bluuebunny/crossref_metadata_2025 huggingface dataset:
Both cGMP and peroxynitrite mediate chronic interleukin‐6‐induced negative inotropy in adult rat ventricular myocytes
Authors: Yu Xin‐Wen , Liu Meei‐Yueh G. , Kennedy Richard H. , Liu Shi J.
Published: May 2005

We previously showed that chronic exposure to interleukin (IL)‐6 decreases contractile and sarcoplasmic reticular (SR) function assessed by postrest potentiation (PRP) via a nitric oxide (NO)‐dependent mechanism in adult rat ventricular myocytes (ARVM). Cyclic GMP (cGMP) has been associated with NO‐associated negative inotropic effects of IL‐6 during acute exposure; however, its role in chronic cardiac effects of IL‐6 remains unclear. The present study examined the roles of cGMP and peroxynitrite (ONOO−) in chronic IL‐6‐induced negative inotropy in ARVM. After ARVM were exposed to IL‐6 for 2–24 h, intracellular cGMP contents were time dependently increased; this was mimicked by a NO donor and abolished by 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one (ODQ), an inhibitor of soluble guanylyl cyclase (sGC), or Rp‐8‐Br‐cGMP, an inhibitor of cGMP‐dependent protein kinase G (PKG). Meanwhile, the IL‐6‐induced decrease in PRP at 2 h was blocked by ODQ or Rp‐8‐Br‐cGMP. By contrast, ODQ or Rp‐8‐Br‐cGMP only attenuated the inhibition of PRP induced by IL‐6 after 24 h exposure. Furthermore, IL‐6 time dependently increased superoxide anion production and ONOO− formation; the latter was abolished by 5,10,15,20‐tetrakis‐(4‐sulphonatophenyl)‐porphyrinato iron (III) (FeTPPS), an ONOO− decomposition catalyst. Interestingly, FeTPPS had no effect on the IL‐6‐elicited decrease in PRP at 2 h, but attenuated it after 24 h exposure. Moreover, inhibition of sGC/cGMP/PKG, but not ONOO− formation, abolished the IL‐6‐induced inhibition of kinetics of myocyte contraction during 24 h exposure. We conclude that while the sGC/cGMP/PKG pathway was the primary mechanism for chronic IL‐6‐induced negative inotropy at 2 h, both sGC/cGMP/PKG and ONOO−, at least in part, mediate the IL‐6‐induced inhibition of SR function after 24 h exposure.
Synaptic input of rat spinal lamina I projection and unidentified neurones in vitro
Authors: Dahlhaus Anne , Ruscheweyh Ruth , Sandkühler Jürgen
Published: May 2005

Spinal lamina I projection neurones that transmit nociceptive information to the brain play a pivotal role in hyperalgesia in various animal models of inflammatory and neuropathic pain. Consistently, activity‐dependent long‐term potentiation can be induced at synapses between primary afferent C‐fibres and lamina I projection neurones but not unidentified neurones in lamina I. The specific properties that enable projection neurones to undergo long‐term potentiation and mediate hyperalgesia are not fully understood. Here, we have tested whether lamina I projection neurones differ from unidentified neurones in types or strength of primary afferent input and/or action potential‐independent excitatory and inhibitory input. We used the whole‐cell patch‐clamp technique to record synaptic currents in projection and unidentified lamina I neurones in a transverse lumbar spinal cord slice preparation from rats between postnatal day 18 and 37. Lamina I neurones with a projection to the parabrachial area or the periaqueductal grey were identified by retrograde labelling with a fluorescent tracer. The relative contribution of NMDA receptors versus AMPA/kainate receptors to C‐fibre‐evoked excitatory postsynaptic currents of lamina I neurones significantly decreased with age between postnatal day 18 and 27, but was independent of the supraspinal projection of the neurones. We did not find a significant contribution of kainate receptors to C‐fibre‐evoked excitatory postsynaptic currents. Lamina I projection and unidentified neurones possessed functional GABAA and glycine receptors but received scarce action potential‐independent spontaneous GABAergic and glycinergic inhibitory input as measured by miniature inhibitory postsynaptic currents. The miniature excitatory postsynaptic current frequencies were five times higher in projection than in unidentified neurones. The predominance of excitatory synaptic input to projection neurones, taken together with the previous finding that their membranes are more easily excitable than those of unidentified neurones, may facilitate the induction of synaptic long‐term potentiation.
A conversion method of air kerma from the primary, scatter, and leakage radiations to effective dose for calculating x‐ray shielding barriers in mammography
Authors: Kharrati Hedi
Published: May 2005

In this study, a new approach has been introduced for derivation of the effective dose from air kerma to calculate shielding requirements in mammography facilities. This new approach has been used to compute the conversion coefficients relating air kerma to the effective dose for the mammography reference beam series of the Netherlands Metrology Institute Van Swinden Laboratorium, National Institute of Standards and Technology, and International Atomic Energy Agency laboratories. The results show that, in all cases, the effective dose in mammography energy range is less than 25% of the incident air kerma for the primary and the scatter radiations and does not exceed 75% for the leakage radiation.
Cyberinfrastructure for e-Science
Authors: Hey Tony , Trefethen Anne E.
Published: May 2005

Here we describe the requirements of an e-Infrastructure to enable faster, better, and different scientific research capabilities. We use two application exemplars taken from the United Kingdom's e-Science Programme to illustrate these requirements and make the case for a service-oriented infrastructure. We provide a brief overview of the UK “plug-and-play composable services” vision and the role of semantics in such an e-Infrastructure.
Service-Oriented Science
Authors: Foster Ian
Published: May 2005

New information architectures enable new approaches to publishing and accessing valuable data and programs. So-called service-oriented architectures define standard interfaces and protocols that allow developers to encapsulate information tools as services that clients can access without knowledge of, or control over, their internal workings. Thus, tools formerly accessible only to the specialist can be made available to all; previously manual data-processing and analysis tasks can be automated by having services access services. Such service-oriented approaches to science are already being applied successfully, in some cases at substantial scales, but much more effort is required before these approaches are applied routinely across many disciplines. Grid technologies can accelerate the development and adoption of service-oriented science by enabling a separation of concerns between discipline-specific content and domain-independent software and hardware infrastructure.
Stories from a Neolithic Site
Authors: Mithen Steven
Published: May 2005

The Goddess and the Bull
Çatalhöyük: An Archaeological Journey to the Dawn of Civilization.
By Michael Balter
. Free Press, New York, 2005. 424 pp. $27, C$39, £18.99. ISBN 0-7432-4360-9.

The author offers nonspecialists an account of the archaeological discoveries at Çatalhöyük, Turkey (a topic that he has covered for
Science
) and the researchers who work there.
Cyberinfrastructure: Empowering a "Third Way" in Biomedical Research
Authors: Buetow Kenneth H.
Published: May 2005

Biomedicine has experienced explosive growth, fueled in parts by the substantial increase of government support, continued development of the biotechnology industry, and the increasing adoption of molecular-based medicine. At its core, it is composed of fiercely independent, innovative, entrepreneurial individuals, organizations, and institutions. The field has developed unprecedented capacity to characterize biologic systems at their most fundamental levels with the use of tools and technologies almost unimaginable a generation ago. Biomedicine is at the precipice of unlocking the very essence of biologic life and enabling a new generation of medicine. Development and deployment of cyberinfrastructure may prove to be on the critical path to obtaining these goals.
The Rotational Spectrum and Structure of the HOOO Radical
Authors: Suma Kohsuke , Sumiyoshi Yoshihiro , Endo Yasuki
Published: May 2005

The adduct of the hydroxyl radical with oxygen has been studied theoretically, in connection with atmospheric reactions, but its stability and structure remained an open question. Pure rotational spectra of the HOOO and DOOO radicals have now been observed in a supersonic jet by using a Fourier-transform microwave spectrometer with a pulsed discharge nozzle. The molecular constants extracted from 12 rotational transitions with fine and hyperfine splittings support a trans planar molecular structure, in contrast to the cis planar structure predicted by most ab initio calculations. The bond linking the HO and O
2
moieties is fairly long (1.688 angstroms) and comparable to the F–O bond in the isoelectronic FOO radical.
Boswellia carteriiExtract Inhibits TH1 Cytokines and Promotes TH2 Cytokines In Vitro
Authors: Chevrier Marc R. , Ryan Abigail E. , Lee David Y.-W. , Zhongze Ma , Wu-Yan Zhang , Via Charles S.
Published: May 2005

Traditional herbal formulas used to treat inflammatory arthritis in China and India includeBoswellia carteriiorBoswellia serrata. They both contain boswellic acids (BAs) which have been shown to exhibit anti-inflammatory and antiarthritic properties. This study tests the hypothesis that mixtures of BAs derived fromB. carteriihave immunomodulatory properties.B. carteriiplant resin obtained from China was prepared as an ethanol extract, and the presence of seven BAs was confirmed by column chromatography, high-performance liquid chromatography, and UV laser desorption/ionization tandem mass spectroscopy. The extract was then tested for its ability to alter in vitro production of TH1 cytokines (interleukin-2 [IL-2] and gamma interferon) and TH2 cytokines (IL-4 and IL-10) by murine splenocytes. Delivery of the resin extract using ethanol as a solvent resulted in significant cellular toxicity not seen with the addition of ethanol alone. By contrast, delivery of the resin extract using a sesame oil solvent resulted in a dose-dependent inhibition of TH1 cytokines coupled with a dose-dependent potentiation of TH2 cytokines. These results indicate that a purified mixture of BAs fromB. carteriiplant resin exhibits carrier-dependent immunomodulatory properties in vitro.
Colonic ulcers in propylthiouracil induced vasculitis with secondary antiphospholipid syndrome
Authors: Gaburri P D , Chebli J M F , Attalla Â , Pereira C M N , Bonfante H L , Martins Junior E V , Gaburri A K
Published: May 2005

A 48 year old white woman was admitted to the hospital because of several bouts of migratory polyarthritis, weight loss, fever, and abdominal pain over a period of 15 months. She had been taking propylthiouracil 100 mg daily for three years for hyperthyroidism treatment. A test for antineutrophil cytoplasmic autoantibodies (ANCA) was positive with a perinuclear pattern of staining. Antiphospholipid antibodies were also detected. Colonoscopy showed several ulcers on intestinal mucosa and the biopsy specimen showed intense microscopic vasculitis. The patient is well after methylprednisolone pulse therapy and eight months of oral azathioprine. A surveillance colonoscopy showed complete healing of intestinal ulcers. No recurrence of symptoms has occurred and autoantibodies are negative, 10 months after treatment finished. The sequence of events suggests a propylthiouracil induced vasculitis p-ANCA positive and an antiphospholipid syndrome. This is the first report of colonic ulcers diagnosed and successfully treated in such circumstances.
Congenital heart disease in pregnancy
Authors: Head C E G , Thorne S A
Published: May 2005

Congenital heart disease is now more prevalent than acquired in pregnancy in the developed world. In pregnancy the fall in systemic vascular resistance and increase in blood volume and cardiac output can cause functional deterioration in certain conditions. A minimally symptomatic woman with good ventricular function, normal oxygen saturation, and no left heart obstruction should tolerate pregnancy well. Women with pulmonary hypertension or dilated aortic root (pre-replacement) should be counselled against pregnancy and given appropriate contraceptive advice. The optimum management of a pregnant woman with a metallic prosthetic valve remains to be determined.
THE ROLE OF THE SPACE–TIME DIMENSIONS AND THE FLUID EQUATION OF STATE IN SPHERICAL GRAVITATIONAL COLLAPSE
Authors: DADHICH NARESH , GHOSH S. G. , DESHKAR D. W.
Published: May 2005

We study the spherically symmetric collapse of a fluid with nonvanishing radial pressure in higher dimensional space–time. We obtain the general exact solution in the closed form for the equation of state (Pr = γρ), which leads to the explicit construction of the root equation governing the nature (black hole versus naked singularity) of the central singularity. A remarkable feature of the root equation is its invariance for the cases; (D, γ = 0) and (D+1, γ = -1) where D is the dimension of space–time. For the ultimate end result of the collapse, these two cases are absolutely equivalent, which is indeed a very interesting new result that brings out the interplay between dimension D of space–time and the equation of state parameter γ.
COMPATIBLE POISSON STRUCTURES OF TODA TYPE DISCRETE HIERARCHY
Authors: ARATYN HENRIK , BERING KLAUS
Published: May 2005

An algebra isomorphism between algebras of matrices and difference operators is used to investigate the discrete integrable hierarchy. We find local and nonlocal families of R-matrix solutions to the modified Yang–Baxter equation. The three R-theoretic Poisson structures and the Suris quadratic bracket are derived. The resulting family of bi-Poisson structures include a seminal discrete bi-Poisson structure of Kupershmidt at a special value.
THE STRANGENESS CHANGING ANTINEUTRINO REACTION ${\bar\nu}_L+P\longrightarrow\Lambda+L^+$
Authors: MINTZ S. L.
Published: May 2005

We obtain the cross sections for the reactions [Formula: see text] where L is a massive lepton, i.e. a muon or a tau lepton. We do this from near threshold to relativistic energies. We further obtain the contributions of various form factors and interference terms to the cross section with a view to discovering if the contributions from hard to observe form factors such as the weak pseudoscalar form factor, FP, and the weak electric form factor, FE might be obtained via these reactions. The form factor FE is particularly interesting as in the more usually observed p↔n transition it is a second class current and forbidden by G-parity. However in the p↔Λ transition it is not forbidden and it would be desirable to learn if it is present. Finally we discuss our results and prospects for these experiments.
HIERARCHY-PROBLEM AND A BOUND STATE OF 6 t AND $6\ \bar{t}$
Authors: FROGGATT C. D. , NIELSEN H. B. , LAPERASHVILI L. V.
Published: May 2005

We propose a unification of some fine-tuning problems – really in this article only the problem of why the weak scale is so small in energy compared to a presumed fundamental scale, being say the Planck scale – by postulating the zero or very small value of the cosmological constant not only for one but for several vacua. This postulate corresponds to what we have called the Multiple Point Principle, namely that there be many "vacuum" states with the same energy density. We further assume that 6 top quarks and 6 anti-top quarks can bind by Higgs exchange so strongly as to become tachyonic and form a condensate. This gives rise to the possibility of having a phase transition between vacua with and without such a condensate. The two vacua distinguished by such a condensate will have the same cosmological constant provided the top Yukawa coupling is about 1.1±0.2, in good correspondence with the experimental value. The further requirement that this value of the Yukawa coupling, at the weak scale, be compatible with the existence of a third vacuum, with a Higgs field expectation value of the order of the fundamental scale, enforces a hierarchical scale ratio between the fundamental and weak scales of order 1016-1020.
UNCONVENTIONAL FERMIONS: THE PRICE OF QUARK-LEPTON UNIFICATION AT TEV SCALES
Authors: HUNG P. Q.
Published: May 2005

The early petite unification (PUT) of quarks and leptons at TeV scales with [Formula: see text] used as a constraint, necessitates the introduction of extra quarks and leptons with unconventional electric charges (up to 4/3 for the quarks and 2 for the leptons). This talk, in honor of Paul Frampton's 60th birthday, will be devoted to the motivation and construction of models of early unification and to their implications, including the issues of rare decays and unconventional fermions.
GENERALIZED HOLONOMY IN M-THEORY
Authors: LIU J. T.
Published: May 2005

This is Generalized holonomy.
TWO-DIMENSIONAL RANGE SEARCH BASED ON THE VORONOI DIAGRAM
Authors: KANDA TAKESHI , SUGIHARA KOKICHI
Published: May 2005

This paper studies the two-dimensional range search problem, and constructs a simple and efficient algorithm based on the Voronoi diagram. In this problem, a set of points and a query range are given, and we want to enumerate all the points which are inside the query range as quickly as possible. In most of the previous researches on this problem, the shape of the query range is restricted to particular ones such as circles, rectangles and triangles, and the improvement on the worst-case performance has been pursued. On the other hand, the algorithm proposed in this paper is designed for a general shape of the query range in the two-dimensional space, and is intended to accomplish a good average-case performance. This performance is actually observed by numerical experiments. In these experiments, we compare the execution time of the proposed algorithm with those of other representative algorithms such as those based on the bucketing technique and the k-d tree. We can observe that our algorithm shows the better performance in almost all the cases.
THE LIE DERIVATIVE OF SPINOR FIELDS: THEORY AND APPLICATIONS
Authors: GODINA MARCO , MATTEUCCI PAOLO
Published: May 2005

Starting from the general concept of a Lie derivative of an arbitrary differentiable map, we develop a systematic theory of Lie differentiation in the framework of reductive G-structures P on a principal bundle Q. It is shown that these structures admit a canonical decomposition of the pull-back vector bundle [Formula: see text] over P. For classical G-structures, i.e. reductive G-subbundles of the linear frame bundle, such a decomposition defines an infinitesimal canonical lift. This lift extends to a prolongation Γ-structure on P. In this general geometric framework the concept of a Lie derivative of spinor fields is reviewed. On specializing to the case of the Kosmann lift, we recover Kosmann's original definition. We also show that in the case of a reductive G-structure one can introduce a "reductive Lie derivative" with respect to a certain class of generalized infinitesimal automorphisms, and, as an interesting by-product, prove a result due to Bourguignon and Gauduchon in a more general manner. Next, we give a new characterization as well as a generalization of the Killing equation, and propose a geometric reinterpretation of Penrose's Lie derivative of "spinor fields". Finally, we present an important application of the theory of the Lie derivative of spinor fields to the calculus of variations.
HUMAN TASTE GENETICS
Authors: Drayna Dennis
Published: May 2005

▪ Abstract  Humans show substantial differences in taste sensitivity to many different substances. Some of this variation is known to be genetic in origin, and many other inter-individual differences are likely to be partially or wholly determined by genetic mechanisms. Recent advances in the understanding of taste at the molecular level have provided candidate genes that can be evaluated for contributions to phenotypic differences in taste abilities. This approach has provided an understanding of variation in the ability to taste phenylthiocarbamide (PTC), and has resolved long-standing controversies about the genetics of this classic human genetic trait. Significant coding sequence variation exists in taste receptor genes, which suggests that PTC tasting may indicate more general taste sensory variation. However, many aspects of taste perception remain poorly characterized. Better understanding of the molecular components of salty and sour tastes is still needed, as is a more complete picture of second messenger and downstream signaling mechanisms for all taste modalities. More general studies of linkage and association between genetic markers and taste phenotypes may reveal genes encoding proteins that were previously unsuspected to be involved in this sensory process.
YEAST EVOLUTION AND COMPARATIVE GENOMICS
Authors: Liti Gianni , Louis Edward J.
Published: May 2005

Recent sequencing efforts and experiments have advanced our understanding of genome evolution in yeasts, particularly the Saccharomyces yeasts. The ancestral genome of the Saccharomyces sensu stricto complex has been subject to both whole-genome duplication, followed by massive sequence loss and divergence, and segmental duplication. In addition the subtelomeric regions are subject to further duplications and rearrangements via ectopic exchanges. Translocations and other gross chromosomal rearrangements that break down syntenic relationships occur; however, they do not appear to be a driving force of speciation. Analysis of single genomes has been fruitful for hypothesis generation such as the whole-genome duplication, but comparative genomics between close and more distant species has proven to be a powerful tool in testing these hypotheses as well as elucidating evolutionary processes acting on the genome. Future work on population genomics and experimental evolution will keep yeast at the forefront of studies in genome evolution.
Transcriptional basis for exercise limitation in male eNOS-knockout mice with age: heart failure and the fetal phenotype
Authors: Ojaimi Caroline , Li Wei , Kinugawa Shintaro , Post Heiner , Csiszar Anna , Pacher Pal , Kaley Gabor , Hintze Thomas H.
Published: May 2005

Endothelium-derived nitric oxide (NO) is pivotal in regulating mitochondrial O2 consumption (V̇o2) and glucose uptake in mice. The aim of this study was to investigate the mechanism of age- and genotype-related exercise limitation in male endothelial NO synthase (eNOS)-knockout (KO, n = 16) and wild-type (WT, n = 19) mice. Treadmill testing was performed at 12, 14, 16, 18, and 21 mo of age. V̇o2, CO2 production, respiratory exchange ratio, and maximal running distance were determined during treadmill running. There were good linear correlations for increase of speed with increase of V̇o2. The difference between KO and WT mice was not significant at 12 mo but was significant at 18 mo. Linear regression showed that KO mice consumed more O2 at the same absolute and relative workloads, suggesting that V̇o2 was not inhibited by NO in KO mice. KO mice performed 30–50% less work than WT mice at each age (work = vertical distance × weight). In contrast to WT mice, the work performed by KO mice significantly decreased from 17 ± 1.4 m·kg at 12 mo to 9.4 ± 1.7 m·kg at 21 mo. Running distance was significantly decreased from 334 ± 27 m at 12 mo to 178 ± 38 m at 21 mo, and maximal V̇o2, CO2 production, and respiratory exchange ratio per work unit were significantly higher in KO than in WT mice. Gene arrays showed evidence of a fetal phenotype in KO mice at 21 mo. In conclusion, age- and genotype-related exercise limitations in maximal work performed and maximal running distance in male eNOS-KO mice indicated that fetal phenotype and age were related to onset of heart failure.
F-DIO obesity-prone rat is insulin resistant before obesity onset
Authors: Levin Barry E. , Magnan Christophe , Migrenne Stephanie , Chua Streamson C. , Dunn-Meynell Ambrose A.
Published: May 2005

We previously created a novel F-DIO rat strain derived by crossing rats selectively bred for the diet-induced obesity (DIO) phenotype with obesity-resistant Fischer F344 rats. The offspring retained the DIO phenotype through 3 backcrosses with F344 rats but also had exaggerated insulin responses to oral glucose before they became obese on a 31% fat high-energy (HE) diet. Here, we demonstrate that chow-fed rats from the subsequent randomly bred progeny required 57% lower glucose infusions to maintain euglycemia during a hyperinsulinemic clamp in association with 45% less insulin-induced hepatic glucose output inhibition and 80% lower insulin-induced glucose uptake than F344 rats. The DIO phenotype and exaggerated insulin response to oral glucose in the nonobese, chow-fed state persisted in the F6 generation. Also, compared with F344 rats, chow-fed F-DIO rats had 68% higher arcuate nucleus proopiomelanocortin mRNA expression which, unlike the increase in F344 rats, was decreased by 26% on HE diet. Further, F-DIO lateral hypothalamic orexin expression was 18% lower than in F344 rats and was increased rather than decreased by HE diet intake. Finally, both maternal obesity and 30% caloric restriction during the third week of gestation produced F-DIO offspring which were heavier and had higher leptin and insulin levels than lean F-DIO dam offspring. Third-gestational week dexamethasone also produced offspring with higher leptin and insulin levels but with lower body weight. Thus F-DIO rats represent a novel and potentially useful model for the study of DIO, insulin resistance, and perinatal factors that influence the development and persistence of obesity.
ANG III induces expression of inducible transcription factors of AP-1 and Krox families in rat brain
Authors: Blume Annegret , Undeutsch Christian , Zhao Yi , Kaschina Elena , Culman Juraj , Unger Thomas
Published: May 2005

In addition to rapid responses comprising increases in blood pressure, drinking, and stimulation of natriuresis, ANG II induces the expression of transcription factors (TF) in the central nervous system. The ANG II metabolite ANG III (ANG 2–8) has been demonstrated to exert physiological effects similar to those of ANG II. We aimed to determine 1) whether ANG III induces TF expression in the brain, 2) which ANG II (AT) receptor subtype is involved, and 3) whether the two peptides, ANG II and ANG III, differ in their efficacy to stimulate TF expression. ANG II (100 pmol), ANG III (100 pmol), or vehicle was injected into the lateral brain ventricle of conscious rats alone or in combination with the AT1 receptor antagonist losartan (10 nmol), the AT2 receptor antagonist PD-123319 (5 nmol), or the aminopeptidase inhibitor amastatin (10 nmol). Similar to ANG II, ANG III induced the expression of c-Fos, c-Jun, and Krox-24 in four brain regions, subfornical organ, median preoptic area, paraventricular nucleus, and supraoptic nucleus of the hypothalamus, with the same efficacy. This effect was AT1 receptor mediated. Pretreatment with amastatin reduced the expression of TF in response to ANG II, indicating that this expression is partly mediated by ANG III. Interestingly, the AT2 receptor antagonist PD-123319 alone slightly enhanced the expression of c-Fos, c-Jun, and Krox-24 in different populations of neurons of the paraventricular nucleus. These data indicate that different populations of neurons in the paraventricular nucleus are tonically inhibited by AT2 receptors under physiological conditions.
Diminished feeding responsiveness to orexin A (hypocretin 1) in aged rats is accompanied by decreased neuronal activation
Authors: Kotz Catherine M. , Mullett Mary A. , Wang ChuanFeng
Published: May 2005

Orexin A is produced in caudal lateral, posterior, perifornical, and dorsomedial hypothalamic areas. Orexin A in the rostro-dorsal lateral hypothalamic area (rLHa) stimulates feeding and activates several feeding-regulatory brain areas. We hypothesized that aging diminishes feeding and c-Fos-immunoreactivity (c-Fos-ir; marker of neuronal activation) response to orexin A. Young (3 mo), middle-aged (12 mo), and old (24 mo) male Fischer 344 rLHa-cannulated rats were injected with orexin A (0.5, 1, and 2 nmol). Food intake was measured at 1, 2, and 4 h. c-Fos-ir in hypothalamic, limbic, and hindbrain regions was measured in two additional sets of rLHa-orexin A injected rats. In a separate study, orexin A effects on feeding and c-Fos-ir were measured in 6-mo-old rats. Orexin A significantly elevated feeding in rats aged 3, 6, and 12 mo in the 0–1 and 1–2- h time intervals, whereas in old rats this was significant in the 1–2 h time interval only. At 1 h, 6–8 (of 14) brain areas showed elevated c-Fos-ir in response to orexin A in 3- and 6-mo-old rats, but 24-mo-old rats exhibited attenuated or absent c-Fos-ir response in all brain regions except the hypothalamic paraventricular nucleus (PVN) and rostral nucleus of the solitary tract (rNTS). Orexin A did not elevate c-Fos-ir in 3-mo-old rats at 2 h after injection, whereas the PVN and mediodorsal thalamic nucleus (MD) showed elevated c-Fos-ir at 2 h in 24-mo-old rats. These data suggest that delayed and diminished feeding responses in old animals may be due to ineffective neural signaling and implicate the orexin A network as one feeding system affected by aging.
Acute intermittent hypoxia improves rat myocardium tolerance to ischemia
Authors: Béguin P. C. , Joyeux-Faure M. , Godin-Ribuot D. , Lévy P. , Ribuot C.
Published: May 2005

In this study, we investigated the influence of depth and duration of intermittent hypoxia (IH) on the infarct size development in isolated rat heart. The role of nitric oxide synthase (NOS) and ATP-sensitive K+ (KATP) channel was also studied. Wistar male rats were exposed to IH [repetitive cycles of 1 min, 40 s with inspired oxygen fraction (FiO2), 5 or 10%, followed by 20-s normoxia], during 30 min or 4 h. Another group was exposed to 4 h of continuous hypoxia with 10% FiO2. Twenty-four hours later, their hearts were isolated and subjected to a 30-min no-flow global ischemia-120-min reperfusion sequence. For some hearts, Nω-nitro-l-arginine methyl ester (l-NAME) (a nonselective inhibitor of NOS) or 5-hydroxydecanoic acid (5-HD) (a selective mitochondrial KATP blocker) was infused before ischemia. Infarct size (in percentage of ventricles) was significantly reduced by prior IH for 4 h (10% FiO2) (21.8 ± 3.1 vs. 33.5 ± 2.5% in sham group). This effect was abolished by l-NAME or 5-HD. Infarct size was not different in groups subjected to either 30 min of IH or to continuous hypoxia compared with sham group. In contrast, IH for 4 h (5% FiO2) significantly increased infarct size (45.1 ± 3.6 vs. 33.5 ± 2.5% in sham group). Acute IH for 4 h with a minimal FiO2 of 10% induced a delayed preconditioning against myocardial infarction in the rat, which was abolished by NOS inhibition and mitochondrial KATP channel blockade. Depth, duration, and intermittence of hypoxia appeared to be critical for cardioprotection to occur.
Influence of gender, menstrual phase, and oral contraceptive use on immunological changes in response to prolonged cycling
Authors: Timmons Brian W. , Hamadeh Mazen J. , Devries Michaela C. , Tarnopolsky Mark A.
Published: May 2005

This study determined the influence of gender, menstrual phase (MP), and oral contraceptive (OC) use on immunological changes in response to endurance exercise. Twelve women and 11 men similar in age, aerobic power, and activity level cycled for 90 min at 65% maximal aerobic power. Women were OC users ( n = 6) or nonusers (NOC) and cycled during the follicular (Fol) and the luteal (Lut) phases. Venous blood was collected before and after exercise to determine leukocyte counts, IL-6 concentrations, and cortisol. Higher resting levels of neutrophils (∼1.5-fold) and cortisol (∼2.5-fold) were found in OC vs. NOC and men. Exercise-induced immune cell count and IL-6 changes were similar between men and NOC, except for an ∼38% greater lymphocyte response in NOC vs. men ( P = 0.07). Neutrophil, monocyte, and lymphocyte responses to exercise during Lut in OC were greater than during Fol and also greater than the responses in men ( P ≤ 0.003). Changes in immune cell counts were consistently greater during Lut in OC vs. NOC, regardless of MP, but only neutrophil responses reached statistical significance ( P = 0.01). The exercise-induced change in IL-6 was ∼80% greater in NOC vs. OC during Fol ( P = 0.06), but it was similar between these groups during Lut. Cortisol changes with exercise were not different between groups or MP. These results highlight the necessity to control for gender, and in particular OC use, when designing studies evaluating exercise and immunology.
Intravascular infusions of plasma into fetal sheep cause arterial and venous hypertension
Authors: Giraud George D. , Faber J. Job , Jonker Sonnet , Davis Lowell , Anderson Debra F.
Published: May 2005

Fetal volume control is driven by an equilibrium between fetal and maternal hydrostatic and oncotic pressures in the placenta. Renal contributions to blood volume regulation are minor because the fetal kidneys cannot excrete fluid from the fetal compartment. We hypothesized that an increase in fetal plasma protein would lead to an increase in plasma oncotic pressure, resulting in an increase in fetal arterial and venous pressures and decreased angiotensin levels. Plasma or lactated Ringer solution was infused into each of five twin fetuses. After 7 days, fetal protein concentration was 71.2 ± 4.2 g/l in the plasma-infused fetuses compared with 35.7 ± 6.3 g/l in the lactated Ringer-solution-infused fetuses. Arterial pressure was 68.0 ± 3.6 compared with 43.4 ± 1.9 mmHg in the lactated Ringer solution-infused fetuses ( P < 0.0003), whereas venous pressure was 4.8 ± 0.3 mmHg in the plasma-infused fetuses compared with 3.3 ± 0.4 mmHg in the lactated Ringer solution-infused fetuses ( P < 0.036). Six fetuses were studied on days 0, 7, and 14 of plasma protein infusion. Fetal protein concentration increased from 31.1 ± 1.5 to 84.8 ± 3.8 g/l after 14 days ( P < 0.01), and arterial pressure increased from 43.1 ± 1.8 to 69.1 ± 4.1 mmHg ( P < 0.01). Venous pressure increased from 3.0 ± 0.4 to 6.2 ± 1.3 mmHg ( P < 0.05). Fetal heart rate did not change. Angiotensin II concentration decreased, from 24.6 ± 5.6 to 2.9 ± 1.3 pg/l, after 14 days ( P < 0.01). Fetal plasma infusions resulted in fetal arterial and venous hypertensions that could not be corrected by reductions in angiotensin II levels.
Discharge Properties of MST Neurons That Project to the Frontal Pursuit Area in Macaque Monkeys
Authors: Churchland Anne K. , Lisberger Stephen G.
Published: May 2005

We have used antidromic activation to determine the functional discharge properties of neurons that project to the frontal pursuit area (FPA) from the medial-superior temporal visual area (MST). In awake rhesus monkeys, MST neurons were considered to be activated antidromically if they emitted action potentials at fixed, short latencies after stimulation in the FPA and if the activation passed the collision test. Antidromically activated neurons ( n = 37) and a sample of the overall population of MST neurons ( n = 110) then were studied during pursuit eye movements across a dark background and during laminar motion of a large random-dot texture and optic flow expansion and contraction during fixation. Antidromically activated neurons showed direction tuning during pursuit (25/37), during laminar image motion (21/37), or both (16/37). Of 27 neurons tested with optic flow stimuli, 14 showed tuning for optic flow expansion ( n = 10) or contraction ( n = 4). There were no statistically significant differences in the response properties of the antidromically activated and control samples. Preferred directions for pursuit and laminar image motion did not show any statistically significant biases, and the preferred directions for eye versus image motion in each sample tended to be equally divided between aligned and opposed. There were small differences between the control and antidromically activated populations in preferred speeds for laminar motion and optic flow; these might have reached statistical significance with larger samples of antidromically activated neurons. We conclude that the population of MST neurons projecting to the FPA is highly diverse and quite similar to the general population of neurons in MST.
Vascular Consequences of Endothelial Nitric Oxide Synthase Uncoupling for the Activity and Expression of the Soluble Guanylyl Cyclase and the cGMP-Dependent Protein Kinase
Authors: Münzel Thomas , Daiber Andreas , Ullrich Volker , Mülsch Alexander
Published: May 2005

Endothelial dysfunction in the setting of cardiovascular risk factors, such as hypercholesterolemia, hypertension, diabetes mellitus, chronic smoking, as well as in the setting of heart failure, has been shown to be at least partly dependent on the production of reactive oxygen species (ROS), such as the superoxide radical, and the subsequent decrease in vascular bioavailability of nitric oxide (NO). Superoxide-producing enzymes involved in increased oxidative stress within vascular tissue include the NAD(P)H oxidase, the xanthine oxidase, and mitochondrial superoxide-producing enzymes. Superoxide produced by the NADPH oxidase may react with NO released by endothelial nitric oxide synthase (eNOS), thereby generating peroxynitrite. Peroxynitrite in turn has been shown to uncouple eNOS, thereby switching an antiatherosclerotic NO-producing enzyme to an enzyme that may initiate or even accelerate the atherosclerotic process by producing superoxide. Increased oxidative stress in the vasculature, however, is not restricted to the endothelium and has also been demonstrated to occur within the smooth muscle cell layer in the setting of hypercholesterolemia, diabetes mellitus, hypertension, congestive heart failure, and nitrate tolerance. Increased superoxide production by the endothelial and/or smooth muscle cells has important consequences with respect to signaling by the soluble guanylyl cyclase (sGC) and the cGMP-dependent protein kinase I (cGK-I), the activity and expression of which has been shown to be regulated in a redox-sensitive fashion. The present review summarizes current concepts concerning eNOS uncoupling and also focuses on the consequences for downstream signaling with respect to activity and expression of the sGC and cGK-I in various diseases.
A Novel αvβ3 Integrin Antagonist Suppresses Neointima Formation for More Than 4 Weeks After Balloon Injury in Rats
Authors: Honda Yayoi , Kitano Tomoko , Fukuya Fumiyo , Sato Yuji , Iwama Seiji , Morie Toshiya , Notake Mitsue
Published: May 2005

Objectives—

We performed a detailed kinetic analysis in a rat balloon injury model to clarify the essential roles of αvβ3 integrin and endothelial cell (EC) regeneration in neointima formation. Using this model, we evaluated the antistenotic effect of Dainippon compound BS-1417, a novel αvβ3 integrin antagonist.

Methods and Results—

Kinetic analysis using RT-PCR showed that αvβ3 integrin-related genes are upregulated before neointima formation. Morphological and functional analyses revealed that EC regeneration requires >4 weeks after injury, and that recovery of EC normal function coincides with the arrest of neointima formation. Subcutaneous infusion of BS-1417 for 2, 4, 7, or 12 weeks after injury potently inhibited neointima formation without affecting EC regeneration. Although withdrawal of treatment with BS-1417 after short-term administration after injury resulted in catch-up growth of neointima, a long-term study suggested that this catch-up growth can be prevented by continuous administration of BS-1417 until EC regeneration.

Conclusion—

We clarified that αvβ3 integrin and EC regeneration play an essential role in neointima formation, and that continuous administration of BS-1417 potently and stably inhibits neointima formation without affecting EC regeneration. These findings suggest that BS-1417 might be useful as a novel systemic drug for the treatment of restenosis.
Sensitivity and Specificity of the Ankle–Brachial Index to Predict Future Cardiovascular Outcomes
Authors: Doobay Anand V. , Anand Sonia S.
Published: May 2005

Objective—

The ankle–brachial index is the ratio of the ankle and the brachial systolic blood pressure and is used to assess individuals with peripheral arterial disease. An ankle–brachial index <0.90 suggests the presence of peripheral arterial disease and is a marker of cardiovascular risk. The objective of this review is to determine the sensitivity and specificity of an ankle–brachial index <0.90 to predict future cardiovascular events, including coronary heart disease, stroke, and death.

Methods and Results—

We conducted a systematic review of the literature and included studies that used an ankle–brachial index cutoff between 0.80 and 0.90 to classify patients with or without peripheral arterial disease, followed patients prospectively, and recorded cardiovascular outcomes (ie, myocardial infarction, stroke, or mortality). Data were combined using a random-effects model meta-analysis to determine the sensitivity, specificity, relative risks, and likelihood ratios of a low ankle–brachial index to predict future cardiovascular disease. A total of 22 studies were identified, 13 were excluded, and 9 studies were included in the meta-analysis. The sensitivity and specificity of a low ankle–brachial index to predict incident coronary heart diseases were 16.5% and 92.7%, for incident stroke were 16.0% and 92.2%, and for cardiovascular mortality were 41.0% and 87.9%, respectively. The corresponding positive likelihood ratios were 2.53 (95% CI, 1.45 to 4.40) for coronary heart disease, 2.45 (95% CI, 1.76 to 3.41) for stroke, and 5.61 (95% CI, 3.45 to 9.13) for cardiovascular death.

Conclusion—

The specificity of a low ankle–brachial index to predict future cardiovascular outcomes is high, but its sensitivity is low. The ankle–brachial index should become part of the vascular risk assessment among selected individuals.
Thymidine Phosphorylase Gene Transfer Inhibits Vascular Smooth Muscle Cell Proliferation by Upregulating Heme Oxygenase-1 and p27
KIP1
Authors: Li Wei , Tanaka Kuniyoshi , Morioka Koichi , Uesaka Takahiko , Yamada Narihisa , Takamori Atsushi , Handa Mitsuteru , Tanabe Sawaka , Ihaya Akio
Published: May 2005

Objective—

Thymidine phosphorylase (TP) reportedly promotes endothelial cell migration and induces heme oxygenase (HO)-1 expression. However, its effect on vascular smooth muscle cells (VSMCs) is poorly understood. In this study, we examined the effect of TP on VSMCs in vitro and in vivo.

Methods and Results—

Phagemid vector encoding human TP gene was transfected into rat VSMCs, and a clone overexpressing TP was selected (C2). C2 showed a slower migration and proliferation than VSMCs cloned with empty vector (pC) under basal, serum-stimulated, and hypoxic conditions. This decrease in proliferation correlated with TP-induced HO-1 expression and was reversed by inhibitors of either TP or HO activity. Furthermore, in C2, the cyclin-dependent kinase inhibitor (p27
KIP1
) was much more abundant than in pC, and the cell cycle was arrested at the G1 phase. TP or HO activity inhibitors decreased p27
KIP1
expression in C2 to the level seen in pC. Adventitial TP gene delivery significantly reduced neointimal VSMC migration and neointima formation in balloon-injured rat carotid arteries.

Conclusions—

TP overexpression upregulated HO-1 expression and consequently increased p27
KIP1
in cultured VSMCs, and inhibited VSMC migration and proliferation in vitro and in vivo. TP represents a promising target for treating vascular obstructive disease.
Endotoxin-Induced Myocardial Dysfunction
Authors: Chagnon Frederic , Metz Christine N. , Bucala Richard , Lesur Olivier
Published: May 2005

The pathophysiology of sepsis-induced myocardial dysfunction still remains controversial. Macrophage migration inhibitory factor (MIF) has recently been identified as a cardiac-derived myocardial depressant factor in septic shock. Putative mechanisms by which MIF affects cardiac function are unknown. In an investigation of possible mechanisms of action, a rat model of endotoxin toxicity was designed using intraperitoneal (I/P) injection of lipopolysaccharides (LPS) with or without coinfusion of neutralizing anti-MIF or isotypic-matched antibodies. Echocardiographic evaluation revealed that MIF neutralization reversed endotoxin-induced myocardial dysfunction at 24 hours after injection. RNase protection assay (RPA) and Western blot established that MIF neutralization prevented LPS-induced mRNA expression and production of heart-derived inflammatory paracrine and autocrine cytokines such as IL-1s and IL-6. Moreover, MIF immunoneutralization increased heart Bcl-2/Bax protein ratio and suppressed endotoxin-induced release of mitochondrial cytochrome-c, as demonstrated by Western blotting. Inhibition of mitochondrial loss of cytochrome-c decreased in heart caspase-3 activity at 6 and 24 hours after injection. MIF neutralization also restored the LPS-induced deficient nuclear translocation of phospho-Akt and consequently the expression of the heart survival nuclear factor GATA-4. The restoration of the translocation/expression of survival factors by MIF inhibition resulted in lowered endotoxin-induced DNA fragmentation at 24 hours, a hallmark of downstream cardiomyocyte apoptosis. Our data indicate that early inactivation of MIF significantly reverses the imbalance of proapoptotic to prosurvival pathways and reduces acute inflammation of the heart thereby improving myocardial dysfunction induced by endotoxin.
Diabetes Induces Endothelial Dysfunction but Does Not Increase Neointimal Formation in High-Fat Diet Fed C57BL/6J Mice
Authors: Molnar Judit , Yu Shuiqing , Mzhavia Nino , Pau Clara , Chereshnev Igor , Dansky Hayes M.
Published: May 2005

Studies of diabetic vascular disease have traditionally used murine models of type 1 diabetes and genetic models of type 2 diabetes. Because the majority of patients with type 2 diabetes have diet induced obesity, we sought to study the effect of diabetes on arterial disease in a mouse model of diet induced obesity/diabetes. C57Bl/6 mice fed a high-fat diet for 9 weeks developed type 2 diabetes characterized by elevated body weight, hyperglycemia, and hyperinsulinemia. Arteries from diabetic mice exhibited a marked decrease in endothelium-dependent vasodilation, a modest decrease in endothelium independent vasodilation, and an increase in sensitivity to adrenergic vasoconstricting agents. Insulin stimulated protein kinase B (akt) and endothelial nitric oxide synthase (eNOS) phosphorylation were preserved in arteries from diabetic mice; however, eNOS protein dimers were markedly diminished. Arterial nitrotyrosine staining indicated that increased levels of peroxynitrite contributed to eNOS dimer disruption in the diabetic mice. The abnormal vasomotion was not an acute response to the high-fat diet, as short term high-fat diet feeding had no effect on endothelium dependent dilation. A trend toward smaller neointimal lesions was noted in high-fat diet fed mice after femoral artery wire denudation injury. In summary, disrupted eNOS dimer formation rather than impaired insulin mediated eNOS phosphorylation contributed to the endothelial dysfunction in diet induced obese/diabetic mice. The lack of an increase in neointimal formation indicates that additional diabetes associated parameters (such as hyperlipidemia and atherosclerotic vascular disease) may need to be present to increase neointimal formation in this model.