell apoptosis with terminal dUTP nick-end labeling staining. Hypercholesterolemia (17±8 versus 268±150 versus 12±10 mg/dL LDL cholesterol, control versus hypercholesterolemic versus cholesterol withdrawal;
P
<0.001) induced atherosclerosis but not stenosis in the left coronary artery. Baseline cardiac output, ejection fraction, and stroke volume were similar in control and hypercholesterolemic pigs. In dobutamine stress test, cardiac output (
P
<0.05) and stroke volume (
P
<0.01) were lower in hypercholesterolemic pigs compared with controls. The impaired response to dobutamine was reversible by dietary cholesterol withdrawal. Hypercholesterolemia reduced endomyocardial coronary flow reserve (
P
<0.01) and capillary density (
P
<0.05) and induced capillary endothelial cell apoptosis. Hypercholesterolemic pigs failed to reduce vascular resistance in response to increased LV workload and pharmacological vasodilation.

Conclusion—

LDL hypercholesterolemia in minipigs impaired LV response to dobutamine stress in the absence of coronary stenosis.
Distinct Renal Injury in Early Atherosclerosis and Renovascular Disease
Authors: Chade Alejandro R. , Rodriguez-Porcel Martin , Grande Joseph P. , Krier James D. , Lerman Amir , Romero J. Carlos , Napoli Claudio , Lerman Lilach O.
Published: August 2002

Background—

Atherosclerotic renovascular disease may augment deterioration of renal function and ischemic nephropathy compared with other causes of renal artery stenosis (RAS), but the underlying mechanisms remain unclear. This study was designed to test the hypothesis that concurrent early atherosclerosis and hypoperfusion might have greater early deleterious effects on the function and structure of the stenotic kidney.

Methods and Results—

Regional renal hemodynamics and function at baseline and during vasoactive challenge (acetylcholine or sodium nitroprusside) were quantified in vivo in pigs by electron-beam computed tomography after a 12-week normal (n=7) or hypercholesterolemic (HC, n=7) diet, RAS (n=6), or concurrent HC and a similar degree of RAS (HC+RAS, n=7). Flash-frozen renal tissue was studied ex vivo. Basal cortical perfusion and single-kidney glomerular filtration rate (GFR) were decreased similarly in the stenotic RAS and HC+RAS kidneys, but tubular fluid reabsorption was markedly impaired only in HC+RAS. Perfusion responses to challenge were similarly blunted in the experimental groups. Stimulated GFR increased in normal, HC, and RAS (38.3±3.6%, 36.4±7.6%, and 60.4±9.3%, respectively,
P
<0.05), but not in HC+RAS (6.5±15.1%). These functional abnormalities in HC+RAS were accompanied by augmented perivascular, tubulointerstitial, and glomerular fibrosclerosis, inflammation, systemic and tissue oxidative stress, and tubular expression of nuclear factor-κB and inducible nitric oxide synthase.

Conclusions—

Early chronic HC+RAS imposes distinct detrimental effects on renal function and structure in vivo and in vitro, evident primarily in the tubular and glomerular compartments. Increased oxidative stress may be involved in the proinflammatory and progrowth changes observed in the stenotic HC+RAS kidney, which might potentially facilitate the clinically observed progression to end-stage renal disease.
Long-Term Survival and Hemodynamics After Endothelin-A Receptor Antagonism and Angiotensin-Converting Enzyme Inhibition in Rats With Chronic Heart Failure
Authors: Mulder Paul , Boujedaini Houssaine , Richard Vincent , Henry Jean-Paul , Renet Sylvanie , Münter Klaus , Thuillez Christian
Published: August 2002

Background—

In patients with congestive heart failure (CHF) receiving ACE inhibitors, acute administration of selective endothelin (ET) antagonists additionally improves systemic and cardiac hemodynamics. We investigated, in a rat model of CHF, whether such acute synergistic effects are sustained and accompanied, in the long term, by an additional limitation of left ventricular remodeling or an increase in survival.

Methods and Results—

Rats were subjected to coronary artery ligation and treated for 3 or 9 months with vehicle or with the ACE inhibitor trandolapril (Tr) (0.3 mg/kg
−1
per day
−1
), the ET
A
antagonist LU 135252 (LU, 30 mg/kg
−1
per day
−1
), or their combination starting 7 days after ligation. After 3 months, the combination decreased LV systolic- and end-diastolic pressures (−32% and −80%, respectively) more markedly than Tr (−21% and −61%, respectively) or LU alone (−14% and −48%, respectively). Echocardiographic studies revealed that all treatments limited LV dilatation and increased LV fractional shortening and cardiac index. All treatments equally reduced left ventricular collagen density, whereas only Tr or the combination reduced LV weight. Finally, although LU did not modify long-term survival, Tr and the combination of Tr with LU induced a similar improvement of survival.

Conclusions—

In this rat model, long-term combined administration of an ET
A
antagonist and an ACE inhibitor induces additional effects in terms of systemic and cardiac hemodynamics; however, this is not associated with an additional increase in long-term survival.
Sildenafil Effects on Exercise, Neurohormonal Activation, and Erectile Dysfunction in Congestive Heart Failure
Authors: Bocchi Edimar Alcides , Guimarães Guilherme , Mocelin Amilcar , Bacal Fernando , Bellotti Giovanni , Ramires José Franchini
Published: August 2002

Background—

Erectile dysfunction (ED) is common in patients with congestive heart failure (CHF). ED reduces quality of life, and it may affect compliance, thereby impairing the success of CHF treatment.

Methods and Results—

In the first phase (fixed-dose double-blind, randomized, placebo-controlled, two-way crossover study), we studied in 23 men with CHF the effects of 50 mg sildenafil on exercise and neurohormonal activation. Patients underwent a treadmill 6-minute cardiopulmonary walking (6′WT) test followed by a maximal cardiopulmonary exercise test (ET). In the second phase, patients received sildenafil, taken as required for ED. Sildenafil reduced the heart rate (HR) (bpm) before the 6′WT (from 75±15 to 71±14,
P
=0.02) and ET (from 75±15 to 71±15,
P
=0.02); the systolic blood pressure (mm Hg) before the 6′WT (from 116±18 to 108±18,
P
=0.004) and ET (from 116±15 to 108±17,
P
=0.001); the diastolic blood pressure before the 6′WT (from 69±9 to 63±11,
P
=0.01) and ET (from 70±8 to 65±10,
P
=0.004); and the Ve/V
co
2
slope during the 6′WT (from 32±7 to 31±6,
P
=0.04) and ET (from 33±8 to 31±5,
P
=0.03). Sildenafil attenuated the HR increment during the 6′WT (
P
=0.003) and ET (
P
=0.000). Sildenafil increased the peak
·
o
2
from 16.6±3.4 to 17.7±3.4 mL/kg per min (
P
=0.025) and the exercise time from 12.3±3.4 to 13.7±3.2 minutes (
P
=0.003). Sildenafil improved most scores of International Index of Erectile Function.

Conclusions—

Sildenafil was tolerated and effective for ED treatment in CHF, and improved the exercise capacity. The reduction of HR during exercise with sildenafil could theoretically decrease the myocardial oxygen consumption during sexual activity.
Patterns of Coronary Compromise Resulting in Acute Right Ventricular Ischemic Dysfunction
Authors: Bowers Terry R. , O’Neill William W. , Pica Mark , Goldstein James A.
Published: August 2002

Background—

Although proximal right coronary artery (RCA) occlusion is the culprit commonly responsible for acute right ventricular (RV) infarction (RVI), the severity of RV dysfunction ranges broadly. This study was designed to delineate the patterns of coronary compromise that determine the magnitude of RV ischemic dysfunction.

Methods and Results—

In 125 patients with acute inferior myocardial infarction undergoing emergency angiography, the culprit infarct lesion was identified, RV branch flow assessed (TIMI flows and frame counts), and individual patient RV perfusion indices calculated by separately averaging the branch flows and frame counts, which were correlated with RV wall motion by ultrasound. RVI occurred in 53 (42%) patients, with the RCA as the culprit vessel and the lesion sufficiently proximal to compromise flow in at least one RV branch in all cases, thereby resulting in depressed RV perfusion (flow index, 0.7±0.2). In patients without RVI, the RCA was the culprit in 89%; the circumflex, in 11%. RCA culprits were proximal in 19% of such cases, with lack of RVI explained by preserved RV perfusion (flow index, 2.7±0.3;
P
=0.001) attributable to at least 1 patent RV branch, spontaneous reperfusion, or prominent collaterals. Overall, there was a strong correlation between RV perfusion and wall motion (Spearman correlation coefficient=0.79).

Conclusions—

Proximal RCA occlusion compromising RV branch perfusion commonly results in RV ischemic dysfunction. In some cases with proximal RCA culprits, collaterals or spontaneous reperfusion preserve RV performance.
Chronobiological Patterns of Acute Aortic Dissection
Authors: Mehta Rajendra H. , Manfredini Roberto , Hassan Fauziya , Sechtem Udo , Bossone Eduardo , Oh Jae K. , Cooper Jeanna V. , Smith Dean E. , Portaluppi Francesco , Penn Marc , Hutchison Stuart , Nienaber Christoph A. , Isselbacher Eric M. , Eagle Kim A.
Published: August 2002

Background—

Chronobiological rhythms have been shown to influence the occurrence of a variety of cardiovascular disorders. However, the effects of the time of the day, the day of the week, or monthly/seasonal changes on acute aortic dissection (AAD) have not been well studied.

Methods and Results—

Accordingly, we evaluated 957 patients enrolled in the International Registry of Acute Aortic Dissection (IRAD) between 1996 and 2000 (mean age 62±14 years, type A 61%). A χ
2
test for goodness of fit and partial Fourier analysis were used to evaluate nonuniformity and rhythmicity of AAD during circadian, weekly, and monthly periods. A significantly higher frequency of AAD occurred from 6:00
am
to 12:00 noon compared with other time periods (12:00 noon to 6:00
pm
, 6:00
pm
to 12:00 midnight, and 12:00 midnight to 6:00
am
;
P
<0.001 by χ
2
test). Fourier analysis showed a highly significant circadian variation (
P
<0.001) with a peak between 8:00
am
and 9:00
am
. Although no significant variation was found for the day of the week, the frequency of AAD was significantly higher during winter (
P
=0.008 versus other seasons by χ
2
test). Fourier analysis confirmed this monthly variation with a peak in January (
P
<0.001). Subgroup analysis identified a significant association for all subgroups with circadian rhythmicity. However, seasonal/monthly variations were observed only among patients aged <70 years, those with type B AAD, and those without hypertension or diabetes.

Conclusions—

Similar to other cardiovascular conditions, AAD exhibits significant circadian and seasonal/monthly variations. Our findings may have important implications for the prevention of AAD by tailoring treatment strategies to ensure maximal benefits during the vulnerable periods.
Constitutive Human Telomerase Reverse Transcriptase Expression Enhances Regenerative Properties of Endothelial Progenitor Cells
Authors: Murasawa Satoshi , Llevadot Joan , Silver Marcy , Isner Jeffrey M. , Losordo Douglas W. , Asahara Takayuki
Published: August 2002

Background—

The regulatory molecule for cell life span, telomerase, was modified by human telomerase reverse transcriptase (hTERT) gene transfer to investigate its effect on regenerative properties of endothelial progenitor cells (EPCs) in neovascularization.

Methods and Results—

Telomerase activity was enhanced in hTERT-transduced EPCs (Td-TERTs) (1.2-fold versus no transduced EPCs [no-Td] and 1.2-fold versus GFP-transduced EPCs [Td/GFPs] at day 8; 5.2-fold versus no-Td and 4.8-fold versus Td/GFP at day 21, respectively) Mitogenic capacity in Td/TERTs exceeded that in Td/GFPs at day 8 (0.62±0.02 versus 0.53±0.01, respectively;
P
<0.01). Vascular endothelial growth factor-induced cell migration in EPCs was markedly enhanced by hTERT overexpression (Td/TERTs versus Td/GFPs, 292±12 versus 174±6 cells, respectively;
P
<0.01). hTERT overexpression has rescued EPCs from starvation-induced cell apoptosis, an outcome that was further enhanced in response to vascular endothelial growth factor. The colony appearance of totally differentiated endothelial cells (tdECs) was detected before day 30 only in Td/TERT, whereas no tdEC colonies could be detected in both Td/GFPs and no-Tds. Finally, we investigated in vivo transplantation of heterologous EPCs. Td/TERTs dramatically improved postnatal neovascularization in terms of limb salvage by 4-fold in comparison with that of Td/GFPs; limb perfusion was measured by laser Doppler (0.77±0.10 versus 0.47±0.06;
P
=0.02), and capillary density (224±78 versus 90±40 capillaries/mm
2
;
P
<0.01).

Conclusions—

These findings provide the novel evidence that telomerase activity contributes to EPC angiogenic properties; mitogenic activity, migratory activity, and cell survival. This enhanced regenerative activity of EPCs by hTERT transfer will provide novel therapeutical strategy for postnatal neovascularization in severe ischemic disease patients.
Randomized Trial of
90
Sr/
90
Y β-Radiation Versus Placebo Control for Treatment of In-Stent Restenosis
Authors: Popma Jeffrey J. , Suntharalingam Mohan , Lansky Alexandra J. , Heuser Richard R. , Speiser Burton , Teirstein Paul S. , Massullo Vincent , Bass Theodore , Henderson Randall , Silber Sigmund , von Rottkay Peter , Bonan Raoul , Ho Kalon K.L. , Osattin, MPH Alison , Kuntz Richard E.
Published: August 2002

Background—

After conventional treatment of in-stent restenosis, the incidence of recurrent clinical restenosis may approach 40%. We report the first multicenter, blinded, and randomized trial of intracoronary radiation with the use of a
90
Sr/
90
Y β-source for the treatment of in-stent restenosis.

Methods and Results—

After successful catheter-based treatment of in-stent restenosis, 476 patients were randomly assigned to receive an intracoronary catheter containing either
90
Sr/
90
Y (n=244) or placebo (n=232) sources. The prescribed dose 2 mm from the center of the source was 18.4 Gy for vessels between 2.70 and 3.35 mm in diameter and 23.0 Gy for vessels between 3.36 and 4.0 mm. The primary end point, ie, clinically driven target-vessel revascularization by 8 months, was observed in 56 (26.8%) of the patients assigned to placebo and 39 (17.0%) of the patients assigned to radiation (
P
=0.015). The incidence of the composite including death, myocardial infarction, and target-vessel revascularization was observed in 60 (28.7%) of the patients assigned to placebo and 44 (19.1%) of the patients assigned to radiation (
P
=0.024). Binary 8-month angiographic restenosis (≥50% diameter stenosis) within the entire segment treated with radiation was reduced from 45.2% in the placebo-treated patients to 28.8% in the
90
Sr/
90
Y-treated patients (
P
=0.001). Stent thromboses occurred in 1 patient assigned to placebo <24 hours after the procedure and in 1 patient assigned to
90
Sr/
90
Y at day 244.

Conclusions—

The results of this study demonstrated that β-radiation using
90
Sr/
90
Y is both safe and effective for preventing recurrence in patients with in-stent restenosis.
Accuracy of Contrast-Enhanced Magnetic Resonance Imaging in Predicting Improvement of Regional Myocardial Function in Patients After Acute Myocardial Infarction
Authors: Gerber Bernhard L. , Garot Jérôme , Bluemke David A. , Wu Kathérine C. , Lima João A.C.
Published: August 2002

Background—

Contrast-enhanced (CE) MRI demonstrates a pattern of hypoenhancement early after contrast injection in acute myocardial infarction (MI) and a pattern of hyperenhancement late after contrast injection. Because the significance of these CE patterns for myocardial viability remains debated, we evaluated their diagnostic accuracy to quantitatively predict late functional improvement of regional contractility.

Methods and Results—

Twenty patients underwent CE and tagged MRI at 4 days and again at 7 months after acute MI. Resting circumferential shortening strain (Ecc) was analyzed in 24 segments per patient, and its improvement was correlated with the presence or absence of the CE patterns. Immediately after MI, 389 segments were considered dysfunctional because of having less than mean±2 SD Ecc of the remote region (−18±4%). At follow-up, significant improvement of Ecc occurred in 170 dysfunctional segments with normal CE (from −4±7% to −12±7%,
P
<0.001) but not in 60 segments with early hypoenhancement (from −2±6% to −6±9% Ecc,
P
=NS). In 240 dysfunctional segments with delayed hyperenhancement, the improvement of Ecc (from −2±6% to −5±8%,
P
<0.001) decreased with increasing transmural extent of hyperenhancement. Receiver operating characteristic analysis demonstrated that absence of delayed hyperenhancement, compared with absence of early hypoenhancement, had better sensitivity (82% versus 19%, respectively;
P
<0.001) and accuracy (74% versus 49%, respectively;
P
<0.001) in predicting recovery of Ecc to any given level.

Conclusions—

Compared with lack of early hypoenhancement, lack of delayed hyperenhancement has better diagnostic accuracy in predicting functional improvement in dysfunctional segments. The early hypoenhanced regions, which represent only the fraction of infarcted tissue with concomitant microvascular obstruction, greatly underestimate the amount of irreversibly injured myocardium present after acute MI.