bluuebunny/crossref_metadata_2025 huggingface dataset:
E' CENTERS IN SILICON DIOXIDE: FIRST-PRINCIPLES MOLECULAR DYNAMICS STUDIES
Authors: BOERO MAURO , OSHIYAMA ATSUSHI , SILVESTRELLI PIER LUIGI
Published: August 2004

The point-like defects known as E' centers are the most abundant natural defects in silicon dioxide ( SiO2) and have been identified as unpaired sp3dangling bonds. Their importance stems from the fact that they deeply affect the quality of electronic and optical devices. For this reason, particular attention has been paid in their characterization since the early 1960s. In this work, we review theoretical and experimental results concerning these kinds of defects, focusing on the related charge and spin states. In particular, the defect known as E' in crystalline quartz and its analogous E'γin amorphous SiO2, detected by electron spin resonance, are shown to be due to the Si dangling bonds that arise either upon removal or displacement of an oxygen atom in a SiO2network, accompanied by an asymmetric relaxation of the network.
FIRST-ORDER MAGNETIC PHASE TRANSITIONS AND COLOSSAL MAGNETORESISTANCE: JOINING MANGANESE PEROVSKITES AND MnAs
Authors: MIRA J. , RIVAS J.
Published: August 2004

We revise some recent results on the nature of the magnetic phase transition of ferromagnetic manganese perovskites with colossal magnetoresistance. It is found that they exhibit first-order magnetic phase transitions mainly due to strong lattice effects. The presence of such first-order transition is strongly linked to the existence of a temperature region above the Curie Temperature with a phase-separated regime of coexisting metallic and insulating clusters. This situation is compared with that of MnAs , paradigm of system with first-order magnetic phase transition, and we observe a parallel phenomenology of these apparently different systems. This serves as a clue for the finding of a phase-separated regime also in MnAs and, moreover, for the finding of a colossal magnetoresistive effect similar to that of manganese perovskites.
STRUCTURAL AND DIELECTRIC STUDIES ON Pb(Mg0.5Mo0.5)O3 COMPOUND
Authors: BARBUR I. , ARDELEAN I. , BORODI G. , CIOMOS D.
Published: August 2004

Structural and dielectric measurements were performed on Pb ( Mg 0.5 Mo 0.5) O 3 (PMM). Polycrystalline samples of PMM were synthesized by solid-state reaction technique at normal pressure. The X-ray measurements indicate formation of single-phase perovskite structure with absence of Mg and Mo ions ordering. The temperature dependence of the relative dielectric constant suggests that PMM undergoes a phase transition (FE or AFE) at 63°C.
FRACTIONAL CONDUCTANCE IN MULTIWALLED CARBON NANOTUBES: A SEMI-CLASSICAL THEORY
Authors: GRADO-CAFFARO M. A. , GRADO-CAFFARO M.
Published: August 2004

An analytical formulation to interpret the quantized electrical conductance in multiwalled carbon nanotubes with defects is presented. In this formulation, free-electron theory is utilized in order to calculate conductance which is found to be fractional according to an inverse proportionality law with respect to the number of layers involved in a given multiwalled tube. Our results agree well with experimental observations.
ENERGY GAP OF THE "METALLIC" SINGLE-WALLED CARBON NANOTUBES
Authors: CHEN JIANGWEI , YANG ZHENGHUI , GU JUN
Published: August 2004

Based upon the Slater–Koster tight-binding calculations, we investigated electronic properties of the "metallic" single-walled carbon nanotubes (SWNTs) in detail. Our results show that tube curvature may produce an energy gap at the Fermi level for zigzag and chiral "metallic" SWNTs, and this effect decreases with the increasing of either the radius or the chiral angle. Our calculated results are in good agreement with experiments.
C-type natriuretic peptide attenuates bleomycin-induced pulmonary fibrosis in mice
Authors: Murakami Shinsuke , Nagaya Noritoshi , Itoh Takefumi , Fujii Takafumi , Iwase Takashi , Hamada Kaoru , Kimura Hiroshi , Kangawa Kenji
Published: July 2004

C-type natriuretic peptide (CNP) has been shown to play an important role in the regulation of vascular tone and remodeling. However, the physiological role of CNP in the lung remains unknown. Accordingly, we investigated whether CNP infusion attenuates bleomycin (BLM)-induced pulmonary fibrosis in mice. After intratracheal injection of BLM or saline, mice were randomized to receive continuous infusion of CNP or vehicle for 14 days. CNP infusion significantly reduced the total number of cells and the numbers of macrophages, neutrophils, and lymphocytes in bronchoalveolar lavage fluid. Interestingly, CNP markedly reduced bronchoalveolar lavage fluid IL-1β levels. Immunohistochemical analysis demonstrated that CNP significantly inhibited infiltration of macrophages into the alveolar and interstitial regions. CNP infusion significantly attenuated BLM-induced pulmonary fibrosis, as indicated by significant decreases in Ashcroft score and lung hydroxyproline content. CNP markedly decreased the number of Ki-67-positive cells in fibrotic lesions of the lung, suggesting antiproliferative effects of CNP on pulmonary fibrosis. Kaplan-Meier survival curves demonstrated that BLM mice treated with CNP had a significantly higher survival rate than those given vehicle. These results suggest that continuous infusion of CNP attenuates BLM-induced pulmonary fibrosis and improves survival in BLM mice, at least in part by inhibition of pulmonary inflammation and cell proliferation.
Upregulation of erythropoietin receptor during postnatal and postpneumonectomy lung growth
Authors: Foster David J. , Moe Orson W. , Hsia Connie C. W.
Published: July 2004

Circulating erythropoietin (EPO) stimulates erythrocytosis, whereas organ-specific local EPO receptor (EPOR) expression has been linked to angiogenesis, tissue growth, and development. On the basis of the observation of concurrent enhancement of lung growth and erythrocyte production during exposure to chronic hypoxia, we hypothesized that a paracrine EPO system is involved in mediating lung growth. We analyzed EPOR protein expression in normal dog lung tissue during postnatal maturation and during compensatory lung growth after right pneumonectomy (PNX). Membrane-bound EPOR was significantly more abundant in the immature lung compared with mature lung and in the remaining lung 3 wk after PNX compared with matched sham controls. COOH-terminal cytosolic EPOR peptides, which were even more abundant than membrane-bound EPOR, were also upregulated in immature lung but differentially processed after PNX. Apoptosis was enhanced during both types of lung growth in direct relationship to cellular proliferation and EPOR expression. We conclude that both developmental and compensatory lung growth involve paracrine EPO signaling with parallel upregulation but differential processing of EPOR.
Fibrogenic cytokine levels in bronchoalveolar lavage aspirates 15 years after exposure to sulfur mustard
Authors: Aghanouri Reza , Ghanei Mostafa , Aslani Jafar , Keivani-Amine Hossein , Rastegar Ferdos , Karkhane Ali
Published: July 2004

Over 100,000 Iranian war veterans suffer from chronic effects of mustard gas exposure. Sulfur mustard was used by Iraq during the Iraqi-imposed war on Iran (between 1980 and 1988). The major complaints of these patients are mild interstitial fibrosis and bronchiolitis. We aimed to determine the state of fibrosis progression and assessed transforming growth factor (TGF)-β1 levels in pulmonary samples and in bronchoalveolar lavage (BAL) aspirates. A total of 126 war veterans confirmed for lung disease were assessed and compared with three control groups: 1) 64 veterans not exposed to chemical agents, 2) 12 idiopathic pulmonary fibrosis civilian patients, and 3) 33 normal persons. BAL was performed via a flexible fiber-optic bronchoscope and the standard manual method. Total protein was measured by Bradford assay, and samples were corrected with regard to coefficients. Samples were concentrated 15-fold by lyophilization and resolubilization. Samples were double-checked using an ELISA test kit. The Mann-Whitney test was used for the data analysis using commercial software. We detected that significant differences between TGF-β1 levels between the case group and control group 1 ( P = 0.001) and control group 3 ( P = 0.003). No significant differences were found between the case group and control group 2 ( P = 0.57). Inflammation and fibrotic processes in lung tissue of patients exposed to sulfur mustard may be progressive so IFN-γ may be a useful drug to these patients' treatment.
BMPR-IIheterozygous mice have mild pulmonary hypertension and an impaired pulmonary vascular remodeling response to prolonged hypoxia
Authors: Beppu Hideyuki , Ichinose Fumito , Kawai Noriko , Jones Rosemary C. , Yu Paul B. , Zapol Warren M. , Miyazono Kohei , Li En , Bloch Kenneth D.
Published: July 2004

Heterozygous mutations of the bone morphogenetic protein type II receptor ( BMPR-II) gene have been identified in patients with primary pulmonary hypertension. The mechanisms by which these mutations contribute to the pathogenesis of primary pulmonary hypertension are not fully elucidated. To assess the impact of a heterozygous mutation of the BMPR-II gene on the pulmonary vasculature, we studied mice carrying a mutant BMPR-II allele lacking exons 4 and 5 ( BMPR-II+/−mice). BMPR-II+/−mice had increased mean pulmonary arterial pressure and pulmonary vascular resistance compared with their wild-type littermates. Histological analyses revealed that the wall thickness of muscularized pulmonary arteries (<100 μm in diameter) and the number of alveolar-capillary units were greater in BMPR-II+/−than in wild-type mice. Breathing 11% oxygen for 3 wk increased mean pulmonary arterial pressure, pulmonary vascular resistance, and hemoglobin concentration to similar levels in BMPR-II+/−and wild-type mice, but the degree of muscularization of small pulmonary arteries and formation of alveolar-capillary units were reduced in BMPR-II+/−mice. Our results suggest that, in mice, mutation of one copy of the BMPR-II gene causes pulmonary hypertension but impairs the ability of the pulmonary vasculature to remodel in response to prolonged hypoxic breathing.
Barrier dysfunction and RhoA activation are blunted by homocysteine and adenosine in pulmonary endothelium
Authors: Harrington Elizabeth O. , Newton Julie , Morin Nicole , Rounds Sharon
Published: July 2004

RhoA GTPases modulate endothelial permeability. We have previously shown that adenosine and homocysteine enhance basal barrier function in pulmonary artery endothelial cells by a mechanism involving diminution of RhoA carboxyl methylation and activity. In the current study, we investigated the effects of adenosine and homocysteine on endothelial monolayer permeability in cultured monolayers. Adenosine and homocysteine significantly attenuated thrombin-induced endothelial barrier dysfunction and intercellular gap formation. We found significantly diminished RhoA associated with the membrane subcellular fraction in endothelial cells pretreated with adenosine and homocysteine, compared with vehicle-treated endothelial cells. Additionally, adenosine and homocysteine significantly blunted RhoA activation following thrombin exposure. Incubation with adenosine and homocysteine also enhanced in vitro interactions between RhoA and RhoGDI, as well as subcellular translocation of p190RhoGAP to the cytosol. These data demonstrate that elevated intracellular concentrations of homocysteine and adenosine enhance endothelial barrier function in cultured endothelial cells isolated from the main pulmonary artery and lung microvasculature, suggesting a potentially protective effect against pulmonary edema in response to lung injury. We speculate that homocysteine and adenosine modulate the level of endothelial barrier dysfunction through modulation of RhoA posttranslational processing resulting in diminished GTPase activity through altered interactions with modulators of RhoA activation.
Superoxide dismutase moderates basal and induced bacterial adherence and interleukin-8 expression in airway epithelial cells
Authors: Arita Yuko , Joseph Ansamma , Koo Hshi-Chi , Li Yuchi , Palaia Thomas A. , Davis Jonathan M. , Kazzaz Jeffrey A.
Published: July 2004

Bacterial infection of the tracheobronchial tree is a frequent, serious complication in patients receiving treatment with oxygen and mechanical ventilation, resulting in increased morbidity and mortality. Using human airway epithelial cell culture models, we examined the effect of hyperoxia on bacterial adherence and the expression of interleukin-8 (IL-8), an important mediator involved in the inflammatory process. A 24-h exposure to 95% O2increased Pseudomonas aeruginosa (PA) adherence 57% in A549 cells ( P < 0.01) and 115% in 16HBE cells ( P < 0.01) but had little effect on Staphylococcus aureus (SA) adherence. Exposure to hyperoxia, followed by a 1-h incubation with SA, further enhanced PA adherence ( P < 0.01), suggesting that hyperoxia and SA colonization may enhance the susceptibility of lung epithelial cells to gram-negative infections. IL-8 expression was also increased in cells exposed to both hyperoxia and PA. Stable or transient overexpression of manganese superoxide dismutase reduced both basal and stimulated levels of PA adherence and IL-8 levels in response to exposure to either hyperoxia or PA. These data indicate that hyperoxia increases susceptibility to infection and that the pathways are mediated by reactive oxygen species. Therapeutic intervention strategies designed to prevent accumulation of intracellular reactive oxygen species may reduce opportunistic pulmonary infections.
Activation of EP4 receptors contributes to prostaglandin E2-mediated stimulation of renal sensory nerves
Authors: Kopp Ulla C. , Cicha Michael Z. , Nakamura Kazuhiro , Nüsing Rolf M. , Smith Lori A. , Hökfelt Tomas
Published: August 2004

Induction of cyclooxygenase-2 (COX-2) in the renal pelvic wall increases prostaglandin E2(PGE2) leading to stimulation of cAMP production, which results in substance P (SP) release and activation of renal mechanosensory nerves. The subtype of PGE receptors involved, EP2 and/or EP4, was studied by immunohistochemistry and renal pelvic administration of agonists and antagonists of EP2 and EP4 receptors. EP4 receptor-like immunoreactivity (LI) was colocalized with calcitonin gene-related peptide (CGRP)-LI in dorsal root ganglia (DRGs) at Th9-L1and in nerve terminals in the renal pelvic wall. Th9-L1DRG neurons also contained EP3 receptor-LI and COX-2-LI, each of which was colocalized with CGRP-LI in some neurons. No renal pelvic nerves contained EP3 receptor-LI and only very few nerves COX-2-LI. The EP1/EP2 receptor antagonist AH-6809 (20 μM) had no effect on SP release produced by PGE2(0.14 μM) from an isolated rat renal pelvic wall preparation. However, the EP4 receptor antagonist L-161,982 (10 μM) blocked the SP release produced by the EP2/EP4 receptor agonist butaprost (10 μM) 12 ± 2 vs. 2 ± 1 and PGE2, 9 ± 1 vs. 1 ± 0 pg/min. The SP release by butaprost and PGE2was similarly blocked by the EP4 receptor antagonist AH-23848 (30 μM). In anesthetized rats, the afferent renal nerve activity (ARNA) responses to butaprost 700 ± 100 and PGE2·780 ± 100%·s (area under the curve of ARNA vs. time) were unaffected by renal pelvic perfusion with AH-6809. However, 1 μM L-161,982 and 10 μM AH-23848 blocked the ARNA responses to butaprost by 94 ± 5 and 78 ± 10%, respectively, and to PGE2by 74 ± 16 and 74 ± 11%, respectively. L-161,982 also blocked the ARNA response to increasing renal pelvic pressure 10 mmHg, 85 ± 5%. In conclusion, PGE2increases renal pelvic release of SP and ARNA by activating EP4 receptors on renal sensory nerve fibers.
Cardiac remodeling and functional adaptations consecutive to altitude training in rats: implications for sea level aerobic performance
Authors: Reboul C. , Tanguy S. , Juan J. M. , Dauzat M. , Obert P.
Published: July 2004

This study questioned the effect of living and training at moderate altitude on cardiac morphological and functional adaptations and tested the incidences of potential specific adaptations compared with aerobic sea level training on maximal left ventricular performance. Sea level-native rats were randomly assigned to N (living in normoxia), NT (living and training 5 days/wk for 5 wk in normoxia), CH (living in hypoxia, 2,800 m), and CHT (living and training 5 days/wk for 5 wk in hypoxia, 2,800 m) groups. Cardiac adaptations were evaluated throughout the study period by Doppler echocardiography. Maximal stroke volume (LVSVmax) was measured during volume overloading before and after the study period. Finally, at the end of the study period, passive pressure-volume relationships on isolated heart and cardiac weighing were obtained. Altitude training resulted in a specific left ventricular (LV) remodeling compared with NT, characterized by an increase in wall thicknesses without any alteration in internal dimensions. These morphological adaptations associated with hypoxia-induced alterations in pulmonary outflow and preload conditions led to a decrease in LV filling and subsequently no improvement in LV performance during resting physiological conditions in CHT compared with NT. Such a lack of improvement was confirmed during volume overloading that simulated maximal effort (LVSVmax pretest: NT = 0.58 ± 0.05, CHT = 0.57 ± 0.08 ml; posttest: NT = 0.72 ± 0.06, CHT = 0.58 ± 0.07 ml; NT vs. CHT in posttest session, P < 0.05). Maximal aerobic velocities increased to the same extent in NT and CHT rats despite marked polycythemia in the latter. The lack of LVSVmax improvement resulting from altitude training-induced cardiac morphological and functional adaptations could be responsible for this phenomenon.
Fluctuations in plantar flexion force are reduced after prolonged tendon vibration
Authors: Yoshitake Yasuhide , Shinohara Minoru , Kouzaki Motoki , Fukunaga Tetsuo
Published: July 2004

The purpose of the study was to examine the effect of prolonged vibration on the force fluctuations during a force-matching task performed at low-force levels. Fourteen young healthy men performed a submaximal force-matching task of isometric plantar flexion before and after Achilles tendon vibration ( n = 8, vibration subjects) or lying without vibration ( n = 6, control subjects) for 30 min. The target forces were 2.5–10% of the previbration maximal voluntary contraction force. The standard deviation of force decreased by a mean of 29 ± 20% across target forces after vibration, whereas it did not decrease significantly in control subjects (−5 ± 12%). This change was significantly greater compared with control subjects ( P < 0.01 for both). Power spectral density of the force was predominantly composed of signals of low-frequency bandwidth (≤5 Hz) with few higher frequency components. In vibration subjects, there was a significant decrease in power in the frequency range ≤2 Hz after vibration. The decrease in power at this frequency range was linearly related to the decrease in the force fluctuations ( r = 0.96, P < 0.001). The results indicate that prolonged Achilles tendon vibration reduces the fluctuations in plantar flexion force in the frequency range ≤2 Hz during low-level contractions. It suggests that Ia afferent inputs contribute to the low-frequency force fluctuations in plantar flexion.
T-cell-mediated inflammation does not contribute to the maintenance of airway dysfunction in mice
Authors: Leigh Richard , Southam David S. , Ellis Russ , Wattie Jennifer N. , Sehmi Roma , Wan Yonghong , Inman Mark D.
Published: July 2004

T-cell-mediated airway inflammation is considered to be critical in the pathogenesis of airway hyperresponsiveness (AHR). We have described a mouse model in which chronic allergen exposure results in sustained AHR and aspects of airway remodeling and here sought to determine whether eliminating CD4+and CD8+cells, at a time when airway remodeling had occurred, would attenuate this sustained AHR. Sensitized BALB/c mice were subjected to either brief or chronic periods of allergen exposure and studied 24 h after brief or 4 wk after chronic allergen exposure. In both models, mice received three treatments with anti-CD4 and -CD8 monoclonal antibodies during the 10 days before outcome measurements. Outcomes included in vivo airway responsiveness to intravenous methacholine, CD4+and CD8+cell counts of lung and spleen using flow cytometric analysis, and airway morphometry using a computer-based image analysis system. Compared with saline control mice, brief allergen challenge resulted in AHR, which was eliminated by antibody treatment. Chronic allergen challenge resulted in sustained AHR and indexes of airway remodeling. This sustained AHR was not reversed by antibody treatment, even though CD4+and CD8+cells were absent in lung and spleen. These results indicate that T-cell-mediated inflammation is critical for development of AHR associated with brief allergen exposure, but is not necessary to maintain sustained AHR.
Fractal fluctuations in human respiration
Authors: Fadel Paul J. , Barman Susan M. , Phillips Shaun W. , Gebber Gerard L.
Published: July 2004

The present study was designed to characterize respiratory fluctuations in awake, healthy adult humans under resting conditions. For this purpose, we recorded respiratory movements with a strain-gauge pneumograph in 20 subjects. We then used Allan factor, Fano factor, and dispersional analysis to test whether the fluctuations in the number of breaths, respiratory period, and breath amplitude were fractal (i.e., time-scale-invariant) or random in occurrence. Specifically, we measured the slopes of the power laws in the Allan factor, Fano factor, and dispersional analysis curves for original time series and compared these with the slopes of the curves for surrogates (randomized data sets). In addition, the Hurst exponent was calculated from the slope of the power law in the Allan factor curve to determine whether the long-range correlations among the fluctuations in breath number were positively or negatively correlated. The results can be summarized as follows. Fluctuations in all three parameters were fractal in nine subjects. There were four subjects in whom only the fluctuations in number of breaths and breath amplitude were fractal, three subjects in whom only the fluctuations in number of breaths were fractal, and two subjects in whom only fluctuations in breath number and respiratory period were fractal. Time-scale-invariant behavior was absent in the two remaining subjects. The results indicate that, in most cases, apparently random fluctuations in respiratory pattern are, in fact, correlated over more than one time scale. Moreover, the data suggest that fractal fluctuations in breath number, respiratory period, and breath amplitude are controlled by separate processes.
Light chains are a ligand for megalin
Authors: Klassen R. Bryan S. , Allen Patricia L. , Batuman Vecihi , Crenshaw Kimberly , Hammond Timothy G.
Published: July 2004

Cubilin and megalin are giant glycoprotein receptors abundant on the luminal surface of proximal tubular cells of the kidney. We showed previously that light chains are a ligand for cubilin. As cubilin and megalin share a number of common ligands, we further investigated the ligand specificity of these receptors. Three lines of evidence suggest that light chains can also bind megalin: 1) anti-megalin antiserum largely displaces brush-border light chain binding and megalin-expressing BN-16 cell uptake more than anti-cubilin antiserum, 2) direct binding studies on isolated proteins using surface plasmon resonance techniques confirm that megalin binds light chains, and 3) light chains compete with known megalin ligands for brush-border membrane binding and BN-16 cell uptake. The megalin-light chain interaction is divalent ion dependent and similar for both κ- and λ-light chains. A fit of the data on light chain binding to megalin over a concentration range 0.078–2.5 mg/ml leads to an estimated dissociation constant of 6 × 10−5 M, corresponding approximately to one light chain-binding site per megalin and in the same range for dissociation constants for cubilin binding. These data suggest that light chains bind the tandem megalin-cubilin complex. Megalin is the major mediator of light chain entry into megalin-expressing membrane such as the apical surface of proximal tubular epithelial cells.
Neural Correlates of the Precedence Effect in the Inferior Colliculus of Behaving Cats
Authors: Tollin Daniel J. , Populin Luis C. , Yin Tom C. T.
Published: August 2004

Several auditory spatial illusions, collectively called the precedence effect (PE), occur when transient sounds are presented from two different spatial locations but separated in time by an interstimulus delay (ISD). For ISDs in the range of localization dominance (<10 ms), a single fused sound is typically located near the leading source location only, as if the location of the lagging source were suppressed. For longer ISDs, both the leading and lagging sources can be heard and localized, and the shortest ISD where this occurs is called the echo threshold. Previous physiological studies of the extracellular responses of single neurons in the inferior colliculus (IC) of anesthetized cats and unanesthetized rabbits with sounds known to elicit the PE have shown correlates of these phenomena though there were differences in the physiologically measured echo thresholds. Here we recorded in the IC of awake, behaving cats using stimuli that we have shown to evoke behavioral responses that are consistent with the precedence effect. For small ISDs, responses to the lag were reduced or eliminated consistent with psychophysical data showing that sound localization is based on the leading source. At longer ISDs, the responses to the lagging source recovered at ISDs comparable to psychophysically measured echo thresholds. Thus it appears that anesthesia, and not species differences, accounts for the discrepancies in the earlier studies.
Hyperthermia-enhanced splenic cytokine gene expression is mediated by the sympathetic nervous system
Authors: Ganta Chanran K. , Blecha Frank , Ganta Roman R. , Helwig Bryan G. , Parimi Sujatha , Lu Ning , Fels Richard J. , Musch Timothy I. , Kenney Michael J.
Published: August 2004

Whole body hyperthermia (WBH) has been used in experimental settings as an adjunct to radiochemotherapy for the treatment of various malignant diseases. The therapeutic effect of WBH has been hypothesized to involve activation of the immune system, although the effect of hyperthermia-induced activation of sympathetic nerve discharge (SND) on splenic immune function is not known. We tested the hypothesis that heating-induced splenic sympathoexcitation would alter splenic cytokine gene expression as determined using gene array and real-time RT-PCR analyses. Experiments were performed in splenic-intact and splenic-denervated anesthetized Sprague-Dawley rats ( n=32). Splenic SND was increased during heating (internal temperature increased from 38° to 41°C) in splenic-intact rats but remained unchanged in nonheated splenic-intact rats. Splenic interleukin-1β (IL-1β), interleukin-6 (IL-6), and growth-regulated oncogene 1 (GRO 1) mRNA expression was higher in heated than in nonheated splenic-intact rats. Splenic IL-1β, IL-6, and GRO 1 mRNA expression was reduced in heated splenic-denervated compared with heated splenic-intact rats, but did not differ between heated splenic-denervated and nonheated splenic-intact rats. These results support the hypothesis that hyperthermia-induced activation of splenic SND enhances splenic cytokine gene expression.
Immunodominant T-cell epitopes in the factor VIII C2 domain are located within an inhibitory antibody binding site
Authors: Okita David , Diethelm-Okita Brenda , Conti-Fine Bianca , Pratt Kathleen , Qian Jiahua , Ellaban Ekram , Scott David
Published: August 2004

Formation of inhibitor antibodies to factor VIII (FVIII) is a major complication of FVIII replacement therapy for hemophilia A patients, and it occurs through a T-cell dependent process. The C2 domain of FVIII contains epitopes that are recognized by antibody inhibitors. We have examined regions of the C2 domain that form epitopes for T cells in mice congenitally deficient in FVIII. We obtained CD4+ T cells from mice immunized by intravenous infusion of therapeutic doses of recombinant human FVIII (rFVIII), or by subcutaneous injections of rFVIII or recombinant human C2 domain in adjuvant. In all cases, the T cells recognized most strongly and consistently two overlapping peptides that spanned residues 2191 to 2220 of the C2 domain. Analysis of the crystal structure of human factor VIII C2 bound to a human monoclonal antibody, BO2C11, showed these residues also constitute part of a human alloimmune B-cell epitope (Spiegel et al., Blood 2001; 98: 13-19).This region includes one of the “hydrophobic spike” protrusions, consisting of M2199 and F2200, as well as the basic residues R2215 and R2220. These residues contribute to membrane binding and to association with von Willebrand factor (vWF).These findings suggest that a major T-cell epitope in the C2 domain recognized by hemophilic mice is located within the same region that binds to inhibitors, vWF, and activated membranes.
The effect of vascular smooth muscle cell-targeted expression of tissue factor pathway inhibitor in a murine model of arterial thrombosis
Authors: Pan Shuchong , Kleppe Laurel , Witt Tyra , Mueske Cheryl , Simari Robert
Published: August 2004

Tissue factor pathway inhibitor (TFPI) is a Kunitz-type protease inhibitor that regulates the extrinsic pathway of coagulation by inhibiting the factor VIIa/tissue factor (TF) catalytic complex. TFPI is expressed by both endothelial and smooth muscle cells in the vasculature and circulates at low levels. The role of local vascular TFPI in thrombosis and the development of vascular disease is unknown. To establish an experimental animal model to directly modulate smooth muscle cell-derived TFPI on the development of arterial thrombosis, transgenic mice in which a cDNA encoding murine TFPI is expressed from the murine SM22α promoter were generated. Expression of transgenic mRNA was 4-fold higher than the level of endogenous TFPI mRNA in arteries from transgenic mice. In situ hybridization confirmed that expression of the transgene was limited to medial vascular smooth muscle cells. Vascular TFPI activity was increased to 2 to 3-fold in carotid homogenates. There was no difference in plasma TFPI levels or hemostatic measures (PT, aPTT and tail vein bleeding times) between these mice and their wildtype littermates. In a ferric chloride-induced model of carotid thrombosis, homozygotic transgenic mice demonstrated resistance to thrombotic occlusion compared to wildtype littermates. In transgenic mice 22% occluded within 30 minutes of application while 84% of wild type mice occluded within the same time frame (p <0.01). Heterozygotic transgenic mice had an intermediate thrombotic phenotype. Taken together, these data indicated that local VSMC-specific TFPI overexpression attenuated ferric chloride-induced thrombosis without systemic or hemostatic effects. Furthermore, this transgenic mouse model should prove useful for studying the role of TFPI in the development and progression of vascular disease.
Effects of heparin and low-molecular-weight heparins on bone mechanical properties in rats
Authors: Janiec Waldemar , Śliwiński Leszek , Folwarczna Joanna
Published: August 2004

Long-term administration of heparin can be associated with development of osteoporosis. The present study was carried out to compare the effects of standard heparin and two low-molecular-weight heparins (nadroparin and enoxaparin) on bone mechanical properties in rats. The experiment was conducted on 3-month-old female Wistar rats. Standard heparin was administered in doses of 1000 or 2000 IU/kg sc daily, nadroparin and enoxaparin were administered in doses of 1000 or 2000 anti-Xa IU/kg sc daily, for 28 days. Bone mass, length, diameter, mineral content and mechanical properties of the whole femur (extrinsic stiffness, ultimate and breaking load, deformation caused by the applied load) and the femoral neck (load at fracture) were examined. Standard heparin (2000 IU/kg sc daily) weakened the femoral neck. Enoxaparin and the higher doses of standard heparin and nadroparin induced similar unfavourable changes in mechanical properties of the whole femur; the changes were noticeable the most after administration of enoxaparin.
Prevention of central venous line-related thrombosis by continuous infusion of low-dose unfractionated heparin, in patients with haemato-oncological disease
Authors: Ben Othman Tarek , Kammoun Leïla , Chelli Mouna , Ben Romdhane Neïla , Kriaa Azza , Ladeb Saloua , Torjman Lamia , Lakhal Amel , Achour Wafa , Ben Hassen Assia , Hsaïri Mohamed , Ladeb Fethi , Ben Abdeladhim Abdeladhim , Abdelkefi Abderrahman
Published: August 2004

We have conducted a prospective randomized controlled trial to evaluate the role of low-dose unfractionated heparin prophylaxis in preventing central venous line-related thrombosis in patients with haemato-oncological disease. Patients were randomly assigned to receive either prophylactic intravenous unfractionated heparin (continuous infusion of 100 IU/kg/daily) or 50 ml/daily of normal saline solution as a continuous infusion. CVLs were externalized, non tunneled, double lumen catheters. All CVLs were placed percutaneously by the same physician in the subclavian vein. Upper limb veins were systematically examined by ultrasonography just before, or < 24 hours after, catheter removal, and in case of clinical signs of thrombosis. One hundred and twenty-eight CVLs were inserted. Catheterrelated thrombosis occurred in 1.5% of the catheters inserted in patients of the heparin group, and in 12.6% in the control group (p = 0.03). No other risk factors were found for the development of catheter-related thrombosis. Two and three patients experienced severe bleeding in the heparin group, and in the control group, respectively (p = 0.18). There were no other side-effects clearly ascribable to the use of unfractionated heparin. This is the first prospective, randomized study, which shows that low-dose of unfractionated heparin is safe and effective to prevent catheter-related thrombosis in patients with haemato-oncological disease.
Paracetamol (acetaminophen) warfarin interaction: NAPQI, the toxic metabolite of paracetamol, is an inhibitor of enzymes in the vitamin K cycle
Authors: Soute Berry , Vervoort Lily , Claessens Jolanda , Thijssen Henk
Published: August 2004

Paracetamol (acetaminophen) is generally considered to be the analgesic of choice for patients undergoing oral anticoagulant therapy. Occasionally, however, interactions have been reported with therapeutic doses of the analgesic, e.g. if the drug is taken for a longer period of time. The mechanism of this interaction is not clearly understood. We investigated the effects of paracetamol and its toxic metabolite N-acetyl-para-benzoquinoneimine (NAPQI) on in vitro vitamin K-dependent γ-carboxylase (VKD-carb) and vitamin K epoxide reductase (VKOR) activities. Paracetamol had no effect in either enzymatic reactions. NAPQI, on the other hand, appeared to interfere with VKD-carb activity via two mechanisms; 1) oxidation of the cofactor vitamin K-hydroquinone, 2) inactivation of the enzyme. The inactivation, in micromolar ranges, is not reversible and may be the result of covalent binding of NAPQI with functional amino acids. NAPQI also inhibited VKOR, but at higher concentrations. Unexpectedly, N-acetylcysteine was found to inhibit VKOR activity at concentrations that are obtained during rescue therapy of paracetamol intoxication. We conclude that, the potentiation of the oral anticoagulant effect by paracetamol is likely to result from NAPQI-induced inhibition of enzymes of the vitamin K cycle, particularly VKD-carb.
A case series of 72 neonates with renal vein thrombosis
Authors: Kuhle Stefan , Massicotte Patti , Chan Anthony , Mitchell Lesley
Published: August 2004

Neonatal renal vein thrombosis (RVT) is a well-recognized clinical entity which is associated with serious morbidity. However, current information regarding RVT has been restricted to case reports and small case series. In this study, it was our objective to describe patient demographics, clinical presentation, location and risk factors of RVT. For our study design, we looked at a case series of 72 neonates with RVT referred to the 1-800-NO-CLOTS consultation service between 9/1996 and 8/2001. Data on age, gender, associated conditions, prothrombotic disorders, family history, location of the thrombosis, diagnostic techniques, and treatment were prospectively recorded using a standardized form. Our results show that RVT affected males (65%, CI 52-76%) significantly more often than females (35%, CI 24-48%). Median age at presentation was 2 days (0-21 days). RVT was unilateral in 72% (left side: 67%, CI 49-81%; right side: 33%, CI 19-51%), and bilateral in 28%. The majority (83%) had at least one associated condition: Prematurity (54%), central venous lines (17%), a diabetic mother (13%), asphyxia (6%), infections (6%). Prothrombotic testing was performed in 21 neonates. Activated protein C resistance was found in 8 children (38%), other defects in three. This is the largest case series of neonatal RVT to date. Data from the study show that i) male infants are affected twice as often as females and ii) there appears to be a left-sided predominance of neonatal RVT. Neonatal RVT is only infrequently associated with the presence of a catheter as compared to thrombosis at other sites. The majority of infants have associated conditions with prematurity being most frequent. A small subset of neonates were screened for prothrombotic abnormalities and 50% of the children screened were positive.
The use of rFVIIa in non-haemophilia bleeding conditions in paediatrics
Authors: Mathew Prasad
Published: August 2004

From its original envisioned use in patients with hemophilia and inhibitors, recombinant factor VIIa has been increasingly used in a variety of non-hemophilia bleeding/hemorrhagic situations with great efficacy. Most of the reported work has been in adult patients. This paper sets out to review its use in the pediatric non-hemophilia patients and the varied conditions it has been tried and used. Most of the published literature has shown that this agent is efficacious, safe and can be used as an adjunctive measure in the achievement of hemostasis. However, most of the published work is mainly anecdotal, case reports or small series. Randomized trials in children are eagerly awaited.
Incidence of post-thrombotic syndrome in patients with previous pulmonary embolism
Authors: Rossi Vincenza , Ricchio Roberto , Greco Antonio , Bloise Antonio , Daniele Filomena , Greco Francesco , Noto Alfonso , Bova Carlo
Published: August 2004

There is little information available about the true incidence of post-thrombotic syndrome (PTS) after pulmonary embolism (PE). The aim of this study was to investigate the incidence of PTS in patients with previous pulmonary embolism without concomitant ultrasonographically-detectable deep vein thrombosis (DVT). A retrospective cohort study was conducted at a single tertiary care centre, Cosenza, Italy. Forty-seven consecutive patients with proved PE without DVT within the previous 2 to 6 years, 45 patients with previous DVT in the same years, and 45 patients with diseases unrelated to venous thrombo-embolism (VTE) underwent a blind assessment for PTS using a clinical score. Two of 47 (4.2%, 95%CI: 0.01-9.9) patients with PE, 2 of 45 (4.4%, 95%CI: 0.01-10.4) patients with diseases unrelated to VTE, and 23 of 45 (53.3%, 95%CI: 38.7-67.9) patients with DVT showed signs and symptoms of PTS. The difference between the first two groups was not statistically significant (p = 0.7). In conclusion, the incidence of PTS after pulmonary embolism without DVT is low, and no different from that of patients without previous VTE.
Differential effects of heparin and low molecular weight heparin on osteoblastogenesis and adipogenesis in vitro
Authors: Osip Stephanie , Butcher Martin , Young Edward , Yang Lufang , Shaughnessy Stephen
Published: August 2004

We have previously demonstrated that heparin produces cancellous bone loss in rats due in part to a decrease in the number of osteoblasts lining the trabecular bone surface. In the present study, we use a stromal-derived cell culture system together with measurements of alkaline phosphatase (ALP) activity, to compare the effects of heparin and the low molecular weight heparin (LMWH), Fragmin, on osteoblast differentiation in vitro. In addition, we examined the possibility that both heparin and LMWH can induce adipogenesis in our stromal cell culture system. Both heparin and LMWH were found to produce a statistically significant (P <0.01) and concentration-dependent decrease in the number of osteoblasts while increasing the number of adipocytes. When the effects of gravimetrically equivalent amounts of heparin and LMWH were compared, heparin had a 4-fold greater effect than LMWH. In contrast to heparin, N-desulfated heparin was found to have minimal effects on both osteoblast and adipocyte differentiation indicating that the heparin effect is not only chain-length dependent but also charge-dependent. The observation that LMWH has less of an effect on bone formation than heparin is compatible with the results of clinical trials indicating that LMWH produces less bone loss after long-term administration.
Mouse models of thrombosis: thrombomodulin
Authors: Weiler Hartmut
Published: August 2004

This review describes animal models of TM-deficiency that cause thrombosis in mice. Thrombomodulin (TM) is a key component of the protein C anticoagulant pathway by facilitating the activation of protein C by thrombin. In addition, TM integrates fibrinolytic and anti-inflammatory responses in a manner that is in part independent of protein C and thrombin. A series of genetically modified mouse strains is available in which the various and distinct functions of TM have been altered by means of site-directed mutagenesis of the TM gene locus (Thbd). The focus of the current review is the pathological activation of the hemostatic mechanism in mice with altered TM function (the pathologic activation of the hemostatic mechanism). The analysis of these mouse models has revealed novel and in part organ-specific functions of TM, most notably in the vascular bed of the placenta. In these mouse models, the severity and phenotypic expression of thrombosis is highly variable and is dependent on interaction with secondary genetic or environmental modifiers. The mutant mouse strains replicate important aspects of thrombophilia and thrombosis in humans, and provide a valuable resource to validate existing, and develop novel concepts of disease mechanisms in human patients.
Role of tissue factor in haemostasis, thrombosis, angiogenesis and inflammation: lessons from low tissue factor mice
Authors: Pawlinski Rafal , Pedersen Brian , Erlich Jonathan , Mackman Nigel
Published: August 2004

Tissue factor (TF) contributes to a variety of biological processes by generating coagulation proteases and by the activation of protease activated receptors (PARs). Studies, using low TF mice, have provided us with novel insights into the role of TF in tissue-specific haemostasis. Low TF mice exhibit defects in the uterus, placenta, heart and lung, which are all tissues that normally express high levels of TF. We propose that these observed defects are primarily due to a reduction in the level of TF to below a critical threshold that is required to maintain adequate haemostasis. Nevertheless, a reduction in TF:FVIIa-dependent signaling may also reduce cell survival and/or compromise the integrity of the vasculature in these organs. Low TF mice are also a useful tool to study the role of TF and the coagulation cascade in other processes, such as thrombosis, inflammation and angiogenesis.
Effect of gap size and process parameters on diffusion brazing of Inconel 738
Authors: Ojo O.A. , Richards N.L , Charturvedi M.C.
Published: July 2004

The influence of gap size and brazing parameters (temperature and time), on the microstructure and properties of diffusion-brazed Inconel 738 (IN-738) superalloy, was investigated using two commercial brazing alloys, Amdry ‘DF3’ and Nicrobraz 150. The residual liquid present at brazing temperature was observed to transform on cooling into centreline eutectic constituents in ‘NB 150’ brazement while three different dispersed intermetallic phases were observed in the ‘DF3’ joint. The volume fraction of the second phases increased with gap size in both ‘NB 150’ and ‘DF3’ brazements. In addition to the centreline eutectic constituents, nickel and chromium rich borides were observed at the melt back zone in samples brazed below the Ni3B eutectic temperature of 1093°C, and above this temperature only chromium rich borides were observed. Joints containing the second phase intermetallics in ‘NB 150’ and ‘DF3’ brazed materials were found to exhibit tensile properties inferior to that of the base alloy.
Description of flow of shielding gases through nozzles in MIG/MAG and TIG welding processes
Authors: Tomc J. , Tušek J.
Published: July 2004

The aim of the paper is to describe some of the characteristics of shielding gas flow in a welding nozzle and at the nozzle outlet. The paper considers welding nozzles used in MIG/MAG and TIG welding processes. First, problems related to shielding gas flow are discussed on the basis of the theory of potential flow which is the first step towards an analysis of flow conditions in the welding nozzle. Some structural design instructions are given related to welding nozzle profiling so that the velocity distribution of the shielding gas is kept as uniform as possible at the nozzle outlet. This prevents the occurrence of vortices and turbulent flow. Turbulent flow strongly disturbs the welding arc, resulting in poor quality of the welded joint. Then follows the calculation of the pressure drop in the welding nozzle. Finally, an analysis is given of an axially symmetric, viscous jet of shielding gas flowing into half space. Findings related to the flow of actual shielding gases, i.e. argon and CO2, and the anticipated shape of the outflowing gases are given.
Characteristic optimisation of dynamic process parameters in rapid solidified treatment
Authors: Jean M.-D.
Published: July 2004

The paper presents a Taguchi dynamic experiment applied in developing a robust, high efficiency electron beam surface hardening process (EBSH). In the present study, a two step parametric design is proposed with methodology using a non-linear system function. In the first step, the system function of the EBSH process is transformed into a linear function and then this model is applied to develop a robust heated treatment process that reduces the variability in maximising the S/N ratio for maximum robustness. In the second step, the ideal function is obtained by adjusting the sensitivity or the slope β of the linear function determined in the first step. The purpose is to adjust the product dimension EBSH machine using the optimised process parameters obtained in the two step design to achieve the desired dimension for the subsequent fine wear resistant surface processing. The results from the experiment show that using the Taguchi dynamic experimental non-linear system with the proposed two step design strategy is a simple, effective and efficient way to develop a robust, high efficiency EBSH process.