bluuebunny/crossref_metadata_2025 huggingface dataset:
Gravitational fragmentation and formation of giant protoplanets on orbits of tens of au
Authors: Vorobyov Eduard I. , Elbakyan Vardan G.
Published: July 2018

Aims. Migration of dense gaseous clumps that form in young protostellar disks via gravitational fragmentation is investigated to determine the likelihood of giant planet formation.

Methods. High-resolution numerical hydrodynamics simulations in the thin-disk limit are employed to compute the formation and long-term evolution of a gravitationally unstable protostellar disk around a solar-mass star.

Results. We show that gaseous clumps that form in the outer regions of the disk (>100 au) through disk fragmentation are often perturbed by other clumps or disk structures, such as spiral arms, and migrate toward the central star on timescales from a few thousand to few tens of thousands of years. The migration timescale is slowest when stellar motion in response to the disk gravity is considered. When approaching the star, the clumps first gain mass (up to several tens of MJup), but then quickly lose most of their diffuse envelopes through tidal torques. Part of the clump envelope can be accreted onto the central star causing an FU-Orionis-type accretion and luminosity outburst. The tidal mass loss helps the clumps to significantly slow down or even halt their inward migration at a distance of a few tens of au from the protostar. The resulting clumps are heavily truncated both in mass and size compared to their wider orbit counterparts, keeping only a dense and hot nucleus. During the inward migration, the temperature in the clump interiors may exceed the molecular hydrogen dissociation limit (2000 K) and the central region of the clump can collapse into a gas giant protoplanet. Moreover, migrating clumps may experience close encounters with other clumps, resulting in the ejection of the least massive (planetary-mass) clumps from the disk. We argue that FU-Orionis-type luminosity outbursts may be the end product of disk fragmentation and clump inward migration, preceding the formation of giant protoplanets on tens of au orbits in systems such as HR 8799.
Disentangling multiple high-energy emission components in the Vela X pulsar wind nebula with the Fermi Large Area Telescope
Authors: Tibaldo L. , Zanin R. , Faggioli G. , Ballet J. , Grondin M.-H. , Hinton J. A. , Lemoine-Goumard M.
Published: July 2018

Context. Vela X is a pulsar wind nebula in which two relativistic particle populations with distinct spatial and spectral distributions dominate the emission at different wavelengths. An extended 2° × 3°
nebula is seen in radio and GeV gamma rays. An elongated cocoon prevails in X-rays and TeV gamma rays.

Aims. We use ~9.5 yr of data from the Fermi Large Area Telescope (LAT) to disentangle gamma-ray emission from the two components in the energy range from 10 GeV to 2 TeV, bridging the gap between previous measurements at GeV and TeV energies.

Methods. We determine the morphology of emission associated to Vela X separately at energies <100 and >100 GeV, and compare it to the morphology seen at other wavelengths. Then, we derive the spectral energy distribution of the two gamma-ray components over the full energy range.

Results. The best overall fit to the LAT data is provided by the combination of the two components derived at energies <100 and >100 GeV. The first component has a soft spectrum, spectral index 2.19 ± 0.16−0.22+0.05, and extends over a region of radius 1.°36±0.°04, consistent with the size of the radio nebula. The second component has a harder spectrum, spectral index
0.9 ± 0.3−0.1+0.3, and is concentrated over an area of radius 0.°63±0.°03, coincident with the X-ray cocoon that had already been established as accounting for the bulk of the emission at TeV energies.

Conclusions. The spectrum measured for the low-energy component corroborates previous evidence for a roll-over of the electron spectrum in the extended radio nebula at energies of a few tens of GeV possibly due to diffusive escape. The high-energy component has a very hard spectrum: if the emission is produced by electrons with a power-law spectrum, the electrons must be uncooled, and there is a hint that their spectrum may be harder than predictions by standard models of Fermi acceleration at relativistic shocks.
Benveniste entre les lignes. Contribution à l’étude de l’imaginaire linguistique des linguistes.
Authors: D’Ottavi Giuseppe , Hérout Raphaëlle
Published: July 2018

Les travaux d’Émile Benveniste développent différents pans théoriques qui, outre leur degré de technicité, donnent à lire une vision du corps imaginaire de la langue que l’on a traditionnellement laissée de côté. Or, ce rapport à l’imaginaire de la langue nous semble pertinent à interroger dans une démarche épistémologique en ce qu’il est révélateur de la circulation des idées et des sources qui nourrissent la conscience de la langue. Nous proposons une relecture des travaux de Benveniste rendant compte, après les travaux de J.-Cl. Milner et F. Provenzano sur l’imaginaire politique à l’oeuvre chez Benveniste, de la façon dont un certain imaginaire littéraire et politique traverse ces textes et se manifeste « dans et par » ses écrits linguistiques. Plus particulièrement, ce sont les figures d’Artaud et de Sartre qui nous permettront d’élucider une part de l’imaginaire linguistique en jeu dans l’oeuvre de Benveniste.
Le rôle de l’adjectif dans la catégorisation des déchets
Authors: Altmanova Jana , Grimaldi Claudio , Domenica Zollo Silvia
Published: July 2018

Dans la présente contribution nous nous proposons d’examiner le statut de l’adjectif à valeur dénominative dans les procédés de catégorisation des déchets en contexte spécialisé et divulgatif. En analysant des séquences dénominatives du typedéchet+Adj. extraites d’un corpus, nous allons observer la valeur sémantique et référentielle d’adjectifs relevant tous de la langue générale (ordinaire, classique, conventionnel, volumineux, encombrant(s), inerte(s), sauvage(s), solide) et qui, en entrant dans la composition du syntagme, semblent acquérir un statut semispécialisé, voire spécialisé surtout dans les typologies textuelles techniques. De même, nous allons analyser certains adjectifs de couleur (vert, marron, brun, blanc, gris, rouge, jaune), classés par Dixon (1977, 1982) parmi les huit classes d’adjectifs primaires, dont les propriétés sémantiques (expression du degré, fonction attributive, valeur descriptive) ne nous semblent pas toujours suffisantes pour expliquer leur emploi dans le contexte du classement des déchets.
La segmentation des romans et des nouvelles au XVIIe siècle : théories et pratiques de la fiction
Authors: Lombardero Emily
Published: July 2018

Dans la seconde moitié du XVIIe siècle, la mise en texte du récit de fiction évolue considérablement : les ornements typographiques sont de moins en moins employés, et se voient préférer l’usage du paragraphe, longtemps réservé à la littérature non fictionnelle. Nous nous proposons d’étudier ici les procédés de segmentation du texte narratif, en faisant l’hypothèse que le passage d’une segmentation externe – qui faisait se côtoyer des textes génériquement divers – au profit d’une segmentation interne, discriminant différentes unités au sein du récit lui-même, est un bon observatoire des théories et des pratiques de la fiction à l’âge classique. Nous essaierons alors de montrer comment l’usage du paragraphe en régime fictionnel, qui se développe avec l’apparition de la nouvelle, révèle l’autonomisation progressive du texte écrit vis-à-vis du régime du discours.
Partager sa connaissance du système lexical pour développer ses savoirs lexicaux en fin d’école primaire (9-11 ans)
Authors: Sardier Anne
Published: July 2018

La présente contribution s’inscrit dans une réflexion sur l’enseignementapprentissage du lexique à l’école primaire. Elle propose d’interroger les effets des échanges entre pairs sur les apprentissages lexicaux d’élèves de fin de cycle 3 (9-11 ans). Des temps de discussions sont proposés dans huit classes de fin d’école primaire. Ces temps permettent aux élèves de mobiliser notamment les différentes structures soustendant le système lexical. Afin de pouvoir en évaluer les effets, le protocole de recherche se déploie sous la forme d’un dispositif comparatif à partir de la variable discussion. Nous rendons compte des premiers résultats de cette recherche encore en cours. Les données constituées notamment de productions d’élèves sont analysées à partir de l’indicateur principal de réussite qui est le réemploi lexical des unités étudiées en classe. Les premiers résultats tendent à montrer que le fait de prévoir, dans les séances consacrées au lexique, des temps de discussion mobilisant les différentes structures du système au lexique favorise le réemploi lexical.
Effets de l'âge d’immersion sur la compréhension initiale d’expressions modales épistémiques en français L2
Authors: Granget Cyrille , Dat Marie-Ange , Cuet Christine , El Haj Pascale , Albochi Fatima , Allawama Ashraf
Published: July 2018

Alors qu’il est établi qu’à l’âge adulte le locuteur précoce d’une, langue seconde dépasse dans de nombreux tests de performance le locuteur, tardif, une question majeure reste de savoir si dès le stade initial l’enfant, dispose d’une forte capacité acquisitive ou d’une marge de progression plus, large. Notre étude observe si dans les 15 premiers mois d’exposition au, français, des locuteurs enfants, adolescents et adultes de l’arabe syrien (L1), comprennent la valeur d’épistémicité de différentes expressions modales. Cet, effet de loupe sur la compréhension d’expressions modales épistémiques dans, les stades initiaux par des apprenants d’âges différents montre des avantages, comparatifs du groupe adulte sur les groupes adolescents et enfants.
« Comme c’est un peu langage des jeunes quoi » : analyse du marqueur discursif quoi dans le discours des Chinois résidant en France
Authors: Deng Delin
Published: July 2018

Il est documenté que dans les décennies récentes quoi, commenceàêtre utilisé comme marqueur discursif dans le discours des, locuteurs natifs du français. Cependant, cet usage n’est mentionné ni, dans le dictionnaire ni dans les méthodes de grammaire. Malgré des, travaux fructueux à la fois qualitatifs et quantitatifs sur sa fonction, syntactique et discursive dans le discours des locuteurs natifs du, français, sa présence dans le discours des locuteurs non-natifs, n’attirent pas encore beaucoup d’attention. Cet article a donc pour, objectif de comparer l’usage du marqueur discursif quoi dans le, discours des locuteurs non-natifs avec celui dans le discours des, locuteurs natifs. Nous nous concentrons sur les divers contextes sous, lesquels il apparaÎt ainsi que comment des facteurs sociaux influencent, son emploi. En conclusion, on constate que les locuteurs non-natifs, utilisent quoi beaucoup moins fréquemment que les locuteurs, natifs. Cependant, ils l’emploient sous des contextes différents tout en, tenant compte que les contextes sont plus complexes et variés chez les, locuteurs natifs. En ce qui concerne les facteurs extralinguistiques, les, hommes utilisent beaucoup plus de quoi que les femmes. La durée, de séjour et le statut professionnel semblent aussi significatifs pour, son emploi dans notre étude.
Ectopic Transcript Analysis Indicates that Allelic Exclusion is an Important Cause of Type I Protein C Deficiency in Patients with Nonsense and Frameshift Mutations in the PROC Gene
Authors: Soria José Manuel , Berg Lutz-Peter , Fontcuberta Jordi , Kakkar Vijay V , Estivill Xavier , Cooper David N , Sala Núria
Published: July 2018

Nonsense mutations, deletions and splice site mutations are a common cause of type I protein C deficiency. Either directly or indirectly by altering the reading frame, these' lesions generate or may generate premature stop codons and could therefore be expected to result in premature termination of translation. In this study, the possibility that such mutations could instead exert their pathological effects at an earlier stage in the expression pathway, through “allelic exclusion” at the RNA level, was investigated. Protein C (PROC) mRNA was analysed in seven Spanish type I protein C deficient patients heterozygous for two nonsense mutations, a 7bp deletion, a 2bp insertion and three splice site mutations. Ectopic RNA transcripts from patient and control lymphocytes were analysed by RT-PCR and direct sequencing of amplified PROC cDNA fragments. The nonsense mutations and the deletion were absent from the cDNAs indicating that only mRNA derived from the normal allele had been expressed. Similarly for the splice site mutations, only normal PROC cDNAs were obtained. In one case, exclusion of the mutated allele could be confirmed by polymorphism analysis. In contrast to these six mutations, the 2 bp insertion was not associated with loss of mRNA from the mutated allele. In this case, cDNA analysis revealed the absence of 19 bases from the PROC mRNA consistent with the generation and utilization of a cryptic splice site 3’ to the site of mutation, which would result in a frameshift and a premature stop codon. It is concluded that allelic exclusion is a common causative mechanism in those cases of type I protein C deficiency which result from mutations that introduce premature stop codons
Increase of Plasminogen Activator Inhibitor Levels Predicts Outcome of Leukocytopenic Patients with Sepsis
Authors: Mesters R M , Flörke N , Ostermann H , Kienast J
Published: July 2018

Variables of the fibrinolytic system were prospectively studied in patients with haematologic malignancies in chemotherapy-induced leukocytopenia at onset and during the course of septicemia to evaluate their prognostic value. This group of patients was chosen because of their high risk of developing severe septic complications, thus allowing serial prospective testing of fibrinolytic variables prior to and during evolving sepsis or septic shock. 62 patients with febrile infectious events were accrued to the study. Of these, 13 patients progressed to severe sepsis and an additional 13 patients to septic shock as defined according to standard diagnostic criteria. At onset of fever, plasminogen activator inhibitor (PAI) activity and PAI-1 antigen levels increased from normal baseline levels and were significantly higher in the group of patients who developed septic shock compared to those with severe sepsis (medians: 10.6 versus 1.3 U/ml, p = 0.0001; 50.0 versus 5.0 ng/ml, p = 0.0002). The increase in PAI activity and antigen in septic shock was accompanied by an increase in tissue-type plasminogen activator antigen and total fibrin(ogen) degradation products and a decrease in alpha2-antiplasmin activity (p < 0.006). In contrast, in the group of patients that developed severe sepsis the variables of the fibrinolytic system remained unchanged at onset of fever. These differences between septic shock apd severe sepsis were sustained throughout the septic episode for all variables (p <0.0001). PAI activity of >5 U/ml at onset of fever predicted a lethal outcome with a sensitivity of 92% and a specificity of 100%. Thus, septic shock in leukocytopenia is associated with significant activation of the fibrinolytic system presumably as a response of the vascular endothelium to inflammatory injury. Furthermore, PAI activity measurements are sensitive markers of an unfavourable prognosis.
Plasminogen Activator Inhibitor (PAI-1) and Non-insulin-dependent Diabetes in Pima Indians, South Asians and Europeans
Authors: Nagi D K , Knowler W C , Hanson R L , Mohamed Ali V , Yudkin J S
Published: July 2018

Activity of plasminogen activator inhibitor-1 (PAI-1), a potent inhibitor of fibrinolysis, is raised in non-insulin-dependent diabetes mellitus (NIDDM) and may contribute to excess macrovascular disease. We investigated the association of PAI-1 activity with NIDDM in Pima Indians, a racial group with low risk of coronary artery disease, but in whom the impact of NIDDM on the occurrence of coronary artery disease is similar to other racial groups. We studied 308 (136 nondiabetic, 172 diabetic) Pima Indians from Arizona, and 138 (98 nondiabetic, 40 diabetic) South Asians and 129 (80 non-diabetic, 49 diabetic) Europeans living in North London. PAI-1 activity was measured by a spectrophotometric assay, and insulin, intact proinsulin and des 31,32 proinsulin concentrations were measured employing highly specific monoclonal antibody-based assays. Compared with non-diabetic subjects, PAI-1 activity was significantly higher in subjects with NIDDM among South Asians (22.8 ± 7.3 vs. 17.4 ± 6.9 AU/ml, p <0.001) and Europeans (23.1 ± 6.6 vs. 16.5 ± 6.1 AU/ml, p <0.001) but not among Pima Indians (19.5 ± 9.6 vs. 18.5 ± 8.6 AU/ml, ns). The association of PAI-1 activity with diabetes remained statistically significant when controlled for age, sex, body mass index and waist-hip ratio, serum triglyceride and fasting insulin concentrations in South Asians (p <0.001) and Europeans (p <0.001). The relationships of PAI-1 activity with clinical and biochemical variables were similar in the three racial groups other than for fasting and 2 h plasma glucose concentrations which were significantly associated with PAI-1 activity in South Asians (partial r = 0.32 and 0.31) and Europeans (partial r = 0.44 and 0.50) but not in Pima Indians (partial r = 0.11 and 0.15). In Pima Indians with NIDDM, PAI-1 activity was similar in those treated with sulphonylureas, insulin, or no drugs for diabetes. In conclusion, the association of PAI-1 with diabetes differs in racial groups who are at different risk of NIDDM and ischaemic heart disease. Previously reported differences in the prevalence of ischaemic heart disease between diabetic and non-diabetic Pima Indians, and between non-diabetic subjects from the three racial groups, are unlikely to be due to differences in PAI-1 activity.
Functional Consequences of Mutations in Amino Acid Residues that Stabilize Calcium Binding to the First Epidermal Growth Factor Homology Domain of Human Protein C
Authors: Geng Jie-Ping , Cheng Chong-Hui , Castellino Francis J
Published: July 2018

Charge-to-alanine mutations of three amino acid residues, viz., D46, D48, and D/Hya71, which are known to be important in stabilizing Ca2+ binding to epidermal growth factor (EGF) domains of vitamin K-de-pendent blood coagulation proteins, have been engineered into recombinant human protein C (r-PC), The resulting variants were then employed to assess the importance of this Ca2+ binding site in the activation properties of r-PC and in the activity of activated protein C (APC). Another mutation, of D48 to E, was constructed in order that a more conservative mutation at the Ca2+ binding site could be similarly examined.

The mutant proteins were fully processed with regard to proper signal peptide cleavage, γ-carboxylation, and β-hydroxylation, except, of course, for the D71A mutant in this latter case. The D48E variant possessed an additional residue of γ-carboxyglutamic acid (Gla), showing that E48 was γ-carboxylated. All of the mutants were reactive against a monoclonal antibody (MAb) specific for a Ca2+-dependent epitope within the amino-terminus of the Gla domain of r-PC, demonstrating that a proper Ca2+-dependent conformation was adopted in this region of the protein. None of the mutants, except for [D48γ]r-PC, were reactive against another Ca2+-dependent MAb which possessed specificity for Ca2+ binding to the EGF1 region of PC-this being the area of the protein that contained the mutated residues. These data strongly suggest that the alanine mutations present at D46, D48, and D71 diminished Ca2+ binding to the EGF1 domain of r-PC.

Steady state kinetic analysis demonstrated that determinants for the Ca2+-dependent inhibition of the thrombin (flla)-catalyzed activation of r-PC, and for the kinetic recognition of the flla/thrombomodulin complex, were not dependent on the integrity of the Ca2+ sites present in EGF1. The lone exception was [D48γ]r-PC, which did not undergo inhibition by Ca2+, an effect likely due to the potential for altered coordination of Ca2+ due to the Gla insertion, rather than to a dependency on D48. Plasma-based anticoagulant assays, as well as individual factor Va and factor Villa inactivation assays, showed that only [D71A]r-APC possessed a significantly reduced activity compared to wild-type r-APC. These observations suggest that D/Hya71 is likely an important determinant for activity of APC toward its physiological substrates, factor Va and factor Villa.
Immunologic Assessment of Patients Treated with Bovine Fibrin as a Hemostatic Agent
Authors: Carroll John F , Moskowitz Keith A , Edwards Niloo M , Hickey Thomas J , Rose Eric A , Budzynski Andrei Z
Published: July 2018

Twenty-one cardiothoracic surgical patients have been treated with fibrin as a topical hemostatic/sealing agent, prepared from bovine fibrinogen clotted with bovine thrombin. Serum samples have been collected before treatment with fibrin and postoperatively between 1 and 9 days, 3 and 12 weeks, and 6 and 8 months. The titers of anti-bovine fibrinogen antibodies, measured by ELISA specific for immunoglobulins IgG or IgM, increased to maximal values after about 8 or 6 weeks, respectively. After 8 months, IgG titers were on average 20-fold lower than the mean maximal value, while IgM titers returned to the normal range. IgG was the predominant anti-bovine fibrinogen immunoglobulin as documented by ELISA, affinity chromatography and electrophoresis. Anti-bovine fibrinogen antibodies present in patients reacted readily with bovine fibrinogen, but did not cross-react with human fibrinogen as measured by ELISA or by immunoelectrophoresis. A significant amount of antibodies against bovine thrombin and factor V has been found, many cross-reacting with the human counterparts. No hemorrhagic or thrombotic complications, or clinically significant allergic reactions, occurred in any patient, in spite of antibody presence against some bovine and human coagulation factors. The treatment of patients with bovine fibrin, without induction of immunologic response against human fibrinogen, appeared to be an effective topical hemostatic/sealing measure.
European Concerted Action on Anticoagulation (ECAA) - The Multicentre Calibration of Rabbit and Human ECAA Reference Thromboplastins
Authors: Poller L , Barrowcliffe T W , van den Besselaar A M H P , Jespersen J , Tripodi A , Houghton D ,   Prepared on behalf of the ECAA by the above steering committee
Published: July 2018

Two candidate ECAA reference preparations have been calibrated in a multicentre exercise at 14 representative national laboratories to provide reference thromboplastin for a large field study in 16 European countries. Two preparations were required because of the established differences in ISI arising from the two main routes of calibration via rabbit and human IRP. To be comparable with working reagents in everyday use a human plain recombinant reagent of low ISI and a rabbit plain preparation of moderately high ISI were selected. A precise calibration of the two candidate preparations has been achieved with the manual PT technique and an ISI of 0.95 (SE 0.0078) for the human reagent and 1.67 (SE 0.0322) for the rabbit reagent.
Isolated Familial Plasminogen Deficiency May not Be a Risk Factor for Thrombosis
Authors: Tait R C , Walker Isobel D , Conkie J A , Islam S I A M , McCall Frances
Published: July 2018

Despite many reports of individuals with congenital plasminogen deficiency and thrombosis, there is still uncertainty whether heterozygous deficiency represents a real thrombophilic risk factor or simply a coincidental finding. We have addressed this issue by testing for plasminogen deficiency in a cohort of 9611 blood donors. Out of 66 donors with reduced plasminogen activity on two occasions 28 were shown to have a familial deficiency state (including 3 with dysplasminogen-aemia). Our observed prevalence rate for familial plasminogen deficiency, calculated at 2.9/1000 (95% Cl = 1.9-4.2 per 1000), was not significantly different from that calculated from published reports of congenital plasminogen deficiency in thrombotic cohorts (5.4/1000). Furthermore, with only two exceptions, all 80 donors and relatives with familial deficiency were asymptomatic with regard to thrombosis -including a 29 year old donor with suspected compound heterozygous hypoplasminogenaemia. These findings add further weight to the argument that familial heterozygous plasminogen deficiency, at least in isolation, does not constitute a significant thrombotic risk factor. However, it remains uncertain whether plasminogen deficiency, when combined with other thrombophilic conditions, may become more clinically important.
Soluble P-selectin as Parameter for Platelet Activation during Storage
Authors: Kostelijk E H , Fijnheer R , Nieuwenhuis H K , Gouwerok C W N , de Korte D
Published: July 2018

Platelet concentrates stored at room temperature deteriorate. The so-called storage lesion is characterised by morphological changes and a loss of functionality. To find an assay for early platelet activation in platelet concentrates the morphological score, β-TG release and P-selectin expression were determined, and compared with the amount of soluble P-selectin. An ELISA was used to quantify soluble P-selectin in the storage medium. We found a significant correlation between the amount of soluble P-selectin and the percentage of P-selectin positive platelets (flow-cytometric analysis) (r = 0.7449; p <0.0001) or the amount of β-TG release (r = 0.6837; p<0.0001). The morphological score also correlated significantly (negative) with the amount of soluble P-selectin (r = -0.7669; p = 0.0002). From day 0 till day 8, the amount of soluble P-selectin increased constantly from 219 ± 49.2ng/ml to 556 ± 102.3 ng/ml. The detection of soluble P-selectin can be used to quantify activation of platelets during storage. The immuno-assay for soluble P-selectin is more sensitive than flow-cytometric analysis of the percentage of P-selectin-positive cells and allows earlier detection of platelet activation.
Ongoing Prothrombotic State in the Portal Circulation of Cirrhotic Patients
Authors: Violi Francesco , Ferro Domenico , Basili Stefania , Lionetti Raffaella , Rossi Elisabetta , Merli Manuela , Riggio Oliviero , Bezzi Mario , Capocaccia Livio
Published: July 2018

Portal thrombosis may complicate the clinical course of cirrhosis, but the pathophysiologic mechanism is unclear. Aim of the study was to evaluate the behavior of clotting system and endotoxemia in portal vein and in peripheral circulation of 11 cirrhotic patients undergoing transjugular port-systemic shunt (TIPS).

Portal blood showed higher values of Fl+2 [Median (range): 2.5 (1.1-5.3) vs. 1.1 (0.6-2.1) nM, p <0.01], D-dimer [765 (184-1713) vs. 192 (64-813) ng/ml, p < 0.01] and endotoxemia [31 (16-47.2) vs. 13.7 (7.5-23.5) pg/ml, p <0.01] than peripheral circulation. In the portal vein, all but one sample had Fl+2 > 1.2 nM (upper limit of control values), all but one had D-dimer > 216 mg/dl (mean + 2 SD of controls) and 100% had values of endotoxemia > 9.6 pg/ml (upper limit of control values). Fibrinogen was lower in the portal circulation compared to peripheral circulation but the difference was not significant [85 (58-195) vs. 134 (75-244) mg/dl, p > 0.05].

Endotoxemia was directly correlated with Fl+2 (Rho = 0.92 p <0.006) and D-dimer (Rho = 0.93, p <0.005).

This study shows that an ongoing prothrombotic state is present in the portal circulation of cirrhotic patients and may play a pivotal role in the thrombotic episodes occurring in this clinical setting.
Enhancement of Plasminogen Binding to U937 Cells and Fibrin by Complestatin
Authors: Tachikawa Kiyoshi , Hasurni Keiji , Endo Akira
Published: July 2018

Plasminogen binds to endothelial and blood cells as well as to fibrin, where the zymogen is efficiently activated and protected from inhibition by α2-antiplasmin. In the present study we have found that complestatin, a peptide-like metabolite of a streptomyces, enhances binding of plasminogen to cells and fibrin. Complestatin, at concentrations ranging from 1 to 5 μM, doubled 125I-plasminogen binding to U937 cells both in the absence and presence of lipoprotein(a), a putative physiological competitor of plasminogen. The binding of 125I-plasminogen in the presence of complestatin was abolished by e-aminocaproic acid, suggesting that the lysine binding site(s) of the plasminogen molecule are involved in the binding. Equilibrium binding analyses indicated that complestatin increased the maximum binding of 125I-plasminogen to U937 cells without affecting the binding affinity. Complestatin was also effective in increasing 125I-plasminogen binding to fibrin, causing 2-fold elevation of the binding at ~1 μM. Along with the potentiation of plasminogen binding, complestatin enhanced plasmin formation, and thereby increased fibrinolysis. These results would provide a biochemical basis for a pharmacological stimulation of endogenous fibrinolysis through a promotion of plasminogen binding to cells and fibrin.
The Ability of Thrombin Inhibitors to Reduce the Thrombin Activity Generated in Plasma on Extrinsic and Intrinsic Activation
Authors: Prasa D , Svendsen L , Stürzebecher J
Published: July 2018

In a thrombin generation test with continuous registration of thrombin activity in plasma we studied the ability of a variety of thrombin inhibitors of different type and mechanism of action to influence the activity of thrombin after activation of the coagulation system. Depending on the inhibitor, the peak of thrombin activity is delayed and/or reduced.

By blocking the active site of generated thrombin inhibitors cause a concentration dependent reduction of the thrombin peak and inhibit feed-back reactions of thrombin resulting in a delay of thrombin generation. Highly potent synthetic active-site directed inhibitors (Ki ≤ 20 nM) reduce the thrombin activity formed in plasma after extrinsic or intrinsic activation with the same efficiency (IC50 0.1 - 0.6 μM) as hirudin. The delay and reduction of thrombin generation by inhibitors of the anion-binding exosite 1 of thrombin is only attributed to an inhibition of feed-back reactions of thrombin. For a 50% reduction of thrombin activity in plasma by this type of inhibitors relatively high concentrations were determined.
Thrombi Formed in a Chandler Loop Mimic Human Arterial Thrombi in Structure and PAI-1 Content and Distribution
Authors: Robbie Linda A , Young Simon P , Bennett Bruce , Booth Nuala A
Published: July 2018

We have previously shown that whole blood clots prepared under static conditions are a poor model for human thrombi formed in vivo. The most striking contrast is in the PAI-1 content, some 100 times lower in static clots than in human thrombi. This study aimed to evaluate thrombi formed in an artificial circulation (Chandler loop) using whole blood augmented with platelets. Citrated blood was recalcified and placed in tubing, which was sealed to form a closed loop and circulated. Immunohistochemical staining revealed morphology very similar to human thrombi formed in vivo, comprising dense platelet-rich heads and fibrin-rich tails. Strong positive staining for PAI-1 was observed in fibrin-rich areas of both the head and the tail. The PAI-1 content of the thrombi increased significantly on augmentation of blood with isolated platelets, and reached levels comparable with those in human thrombi. These Chandler thrombi thus provide an appropriate model system for the study of thrombus lysis, in contrast to static blood clots.
Surface-Secreted von Willebrand Factor Mediates Aggregation of ADP-Activated Platelets at Moderate Shear Stress: Facilitated by GPIb but Controlled by GPIIb-IIIa
Authors: Frojmovic M M , Kasirer-Friede A , Goldsmith H L , Brown E A
Published: July 2018

We previously showed that ADP activation of washed human platelets in plasma-free suspensions supports aggregation at moderate shear stress (0.4-1.6 Nm-2) in Poiseuille flow. Although most activated platelets expressed maximal fibrinogen-occupied GPIIb-IIIa receptors, aggregation appeared to be independent of bound fibrinogen, but blocked by the hexapeptide GRGDSP. Here, we tested the hypothesis that von Willebrand factor (vWF) secreted and expressed on activated platelets mediates aggregation at moderate shear rates from 300 to 1000 s_1 corresponding to shear stresses from 0.3 to 1.1 Nm-2. Relatively unactivated platelets (<15% expressing prebound fibrinogen) were prepared from acidified citrated platelet rich plasma (cPRP) by single centrifugation with 50 nM stable prostacyclin derivative ZK 36374 and resuspended in Tyrodes-albumin at 5 X 104 cells ε_1. Flow cytometric measurements with monoclonal antibody (mAb) 2.2.9 reporting on surface-bound vWF, and with mAb S12 reporting on a-granule secreted P-selectin, showed that 65% and 80%, respectively, of all platelets were maximally activated with respect to maximal secretion and surface expression of these proteins. “Resting” washed platelets exhibited both surface-bound vWF and significant P-selectin secretion. We showed that mAbs 6D1 and NMC4, respectively blocking the adhesive domains on the GPIb receptor recognizing vWF, and on the vWF molecule recognizing the GPIb receptor, partially inhibited ADP-induced aggregation under shear in Couette flow, the degree of inhibition increasing with increasing shear stress. In contrast, mAb 10E5, blocking the vWF binding domain on GPIIb-IIIa, essentially blocked all aggregation at the shear rates tested. We conclude that vWF, expressed on ADP-activated platelets, is at least the predominant cross-bridging molecule mediating aggregation at moderate shear stress. There is an absolute requirement for free activated GPIIb-IIIa receptors, postulated to interact with platelet-secreted, surface bound vWF. The GPIb-vWF cross-bridging reaction plays a facilitative role becoming increasingly important with increasing shear stress. Since aurin tricarboxylic acid, which blocks the GPIb binding domain on vWF, was also found to completely block aggregation in Poiseuille flow, we conclude that it too affects the GPIIb-IIIa interaction.
Long-term Follow-up of Hemostatic Molecular Markers during Remission Induction Therapy with All-Trans Retinoic Acid for Acute Promyelocytic Leukemia
Authors: Watanabe Reiko , Murata Mitsuru , Takayama Nobuyuki , Tokuhira Michihide , Kizaki Masahiro , Okamoto Shinichiro , Kawai Yohko , Watanabe Kiyoaki , Murakami Hiroshi , Kikuchi Masao , Nakamura Shin , Ikeda Yasuo ,   For Keio Hematology-Oncology Cooperative Study Group (KHOCS)
Published: July 2018

Hemostatic molecular markers were serially monitored in a prospective fashion during remission induction therapy with all-trans retinoic acid (ATRA) in sixteen patients with acute promyelocytic leukemia (APL). One patient with leukocytosis before treatment and three patients who later developed hyperleukocytosis also received chemotherapy with behenoyl Ara-C and daunorubicin. Plasma levels of E-fragment of fibrin and fibrinogen degradation product (FDP-E), FDP-D dimer (D-D), thrombin-antithrombin complex (TAT), and plasmin-α2 plasmin inhibitor complex (PIC) were markedly elevated in all but one patient before treatment, and these parameters decreased to normal or near normal ranges in most patients within the first 7 days of treatment. Interestingly, we have found that these parameters were again elevated during the later course of ATRA therapy (after day +7) in eleven patients for various reasons including cytotoxic chemotherapy (3 cases), fever (5 cases; 2 cases with apparent infection, 3 cases without known etiology), Caesarean section (1 case), and no apparent etiology (2 cases). Three patients showed bleeding complications during reelevation of molecular markers, but none developed thrombosis. Plasma elastase-α1 proteinase inhibitor complex (E-α1PI) was markedly elevated in all patients at diagnosis and did not decrease significantly during ATRA therapy. Plasma tissue factor antigen was mildly elevated in one out of four patients studied, and thrombomodulin was elevated in two out of ten patients tested. These results confirmed the rapid normalization of coagulopathy during the early phase of remission induction therapy with ATRA but suggest that re-elevation of molecular markers occurs frequently during the later course of ATRA therapy.
Gender Differences in Platelet GPIIb-IIIa Activation
Authors: Faraday Nauder , Goldschmidt-Clermont Pascal J , Bray Paul F
Published: July 2018

Gender differences in the development of thrombotic diseases have been described in numerous clinical settings. Enhanced platelet reactivity in both sexes is associated with the development of vascular thromboses. Because activation of platelet GPIIb-IIIa receptors is a central event in thrombus formation, we examined GPIIb-IIIa function in normal male and female volunteers. Using flow cytometry, we quantitated gender differences in the number of binding sites for FITC-labeled fibrinogen (FITC-FGN) and FITC-labeled PAC-1 antibody (FITC-PAC-1). Washed platelets were incubated with either FITC-FGN or FITC-PAC-1 and activated with either ADP or thrombin receptor activating peptide (TRAP) prior to cytometric acquisition of data. The dissociation constant for FITC-FGN was the same in both sexes (approx. 1.6 x 10-7M), however, the number of GPIIb-IIIa receptors per platelet capable of binding fibrinogen was significantly greater in women than men in response to 20μM ADP (16,319 ± 1871 vs 9669±1994, p = 0.02), 20μM ADP (39,951 ± 4711 vs 25,948 ± 4953, p = 0.05) and 50μM TRAP (39,236 ± 3965 vs 21,848 ± 4159, p = 0.007). Similarly, the number of GPIIb-IIIa receptors capable of binding PAC-1 in response to ADP and TRAP was 50% to 80% greater in women than men. Binding experiments using specific anti-GPIIb-IIIa monoclonal antibodies (P2 and 10E5), as well as quantitative Western blotting experiments, showed no gender difference in the total number of GPIIb-IIIa molecules expressed. Analysis of data from female subgroups demonstrated an association of GPIIb-IIIa reactivity with menstrual phase. We conclude that GPIIb-IIIa receptors on platelets from premenopausal women are more “activatable” than those on platelets from young men. Variations in the serum concentrations of estrogens and/or progestins may modulate GPIIb-IIIa function.
Modulation of Glomerular ECTO-ADPase Expression by Oestradiol
Authors: Faas M M , Bakker W W , Klok P A , Baller J F W , Schuiling G A
Published: July 2018

The effect of 17-β-oestradiol (0E2) upon the activity of the glomerular anti-thrombotic ecto-enzyme ADPase was studied in cyclic and ovariectomized (OVX) Wistar rats. On day 0 (i.e. at the time of ovariectomy or 11 days after ovariectomy) ratsreceived OE2-releasing Silastic implants or empty implants and were sacrificed on day 3,10 or 21. Cryostat kidney sections were histochemically stained for ecto-ADPase activity using enzyme-histochemistry and glomerular reaction product was quantitatively evaluated by computerized image analysis. Both the histological distribution of reaction product in each glomerulus, as reflectedby the relative glomerular area covered with reaction product, as well as enzyme activity, as reflected by staining intensity of thereaction product, were scored. The results show significantly decreased histological distribution after OVX; OVX, however, did not change enzyme activity. It further appeared that OE2 (partly) prevented the decrease of histological distribution in OVX rats, while the enzyme activity was significantly increased by exogenous OE2. In cyclic rats, OE2 did not change histological distribution, although OE2 significantly increased enzyme activity in these rats.

It is concluded that glomerular ecto-ADPase expression in the rat kidney is influenced by one or more ovarian factor(s), a very likely candidate being oestradiol. These results may thus point to a dual action of OE2 upon haemostasis: In addition to the known enhancement of procoagulatory plasma factors by OE2, also anti-aggregatory effects may be stimulated by OE2 as reflected by upregulation of vessel wall associated ecto-ADPase activity.
Factor VII and Fibrinogen Levels Examined by Age, Sex, and other Atherosclerotic Risk Factors in a Japanese Population
Authors: Ishikawa Shizukiyo , Kario Kazuomi , Nago Naoki , Kayaba Kazunori , Hiraoka Jun , Matsuo Hitoshi , Goto Tadao , Miyamoto Takeshi , Tsutsumi Akizumi , Nakamura Yoshikazu , Shimada Kazuyuki , Inoue Kazuo , Igarashi Masahiro
Published: July 2018

Factor VII coagulant activity (FVIIc) and fibrinogen (Fbg) levels have been investigated as cardiovascular risk factors. We studied these two factors with stratification for age, sex and blood pressure, and the relation with other atherosclerotic risk factors in a Japanese general population. The subjects were 3,139 Japanese (1,315 males and 1,824 females) aged 30 to 89 in 1992 and 1993. A linear increase with age was observed in the levels of Fbg in both men and women, but no differences were observed between men and women in each age group. A linear increase with age was also seen in the levels of FVIIc in women, but the levels of FVIIc in men were significantly higher for the age group 40-49 years than for any other age group. The levels of FVIIc in women were significantly higher than in men at age ≥60 years. As concerning the effect of alcohol intake status, Fbg had a tendency to decrease with alcohol intake. Fbg and FVIIc levels were associated with an increase in smoking status in men, but no association was seen in women in either Fbg or FVIIc. FVIIc was positively correlated with age, body mass index, total cholesterol, triglycerides and fasting insulin level. Fbg was positively correlated with age, systolic blood pressure, diastolic blood pressure, total cholesterol, LDL-cholesterol and triglycerides in women, but Fbg had few positive correlations with risk factors in men.

A comparison with previous Western studies showed that the Fbg levels of our Japanese population were lower than those of the Caucasians studied, but the present FVIIc levels were nearly the same level or slightly higher than theirs. The association of Fbg and FVIIc and with other cardiovascular risk factors in Japanese was similar to those observed in Caucasians.
Pharmacodynamic and Safety Results of PEG-Hirudin in Healthy Volunteers
Authors: Esslinger Hans-Ulrich , Haas Sylvia , Maurer Robert , Lassmann Axel , Dübbers Katrin , Müller-Peltzer Herbert
Published: July 2018

PEG-Hirudin, a chemically defined conjugate of recombinant hirudin and two molecules of polyethylene glycol (PEG)-5000 is a highly selective direct thrombin inhibitor with a significantly longer duration of action than non-conjugated recombinant hirudin permitting once daily subcutaneous administration. A series of placebo-controlled, randomized, Phase I clinical trials were conducted in 75 healthy volunteers to investigate the anticoagulant effects, safety and pharmacodynamics of PEG-Hirudin when administered intravenously as a bolus injection, infusion, and subcutaneously. After single i.v. injections of various doses of PEG-Hirudin (0.03-0.3 mg/kg) dose-dependent increases in anti-IIa activity and APTT were observed. Four hours after injection of 0.3 mg/kg, mean plasma concentration expressed in terms of anti-IIa activity was still 0.89 µg/ml, corresponding to a 1.8-fold prolongation of APTT. Continuous intravenous infusions of 0.01 and 0.02 mg/kg/h PEG-Hirudin resulted in maximum anti-IIa activities of 0.42 µg/ml and 0.77 µg/ml, respectively, at the end of a six-hour infusion period without having reached steady state at this time. After termination of the infusion, anticoagulant activity displayed an immediate exponential decrease. The anticoagulant activities of single subcutaneous doses of 0.05 to 0.6 mg/kg were studied in a further series of investigations and slow increases and prolonged durations of anti-IIa activity and APTT prolongation were found. Repeated, once daily subcutaneous administrations of 0.2 to 0.4 mg/kg for five days resulted in dose-dependent prolongations of APTT and increases in anti-IIa activity without completely reaching steady state conditions. In a further study, 0.3 mg/kg of PEG-Hirudin was given as an i.v. bolus injection followed by three repeated single daily s.c. injections. In this trial, the APTT was shorter than expected from previous studies; therefore, a direct comparison of various APTT reagents was made in the intravenous infusion trial. Of the APTT reagents tested, BioMérieux Silimat and IL-ellagic acid proved to be the most sensitive to PEG- Hirudin. The hirudin derivative PEG-Hirudin was. tolerated very well without immuno-allergic side effects. In view of the significantly prolonged anticoagulant efficacy in comparison to non-conjugated r-hirudin, PEG-Hirudin is a promising compound especially for repeated once daily subcutaneous administration.
Developing a Three-Layered Synthetic Microsurgical Simulation Vessel
Authors: Sindali Katia , Srinivasan Karthik , Jones Martin , Nugent Nora , Cooper Lilli
Published: July 2018

Background Microsurgery is increasingly relevant, and is difficult to learn. Simulation is relied upon ever more in microvascular training. While living models provide the ultimate physiological feedback, we are ethically obliged to optimize non-living models to replace, refine, and reduce the use of animals in training. There is currently no three-layered synthetic vessel available for microsurgical training.

Methods A three-layered synthetic vessel was designed with a simulation company. One anastomosis was performed by 14 microsurgical experts at one center. The realism of the vessel was assessed via user questionnaires and the construct validity using objective, validated task scores to assess the anastomosis performance and the final product. Videos were obtained, which were anonymized and marked remotely by a consultant plastic surgeon.

Results The synthetic vessel intima and media displayed reasonable realism, while the adventitia was less realistic. Areas for improvement were identified. Both the task specific assessment score and the final product assessment appropriately identified experts.

Conclusion A three-layered synthetic model for microvascular training is a hygienic and useful intermediate-level alternative to commonly used synthetic and ex vivo alternatives.
Suppression of the critical collapse for one-dimensional solitons by saturable quintic nonlinear lattices
Authors: Shi Jincheng , Zeng Jianhua , Malomed Boris A.
Published: July 2018

The stabilization of one-dimensional solitons by a nonlinear lattice against the critical collapse in the focusing quintic medium is a challenging issue. We demonstrate that this purpose can be achieved by combining a nonlinear lattice and saturation of the quintic nonlinearity. The system supports three species of solitons, namely, fundamental (even-parity) ones and dipole (odd-parity) modes of on- and off-site-centered types. Very narrow fundamental solitons are found in an approximate analytical form, and systematic results for very broad unstable and moderately broad partly stable solitons, including their existence and stability areas, are produced by means of numerical methods. Stability regions of the solitons are identified by means of systematic simulations. The stability of all the soliton species obeys the Vakhitov-Kolokolov criterion.
Note: Precision control of nano-positioning stage: An iterative learning-based model predictive control approach
Authors: Xie Shengwen , Ren Juan
Published: July 2018

Due to mechanical vibration and nonlinearities such as hysteresis and creep effect, it is difficult to achieve precise control of nano-positioning stages for high-speed/bandwidth trajectory tracking. In this paper, we propose an iterative learning-based model predictive control (IL-MPC) approach to achieve this goal. IL-MPC strategically combines both model predictive control (MPC) and iterative learning control (ILC) tools: the MPC is applied to ensure that the tracking error is limited through all iterations and the ILC is applied to the system consisting of the MPC and the stage to guarantee high precision trajectory tracking with the existence of MPC modeling uncertainty and system nonlinearity. For experimental validation, IL-MPC was implemented to control a nano-piezo actuator to track both repetitive high-speed/broadband trajectories and trajectories with varying amplitude, phase, and frequency, respectively.