bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential Expansion of Zinc-Finger Transcription Factor Loci in Homologous Human and Mouse Gene Clusters
Authors: Shannon Mark , Hamilton Aaron T. , Gordon Laurie , Branscomb Elbert , Stubbs Lisa
Published: May 2003

Mammalian genomes carry hundreds ofKrüppel-type zinc finger (ZNF) genes, most of which reside in familial clusters. ZNF genes encodingKrüppel-associated box (KRAB) motifs are especially prone to this type of tandem organization. Despite their prevalence, little is known about the functions or evolutionary histories of these clustered gene families. Here we describe a homologous pair of human and mouse KRAB-ZNF gene clusters containing 21 human and 10 mouse genes, respectively. Evolutionary analysis uncovered only three pairs of putative orthologs and two cases where a single gene in one species is related to multiple genes in the other; several human genes have no obvious homolog in mouse. We deduce that duplication and loss of ancestral cluster members occurred independently in the primate and rodent lineages after divergence, yielding substantially different ZNF gene repertoires in humans and mice. Differences in expression patterns and sequence divergence within the DNA binding regions of predicted proteins suggest that the duplicated genes have acquired novel functions over evolutionary time. Since KRAB-ZNF proteins are predicted to function as transcriptional regulators, the elaboration of new lineage-specific genes in this and other clustered ZNF families is likely to have had a significant impact on species-specific aspects of biology.
An Appraisal of the Potential for Illegitimate Recombination in Bacterial Genomes and Its Consequences: From Duplications to Genome Reduction
Authors: Rocha Eduardo P.C.
Published: May 2003

An exhaustive search for shortly spaced repeats in 74 bacterial chromosomes reveals that they are much more numerous than is usually acknowledged. These repeats were divided into five classes: close repeats (CRs), tandem repeats (TRs), simple sequence repeats (SSRs), spaced interspersed direct repeats, and “others.” CRs are widespread and constitute the most abundant class, particularly in coding sequences. The other classes are less frequent, but each individual element shows a higher potential for recombination, when the number of repeats and their distances are taken into account. SSRs and TRs are more frequent in pathogens, as expected given their role in contingency loci, but are also widespread in the other bacteria. The analysis of CRs shows that they have an important role in the evolution of genomes, namely by generating duplications and deletions. Several cases compatible with a significant role of small CRs in the formation of large repeats were detected. Also, gene deletion in Buchnera correlates with repeat density, suggesting that CRs may lead to sequence deletion in general and genome reductive evolution of obligatory intracellular bacteria in particular. The assembly of these results indicates that shortly spaced repeats are key players in the dynamics of genome evolution.
Differential Effects of Elevated Ozone on Two Hybrid Aspen Genotypes Predisposed to Chronic Ozone Fumigation. Role of Ethylene and Salicylic Acid
Authors: Vahala Jorma , Keinänen Markku , Schützendübel Andres , Polle Andrea , Kangasjärvi Jaakko
Published: May 2003

The role of ethylene (ET) signaling in the responses of two hybrid aspen (Populus tremula L. × P.tremuloides Michx.) clones to chronic ozone (O3; 75 nL L−1) was investigated. The hormonal responses differed between the clones; the O3-sensitive clone 51 had higher ET evolution than the tolerant clone 200 during the exposure, whereas the free salicylic acid concentration in clone 200 was higher than in clone 51. The cellular redox status, measured as glutathione redox balance, did not differ between the clones suggesting that the O3 lesions were not a result of deficient antioxidative capacity. The buildup of salicylic acid during chronic O3 exposure might have prevented the up-regulation of ET biosynthesis in clone 200. Blocking of ET perception with 1-methylcyclopropene protected both clones from the decrease in net photosynthesis during chronic exposure to O3. After a pretreatment with low O3 for 9 d, an acute 1.5-fold O3 elevation caused necrosis in the O3-sensitive clone 51, which increased substantially when ET perception was blocked. The results suggest that in hybrid aspen, ET signaling had a dual role depending on the severity of the stress. ET accelerated leaf senescence under low O3, but under acute O3 elevation, ET signaling seemed to be required for protection from necrotic cell death.
Ethylene Insensitivity Modulates Ozone-Induced Cell Death in Birch
Authors: Vahala Jorma , Ruonala Raili , Keinänen Markku , Tuominen Hannele , Kangasjärvi Jaakko
Published: May 2003

We have used genotypic variation in birch (Betula pendula Roth) to investigate the roles of ozone (O3)-induced ethylene (ET), jasmonic acid, and salicylic acid in the regulation of tissue tolerance to O3. Of these hormones, ET evolution correlated best with O3-induced cell death. Disruption of ET perception by transformation of birch with the dominant negative mutant allele etr1-1 of the Arabidopsis ET receptor gene ETR1 or blocking of ET perception with 1-methylcyclopropene reduced but did not completely prevent the O3-induced cell death, when inhibition of ET biosynthesis with aminooxyacetic acid completely abolished O3 lesion formation. This suggests the presence of an ET-signaling-independent but ET biosynthesis-dependent component in the ET-mediated stimulation of cell death in O3-exposed birch. Functional ET signaling was required for the O3 induction of the gene encoding β-cyanoalanine synthase, which catalyzes detoxification of the cyanide formed during ET biosynthesis. The results suggest that functional ET signaling is required to protect birch from the O3-induced cell death and that a decrease in ET sensitivity together with a simultaneous, high ET biosynthesis can potentially cause cell death through a deficient detoxification of cyanide.
Action research: an approach to student work based learning
Authors: Rowley Jennifer
Published: May 2003

This article seeks to draw out some of the principles and concepts of action research in order to better inform student work based learning. After an introduction that explains the application of action research to work based learning, the article explores the essence of action research. The action research cycle and the notion of meta learning are introduced. A section on taking action research forward addresses pragmatic issues such as: journal keeping, managing role duality, and managing politics and ethics. Finally suggestions are offered for writing an action research dissertation or work based project report.
Professional women in computer programming occupations: the case of Turkey
Authors: Ecevit Yildiz , Gündüz‐Hosgör Ayse , Tokluoglu Ceylan
Published: May 2003

This paper focuses on the professional women, who work in high status jobs, such as system analysts and computer programming, in Turkey. It aims to explain their high share in the sector and the various coping strategies employed by the women as a response to the demands of their work. The findings of the research illustrate that these women appear to be young, university graduates who were born and live in urban centres and who are demanded by the sector particularly for their high qualifications. On the other hand, these women work hard, postpone marriage or not marry at all. Those women, who are married, manage work without a radical redefinition of their marital roles. This research is relevant as empirical research has not been conducted with the women in this sector in Turkey. Further empirical work is now necessary in order to explain their working conditions in detail. Future research should also inquire whether this sector would open up new windows of opportunity for women.
Regulation and Rights in Networked Space
Authors: Murray Andrew D.
Published: May 2003

The Internet is often described as inherently free from regulation; a space where freedoms and liberties are guaranteed by the design of the network environment. The naivety of this view has, however, been exposed by commentators such as Shapiro, Reidenberg, and Lessig who have clearly demonstrated the inherent regulability of networked space. The question no longer is: can networked space be regulated? but rather, how and by whom is it regulated? This paper examines the regulation of rights in networked space. Property rights and rights to free speech, or free expression, are examined in relation to a number of issues that have emerged in the networked environment, or cyberspace. Its aim is to examine whether the embryonic regulatory structure of cyberspace, which has the advantage of starting with a completely clean slate, is sufficiently sympathetic to the unique qualities of this fledgling jurisdiction.
Railtrack is Dead – Long Live Network Rail? Nationalization Under the Third Way
Authors: Whitehouse Lisa
Published: May 2003

This essay offers, by way of an examination of the proposals to reform the railway industry, a case study of the government's attempt to operationalize the third way. That these proposals are consistent with the third way is identified within this essay and yet they would appear to give rise to the de facto renationalization of the railway infrastructure. In accounting for this apparent contradiction in the (third way) means used and the (old‐style democracy) ends achieved, it will be argued that this new form of nationalization is consistent with the third way rather than any socialist understanding of the term. To this extent, therefore, New Labour have attempted to reconceptualize the process of nationalization in pursuit of the ‘new mixed economy’.
Toward a Pluralist Account of Parenthood
Authors: Bayne Tim , Kolers Avery
Published: May 2003

What is it that makes someone a parent? Many writers – call them ‘monists’– claim that parenthood is grounded solely in one essential feature that is both necessary and sufficient for someone's being a parent. We reject not only monism but also ‘necessity’ views, in which some specific feature is necessary but not also sufficient for parenthood. Our argument supports what we call ‘pluralism’, the view that any one of several kinds of relationship is sufficient for parenthood. We begin by challenging monistic versions of gestationalism, the view that gestation uniquely grounds parenthood. Monistic and necessity gestationalism are implausible. First, we raise the ‘paternity problem’– necessity gestationalists lack an adequate account of how men become fathers. Second, the positive arguments that necessity gestationalists give are not compelling. However, although gestation may not be a necessary condition for parenthood, there is good reason to think that it is sufficient. After further rebutting an ‘intentionalist’ account of parenthood, in which having and acting on intentions to procreate and rear is necessary for parenthood, we end by sketching a pluralist picture of the nature of parenthood, rooted in causation, on which gestation, direct genetic derivation, extended custody, and even, sometimes, intentions, may be individually sufficient for parenthood.
Managing innovative R&D teams
Authors: Thamhain Hans J.
Published: May 2003

Successful R&D groups not only generate innovative ideas, but also transfers these newly created concepts through the organizational system for economic gain. While innovation is not a random process, managers often argue that R&D performance is hard to measure and even more difficult to manage. An exploratory field study into technology‐oriented R&D environments determines the principle factors that influence innovation‐based performance of R&D teams. The results identify specific barriers and drivers to innovative team performance and provide insight into the type of an organizational environment and managerial leadership that is conducive to innovative R&D team performance. The data further suggest that many of the performance variables have their locus outside the R&D organization. Yet, managerial leadership style, both at the R&D team level and at senior management, has significant impact on creativity that ultimately affects R&D performance.
Is Representation Rife?
Authors: Papineau David
Published: May 2003

This paper applies a teleosemantic perspective to the question of whether there is genuine representation outside the familiar realm of belief‐desire psychology. I first explain how teleosemantics accounts for the representational powers of beliefs and desires themselves. I then ask whether biological states which are simpler than beliefs and desires can also have representational powers. My conclusion is that such biologically simple states can be ascribed representational contents, but only in a system‐relative way: such states must be ascribed varying contents when viewed as components in different biological systems. I conclude by arguing that ‘the genetic code’ does not even embody this kind of system‐relative representation.
Ontology, Understanding, and the A Priori
Authors: Sosa Ernest
Published: May 2003

How might one explain the reliability of one's a priori beliefs? What if anything is implied about the ontology of a certain realm of knowledge by the possibility of explaining one's reliability about that realm? Very little, or so it is argued here.
Review
Authors: Pearce Toby M.
Published: May 2003

Book reviewed:

Peter Carruthers, Phenomenal Consciousness: A Naturalistic Theory.
An Important Role for the Na+‐Ca2+ Exchanger in the Decrease in Cytosolic Ca2+ Concentration induced by Isoprenaline in the Porcine Coronary Artery
Authors: Yamanaka Jun , Nishimura Junji , Hirano Katsuya , Kanaide Hideo
Published: May 2003

The role of the Na+‐Ca2+ exchanger (NCX) in the mechanism of the isoprenaline (Iso)‐induced vasorelaxation was investigated by simultaneously monitoring the intracellular Ca2+ concentration ([Ca2+]i) and tension of fura‐2‐loaded medial strips of porcine coronary arteries. Normal physiological salt solution (PSS) contained 137.3 mm Na+ and 5.9 mm K+. During the sustained phase of contraction, Iso induced only a transient decrease in [Ca2+]i when contraction was induced by depolarization with 118 mm K+ solution containing 25.2 mm Na+. When contraction was induced with 30 mm K+ in PSS containing 113.2 mm Na+, Iso induced a sustained decrease in [Ca2+]i, whereas in contractions induced by 30 mm K+ in a low Na+ (25.2 mm Na+) PSS, Iso transiently decreased [Ca2+]i. Replacement of Ca2+ with Ba2+ (which cannot be extruded by the Ca2+ pumps but can be extruded through the NCX) resulted in decreased [Ba2+]i induced by Iso in normal but not in low Na+ PSS. On the other hand, Iso induced a sustained decrease in [Ca2+]i when strips were pre‐contracted by U46619, a thromboxane A2 analogue, in PSS. Various types of K+ channel blockers (iberiotoxin, 4‐aminopyridine, apamin or glibenclamide) or combinations of these blockers failed to completely inhibit the Iso‐induced decreases in [Ca2+]i and tension. However, Iso‐induced sustained decreases in [Ca2+]i during the contraction induced by U46619 were greatly inhibited in a low Na+ PSS. The Iso‐induced decrease in tension during contraction by U46619 was greatly inhibited by 2′,4′‐dichlorobenzamil, a forward‐ and reverse‐mode NCX inhibitor, but not by ouabain, a selective inhibitor of Na+,K+‐ATPase. These results indicate that the NCX is involved in the Iso‐induced reduction of [Ca2+]i and tension of the porcine coronary arterial smooth muscle.
The relationship between transplacental O2 diffusion and placental expression of PlGF, VEGF and their receptors in a placental insufficiency model of fetal growth restriction
Authors: Regnault Timothy R. H. , de Vrijer Barbra , Galan Henry L. , Davidsen Meredith L. , Trembler Karen A. , Battaglia Frederick C. , Wilkening Randall B. , Anthony Russell V.
Published: May 2003

Placental growth factor (PlGF) and vascular endothelial growth factor (VEGF) are involved in placental angiogenesis through interactions with the VEGFR‐1 and VEGFR‐2 receptors. The placenta of pregnancies whose outcome is fetal growth restriction (FGR) are characterized by abnormal angiogenic development, classically associated with hypoxia. The present study evaluated the near‐term expression of this growth factor family in an ovine model of placental insufficiency–FGR, in relationship to uteroplacental oxygenation. Compared to controls, FGR pregnancies demonstrated a 37 % increase in uterine blood flow (FGR vs. control, 610.86 ± 48.48 vs. 443.17 ± 37.39 ml min−1 (kg fetus)−1; P < 0.04), which was associated with an increased maternal uterine venous PO2 (58.13 ± 1.00 vs. 52.89 ± 1.26 mmHg; P < 0.02), increased umbilical artery systolic/diastolic ratio (3.90 ± 0.33 vs. 2.12 ± 0.26, P < 0.05), and fetal hypoxia (arterial PO2; 12.79 ± 0.97 vs. 18.65 ± 1.6 mmHg, P < 0.005). Maternal caruncle PlGF mRNA was increased in FGR (P < 0.02), while fetal cotyledon VEGF mRNA was reduced (P < 0.02). VEGFR‐1 mRNA was also reduced in FGR fetal cotyledon (P < 0.001) but was not altered in caruncle tissue. Immunoblot analysis of PlGF and VEGF demonstrated single bands at 19 000 and 18 600 Mr, respectively. Caruncle PlGF concentration was increased (P < 0.04), while cotyledon VEGF was decreased (P < 0.05) in FGR placentae. The data establish that uterine blood flow is not reduced in relationship to metabolic demands in this FGR model and that the transplacental PO2 gradient is increased, maintaining umbilical oxygen uptake per unit of tissue. Furthermore, these data suggest that an increased transplacental gradient of oxygen generates changes in angiogenic growth factors, which may underline the pathophysiology of the post‐placental hypoxic FGR.
Inhibition of HERG K+ Current and Prolongation of the Guinea‐Pig Ventricular Action Potential by 4‐Aminopyridine
Authors: Ridley J. M. , Milnes J. T. , Zhang Y. H. , Witchel H. J. , Hancox J. C.
Published: May 2003

4‐Aminopyridine (4‐AP) has been used extensively to study transient outward K+ current (ITO,1) in cardiac cells and tissues. We report here inhibition by 4‐AP of HERG (the human ether‐à‐go‐go‐related gene) K+ channels expressed in a mammalian cell line, at concentrations relevant to those used to study ITO,1. Under voltage clamp, whole cell HERG current (IHERG) tails following commands to +30 mV were blocked with an IC50 of 4.4 ± 0.5 mm. Development of block was contingent upon HERG channel gating, with a preference for activated over inactivated channels. Treatment with 5 mm 4‐AP inhibited peak IHERG during an applied action potential clamp waveform by ∼59 %. It also significantly prolonged action potentials and inhibited resurgent IK tails from guinea‐pig isolated ventricular myocytes, which lack an ITO,1. We conclude that by blocking the α‐subunit of the IKr channel, millimolar concentrations of 4‐AP can modulate ventricular repolarisation independently of any action on ITO,1.
Crystal Structure of the Potassium Channel KirBac1.1 in the Closed State
Authors: Kuo Anling , Gulbis Jacqueline M. , Antcliff Jennifer F. , Rahman Tahmina , Lowe Edward D. , Zimmer Jochen , Cuthbertson Jonathan , Ashcroft Frances M. , Ezaki Takayuki , Doyle Declan A.
Published: May 2003

The KirBac1.1 channel belongs to the inward-rectifier family of potassium channels. Here we report the structure of the entire prokaryotic Kir channel assembly, in the closed state, refined to a resolution of 3.65 angstroms. We identify the main activation gate and structural elements involved in gating. On the basis of structural evidence presented here, we suggest that gating involves coupling between the intracellular and membrane domains. This further suggests that initiation of gating by membrane or intracellular signals represents different entry points to a common mechanistic pathway.
NUMERICAL ANALYSIS OF RANDOM DOPANT-INDUCED EFFECTS IN SEMICONDUCTOR DEVICES
Authors: MAYERGOYZ I. D. , ANDREI P.
Published: May 2003

A new approach to the analysis of random dopant-induced effects in semiconductor devices is presented. It is based on the "small signal analysis" (perturbation) technique. This approach is computationally much more efficient than the existing purely "statistical" techniques, and it yields the information that can be directly used for the design of dopant fluctuation-resistant structures of semiconductor devices. This approach is applied to the analysis of random dopant-induced fluctuations of threshold voltages and frequency response characteristics of MOSFET devices.
OPTICAL WAVE PROPAGATION IN PERIODIC STRUCTURES
Authors: YARIV AMNON , MOOKHERJEA SHAYAN
Published: May 2003

We present a formalism for optical waveguiding in two-dimensional periodic structures by means of Bragg reflection. The theory provides analytic expressions for the field modal profiles, dispersion, and attenuation or gain in the waveguide. Line defects in two-dimensional photonic crystal slabs are used as the principal example.
ISSUES, ACHIEVEMENTS AND CHALLENGES TOWARDS INTEGRATION OF HIGH-k DIELECTRICS
Authors: CAYMAX M. , DE GENDT S. , VANDERVORST W. , HEYNS M. , BENDER H. , CARTER R. , CONARD T. , DEGRAEVE R. , GROESENEKEN G. , KUBICEK S. , LUJAN G. , PANTISANO L. , PETRY J. , ROHR E. , VAN ELSHOCHT S. , ZHAO C. , CARTIER E. , CHEN J. , COSNIER V. , JANG S. E. , KAUSHIK V. , KERBER A. , KLUTH J. , LIN S. , TSAI W. , YOUNG E. , MANABE Y.
Published: May 2003

Once the thickness of the gate dielectric layer in CMOS devices gets thinner than 1.2 nm, excessive gate leakage due to direct tunneling makes the use of alternative materials obligatory. Candidate high-k materials are metal oxides such as Al 2 O 3, ZrO 2 and HfO 2 as well as their mixtures. Very promising results have been reported world-wide. Here, however, we show that there are a number of issues related to materials and electrical characteristics as well as to processing which are not always recognized and that necessitate more work to find solutions. Among these are problems with density, interface layer growth and island formation which are clearly related to the deposition process. Also thermal instabilities as well as interactions between the high-k material and poly-Si need attention. Further possible show-stoppers are electrical reliability issues and strongly reduced carrier mobility.
SYSTEM IMPACT OF SILICON CARBIDE POWER DEVICES
Authors: OZPINECI BURAK , TOLBERT LEON M. , ISLAM SYED K. , HASANUZZAMAN MD.
Published: May 2003

The emergence of silicon carbide- (SiC-) based power semiconductor switches, with their superior features compared with silicon- (Si-) based switches, has resulted in substantial improvements in the performance of power electronics converter systems. These systems with SiC power devices have the qualities of being more compact, lighter, and more efficient; thus, they are ideal for high voltage power electronics applications such as a hybrid electric vehicle (HEV) traction drive. More research is required to show the impact of SiC devices in power conversion systems. In this study, findings of SiC research at Oak Ridge National Laboratory (ORNL) including SiC device design and system modeling studies, will be given.
THz DETECTION BY RESONANT 2-D PLASMONS IN FIELD EFFECT DEVICES
Authors: PERALTA XOMALIN , KNAP WOJTEK
Published: May 2003

We demonstrate the resonant detection by the two-dimensional electron plasma waves in gated two-dimensional electron gas. Such detection was demonstrated for two devices: for a field effect transistor (FET) THz detector, where the standing 2-D plasmon is tuned to the frequency of the THz radiation by varying the gate bias and for double quantum well field effect transistors with a periodic grating gate, which exhibit a rich spectrum corresponding to standing 2-D plasmons under the metal part of the periodic gate.
NOISE MEASUREMENT OF III-V COMPOUND DETECTORS FOR 2 μm LIDAR/DIAL REMOTE SENSING APPLICATIONS
Authors: ABEDIN M. NURUL , REFAAT TAMER F. , SINGH UPENDRA N.
Published: May 2003

Noise of a photodetector plays a vital role in determining the minimum detectable signal for lidar and DIAL receivers. A low noise trans-impedance amplifier circuit has been employed to examine the noise of III-V compound infrared detectors. These infrared detectors include InGaAs PIN diodes and newly developed InGaAsSb avalanche photodiodes (APDs) with separate absorption and multiplication (SAM) structure. The noise of these detectors are compared with well-established Si APDs. These measured noises are utilized to compute the figures-of-merit, such as noise-equivalent-power (NEP) and detectivity (D*) of these devices and are presented in this paper.
FULL-CHIP POWER-SUPPLY NOISE: THE EFFECT OF ON-CHIP POWER-RAIL INDUCTANCE
Authors: FOK C. W. , PULFREY D. L.
Published: May 2003

The importance of on-chip power-rail inductance in generating delta-I power-supply noise is examined in this paper using systematic circuit simulation of the complete integrated-circuit power net. This source of noise is compared to the resistive IR drop in the net, and to the delta-I noise due to both high-inductance- and low-inductance-bonding packages. Results are presented for a typical on-chip power net in 0.18 μm CMOS technology, and it is demonstrated that the inductance of this on-chip power net is the dominant contributor to the full-chip power-supply noise. The simultaneous switching events which produce the triggering current transients for the delta-I noise are taken to arise from core-logic switching; the mitigating, de-coupling role of the capacitance of non-switching gates within the core-logic block is considered.
Long-Term Stable Expression of Human Apolipoprotein A-I Mediated by Helper-Dependent Adenovirus Gene Transfer Inhibits Atherosclerosis Progression and Remodels Atherosclerotic Plaques in a Mouse Model of Familial Hypercholesterolemia
Authors: Belalcazar L. Maria , Merched Aksam , Carr Boyd , Oka Kazuhiro , Chen Kuang-Hua , Pastore Lucio , Beaudet Arthur , Chan Lawrence
Published: May 2003

Background—

Epidemiologic studies and transgenic mouse experiments indicate that high plasma HDL and apolipoprotein (apo) A-I protect against atherosclerosis. We used helper-dependent adenovirus (HD-Ad) gene transfer to examine the effect of long-term hepatic apoA-I expression on atherosclerotic lesion progression and remodeling in a mouse model of familial hypercholesterolemia.

Methods and Results—

We treated LDL receptor–deficient (LDLR
−/−
) mice maintained on a high-cholesterol diet for 6 weeks with either a HD-Ad containing human apoA-I gene (HD-Ad-AI) or saline (control). HD-Ad-AI treatment did not affect plasma liver enzymes but induced the appearance of plasma human apoA-I at or above human levels for the duration of the study. Substantial amounts of human apoA-I existed in lipid-free plasma. Compared with controls, HDLs from treated mice were larger and had a greater inhibitory effect on tumor necrosis factor-α–induced vascular cellular adhesion molecule-1 expression in cultured endothelial cells. Twenty-four weeks after injection, aortic atherosclerotic lesion area in saline-treated mice progressed ≈700%; the rate of progression was reduced by >50% by HD-Ad-AI treatment. The lesions in HD-Ad-AI–treated mice contained human apoA-I that colocalized mainly with macrophages; they also contained less lipid, fewer macrophages, and less vascular cellular adhesion molecule-1 immunostaining but more smooth muscle cells (α-actin staining) and collagen.

Conclusions—

HD-Ad-AI treatment of LDLR
−/−
mice leads to long-term overexpression of apoA-I, retards atherosclerosis progression, and remodels the lesions to a more stable-appearing phenotype. HD-Ad–mediated transfer of apoA-I may be a useful clinical approach for protecting against atherosclerosis progression and stabilizing atherosclerotic lesions associated with dyslipidemia in human patients.
Synergistic Effect of Persistent
Chlamydia pneumoniae
Infection, Autoimmunity, and Inflammation on Coronary Risk
Authors: Huittinen Tiina , Leinonen Maija , Tenkanen Leena , Virkkunen Hanna , Mänttäri Matti , Palosuo Timo , Manninen Vesa , Saikku Pekka
Published: May 2003

Background—

Given the role of chronic infections, autoimmunity, and inflammation in atherosclerosis, we studied the joint effect of chronic
Chlamydia pneumoniae
infection, persistently elevated human heat-shock protein 60 (hHsp60) antibodies, and C-reactive protein (CRP) on coronary risk.

Methods and Results—

The participants for this prospective nested case-control study were obtained from the Helsinki Heart Study, during which 241 nonfatal myocardial infarctions or coronary deaths occurred among 4081 dyslipidemic middle-aged men. Serum samples taken at baseline and 3 to 6 months before the coronary events that occurred during the 8.5-year period were analyzed for antibodies to
C pneumoniae
and hHsp60 and the CRP concentration. Compared with persistently low levels, the risk of coronary events was 2-fold for persistently elevated immunocomplex (IC)-bound and/or serum IgA antibodies to
C pneumoniae
(OR, 1.96; 95% CI, 1.14 to 3.36) and also for serum IgA antibodies to hHsp60 (OR, 2.11; 95% CI, 1.08 to 4.13). The risks associated with elevated antibodies were much higher when CRP was also elevated. Compared with low or transiently elevated levels, the risk of coronary events, with adjustment for age and smoking, was 4.5-fold for persistently elevated CRP and
C pneumoniae
IC/IgA antibodies together (OR, 4.47; 95% CI, 1.84 to 10.83) and was similar for CRP and hHsp60 IgA antibodies together (OR, 4.36; 95% CI, 1.53 to 12.39).

Conclusions—

Persistently but not transiently elevated
C pneumoniae
IC/IgA and hHsp60 IgA antibodies, especially when present together with an elevated CRP level, predicted coronary events.
Sudden Death in Noncoronary Heart Disease Is Associated With Delayed Paced Ventricular Activation
Authors: Saumarez Richard C. , Chojnowska Lidia , Derksen Richard , Pytkowski Mariusz , Sterlinski Maciej , Huang Christopher L.-H. , Sadoul Nicolas , Hauer Richard N.W. , Ruzyłło Witold , Grace Andrew A.
Published: May 2003

Background—

Slowed or delayed myocardial activation and dispersed refractoriness predispose to reentrant excitation that may lead to ventricular fibrillation (VF). Increased ventricular electrogram duration (ΔED) in response to extrastimuli and increased S1S2 coupling intervals at which electrogram duration starts to increase (S1S2
delay
) are seen both in hypertrophic cardiomyopathy (HCM) in those at risk of VF and in patients with idiopathic VF (IVF).

Methods and Results—

ΔED and S1S2
delay
have been measured using paced electrogram fractionation analysis in 266 patients with noncoronary heart disease. Of these, one group of 61 patients had a history of VF and included 21 HCM, 17 IVF, 13 long-QT syndrome (LQTS), 5 dilated cardiomyopathy (DCM), and 5 others. These were compared with 205 patients with similar diseases with no VF history (non-VF group) and a control group (n=12) without heart disease. Results from HCM VF patients (ΔED, 19±3.3 ms; S1S2
delay
, 350±9.7 ms) differed sharply from observations in HCM non-VF patients (ΔED, 7.3±1.35 ms; S1S2
delay
, 312±6.7 ms;
P
<0.001). DCM VF patients had longer delays (ΔED, 14.3±5.9; S1S2
delay
, 344±11.2) than DCM non-VF patients (ΔED, 5.8±1.87 ms; S1S2
delay
, 311±5.7 ms;
P
<0.001), with major differences also seen comparing LQTS VF (ΔED, 12.4±5.3 ms; S1S2
delay
, 343±13.8 ms) and LQTS non-VF patients (ΔED, 11.0±2.7 ms; S1S2
delay
, 320±5.4 ms;
P
<0.001). IVF patients had both severely abnormal and normal areas of myocardium.

Conclusions—

Slowed or delayed myocardial activation is a common feature in patients with noncoronary heart disease with a history of VF, and its assessment may allow the prospective prediction of VF risk in these patients.
Use of Rapamycin Slows Progression of Cardiac Transplantation Vasculopathy
Authors: Mancini Donna , Pinney Sean , Burkhoff Daniel , LaManca John , Itescu Silviu , Burke Elizabeth , Edwards Niloo , Oz Mehmet , Marks Andrew R.
Published: May 2003

Background—

Cardiac transplantation vasculopathy is the leading cause of late death in heart transplantation recipients. Rapamycin is an immunosuppressant drug with potent antiproliferative and antimigratory effects. We investigated whether rapamycin could prevent progression of graft vasculopathy in 46 patients (age, 54±10 years; 4.3±2.3 years after transplantation) with severe disease.

Methods and Results—

At annual cardiac catheterization, patients were randomly assigned to treatment with rapamycin (n=22) versus continued current immunosuppression (n=24). Clinical characteristics including recipient age and sex, underlying cause of congestive heart failure, donor age and sex, and ischemic time were recorded. Cardiac catheterization was graded with the use of a semiquantitative scale and repeated annually. Clinically significant adverse events were defined as death, need for angioplasty or bypass surgery, myocardial infarction, and a >25% worsening of the catheterization score. These events were monitored as primary study end points. Anti-HLA class I and II antibody production and lymphocyte growth assays were measured with each biopsy. Patients selected for rapamycin had azathioprine or mycophenolate mofetil discontinued and were given rapamycin. Outcomes were compared by means of log-rank analysis. There were no significant differences in baseline characteristics. Duration of follow-up was comparable (rapamycin, 689±261; control, 630±207 days; NS). In the rapamycin group, 3 patients reached primary end points versus 14 patients in the control group (
P
<0.001). There was no difference in baseline or subsequent anti-HLA class I or II antibody production.

Conclusions—

In this patient cohort with cardiac vasculopathy, treatment with rapamycin slowed disease progression probably by its antiproliferative and antimigratory effects.
Interleukin-7–Mediated Inflammation in Unstable Angina
Authors: Damås Jan Kristian , Wæhre Torgun , Yndestad Arne , Otterdal Kari , Hognestad Aina , Solum Nils Olav , Gullestad Lars , Frøland Stig S. , Aukrust Pål
Published: May 2003

Background—

Atherogenesis and plaque destabilization involve immune-mediated mechanisms, but the actual mediators have not been fully clarified. Interleukin (IL)-7 is a regulator of T-cell homeostasis but also may be involved in inflammation. We hypothesized that IL-7 could be involved in the inflammatory processes observed in atherosclerosis and acute coronary syndromes.

Methods and Results—

To study the role of IL-7 in coronary artery disease, we analyzed IL-7 levels and the effect of this cytokine on inflammatory mediators in patients with stable and unstable angina and in healthy control subjects. Our major findings were (1) Plasma levels of IL-7 were significantly increased in patients with stable (n=30) and unstable angina (n=30) comparing healthy control subjects (n=20), particularly in those with unstable disease. (2) Increased release from activated platelets appeared to be a major contributor to the raised IL-7 levels in patients with angina. (3) IL-7 enhanced the expression of several inflammatory chemokines in peripheral blood mononuclear cells from both healthy control subjects and patients with angina, particularly in those with unstable disease. Similar effects were seen in monocytes but not in T cells. (4) MIP-1α further increased the release of IL-7 from platelets in a dose-dependent manner. (5) Aspirin reduced both the spontaneous and the SFLLRN-stimulated release of IL-7 from platelets, and when administered to healthy control subjects for 7 days (160 mg qd), it reduced plasma levels of IL-7.

Conclusions—

Our findings suggest a role for IL-7-driven inflammation in atherogenesis and the promotion of clinical instability in coronary artery disease involving interactions between platelets, monocytes, and chemokines.
Cerebral Microembolism Is Blocked by Tirofiban, a Selective Nonpeptide Platelet Glycoprotein IIb/IIIa Receptor Antagonist
Authors: Junghans Ulrich , Siebler Mario
Published: May 2003

Background—

Microembolic signals (MES) as detected by transcranial Doppler ultrasound define an individual stroke risk in patients with carotid artery disease. To study the composition of MES in vivo, we used the glycoprotein IIb/IIIa (GPIIb/IIIa) receptor antagonist tirofiban, a highly selective platelet aggregation inhibitor.

Methods and Results—

Twenty-four patients with recent cerebral or retinal embolism of arterial origin and a MES rate >6 per hour on initial transcranial Doppler ultrasonography recording received the short-acting GPIIb/IIIa antagonist tirofiban. With tirofiban, the MES rate dropped from a median (range) of 38 (9 to 324) to zero in all patients. After cessation of infusion, the inhibitory effect of tirofiban was reversible, with a significant increase of MES (median 13.5; range, 0 to 35; n=16;
P
=0.001). Six patients received overlapping oral antiplatelet agents and remained MES-negative.

Conclusions—

Cerebral microembolism of arterial origin has the property of solid emboli, with platelet-fibrinogen units as predominant constituent parts. GPIIb/IIIa antagonists may have the potential to bridge the ischemic risk in patients with unstable carotid disease.
Cardiopulmonary Bypass to Repair an Atrial Septal Defect Does Not Affect Cognitive Function in Children
Authors: Stavinoha Peter L. , Fixler David E. , Mahony Lynn
Published: May 2003

Background—

Changes in neurocognitive function after cardiopulmonary bypass (CPB) are difficult to assess in children with congenital cardiovascular malformations in part because identification of a suitable control group of children is difficult.

Methods and Results—

We evaluated neurocognitive function in subjects aged 3 to 17 years both before and after surgical repair of an atrial septal defect (ASD). Eighteen subjects underwent testing within a median of 3 days (range, 1 to 27) before surgery and 5.8 months (range, 5.5 to 9) after surgery. The Differential Ability Scales was administered to subjects in a single testing session. All subjects were considered to be healthy, and they had no activity limitations. The mean General Conceptual Ability (GCA) scores (analogous to IQ) for the group were in the normal range before and after ASD repair. No significant difference was detected between the GCA scores before and after surgery. The GCA score was 90.8±18.6 before surgery and 93.1±16.3 after surgery.

Conclusions—

Use of CPB was not associated with changes in cognitive function in our subjects who underwent repair of an ASD.
Prognostic Role of Brain Natriuretic Peptide in Acute Pulmonary Embolism
Authors: Kucher Nils , Printzen Gert , Goldhaber Samuel Z.
Published: May 2003

Background—

Rapid, noninvasive, and accurate prognostic assessment with an inexpensive cardiac biomarker is an appealing approach for patients with acute pulmonary embolism (PE).

Methods and Results—

We measured at the time of admission the plasma level of plasma brain natriuretic peptide (BNP) to determine its utility in prognosticating the clinical course of 73 consecutive patients with acute PE. We used a prespecified BNP cut-off level (<90 pg/mL) for the prediction of the absence of a major adverse cardiovascular event, defined as any of the following: death, cardiopulmonary resuscitation, mechanical ventilation, or use of pressors, thrombolysis, catheter fragmentation, or surgical embolectomy. In the 20 (27%) patients with adverse events, median BNP (194.2, range 3.7 to 1201.1 pg/mL) was higher than in patients with a benign course (39.1, range 1.0 to 1560.0 pg/mL;
P
<0.001). However, 3 patients with adverse outcomes had low BNP levels on admission: 1 death, BNP 52 pg/mL; 1 patient with prolonged cardiopulmonary resuscitation, BNP 3.7 pg/mL; and 1 patient undergoing rescue thrombolysis, BNP 75 pg/mL. Sensitivity, specificity, and negative and positive predictive value of BNP levels <90 pg/mL for absence of adverse outcomes were 85% (64% to 95%), 75% (62% to 85%), 93% (95% CI 81% to 98%), and 57% (39% to 73%), respectively. The optimal BNP cut-off level, identified by receiver operating characteristic analysis, was <50 pg/mL.

Conclusions—

Low BNP levels do not guarantee an uncomplicated hospital course in patients with acute PE, using a “congestive heart failure” cut-off level of 90 pg/mL. A lower cut-off level of <50 pg/mL identifies 95% of patients with a benign clinical course.
Angiotensinogen Single Nucleotide Polymorphisms, Elevated Blood Pressure, and Risk of Cardiovascular Disease
Authors: Sethi Amar A. , Nordestgaard Børge G. , Grønholdt Marie-Louise M. , Steffensen Rolf , Jensen Gorm , Tybjærg-Hansen Anne
Published: May 2003

In this study of 10 690 individuals, associations with elevated blood pressure, ischemic heart disease, and ischemic cerebrovascular disease were determined for two noncoding [A(−20)C, G(−6)A] and two coding (T174M, M235T) single nucleotide polymorphisms, analyzed alone and in combination (haplotypes). Participants from the general population with (n=4950) and without (n=4234) elevated blood pressure were compared (study 1), as were participants from the general population without ischemic heart disease and ischemic cerebrovascular disease (n=7965) and cases with either ischemic heart disease (n=1850, study 2) or ischemic cerebrovascular disease (n=848, study 3). Finally, 22-year follow-up of 9184 individuals from the general population examined risk of ischemic heart disease (study 4) and ischemic cerebrovascular disease (study 5). Individuals with −6AA, 174TT, or 235TT had plasma angiotensinogen levels increased by 80 ng/mL (
P
=0.01 and 0.05 for women and men) compared with individuals with −6GG, 174TT, or 235 MM. In women, this difference was associated with an odds ratio of elevated blood pressure of 1.25 (1.03 to 1.51), which increased to 1.63 (1.05 to 2.51) in postmenopausal women receiving hormone replacement therapy. The promoter single nucleotide polymorphisms alone or as haplotypes did not predict the continuous variables of systolic, diastolic, or pulse pressure in cross section or the risk of ischemic heart disease or ischemic cerebrovascular disease in either gender in case-control or prospective studies. Individuals with −6AA, 174TT, or 235TT in the angiotensinogen gene have increased plasma angiotensinogen levels and moderately increased risk of elevated blood pressure (women only) but unaltered blood pressure examined as a continuous variable and unaltered risk of ischemic heart disease and ischemic cerebrovascular disease.
Influence of Vitamin C on Baroreflex Sensitivity in Chronic Heart Failure
Authors: Piccirillo Gianfranco , Nocco Marialuce , Moisè Antonio , Lionetti Marco , Naso Camilla , di Carlo Silvia , Marigliano Vincenzo
Published: May 2003

Chronic heart failure (CHF) reduces baroreflex sensitivity. Low baroreflex sensitivity, a risk factor for sudden death, could arise partly from CHF-dependent endothelial dysfunction. Vitamin C at high doses has a protective role against CHF-related endothelial damage. This study was conducted to investigate the effect of vitamin C on baroreflex sensitivity in CHF. A study group of 33 subjects with CHF secondary to postischemic dilated cardiomyopathy with an ejection fraction ≤35% and a control group (11 subjects) underwent assessment of baroreflex sensitivity by the phenylephrine method and an autonomic nervous system study by power spectral analysis. Variables were assessed after infusion of placebo and high doses of vitamin C (2.5 mg). In subjects with CHF, baroreflex sensitivity was significantly higher after vitamin C than after placebo infusion (placebo: 4.1±0.4 versus vitamin C: 5.3±0.5 ms/mm Hg,
P
<0.001). Low-frequency of R-R (LF
RR
), expressed in normalized units (NU) (
P
<0.05); LF/high-frequency (HF) ratio (
P
<0.05), and LF of SBP (LF
SBP
) decreased significantly; HF power (
P
<0.05), and α-HF (
P
<0.001) increased. Conversely, in the control group, baroreflex sensitivity and other spectral variables measured at baseline, after placebo, and after vitamin C infusion remained statistically unchanged (placebo: 10.2±0.1 versus vitamin C: 10.0±0.2 ms/mm Hg, NS). Acute administration of vitamin C at high doses improves baroreflex sensitivity and vagal sinus modulation in patients with CHF. This finding could have notable clinical and therapeutic implications. Key issues to understand are whether the beneficial effect persists during chronic administration and whether it helps to improve survival.
Functional Neuroimaging Studies of Motor Recovery After Stroke in Adults
Authors: Calautti Cinzia , Baron Jean-Claude
Published: May 2003

Background—

The precise mechanisms of and biological basis for motor recovery after stroke in adults are still largely unknown. Reorganization of the motor system after stroke as assessed by functional neuroimaging is an intriguing but challenging new field of research. Provocative but equivocal findings have been reported to date.

Summary of Review—

We present an overview of functional neuroimaging studies (positron emission tomography or functional MRI) of motor tasks in patients recovered or still recovering from motor deficit after stroke. After a brief account of the connectivity of motor systems and the imaging findings in normal subjects, the literature concerning stroke patients is reviewed and discussed, and a general model is proposed.

Conclusions—

Both cross-sectional and longitudinal studies have demonstrated that the damaged adult brain is able to reorganize to compensate for motor deficits. Rather than a complete substitution of function, the main mechanism underlying recovery of motor abilities involves enhanced activity in preexisting networks, including the disconnected motor cortex in subcortical stroke and the infarct rim after cortical stroke. Involvement of nonmotor and contralesional motor areas has been consistently reported, with the emerging notion that the greater the involvement of the ipsilesional motor network, the better is the recovery. This hypothesis is supported by the enhanced activity of the ipsilesional primary motor cortex induced by motor training and acute pharmacological interventions, in parallel with improved motor function. Further longitudinal studies assessing the relationships between such changes and actual recovery, as well as manipulating such changes by rehabilitation or pharmacological maneuvers, should provide further information on these fundamental questions. This review closes with some perspectives for future research.