bluuebunny/crossref_metadata_2025 huggingface dataset:
Overexpression ofTRPC1enhances pulmonary vasoconstriction induced by capacitative Ca2+entry
Authors: Kunichika Naomi , Yu Ying , Remillard Carmelle V. , Platoshyn Oleksandr , Zhang Shen , Yuan Jason X.-J.
Published: June 2004

Transient receptor potential (TRP) cation channels are a critical pathway for Ca2+entry during pulmonary artery (PA) smooth muscle contraction. However, whether canonical TRP (TRPC) subunits and which TRP channel isoforms are involved in store depletion-induced pulmonary vasoconstriction in vivo remain unclear. This study was designed to test whether overexpression of the human TRPC1 gene ( hTRPC1) in rat PA enhances pulmonary vasoconstriction due to store depletion-mediated Ca2+influx. The hTRPC1 was infected into rat PA rings with an adenoviral vector. RT-PCR and Western blot analyses confirmed the mRNA and protein expression of hTRPC1 in the arterial rings. The amplitude of active tension induced by 40 mM K+(40K) in PA rings infected with an empty adenoviral vector (647 ± 88 mg/mg) was similar to that in PA rings infected with hTRPC1 (703 ± 123 mg/mg, P = 0.3). However, the active tension due to capacitative Ca2+entry (CCE) induced by cyclopiazonic acid was significantly enhanced in PA rings overexpressing hTRPC1 (91 ± 13% of 40K-induced contraction) compared with rings infected with an empty adenoviral vector (61 ± 14%, P < 0.001). Endothelial expression of hTRPC1 was not involved since the CCE-induced vasoconstriction was also enhanced in endothelium-denuded PA rings infected with the adenoviral vector carrying hTRPC1. These observations demonstrate that hTRPC1 is an important Ca2+-permeable channel that mediates pulmonary vasoconstriction when PA smooth muscle cell intracellular Ca2+stores are depleted.
Functional magnetic resonance imaging during hypotension in the developing animal
Authors: Henderson Luke A. , Macey Paul M. , Richard Chris A. , Runquist Matthew L. , Harper Ronald M.
Published: June 2004

Hypotension in adult animals recruits brain sites extending from cerebellar cortex to the midbrain and forebrain, suggesting a range of motor and endocrine reactions to maintain perfusion. We hypothesized that comparable neural actions during development rely more extensively on localized medullary processes. We used functional MRI to assess neural responses during sodium nitroprusside challenges in 14 isoflurane-anesthetized kittens, aged 14–25 days, and seven adult cats. Baseline arterial pressure increased with age in kittens, and basal heart rates were higher. The magnitude of depressor responses increased with age, while baroreceptor reflex sensitivity initially increased over those of adults. In contrast to a decline in adult cats, functional MRI signal intensity increased significantly in dorsal and ventrolateral medullary regions and the midline raphe in the kittens during the hypotensive challenges. In addition, significant signal intensity differences emerged in cerebellar cortex and deep nuclei, dorsolateral pons, midbrain tectum, hippocampus, thalamus, and insular cortex. The altered neural responses in medullary baroreceptor reflex sites may have resulted from disinhibitory or facilitatory influences from cerebellar and more rostral structures as a result of inadequately developed myelination or other neural processes. A comparable immaturity of blood pressure control mechanisms in humans would have significant clinical implications.
Oscillation mechanics of the human lung periphery in asthma
Authors: Kaminsky David A. , Irvin Charles G. , Lundblad Lennart , Moriya Henrique T. , Lang Sherburn , Allen Jennifer , Viola Tracey , Lynn Mary , Bates Jason H. T.
Published: June 2004

To more precisely measure the mechanical properties of the lung periphery in asthma, we have developed a forced oscillation technique that applies a broad-band flow signal through a wedged bronchoscope. We interpreted the data from four healthy and eight mildly asthmatic subjects in terms of an anatomically accurate computer model of the wedged segment. There was substantial overlap in impedance between the two groups, with resistance (R) showing minimal frequency dependence and elastance (E) showing positive and negative frequency dependence across subjects. After direct instillation of methacholine, R rose in both groups, but compared with healthy subjects, the asthmatic subjects displayed upward, parallel shifts in their dose-response curves. The baseline frequency-response patterns of E were enhanced after methacholine. Frequency dependencies of R and E were well reproduced in two normal subjects by a computational model that employed rigid airways connected to constant-phase tissue units but were better reproduced in the other two normal and three asthmatic subjects when the model employed heterogeneous, peripheral airway narrowing and compliant airways. To capture the frequency dependencies of R and E in the remaining five asthmatic subjects, the model was modified by increasing airway wall stiffness. These results indicate that the lung periphery of mildly asthmatic subjects is not well distinguished from that of healthy subjects by measurement of mechanical impedance at baseline, but group differences are seen after challenge with methacholine. Modeling of the response suggests that variable contributions of airway narrowing and wall compliance are operative in determining overall mechanical impedance of the lung periphery in humans with asthma, likely reflecting the functional consequences of airway inflammation and remodeling.
Improvement of alveolar-capillary membrane diffusing capacity with exercise training in chronic heart failure
Authors: Guazzi Marco , Reina Giuseppe , Tumminello Gabriele , Guazzi Maurizio D.
Published: June 2004

Chronic heart failure (CHF) may impair lung gas diffusion, an effect that contributes to exercise limitation. We investigated whether diffusion improvement is a mechanism whereby physical training increases aerobic efficiency in CHF. Patients with CHF ( n = 16) were trained (40 min of stationary cycling, 4 times/wk) for 8 wk; similar sedentary patients ( n = 15) were used as controls. Training increased lung diffusion (DlCO, +25%), alveolar-capillary conductance (DM, +15%), pulmonary capillary blood volume (VC, +10%), peak exercise O2 uptake (peak V̇o2, +13%), and V̇o2 at anaerobic threshold (AT, +20%) and decreased the slope of exercise ventilation to CO2 output (V̇e/V̇co2, −14%). It also improved the flow-mediated brachial artery dilation (BAD, from 4.8 ± 0.4 to 8.2 ± 0.4%). These changes were significant compared with baseline and controls. Hemodynamics were obtained in the last 10 patients in each group. Training did not affect hemodynamics at rest and enhanced the increase of cardiac output (+226 vs. +187%) and stroke volume (+59 vs. +49%) and the decrease of pulmonary arteriolar resistance (−28 vs. −13%) at peak exercise. Hemodynamics were unchanged in controls after 8 wk. Increases in Dlco and DM correlated with increases in peak V̇o2 ( r = 0.58, P = 0.019 and r = 0.51, P = 0.04, respectively) and in BAD ( r = 0.57, P < 0.021 and r = 0.50, P = 0.04, respectively). After detraining (8 wk), Dlco, DM, VC, peak V̇o2, V̇o2 at AT, V̇e/V̇co2 slope, cardiac output, stroke volume, pulmonary arteriolar resistance at peak exercise, and BAD reverted to levels similar to baseline and to levels similar to controls. Results document, for the first time, that training improves DlCO in CHF, and this effect may contribute to enhancement of exercise performance.
Effects of 7 wk of endurance training on human skeletal muscle metabolism during submaximal exercise
Authors: LeBlanc Paul J. , Howarth Krista R. , Gibala Martin J. , Heigenhauser George J. F.
Published: June 2004

This is the first study to examine the effects of endurance training on the activation state of glycogen phosphorylase (Phos) and pyruvate dehydrogenase (PDH) in human skeletal muscle during exercise. We hypothesized that 7 wk of endurance training (Tr) would result in a posttransformationally regulated decrease in flux through Phos and an attenuated activation of PDH during exercise due to alterations in key allosteric modulators of these important enzymes. Eight healthy men (22 ± 1 yr) cycled to exhaustion at the same absolute workload (206 ± 5 W; ∼80% of initial maximal oxygen uptake) before and after Tr. Muscle biopsies (vastus lateralis) were obtained at rest and after 5 and 15 min of exercise. Fifteen minutes of exercise post-Tr resulted in an attenuated activation of PDH (pre-Tr: 3.75 ± 0.48 vs. post-Tr: 2.65 ± 0.38 mmol·min−1·kg wet wt−1), possibly due in part to lower pyruvate content (pre-Tr: 0.94 ± 0.14 vs. post-Tr: 0.46 ± 0.03 mmol/kg dry wt). The decreased pyruvate availability during exercise post-Tr may be due to a decreased muscle glycogenolytic rate (pre-Tr: 13.22 ± 1.01 vs. post-Tr: 7.36 ± 1.26 mmol·min−1·kg dry wt−1). Decreased glycogenolysis was likely mediated, in part, by posttransformational regulation of Phos, as evidenced by smaller net increases in calculated muscle free ADP (pre-Tr: 111 ± 16 vs. post-Tr: 84 ± 10 μmol/kg dry wt) and Pi(pre-Tr: 57.1 ± 7.9 vs. post-Tr: 28.6 ± 5.6 mmol/kg dry wt). We have demonstrated for the first time that several signals act to coordinately regulate Phos and PDH, and thus carbohydrate metabolism, in human skeletal muscle after 7 wk of endurance training.
Soluble gas exchange in the pulmonary airways of sheep
Authors: Schimmel Carmel , Bernard Susan L. , Anderson Joseph C. , Polissar Nayak L. , Lakshminarayan S. , Hlastala Michael P.
Published: June 2004

We studied the airway gas exchange properties of five inert gases with different blood solubilities in the lungs of anesthetized sheep. Animals were ventilated through a bifurcated endobronchial tube to allow independent ventilation and collection of exhaled gases from each lung. An aortic pouch at the origin of the bronchial artery was created to control perfusion and enable infusion of a solution of inert gases into the bronchial circulation. Occlusion of the left pulmonary artery prevented pulmonary perfusion of that lung so that gas exchange occurred predominantly via the bronchial circulation. Excretion from the bronchial circulation (defined as the partial pressure of gas in exhaled gas divided by the partial pressure of gas in bronchial arterial blood) increased with increasing gas solubility (ranging from a mean of 4.2 × 10−5 for SF6 to 4.8 × 10−2 for ether) and increasing bronchial blood flow. Excretion was inversely affected by molecular weight (MW), demonstrating a dependence on diffusion. Excretions of the higher MW gases, halothane (MW = 194) and SF6 (MW = 146), were depressed relative to excretion of the lower MW gases ethane, cyclopropane, and ether (MW = 30, 42, 74, respectively). All results were consistent with previous studies of gas exchange in the isolated in situ trachea.
The flow of a non‐Newtonian fluid induced due to the oscillations of a porous plate
Authors: Asghar S. , Mohyuddin M. R. , Hayat T. , Siddiqui A. M.
Published: June 2004

An analytic solution of the flow of a third‐grade fluid on a porous plate is constructed. The porous plate is executing oscillations in its own plane with superimposed injection or suction. An increasing or decreasing velocity amplitude of the oscillating porous plate is also examined. It is also shown that in case of third‐grade fluid, a combination of suction/injection and decreasing/increasing velocity amplitude is possible as well. Several limiting situations with their implications are given and discussed.
Adaptive stabilization of continuous‐time systems through a controllable modified estimation model
Authors: de la Sen M.
Published: June 2004

This paper presents an indirect adaptive control scheme of continuous‐time systems. The estimated plant model is controllable and then the adaptive scheme is free from singularities. Such singularities are avoided through a modification of the estimated plant parameter vector so that its associated Sylvester matrix is guaranteed to be nonsingular. That property is achieved by ensuring that the absolute value of its determinant does not lie below a positive threshold. An alternative modification scheme based on the achievement of a modifieddiagonally dominant Sylvester matrix of the parameter estimates is also proposed. This diagonal dominance is achieved through estimates modification as a way to guarantee the controllability of the modified estimated model when a controllability measure of the estimation model without modification fails. In both schemes, the use of an explicit hysteresis switching function for the modification of the estimates is not required to ensure the controllability of the modified estimated model. Both schemes ensure that chattering due to switches associated with the modification is not present.
Higher‐order Melnikov functions for single‐DOF mechanical oscillators: theoretical treatment and applications
Authors: Lenci Stefano , Rega Giuseppe
Published: June 2004

A Melnikov analysis of single‐degree‐of‐freedom (DOF) oscillators is performed by taking into account the first (classical) and higher‐order Melnikov functions, by considering Poincaré sections nonorthogonal to the flux, and by explicitly determining both the distance between perturbed and unperturbed manifolds (“one‐half” Melnikov functions) and the distance between perturbed stable and unstable manifolds (“full” Melnikov function). The analysis is developed in an abstract framework, and a recursive formula for computing the Melnikov functions is obtained. These results are then applied to various mechanical systems. Softening versus hardening stiffness and homoclinic versus heteroclinic bifurcations are considered, and the influence of higher‐order terms is investigated in depth. It is shown that the classical (first‐order) Melnikov analysis is practically inaccurate at least for small and large excitation frequencies, in correspondence to degenerate homo/heteroclinic bifurcations, and in the case of generic periodic excitations.
Reliability for Laplace distributions
Authors: Nadarajah Saralees
Published: June 2004

In the area of stress‐strength models there has been a large amount of work as regards estimation of the reliability R = Pr(X2 < X1) when X1 and X2 are independent random variables belonging to the same univariate family of distributions. The algebraic form for R = Pr(X2 < X1) has been worked out for the majority of the well‐known distributions in the standard forms. However, there are still many other distributions (including generalizations of the well‐known distributions) for which the form of R has not been derived. In this paper, we consider several Laplace distributions and derive the corresponding forms for the reliability R. The calculations involve the use of special functions.
Nonuniqueness theorem for a singular Cauchy‐Nicolettiproblem
Authors: Kalas Josef
Published: June 2004

The problem of nonuniqueness for a singular Cauchy‐Nicoletti
boundary value problem is studied. The general nonuniqueness
theorem ensuring the existence of two different solutions is given
such that the estimating expressions are nonlinear, in general,
and depend on suitable Lyapunov functions. The applicability of
results is illustrated by several examples.
Accurate solution estimates for nonlinear nonautonomous vector difference equations
Authors: Medina Rigoberto , Gil′ M. I.
Published: June 2004

The paper deals with the vector discrete dynamical system
xk+1 = Akxk + fk(xk). Thewell‐known result by
Perron states that this system is asymptotically stable if
Ak ≡ A = const
is stable and . Perron′s result gives no information about the
size of the region of asymptotic stability and norms of
solutions. In this paper, accurate estimates for the norms of
solutions are derived. They give us stability conditions for
(1.1) and bounds for the region of attraction of the
stationary solution. Our approach is based on the “freezing”
method for difference equations and on recent estimates for the
powers of a constant matrix. We also discuss applications of our
main result to partial reaction‐diffusion difference equations.
Generalizations of the Bernoulli and Appell polynomials
Authors: Bretti Gabriella , Natalini Pierpaolo , Ricci Paolo E.
Published: June 2004

We first introduce a generalization of the Bernoulli polynomials,
and consequently of the Bernoulli numbers, starting from suitable
generating functions related to a class of Mittag‐Leffler
functions. Furthermore, multidimensional extensions of the
Bernoulli and Appell polynomials are derived generalizing the
relevant generating functions, and using the Hermite‐Kampé de
Fériet (or Gould‐Hopper) polynomials. The main properties of
these polynomial sets are shown. In particular, the differential
equations can be constructed by means of the factorization method.
Nonmonotone impulse effects in second‐order periodicboundary value problems
Authors: Rachůnková Irena , Tvrdý Milan
Published: June 2004

We deal with the nonlinear impulsive periodic boundary value
problem u″ = f(t, u, u′), u(ti+) = Ji(u(ti)), u′(ti+) = Mi(u′(ti)), i = 1, 2, …, m, u(0) = u(T), u′(0) = u′(T). We establish the existence results which rely on
the presence of a well‐ordered pair (σ1, σ2) of
lower/upper functions (σ1 ≤ σ2 on [0, T]) associated with the problem. In contrast to previous papers
investigating such problems, the monotonicity of the impulse
functions Ji, Mi is not required here.
Conditions for the oscillation of solutions ofiterative equations
Authors: Nowakowska Wiesława , Werbowski Jarosław
Published: June 2004

We give some oscillation criteria for linear iterative functional
equations. We compare obtained theorems with
known results. We give applications to discrete equations too.
The operator B*L for the wave equation withDirichlet control
Authors: Lasiecka I. , Triggiani R.
Published: June 2004

In the case of the wave equation, defined on a sufficiently smooth
bounded domain of arbitrary dimension, and subject to Dirichlet
boundary control, the operator B*L from boundary to boundary is
bounded in the L2‐sense. The proof combines hyperbolic
differential energy methods with a microlocal elliptic component.
Deleterious Effect of Coronary Brachytherapy on Vasomotor Response to Exercise
Authors: Togni Mario , Windecker Stephan , Wenaweser Peter , Tueller David , Kaisaier Abudukadier , Maier Willibald , Meier Bernhard , Hess Otto M.
Published: June 2004

Background—

Intracoronary radiotherapy (brachytherapy) has been proposed as treatment option for in-stent restenosis. Long-term results of brachytherapy with regard to vascular integrity and vasomotor responsiveness are unknown. The purpose of the present study was to determine the vasomotor response after brachytherapy and to assess its influence on vasomotion during exercise.

Methods and Results—

Biplane quantitative coronary angiography was performed at rest and during bicycle exercise in 27 patients with coronary artery disease. Fourteen patients underwent coronary stenting and were studied 10±3 months after intervention (control group). Thirteen patients were treated with brachytherapy (Guidant Galileo System) for in-stent restenosis with a mean dosis of 20 Gy at 1 mm into the vessel wall and were studied 9±1 months after radiation (brachytherapy group). Minimal luminal area, stent area, and proximal, distal, and a reference vessel area were determined. The reference vessel showed exercise-induced vasodilation (26±4%,
P
<0.001) in both groups. Vasomotion within the stented vessel segments was abolished. In control subjects, the proximal and distal segments showed exercise-induced vasodilation (17±2% and 22±7%, respectively;
P
<0.005). In contrast, there was exercise-induced vasoconstriction in the proximal and distal vessel segments of the brachytherapy group (−14±3% and −16±4%, respectively;
P
<0.01). Sublingual nitroglycerin was associated with maximal vasodilation of the proximal and distal vessel segments in both groups.

Conclusions—

Normal vessel segments elicit flow-mediated vasodilation during exercise. Stent implantation does not affect physiological response to exercise proximal and distal to the stent. Brachytherapy eliminates exercise-induced vasodilation, although dilatory response to nitroglycerin is maintained, suggesting endothelial dysfunction as the underlying mechanism.
Creation of an Atrial Septal Defect In Utero for Fetuses With Hypoplastic Left Heart Syndrome and Intact or Highly Restrictive Atrial Septum
Authors: Marshall Audrey C. , van der Velde Mary E. , Tworetzky Wayne , Gomez Carlen A. , Wilkins-Haug Louise , Benson Carol B. , Jennings Russell W. , Lock James E.
Published: June 2004

Background—

Infants born with hypoplastic left heart syndrome and an intact or highly restrictive atrial septum face a neonatal mortality of at least 48% despite early postnatal left atrial decompression and palliative surgery. Prenatal left atrial decompression has been suggested as a means of improving these outcomes. This study reports the feasibility of fetal catheterization to create an interatrial communication and describes technical considerations.

Methods and Results—

Seven fetuses at 26 to 34 weeks’ gestation with hypoplastic left heart syndrome and intact or highly restrictive atrial septum underwent attempted prenatal intervention. Under ultrasound guidance, the atrial septum was approached with a needle introduced percutaneously from the maternal abdominal surface. In 6 of 7 fetuses, the atrial septum was successfully perforated, with balloon dilation of this iatrogenic defect resulting in a small but persistent interatrial communication. There were no maternal complications. One fetus died after the procedure. The remaining fetuses were liveborn at term, although 4 died as neonates.

Conclusions—

Ultrasound-guided fetal atrial septoplasty consisting of septal puncture and balloon dilation is feasible and can be performed percutaneously to minimize maternal risk. Although we have not demonstrated any positive clinical impact to date, it is our hope that further technical evolution will ultimately enable prenatal left atrial decompression and improvement of outcomes in fetuses with hypoplastic left heart syndrome and intact atrial septum.
Heart Failure and Sudden Death in Patients With Tachycardia-Induced Cardiomyopathy and Recurrent Tachycardia
Authors: Nerheim Pamela , Birger-Botkin Sally , Piracha Lubna , Olshansky Brian
Published: June 2004

Background—

Tachycardia-induced cardiomyopathy is a reversible cause of heart failure. We hypothesized that although left ventricular ejection fraction measurements normalize after heart rate or rhythm control in patients with tachycardia-induced cardiomyopathy, recurrent tachycardia may have abrupt and deleterious consequences.

Methods and Results—

Patients with tachycardia-induced cardiomyopathy that developed over years were evaluated and treated. Tachycardia episodes and outcomes were assessed. Twenty-four patients were identified. All had NYHA functional class III heart failure or greater on presentation. One third were heart transplant candidates. There were 17 men and 7 women with a mean age of 46±16 years and mean left ventricular ejection fraction of 0.26±0.09 at the index visit. The cause was atrial fibrillation (n=13), atrial flutter (n=4), atrial tachycardia (n=3), idiopathic ventricular tachycardia (n=1), permanent junctional reciprocating tachycardia (n=2), and bigeminal ventricular premature contractions (n=1). Within 6 months of rate control or correction of the rhythm, left ventricular ejection fraction improved or normalized and symptoms abated in all. Five patients had tachycardia recur. In these patients, left ventricular ejection fraction dropped precipitously and heart failure ensued within 6 months, even though the initial impairment took years. Rate control eliminated heart failure and improved or normalized ejection fraction in 6 months. Three of 24 patients died suddenly and unexpectedly.

Conclusions—

Tachycardia-induced cardiomyopathy develops slowly and appears reversible by left ventricular ejection fraction improvement, but recurrent tachycardia causes rapid decline in left ventricular function and development of heart failure. Sudden death is possible.
Heme Oxygenase-1 Inhibits Angiotensin II-Induced Cardiac Hypertrophy In Vitro and In Vivo
Authors: Hu Chien-Ming , Chen Yen-Hui , Chiang Ming-Tsai , Chau Lee-Young
Published: June 2004

Background—

Heme oxygenase-1 (HO-1) is a stress-response enzyme implicated in cardioprotection. To explore whether HO-1 has a role in cardiac remodeling response, the effect of its overexpression on angiotensin II (Ang II)-induced cardiac hypertrophy was examined.

Methods and Results—

HO-1 was induced in cultured rat neonatal cardiomyocytes by treatment with cobalt protoporphyrin IX (CoPPIX) or a recombinant adenovirus carrying the human HO-1 gene. Ang II-induced myocyte hypertrophy assessed by increments in cell size, [
3
H]leucine uptake, and protein content was suppressed by HO-1 overexpression. Cotreatment of cells with tin protoporphyrin IX, a HO inhibitor, significantly reversed the suppressive effect of HO-1. Bilirubin, one of the byproducts of heme degradation by HO-1, mediated the suppressive effect through the inhibition of Ang II-induced production of reactive oxygen species, as detected by a 2′,7′-dichlorofluorescein probe. The antihypertrophic effect of HO-1 was also demonstrated in rats receiving chronic Ang II infusions. Cotreatment of animals with CoPPIX significantly attenuated Ang II-induced left ventricular hypertrophy and hyperdynamic contractions, whereas concomitant treatment with tin protoporphyrin IX abolished CoPPIX-mediated cardioprotection in vivo.

Conclusions—

HO-1 attenuates Ang II-induced cardiac hypertrophy both in vitro and in vivo, and bilirubin mediates, at least in part, the antihypertrophic effect of HO-1 via inhibition of reactive oxygen species production after Ang II stimulation.
Unstable Carotid Plaques Exhibit Raised Matrix Metalloproteinase-8 Activity
Authors: Molloy K.J. , Thompson M.M. , Jones J.L. , Schwalbe E.C. , Bell P.R.F. , Naylor A.R. , Loftus I.M.
Published: June 2004

Background—

The fibrous cap of atherosclerotic plaques is composed predominantly of type I and III collagen. Unstable carotid plaques are characterized by rupture of their cap, leading to thromboembolism and stroke. The proteolytic mechanisms causing plaque disruption are undefined, but the collagenolytic matrix metalloproteinase (MMP) -1, -8, and -13 may be implicated. The aim of this study was to quantify the concentrations of these collagenases in carotid plaques and to determine their relationship to markers of plaque instability.

Methods and Results—

Atherosclerotic plaques were collected from 159 patients undergoing carotid endarterectomy. The presence and timing of carotid territory symptoms were ascertained. Preoperative embolization was recorded by transcranial Doppler. Each plaque was assessed for histological features of instability. Plaque MMP concentrations were quantified with ELISA. Significantly higher concentrations of active MMP-8 were observed in the plaques of symptomatic patients (20.5 versus 11.4 ng/g;
P
=0.0002), in plaques of emboli-positive patients (22.7 versus 13.5 ng/g;
P
=0.0037), and in those plaques showing histological evidence of rupture (20.8 versus 14.7 ng/g;
P
=0.0036). No differences were seen in the levels of MMP-1 and MMP-13. Immunohistochemistry, in situ hybridization, and colocalization studies confirmed the presence of MMP-8 protein and mRNA within the plaque, which colocalized with macrophages.

Conclusions—

These data suggest that the active form of MMP-8 may be partly responsible for degradation of the collagen cap of atherosclerotic plaques. This enzyme represents an attractive target for drug therapy aimed at stabilizing vulnerable plaques.
Prevalence of Fetal-Type Smooth Muscle Cells in the Media of Microvessels From Hypertensive Patients
Authors: Puato Massimo , Faggin Elisabetta , Favaretto Elisabetta , Bertipaglia Barbara , Rattazzi Marcello , Rizzoni Damiano , Gamba Gian Paolo , Sartore Saverio , Rosei Enrico Agabiti , Pessina Achille Cesare , Pauletto Paolo
Published: June 2004

Significant structural and functional changes in smooth muscle cells (SMCs) of microvessels (diameter 30 to 300 μm) occur in hypertension. However, in microvessels of hypertensive patients, the differentiation pattern of SMCs underlying such changes remains undefined. To analyze the differentiation pattern of SMCs (adult, postnatal, or fetal), 49 muscle biopsies (rectus abdominis) were analyzed: 16 from children (aged 11 months to 11 years), 15 from normotensive adults (aged 55 to 74 years), 18 from hypertensive adults (aged 55 to 74 years). Transverse cryosections of specimens were studied by immunocytochemistry using monoclonal antibodies SM-E7 and NM-F6, which recognize smooth muscle myosin heavy chain (MyHC) and A
pla1
-like nonmuscle MyHC, respectively. The total number of microvessels was assessed via SM-E7 staining. The number of NM-F6 positive (fetal-type SMC) or negative (adult-type SMC) microvessels was assessed. The number of microvessels per area unit was considerably lower (
P
<0.0005) in normotensive adults (0.22±0.17) than in children (0.98±0.61). Even more significant reduction was found in hypertensive adults compared with control adults (
P
=0.013) and children (
P
<0.0005). The qualitative immunocytochemistry analysis by NM-F6 revealed 2 differentiation patterns of the media layer of microvessels: positive or negative. In hypertensive subjects, the percentage of microvessels positive to NM-F6 was 49.8±35.6%, close to that found in children (50.6±12.6%), whereas in normotensive subjects it was significantly lower (24.4±21.1%). The following conclusions were drawn. (1) The medial layer of microvessels is heterogeneous in terms of SMC differentiation. (2) In hypertension, a prevalence of fetal-type SMCs takes place in microvessels, resembling that of children. Compared with children, a rarefaction of microvessels is present in normotensive adults that is even more remarkable in hypertensive adults.
New Gender-Specific Partition Values for ECG Criteria of Left Ventricular Hypertrophy
Authors: Alfakih Khaled , Walters Kevin , Jones Tim , Ridgway John , Hall Alistair S. , Sivananthan Mohan
Published: June 2004

ECG criteria for left ventricular hypertrophy (LVH) were mostly validated using left ventricular mass (LVM) as measured by M-mode echocardiography. LVM as measured by cardiac MRI has been demonstrated to be much more accurate and reproducible. We reevaluated the sensitivity and specificity of 4 ECG criteria of LVH against LVM as measured by cardiac MRI. Patients with systemic hypertension (n=288) and 60 normal volunteers had their LVM measured using a 1.5-Tesla MRI system. A 12-lead ECG was recorded, and 4 ECG criteria were evaluated: Sokolow-Lyon voltage, Cornell voltage, Cornell product, and Sokolow-Lyon product. Based on a cardiac MRI normal range, 39.9% of the hypertensive males and 36.7% of the hypertensive females had elevated LVM index. At a specificity of 95%, the Sokolow-Lyon product criterion had the highest sensitivity in females (26.2%), the Cornell criterion had the highest sensitivity in males (26.2%), and the Cornell product criteria had a relatively high sensitivity in both males and females (25.0% and 23.8%). Receiver operating characteristic curves showed the Cornell and Cornell product criteria to be superior for males whereas the Sokolow-Lyon product criterion was superior for females. Comparing the mean LVM index values of the subjects who were ECG LVH positive to the normal volunteers indicated that the ECG LVH criteria detect individuals with an LVM index substantially above the normal range. We have redefined the partition values for 4 different ECG LVH criteria, according to gender, and found that they detect subjects with markedly elevated LVM index.
Enhancement of Collecting Duct Renin in Angiotensin II–Dependent Hypertensive Rats
Authors: Prieto-Carrasquero Minolfa C. , Harrison-Bernard Lisa M. , Kobori Hiroyuki , Ozawa Yuri , Hering-Smith Kathleen S. , Hamm L. Lee , Navar L. Gabriel
Published: June 2004

Distal nephron renin may provide a possible pathway for angiotensin (Ang) I generation from proximally delivered angiotensinogen. To examine the effects of Ang II on distal nephron renin, we compared renin protein and mRNA expression in control and Ang II–infused rats. Kidneys from sham (n=9) and Ang II–infused (80 ng/kg per minute, 13 days, n=10) Sprague-Dawley rats were processed by immunohistochemistry, Western blot, reverse transcriptase–polymerase chain reaction (RT-PCR), and quantitative real-time RT-PCR. Ang II infusion increased systolic blood pressure (181±4 versus 115±5 mm Hg) and suppressed plasma and kidney cortex renin activity. Renin immunoreactivity was suppressed in juxtaglomerular apparatus (JGA) cells in Ang II–infused rats compared with sham (0.1±0.1 versus 1.0±0.1 relative ratio) but increased in distal nephron segments (6.4±1.4 versus 1.0±0.1 cortex; 2.5±0.3 versus 1.0±0.2 medulla). Tubular renin immunostaining was apically distributed in principal cells colocalizing with aquaporin-2 in connecting tubules and cortical and medullary collecting ducts. Renin protein levels were decreased in the kidney cortex of Ang II–infused rats compared with that of sham (0.4±0.2 versus 1.0±0.4) rats but higher in the kidney medulla (1.2±0.4 versus 1.0±0.1). In kidney medulla, RT-PCR and quantitative real-time PCR showed similar levels of renin transcript in both groups. In summary, the detection of renin mRNA in the renal medulla, which is devoid of JGA, indicates local synthesis rather than an uptake of JGA renin. In contrast to the inhibitory effect of Ang II on JGA renin, Ang II infusion stimulates renin protein expression in collecting ducts and maintains renin transcriptional levels in the medulla, which may contribute to the increased intrarenal Ang II levels in Ang II–dependent hypertension.
Upregulation of Endothelial Nitric Oxide Synthase by Cyanidin-3-Glucoside, a Typical Anthocyanin Pigment
Authors: Xu Jin-Wen , Ikeda Katsumi , Yamori Yukio
Published: June 2004

Endothelial nitric oxide synthase (eNOS) plays an important role in maintaining blood pressure homeostasis and vascular integrity. Natural dietary flavoniods are thought to protect against cardiovascular diseases by acting as antioxidants and vasodilatants. This study examined the effect of cyanidin-3-glucoside (Cy3G), a typical anthocyanin pigment, on eNOS expression. Treatment of bovine artery endothelial cells (BAECs) with Cy3G for 8 hours of enhanced eNOS protein expression in a dose- and time-dependent manner was determined by Western blot analysis. Longer incubation (12, 16, and 24 hours) of BAECs with 0.1 μmol/L of Cy3G caused a further increase in eNOS expression, and subsequently Cy3G also significantly increased nitric oxide output 2-fold (24 hours). Furthermore, Cy3G stimulated the phosphorylation of Src and extracellular signal-regulated kinase 1/2 (ERK1/2) in a time-dependent manner. An Src kinase inhibitor, pp2, and MEK inhibitor, PD98059, blocked the ERK1/2 phosphorylation and eNOS expression. Transfection with dominant-negative Src cDNA also inhibited the eNOS expression stimulated by Cy3G. In addition, stimulation with Cy3G for 30 minutes resulted in a phosphorylation of Sp1 that was blocked by PD98059. Cy3G enhanced the binding activity of the transcription factor Sp1 to the GC box in the proximal eNOS promoter of BAECs, as revealed by chromatin immunoprecipitation assay. The present study demonstrated that Cy3G induced eNOS expression and escalated NO production via an Src-ERK1/2-Sp1 signaling pathway in vascular endothelial cells. Increased eNOS expression may help to ameliorate endothelial dysfunction, harmonize blood pressure, and prevent atherosclerosis as long-term beneficial effects of flavoniods.
Relationship Between COX-2 Specific Inhibitors and Hypertension
Authors: Solomon Daniel H. , Schneeweiss Sebastian , Levin Raisa , Avorn Jerry
Published: June 2004

There is controversy whether cyclooxygenase-2 (COX-2) specific inhibitors are associated with elevations in blood pressure requiring treatment in typical clinical practice. We examined the risk of new onset hypertension in a retrospective case-control study involving 17 844 subjects aged ≥65 years from 2 US states. Multivariable logistic models were examined to assess the relative risk of new onset hypertension requiring treatment in patients who used celecoxib or rofecoxib compared with patients taking either the other COX-2 specific inhibitor, a nonspecific NSAID, or no NSAID. During the 1999 to 2000 study period, 3915 patients were diagnosed and began treatment for hypertension; 4 controls were selected for every case. In no model was celecoxib significantly associated with the development of hypertension. Rofecoxib users were at a significantly increased relative risk of new onset hypertension compared with patients taking celecoxib (odds ratio [OR] 1.6; 95% confidence interval [CI], 1.2 to 2.1), taking a nonspecific NSAID (OR 1.4; 95% CI, 1.1 to 1.9), or taking no NSAID (OR 1.6; 95% CI, 1.3 to 2.0). There were no clear dosage or duration effects. In patients with a history of chronic renal disease, liver disease, or congestive heart failure, the relative risk of new onset hypertension was twice as high in those taking rofecoxib compared with celecoxib (OR 2.1; 95% CI, 1.0 to 4.3). In this retrospective case-control study of patients aged ≥65 years, rofecoxib use was associated with an increased relative risk of new onset hypertension; this was not seen in patients taking celecoxib.
Preventing Cancer, Cardiovascular Disease, and Diabetes
Authors: Eyre Harmon , Kahn Richard , Robertson Rose Marie
Published: June 2004

Collectively, cardiovascular disease (including stroke), cancer, and diabetes account for approximately two thirds of all deaths in the United States and about $700 billion in direct and indirect economic costs each year. Current approaches to health promotion and prevention of cardiovascular disease, cancer, and diabetes do not approach the potential of the existing state of knowledge. A concerted effort to increase application of public health and clinical interventions of known efficacy to reduce prevalence of tobacco use, poor diet, and insufficient physical activity—the major risk factors for these diseases—and to increase utilization of screening tests for their early detection could substantially reduce the human and economic cost of these diseases. In this article, the ACS, ADA, and AHA review strategies for the prevention and early detection of cancer, cardiovascular disease, and diabetes, as the beginning of a new collaboration among the three organizations. The goal of this joint venture is to stimulate substantial improvements in primary prevention and early detection through collaboration between key organizations, greater public awareness about healthy lifestyles, legislative action that results in more funding for and access to primary prevention programs and research, and reconsideration of the concept of the periodic medical checkup as an effective platform for prevention, early detection, and treatment. (
Stroke
. 2004;35:1999-2010)
Autopoiesis and Cognition in the Game of Life
Authors: Beer Randall D.
Published: June 2004

Maturana and Varela's notion of autopoiesis has the potential to transform the conceptual foundation of biology as well as the cognitive, behavioral, and brain sciences. In order to fully realize this potential, however, the concept of autopoiesis and its many consequences require significant further theoretical and empirical development. A crucial step in this direction is the formulation and analysis of models of autopoietic systems. This article sketches the beginnings of such a project by examining a glider from Conway's game of life in autopoietic terms. Such analyses can clarify some of the key ideas underlying autopoiesis and draw attention to some of the central open issues. This article also examines the relationship between an autopoietic perspective on cognition and recent work on dynamical approaches to the behavior and cognition of situated, embodied agents.
Thirty Years of Computational Autopoiesis: A Review
Authors: McMullin Barry
Published: June 2004

Computational autopoiesis—the realization of autopoietic entities in computational media—holds an important and distinctive role within the field of artificial life. Its earliest formulation by Francisco Varela, Humberto Maturana, and Ricardo Uribe was seminal in demonstrating the use of an artificial, computational medium to explore the most basic question of the abstract nature of living systems—over a decade in advance of the first Santa Fe Workshop on Artificial Life. The research program it originated has generated substantive demonstrations of progressively richer, lifelike phenomena. It has also sharply illuminated both conceptual and methodological problems in the field. This article provides an integrative overview of the sometimes disparate work in this area, and argues that computational autopoiesis continues to provide an effective framework for addressing key open problems in artificial life.
Autopoiesis and Cognition
Authors: Bourgine Paul , Stewart John
Published: June 2004

This article revisits the concept of autopoiesis and examines its relation to cognition and life. We present a mathematical model of a 3D tesselation automaton, considered as a minimal example of autopoiesis. This leads us to a thesis T1: “An autopoietic system can be described as a random dynamical system, which is defined only within its organized autopoietic domain.” We propose a modified definition of autopoiesis: “An autopoietic system is a network of processes that produces the components that reproduce the network, and that also regulates the boundary conditions necessary for its ongoing existence as a network.” We also propose a definition of cognition: “A system is cognitive if and only if sensory inputs serve to trigger actions in a specific way, so as to satisfy a viability constraint.” It follows from these definitions that the concepts of autopoiesis and cognition, although deeply related in their connection with the regulation of the boundary conditions of the system, are not immediately identical: a system can be autopoietic without being cognitive, and cognitive without being autopoietic. Finally, we propose a thesis T2: “A system that is both autopoietic and cognitive is a living system.”
Autopoiesis and Natural Drift: Genetic Information, Reproduction, and Evolution Revisited
Authors: Etxeberria Arantza
Published: June 2004

The contribution of the theory of autopoiesis to the definition of life and biological theory affirms biological autonomy as a central notion of scientific and philosophical inquiry, and opposes other biological approaches, based on the notion of genetic information, that consider reproduction and evolution to be the central aspects of life and living phenomenology. This article reviews the autopoietic criticisms of genetic information, reproduction, and evolution in the light of a biology that can solve the problem of living organization.
Basic Autonomy as a Fundamental Step in the Synthesis of Life
Authors: Ruiz-Mirazo Kepa , Moreno Alvaro
Published: June 2004

In the search for the primary roots of autonomy (a pivotal concept in Varela's comprehensive understanding of living beings), the theory of autopoiesis provided an explicit criterion to define minimal life in universal terms, and was taken as a guideline in the research program for the artificial synthesis of biological systems. Acknowledging the invaluable contribution of the autopoietic school to present biological thinking, we offer an alternative way of conceiving the most basic forms of autonomy. We give a bottom-up account of the origins of “self-production” (or self-construction, as we propose to call it), pointing out which are the minimal material and energetic requirements for the constitution of basic autonomous systems. This account is, indeed, committed to the project of developing a general theory of biology, but well grounded in the universal laws of physics and chemistry. We consider that the autopoietic theory was formulated in highly abstract terms and, in order to advance in the implementation of minimal autonomous systems (and, at the same time, make major progress in exploring the origins of life), a more specific characterization of minimal autonomous systems is required. Such a characterization will not be drawn from a review of the autopoietic criteria and terminology (à la Fleischaker) but demands a whole reformulation of the question: a proper naturalization of the concept of autonomy. Finally, we also discuss why basic autonomy, according to our account, is necessary but not sufficient for life, in contrast with Varela's idea that autopoiesis was a necessary and sufficient condition for it.
The Affirmation of Self: A New Perspective on the Immune System
Authors: Stewart John , Coutinho Antonio
Published: June 2004

The fundamental concepts of autopoiesis, which emphasize the circular organization underlying both living organisms and cognition, have been criticized on the grounds that since they are conceived as a tight logical chain of definitions and implications, it is often not clear whether they are indeed a scientific theory or rather just a potential scientific vocabulary of doubtful utility to working scientists. This article presents the deployment of the concepts of autopoiesis in the field of immunology, a discipline where working biologists themselves spontaneously have long had recourse to “cognitive” metaphors: “recognition”; a “repertoire” of recognized molecular shapes; “learning” and “memory”; and, most striking of all, a “self versus non-self” distinction. It is shown that in immunology, the concepts of autopoiesis can be employed to generate clear novel hypotheses, models demonstrating these ideas, testable predictions, and novel therapeutic procedures. Epistemologically, it is shown that the self–non-self distinction, while quite real, is misleadingly named. When a real mechanism for generating this distinction is identified, it appears that the actual operational distinction is between (a) a sufficiently numerous set of initial antigens, present from the start of ontogeny, in conditions that allow for their participation in the construction of the system's organization and operation, and (b) single antigens that are first presented to the system after two successive phases of maturation. To call this a self–non-self distinction obscures the issue by presupposing what it ought to be the job of scientific investigation to explain.