bluuebunny/crossref_metadata_2025 huggingface dataset:
A Mechanical Comparison of 4.5 mm Narrow and 3.5 mm Broad Plating Systems for Stabilization of Gapped Fracture Models
Authors: Silbernagel John T. , Johnson Ann L. , Pijanowski Gerald J. , Ehrhart Nichole , Schaeffer David J.
Published: February 2004

Objective— To evaluate and compare the mechanical properties of 4.5 narrow and 3.5 broad plating systems using their respective cortical and cancellous screws in unstable, central, and eccentric gap fracture models.

Study Design— Mechanical evaluation and comparison of 2 dynamic compression plate (DCP) systems.

Sample population— Eighteen cortical and 30 cancellous gapped fracture models.

Methods— DCP (4.5 mm narrow, 3.5 mm broad) with their respective cortical screws were applied to cortical bone density polyurethane foam blocks to construct center gap cortical fracture models that were tested in gap closing monotonic 4‐point bending. DCP (4.5 mm narrow, 3.5 mm broad) with their respective cancellous screws were applied to cancellous bone density polyurethane foam blocks to construct eccentric gap cancellous fracture models. The cancellous constructs were tested in monotonic gap opening and gap closing cantilever bending and in cyclic axial loading. Univariate and multivariate repeated measures ANOVA were used to compare the maximum loads at failure of the 4.5 mm constructs and 3.5 mm constructs.

Results— The 4.5 mm narrow plating system withstood significantly higher loads at failure than the 3.5 mm broad plating system in 4‐point bending (P<.0001) and gap opening cantilever bending (P<.0001). The 4.5 mm system failed in gap closing cantilever bending by plastic deformation of the plate, whereas the 3.5 mm system failed by screw pullout. There was no difference between the 2 systems in cyclic axial loading.

Conclusion— Results indicate that the 4.5 mm narrow plating system has a mechanical advantage over the 3.5 mm broad plating system for stabilization of gapped fracture models.

Clinical Relevance— The 4.5 mm narrow plating system may be mechanically advantageous compared with the 3.5 mm broad plating system for stabilizing unreconstructed comminuted long bone fractures in large dogs.
ATP is a key mediator of central and peripheral chemosensory transduction
Authors: Spyer K. Michael , Dale Nicholas , Gourine Alexander V.
Published: February 2004

Recent evidence suggests that ATP is a mediator of central (within the ventral surface of the medulla) and peripheral (within the carotid body) chemosensory transduction. This short review discusses the data obtained in experimentsin vivoandin vitrosupporting this hypothesis. P2 receptors for ATP are expressed within the ventrolateral medulla as well as by the peripheral chemosensory afferent neurones. Blockade of P2 receptors in the ventrolateral medulla attenuates the CO2‐induced increase in respiration while blockade of purinergic signalling impairs carotid body function and diminishes the ventilatory response to hypoxia. Furthermore, ATP is released from the ventral surface of the medulla during hypercapnia and from the carotid body during hypoxia. Finally, exogenous ATP applied on the ventral surface of the medulla evokes rapid increase in phrenic nerve activity, while ATP applied to the carotid body evokes marked excitation of the carotid sinus nerve afferents. We suggest that in the ventrolateral medulla ATP is produced following CO2/H+‐induced activation of central chemosensory elements (neuronal and/or glial) and acts within the respiratory network to produce physiologically relevant changes in ventilation. In the carotid body, ATP contributes in a significant manner to the transmission of the sensitivity of the carotid body to changes in arterialPand may be considered as a key transmitter released by chemoreceptor cells to activate endings of the sinus nerve afferent fibres.
NMDA receptor antagonism blocks the cardiovascular responses to microinjection of trans‐ACPD into the NTS of awake rats
Authors: Antunes Vagner R. , Bonagamba Leni G. H. , Machado Benedito H.
Published: February 2004

The possible interaction of glutamatergic metabotropic agonists and N‐methyl‐d‐aspartate (NMDA) receptors was investigated in the nucleus tractus solitarii (NTS) of awake rats. The cardiovascular responses to unilateral microinjection of trans‐1‐amino‐1,3‐cyclopentanediocarboxylic acid (trans‐ACPD; 250 pmol/50 nL) into the NTS (n= 8) produced hypotension (−64 ± 4 mmHg) and bradycardic (−206 ± 11 bpm) responses, which were blocked by previous microinjection of 2‐amino‐5‐phosphonovaleric acid (AP‐5; 10 nmol/50 nL), a selective antagonist of NMDA ionotropic receptors, into the same site. Intravenous injection of methyl‐atropine blocked both the bradycardic and hypotensive responses to microinjection of trans‐ACPD into the NTS, indicating that the hypotension was secondary to the intense bradycardic response. The data also showed that the bradycardic and hypotensive responses to microinjection of an NMDA agonist (10 pmol/50 nL) into the NTS were not affected by previous microinjection of α‐methyl‐4‐carboxyphenylglycine (MCPG; 5 nmol/50 nL), a non‐selective antagonist of metabotropic receptors. The results showing that the cardiovascular responses to microinjection of trans‐ACPD into the NTS were blocked by AP‐5 indicate that the responses to metabotropic agonists in the NTS involves NMDA receptors.
Stress-Dependent Regulation of FOXO Transcription Factors by the SIRT1 Deacetylase
Authors: Brunet Anne , Sweeney Lora B. , Sturgill J. Fitzhugh , Chua Katrin F. , Greer Paul L. , Lin Yingxi , Tran Hien , Ross Sarah E. , Mostoslavsky Raul , Cohen Haim Y. , Hu Linda S. , Cheng Hwei-Ling , Jedrychowski Mark P. , Gygi Steven P. , Sinclair David A. , Alt Frederick W. , Greenberg Michael E.
Published: February 2004

The Sir2 deacetylase modulates organismal life-span in various species. However, the molecular mechanisms by which Sir2 increases longevity are largely unknown. We show that in mammalian cells, the Sir2 homolog SIRT1 appears to control the cellular response to stress by regulating the FOXO family of Forkhead transcription factors, a family of proteins that function as sensors of the insulin signaling pathway and as regulators of organismal longevity. SIRT1 and the FOXO transcription factor FOXO3 formed a complex in cells in response to oxidative stress, and SIRT1 deacetylated FOXO3 in vitro and within cells. SIRT1 had a dual effect on FOXO3 function: SIRT1 increased FOXO3's ability to induce cell cycle arrest and resistance to oxidative stress but inhibited FOXO3's ability to induce cell death. Thus, one way in which members of the Sir2 family of proteins may increase organismal longevity is by tipping FOXO-dependent responses away from apoptosis and toward stress resistance.
In Vitro Activity of Daptomycin against Gram-Positive European Clinical Isolates with Defined Resistance Determinants
Authors: Fluit Ad C. , Schmitz Franz-Josef , Verhoef Jan , Milatovic Dana
Published: February 2004

The in vitro activity of daptomycin against 337 gram-positive European clinical isolates with known resistance genes was determined. The MIC ranges for
Staphylococcus aureus
, enterococci, pneunococci, and streptococci were 0.03 to 1, 0.25 to 8, 0.12 to 1, and 0.06 to 8 μg/ml, respectively. For only one streptococcus isolate and seven enterococcus isolates was the MIC 8 μg/ml.
Quantitative Analysis of a Parasitic Antiviral Strategy
Authors: Kim Hwijin , Yin John
Published: February 2004

We extended a computer simulation of viral intracellular growth to study a parasitic antiviral strategy that diverts the viral replicase toward parasite growth. This strategy inhibited virus growth over a wide range of conditions, while minimizing host cell perturbations. Such parasitic strategies may inhibit the development of drug-resistant virus strains.
In Vitro Activities of Tigecycline against the
Bacteroides fragilis
Group
Authors: Jacobus N. V. , McDermott L. A. , Ruthazer R. , Snydman D. R.
Published: February 2004

The in vitro activities of tigecycline were tested against 831 isolates of the
Bacteroides fragilis
group representing all of the species within the group. On a weight-to-weight basis (8 μg/ml), tigecycline was more active than clindamycin, minocycline, trovafloxacin, and cefoxitin and less active than imipenem or piperacillin-tazobactam against all isolates of the
B. fragilis
group. Tigecycline geometric mean MICs were statistically higher against
B. distasonis
than other
Bacteroides
species (
P
value of 0.0001).
Relative Bioavailability of Three Newly Developed Albendazole Formulations: a Randomized Crossover Study with Healthy Volunteers
Authors: Rigter I. M. , Schipper H. G. , Koopmans R. P. , van Kan H. J. M. , Frijlink H. W. , Kager P. A. , Guchelaar H.-J.
Published: February 2004

This study of healthy volunteers shows that the relative bioavailability of albendazole formulations that use arachis oil-polysorbate 80 or hydroxypropyl-β-cyclodextrin as an excipient was enhanced 4.3- and 9.7-fold compared to the results seen with commercial tablets. Administration of macrogol suppositories did not result in measurable plasma concentrations of albendazole sulfoxide.
Synergistic Activities of Moxifloxacin Combined with Piperacillin-Tazobactam or Cefepime against
Klebsiella pneumoniae
,
Enterobacter cloacae
, and
Acinetobacter baumannii
Clinical Isolates
Authors: Jung Rose , Husain Maroof , Choi Michael K. , Fish Douglas N.
Published: February 2004

The bactericidal activity of moxifloxacin alone and in combination with cefepime or piperacillin-tazobactam against clinical isolates of
Klebsiella pneumoniae
,
Enterobacter cloacae
, and
Acinetobacter baumannii
was evaluated by using time-kill methods and antimicrobial concentrations of one-half and one times the MIC. Synergy was observed in 58 to 88% of the strains and resulted in bactericidal activity against 60 to 100% of the strains. Combinations including moxifloxacin demonstrated enhanced bactericidal activity compared with that of either agent tested alone.
Inhibition of β-Lactamase II of
Bacillus cereus
by Penamaldic Derivatives of Penicillins
Authors: Navarro Pilar Gutiérrez , Osso Bartolomé Quintero , Ortiz Raquel García , Martínez de las Parras Pedro J. , Martínez Puentedura María I. , Cabeza González M. Carmen
Published: February 2004

The penamaldic derivatives of amoxicillin, ampicillin, and penicillins G and V, stabilized with Zn
2+
, were obtained from a methanolic medium. The enzymatic kinetic results show that the these derivatives elicit reversible inhibition of the enzyme metallo-β-lactamase from
Bacillus cereus
, with inhibition constant values determined at pH 7.0 and 25°C.
Lymphohaematopoietic cancer risk among chemical workers exposed to benzene
Authors: Bloemen L J , Youk A , Bradley T D , Bodner K M , Marsh G
Published: February 2004

Aims:To determine cause specific mortality in a cohort of 2266 chemical workers exposed to benzene in various manufacturing processes after 1935.

Methods:The cohort has accumulated over 80 000 person-years of observation; about 70% of the workers were followed for more than 30 years since first exposure.

Results:Mortality from non-malignant diseases of the blood was increased (SMR 2.17, 95% CI 0.87 to 4.48), and correlated with duration of benzene exposure, although risk had decreased from the previous investigation of this cohort. The risk for leukaemia was slightly above background (SMR 1.14, obs 12, 95% CI 0.59 to 1.99) but has also decreased since the earlier study of this cohort. SMRs for acute non-lymphocytic leukaemia (ANLL), chronic lymphatic leukaemia, and non-Hodgkin’s lymphoma were 1.11, 0.42, and 1.06 respectively. There was evidence of a weak trend of increasing SMRs for leukaemia and possibly ANLL with increasing low-level cumulative exposure but not with other measures.

Conclusion:Leukaemia and ANLL results were consistent with the mildly increased risk estimates from lower exposure subgroups of the Pliofilm cohort.
Reciprocal differences of morphological and DNA characters in interspecific hybridization inCucumis
Authors: Chen Jin Feng , Zhuang Fei Yun , Liu Xian An , Qian Chun Tao
Published: February 2004

Plant materials with different ploidy levels from a series of reciprocal crosses between a wild Cucumis species (Cucumis hystrix Chakr., 2n = 2x = 24) and cucumber (Cucumis sativus L., 2n = 2x = 14) were used to investigate reciprocal differences in morphology, fertility, and DNA characteristics. Diameter of the stem, length of the petiole, and shape and size of the leaves of the hybrids were intermediate when compared with their parents. The length of the internode of the main stem showed maternal transmission in all hybrids, but the branching number and appearance of the first female flower showed paternal transmission. The differences in fertility of reciprocal plants were significant. When C. hystrix was used as the female parent, the diploid (2n = 2x = 19) hybrids set fruit without seeds, whereas the amphidiploid (2n = 4x = 38) plants produced fruits with viable seeds. However, when cucumber was used as the female parent, both tetraploid and diploid hybrid plants were highly sterile and did not set fruits. To further investigate variation in hybrid genomes, 21 arbitrary primers were used for random amplified polymorphic DNA analysis. Reciprocal differences were detected for 15 primers. The banding patterns were different among the four types of hybrids, but there was no significant difference in the total and (or) average numbers of bands observed. We suggest that the differences in random amplified polymorphic DNA banding patterns of the hybrids are probably related to the paternal- and (or) maternal-transmitted morphological characteristics in the reciprocal cross.Key words: Cucumis, interspecific hybridization, reciprocal differences, random amplified polymorphic DNA markers, paternal and (or) maternal transmission.
Morphological variation in Bromus sect. Ceratochloa germplasm of Patagonia
Authors: Massa Alicia N , Jensen Kevin B , Larson Steve R , Hole David J
Published: February 2004

South American representatives of Bromus sect. Ceratochloa make up a morphologically diverse group of grasses indigenous to the southern Andes of Argentina and Chile. The objectives of the present study were to describe patterns of morphological variation among 30 accessions representing six species (Bromus catharticus Vahl, Bromus coloratus Steud., Bromus lithobius Trin., Bromus mango E. Desv., Bromus stamineus E. Desv., and Bromus tunicatus Phil.) in a common garden, correlate morphological and previously obtained molecular data, and develop a taxonomic treatment within sect. Ceratochloa of South America. Plant materials included 28 hexaploid (2n = 6x = 42) and 2 octoploid (2n = 8x = 56) accessions. Based on multivariate analyses of 24 characters, the two octoploid accessions formed an isolated, well-defined group, while the hexaploids formed two less-defined groups. Characterized by lemma awns longer than 3 mm, one group consisted of those accessions of B. coloratus, B. lithobius, and B. stamineus, whereas the other group consisted of B. catharticus, B. mango, and B. tunicatus. A significant Mantel test statistic (r = 0.70, P = 0.001) suggested a high correlation between morphological variation and DNA polymorphism. Taken together, our results indicated that the hexaploid complex should be described as a single variable species (B. cathar ticus), with two nearly continuous groups: B. catharticus subsp. catharticus (Vahl) Herter and B. catharticus subsp. stamineus (E. Desv.) Massa. Based on nomenclature priority and type specimen designations, the octoploid accessions should be described as Bromus coloratus.Key words: Bromus, morphology, multivariate analysis, Patagonia, taxonomy.
Arbuscular mycorrhizas influence plant diversity, productivity, and nutrients in boreal grasslands
Authors: Dhillion Shivcharn S , Gardsjord Tone L
Published: February 2004

The effect of reduced arbuscular mycorrhiza (AM) colonization on nitrogen and phosphorus concentration in grass tissue, species diversity, cover, and productivity was investigated after 4 years of benomyl application in two boreal grasslands, Storvordlia (a high plant diversity field) and Kalvsvangen (a low plant diversity field), in Eastern Norway. In addition, AM colonization, spore numbers, and mycorrhizal inoculum potential was studied during one season. A split-plot design was used, with grazing as the main treatment and the application of benomyl as a subtreatment. AM colonization was significantly reduced because of benomyl application, whereas spore numbers were not significantly affected by the treatment. Mycorrhizal inoculum potential was reduced, but not consistently. In both sites nitrogen and phosphorus concentration of grass tissue was significantly higher in grazed plots than in ungrazed ones, and significantly lower in benomyl subplots than in controls. Plant diversity, composition, and cover had changed significantly after 4 years in grazed controls in Storvordlia, but this was not seen in Kalvsvangen. In both sites, total productivity increased significantly after 4 years of benomyl application. This experiment indicates that AM associations can influence grass nutrient contents and species responses, plant diversity, and productivity in boreal grasslands. These differences were larger in the higher plant diversity site, which is situated at a higher elevation and is under more marginal growth conditions.Key words: arbuscular mycorrhiza, benomyl, productivity, biodiversity, boreal grasslands, ecosystem processes.
THE CONSTRAINTS ON CP VIOLATING PHASES IN MODELS WITH A DYNAMICAL GLUINO PHASE
Authors: BOZ MÜGE
Published: February 2004

We analyze the electric dipole moment and the Higgs mass constraints on the supersymmetric model which offers dynamical solutions to the μ and strong CP problems. The trilinear coupling phases, and tan β-|μ| are strongly correlated, particularly in the low-tan β regime. Certain values of the phases of the trilinear couplings are forbidden, whereas the CP violating phase from the chargino sector is imprisoned to lie near a CP conserving point, by the Higgs mass and electric dipole moment constraints.
PHENOMENOLOGICAL TESTS FOR THE FREEZING OF THE QCD RUNNING COUPLING CONSTANT
Authors: AGUILAR A. C. , MIHARA A. , NATALE A. A.
Published: February 2004

We discuss phenomenological tests for the frozen infrared behavior of the running coupling constant and gluon propagators found in some solutions of Schwinger–Dyson equations of the gluonic sector of QCD. We verify that several observables can be used in order to select the different expressions of αs found in the literature. We test the effect of the nonperturbative coupling in the τ-lepton decay rate into nonstrange hadrons, in the ρ vector meson helicity density matrix that are produced in the χc2→ρρ decay, in the photon to pion transition form factor, and compute the cross-sections for elastic proton–proton scattering and exclusive ρ production in deep inelastic scattering. These quantities depend on the infrared behavior of the coupling constant at different levels, we discuss the reasons for this dependence and argue that the existent and future data can be used to test the approximations performed to solve the Schwinger–Dyson equations and they already seem to select one specific infrared behavior of the coupling.
RESUMMATION STUDY ON VECTOR MESON DECAYS AND CHIRAL SYMMETRY SPONTANEOUSLY BREAKING IN CHIRAL CONSTITUENT QUARK MODEL
Authors: HUANG YI-BIN , YAN MU-LIN , WANG XIAO-JUN
Published: February 2004

We study on-shell decays of light vector meson resonances ρ, K* and ϕ in the framework of chiral constituent quark model using resummation calculations. Such studies are necessary for showing that dynamics described by chiral Lagrangian works well at this energy scale. The effective action is derived by a proper vertex method, where resummation of all orders of momentum expansion is accomplished. Also studied are the loop effects of pseudoscalar meson, which play an important role at this energy scale. The numerical results agree well with the experimental data. A new method to explore the chiral symmetry spontaneously breaking (CSSB) is proposed. It is found that the unitarity of the effective meson theory resulted from resummation derivations demands an upper-limit to the momentum of vector meson. This upper-limit, being critical point, is just the energy scale of CSSB, and is found to be flavor-dependent.
NEXT-TO-NEXT-TO-LEADING-ORDER SOFT-GLUON CORRECTIONS IN DIRECT PHOTON PRODUCTION
Authors: KIDONAKIS NIKOLAOS , OWENS J. F.
Published: February 2004

Previous work on soft-gluon resummation for direct photon production is extended to include additional subleading logarithmic terms through [Formula: see text] and some representative comparisons are made to experimental results from the E-706 and UA-6 Collaborations. The additional terms are small in magnitude, indicating good convergence properties to the level of accuracy calculated. The scale dependence remains much smaller than that of the next-to-leading-order calculation.
Total branched-chain amino acids requirement in patients with maple syrup urine disease by use of indicator amino acid oxidation withl-[1-13C]phenylalanine
Authors: Riazi Roya , Rafii Mahroukh , Clarke Joe T. R. , Wykes Linda J. , Ball Ronald O. , Pencharz Paul B.
Published: February 2004

Maple syrup urine disease (MSUD) is an autosomal recessive disorder caused by defects in the mitochondrial multienzyme complex branched-chain α-keto acid dehydrogenase (BCKD; EC 1.2.4.4 ), responsible for the oxidative decarboxylation of the branched-chain ketoacids (BCKA) derived from the branched-chain amino acids (BCAA) leucine, valine, and isoleucine. Deficiency of the enzyme results in increased concentrations of the BCAA and BCKA in body cells and fluids. The treatment of the disease is aimed at keeping the concentration of BCAA below the toxic concentrations, primarily by dietary restriction of BCAA intake. The objective of this study was to determine the total BCAA requirements of patients with classical MSUD caused by marked deficiency of BCKD by use of the indicator amino acid oxidation (IAAO) technique. Five MSUD patients from the MSUD clinic of The Hospital for Sick Children participated in the study. Each was randomly assigned to different intakes of BCAA mixture (0, 20, 30, 50, 60, 70, 90, 110, and 130 mg·kg−1·day−1), in which the relative proportion of BCAA was the same as that in egg protein. Total BCAA requirement was determined by measuring the oxidation of l-[1-13C]phenylalanine to13CO2. The mean total BCAA requirement was estimated using a two-phase linear regression crossover analysis, which showed that the mean total BCAA requirement was 45 mg·kg−1·day−1, with the safe level of intake (upper 95% confidence interval) at 62 mg·kg−1·day−1. This is the first time BCAA requirements in patients with MSUD have been determined directly.
Inducible nitric oxide synthase upregulates cyclooxygenase-2 in mouse cholangiocytes promoting cell growth
Authors: Ishimura Norihisa , Bronk Steven F. , Gores Gregory J.
Published: February 2004

Both inducible nitric oxide (NO) synthase (iNOS) and cyclooxygenase-2 (COX-2) have been implicated in the biliary tract carcinogenesis. However, it is not known whether these inflammatory mediators are induced by interdependent or parallel pathways. Because iNOS activity has been associated with diverse gene expression, the aim of this study was to determine whether iNOS induces COX-2. To address this objective, immortalized, but nonmalignant, murine cholangiocytes, 603B cells were employed for these studies. Both iNOS and COX-2 protein and mRNA were expressed in these cells. However, iNOS inhibition with either N-[3-(aminomethyl) benzyl]acetamidine or stable transfection with an iNOS antisense construct inhibited COX-2 mRNA and protein expression, an effect that was reversed by NO donors. COX-2 mRNA expression in 603B cells was reduced by pharmacological inhibitors of the p38 MAPK and JNK1/2 pathways. In contrast, neither inhibitors of the soluble guanylyl cyclase inhibitor/protein kinase G nor p42/44 MAPK pathways attenuated COX-2 mRNA expression. Finally, 603B cells grew at a rate threefold greater than 603B-iNOS antisense cells. The low growth rate of 603B-iNOS antisense cells could be restored to near that of the parent cell line with exogenous PGE2. In conclusion, iNOS induces COX-2 expression in cholangiocytes, which promotes cell growth. COX-2 induction may contribute to iNOS-associated carcinogenesis.
Angiotensin II mediates uterine vasoconstriction through α-stimulation
Authors: Cox Blair E. , Roy Timothy A. , Rosenfeld Charles R.
Published: February 2004

Intravenous angiotensin II (ANG II) increases uterine vascular resistance (UVR), whereas uterine intra-arterial infusions do not. Type 2 ANG II (AT2) receptors predominate in uterine vascular smooth muscle; this may reflect involvement of systemic type 1 ANG II (AT1) receptor-mediated α-adrenergic activation. To examine this, we compared systemic pressor and UVR responses to intravenous phenylephrine and ANG II without and with systemic or uterine α-receptor blockade and in the absence or presence of AT1 receptor blockade in pregnant and nonpregnant ewes. Systemic α-receptor blockade inhibited phenylephrine-mediated increases in mean arterial pressure (MAP) and UVR, whereas uterine α-receptor blockade alone did not alter pressor responses and resulted in proportionate increases in UVR and MAP. Although neither systemic nor uterine α-receptor blockade affected ANG II-mediated pressor responses, UVR responses decreased >65% and also were proportionate to increases in MAP. Systemic AT1 receptor blockade inhibited all responses to intravenous ANG II. In contrast, uterine AT1 receptor blockade + systemic α-receptor blockade resulted in persistent proportionate increases in MAP and UVR. Uterine AT2 receptor blockade had no effects. We have shown that ANG II-mediated pressor responses reflect activation of systemic vascular AT1 receptors, whereas increases in UVR reflect AT1 receptor-mediated release of an α-agonist and uterine autoregulatory responses.
Effects of specific signal transduction inhibitors on increased permeability across rat endothelial monolayers induced by neuropeptide Y or VEGF
Authors: Kurimoto Nakako , Nan Yong-Shan , Chen Zhi-Yong , Feng Guo-Gang , Komatsu Toru , Kandatsu Nobuhisa , Ko Junken , Kawai Norio , Ishikawa Naohisa
Published: February 2004

Neuropeptide Y (NPY) elevates the permeability of cultured rat aortic endothelial cells (RAECs) in monolayer cultures under hypoxic conditions (5% O2) possibly by binding to the NPY Y3 receptor. The present study evaluated the effects of NPY compared to vascular endothelial growth factor (VEGF). RAECs were cultured on the upper chamber base of a double-chamber culture system, FITC-labeled albumin was introduced into the chamber, and permeation into the lower chamber was measured. Treatment was with 3 × 10−7 M NPY or 10−7 g/ml VEGF for 2 h along with specific inhibitors. The VEGF receptor-2 tyrosine kinase inhibitor tyrphostin SU-1498 and the protein kinase C inhibitor bis-indolylmaleimide I (GF-109203X) suppressed the VEGF-induced increase in monolayer permeability but not that caused by NPY. Furthermore, although the action of NPY was blocked in a concentration-dependent manner by phospholipase C inhibitor 1-(6-{[(17β)-3-methoxyestra-1,3,5( 10 )-trien-17-yl]amino}hexyl)-1 H-pyrrole-2,5-dione (U-73122), it was less sensitive than VEGF. However, the effects of both NPY and VEGF on the permeability of the RAEC monolayer were blocked with equal concentration dependence by STI571 (imatinib mesylate), which is an inhibitor of Abl tyrosine kinase in the nucleus and/or cytoplasm. The myosin light-chain kinase inhibitor 1-(5-chloronaphthalene-1-sulfonyl)-1 H-hexahydro-1,4-diazepine HCl (ML-9) suppressed both NPY- and VEGF-induced increment in permeability by ∼70%, whereas the calmodulin-dependent kinase inhibitor DY-9760e could decrease to below the baseline. These results indicate that the NPY Y3-receptor subtype is specifically linked to the effects of STI571 on endothelial cells, and that NPY, a sympathetic coneurotransmitter, may increase vascular permeability in association with altered intracellular or nuclear signal transduction.
Antioxidant-independent ascorbate enhancement of catecholamine-induced contractions of vascular smooth muscle
Authors: Dillon P. F. , Root-Bernstein R. S. , Lieder C. M.
Published: February 2004

Ascorbate reduces the oxidation rate of catecholamines and, by an independent mechanism, enhances rabbit aortic ring contractions initiated by catecholamines. The largest significantly different fractional increases in force produced by ascorbate enhancement of norepinephrine (NE), epinephrine, phenylpropanolamine (PPA), and ephedrine (Eph) are 5.5, 1.8, 1.6, and 1.3 times, respectively. In physiological salt solutions bubbled with 95% O2 at 37°C, NE, PPA, and Eph have oxidation rate constants of 1.24, 247, and 643 h, respectively. Ascorbate significantly enhances 100 nM NE contractions by at least twofold at all ascorbate concentrations >15 μM, including the entire physiological range of 40–100 μM. Ascorbate preloading and washout followed by NE exposure produces significantly greater contractions than NE without ascorbate preloading but significantly lower than NE simultaneously with ascorbate. Ascorbate does not enhance K+- or angiotensin II-induced contractions. Ascorbate enhancement of catecholamine contractions occurs in addition to the reduction in oxidation rate, because the increases in force occur faster than oxidation can occur, the increases occur with compounds that have negligible oxidation rates, and the increases occur when ascorbate and NE are not physically present together. These results are consistent with ascorbate acting on the adrenergic receptor. Ascorbate may play a role in shock and asthma treatments and potentiate the cardiovascular health consequences of PPA and Eph (Ephedra).
Augmentation of moxonidine-induced increase in ANP release by atrial hypertrophy
Authors: Cao Chunhua , Kang Chang Won , Kim Sung Zoo , Kim Suhn Hee
Published: February 2004

Imidazoline receptors are divided into I1 and I2 subtypes. I1-imidazoline receptors are distributed in the heart and are upregulated during hypertension or heart failure. The aim of this study was to define the possible role of I1-imidazoline receptors in the regulation of atrial natriuretic peptide (ANP) release in hypertrophied atria. Experiments were performed on isolated, perfused, hypertrophied atria from remnant-kidney hypertensive rats. The relatively selective I1-imidazoline receptor agonist moxonidine caused a decrease in pulse pressure. Moxonidine (3, 10, and 30 μmol/l) also caused dose-dependent increases in ANP secretion, but clonidine (an α2-adrenoceptor agonist) did not. Pretreatment with efaroxan (a selective I1-imidazoline receptor antagonist) or rauwolscine (a selective α2-adrenoceptor antagonist) inhibited the moxonidine-induced increases in ANP secretion and interstitial ANP concentration and decrease in pulse pressure. However, the antagonistic effect of efaroxan on moxonidine-induced ANP secretion was greater than that of rauwolscine. Neither efaroxan nor rauwolscine alone has any significant effects on ANP secretion and pulse pressure. In hypertrophied atria, the moxonidine-induced increase in ANP secretion and decrease in pulse pressure were markedly augmented compared with nonhypertrophied atria, and the relative change in ANP secretion by moxonidine was positively correlated to atrial hypertrophy. The accentuation by moxonidine of ANP secretion was attenuated by efaroxan but not by rauwolscine. These results show that moxonidine increases ANP release through (preferentially) the activation of atrial I1-imidazoline receptors and also via different mechanisms from clonidine, and this effect is augmented in hypertrophied atria. Therefore, we suggest that cardiac I1-imidazoline receptors play an important role in the regulation of blood pressure.
Defective D1-like receptor-mediated inhibition of the Cl−/HCO3−exchanger in immortalized SHR proximal tubular epithelial cells
Authors: Pedrosa Rui , Jose Pedro A. , Soares-da-Silva P.
Published: February 2004

The sensitivity of the Cl−/HCO3−exchanger to dopamine D1- and D2-like receptor stimulation in immortalized renal proximal tubular epithelial cells from the spontaneous hypertensive rat (SHR) and Wistar-Kyoto rat (WKY) was examined. The activity of the Cl−/HCO3−exchanger (in pH U/s) in SHR cells (0.00191) was greater than in WKY cells (0.00126). The activity of Cl−/HCO3−exchanger was exclusively observed at the apical cell side and probably occurs through the SLC26A6 anion transporter that is expressed in both WKY and SHR cells. Stimulation of D1-like receptors with SKF-38393 markedly attenuated the HCO3−-dependent intracellular pH recovery in WKY cells but not in SHR cells. Stimulation of D2-like receptors with quinerolane did not alter Cl−/HCO3−exchanger activity in both WKY and SHR cells. The selective D1-like receptor antagonist SKF-83566 prevented the effect of SKF-38393. Both WKY and SHR cells responded to dibutyryl-cAMP (DBcAMP) with inhibition of the Cl−/HCO3−exchanger, and downregulation of PKA (overnight exposure to DBcAMP) abolished the inhibitory effect of both DBcAMP and SKF-38393 in WKY cells. Both SHR and WKY cells responded to forskolin with increases in the formation of cAMP. However, only WKY responded to SKF-38393 with increases in the formation of cAMP that was prevented by SKF-83566. It is concluded that WKY cells respond to D1-like dopamine receptor stimulation with inhibition of the apical Cl−/HCO3−(SLC26A6) exchanger and SHR cells have a defective D1-like dopamine response.
Parasympathetic control of the heart. III. Neuropeptide Y-immunoreactive nerve terminals synapse on three populations of negative chronotropic vagal preganglionic neurons
Authors: Gray Alrich L. , Johnson Tannis A. , Lauenstein Jean-Marie , Newton Stephen S. , Ardell Jeffrey L. , Massari V. John
Published: February 2004

The vagal postganglionic control of cardiac rate is mediated by two intracardiac ganglia, i.e., the sinoatrial (SA) and posterior atrial (PA) ganglia. Nothing is known about the vagal preganglionic neurons (VPNs) that innervate the PA ganglion or about the neurochemical anatomy of central afferents that innervate these VPNs. These issues were examined using light microscopic retrograde labeling methods and dual-labeling electron microscopic histochemical and immunocytochemical methods. VPNs projecting to the PA ganglion are found in a narrow column exclusively in the ventrolateral nucleus ambiguus (NA-VL). These neurons are relatively large (37.6 ± 2.7 μm by 21.3 ± 3.4 μm) with abundant cytoplasm and intracellular organelles, rare somatic and dendritic spines, round uninvaginated nuclei, and myelinated axons. Previous physiological data indicated that microinjections of neuropeptide Y (NPY) into the NA-VL cause negative chronotropic effects. The present morphological data demonstrate that NPY-immunoreactive nerve terminals formed 18 ± 4% of the axodendritic or axosomatic synapses and close appositions on VPNs projecting to the PA ganglion. Three approximately equal populations of VPNs in the NA-VL were retrogradely labeled from the SA and PA ganglia. One population each projects to the SA ganglion, the PA ganglion, or to both the SA and PA ganglia. Therefore, there are both shared and independent pathways involved in the vagal preganglionic controls of cardiac rate. These data are consistent with the hypothesis that the central and peripheral parasympathetic controls of cardiac rate are coordinated by multiple potentially redundant and/or interacting pathways and mechanisms.
Exertional heat injury and gene expression changes: a DNA microarray analysis study
Authors: Sonna Larry A. , Wenger C. Bruce , Flinn Scott , Sheldon Holly K. , Sawka Michael N. , Lilly Craig M.
Published: February 2004

This study examined gene expression changes associated with exertional heat injury (EHI) in vivo and compared these changes to in vitro heat shock responses previously reported by our laboratory. Peripheral blood mononuclear cell (PBMC) RNA was obtained from four male Marine recruits (ages 17-19 yr) who presented with symptoms consistent with EHI, core temperatures ranging from 39.3 to 42.5°C, and elevations in serum enzymes such as creatine kinase. Controls were age- and gender-matched Marines from whom samples were obtained before and several days after an intense field-training exercise in the heat (“The Crucible”). Expression analysis was performed on Affymetrix arrays (containing ∼12,600 sequences) from pooled samples obtained at three times for EHI group (at presentation, 2-3 h after cooling, and 1-2 days later) and compared with control values (average signals from two chips representing pre- and post-Crucible samples). After post hoc filtering, the analysis identified 361 transcripts that had twofold or greater increases in expression at one or more of the time points assayed and 331 transcripts that had twofold or greater decreases in expression. The affected transcripts included sequences previously shown to be heat-shock responsive in PBMCs in vitro (including both heat shock proteins and non-heat shock proteins), a number of sequences whose changes in expression had not previously been noted as a result of in vitro heat shock in PBMCs (including several interferon-induced sequences), and several nonspecific stress response genes (including ubiquitin C and dual-specificity phosphatase-1). We conclude that EHI produces a broad stress response that is detectable in PBMCs and that heat stress per se can only account for some of the observed changes in transcript expression. The molecular evidence from these patients is thus consistent with the hypothesis that EHI can result from cumulative effects of multiple adverse interacting stimuli.
Hypergravity-induced immunomodulation in a rodent model: hematological and lymphocyte function analyses
Authors: Pecaut Michael J. , Miller Glen M. , Nelson Gregory A. , Gridley Daila S.
Published: February 2004

The major purpose of this study was to quantify hypergravity-induced changes in erythrocyte and thrombocyte characteristics, spontaneous and mitogen-induced lymphoblastogenesis, and capacity of splenocytes to secrete immunoregulatory cytokines. C57BL/6 mice were subjected to chronic 1, 2, and 3 G; subsets were euthanized after 1, 4, 7, 10, and 21 days of centrifugation. Erythrocyte counts, hematocrit, and hemoglobin were significantly reduced by day 21 in both centrifuged groups. Hemoglobin concentration and volume per red blood cell were generally low, but an early, transient spike above normal was noted in thrombocyte counts in the 3-G group. Fluctuations above and below normal in blood and spleen cell spontaneous blastogenesis were dependent on the length of centrifugation time and not on the level of gravity. Depression in splenocyte responses to phytohemagglutinin and lipopolysaccharide due to gravity were noted when the data were expressed as stimulation indexes. Cytokine production by spleen cells was primarily affected during the first week of centrifugation: IL-2, IL-4, and tumor necrosis factor-α increased, whereas interferon-γ decreased. These findings, although not identical to those reported for spaceflight, indicate that altered gravity can influence both hematological and functional variables that may translate into serious health consequences during extended missions.
Centrifugal Inputs Modulate Taste Aversion Learning Associated Parabrachial Neuronal Activities
Authors: Tokita Ken'ichi , Karádi Zoltán , Shimura Tsuyoshi , Yamamoto Takashi
Published: February 2004

Our previous studies have demonstrated that gustatory neurons in the parabrachial nucleus (PBN) show altered responses after the acquisition of conditioned taste aversion (CTA) to NaCl. The present study was conducted 1) to examine centrifugal influences on the altered gustatory activity of CTA-trained rats, and 2) to evaluate the role of amiloride-sensitive (ASN) and -insensitive NaCl (AIN) best units in coding the taste of NaCl. Animals were separated into 2 groups: a CTA group that had acquired taste aversion to 0.1 M NaCl and a control group that underwent pseudoconditioning before the recording experiment. Single-neuron activity, in 2 separate series of experiments, was extracellularly recorded in anesthetized rats. In the stimulation studies, the effects of electrical stimulation of the gustatory cortex (GC) or the central nucleus of amygdala (CeA) were examined on firing of PBN taste units. CeA stimulation produced excitatory effect in significantly more neurons in the CTA group ( n = 8) than in the control group ( n = 1). Furthermore, ASN-best units in the CTA group showed larger responses to NaCl than similar units in the control group. In the decerebration experiment, there was no statistical difference among the taste responses between the 2 groups in any best-stimulus category. These results suggest that CTA conditioning uses an effective central amygdaloid input to modulate activity of gustatory neurons in the PBN. Data also substantiate that amiloride-sensitive components of NaCl-best neurons play a critical role in the recognition of distinctive taste of NaCl.
Uncoupling protein 2 and 3 in marsupials: identification, phylogeny, and gene expression in response to cold and fasting in Antechinus flavipes
Authors: Jastroch Martin , Withers Kerry , Klingenspor Martin
Published: February 2004

We searched for the presence of uncoupling protein genes so far unknown in marsupials and monotremes and identified uncoupling protein 2 (UCP2) and UCP3 full-length cDNAs in libraries constructed from the marsupials Antechinus flavipes and Sminthopsis macroura. Marsupial UCP2 is 89–90% identical to rodent UCP2, whereas UCP3 exhibits 80% identity to mouse UCP3. A phylogenetic tree including all known UCPs positions the novel marsupial UCP2 and UCP3 at the base of the mammalian orthologs. In the 5′-untranslated region of UCP2 a second open reading frame encoding for a 36-amino acid peptide was identified which is highly conserved in all vertebrate UCP2 transcripts. Analysis of tissue specificity in A. flavipes with homologous cDNA probes revealed ubiquitous presence of UCP2 mRNA and striated muscle specificity of UCP3 mRNA resembling the known expression pattern in rodents. Neither UCP2 nor UCP3 gene expression was stimulated in adipose tissue and skeletal muscle of cold exposed A. flavipes. However, UCP3 mRNA expression was upregulated 6-fold in heart and 2.5-fold in skeletal muscle as reported for rodents in response to fasting. Furthermore, UCP3 mRNA seems to be coregulated with PDK4 mRNA, indicating a relation to enhanced lipid metabolism. In contrast, UCP2 gene expression was not regulated in response to fasting in adipose tissue and skeletal muscle but was diminished in the lung and increased in adipose tissue. Taken together, the sequence analysis, tissue specificity and physiological regulation suggest a conserved function of UCP2 and UCP3 during 130 million years of mammalian evolution.
Tests of linkage and/or association of the LEPR gene polymorphisms with obesity phenotypes in Caucasian nuclear families
Authors: Liu Yong-Jun , Rocha-Sanchez Sonia M.S. , Liu Peng-Yuan , Long Ji-Rong , Lu Yan , Elze Leo , Recker Robert R. , Deng Hong-Wen
Published: February 2004

Genetic variations in the leptin receptor (LEPR) gene have been conceived to affect body weight in general populations. In this study, using the tests implemented in the statistical package QTDT, we evaluated association and/or linkage of the LEPR gene with obesity phenotypes in a large sample comprising 1,873 subjects from 405 Caucasian nuclear families. Obesity phenotypes tested include body mass index (BMI), fat mass, percentage fat mass (PFM), and lean mass, with the latter three measured by dual-energy X-ray absorptiometry (DXA). Three single nucleotide polymorphisms (SNPs), namely Lys109Arg (A/G), Lys656Asn (G/C), Pro1019Pro (G/A), in the LEPR gene were analyzed. Significant linkage disequilibrium (0.394 ≤ | D′| ≤ 0.688, P < 0.001) was observed between pairs of the three SNPs. No significant population stratification was found for any SNP/phenotype. In single-locus analyses, evidence of association was observed for Lys656Asn with lean mass ( P = 0.002) and fat mass ( P = 0.015). The contribution of this polymorphism to the phenotypic variation of lean mass and fat mass was 2.63% and 1.15%, respectively. Subjects carrying allele G at the Lys656Asn site had, on average, 3.16% higher lean mass and 2.71% higher fat mass than those without it. In the analyses for haplotypes defined by the three SNPs, significant associations were detected between haplotype GCA ( P = 0.005) and lean mass. In addition, marginally significant evidence of association was observed for this haplotype with fat mass ( P = 0.012). No statistically significant linkage was found, largely due to the limited power of the linkage approach to detect small genetic effects in our data sets. Our results suggest that the LEPR gene polymorphisms contribute to variation in obesity phenotypes.
Long-Term Heart Rate Reduction Induced by the Selective
I
f
Current Inhibitor Ivabradine Improves Left Ventricular Function and Intrinsic Myocardial Structure in Congestive Heart Failure
Authors: Mulder Paul , Barbier Stephane , Chagraoui Abdeslam , Richard Vincent , Henry Jean Paul , Lallemand Françoise , Renet Sylvanie , Lerebours Guy , Mahlberg-Gaudin Florence , Thuillez Christian
Published: February 2004

Background—

Heart rate reduction (HRR) improves left ventricular (LV) filling, increases myocardial O
2
supply, and reduces myocardial O
2
consumption, which are all beneficial in congestive heart failure (CHF). However, the long-term effects of HRR on cardiac function and remodeling are unknown.

Methods and Results—

We assessed, in rats with CHF, the effects of long-term HRR induced by the selective
I
f
current inhibitor ivabradine (as food admix for 90 days starting 7 days after coronary artery ligation). To assess intrinsic modifications of LV tissue induced by long-term HRR, all parameters were reassessed 3 days after interruption of treatment. Ivabradine decreased heart rate over the 90-day treatment period (−18% versus untreated at 10 mg · kg
−1
· d
−1
), without modifying blood pressure, LV end-diastolic pressure, or dP/dt
max/min
. Ivabradine significantly reduced LV end-systolic but not end-diastolic diameter, which resulted in preserved cardiac output due to increased stroke volume. In the Langendorff preparation, ivabradine shifted LV systolic but not end-diastolic pressure-volume relations to the left. Ivabradine decreased LV collagen density and increased LV capillary density without modifying LV weight. Three days after interruption of treatment, the effects of ivabradine on LV geometry, shortening, and stroke volume persisted despite normalization of heart rate.

Conclusions—

In rats with CHF, long-term HRR induced by the selective
I
f
inhibitor ivabradine improves LV function and increases stroke volume, preserving cardiac output despite the HRR. The improvement of cardiac function is related not only to the HRR per se but also to modifications in the extracellular matrix and/or function of myocytes as a consequence of long-term HRR.