bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular Typing of
Clostridium perfringens
from a Food-Borne Disease Outbreak in a Nursing Home: Ribotyping versus Pulsed-Field Gel Electrophoresis
Authors: Schalch Barbara , Bader Lutz , Schau Hans-Peter , Bergmann Rolf , Rometsch Andrea , Maydl Gertraud , Keßler Silvia
Published: February 2003

In 1998, 21 inhabitants of a German nursing home fell ill with acute gastroenteritis after consumption of minced beef heart (P. Graf and L. Bader, Epidemiol. Bull. 41:327-329, 2000). Two residents died during hospital treatment. Seventeen
Clostridium perfringens
strains were collected from two different dishes and from patients' stool samples and autopsy materials. A majority of these isolates was not typeable by restriction fragment length polymorphism-pulsed-field gel electrophoresis (PFGE). Subsequent ribotyping of
C. perfringens
distinguished four different groups. The same ribopattern was detected in a minced beef heart dish, in autopsy material from the two deceased patients, and additionally in stool samples from six further residents who had fallen ill with diarrhea. Three further ribopatterns from food and autopsy materials could be differentiated. As chromosomal macrorestriction with subsequent PFGE is generally regarded more useful than ribotyping for molecular strain analysis, four selected isolates were lysed in parallel with a standard protocol and two nucleases inhibiting modifications. Neither of these methods could differentiate all of the isolates. These results suggest that PFGE with the current standard protocols is not able to characterize all
C. perfringens
isolates from food-borne disease investigations and that ribotyping is still a helpful method for molecular identification of clonal relationships.
Identification and Quantification of Ovine Gammaherpesvirus 2 DNA in Fresh and Stored Tissues of Pigs with Symptoms of Porcine Malignant Catarrhal Fever
Authors: Albini Sarah , Zimmermann Werner , Neff Felix , Ehlers Bernhard , Häni Hansjürg , Li Hong , Hüssy Daniela , Engels Monika , Ackermann Mathias
Published: February 2003

Cases of porcine malignant catarrhal fever were analyzed by a combination of identification and quantitation of ovine gammaherpesvirus 2 DNA in a variety of paraffin-embedded tissues from diseased pigs, serology, and exclusion of primary porcine gammaherpesviruses. In spite of reduced signal due to fixation and paraffin embedding, ovine gammaherpesvirus 2 DNA in pig brains exceeded the amounts found in sheep brains by orders of magnitude.
Nocardia africana
Isolated from a Feline Mycetoma
Authors: Hattori Yousuke , Kano Rui , Kunitani Yasuko , Yanai Tokuma , Hasegawa Atsuhiko
Published: February 2003

Nocardia africana
was isolated from a subcutaneous nodule of a cat. The isolate developed orange, wrinkled colonies. The bacteria were rod shaped to coccoid (1 by 5 μm) and gram positive. Analysis of the 16S ribosomal DNAs of the isolate and a reference strain of
N. africana
showed 100% homology.
GENERATION-RECOMBINATION AND 1/f NOISE IN Al0.4Ga0.6N THIN FILMS
Authors: PALA N. , RUMYANTSEV S. , SHUR M. , GASKA R. , HU X. , YANG J. , SIMIN G. , KHAN M. A.
Published: February 2003

Low-frequency noise in Al 0.4 Ga 0.6 N thin films (50 nm) was measured at room and elevated temperatures as function of gate and drain voltages. Both 1/f noise and generation-recombination noise were observed. Hooge parameter, α, was estimated to be about 7. The activation energy for observed generation-recombination noise was found to be Ea ~ 1.0 eV . This activation energy is consistent with the activation energy observed for g-r noise in AlGaN/GaN HFETs.
PLAYING PRISONER'S DILEMMA WITH QUANTUM RULES
Authors: DU JIANGFENG , XU XIAODONG , LI HUI , ZHOU XIANYI , HAN RONGDIAN
Published: February 2003

Quantum game theory is a recently developing field of physical research. In this paper, we investigate quantum games in a systematic way. With the famous instance of the Prisoner's Dilemma, we present the fascinating properties of quantum games in different conditions, i.e. different number of the players, different strategic space of the players and different amount of the entanglement involved.
AN EXPLORATORY STUDY OF PROJECT VISION: ITS COMPONENTS AND IMPACT ON INNOVATION SUCCESS
Authors: LYNN GARY S.
Published: February 2003

The concept of corporate vision has been receiving considerable attention in the strategy scholarship. A clear and lofty organisational vision can provide direction to a company and can positively impact on its ability to succeed. Yet research on vision at the project level has been curiously lacking. The purpose of this research is to define project vision, discuss its components and its impact on successful new product development. By studying the vision on a series of innovations at one company (IBM), we identified several components of an effective vision that include clarity, agreement, support and stability. This article concludes with an assessment of the applicability of these vision components for the extreme form of innovation called radical innovation.
ON THE CHARACTERISTICS OF INNOVATIVE FIRMS IN KOREA: THE ROLE OF R&D AND INNOVATION TYPE
Authors: PARK YONG-TAE , KIM CHUL-HYUN , LEE JI-HYO
Published: February 2003

In spite of the recent extension of our knowledge on technological innovation, little inquiry has been made of the distinctive characteristics between R&D firms and non-R&D firms, as well as between product-innovative firms and process-innovative firms. To this end, the main objective of this empirical study, grounded on a large-scale innovation survey of Korean manufacturing firms, is to contrast these two types of firms. The results were mixed. Some hypotheses were confirmed while others were discordant with expectation. By and large, R&D firms and product-innovative firms seem to share a similar propensity, whereas non-R&D firms and process-innovative firms are alike in character. However, there were some unexpected findings which merit attention and are worthy of in-depth examination. Although the study is subject to limitations in terms of its research design and data gathering, the results render some important policy implications. Furthermore, comparative analyses between different types of innovations need to be addressed more extensively in future research.
BRIDGING EAST AND WEST TO DEVELOP NEW PRODUCTS AND TRUST: INTERDEPENDENCE AND INTERACTION BETWEEN A HONG KONG PARENT AND NORTH AMERICAN SUBSIDIARY
Authors: TJOSVOLD DEAN
Published: February 2003

Trusting relationships have been theorised to be critical for specialists to work together but little research has clarified how trust can be fostered. Deutsch's theory of cooperation and competition was used to examine how trust is developed among new product specialists based in the Hong Kong parent and its Canadian subsidiary. Effective conflict management may be critical for both the innovation needed to create new products and for trust. The study proposes that trust is tested and strengthened when people disagree with each other openly and use each other's ideas to be more productive. Results indicate that cooperative goals contribute to an open-minded discussion of views that lead to productive collaborative work, which in turn, results in trust.
OPERATIONALISING KNOWLEDGE MANAGEMENT CONCEPTS: THE DEVELOPMENT OF A TECHNIQUE FOR SHARING KNOWLEDGE IN NEW PRODUCT DEVELOPMENT PROJECTS
Authors: HALL RICHARD , ANDRIANI PIERPAOLO
Published: February 2003

This paper will summarise some of the main concepts and theories which have been developed in the area of Knowledge Management and will adapt these to develop a new technique for sharing knowledge in a new product development project. The bulk of the literature on Knowledge Management has been concerned with concepts and theory, there is relatively little concerned with the operationalisation of the concepts. This paper will report the results of the testing of a new technique in an ex post case study which was carried out at Flymo Ltd. The research project has been funded by the Engineering & Physical Sciences Research Council (EPSRC).
Antihypertensive Treatments Obscure Familial Contributions to Blood Pressure Variation
Authors: Cui Jisheng S. , Hopper John L. , Harrap Stephen B.
Published: February 2003

The linkage and association between inherent blood pressure and underlying genotype is potentially confounded by antihypertensive treatment. We estimated blood pressure variance components (genetic, shared environmental, individual-specific) in 767 adult volunteer families by using a variety of approaches to adjusting blood pressure of the 244 subjects (8.2%) receiving antihypertensive medications. The additive genetic component of variance for systolic pressure was 73.9 mm Hg
2
(SE, 8.8) when measured pressures (adjusted for age by gender within each generation) were used but fell to 61.4 mm Hg
2
(SE, 8.0) when treated subjects were excluded. When the relevant 95th percentile values were substituted for treated systolic pressures, the additive genetic component was 81.9 mm Hg
2
(SE, 9.5), but individual adjustments in systolic pressure ranged from −53.5 mm Hg to +64.5 mm Hg (mean, +17.2 mm Hg). Instead, when 10 mm Hg was added to treated systolic pressure, the additive genetic component rose to 86.6 mm Hg
2
(SE, 10.1). Similar changes were seen in the shared environment component of variance for systolic pressure and for the combined genetic and shared environmental (ie, familial) components of diastolic pressure. There was little change in the individual-specific variance component across any of the methods. Therefore, treated subjects contribute important information to the familial components of blood pressure variance. This information is lost if treated subjects are excluded and obscured by treatment effects if unadjusted measured pressures are used. Adding back an appropriate increment of pressure restores familial components, more closely reflects the pretreatment values, and should increase the power of genomic linkage and linkage disequilibrium analyses.
Radical-Trapping Activity, Blood Pressure, and Carotid Enlargement in Women
Authors: Iannuzzi Arcangelo , De Michele Mario , Panico Salvatore , Celentano Egidio , Tang Rong , Bond M. Gene , Sacchetti Lucia , Zarrilli Federica , Galasso Rocco , Mercuri Michele , Rubba Paolo
Published: February 2003

The aim of this study was to evaluate the influence of traditional and nontraditional (oxidation markers) cardiovascular risk factors on the degree of adaptive response of the carotid wall to atherosclerotic disease, a process known as arterial enlargement. Five thousand sixty-two clinically healthy, middle-aged women living in the area of Naples participated in the “Progetto Atena” study; 310 of these women (potentially at higher atherosclerotic risk) underwent a high-resolution ultrasound scan of the carotid arteries. In addition to routine biochemical tests, these women had the determination of serum IgG antibody titer against oxidized LDL and measurement of thiobarbituric acid reactive substances and total radical-trapping activity potential of plasma. Age, systolic blood pressure, body mass index, and radical-trapping activity were all positively correlated with external and internal common carotid diameters, whereas triglycerides (positively) and HDL cholesterol (inversely) were related only to external diameter. After controlling for traditional cardiovascular risk factors, associations still persisted for age, systolic blood pressure, and plasma radical-trapping activity with external carotid diameters. However, in the quartile of women with highest total cholesterol (>7.38 mmol/L), the slope of the regression line between systolic blood pressure and external diameter was significantly flatter than in the three other quartiles (test for difference,
P
=0.014). Outward carotid enlargement is related to traditional and nontraditional risk factors and comes even before plaque development. Women with poor resistance to oxidative stress potentially have a difficulty to remodel their arteries in response to atherosclerotic stimuli.
Coronary Vasodilator Capacity and Hypertension-Induced Increase in Left Ventricular Mass
Authors: Kozàkovà Michaela , de Simone Giovanni , Morizzo Carmela , Palombo Carlo
Published: February 2003

An increase in left ventricular mass represents a compensatory response of hypertensive heart to augmented loading conditions. The concept of inappropriate mass has been proposed to define an increase in left ventricular mass higher than needed to compensate for increased workload. To assess whether inappropriate left ventricular mass is associated with more severe impairment of coronary vasodilator capacity, 64 untreated middle-aged hypertensive patients without significant coronary artery stenosis and 14 normotensive volunteers comparable for age and gender were studied by transthoracic and transesophageal echocardiography to evaluate left ventricular mass, geometry, and coronary flow velocity response to adenosine. Thirty-three patients had appropriate and 31 had inappropriate increase in left ventricular mass, whereas all normotensive control subjects had appropriate left ventricular mass. Compared with control subjects, minimum coronary resistance (0.87±0.18 mm Hg per second/centimeter) was increased in both hypertensive subgroups, more in those with inappropriate left ventricular mass (1.34±0.23 versus 1.19±0.23 mm Hg per second/centimeter,
P
<0.01), who also exhibited lower afterload-corrected midwall shortening and ratio of peak early and peak late velocities of transmitral flow profile. In hypertensive patients, minimum coronary resistance was related positively to absolute and relative left ventricular wall thickness (
r
=+0.33 and +0.35, both
P
<0.01) and negatively to midwall shortening and ratio of peak early and peak late velocities of transmitral flow (
r
=−0.32 and −0.31, both
P
<0.02). Thus, in the hypertensive heart, a deviation of left ventricular mass from values compensatory for increased cardiac workload is associated with lower coronary vasodilator capacity, depressed left ventricular wall mechanics, and abnormal left ventricular diastolic filling pattern.
Effects of Severe Hypertension on Endothelial and Platelet Microparticles
Authors: Preston Richard A. , Jy Wenche , Jimenez Joaquin J. , Mauro Lucia M. , Horstman Lawrence L. , Valle Madelyn , Aime Gerard , Ahn Yeon S.
Published: February 2003

The molecular mechanisms by which extreme blood pressure elevation leads to vascular injury are not defined. To explore the hypothesis that activation of endothelium and platelets as manifested by increased concentrations of circulating endothelial microparticles and platelet microparticles could play a role in this target organ injury, we conducted a cross-sectional study of these markers in 3 groups: (1) untreated patients referred specifically for treatment of severe uncontrolled hypertension; (2) untreated patients with established mild hypertension; and (3) normotensive volunteer subjects. By ANOVA, endothelial (
P
=0.002) and platelet (
P
=0.01) microparticles were greatest in the severely hypertensive group. There was a significant correlation between both of these markers and blood pressure, even in the setting of multiple risk factors. Our results suggest that these markers may be useful and specific for pressure-induced endothelial and platelet activation in hypertension. Furthermore, because of the combined effects of endothelial and platelet microparticles on coagulation, leukocytes, and endothelium, it is possible that they may play a pathogenic role in mediating target organ injury in severe hypertension.
Haplotype Analysis of the Human Renin Gene and Essential Hypertension
Authors: Hasimu Buaijiaer , Nakayama Tomohiro , Mizutani Yoshihiro , Izumi Yoichi , Asai Satoshi , Soma Masayoshi , Kokubun Shinichiro , Ozawa Yukio
Published: February 2003

The human renin gene is an attractive candidate for involvement in the underlying cause of essential hypertension (EH). Despite extensive examination, the relation between the renin gene and hypertension remains unclear. The aims of the present study were to discover new genetic markers of EH and to investigate the relations between polymorphisms of the renin gene and EH in the Japanese. Using the polymerase chain reaction–single strand conformation polymorphism (PCR-SSCP) method, we isolated 3 novel variants of the renin gene; a single nucleotide polymorphism (SNP) in intron 4 (T+17int4G), a variable number of tandem repeats (VNTR) polymorphism in intron 7, and a missense mutation in exon 9 (G1051A). We performed an association study with these polymorphisms in 212 patients with EH and 209 age-matched normotensive (NT) subjects. The frequency of genotypes VNTR and T+17int4G did not differ significantly between the 2 groups, whereas the overall distribution of G1051A was significantly different between EH and NT. Haplotype analysis revealed that the overall distribution of haplotypes differed significantly between the EH and NT groups. PRA levels in patients with EH with the G/G genotype were significantly higher than in subjects with EH with G/A and A/A genotypes. These data suggest that the missense mutation in exon 9 may affect the enzymatic function of renin and consequently may be involved in the etiology of hypertension.
Prenatal Dexamethasone Programs Hypertension and Renal Injury in the Rat
Authors: Ortiz Luis A. , Quan Albert , Zarzar Francisco , Weinberg Arthur , Baum Michel
Published: February 2003

Dexamethasone is frequently administered to the developing fetus to accelerate pulmonary development. The purpose of the present study was to determine if prenatal dexamethasone programmed a progressive increase in blood pressure and renal injury in rats. Pregnant rats were given either vehicle or 2 daily intraperitoneal injections of dexamethasone (0.2 mg/kg body weight) on gestational days 11 and 12, 13 and 14, 15 and 16, 17 and 18, or 19 and 20. Offspring of rats administered dexamethasone on days 15 and 16 gestation had a 20% reduction in glomerular number compared with control at 6 to 9 months of age (22 527±509 versus 28 050±561,
P
<0.05), which was comparable to the percent reduction in glomeruli measured at 3 weeks of age. Six- to 9-month old rats receiving prenatal dexamethasone on days 17 and 18 of gestation had a 17% reduction in glomeruli (23 380±587) compared with control rats (
P
<0.05). Male rats that received prenatal dexamethasone on days 15 and 16, 17 and 18, and 13 and 14 of gestation had elevated blood pressures at 6 months of age; the latter group did not have a reduction in glomerular number. Adult rats given dexamethasone on days 15 and 16 of gestation had more glomeruli with glomerulosclerosis than control rats. This study shows that prenatal dexamethasone in rats results in a reduction in glomerular number, glomerulosclerosis, and hypertension when administered at specific points during gestation. Hypertension was observed in animals that had a reduction in glomeruli as well as in a group that did not have a reduction in glomerular number, suggesting that a reduction in glomerular number is not the sole cause for the development of hypertension.
Mice Lacking Endothelial ACE
Authors: Cole Justin M. , Khokhlova Nata , Sutliff Roy L. , Adams Jonathan W. , Disher Kevin M. , Zhao Hui , Capecchi Mario R. , Corvol Pierre , Bernstein Kenneth E.
Published: February 2003

Recently, the concept of local renin-angiotensin systems (RAS) capable of generating angiotensin II apart from the circulation has received considerable attention. To investigate this, we generated ACE 1/3 mice in which one allele of ACE is null and the second allele was engineered to express ACE on the surface of hepatocytes. ACE 1/3 mice express no endothelial ACE and lack ACE within the lungs. Their kidneys contain <7.8% the enzyme levels present in control mice. Plasma conversion of angiotensin I to angiotensin II was 43.3% normal. The baseline blood pressure and renal function of the ACE 1/3 mice were normal, probably as a function of a marked increase of both plasma angiotensin I and angiotensin II. When exposed to 2 weeks of a salt-free diet (a stress diet stimulating the RAS), blood pressure in ACE 1/3 mice decreased to 92.3±2.0 mm Hg, a level significantly lower than that of wild-type control mice. The ACE 1/3 mice demonstrate the plasticity of the RAS and show that significant compensation is required to maintain normal, basal blood pressure in a mouse with an impaired local vascular and renal RAS.
Lipid Peroxidation Is Not Increased in Patients With Untreated Mild-to-Moderate Hypertension
Authors: Cracowski Jean-Luc , Baguet Jean-Philippe , Ormezzano Olivier , Bessard Janine , Stanke-Labesque Françoise , Bessard Germain , Mallion Jean-Michel
Published: February 2003

In contrast with the huge amount of experimental data available, only few and somewhat unconvincing clinical studies support the hypothesis that oxidative stress is involved in the early stages of essential hypertension in humans. Isoprostanes are chemically stable lipid peroxidation products of arachidonic acid, the quantification of which provides a novel approach to the assessment of oxidative stress in vivo. The main objective of this study was to quantify the urinary levels of 15-F
2t
-IsoP in the early stages of essential hypertension, using gas chromatography/mass spectrometry, by comparing 30 patients with never-treated mild-to-moderate hypertension with 30 gender- and age-paired healthy controls. Urinary 15-F
2t
-IsoP levels were not significantly different in hypertensive patients (69±36 pmol/mmol creatinine) compared with controls (75±34 pmol/mmol creatinine, 95% confidence intervals on differences: −23 to 13). No significant correlation was found between basal urinary 15-F
2t
-IsoP levels and age, low-density lipoprotein cholesterol, glucose, clinical pulse pressure, carotid intima-media thickness, left ventricular mass index, or aortic pulse wave velocity. In conclusion, this study shows that lipid peroxidation is not increased in never-treated mild-to-moderate hypertension. This suggests that oxidative stress is not implicated in the pathogenesis of human essential hypertension, at least in the early stages.
Guanylyl Cyclase Receptors Mediate Cardiopulmonary Vagal Reflex Actions of ANP
Authors: Thomas Colleen J. , Woods Robyn L.
Published: February 2003

Atrial natriuretic peptide (ANP) potentiates vagal cardiopulmonary reflexes due to chemosensory (Bezold-Jarisch [B-J] reflex) or mechanosensory (ramp baroreflex) activation. The ANP receptor mediating these actions is unknown. We examined the role of particulate guanylyl-cyclase (pGC) receptors in ANP-induced enhancement of cardiopulmonary vagal reflexes. Cardiopulmonary baroreceptor reflex function was assessed by bradycardic responses to ramp blood pressure rises after rapid intravenous methoxamine (100 μg/kg bolus dose). The B-J reflex was evoked by 3 intravenous doses of serotonin (1 to 10 μg/kg). In conscious, chronically instrumented rats (n=9), these tests were performed on each animal during randomized infusions of rat ANP (150 ng/kg per minute IV), saline (270 μL/h IV), the pGC receptor antagonist HS-142-1 (3 mg/kg IV), or combined HS-142-1+ANP treatment. HS-142-1 alone attenuated normal B-J reflex (by 33±8%,
P
<0.05) but not ramp baroreflex responses. As we showed previously, ANP enhanced baroreflex and B-J reflex bradycardia (by ≈140% and ≈30%, respectively,
P
<0.05), compared with saline infusion. These ANP effects were completely blocked by HS-142-1, demonstrating that the cardiopulmonary vagal reflex actions of ANP occurred through pGC natriuretic peptide receptors. Additionally, we have provided evidence for the first time that pGC natriuretic peptide receptors are essential for the full expression of the B-J reflex but not for that of cardiopulmonary vagal baroreflexes. This tonic interaction between pGC natriuretic peptide receptors and cardiopulmonary chemosensitive receptors may be important during pathophysiological activation of B-J reflex, such as with myocardial infarction.
Blood Pressure Response to Hyperventilation Test Reflects Daytime Pressor Profile
Authors: Fontana Fiorella , Bernardi Pasquale , Lanfranchi Giuseppina , Pisati Maria Sole , Merlo Pich Emilio
Published: February 2003

Recent studies show that healthy subjects and patients with moderate hypertension have different pressor responses to hyperventilation, depending on their sympathoadrenergic reactivity. In the present study, we investigated whether a different response to the hyperventilation test is related to differences in the daily blood pressure profiles recorded with noninvasive ambulatory monitoring. Forty-five healthy subjects and 67 patients with essential hypertension of grades 1 and 2 (Joint National Committee VI and World Health Organization) were investigated. Healthy subjects and hypertensive patients responding to hyperventilation with an increase in systolic blood pressure had, during daytime ambulatory blood pressure assessment, peak systolic blood pressure values (146.0±5.0 mm Hg, 182.2±9.0 mm Hg, respectively) similar to the hyperventilation peak systolic blood pressure values (147.2±3.5 mm Hg, 183.0±4.7 mm Hg, respectively). Hypertensive patients responding to hyperventilation with a decrease in blood pressure showed clinic systolic blood pressure values (178.4±3.2 mm Hg) higher than daytime average ambulatory systolic blood pressure (155.2±7.1 mm Hg;
P
<0.01). Our results indicate that a hyperventilation test yields information on daily peak blood pressure values in healthy subjects and hypertensive patients when it induces a pressor increase and can identify hypertensive patients with the so-called “white coat effect” when it induces a pressor decrease.
Differential Actions of Cardioprotective Agents on the Mitochondrial Death Pathway
Authors: Akao Masaharu , O’Rourke Brian , Kusuoka Hideo , Teshima Yasushi , Jones Steven P. , Marbán Eduardo
Published: February 2003

We examined the effect of cardioprotective agents on three distinct phases of the H
2
O
2
-induced response that leads to loss of mitochondrial membrane potential (ΔΨ
m
) and cell death in cultured cardiac myocytes: (1) priming, consisting of calcium-dependent morphological changes in mitochondria (swelling and loss of cristae), with preserved ΔΨ
m
, (2) depolarization, the rapid ΔΨ
m
depolarization caused by mitochondrial permeability transition pore (PTP) opening, and (3) cell fragmentation. The mitochondrial ATP-sensitive potassium (mitoK
ATP
) channel opener diazoxide markedly decreased the likelihood that cells would undergo priming: many mitochondria remained fully polarized and morphologically intact. Diazoxide not only decreased the number of cells undergoing ΔΨ
m
depolarization but also delayed the onset of ΔΨ
m
loss, whereas it did not change the duration of depolarization in unprotected cells. The adenine nucleotide translocase inhibitor bongkrekic acid mimicked the effect of diazoxide to suppress priming, except that its effects were not blocked by the mitoK
ATP
channel blocker 5-hydroxydecanoate. In contrast, the PTP inhibitor cyclosporin A (CsA) did not prevent priming: neither latency for ΔΨ
m
depolarization nor mitochondrial morphological changes were affected. However, CsA slowed the process of depolarization and blunted its severity. Importantly, coapplication of diazoxide and CsA exhibited additive effects, improving the efficacy of protection. Activation of mitoK
ATP
channels suppresses the cell death process at its earliest stage, by preserving mitochondrial integrity during oxidative stress. By virtue of its pharmacology and its phenotypic consequences, this mode of action is distinguishable from that of other cardioprotective interventions.
Insulin-Like Growth Factor-1 Exerts Ca
2+
-Dependent Positive Inotropic Effects in Failing Human Myocardium
Authors: von Lewinski Dirk , Voß Kerstin , Hülsmann Swen , Kögler Harald , Pieske Burkert
Published: February 2003

Myocardial generation of insulin-like growth factor-1 (IGF-1) is altered in hypertrophy and heart failure, but there are no reports on acute functional effects of IGF-1 in human cardiac muscle. We examined inotropic responses and signal transduction mechanisms of IGF-1 in human myocardium. Experiments were performed in isolated trabeculae or cardiomyocytes from 46 end-stage failing hearts. The effect of IGF-1 (0.001 to 0.2 μmol/L) on isometric twitch force (37°C, 1 Hz), intracellular Ca
2+
transients (aequorin method), sarcoplasmic reticulum (SR) Ca
2+
content (rapid cooling contractures), L-type Ca
2+
current (whole-cell voltage clamp), and cAMP concentrations was assessed. In addition, the effects of blocking IGF-1 receptors, phosphoinositide 3-kinase (PI3-kinase), protein kinase C (PKC), or transsarcolemmal Ca
2+
entry were tested. IGF-1 exerted concentration-dependent positive inotropic effects (twitch force increased to maximally 133±4% of baseline values at 0.1 μmol/L;
P
<0.05). The IGF-1 receptor antibody αIR3 or the PI3-kinase inhibitor wortmannin prevented the functional effects. The inotropic response was paralleled by increases in Ca
2+
transients and SR Ca
2+
content. IGF-1 (0.1 μmol/L) increased L-type Ca
2+
current amplitude by 24±7% (
P
<0.05). Blockade of SR function did not affect the inotropic response to IGF-1. In contrast, L-type Ca
2+
channel blockade with diltiazem partially prevented (≈50%) the inotropic response to IGF-1. Inhibition of PKC (GF109203X), Na
+
-H
+
exchange (HOE642), or reverse-mode Na
+
-Ca
2+
exchange (KB-R7943) reduced the response to IGF-1 by ≈60% to 70%. IGF-1 exerts Ca
2+
-dependent positive inotropic effects through activation of IGF-1 receptors and a PI3-kinase-dependent pathway in failing human myocardium. The increased [Ca
2+
]
i
with IGF-1 originates from both enhanced L-type Ca
2+
currents and enhanced Na
+
-H
+
exchange-dependent reverse-mode Na
+
-Ca
2+
exchange. These nongenomic functional effects of IGF-1 may be of clinical relevance.
Selective Matrix Metalloproteinase Inhibition With Developing Heart Failure
Authors: King Mary K. , Coker Mytsi L. , Goldberg Aaron , McElmurray James H. , Gunasinghe Himali R. , Mukherjee Rupak , Zile Michael R. , O’Neill Timothy P. , Spinale Francis G.
Published: February 2003

The matrix metalloproteinases (MMPs) are an endogenous family of proteolytic enzymes implicated to contribute to LV remodeling. However, broad-spectrum MMP inhibition (MMPi), particularly inhibition of interstitial collagenase (MMP-1), may not be clinically applicable. This study examined the effects of selective MMPi (sparing MMP-1) in a model of developing congestive heart failure. Pigs were randomly assigned to 3 groups: (1) rapid pacing for 3 weeks (240 bpm, n=10); (2) selective MMPi (20 mg/kg per day-PO;PGE7113313) and rapid pacing (n=12); and (3) controls (n=10). LV peak wall stress increased from controls with rapid pacing (140±6 versus 319±18 g/cm
2
;
P
<0.05) and was reduced with selective MMPi (208±9 g/cm
2
;
P
<0.05. Preload recruitable stroke work was reduced with rapid pacing (4.3±0.4 versus 1.2±0.2 dyne · cm/mm Hg;
P
<0.05) and was increased with selective MMPi (2.6±0.3 dyne · cm/mm Hg;
P
<0.05). Plasma norepinephrine increased by 6-fold in the rapid pacing group (
P
<0.05) and was reduced from untreated values with selective MMPi (
P
<0.05). At the myocardial level, myocyte cross-sectional area was increased with selective MMPi but fibrillar collagen volume fraction remained unchanged relative to control values. These results suggest that targeting a selective portfolio of myocardial MMP species for inhibition may provide a more rational therapeutic strategy in the setting of congestive heart failure.
Mimicking Phosphorylation of αB-Crystallin on Serine-59 Is Necessary and Sufficient to Provide Maximal Protection of Cardiac Myocytes From Apoptosis
Authors: Morrison Lisa E. , Hoover Holly E. , Thuerauf Donna J. , Glembotski Christopher C.
Published: February 2003

αB-Crystallin (αBC), a small heat shock protein expressed in high levels in the heart, is phosphorylated on Ser-19, 45, and 59 after stress. However, it is not known whether αBC phosphorylation directly affects cell survival. In the present study, constructs were prepared that encode forms of αBC harboring Ser to Ala (blocks phosphorylation) or Ser to Glu (mimics phosphorylation) mutations at positions 19, 45, and 59. The effects of each form on apoptosis of cultured cardiac myocytes after hyperosmotic or hypoxic stress were assessed. Compared with controls, cells that expressed αBC with Ser to Ala substitutions at all three positions, αBC(AAA), exhibited more stress-induced apoptosis. Cells expressing either αBC(AAE) or (EEE) exhibited 3-fold less apoptosis than cells expressing αBC(AAA), indicating that phosphorylation of Ser-59 confers protection. αBC is known to bind to procaspase-3 and to decrease caspase-3 activation. Compared with cells expressing αBC(AAA), the activation of caspase-3 was decreased by 3-fold in cells expressing αBC(AAE). These results demonstrate that mimicking the phosphorylation of αBC on Ser-59 is necessary and sufficient to confer caspase-3 inhibition and protection of cardiac myocytes against hyperosmotic or hypoxic stress. These findings provide direct evidence that αBC(S59P) contributes to the cardioprotection observed after physiologically relevant stresses, such as transient hypoxia. Identifying the targets of αBC(S59P) will reveal important details about the mechanism underlying the cytoprotective effects of this small heat shock protein.
Microarray Analysis Reveals Complex Remodeling of Cardiac Ion Channel Expression With Altered Thyroid Status
Authors: Bouter Sabrina Le , Demolombe Sophie , Chambellan Arnaud , Bellocq Chloé , Aimond Franck , Toumaniantz Gilles , Lande Gilles , Siavoshian Sepideh , Baró Isabelle , Pond Amber L. , Nerbonne Jeanne M. , Léger Jean J. , Escande Denis , Charpentier Flavien
Published: February 2003

Although electrophysiological remodeling occurs in various myocardial diseases, the underlying molecular mechanisms are poorly understood. cDNA microarrays containing probes for a large population of mouse genes encoding ion channel subunits (“IonChips”) were developed and exploited to investigate remodeling of ion channel transcripts associated with altered thyroid status in adult mouse ventricle. Functional consequences of hypo- and hyperthyroidism were evaluated with patch-clamp and ECG recordings. Hypothyroidism decreased heart rate and prolonged QTc duration. Opposite changes were observed in hyperthyroidism. Microarray analysis revealed that hypothyroidism induces significant reductions in KCNA5, KCNB1, KCND2, and KCNK2 transcripts, whereas KCNQ1 and KCNE1 expression is increased. In hyperthyroidism, in contrast, KCNA5 and KCNB1 expression is increased and KCNQ1 and KCNE1 expression is decreased. Real-time RT-PCR validated these results. Consistent with microarray analysis, Western blot experiments confirmed those modifications at the protein level. Patch-clamp recordings revealed significant reductions in
I
to,f
and
I
K,slow
densities, and increased
I
Ks
density in hypothyroid myocytes. In addition to effects on K
+
channel transcripts, transcripts for the pacemaker channel HCN2 were decreased and those encoding the α1C Ca
2+
channel (CaCNA1C) were increased in hypothyroid animals. The expression of Na
+
, Cl
−
, and inwardly rectifying K
+
channel subunits, in contrast, were unaffected by thyroid hormone status. Taken together, these data demonstrate that thyroid hormone levels selectively and differentially regulate transcript expression for at least nine ion channel α- and β-subunits. Our results also document the potential of cDNA microarray analysis for the simultaneous examination of ion channel transcript expression levels in the diseased/remodeled myocardium.
Peroxisome Proliferator-Activated Receptor α Reduces Cholesterol Esterification in Macrophages
Authors: Chinetti G. , Lestavel S. , Fruchart J.-C. , Clavey V. , Staels B.
Published: February 2003

Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor activated by fatty acid derivatives and hypolipidemic drugs of the fibrate class. PPARα is expressed in monocytes, macrophages, and foam cells, suggesting a role for this receptor in macrophage lipid homeostasis with consequences for atherosclerosis development. Recently, it was shown that PPARα activation promotes cholesterol efflux from macrophages via induction of the ABCA1 pathway. In the present study, the influence of PPARα activators on intracellular cholesterol homeostasis was investigated. In human macrophages and foam cells, treatment with fibrates, synthetic PPARα activators, led to a decrease in the cholesteryl ester (CE):free cholesterol (FC) ratio. In these cells, PPARα activation reduced cholesterol esterification rates and Acyl-CoA:cholesterol acyltransferase-1 (ACAT1) activity. However, PPARα activation did not alter ACAT1 gene expression, whereas mRNA levels of carnitine palmitoyltransferase type 1 (CPT-1), a key enzyme in mitochondrial fatty acid catabolism, were induced. Finally, PPARα activation blocked CE formation induced by TNF-α, possibly due to the inhibition of neutral sphingomyelinase activation by TNF-α. In conclusion, our results identify a role for PPARα in the control of cholesterol esterification in macrophages, resulting in an enhanced availability of FC for efflux through the ABCA1 pathway.
Role for Hydrogen Peroxide in Flow-Induced Dilation of Human Coronary Arterioles
Authors: Miura Hiroto , Bosnjak John J. , Ning Gang , Saito Takashi , Miura Mamoru , Gutterman David D.
Published: February 2003

Flow-induced dilation (FID) is dependent largely on hyperpolarization of vascular smooth muscle cells (VSMCs) in human coronary arterioles (HCA) from patients with coronary disease. Animal studies show that shear stress induces endothelial generation of hydrogen peroxide (H
2
O
2
), which is proposed as an endothelium-derived hyperpolarizing factor (EDHF). We tested the hypothesis that H
2
O
2
contributes to FID in HCA. Arterioles (135±7 μm, n=71) were dissected from human right atrial appendages at the time of cardiac surgery and cannulated with glass micropipettes. Changes in internal diameter and membrane potential of VSMCs to shear stress, H
2
O
2
, or to papaverine were recorded with videomicroscopy. In some vessels, endothelial H
2
O
2
generation to shear stress was monitored directly using confocal microscopy with 2′,7′-dichlorofluorescin diacetate (DCFH) or using electron microscopy with cerium chloride. Catalase inhibited FID (%max dilation; 66±8 versus 25±7%;
P
<0.05, n=6), whereas dilation to papaverine was unchanged. Shear stress immediately increased DCFH fluorescence in the endothelial cell layer, whereas treatment with catalase abolished the increase in fluorescence. Electron microscopy with cerium chloride revealed shear stress–induced increase in cerium deposition in intimal area surrounding endothelial cells. Exogenous H
2
O
2
dilated (%max dilation; 97±1%, ED
50
; 3.0±0.7×10
−5
mol/L) and hyperpolarized HCA. Dilation to H
2
O
2
was reduced by catalase, 40 mmol/L KCl, or charybdotoxin plus apamin, whereas endothelial denudation, deferoxamine, 1H-
1,2,4
-oxadiazole-[4,3-a]quinoxalin-1-one, or glibenclamide had no effect. These data provide evidence that shear stress induces endothelial release of H
2
O
2
and are consistent with the idea that H
2
O
2
is an EDHF that contributes to FID in HCA from patients with heart disease. The full text of this article is available at http://www.circresaha.org.
Genetic and Environmental Contributions to Atherosclerosis Phenotypes in Men and Women
Authors: Fox Caroline S. , Polak Joseph F. , Chazaro Irmarie , Cupples Adrienne , Wolf Philip A. , D’Agostino Ralph A. , O’Donnell Christopher J.
Published: February 2003

Background and Purpose—

Carotid intima-media thickness (IMT) is a quantitative measure of subclinical atherosclerosis that is predictive of subsequent myocardial infarction and stroke. There is controversy regarding the proportion of variability in IMT explained by genetic factors. Thus, it is uncertain whether carotid IMT is a heritable trait that can be used in genetic studies.

Methods—

From 1996 to 1998, we measured carotid IMT in 906 men (mean age, 56.7 years) and 980 women (mean age, 57.4 years) from 586 extended families (1630 sib pairs) in the Framingham Offspring cohort. B-mode carotid ultrasonography was used to define mean and maximum IMT of the common carotid artery (CCA) and internal carotid artery (ICA). Correlation coefficients were calculated in pairs of siblings. Variance component methods were used to estimate heritability with crude, age- and sex-adjusted, and multivariable-adjusted normalized deviates.

Results—

Multivariable-adjusted correlation coefficients for mean CCA and ICA IMT were 0.16 and 0.16, respectively. Crude, age- and sex-adjusted, and multivariable-adjusted heritabilities were 0.67, 0.44, and 0.38 for the mean CCA IMT (all
P
<0.001) and 0.43, 0.37, and 0.35 for the mean ICA IMT (all
P
<0.001). For CCA IMT, 27% of the overall variance was due to measured covariates; 38% was due to heritable factors.

Conclusions—

These data suggest that a substantial proportion of the variability in carotid IMT is explained by genetic factors. Further studies of genetic linkage and candidate gene association are warranted to identify specific genetic variants predisposing to subclinical atherosclerosis and stroke.
Vampire Bat Salivary Plasminogen Activator (Desmoteplase)
Authors: Liberatore Gabriel T. , Samson André , Bladin Christopher , Schleuning Wolf-Dieter , Medcalf Robert L.
Published: February 2003

Background and Purpose—

Tissue-type plasminogen activator (tPA) promotes excitotoxic and ischemic injury within the brain. These findings have implications for the use of tPA in the treatment of acute ischemic stroke. The plasminogen activator from vampire bat (
Desmodus rotundus
) saliva (
D rotundus
salivary plasminogen activator [DSPA]; desmoteplase) is an effective plasminogen activator but, in contrast to tPA, is nearly inactive in the absence of a fibrin cofactor. The purpose of this study was to compare the ability of DSPA and tPA to promote kainate- and
N
-methyl-
d
-aspartate (NMDA)–induced neurodegeneration in tPA−/− mice and wild-type mice, respectively.

Methods—

tPA−/− mice were infused intracerebrally with either tPA or DSPA. The degree of neuronal survival after hippocampal injection of kainate was assessed histochemically. Wild-type mice were used to assess the extent of neuronal damage after intrastriatal injection of NMDA in the presence of tPA or DSPA. Immunohistochemistry and fibrin zymography were used to evaluate DSPA and tPA antigen or activity.

Results—

Infusion of tPA into tPA−/− mice restored sensitivity to kainate-mediated neurotoxicity and activation of microglia. DSPA was incapable of conferring sensitivity to kainate treatment, even when infused at 10-fold higher molar concentration than tPA. The presence of tPA also increased the lesion volume induced by NMDA injection into the striatum of wild-type mice, whereas DSPA had no effect.

Conclusions—

DSPA does not promote kainate- or NMDA-mediated neurotoxicity in vivo. These results provide significant impetus to evaluate DSPA in patients with ischemic stroke.
Inhibition of Factor Xa Reduces Ischemic Brain Damage After Thromboembolic Stroke in Rats
Authors: Wang Xinkang , Xu Lin , Wang Hugh , Grzanna Reinhard , Zhan Yutian , Knabb Robert M. , Luettgen Joseph M. , Bozarth Tracy A. , Galemmo Robert A. , Wong Pancras C. , Bernard Roberta , Vargas Hugo , Chopp Michael , Friedman Steven M. , Feuerstein Giora Z.
Published: February 2003

Background and Purpose—

Factor Xa (FXa) is a key coagulation protease and target for novel antithrombotic agents for prevention and treatment of diverse thromboembolic disorders. In the present study we describe the effect of a novel, potent, and selective FXa inhibitor, DPC602, on brain damage and neurobehavioral consequence in a rat thromboembolic model of stroke.

Methods—

Thromboembolic stroke was induced in rats by placement of an autologous clot into the middle cerebral artery.

Results—

Laser-Doppler monitoring of cerebral blood flow demonstrated that DPC602 (8 mg/kg, single IV/IP bolus pretreatment) markedly improved cerebral blood flow after thromboembolic stroke by 25% to 160% (n=6;
P
<0.001) at 1 to 6 hours. DPC602 demonstrated concentration- and time-dependent reductions in infarct size, with maximal effect (89% reduction; n=14;
P
<0.001) at the highest dose over controls. Neurological function was also significantly improved in DPC602-treated rats at days 1, 3, and 7 (n=13;
P
<0.01). DPC602 treatment did not cause cerebral hemorrhage, assessed by free hemoglobin in the ischemic brain tissues.

Conclusions—

These data suggest that anticoagulation with a selective FXa inhibitor might ameliorate the extent of ischemic brain damage and neurological deficits after a thromboembolic event. Enhanced clot dissolution and early reperfusion may account for the cerebrovascular-protective effect of the drug.
Costs and Caregiver Consequences of Early Supported Discharge for Stroke Patients
Authors: Teng Josephine , Mayo Nancy E. , Latimer Eric , Hanley Jim , Wood-Dauphinee Sharon , Côté Robert , Scott Susan
Published: February 2003

Background and Purpose—Early supported discharge (ESD) for stroke has been shown to yield outcomes similar to or better than those of conventional care, but there is less information on the impact on costs and on the caregiver. The purpose of this study is to estimate the costs associated with an ESD program compared with those of usual care.

Methods—We conducted a randomized controlled trial of stroke patients who required rehabilitation services and who had a caregiver at home.

Results—Acute-care costs incurred before randomization when patients were medically ready for discharge averaged $3251 per person. The costs for the balance of the acute-care stay, from randomization to discharge, were $1383 for the home group and $2220 for the usual care group. The average cost of providing the 4-week home intervention service was $943 per person. The total cost generated by persons assigned to the home group averaged $7784 per person, significantly lower than the $11 065 per person for those assigned to usual care. A large proportion of the cost differential between the 2 groups arose from readmissions, for which the usual care group generated costs more than quadruple those of the home intervention group.

Conclusions—Providing care at home was no more (or less) expensive for those with greater functional limitation than for those with less. Caregivers in the ESD group scored consistently lower on the Burden Index than caregivers with usual care, even caregivers of persons with major functional limitations. For persons recovering from stroke and their families, ESD provides a cost-effective alternative to usual care.