bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of long-term captopril andl-arginine treatment on ventilation and blood pressure in obese male SHHF rats
Authors: Schlenker E. H. , Kost C. K. , Likness M. M.
Published: May 2004

We investigated the effects of captopril (Cap) and l-arginine (Arg) on hypertension and cardiopulmonary function. Our hypothesis was that Cap therapy or Arg will improve cardiopulmonary risk factors for hypertension and hypoventilation in the obese spontaneously hypertensive heart failure rat, which is characterized by hypertension, obesity, and disorders of lipid and carbohydrate metabolism. For the first study, one group of rats received Cap in drinking water, and a second group received deionized water (DI). For the second study, rats were further subdivided. Some Cap-treated rats continued on this treatment, and the other half were now given DI to determine whether there would be residual effects of Cap treatment. A subgroup of rats who had received DI was then given Arg, whereas the rest remained on DI. In the first study, Cap-treated rats exhibited decreases in systolic and diastolic blood pressures, frequency of breathing, and minute ventilation, but ventilatory control was maintained. In contrast, blood pressures and relative ventilation to metabolism were higher in the DI-treated group. Removal of Cap increased blood pressure and decreased tidal volume while these rats maintained frequency. Although Arg-treated rats did not exhibit a decrease of blood pressure, ventilation was maintained in this group by preserving tidal volume. Thus Cap and Arg affected ventilation through different mechanisms independent of blood pressure.
Cyclical elongation regulates contractile responses of isolated airways
Authors: Khangure S. R. , Noble P. B. , Sharma A. , Chia P. Y. , McFawn P. K. , Mitchell H. W.
Published: May 2004

Bronchoconstrictor responses are quantitatively different when they are evoked under static conditions and during or after periods of deep inspiration. In vivo, deep inspirations produce bronchodilation and protect the lung from subsequent bronchoconstriction (termed bronchoprotection). These effects may be due in part to dynamic stretch on airways produced by cyclical expansion of airway diameter. However, airways also lengthen cyclically during breathing. The effects of cyclical airway elongation on evoked bronchoconstriction have not been examined. This study recorded evoked contractions of pig bronchial segments 1) at different airway lengths, 2) after a period of cyclical lengthening in relaxed airways, and 3) during cyclical lengthening in pretoned airways. Airway segments were mounted in organ baths and bathed in Krebs solution luminally and on the adventitia. Airways were cyclically lengthened by 5–30% of their deflated length at 0.5–2 Hz for 5 min. Contractions were evoked by electrical field stimulation or carbachol and were recorded under isovolumic conditions. Under static conditions, there was a blunt relationship between length and response to electrical field stimulation. After a period of airway length cycling, electrical field stimulation-induced contractions were increased. In airways pretoned with carbachol, cyclical lengthening produced a transient bronchodilation and a sustained increase in contraction. Contractile responses were not blocked by indomethacin. The results show that isolated airways respond actively to dynamic changes in length. Our results indicate that cyclical lengthening of airways could contribute to lung function in vivo but does not appear to account for the phenomenon of bronchoprotection.
Effect of prior multiple-sprint exercise on pulmonary O2 uptake kinetics following the onset of perimaximal exercise
Authors: Wilkerson Daryl P. , Koppo Katrien , Barstow Thomas J. , Jones Andrew M.
Published: May 2004

We hypothesized that the metabolic acidosis resulting from the performance of multiple-sprint exercise would enhance muscle perfusion and result in a speeding of pulmonary oxygen uptake (V̇o2) kinetics during subsequent perimaximal-intensity constant work rate exercise, if O2 availability represented a limitation to V̇o2 kinetics in the control (i.e., no prior exercise) condition. On two occasions, seven healthy subjects completed two bouts of exhaustive cycle exercise at a work rate corresponding to ∼105% of the predetermined V̇o2 peak, separated by 3 × 30-s maximal sprint cycling and 15-min recovery (MAX1 and MAX2). Blood lactate concentration (means ± SD: MAX1: 1.3 ± 0.4 mM vs. MAX2: 7.7 ± 0.9 mM; P < 0.01) was significantly greater immediately before, and heart rate was significantly greater both before and during, perimaximal exercise when it was preceded by multiple-sprint exercise. Near-infrared spectroscopy also indicated that muscle blood volume and oxygenation were enhanced when perimaximal exercise was preceded by multiple-sprint exercise. However, the time constant describing the primary component (i.e., phase II) increase in V̇o2 was not significantly different between the two conditions (MAX1: 33.8 ± 5.5 s vs. MAX2: 33.2 ± 7.7 s). Rather, the asymptotic “gain” of the primary V̇o2 response was significantly increased by the performance of prior sprint exercise (MAX1: 8.1 ± 0.9 ml·min−1·W−1 vs. MAX2: 9.0 ± 0.7 ml·min−1·W−1; P < 0.05), such that V̇o2 was projecting to a higher “steady-state” amplitude with the same time constant. These data suggest that priming exercise, which apparently increases muscle O2 availability, does not influence the time constant of the primary-component V̇o2 response but does increase the amplitude to which V̇o2 may rise following the onset of perimaximal-intensity cycle exercise.
Age-related enhancement of fatigue resistance is evident in men during both isometric and dynamic tasks
Authors: Lanza Ian R. , Russ David W. , Kent-Braun Jane A.
Published: May 2004

It has been suggested that the effects of old age on the ability to resist fatigue may be task dependent. To test one aspect of this hypothesis, we compared the neuromuscular responses of nine young (26 ± 4 yr, mean ± SD) and nine older (72 ± 4 yr) healthy, relatively sedentary men to intermittent isometric (3 min, 5 s contract/5 s rest) and dynamic (90 at 90°/s) maximum voluntary contractions (MVC) of the ankle dorsiflexor muscles. To assess the mechanisms of fatigue (defined as the ratio of postexercise MVC to preexercise MVC), we also measured isometric central activation ratios (CAR), tetanic torque, contractile properties, and compound muscle action potentials before and immediately after exercise. Because dynamic contractions are more neurally complex and metabolically demanding than isometric contractions, we expected an age-related fatigue resistance observed during isometric exercise to be absent during dynamic exercise. In contrast, older men (O) fatigued less than young (Y) during both isometric (O = 0.77 ± 0.07, Y = 0.66 ± 0.02, mean ± SE; P < 0.01) and dynamic (O = 0.45 ± 0.07, Y = 0.27 ± 0.02; P = 0.04) contractions (ratio of postexercise to preexercise MVC), with no evidence of peripheral activation failure in either group. We observed no obvious limitations in central activation in either group, as assessed using isometric CAR methods, after both isometric and dynamic contractions. Preexercise half-time of tetanic torque relaxation, which was longer in O compared with Y, was linearly associated with fatigue resistance during both protocols ( r = 0.62 and 0.66, P ≤ 0.004, n = 18). These results suggest that relative fatigue resistance is enhanced in older adults during both isometric and isokinetic contractions and that age-related changes in fatigue may be due largely to differences within the muscle itself.
Quantitative Investigation of Calcium Signals for Locomotor Pattern Generation in the Lamprey Spinal Cord
Authors: Viana Di Prisco Gonzalo , Alford Simon
Published: May 2004

Locomotor pattern generation requires the network coordination of spinal ventral horn neurons acting in concert with the oscillatory properties of individual neurons. In the spinal cord, N-methyl-d-aspartate (NMDA) activates neuronal oscillators that are believed to rely on Ca2+entry to the cytosol through voltage-operated Ca2+channels and synaptically activated NMDA receptors. Ca2+signaling in lamprey ventral horn neurons thus plays a determinant role in the regulation of the intrinsic membrane properties and network synaptic interaction generating spinal locomotor neural pattern activity. We have characterized aspects of this signaling quantitatively for the first time. Resting Ca2+concentrations were between 87 and 120 nM. Ca2+concentration measured during fictive locomotion increased from soma to distal dendrites [from 208 ± 27 (SE) nM in the soma to 335 ± 41 nM in the proximal dendrites to 457 ± 68 nM in the distal dendrites]. We sought to determine the temporal and spatial properties of Ca2+oscillations, imaged with Ca2+-sensitive dyes and correlated with fluctuations in membrane potential, during lamprey fictive locomotion. The Ca2+signals recorded in the dendrites showed a great deal of spatial heterogeneity. Rapid changes in Ca2+-induced fluorescence coincided with action potentials, which initiated significant Ca2+transients distributed throughout the neurons. Ca2+entry to the cytosol coincided with the depolarizing phase of the locomotor rhythm. During fictive locomotion, larger Ca2+oscillations were recorded in dendrites compared with somata in motoneurons and premotor interneurons. Ca2+fluctuations were barely detected with dyes of lower affinity providing alternative empirical evidence that Ca2+responses are limited to hundreds of nanomolars during fictive locomotion.
Acid-Sensitive Two-Pore Domain Potassium (K2P) Channels in Mouse Taste Buds
Authors: Richter Trevor A. , Dvoryanchikov Gennady A. , Chaudhari Nirupa , Roper Stephen D.
Published: May 2004

Sour (acid) taste is postulated to result from intracellular acidification that modulates one or more acid-sensitive ion channels in taste receptor cells. The identity of such channel(s) remains uncertain. Potassium channels, by regulating the excitability of taste cells, are candidates for acid transducers. Several 2-pore domain potassium leak conductance channels (K2P family) are sensitive to intracellular acidification. We examined their expression in mouse vallate and foliate taste buds using RT-PCR, and detected TWIK-1 and -2, TREK-1 and -2, and TASK-1. Of these, TWIK-1 and TASK-1 were preferentially expressed in taste cells relative to surrounding nonsensory epithelium. The related TRESK channel was not detected, whereas the acid-insensitive TASK-2 was. Using confocal imaging with pH-, Ca2+-, and voltage-sensitive dyes, we tested pharmacological agents that are diagnostic for these channels. Riluzole (500 μM), selective for TREK-1 and -2 channels, enhanced acid taste responses. In contrast, halothane (≤ ∼17 mM), which acts on TREK-1 and TASK-1 channels, blocked acid taste responses. Agents diagnostic for other 2-pore domain and voltage-gated potassium channels (anandamide, 10 μM; Gd3+, 1 mM; arachidonic acid, 100 μM; quinidine, 200 μM; quinine, 100 mM; 4-AP, 10 mM; and TEA, 1 mM) did not affect acid responses. The expression of 2-pore domain channels and our pharmacological characterization suggest that a matrix of ion channels, including one or more acid-sensitive 2-pore domain K channels, could play a role in sour taste transduction. However, our results do not unambiguously identify any one channel as the acid taste transducer.
Neuronal Activity Throughout the Primate Mediodorsal Nucleus of the Thalamus During Oculomotor Delayed-Responses. I. Cue-, Delay-, and Response-Period Activity
Authors: Watanabe Yumiko , Funahashi Shintaro
Published: May 2004

The thalamic mediodorsal nucleus (MD) has strong reciprocal connections with the dorsolateral prefrontal cortex (DLPFC), suggesting that the MD, like the DLPFC, participates in higher cognitive functions. To examine MD's participation in cognitive functions, we analyzed the characteristics of task-related activities sampled homogeneously from the MD while two monkeys performed a spatial working memory task using oculomotor responses. Of 141 task-related MD neurons, 26, 53, and 84% exhibited cue-, delay-, and response-period activity, respectively. Most of cue- and response-period activities showed phasic excitation, and most of delay-period activity showed tonic sustained activation. Among neurons with response-period activity, 74% exhibited presaccadic activity. Most cue-period, delay-period, and presaccadic activities were directional, whereas most postsaccadic activity was omni-directional. A significant contralateral bias in the best directions was present in cue-period and presaccadic activity. However, such bias was not present in delay-period activity, although most neurons had a best direction toward the contralateral visual field. We compared these characteristics with those observed in DLPFC neurons. Response-period activity was more frequently observed in the MD (84%) than in the DLPFC (56%). The directional selectivity and bias of task-related activities and the ratios of pre- and postsaccadic activities were different between MD and DLPFC. These results indicate that the MD participates in higher cognitive functions such as spatial working memory. However, the manner in which these two structures participate in these processes differs, in that the MD participates more in motor control aspects compared with the DLPFC.
Neuronal Activity Throughout the Primate Mediodorsal Nucleus of the Thalamus During Oculomotor Delayed-Responses. II. Activity Encoding Visual Versus Motor Signal
Authors: Watanabe Yumiko , Funahashi Shintaro
Published: May 2004

We collected single-neuron activity from the mediodorsal (MD) nucleus of the thalamus, examined the information that was represented by task-related activity during performance of a spatial working memory task, and compared the present results with those obtained in the dorsolateral prefrontal cortex (DLPFC). We used two oculomotor delayed-response (ODR) tasks. In the ordinary ODR task, monkeys were required to make a memory-guided saccade to the location where a visual cue had been presented 3 s previously, whereas in the rotatory ODR task, they were required to make a memory-guided saccade 90° clockwise from the cue direction. By comparing the best directions of the same task-related activity between the two tasks, we could determine whether this activity represented the cue location or the saccade direction. All cue-period activity represented the cue location. In contrast, 56% of delay-period activity represented the cue location and 41% represented the saccade direction. Almost all response-period activity represented the saccade direction. These results indicate that task-related MD activity represents either visual or motor information, suggesting that the MD participates in sensory-to-motor information processing. However, a greater proportion of delay- and response-period activities represented the saccade direction in the MD than in the DLPFC, indicating that more MD neurons participate in prospective information processing than DLPFC neurons. These results suggest that although functional interactions between the MD and DLPFC are crucial to cognitive functions such as working memory, there is a difference in how the MD and DLPFC participate in these functions.
Gene expression analysis suggests that 1,25-dihydroxyvitamin D3reverses experimental autoimmune encephalomyelitis by stimulating inflammatory cell apoptosis
Authors: Spach Karen M. , Pedersen Laura B. , Nashold Faye E. , Kayo Tsuyoshi , Yandell Brian S. , Prolla Tomas A. , Hayes Colleen E.
Published: May 2004

Multiple sclerosis (MS) is a debilitating autoimmune disease of the central nervous system (CNS) that develops in genetically susceptible individuals who are exposed to undefined environmental risk factors. Epidemiological, genetic, and biological evidence suggests that insufficient vitamin D may be an MS risk factor. However, little is known about how vitamin D might be protective in MS. We hypothesized that 1,25-dihydroxyvitamin D3[1,25-(OH)2D3] might regulate gene expression patterns in a manner that would resolve inflammation. To test this hypothesis, experimental autoimmune encephalomyelitis (EAE) was induced in mice, 1,25-(OH)2D3or a placebo was administered, and 6 h later, DNA microarray hybridization was performed with spinal cord RNA to analyze the gene expression patterns. At this time, clinical, histopathological, and biological studies showed that the two groups did not differ in EAE disease, but changes in several 1,25-(OH)2D3-responsive genes indicated that the 1,25-(OH)2D3had reached the CNS. Compared with normal mice, placebo-treated mice with EAE showed increased expression of many immune system genes, confirming the acute inflammation. When 1,25-(OH)2D3was administered, several genes like glial fibrillary acidic protein and eukaryotic initiation factor 2α kinase 4, whose expression increased or decreased with EAE, returned to homeostatic levels. Also, two genes with pro-apoptotic functions, calpain-2 and caspase-8-associated protein, increased significantly. A terminal deoxynucleotidyl transferase-mediated dUTP nicked end labeling study detected increased nuclear fragmentation in the 1,25-(OH)2D3-treated samples, confirming increased apoptosis. Together, these results suggest that sensitization of inflammatory cells to apoptotic signals may be one mechanism by which the 1,25-(OH)2D3resolved EAE.
Genome-wide linkage analysis of chromogranin B expression in the CEPH pedigrees: implications for exocytotic sympathochromaffin secretion in humans
Authors: Greenwood Tiffany A. , Cadman Peter E. , Stridsberg Mats , Nguyen Susan , Taupenot Laurent , Schork Nicholas J. , O’Connor Daniel T.
Published: May 2004

Chromogranin B (CgB), a major member of the chromogranin/secretogranin family of catecholamine storage vesicle secretory proteins, plays both intracellular (vesiculogenic) and extracellular (prohormone) roles in the neuroendocrine system, and its biosynthesis and release are under the control of efferent sympathetic nerve traffic (“stimulus-transcription coupling”). To explore the role of heredity in control of CgB, we conducted a genome-wide linkage analysis of CgB release in 12 extended CEPH (Centre d’Etude du Polymorphisme Humain) pedigrees. Region-specific radioimmunoassays were used to measure five CgB fragments in plasma: CgB1–16, CgB312–331, CgB439–451, CgB568–577, and CgB647–657. Substantial heritability, as measured by h2r, was observed for three of the fragment concentrations, CgB312–331, CgB439–451, and CgB568–577, which yielded h2r estimates ranging from 0.378 ( P = 0.002) to 0.910 ( P < 0.0000001). Variance-component genome-wide linkage analysis with 654 microsatellite markers at ∼5 cM spacing identified a major quantitative trait locus for CgB312–331 on chromosome 11q24-q25 with a maximum multipoint LOD score of 5.84. Significant allelic associations between markers in the region and CgB levels were also observed. Although the 2-LOD confidence interval for linkage did not include the CgB locus itself, known trans-activators of the CgB gene promoter, or prohormone cleaving proteases, examination of positional candidate loci within this region yielded novel and plausible physiological candidates for further exploration. Allelic variation in this region may thus influence effects of sympathetic outflow on target organs in humans.
Nonanalytic solutions of the KdV equation
Authors: Byers Peter , Himonas A. Alexandrou
Published: May 2004

We construct nonanalytic solutions to the initial value problem for the KdV equation with analytic initial data in both the periodic and the nonperiodic cases.
Subdominant positive solutions of the discrete equation Δu(k + n) = −p(k)u(k)
Authors: Baštinec Jaromír , Diblík Josef
Published: May 2004

A delayed discrete equation Δu(k + n) = −p(k)u(k) with positive coefficient p is considered. Sufficient conditions with respect to p are formulated in order to guarantee the existence of positive solutions if k → ∞. As a tool of the proof of corresponding result, the method described in the author′s previous papers is used. Except for the fact of the existence of positive solutions, their upper estimation is given. The analysis shows that every positive solution of the indicated family of positive solutions tends to zero (if k → ∞) with the speednot smaller than the speed characterized by the function . A comparison with the known results is given and some open questions are discussed.
Which solutions of the third problem for the Poisson equation are bounded?
Authors: Medková Dagmar
Published: May 2004

This paper deals with the problem Δu = g on G and ∂u/∂n + uf = L on ∂G. Here, G ⊂ ℝm, m > 2, is a bounded domain with Lyapunov boundary, f is a bounded nonnegative function on the
boundary of G, L is a bounded linear functional on W1,2(G) representable by a real measure μ on the boundary of G, and g ∈ L2(G)∩Lp(G), p > m/2. It is shown that a weak solution of this problem is bounded in G if and only if the Newtonian potential corresponding to the boundary
condition μ is bounded in G.
Multivalued semilinear neutral functional differential equations with nonconvex‐valued right‐hand side
Authors: Benchohra M. , Gatsori E. , Ntouyas S. K.
Published: May 2004

We investigate the existence of mild solutions on acompact
interval to some classes of semilinear neutral functional
differential inclusions. We will rely on a fixed‐point theorem for
contraction multivalued maps due to Covitz and Nadler and on
Schaefer′s fixed‐point theorem combined with lower semicontinuous
multivalued operators with decomposable values.
Electromagnetic fields in linear and nonlinear chiral media: a time‐domain analysis
Authors: Stratis Ioannis G. , Yannacopoulos Athanasios N.
Published: May 2004

We present several recent and novel results on the formulation
and the analysis of the equations governing the evolution of
electromagnetic fields in chiral media in the time domain. In
particular, we present results concerning the well‐posedness and
the solvability of the problem for linear, time‐dependent, and
nonlocal media, andresults concerning the validity of the local
approximation of the nonlocal medium (optical response
approximation). The paper concludes with the study of a class of
nonlinear chiral media exhibiting Kerr‐like nonlinearities, for
which the existence of bright and dark solitary waves is shown.
On some sufficient conditions for the blow‐up solutions of the nonlinear Ginzburg‐Landau‐Schrödinger evolution equation
Authors: Nasibov Sh. M.
Published: May 2004

Investigation of the
blow‐up solutions of the problem in finite time of the first
mixed‐value problem with a homogeneous boundary condition on a
bounded domain of n‐dimensional Euclidean space for a class of
nonlinear Ginzburg‐Landau‐Schrödinger evolution equation is
continued. New simple sufficient conditions have been obtained
for a wide class of initial data under which collapse happens for
the given new values of parameters.
Asymptotics for orthogonal polynomials off the circle
Authors: Khaldi R. , Benzine R.
Published: May 2004

We study the strong asymptotics of orthogonal polynomials with respect to a measure of the type , where μ is a positive measure on the unit circle Γ satisfying the Szegö condition and are fixed points outside Γ. The masses are positive numbers such that . Our main result is the explicit strong asymptotic formulas for the corresponding orthogonal polynomials.
A note on point source diffraction by a wedge
Authors: Rawlins A. D.
Published: May 2004

The object of this paper is to give new expressions for the wave
field produced when a time harmonic point source is diffracted by
a wedge with Dirichlet or Neumann boundary conditions on its
faces. The representation of the total field is expressed in
terms of quadratures of elementary functions, rather than Bessel
functions, which is usual in the literature. An analogous
expression is given for the three‐dimensional free‐space Green′s
function.
Magnetohydrodynamic boundary layer flow past a stretching plate and heat transfer
Authors: Ezzat M. , Zakaria M. , Moursy M.
Published: May 2004

The present work is concerned with unsteady two‐dimensional
laminar flow of an incompressible, viscous,
perfectly electrically conducting fluid past a nonisothermal
stretching sheet in the presence of a transverse magnetic field
acting perpendicularly to the direction of fluid. By means of the
successive approximation method, the governing equations for
momentum and energy have been solved. The effects of surface mass
transfer fω, Alfven velocity α, Prandtl number
P, and relaxation time parameter τ0 on the velocity and temperature have been discussed. Numerical results are given and illustrated graphically for the problem considered.
Dynamic crack propagation between two bonded orthotropic plates
Authors: Matbuly M. S.
Published: May 2004

The problem of crack propagation along the interface of two bonded
dissimilar orthotropic plates is considered. Using
Galilean transformation, the problem is reduced to a
quasistatic one. Then, using Fourier transforms and asymptotic
analysis, the problem is reduced to a pair of singular integral
equations with Cauchy‐type singularity. These equations are
solved using Gauss‐Chebyshev quadrature formulae. The dynamic
stress intensity factors are obtained in closed form
expressions. Furthermore, a parametric study is introduced to
investigate the effect of crack growth rate and geometric and
elastic characteristics of the plates on values of dynamic stress
intensity factors.
On the flexural and extensional thermoelastic waves in orthotropic plates with two thermal relaxation times
Authors: Verma K. L. , Hasebe Norio
Published: May 2004

Analysis for the propagation of plane harmonic thermoelastic
waves in an infinite homogeneous orthotropic plate of finite
thickness in the generalized theory of thermoelasticity with two
thermal relaxation times is studied. The frequency
equations corresponding to the extensional (symmetric) and
flexural (antisymmetric) thermoelastic modes of vibration are
obtained and discussed. Special cases of the frequency equations
are also discussed. Numerical solution of the frequency
equations for orthotropic plate is carried out, and the
dispersion curves for the first six modes are presented for a
representative orthotropic plate. The three motions, namely,
longitudinal, transverse, and thermal, of the medium are found
dispersive and coupled with each other due to the thermal and
anisotropic effects. The phase velocity of the waves gets
modified due to the thermal and anisotropic effects and is also
influenced by the thermal relaxation time. Relevant results of
previous investigations are deduced as special cases.
Applications of mathematical programming in graceful labeling of graphs
Authors: Eshghi Kourosh , Azimi Parham
Published: May 2004

Graceful labeling is one of the best known labeling methods of
graphs. Despite the large number of papers published on the
subject of graph labeling, there are few particular techniques to
be used by researchers to gracefully label graphs. In this paper,
first a new approach based on the mathematical programming
technique is presented to model the graceful labeling problem.
Then a “branching method” is developed to solve the problem for
special classes of graphs. Computational results show the
efficiency of the proposed algorithm for different classes of
graphs. One of the interesting results of our model is in the
class of trees. The largest tree known to be graceful has at most
27 vertices but our model can easily solve the graceful labeling
for trees with 40 vertices.
Microtubules Regulate Angiotensin II Type 1 Receptor and Rac1 Localization in Caveolae/Lipid Rafts
Authors: Zuo Lian , Ushio-Fukai Masuko , Hilenski Lula L. , Alexander R. Wayne
Published: May 2004

Objective—

Microtubules are important in signal transduction temporal–spatial organization. Full expression of angiotensin II (Ang II) signaling in vascular smooth muscle cells (VSMCs) is dependent on the reactive oxygen species (ROS) derived from nicotinamide-adenine dinucleotide phosphate (NAD(P)H) oxidase and the dynamic association of the Ang II type 1 receptor (AT
1
R) with caveolae/lipid rafts. Translocation of the small GTPase Rac1 to the plasma membrane is an essential step for activation of NAD(P)H oxidase; however, its precise localization in the plasma membrane after agonist stimulation and how it is targeted are unknown. We hypothesized that microtubules are involved in regulating multiphasic Ang II signaling events in VSMC.

Methods and Results—

We show that Ang II promotes Rac1 and AT
1
R trafficking into caveolae/lipid rafts, which is blocked by disruption of microtubules with nocodazole. As a consequence, nocodazole significantly inhibits Ang II–stimulated H
2
O
2
production, its downstream ROS-dependent epidermal growth factor receptor transactivation, Akt phosphorylation, and vascular hypertrophy without affecting Rac1 activation or ROS-independent extracellular signal-regulated kinase 1/2 phosphorylation.

Conclusions—

These results suggest that proper Rac1 and AT
1
R trafficking into caveolae/lipid rafts requires the integrity of microtubules and provide insight into the essential role of microtubules for the spatial–temporal organization of ROS-dependent and caveolae/lipid rafts–dependent AT
1
R signaling linked to vascular hypertrophy.
Atherosclerotic Plaque Smooth Muscle Cells Have a Distinct Phenotype
Authors: Mulvihill Eileen R. , Jaeger Jochen , Sengupta Rimli , Ruzzo Walter L. , Reimer Cecile , Lukito Sheila , Schwartz Stephen M.
Published: May 2004

Objective—The present study addresses the question, “Are plaque smooth muscles cells (SMCs) genetically distinct from medial SMCs as reflected by the ability to maintain a distinctive expression phenotype in vitro?”

Methods and Results—Multiple cell strains were developed from carotid endarcterectomy specimens, and quadruplicate array hybridizations were completed for each sample. A new normalization protocol was developed and used to analyze the data. Permutation analysis suggests that most of the significant differences in expression could not have occurred by chance. A broad pattern of significant expression differences, consisting of almost 5% of the genes probed, was detected. Quantitative polymerase chain reaction (QPCR) confirmation was found in 70% of a subset of genes selected for validation.

Conclusions—The SMC cultures were nearly indistinguishable by morphological features, population doubling time, and sensitivity to cell death induced by Fas cross-linking. Surprisingly, array expression analysis identified differences so extensive that we conclude that plaque and medial SMCs are distinctly different SMC cell types.
Gene Transfer of Stromal Cell–Derived Factor-1α Enhances Ischemic Vasculogenesis and Angiogenesis via Vascular Endothelial Growth Factor/Endothelial Nitric Oxide Synthase–Related Pathway
Authors: Hiasa Ken-ichi , Ishibashi Minako , Ohtani Kisho , Inoue Shujiro , Zhao Qingwei , Kitamoto Shiro , Sata Masataka , Ichiki Toshihiro , Takeshita Akira , Egashira Kensuke
Published: May 2004

Background—

Stromal cell–derived factor-1α (SDF-1α) is implicated as a chemokine for endothelial progenitor cells (EPCs). We therefore hypothesized that SDF-1α gene transfer would induce therapeutic neovascularization in vivo by functioning as a chemokine of EPC.

Methods and Results—

To examine SDF-1α–induced mobilization of EPC, we used bone marrow–transplanted mice whose blood cells ubiquitously express β-galactosidase (LacZ). We produced unilateral hindlimb ischemia in the mice and transfected them with plasmid DNA encoding SDF-1α or empty plasmids into the ischemic muscles. SDF-1α gene transfer mobilized EPCs into the peripheral blood, augmented recovery of blood perfusion to the ischemic limb, and increased capillary density associated with partial incorporation of LacZ-positive cells into the capillaries of the ischemic limb, suggesting that SDF-1α induced vasculogenesis and angiogenesis. SDF-1α gene transfer did not affect ischemia-induced expression of vascular endothelial growth factor (VEGF) but did enhance Akt and endothelial nitric oxide synthase (eNOS) activity. Blockade of VEGF or NOS prevented all such SDF-1α–induced effects.

Conclusions—

SDF-1α gene transfer enhanced ischemia-induced vasculogenesis and angiogenesis in vivo through a VEGF/eNOS-related pathway. This strategy might become a novel chemokine therapy for next generation therapeutic neovascularization.
Diagnostic Use of Serum Deoxyribonuclease I Activity as a Novel Early-Phase Marker in Acute Myocardial Infarction
Authors: Kawai Yasuyuki , Yoshida Masahiro , Arakawa Kenichiro , Kumamoto Teruhiko , Morikawa Norihiro , Masamura Katsuhiko , Tada Hiroshi , Ito Sachiko , Hoshizaki Hiroshi , Oshima Shigeru , Taniguchi Koichi , Terasawa Hidekazu , Miyamori Isamu , Kishi Koichiro , Yasuda Toshihiro
Published: May 2004

Background—

The delayed release of serum cardiac markers such as creatine kinase isoenzyme MB and equivocal early electrocardiographic changes have hampered a diagnosis of acute myocardial infarction (AMI) in the early phase after its onset. Therefore, a reliable serum biochemical marker for the diagnosis of AMI in the very early phase is desirable.

Methods and Results—

Serum samples were collected from the patients with AMI, unstable angina pectoris, stable angina pectoris, and other diseases. Levels of serum deoxyribonuclease I (DNase I) activity in the patients were determined. An abrupt elevation of serum DNase I activity was observed within approximately 3 hours of the onset of symptoms in patients with AMI, with significantly higher activity levels (21.7±5.10 U/L) in this group compared with the other groups with unstable angina pectoris (10.4±4.41 U/L), angina pectoris (10.8±3.70 U/L), and other diseases (9.22±4.16 U/L). Levels of the DNase I activity in serum then exhibited a marked time-dependent decline within 12 hours and had returned to basal levels within 24 hours.

Conclusions—

We suggest that serum DNase I activity could be used as a new diagnostic marker for the early detection of AMI.
Right Ventricular Enlargement on Chest Computed Tomography
Authors: Quiroz Rene , Kucher Nils , Schoepf U. Joseph , Kipfmueller Florian , Solomon Scott D. , Costello Philip , Goldhaber Samuel Z.
Published: May 2004

Background—

We investigated the prognostic role of right ventricular enlargement on multidetector-row chest CT in acute pulmonary embolism (PE).

Methods and Results—

We studied 63 patients with CT-confirmed PE who underwent echocardiography within the ensuing 24 hours. Adverse clinical events, defined as 30-day mortality or the need for cardiopulmonary resuscitation, mechanical ventilation, pressors, rescue thrombolysis, or surgical embolectomy, were present in 24 patients. We performed off-line CT measurements of right and left ventricular dimensions (RV
D
, LV
D
) with axial and 2-dimensional reconstructed 4-chamber (4-CH) views. The proportion of patients with RV
D
/LV
D
>0.9 on the axial view was similar in patients with (70.8%) and those without adverse events (71.8%;
P
=0.577). In contrast, RV
D
/LV
D
>0.9 on the 4-CH view was more common in patients with (80.3%) than without (51.3%;
P
=0.015) adverse events. The area under the curve of RV
D
/LV
D
from the axial and 4-CH views for predicting adverse events was 0.667 and 0.753, respectively. Sensitivity and specificity of RV
D
/LV
D
>0.9 for predicting adverse events were 37.5% and 92.3% on the axial view and 83.3% and 48.7% on the reconstructed 4-CH view, respectively. RV
D
/LV
D
>0.9 on the 4-CH view was an independent predictor for adverse events (OR, 4.02; 95% CI, 1.06 to 15.19;
P
=0.041) when adjusted for age, obesity, cancer, and recent surgery.

Conclusions—

Right ventricular enlargement on the reconstructed CT 4-CH views predicts adverse clinical events in patients with acute PE. Ventricular CT measurements obtained from 4-CH views are superior to those from axial views for identifying high-risk patients.
Heparin Cofactor II Is a Novel Protective Factor Against Carotid Atherosclerosis in Elderly Individuals
Authors: Aihara Ken-ichi , Azuma Hiroyuki , Takamori Nobuyuki , Kanagawa Yasuhiko , Akaike Masashi , Fujimura Mitsunori , Yoshida Tomonori , Hashizume Shunji , Kato Midori , Yamaguchi Hiroshi , Kato Shuji , Ikeda Yasumasa , Arase Tomoko , Kondo Akira , Matsumoto Toshio
Published: May 2004

Background—

Thrombin plays a crucial role in atherothrombotic changes. Because heparin cofactor II (HCII) inhibits thrombin actions after binding to dermatan sulfate at injured arterial walls, HCII may negatively regulate thrombin actions in vascular walls. We hypothesized that plasma HCII activity is a preventive factor against atherosclerotic changes, especially in elderly individuals who already have atherosclerotic vascular injuries.

Methods and Results—

Maximum plaque thickness (MPT) in the carotid artery was measured by ultrasonography in 306 Japanese elderly individuals (154 men and 152 women; age, 40 to 91 years; 68.9±11.1 years, mean±SD). The relevance of cardiovascular risk factors including plasma HCII activity to the severity of MPT was statistically evaluated. Plasma HCII activity decreased with age. Simple linear regression analysis after adjustments for age and sex showed that lipoprotein(a), glycosylated hemoglobin A1c, and presence of diabetes mellitus significantly contributed to an increase in MPT values (
r
=0.119,
P
<0.05;
r
=0.196,
P
<0.001; and
r
=0.227,
P
<0.0001, respectively). In contrast, high-density lipoprotein (HDL) cholesterol and HCII activity were negatively correlated with MPT values (
r
=−0.117,
P
<0.05, and
r
=−0.202,
P
<0.0005, respectively). Multiple regression analysis revealed that plasma HCII activity and HDL cholesterol independently contributed to the suppression of MPT values and that the antiatherogenic contribution of HCII activity was stronger than that of HDL cholesterol (
P
<0.001 and
P
<0.05, respectively).

Conclusions—

These results suggest that HCII can be a novel and independent antiatherogenic factor. Moreover, HCII is a stronger predictive factor than HDL cholesterol against carotid atherosclerosis in elderly individuals.
Post–Sirolimus-Eluting Stent Restenosis Treated With Repeat Percutaneous Intervention
Authors: Lemos Pedro A. , van Mieghem Carlos A.G. , Arampatzis Chourmouzios A. , Hoye Angela , Ong Andrew T.L. , McFadden Eugene , Sianos Georgios , van der Giessen Willem J. , de Feyter Pim J. , van Domburg Ron T. , Serruys Patrick W.
Published: May 2004

Background—

We evaluated the clinical and angiographic outcomes of patients presenting with restenosis after sirolimus-eluting stent (SES) implantation treated with repeated percutaneous intervention.

Methods and Results—

A total of 24 consecutive patients have undergone repeated percutaneous intervention to treat post-SES restenosis (27 lesions). The restenosis was located within the stent in 93% of lesions. From the 27 lesions, 1 (4%) was re-treated with a bare stent, 3 (11%) were treated with balloon dilatation, and the remaining 23 lesions (85%) were treated with repeated drug-eluting stent implantation (SES in 12 lesions [44%], paclitaxel-eluting stents in 11 lesions [41%]). The event-free survival rate was 70.8% after a median follow-up of 279 days from the post-SES treatment. The overall recurrent restenosis rate was 42.9%. The risk of recurrent restenosis was increased for patients with hypercholesterolemia, previous angioplasty, failed brachytherapy, post-SES restenosis needing early (<6 months) treatment, and post-SES restenosis treated with balloon dilatation. The recurrent restenosis rate of originally de novo lesions re-treated with drug-eluting stents was 18.2%.

Conclusions—

Even though de novo lesions treated with SES at baseline and re-treated with drug-eluting stents had reasonably better outcomes than other lesion types and strategies, our study shows that the treatment of post-SES restenosis is currently suboptimal and warrants further investigation.
Intraprocedural Stent Thrombosis During Implantation of Sirolimus-Eluting Stents
Authors: Chieffo Alaide , Bonizzoni Erminio , Orlic Dejan , Stankovic Goran , Rogacka Renata , Airoldi Flavio , Mikhail Ghada W. , Montorfano Matteo , Michev Iassen , Carlino Mauro , Colombo Antonio
Published: May 2004

Background—

Intraprocedural stent thrombosis (IPST) is a rare event (<0.01% in our experience with bare metal stents), with the exception of specific settings such as acute myocardial infarction, thrombus-containing lesions, and dissections. We report the occurrence of this event during elective implantation of sirolimus-eluting stents.

Methods and Results—

Between April 2002 and August 2003, 670 patients with 1362 lesions were treated with Cypher (Cordis, Johnson and Johnson Co) sirolimus-eluting stent implantation in San Raffaele Hospital and EMO Centro Cuore Columbus. Diabetes mellitus was present in 142 patients (21%), and 164 (24.5%) had unstable angina. Pretreatment with glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitors was carried out in 235 patients (35%). Total stent length per vessel was 42.9±28.3 mm. IPST occurred in 5 patients (0.7%). None of the patients with IPST were pretreated with GP IIb/IIIa inhibitors. Using univariate exact logistic regression, only total stent length per vessel, in millimeters (exact OR, 1.03; 95% CI, 1.011 to 1.046;
P
=0.0028), was associated with the occurrence of IPST.

Conclusions—

Stent length was associated with the occurrence of IPST. Particular attention will need to be directed to this potential complication when long sirolimus-eluting stents are being used.
Sex Differences in Age-Related Stiffening of the Aorta in Subjects With Type 2 Diabetes
Authors: De Angelis Lorenita , Millasseau Sandrine C. , Smith Andrew , Viberti GianCarlo , Jones Richard H. , Ritter James M. , Chowienczyk Philip J.
Published: May 2004

Hypertension and type 2 diabetes are associated with increased aortic pulse wave velocity (PWV), a measure of aortic stiffness and a powerful risk factor for cardiovascular events. The association of hypertension with type 2 diabetes may obscure the degree to which diabetes rather than hypertension contributes to an elevated PWV. The objective of this study was to determine whether the presence of type 2 diabetes is associated with an elevated PWV compared with nondiabetic subjects matched for mean arterial blood pressure. PWV was determined by measuring carotid to femoral transit time using applanation tonometry in 186 subjects (104 women) with (n=93) and without (n=93) type 2 diabetes. Diabetic and nondiabetic subjects were matched for age and mean arterial pressure (to ±5 years and 5 mm Hg, respectively). PWV was strongly correlated with age and mean arterial blood pressure (
R
=0.59 and 0.29 respectively, each
P
<0.0001). PWV increased significantly more with age in women with diabetes (slope of regression line±SE: 0.19±0.03 m · s
−1
· year
−1
) than in nondiabetic women (0.08±0.02 m · s
−1
· year
−1
,
P
<0.01 for difference). In men, however, the age-related increase in PWV was similar in diabetic (0.15±0.03 m · s
−1
· year
−1
) and nondiabetic subjects (0.13±0.03 m · s
−1
· year
−1
, P=NS). The interaction of diabetic status with age and with sex was significant (
P
=0.01). Type 2 diabetes is associated with a greater age-related stiffening of the aorta in women compared with men, and this is not explained by hypertension.
C-Reactive Protein: Risk Marker or Mediator in Atherothrombosis?
Authors: Jialal Ishwarlal , Devaraj Sridevi , Venugopal Senthil K.
Published: May 2004

Inflammation appears to be pivotal in all phases of atherosclerosis from the fatty streak lesion to acute coronary syndromes. An important downstream marker of inflammation is C-reactive protein (CRP). Numerous studies have shown that CRP levels predict cardiovascular disease in apparently healthy individuals. This has resulted in a position statement recommending cutoff levels of CRP <1.0, 1.0 to 3.0, and >3.0 mg/L equating to low, average, and high risk for subsequent cardiovascular disease. More interestingly, much in vitro data have now emerged in support of a role for CRP in atherogenesis. To date, studies largely in endothelial cells, but also in monocyte-macrophages and vascular smooth muscle cells, support a role for CRP in atherogenesis. The proinflammatory, proatherogenic effects of CRP that have been documented in endothelial cells include the following: decreased nitric oxide and prostacyclin and increased endothelin-1, cell adhesion molecules, monocyte chemoattractant protein-1 and interleukin-8, and increased plasminogen activator inhibitor-1. In monocyte-macrophages, CRP induces tissue factor secretion, increases reactive oxygen species and proinflammatory cytokine release, promotes monocyte chemotaxis and adhesion, and increases oxidized low-density lipoprotein uptake. Also, CRP has been shown in vascular smooth muscle cells to increase inducible nitric oxide production, increase NFκb and mitogen-activated protein kinase activities, and, most importantly, upregulate angiotensin type-1 receptor resulting in increased reactive oxygen species and vascular smooth muscle cell proliferation. Future studies should be directed at delineating the molecular mechanisms for these important in vitro observations. Also, studies should be directed at confirming these findings in animal models and other systems as proof of concept. In conclusion, CRP is a risk marker for cardiovascular disease and, based on future studies, could emerge as a mediator in atherogenesis.
Genetic Variation in White Matter Hyperintensity Volume in the Framingham Study
Authors: Atwood Larry D. , Wolf Philip A. , Heard-Costa Nancy L. , Massaro Joseph M. , Beiser Alexa , D’Agostino Ralph B. , DeCarli Charles
Published: May 2004

Background and Purpose—

In a previous study of normal elderly male twins, the heritability of quantitative white matter hyperintensity (WMH) volume has been estimated to be high (0.73). We investigated heritability of WMH in a family-based sample of the Framingham Heart Study for sex differences and the impact of age.

Methods—

Brain magnetic resonance scans were performed on 2012 individuals in the cohort and offspring of the Framingham study. This report was limited to 1330 stroke-free and dementia-free members (mean age 61.0 years) of the Framingham offspring. Individuals with a history of multiple sclerosis, stroke, dementia, or other neurological condition including traumatic brain injury were excluded from this analysis. WMH volume and total cranial volume (TCV) were quantified using a previously published algorithm. Because of extreme skewing, measures of WMH were log-transformed before analysis. Variance components methods were used to estimate heritability of WMH after adjusting for sex, age, age
2
, and TCV.

Results—

In the full dataset, WMH heritability was 0.55 (
P
<0.0001). Heritability among women was 0.78 (
P
<0.0001) whereas heritability among men was 0.52 (
P
<0.0003). Heritability varied as average age increased, with a peak of 0.68 (
P
<0.0001) in individuals aged 55 or older.

Conclusion—

Using a family-based study design comprising generally healthy individuals, this study found high heritability of WMH overall and similar heritability for both men and women. In addition, the heritability of WMH remained high among individuals in whom the prevalence of cerebrovascular brain injury was generally low, suggesting that WMH is also likely to be an excellent genetic marker of brain aging.