bluuebunny/crossref_metadata_2025 huggingface dataset:
Synthesis and characterization of [MII(bqb)] (M = Co, Ni, Cu), [N(n-Bu)4][CoIII(bqb)(CN)2], and [N(n-Bu)4][CoIII(bqb)(N3)2] containing deprotonated N,N'-bis(2-quinolinecarboxamide)-1,2-benzene (bqb)  X-ray crystal structures of [NiII(bqb)] and [N(n-Bu)4][CoIII(bqb)(N3)2]
Authors: Meghdadi Soria , Amirnasr Mehdi , Langer Vratislav , Zamanpoor Alison
Published: September 2006

Cobalt(II), nickel(II), copper(II), and two cobalt(III) complexes of a new dianionic ligand, bqb, [H2bqb = N,N'-bis(2-quinolinecarboxamide)-1,2-benzene] have been synthesized and characterized by elemental analyses, IR, and 1H NMR spectroscopy. The crystal and molecular structures of the [Ni(bqb)] (2) and [N(n-Bu)4][CoIII(bqb)(N3)2] (5) complexes were determined by X-ray crystallography. Complex 2 crystallizes in the monoclinic space group C2/c with a distorted square-planar structure including two short NiN (1.848 Å) and two long NiN (1.958 Å) bonds. The structure consists of sheets formed in the plane parallel to the b axis and diagonal to vectors a and c by intermolecular hydrogen bonds. Complex 5 crystallizes in the monoclinic space group C2 with a distorted octahedral structure. The [N(n-Bu)4]+ ion is disordered at the C3A and C4A atoms of one Bu. The IR and 1H NMR spectra of the complexes are also discussed.Key words: N4-dianionic amido ligand (bqb), (bqb) complexes of Co(II), Ni(II), Cu(II), and Co(III), azide, cyanide, X-ray crystal structures.
Microwave-assisted N-nitroarylation of some pyrimidine and purine nucleobases
Authors: Khalafi-Nezhad Ali , Zare Abdolkarim , Parhami Abolfath , Rad Mohammad Navid Soltani , Nejabat Gholam Reza
Published: September 2006

An efficient procedure for the synthesis of some N-nitroaryl derivatives of nucleobases via microwave-assisted N-nitroarylation of nucleobases in the presence of SiO2 and Cs2CO3 in DMSO, as the homogenizing solvent, is described. In this method, some pyrimidine and purine nucleobases are nitroarylated regioselectively in moderate to high yields and short reaction times.Key words: microwave, N-nitroarylation, pyrimidine, purine, SNAr.
COMPUTATIONAL METHODS FOR GUIDED ULTRASONIC WAVES IN PLATES
Authors: SHAH ARVIND , MAHMOUD ABDEL-RAHMAN
Published: September 2006

Reducing the general problem of computing three-dimensional Green's function in a transversely isotropic plate to a finite summation of contributions from a series of planar problems can efficiently yield an accurate solution. Hence, solving the planar scattering problem, of the Pressure-Shear-Vertical (PSV) type or the Shear-Horizontal (SH) type, was performed by three different techniques: The boundary element method; the hybrid method; and the perfectly matched layer method. In the pursuit of these methods, the objective was to highlight their pros and cons in terms of accuracy and efficiency.
A SMOOTHING METHOD FOR SHAPE OPTIMIZATION: TRACTION METHOD USING THE ROBIN CONDITION
Authors: AZEGAMI HIDEYUKI , TAKEUCHI KENZEN
Published: September 2006

This paper presents an improved version of the traction method that was proposed as a solution to shape optimization problems of domain boundaries in which boundary value problems of partial differential equations are defined. The principle of the traction method is presented based on the theory of the gradient method in Hilbert space. Based on this principle, a new method is proposed by selecting another bounded coercive bilinear form from the previous method. The proposed method obtains domain variation with a solution to a boundary value problem with the Robin condition by using the shape gradient.
A METHOD FOR QUASI-STATIC ANALYSIS OF TOPOLOGICALLY VARIABLE LATTICE STRUCTURES
Authors: YE. TELITCHEV IGOR , VINOGRADOV OLEG
Published: September 2006

The proposed time-independent quasi-static approach for simulations of lattice structures with imperfections is based on integration of the Inverse Broyden's Method suitable for finding the equilibrium state for a large system of atoms interacting through strongly nonlinear potentials and the Recursive Inverse Matrix Algorithm (RIMA) capable of updating the inverse matrix when topological changes (broken or new bonds between the atoms) take place. In this approach, the crystal structure is treated as a truss system while the forces between the atoms situated at the nodes are defined by the inter-atomic potentials. Since both the Broyden's and the RIMA algorithms deal with the inverse matrices of the structure their coupling makes the procedure computationally efficient. In addition, the method allows analysis of lattices subjected to mixed boundary conditions. The developed code was verified by the comparison with an alternative numerical procedure based on energy minimization technique. The model and the code developed were applied to the case of a 2D hexagonal lattice with the mode I crack embedded into the structure. For the cases considered, it was observed that the crack nucleation and growth were accompanied by the dislocation emission.
A PIEZOELECTRIC INHOMOGENEITY INTERACTING WITH A BRANCHED CRACK
Authors: XIAO Z. M. , GUO J. Y. , WENG G. J.
Published: September 2006

This paper deals with the interaction between a circular piezoelectric inhomogeneity (a circular piezoelectric fiber sensor) and a symmetrically branched crack. The piezoelectric inhomogeneity is embedded in a nonpiezoelectric, elastic matrix with a symmetrically branched crack near the inhomogeneity. The matrix is under a far field in-plane uniform tensile stress and an anti-plane electric field. By using the solution of a single dislocation interacting with an inhomogeneity as Green's function, the main crack and its two symmetrical branches are simulated by continuously distributed edge dislocations. The formulation results in a group of singular integral equations (SIEs). Through solving the singular integral equations numerically, the unknown distributed dislocation density functions can be obtained, and both the Mode I and Mode II stress intensity factors at the branch tips are thus evaluated. The influence of materials constants, geometrical configurations, as well as the far field electric and mechanical loading on the interaction between the branched crack and the piezoelectric inhomogeneity is discussed in detail. As the derivation procedure is very tedious, the analytical results obtained are verified by finite element computation.
ON THE ANALYSIS OF THE PERFORMANCES OF PARTICLE SWARM OPTIMIZATION ALGORITHM WITH GLOBALLY AND LOCALLY TUNED INERTIA WEIGHT VARIANTS
Authors: SENTHIL ARUMUGAM M. , RAO MACHAVARAM VENKATA CHALAPATHY
Published: September 2006

The investigation of the performance of Particle Swarm Optimization (PSO) algorithm with the new variants to inertia weight in computing the optimal control of a single stage hybrid system is presented in this paper. Three new variants for inertia weight are defined and their applicability with the PSO algorithm is thoroughly explained. The results obtained through the new proposed methods are compared with the existing PSO algorithm, which has a time varying inertia weight from a higher value to a lower value. The proposed methods provide both faster convergence and optimal solution with better accuracy.
Functional consequences of mitochondrial proteome heterogeneity
Authors: Johnson D. Thor , Harris Robert A. , Blair Paul V. , Balaban Robert S.
Published: September 2006

Potential functional consequences of the differences in protein distribution between the mitochondria of the rat liver, heart, brain, and kidney, as determined in the companion paper in this issue (Johnson DT, French S, Blair PV, You JS, Bemis KG, Wang M, Harris RA, and Balaban RS. The tissue heterogeneity of the mammalian mitochondrial proteome. Am J Physiol Cell Physiol292: C689–C697, 2006), were analyzed using a canonical metabolic pathway approach as well as a functional domain homology analysis. These data were inserted into the Kyoto Encyclopedia of Genes and Genomes pathway framework to give global and metabolic pathway-specific information on the impact of the differential protein distribution on mitochondrial function. Custom pathway analysis was also performed using pathways limited to the mitochondrion. With the use of this approach, several well-known functional differences between these mitochondrial populations were confirmed. These included GABA metabolism in the brain, urea synthesis in the liver, and the domination of oxidative phosphorylation in the heart. By comparing relative protein amounts of mitochondria across tissues, a greater understanding of functional emphasis is possible as well as the nuclear “programming” required to enhance a given function within the mitochondria. For proteins determined to be mitochondrial and lacking a defined role functional domain BLAST analyses were performed. Several proteins associated with DNA structural modification and a novel CoA transferase were identified. A protein was also identified capable of catalyzing the first three steps of de novo pyrimidine synthesis. This analysis demonstrates that the distribution of nuclear encoded proteins significantly modifies the overall functional emphasis of the mitochondria to meet tissue-specific needs. These studies demonstrate the existence of mitochondrial biochemical functions that at present are poorly defined.
Stable overexpression of human macrophage cholesteryl ester hydrolase results in enhanced free cholesterol efflux from human THP1 macrophages
Authors: Zhao Bin , Song Jingmei , St. Clair Richard W. , Ghosh Shobha
Published: September 2006

Reduction of the lipid burden of atherosclerotic lesion-associated macrophage foam cells is a logical strategy to reduce the plaque volume. Since extracellular cholesterol acceptor-mediated cholesterol efflux is the only recognized mechanism of cholesterol removal from foam cells and this process is rate limited at the level of intracellular cholesterol ester hydrolysis, a reaction catalyzed by neutral cholesteryl ester hydrolase (CEH), we examined the hypothesis that CEH overexpression in the human macrophage monocyte/macrophage cell line THP1 results in increased cholesterol efflux, as well as decreased cellular cholesterol ester accumulation. We generated THP1-CEH cells with stable integration of human macrophage CEH cDNA driven by the cytomegalovirus promoter. Compared with wild-type THP1 cells (THP1-WT), THP1-CEH cells showed increased CEH mRNA expression and increased CEH activity. Efflux of free or unesterified cholesterol by acetylated LDL-loaded THP1-CEH cells to ApoA-I by an ABCA1-dependent pathway or to HDL by an ABCG1-dependent pathway was significantly higher than that in THP1-WT cells. In addition, THP1-CEH cells accumulated significantly lower amount of esterified cholesterol. CEH overexpression, therefore, not only enhances cholesterol efflux but also reduces cellular accumulation of cholesteryl esters. Taken together, these data provide evidence for evaluating CEH expression in human macrophages as a potential target for attenuation of foam cell formation and regression of atherosclerotic plaques.
Unique uptake and efflux systems of inorganic phosphate in osteoclast-like cells
Authors: Ito Mikiko , Haito Sakiko , Furumoto Mari , Uehata Yoko , Sakurai Aya , Segawa Hiroko , Tatsumi Sawako , Kuwahata Masashi , Miyamoto Ken-ichi
Published: September 2006

During bone resorption, a large amount of inorganic phosphate (Pi) is generated within the osteoclast hemivacuole. The mechanisms involved in the disposal of this Pi are not clear. In the present study, we investigated the efflux of Pi from osteoclast-like cells. Pi efflux was activated by acidic conditions in osteoclast-like cells derived by the treatment of RAW264.7 cells with receptor activator of nuclear factor-κB ligand. Acid-induced Pi influx was not observed in renal proximal tubule-like opossum kidney cells, osteoblast-like MC3T3-E1 cells, or untreated RAW264.7 cells. Furthermore, Pi efflux was stimulated by extracellular Pi and several Pi analogs [phosphonoformic acid (PFA), phosphonoacetic acid, arsenate, and pyrophosphate]. Pi efflux was time dependent, with 50% released into the medium after 10 min. The efflux of Pi was increased by various inhibitors that block Pi uptake, and extracellular Pi did not affect the transport of [14C]PFA into the osteoclast-like cells. Preloading of cells with Pi did not stimulate Pi efflux by PFA, indicating that the effect of Pi was not due to transstimulation of Pi transport. Pi uptake was also enhanced under acidic conditions. Agents that prevent increases in cytosolic free Ca2+ concentration, including acetoxymethyl ester of 1,2-bis(2-aminophenoxy)ethane- N,N,N′,N′-tetraacetic acid, 2-aminoethoxydiphenyl borate, and bongkrekic acid, significantly inhibited Pi uptake in the osteoclast-like cells, suggesting that Pi uptake is regulated by Ca2+ signaling in the endoplasmic reticulum and mitochondria of osteoclast-like cells. These results suggest that osteoclast-like cells have a unique Pi uptake/efflux system and can prevent Pi accumulation within osteoclast hemivacuoles.
The role of the activin system in keloid pathogenesis
Authors: Mukhopadhyay Anandaroop , Chan Sui Yung , Lim Ivor J. , Phillips David J. , Phan Thang T.
Published: September 2006

Keloid scars represent a pathological response to cutaneous injury under the regulation of many growth factors. Activin-A, a dimeric protein and a member of the transforming growth factor-β superfamily, has been shown to regulate various aspects of cell growth and differentiation in the repair of the skin mesenchyme and the epidermis. Thus our aim was to study the role of activin and its antagonist, follistatin, in keloid pathogenesis. Increased mRNA expression for activin was observed in keloid scar tissue by performing RNase protection assay. Immunohistochemistry showed increased localization of both activin-A and follistatin in the basal layer of epidermis of keloid tissue compared with normal tissue. ELISA demonstrated a 29-fold increase in concentration of activin-A and an ∼5-fold increase in follistatin in conditioned media in keloid fibroblasts compared with normal fibroblasts. Although keloid keratinocytes produced 25% more follistatin than normal keratinocytes, the amounts of activin-A, in contrast, was ∼77% lower. Proliferation of fibroblasts was stimulated when treated with exogenous activin-A (46% increase in keloids fibroblasts) or following co-culture with hβAHaCaT cells (66% increase). Activin-A upregulated key extracellular matrix components, namely collagen, fibronectin, and α-smooth muscle actin, in normal and keloid fibroblasts. Co-treatment of follistatin with activin-A blocked the stimulatory effects of activin on extracellular matrix components. These findings emphasize the importance of the activin system in keloid biology and pathogenesis and suggest a possible therapeutic potential of follistatin in the prevention and treatment of keloids.
Methoxyflavones protect cells against endoplasmic reticulum stress and neurotoxin
Authors: Takano Katsura , Tabata Yoshiyuki , Kitao Yasuko , Murakami Rika , Suzuki Hiroto , Yamada Masashi , Iinuma Munekazu , Yoneda Yukio , Ogawa Satoshi , Hori Osamu
Published: September 2006

Enhanced endoplasmic reticulum (ER) stress leads to cell death in various pathophysiological situations. During a search for compounds that regulate ER stress, we identified methoxyflavones, a group of flavonoids, as strong protective agents against ER stress. Analysis in mouse insulinoma MIN6 cells revealed that methoxyflavones mildly activated the eukaryotic initiation factor 2α and nuclear factor erythroid 2-related factor pathways, but not the XBP1 pathway, and induced downstream genes, including glucose-regulated protein (GRP) 78, a molecular chaperone in the ER. The protective effect of methoxyflavones was enhanced by agents that increase intracellular cAMP levels such as forskolin, dibutyryl-cAMP and IBMX, but suppressed by the protein kinase A (PKA) inhibitor H-89, suggesting involvement of the PKA pathway in the regulation of ER stress by methoxyflavones. Consistent with the results in cultured cells, pretreatment of mice with tangeretin, a methoxyflavone, enhanced expression of GRP78 and HO-1 without causing ER stress in renal tubular epithelium and prevented tunicamycin-induced cell death. Furthermore, preadministration of tangeretin in mice enhanced expression of GRP78 in the substantia nigra pars compacta and protected dopaminergic neurons against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a neurotoxin that induces both oxidative and ER stress. These results suggest that methoxyflavones play an important role in the regulation of ER stress and could be a therapeutic target for the ER stress-related diseases.
Rapid effects of aldosterone on clonal human vascular smooth muscle cells
Authors: Gros Robert , Ding Qingming , Armstrong Souzan , O'Neil Caroline , Pickering J. Geoffrey , Feldman Ross D.
Published: September 2006

It has been increasingly appreciated that aldosterone elicits acute vascular effects through nongenomic signaling pathways. Our previous studies demonstrated that aldosterone attenuated phenylephrine-mediated constriction in intact vessels [via phosphatidylinositol 3-kinase-dependent nitric oxide synthase activation] but enhanced vasoconstrictor responses in endothelium-denuded arteries. To determine the mechanism of this vasoconstrictor response, we assessed the effect of aldosterone on myosin light-chain phosphorylation and contraction in clonal adult human vascular smooth muscle cells. Acute aldosterone exposure mediated dose-dependent myosin light-chain phosphorylation, inhibited by spironolactone and phosphatidylinositol 3-kinase inhibition. These rapid effects of aldosterone were mimicked by estradiol and hydrocortisone and were also inhibitable by both spironolactone and eplerenone. In parallel to its effects on myosin light-chain phosphorylation, aldosterone mediated dose-dependent contraction responses that were inhibited by spironolactone. Comparable contractile responses were seen with both 17β-estradiol and hydrocortisone. In total, these data are consistent with a mechanism of acute aldosterone-mediated contraction common to both glucocorticoids and estrogen. Steroid-mediated vasoconstriction may represent an important pathobiological mechanism of vascular disease, especially in the setting of preexisting endothelial dysfunction.
Resveratrol attenuates TNF-α-induced activation of coronary arterial endothelial cells: role of NF-κB inhibition
Authors: Csiszar Anna , Smith Kira , Labinskyy Nazar , Orosz Zsuzsanna , Rivera Aracelie , Ungvari Zoltan
Published: September 2006

Epidemiological studies suggest that Mediterranean diets rich in resveratrol are associated with reduced risk of coronary artery disease. However, the mechanisms by which resveratrol exerts its cardioprotective effects are not completely understood. Because TNF-α-induced endothelial activation and vascular inflammation play a critical role in vascular aging and atherogenesis, we evaluated whether resveratrol inhibits TNF-α-induced signal transduction in human coronary arterial endothelial cells (HCAECs). We found that TNF-α significantly increased adhesiveness of the monocytic THP-1 cells to HCAECs, an effect that could be inhibited by pretreatment with resveratrol and the NF-κB inhibitor pyrrolidine dithiocarbamate. Previously, we found that TNF-α activates NAD(P)H oxidases, and our recent data showed that TNF-α-induced endothelial activation was prevented by the NAD(P)H oxidase inhibitor apocynin or catalase plus SOD. Resveratrol also inhibited H2O2-induced monocyte adhesiveness. Using a reporter gene assay, we found that, in HCAECs, TNF-α significantly increased NF-κB activity, which could be inhibited by resveratrol (>50% inhibition at 10−6 mol/l) and pyrrolidine dithiocarbamate. Resveratrol also inhibited TNF-α-induced, NF-κB-driven luciferase expression in rat aortas electroporated with the reporter gene construct. In TNF-α-treated HCAECs, resveratrol (in the submicromolar range) significantly attenuated expression of NF-κB-dependent inflammatory markers inducible nitric oxide synthase, IL-6, bone morphogenetic protein-2, ICAM-1, and VCAM. Thus resveratrol at nutritionally relevant concentrations inhibits TNF-α-induced NF-κB activation and inflammatory gene expression and attenuates monocyte adhesiveness to HCAECs. We propose that these anti-inflammatory actions of resveratrol are responsible, at least in part, for its cardioprotective effects.
Neonatal immune challenge exacerbates experimental colitis in adult rats: potential role for TNF-α
Authors: Spencer Sarah J. , Hyland Niall P. , Sharkey Keith A. , Pittman Quentin J.
Published: September 2006

Early life events and childhood infections have been associated with the development and onset of inflammatory bowel disease in adulthood. However, the consequences of neonatal infection in the development and severity of colitis are not established. We investigated the effects of a neonatal (postnatal day 14) or juvenile (postnatal day 28) immune challenge with LPS on 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced damage and weight loss, as well as on food intake and body temperature in adult rats. Neonatally (n)LPS-treated rats developed more severe colitis than control animals, reflected in a greater loss of weight and a significantly increased macroscopic tissue damage score. These findings were associated with a hypothermic response after TNBS treatment in nLPS rats, but not in neonatally saline-treated rats receiving TNBS. These differences were not seen after TNBS in rats that had received LPS on postnatal day 28. Plasma corticosterone was measured as an index of adult hypothalamic-pituitary-adrenal (HPA) axis activation as was TNF-α, a proinflammatory cytokine associated with inflammatory bowel disease. Four days after TNBS treatment, plasma corticosterone was unaltered in all groups; however, TNF-α was significantly increased in adult TNBS-treated rats that had LPS as neonates compared with all other groups. In conclusion, neonatal, but not later, exposure to LPS produces long-term exacerbations in the development of colitis in adults. This change is independent of HPA axis activation 4 days after TNBS treatment but is associated with increased circulating TNF-α, suggestive of an exaggerated immune response in adults exposed to neonatal infection.
PKC Modulation of Transmitter Release by SNAP-25 at Sensory-to-Motor Synapses in Aplysia
Authors: Houeland Gry , Nakhost Arash , Sossin Wayne S. , Castellucci Vincent F.
Published: September 2006

Activation of phosphokinase C (PKC) can increase transmitter release at sensory–motor neuron synapses in Aplysia, but the target of PKC phosphorylation has not been determined. One putative target of PKC at synapses is the synaptosomal-associated protein of 25 kDa (SNAP-25), a member of the SNARE protein complex implicated in synaptic vesicle docking and fusion. To determine whether PKC regulated transmitter release through phosphorylation of SNAP-25, we cloned Aplysia SNAP-25 and expressed enhanced green fluorescent protein (EGFP)–coupled SNAP-25 constructs mutated at the PKC phosphorylation site Ser198 in Aplysia sensory neurons. We found several distinct effects of expression of EGFP–SNAP-25 constructs. First, the rates of synaptic depression were slowed when cells contained SNAP-25 with phosphomimetic residues Glu or Asp. Second, PDBu-mediated increases in transmitter release at naïve synapses were blocked in cells expressing nonphosphorylated-state SNAP-25. Finally, expression of EGFP-coupled SNAP-25 but not uncoupled SNAP-25 inhibited 5-HT–mediated reversal of depression and the ability of EGFP-coupled SNAP-25 to inhibit the reversal of depression was affected by changes at Ser198. These results suggest SNAP-25 and phosphorylation of SNAP-25 by PKC can regulate transmitter release at Aplysia sensory–motor neuron synapses by a number of distinct processes.
Forelimb Movements and Muscle Responses Evoked by Microstimulation of Cervical Spinal Cord in Sedated Monkeys
Authors: Moritz Chet T. , Lucas Timothy H. , Perlmutter Steve I. , Fetz Eberhard E.
Published: September 2006

Documenting the forelimb responses evoked by stimulating sites in primate cervical spinal cord is significant for understanding spinal circuitry and for potential neuroprosthetic applications involving hand and arm. We examined the forelimb movements and electromyographic (EMG) muscle responses evoked by intraspinal microstimulation in three M. nemestrina monkeys sedated with ketamine. Trains of three stimulus pulses (10–80 μA) at 300 Hz were delivered at sites in regularly spaced tracks from C6 to T1. Hand and/or arm movements were evoked at 76% of the 745 sites stimulated. Specifically, movements were evoked in digits (76% of effective sites), wrist (15% of sites), elbow (26%), and shoulder (17%). To document the muscle activity evoked by a stimulus current just capable of eliciting consistent joint rotation, stimulus-triggered averages of rectified EMG were calculated at each site where a movement was observed. Typically, many muscles were coactivated at threshold currents needed to evoke movements. Out of the 13–15 muscles recorded per animal, only one muscle was active at 14% of the effective sites and two to six muscles were coactivated at 47% of sites. Thus intraspinal stimulation at threshold currents adequate for evoking movement typically coactivated multiple muscles, including antagonists. Histologic reconstruction of stimulation sites indicated that responses were elicited from the dorsal and ventral horn and from fiber tracts in the white matter, with little somatotopic organization for movement or muscle activation. The absence of a clear somatotopic map of output sites is probably a result of the stimulation of complex mixtures of fibers and cells.
Properties of a Population of GABAergic Cells in Murine Auditory Cortex Weakly Excited by Thalamic Stimulation
Authors: Verbny Yakov I. , Erdélyi Ferenc , Szabó Gábor , Banks Matthew I.
Published: September 2006

Feedforward inhibition triggered by thalamocortical (TC) afferents sharpens onset responses and shapes receptive fields of pyramidal cells in auditory cortex (ACx). Previous studies focused only on interneurons located in and around layer IV in primary ACx, target of the dense thalamic projections from ventral medial geniculate. We investigated a population of feedforward interneurons located throughout layers I–V and activated by both afferents from primary and nonprimary thalamus using recordings from auditory TC brain slices obtained from mice expressing green fluorescent protein under control of the glutamic acid decarboxylase (GAD65) promoter in a subpopulation of cortical GABAergic cells. We studied the responses of these interneurons and of pyramidal cells in ACx to thalamic stimulation and to hyper- and depolarizing current pulses. Most interneurons exhibited monosynaptic responses to thalamic stimulation, but this excitation was weak and subthreshold. Interneurons had multipolar dendritic morphology with widespread and dense axonal projections extending several hundred micrometers from the soma. In pyramidal cells from layers II–IV, thalamic excitatory postsynaptic potentials were significantly larger than in interneurons and were superthreshold in 40% of cells, but in these cells, there was no evidence of feedforward inhibition. By contrast, feedforward inhibition was observed in 12 of 18 layer V pyramidal cells. Thus feedforward inhibition in supragranular layers of ACx is weak, and these interneurons require coincident excitation to be activated by thalamic inputs.
Plasmin/plasminogen is essential for the healing of tympanic membrane perforations
Authors: Li Jinan , Eriksson Per-Olof , Hansson Annika , Hellström Sten , Ny Tor
Published: September 2006

Plasminogen has been proposed to play an important role in different tissue remodeling processes such as wound healing and tissue regeneration after injuries. The healing of tympanic membrane perforations is a well-organized chain of inflammatory events, with an initial invasion of inflammatory cells followed by reparative and restoration phases. Here we show that the healing of tympanic membrane perforations is completely arrested in plasminogen-deficient mice, with no signs of any healing even 143 days after perforation. Inflammatory cells were recruited to the wounded area, but there were no signs of tissue debridement. In addition, removal of fibrin, keratinocyte migration and in-growth of connective tissue were impaired. This contrasts with skin wound healing, where studies have shown that, although the healing process is delayed, it reaches completion in all plasminogen-deficient mice. Our finding that keratinocyte migration and re-epithelialization were completely arrested in plasminogen-deficient mice indicates that plasminogen/plasmin plays a more profound role in the healing of tympanic membrane perforations than in the healing of other epithelial wounds.
A direct thrombin inhibitor studied by dynamic whole blood clot formation
Authors: Ingerslev Jørgen , Sørensen Benny
Published: September 2006

Direct thrombin inhibitors have proven efficacious in prevention of venous thromboembolism. Bleeding complications are rare, but in case of acute serious bleeding, an effective and instant haemostatic intervention may be required. In the present study it was demonstrated that the direct thrombin inhibitor melagatran induces dose-dependent abnormalities in whole blood (WB) clotting profiles as recorded bya recently described modified thrombelastographic model, and that rFVIIa or APCC are capable of improving the haemostatic capacity. Experiments were performed using WB from 30 healthy males. In-vitro titration experiments (n=10) with addition of melagatran to WB corresponding to plasma concentrations ranging from 0 to 5.0 µM (12 steps) showed a dose-dependent prolongation of the clot initiation and characteristic decrease of the maximum rate of clot propagation. In-vitro intervention studies (n=20) were completed with four different concentrations of melagatran as well as addition of four different levels of rFVIIa or APCC. At all tested concentrations of melagatran, rFVIIa significantly shortened the melagatran-induced prolonged clot initiation but induced only minor improvements of the reduced clot propagation. In contrast, APCC significantly and dose-dependently shortened the clot initiation and accelerated the clot propagation. In conclusion, our thrombelastographic model appears useful for evaluating the effect of direct thrombin inhibitors on dynamic WB clot formation and rFVIIa, but especially APCC significantly improved theWB clot formation. The pronounced stabilizing effect of APCC may be caused by its content of prothrombin and activated coagulation factors.
Increased red blood cell aggregation in patients with idiopathic intracranial hypertension
Authors: Kesler Anat , Yatziv Yossi , Shapira Itzhak , Ben Assayag Einor , Berliner Shlomo
Published: September 2006

It was the objective of this study to explore the possibility that the aggregation of red blood cells is enhanced in individuals with increased intracranial hypertension (IIH). This is a prospective cross sectional examination in a cohort of patients with IIH and matched controls.The aggregation of red blood cells in the peripheral venous blood was determined by using a slide test and image analysis.We have presently included a group of 33 women with IIH and the same number of women matched for age, body mass index, vascular risk factors and medications. A significant (p=0.038) increment in fibrinogen concentrations was noted in the patients (341 ± 60.8 mg/dl) as opposed to the controls 307.9 ± 64.8).The same stands for the aggregation of red blood cells (aggregation parameter of 8.7 ± 4.9 in patients vs.5.9 ± 3.2 in the controls, p=0.001).We noted an increment in the aggregation of red blood cells in the peripheral blood of 33 women with IIH as opposed to matched controls. Being associated with capillary slow flow,these findings might be relevant to the ethiopathogenesis of this disease.
Elevated complement C3 is associated with early restenosis after eversion carotid endarterectomy
Authors: Széplaki Gábor , Varga Lilian , Laki Judit , Doása Edit , Madsen Hans , Prohászka Zoltán , Szabó Attila , Acsády György , Selmeci László , Garred Peter , Entz László , Füst George
Published: September 2006

Early restenosis following carotid endarterectomy (CEA) is an inflammatory process leading to myointimal hyperplasia of smooth muscle cells. The risk for restenosis is increased in homozygous carriers of the normal (A) allele of mannose-binding lectin (MBL2) gene. Our objective was to study the associ-ations of C3 and as control three non-complement acute-phase reactants (APRs) (C-reactive protein, haptoglobin and α2HS-glycoprotein) with early restenosis following CEA.We also considered, whether MBL2 genotype relates to C3 levels and to the risk of restenosis. Concentrations of the APRs were determined by radial immunodiffusion or immunoturbidimetric methods in 64 patients who underwent eversion CEA and were followed up with carotid duplex scan (CDS) examinations for at least one year. MBL2 genotypes were determined by a PCR-SSP method. C3 levels increased during the follow-up and correlated with the percentage of restenosis detected by CDS at 14 months postsurgery, in MBL2 A/A allele carriers. Patients with high C3 levels had nearly five-fold higher odds for the presence of significant restenosis (>50% reduction in diameter) even after adjusting for MBL2 genotype, age and gender. By contrast, no such associations were detected between the non-complement APRs and early restenosis. C3 is associated with and might have a direct role in the development of an early restenosis following CEA, which is partially related to an intact MBL lectin pathway, thus determining C3 levels might have clinical importance. On the other hand, our results indicate that the regulation of C3 differs from non-complement APRs.
Prevalence of thromboembolic events among 8,860 patients with thalassaemia major and intermedia in the Mediterranean area and Iran
Authors: Taher Ali , Isma’eel Hussain , Mehio Ghassan , Bignamini Daniela , Kattamis Antonis , Rachmilewitz Eliezer , Cappellini Maria
Published: September 2006

Beta-thalassaemia isa congenital haemolytic anaemia characterized by partial (intermedia, TI) or complete (major, TM) deficiency in the production of β-globin chains.The primary aim of this study was to determine the prevalence of thromboembolic events in patients with β-thalassaemia.To achieve this,a multiple-choice questionnaire was sent to 56 tertiary referral centres in eight countries (Lebanon, Italy, Israel, Greece, Egypt, Jordan, Saudi Arabia and Iran), requesting specific information on patients who had experienced a thromboembolic event.The study demonstrated that thromboembolic events occurred ina clinically relevant proportion (1.65%) of 8,860 thalassaemia patients (TI – 24.7% or TM – 75.3%) from the Mediterranean and Iran. Thromboembolism occurred 4.38 times more frequently in TI thanTM (p<0.001), with more venous events occurring inTI and more arterial events occurring in TM.Thrombosis in thalassaemia was also more common in females, splenectomized patients and those with profound anaemia (haemoglobin <9 g/dl). Due to the increased risk of thromboembolic events, the rationale for splenectomy should perhaps be re-assessed and the role of transfusion therapy for the prophylaxis of thrombosis, among other complications, be evaluated prospectively.
Genetic variations of the endothelial nitric oxide synthase gene are related to increased levels of C-reactive protein and macrophage-colony stimulating-factor in patients with coronary artery disease
Authors: Ikonomidis Ignatios , Tsibida Maria , Protogerou Athanasios , Papada Aggeliki , Papapanagiotou Aggeliki , Revela Ioanna , Papamichael Christos , Kalofoutis Anastasios , Kremastinos Dimitrios , Lekakis John
Published: September 2006

It was the objective of this study to investigate the relation between nitric oxide synthase (NOS3) gene polymorphisms, vascular inflammation, endothelial function, and atherosclerosis. We examined the effects of a variable nucleotide tandem repeats (VNTR ) in intron 4, G894T in exon 7 and T-786C at the promoter region of NOS3 on i) C-reactive protein (CRP) and macrophage-colony stimulating-factor (MCSF), and ii) augmentation index (AI) measured by pulse-wave analysis, flow-mediated dilation (FMD) of the brachial artery, intima-media thickness (IMT) of the carotid and femoral artery using ultrasonography and ankle-brachial index (ABI) in 122 patients with chronic coronary artery disease (CAD) who underwent coronary angiography. MCSF and CRP were increased in patients with T-786C (77/122) or VNTR (40/122) allele compared to those without (F=10.8, p=0.002 and F=3.8, p=0.04 for T-786C and F=3.65, p=0.04 and F=3.2 p=0.049 for VNTR), even after adjustment for traditional risk factors and medication. Patients with combination of VNTR and T-786C (31/122) had higher MCSF or CRP than patients with one or none of these alleles (p<0.05). Among patients with T-786C, those with MCSF>262 pg/ml or CRP>3.2 mg/l (n=33/77) had a higher femoral and carotid IMT and number of plaques in the peripheral arteries than those with lower values of these inflammatory indices (p<0.05). Patients with MCSF >262 pg/ml had also lower FMD and higher Gensini score than those with lower MCSF (p<0.05).The intron 4-VNTR and T-786C mutation of NOS3 gene enhance the inflammatory process in patients with chronic CAD.
COX-2 inhibitors and cardiovascular risk
Authors: Marwali Muhammad , Mehta Jawahar
Published: September 2006

Even though non-steroidal anti-inflammatory drugs (NSAIDs) have been widely used for a long time, the search continues for anti-inflammatory drugs with few side-effects. COX-2 inhibitors are currently most debated, because they have less gastrointestinal side effects but have been linked to increased cardiovascular morbidity and mortality, presumably related to thrombotic events. This has brought about the withdrawal of rofecoxib and other COX-2 inhibitors from the market. Although the results of several large studies with prospective, randomized design and meta-analysis of different trials have led to the demise of many popular COX-2 inhibitors, yet the conclusion seems to be rather simplistic. This review presents evidence from basic biology and clinical studies with the expectation that a balanced position, particularly in relation to increase in cardiovascular events, may be elucidated.
Transcription-based COX-2 inhibition: A therapeutic strategy
Authors: Wu Kenneth
Published: September 2006

Potent selective cyclooxygenase-2 (COX-2) inhibitors are effective in controlling inflammatory disorders but are associated with cardiovascular complications. Their clinical use has been severely limited. We propose that transcription-based inhibition of COX-2 expression represents a therapeutic strategy that may circumvent the undesired complications of COX-2 inhibitors. Reported data from several laboratories including ours have identified C/EBPβ as a key transactivator mediating COX-2 transcriptional activation induced by diverse pro-inflammatory mediators. Results from our recent work show that sodium salicylate at pharmacological concentrations inhibits C/EBPβ binding to COX-2 promoter by direct inhibition of p90 ribosomal S6 kinase (RSK). RSK phosphorylates C/EBPβ and stimulates its binding to enhancer elements. We propose that RSK1/2 is a potential target for screening drugs with novel anti-inflammatory and anti-neoplastic therapeutic potentials.
Prognostic value of D-dimer in patients with pulmonary embolism
Authors: Roy Pierre-Marie , Guy Meyer , Cornuz Jacques , Sanchez Olivier , Perrier Arnaud , Aujesky Drahomir
Published: September 2006

D-dimer levels appear to be associated with the extent of the thromboembolic burden in patients with pulmonary embolism (PE).We therefore hypothesized that D-dimer levels at admission would be associated with prospective risk of mortality in patients with PE. We used data from 366 patients diagnosed with PE at four hospital emergency departments. A highly sensitive D-dimer test was prospectively performed at admission. The outcome was overall mortality within three months. We divided patients into quartiles on the basis of their D-dimer levels and compared mortality rates by quartile. We estimated sensitivity, specificity, and predictive values for mortality in the first and fourth quartile. Overall mortality was 5.2%. Patients who died had higher median D-dimer levels than patients who survived (4578 versus 2946 µg/l; P=0.005). Mortality increased with increasing D-dimer levels, rising from 1.1% in the first quartile (<1500 µg/l) to 9.1% in the fourth quartile (>5500 µg/l) (P=0.049). Sensitivity, specificity, and positive and negative predictive values of D-dimer levels <1500 µg/l to predict mortality were 95%, 26%, 7%, and 99%, respectively. Patients with PE who have D-dimer levels below 1500 µg/l havea very low mortality. Further studies must assess whether D-dimer, alone or combined with other prognostic instruments for PE, can be used to identify low-risk patients with PE who are potential candidates for outpatient treatment or an abbreviated hospital stay.
Does a coxib-associated thrombotic risk limit the clinical use of the compounds as analgesic, antiinflammatory drugs?
Authors: Hohlfeld Thomas , Harder Sebastian , Weber Artur-Aron
Published: September 2006

The issue of the risk-benefit assessment of cyclooxygenase-2 (COX-2) inhibitors, as compared to traditional non-steroidal anti-inflammatory drugs (tNSAIDs), is far from being resolved. These compounds need to be carefully re-evaluated in order to avoid hasty conclusions, as it happened when COX-2 inhibitors were introduced into clinical practice. Several arguments support the concept, that COX-2 inhibitors remain a valuable therapeutic option at least for selected patients.
Selective COX-2 inhibitors and risk of thromboembolic events – regulatory aspects
Authors: Broich Karl , Heim Hans-Karl
Published: September 2006

In the 1990s, the pharmaceutical industry developed selective COX-2 inhibitors (coxibs) as alternatives to conventional nonsteroidal anti-inflammatory drugs (NSAIDs), with the expectation of similar analgetic and anti-inflammatory efficacy but a reduced risk of adverse gastrointestinal (GI) effects. Marketing authorisation (MA) was granted for rofecoxib and celecoxib as first representatives of this new pharmacological class at the end of the 1990s in the EU. In the following years MAs were granted for the ´second generation` coxibs etoricoxib, parecoxib/valdecoxib and lumiracoxib. However, data from large clinical ´outcome studies` as well as epidemiological data raised concerns about the cardiovascular (CV) safety of the coxibs. In consequence, two comprehensive review processes (referrals) were initiated by the European Medicines Agency (EMEA).As a result, in the EU the use of coxibs has been contraindicated in patients with established coronary heart disease, cerebrovascular disease and peripheral arterial disease and a number of warning statements concerning CV, GI and skin toxicity have been introduced in the coxib product informations. This article provides a description of the regulatory actions taken and discusses some specific aspects of the past and future regulatory assessment of coxibs.
The APPLE project: An investigation of the barriers and promoters of healthy eating and physical activity in New Zealand children aged 5-12 years
Authors: Williden Micalla , Taylor Rachael W , McAuley Kirsten A , Simpson Jean C , Oakley Maggie , Mann Jim I
Published: September 2006

Objective To use the Analysis Grid for Environments Linked to Obesity (ANGELO) framework to determine the barriers and promoters of healthy eating and physical activity in children aged 5-12 years, as a basis for the development of a pilot community-based programme for preventing obesity in children (APPLE project: A Pilot Programme for Lifestyle and Exercise).

Methods Semi-structured interviews were held with nine community stakeholders including doctors, school staff and food outlet operators. This information was used to develop a telephone-administered questionnaire to 101 parents of children in the intervention communities. Finally, structured interviews were undertaken with intervention school principals (n=4) regarding the school environment pertaining to physical activity and healthy eating.

Results Major barriers to physical activity identified included lack of facilities, coaches and equipment. Work commitments prevented 40 per cent of parents being physically active with their children. Shared transport would increase opportunities for activity. Socio-cultural influences included family support for sport, lack of initiative to instigate activities and preference for more sedentary options; 70 per cent of parents thought their child preferred TV or computers over sport/games. Cost prevented one-third of children being involved in activity and 45 per cent of parents buying healthier foods. Political barriers to healthy eating included the absence of parental rules regarding purchasing less healthy food options, using treat foods to coerce children to behave and the lack of fruit and vegetable advertising. Over two-thirds of parents thought banning particular foods would have a positive effect on eating habits. One third of parents said their children didn’t like healthy foods and 25 per cent thought it did not matter what their child ate as long as they were growing properly.

Conclusions The ANGELO framework used in this assessment identified potential environmental barriers to healthy eating and physical activity in children and provides the basis for an obesity prevention programme in youngsters aged 5-12 years.
Assessment of the undergraduate medical education environment in a large UK medical school
Authors: Dunne Fidelma , McAleer Sean , Roff Susan
Published: September 2006

Objective To assess the undergraduate educational environment in a large UK medical school.

Method Prospective study using the already validated Dundee Ready Education Environment (DREEM) questionnaire ( Appendix 1).

Setting A large UK medical school.

Participants All medical students enrolled in the academic year 2002/2003.

Main outcome measures Perception of the overall educational environment. In addition the impact of year of study and gender were examined.

Results The DREEM questionnaire consisting of 50 items scored on a 0-4 Likert scale was completed by 749 medical students (55 per cent) in the academic year 2002/2003. The mean total score was 124 (out of a maximum of 200) indicating relative satisfaction with the perceived environment. There were no individual areas of excellence (that is no item scored >3.5). Some items scored consistently badly indicating cause for concern, for example lack of a support system for stressed students, school time-tabling, feedback from teachers and memorisation of facts. Clinical students perceived the environment to be significantly more positive than preclinical students (127 v 119, p<0.05). Female students perceived the environment to be significantly more positive compared to male students (126 v 123, p<0.05).

Conclusions This tool identified areas of concern within a large UK medical school. Further use of the DREEM as a monitoring tool would be useful to re-evaluate the environment following appropriate intervention.