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Research on fear of crime has often found that elderly are more afraid of crime. The present paper analyzes predictors of fear of crime among the elderly using the concept of vulnerability. With survey data from Munich, Germany, (N = 2203; ages 55–75 years) we can assess a broad range of physical and social vulnerability dimensions including the role of one’s neighborhood. The results show that females and persons with bad health feel less safe. Education and place attachment reduce fear. Perceived neighborhood disorder increases feelings of insecurity. Also the urban design of the neighborhood is related to fear, however, the explanation for these findings are only partly due to walkability and natural surveillance. The results make clear that the elderly should not be treated as a homogenous group, vulnerability dimensions seem to be more important for fear of crime than age. Furthermore, the findings stress the neighborhood as central place for measures to fight fear of crime.

Oxidation products of low-density lipoproteins have been suggested to promote inflammation during atherogenesis, and reticulocyte-type 15-lipoxygenase has been implicated to mediate this oxidation. In addition, the 5-lipoxygenase cascade leads to formation of leukotrienes, which exhibit strong proinflammatory activities in cardiovascular tissues. Here, we studied both lipoxygenase pathways in human atherosclerosis. The 5-lipoxygenase pathway was abundantly expressed in arterial walls of patients afflicted with various lesion stages of atherosclerosis of the aorta and of coronary and carotid arteries. 5-lipoxygenase localized to macrophages, dendritic cells, foam cells, mast cells, and neutrophilic granulocytes, and the number of 5-lipoxygenase expressing cells markedly increased in advanced lesions. By contrast, reticulocyte-type 15-lipoxygenase was expressed at levels that were several orders of magnitude lower than 5-lipoxygenase in both normal and diseased arteries, and its expression could not be related to lesion pathology. Our data support a model of atherogenesis in which 5-lipoxygenase cascade-dependent inflammatory circuits consisting of several leukocyte lineages and arterial wall cells evolve within the blood vessel wall during critical stages of lesion development. They raise the possibility that antileukotriene drugs may be an effective treatment regimen in late-stage disease.

L’analyse fractale des réseaux hydrographiques a donné lieu à de nombreux travaux (Tarboton et al., 1988 ; Rodriguez-Iturbe et Rinaldo, 1997 ; Hauchard et al., 1999 ; Forriez et al., 2010), alors même que les valeurs du principal indicateur fractal – la dimension fractale – n’ont que rarement alimenté des comparaisons selon leur mode d’obtention ou des discussions sur l’incertitude qui les caractérise. Les réseaux hydrographiques sont un cas particulier, relativement simple, de la grande famille des réseaux de transport qui de Hagget et Chorley (1969) à Strano et al. (2012) ont suscité réflexion théorique et applications en géographie prospective et aménagement (Dupuy, 1991 ; Frankhauser et Genre-Grandpierre, 1998 ; Porta et al., 2006). Nous nous intéressons ici aux réseaux vectoriels, typiquement des réseaux construits comme assemblage déterministe ou aléatoire de segments unitaires (fig. 2) ou des réseaux extraits à partir de modèles numériques de terrain de type raster avec une taille de cellule fixée (fig. 4, fig. 7), au-dessous de laquelle il n’existe plus de données informatives. Nous nous focalisons sur les méthodes d’estimation de dimensions fractales, qui soient, autant que faire se peut, dans le droit fil des méthodes mathématiques de calcul d’une dimension asymptotique et privilégions une analyse de type monofractal.Partant, d’une part, de la distinction entre fractale mathématique infinie et fractale de la nature, d’autre part, du rappel des différentes dimensions théoriques (asymptotiques) auxquelles se rattachent les dimensions empiriques que nous utilisons, nous mettons ici l’accent sur trois résultats méthodologiques. Le premier, l’apport des réseaux simulés – dont le mode de construction est connu –, permet d’apprécier la pertinence des divers estimateurs selon les caractéristiques des réseaux (leur ramification, leur degré de hiérarchisation, par exemple) et, au total, autorise une mise en garde vis-à-vis de certaines procédures très répandues – lorsqu’elles sont appliquées à de petits réseaux notamment. Le second concerne la détermination nécessaire à nos yeux d’un domaine de fractalité enserré dans des limites obtenues selon une procédure non subjective, et entre lesquelles est calculée la valeur de l’estimateur fractal (fig. 8 et fig. 11) ; cette procédure exigeante peut conduire à une réduction conséquente de l’intervalle de validité mais est utile pour des comparaisons. Enfin, l’importance de la notion d’instabilité des résultats selon le niveau hiérarchique du réseau (fig. 13, fig. 14, tab. 1), distincte de l’incertitude qui, pour les réseaux aléatoires, a pu être évaluée pour chaque niveau hiérarchique en répétant les mesures un grand nombre de fois (50 et 100 réalisations – réseau de Scheidegger et réseau binaire bruité, respectivement ; tab. 1) est mise en valeur.Les trois estimateurs de dimension fractale que nous comparons sont, l’un, un estimateur traditionnel en hydrographie (DHS) car fondé sur la topologie du réseau, plus particulièrement sur les rapports de Horton-Strahler (Horton, 1945 ; Strahler, 1957) ; les autres, la dimension obtenue par comptage de boîtes (DB) et la dimension de corrélation (DC). Le cas d’un réseau de talwegs extrait à partir de MNT semble montrer que les résultats d’estimation les plus stables sont obtenus à partir de cette dernière méthode (tab. 3). Streams networks are part of transport networks and more generally of “spatial networks” that gave rise to fundamental researches (Barthelemy, 2011) and applied geography (Strano et al., 2012). Numerous studies have focused on fractal analysis of stream networks. However, only few papers compare or discuss the estimation methods and the uncertainty of the main fractal indicator, the fractal dimension. This work focuses on the fractal properties of vector networks both virtual and actual. We first mention the essential distinction between infinite mathematical fractal and nature fractal. Then, we present different theoretical and empirical dimensions that we use. In particular, we compare three fractal dimension estimators: the most classical estimator for stream networks, based on a topological approach with the Horton-Strahler ratios, and two other estimators based on a geometric approach, the box-counting dimension and the correlation dimension. Three main methodological results can be highlighted: 1- the study of virtual network contributes to the assessment of the various estimators’ relevance, according to the characteristics of networks; 2- an empirical fractal domain must be determined with an objective method to estimate fractal dimensions that can be compared; 3- the observation of uncertainty and stability of the fractal dimension is necessary for any valid comparison.

Le glacier rocheux de taille kilometrique qui s'etend au pied sudest du Cerro Caquella (5960 m) a ete analyse par sondages electriques. Dans ce milieu de haute montagne tropicale aride sans glaciers et sans manteau neigeux saisonnier durable, les glaciers rocheux representent un important indicateur du changement climatique. Ce sont en outre les seules reserves hydriques susceptibles de jouer un role actif dans le cycle hydrologique actuel. Les sondages electriques et les observations directes montrent la presence d'un permafrost comportant de la glace en certaines parties du glacier rocheux aux alentours de 5450 m d'altitude. Cependant, la forme des courbes de resistivite obtenues et plusieurs indices venant de la topographie de la surface tendent a prouver que ce glacier rocheux est en regression. Sa formation est le resultat d'une longue evolution qui a peut-etre commence au debut de l'Holocene. Par ailleurs, dans le secteur amont, la presence a 5600 m d'une moraine plus recente montre que la ligne d'equilibre glaciaire s'est etablie pres de 400 m plus bas qu'actuellement, pendant la periode historique (Petit Age de Glace) ou protohistorique.

The proteolytic enzyme thrombin activates its receptor by cleavage of a peptide from the extracellular N-terminus. The newly generated N-terminus acts as a tethered ligand to activate the receptor. Receptor-mediated cellular effects of thrombin can be mimicked by synthetic peptides, which correspond to the amino acid sequence of the newly formed N-terminus. The aim of the present study was to investigate vascular effects of thrombin and the thrombin receptor activating peptide (TRAP: SFLLRN) in vitro and in vivo in rats. In precontracted rat aortic rings, both thrombin (0.3, 1, 3 U/ml) and TRAP (1, 3, 10, 20, 40 μM) induced endothelium-dependent relaxant responses. In anaesthetized rats, the mean arterial blood pressure (MAP) was measured continuously in the carotid artery by a pressure transducer. Thrombin and TRAP were administered as intravenous bolus injection via the femoral vein. Thrombin at doses of 3–100 U/kg, as well as TRAP at doses of 0.1–0.6 mg/kg iv, caused a reversible decrease in MAP. Administration of TRAP at doses of 0.3 and 0.6 mg/kg led to a triphasic response in most of the animals treated (50% and 75%, respectively), i.e. a short drop of MAP was followed by an increase and finally a longer lasting decrease in MAP. Pretreatment with the nitric oxide (NO)-synthase inhibitor NG-nitro- l -arginine-methylester ( l -NAME) suppressed the dose-dependent vasodilator effects of thrombin. Heparin and hirudin also inhibited the hypotensive response to thrombin. The TRAP-induced triphasic reaction on MAP was not affected by the serotonin antagonists ketanserin and tropisetron, as well as the aminopeptidase inhibitor amastatin. Pretreatment with l -NAME led to an inhibition of hypotension induced by TRAP at 0.1 mg/kg, as well as of the initial transient fall in blood pressure at doses of 0.3 and 0.6 mg/kg. The studies suggest that the thrombin- and TRAP-induced vasodilation in vitro and in vivo is in part due to the release of endothelial NO. In the blood pressure response to TRAP, additional effects seem to be involved.

The tissue factor (TF) pathway of coagulation plays a decisive role for normal haemostasis as well as in the pathophysiology of various diseases. As endogenous inhibitor of TF-mediated coagulation, the Kunitz-type proteinase inhibitor tissue factor pathway inhibitor (TFPI) is an important factor in the regulation of haemostasis and the control of clotting activation. TFPI exerts its biological effects by the binding of Factor Xa (FXa) forming a TFPI/FXa complex which then, in a second step, binds to and effectively inhibits the TF/Factor VIIa (FVIIa) complex. Due to its mechanism of action TFPI causes strong anticoagulant and antithrombotic effects under experimental conditions. Furthermore, the inhibitor was shown to be a potent antiproliferative agent both in vitro and in vivo. Based on the pathogenetic role of TF and the TF/FVIIa complex and on the effectiveness of TFPI demonstrated in preclinical studies it is assumed that TFPI might become an important drug for various clinical indications, especiall...

ZusammenfassungFür die Pathogenese thromboembolischer und vaskulärer Erkrankungen spielen sowohl aktivierte Gerinnungsfaktoren wie Thrombin und Faktor Xa als auch die Aktivierung von Plättchen eine entscheidende Rolle. In der Prophylaxe und/oder Therapie dieser Erkrankungen nehmen neue Plättchenfunktionshemmstoffe wie GPIIb/llla-Antagonisten ebenso wie neuentwickelte Inhibitoren von Gerinnungsenzymen wie Thrombin- und Faktor-Xa-Inhibitoren einen zentralen Platz ein. Es gibt Ansätze dafür, derartige Substanzen miteinander zu kombinieren, um synergistische Wirkungen zu erzielen und auf diese Weise den therapeutischen Effekt zu erhöhen. Bei einer Kombination von Wirkstoffen mit unterschiedlichen Angriffspunkten und Wirkungsmechanismen treten zahlreiche Interaktionen auf, die zu einer Verbesserung der Wirksamkeit führen, aber auch einen Anstieg unerwünschter Nebenwirkungen bedingen können. Bei gleichzeitiger Gabe von GPIIb/IIIa-Antagonisten und Thrombin- oder Faktor-Xa-Inhibitoren wurde eine Potenzierung antikoagulatorischer und antithrombotischer Effekte sowie eine verstärkte Hemmung der Thrombinbildung beobachtet. Die unerwünschten Wirkungen betrafen vor allem eine verstärkte Blutungsneigung bei Kombination von GPIIb/lla-Antagonisten mit Thrombininhibitoren.

ZusammenfassungDie immunologisch bedingte Heparin-induzierte Thrombozytopenie (HIT II) ist eine schwerwiegende Nebenwirkung einer Therapie mit unfraktionierten Heparinen, die mit lebensbedrohlichen thromboembolischen Komplikationen einhergeht. Die HIT II wird durch IgG-Antikörper gegen den Heparin/PF4-Komplex hervorgerufen, wodurch es in der Folge zur Plättchenaktivierung über den Fc-γlI-A-Rezeptor kommt. Wenn Plättchen von gesunden Spendern mit Heparin und Serum von Patienten mit HIT II inkubiert werden, kommt es zur Freisetzung von zytosolischem Kalzium, zur Aggregation, Thromboxanbildung und Expression von P-Selektin. Der GPIIb/IIIa-Antagonist Abciximab (ReoPro®) (5-50 nM) und Iloprost (1-10 nM), das die Adenylylzyklase aktiviert, hemmen konzentrationsabhängig die HIT-Serum/Heparin-induzierte Plättchenaggregation und Thromboxanbildung. Bei Konzentrationen, die eine vollständige Hemmung der Aggregation bewirkten, wurde die Expression von P-Selektin nur um 20% gehemmt. Es wurden keine signifikanten Unterschiede gefunden, wenn die Plättchenfunktionen im Zitrat-oder Hirudinplasma geprüft wurden. Plättchenfunktionshemmstoffe könnten sich als günstige zusätzliche Pharmaka zur Therapie einer HIT II erweisen.

SummaryIt is now well recognized that drugs with sole anti-Xa activity are capable of producing antithrombotic effects. The basic and clinical studies with pentasaccharide have validated this hypothesis. Synthetic heparin pentasaccharide is currently undergoing clinical trials in the prophylaxis of DVT in orthopedic surgery. While the naturally occuring direct anti-Xa agents such as antistatin, TAP and Yagin are potent anti-Xa agents their clinical development is delayed due to several unresolved developmental issues. On the other hand, several peptidomi-metic agents also demonstrate varying degrees of oral and subcutaneous bioavailability. One of these agents namely the DX 9065a is in clinical trials at this time. The factor Xa inhibitors exhibit a higher margin of safety in contrast to the antithrombin agents, however, their anticoagulant effects are somewhat weaker than the antithrombin agents. Thus, these agents may prove to be very useful in the prophylactic management of both the thrombotic and cardiovascular disorders. However, their use as an anticoagulant may not be very practical. These agents can be given as adjunct agents with hirudin and related antithrombin agents. These agents may also be of value in the outpatient management of thrombotic disorders. These agents may also be of value as an adjunct to various other antithrombotic drugs. Additional adjunct uses as with the antithrombin drugs, GP llb/llla inhibitors, thrombolytic agents and TFPI may increase the therapeutic index of many of these agents. It should be emphasized that each of these individual anti-Xa agents represent distinct drugs which require individual specific dosage optimization.

In the Beaufortin crystalline group (Savoy, Northern French Alps), the authors have discovered several rectilinear scarps 1 to 5 meters high, which are up-hill facing scarps located at the foot of steep slopes. The detailed geomorphological analysis of two areas (La Légette du Grand Mont, 2366; Tête Rouge, 2219 m) allows to show the continuation of these scarps in fossil rock glaciers and several periglacial and glacial materials, as well as their coincidence with main structural trends (N 25° E to N 40° E). For these scarps, two hypothesis are discussed: the neotectonic one (fault reactivation) and the gravitational gliding of the rock mass in response to the last generalized glacier retreat. In spite of quantitative data concerning the present relative displacements of alpine ranges and earthquakes occurrence in a regional extent (in La Savoie), the first hypothesis cannot be selected for lack of doubtless argument. The second one is consistent with the local morphological context and with different models built for large-scale spreading of steep-sided rock mass., Résumé Dans le massif cristallin externe du Beaufortin (Savoie, Alpes françaises du Nord), les auteurs ont repéré plusieurs ensembles d'abrupts rectilignes de hauteur modeste (1 à 5 m), inscrits à contre-pente au pied des versants en pente forte. L'analyse géomorphologique détaillée des deux secteurs proches de la Légette du Grand Mont (2366 m) et de Tête Rouge (2219 m) permet de montrer la continuité de tels abrupts dans des modelés de glaciers rocheux fossiles, et au-delà, dans des matériaux périglaciaires et glaciaires variés, ainsi que la coïncidence de leur tracé avec des directions structurales majeures (N 25° E à N 40° E). Deux hypothèses relatives à l'origine de ces abrupts sont discutées : celle d'un rejeu de failles, et celle d'un fonctionnement gravitaire des massifs rocheux, consécutif à la dernière déglaciation généralisée. En dépit des mouvements actuels mesurés en divers massifs de Savoie et d'une activité sismique attestée à l'échelle régionale, l'absence d'argument décisif de terrain ne permet pas de conclure en faveur de l'hypothèse néotectonique. L'hypothèse gravitaire paraît plus compatible avec le contexte morphostructural local et s'appuie sur divers modèles d'affaissement des versants rocheux en pente forte., Jaurand Emmanuel, Kaiser Brigitte. Accidents cassants dans des glaciers rocheux du Beaufortin (Alpes françaises du Nord) : origine gravitaire ou néotectonique ?/Scarps in rock glaciers of Beaufortin (Northern French Alps): a gravity or neotectonic origin?. In: Géomorphologie : relief, processus, environnement, Décembre 1999, vol. 5, n°4. pp. 305-325.

Unfractionated as well as low-molecular-weight heparins (LMWH) are known to cause an increase in blood levels of tissue factor pathway inhibitor (TFPI). To study the effect of a newly developed supersulfated LMWH (IK-SSH, Iketon Farmaceutici) on TFPI concentrations in human plasma, the compound was injected into volunteers at doses of 0.14, 0.33 and 0.66 mg/kg intravenously or 0.33, 0.66 and 1.0 mg/kg subcutaneously. At certain known times blood was drawn and plasma levels of both total and free TFPI were measured using enzyme-linked immunosorbent assay methodology. Baseline plasma concentrations of TFPI were 72.2+/-3.1 ng/ml for total and 10.8+/-0.8 ng/ml for free TFPI. Intravenous or subcutaneous injection of IK-SSH led to a strong and long-lasting rise in TFPI levels which were increased more than 5-fold for total TFPI and more than 30-fold for free TFPI. Maximum TFPI levels were reached 5-10 min after intravenous and 60 min after subcutaneous administration. IK-SSH caused prolongation of ex-vivo clotting times in the APTT and Heptest assay, whereas thrombin time was not affected. Anticoagulant actions of IK-SSH showed a significant correlation to plasma concentrations of TFPI and they are thought to be based at least partially on the release of TFPI from vascular sites.

As the final enzyme in the activation of the coagulation system, the serine protease, thrombin, is believed to be an important target for the development of new anticoagulant/antithrombotic drugs. Direct thrombin inhibitors are either derived from natural sources, such as hirudin or are chemically synthesised, such as argatroban. The coupling of hirudin or parts of it with other entities leads to novel agents with different pharmacokinetic and pharmacodynamic characteristics, such as polyethylene glycol (PEG)-hirudin or the hirulogs. Due to the reversible or irreversible inactivation of the enzyme, thrombin inhibitors exert strong anticoagulant effects that can be measured in global clotting assays. Furthermore, these compounds inhibit thrombin-induced platelet reactions and influence other cellular, receptor-mediated actions of thrombin, e.g., on vascular cells. Directly acting thrombin inhibitors prevent blood clotting and are also capable of inhibiting clot-associated thrombin; however, they do not effectively block the further generation of the enzyme. Comprehensive experimental studies suggest that thrombin inhibitors may be effective drugs in a wide range of intravascular thrombus formation, also including the inhibition of vascular restenosis. Recent clinical trials revealed the effectiveness of direct thrombin inhibitors in various thrombotic and cardiovascular indications, but also a tendency to an increased risk of bleeding complications. At present, thrombin inhibitors are the most promising class of drugs for the initial therapy of patients with heparin-induced thrombocytopaenia (HIT) or the heparin-induced thrombocytopaenia and thrombosis syndrome (HITTS). They are also useful for the management of venous thrombosis and for acute ischaemic syndromes as well as for invasive procedures. However, with regard to the long-term outcome, a superiority of thrombin inhibitors over heparin has not yet been demonstrated. Several important issues, such as monitoring, pharmacological antagonism and drug interactions will also play an important role in the development of these new drugs. Further clinical trials are required to confirm the effectiveness of direct thrombin inhibitors in the prophylaxis and treatment of various thromboembolic and cardiovascular disorders.

The effect of activated protein C (APC) on agonist-induced platelet activation and on thrombin generation after intrinsic (IA) and extrinsic (EA) activation of the coagulation system was studied by flow cytometry and by measuring levels of prothrombin fragment F1+2. In platelet activation studies blood drawn from healthy volunteers was anticoagulated with 10 μg/ml APC and incubated at 37°C either with saline, recombinant tissue factor (r-TF), arachidonic acid (AA), ADP or collagen. At definite times aliquots were taken and processed for flow studies. Platelet activation was measured using fluorescent monoclonal antibodies to platelet surface receptors GPIIIa (CD-61) and P-selectin (CD-62). Flow cytometric analysis showed platelet activation after all agonists used. APC did not influence AA-, ADP- and collagen-induced platelet activation but completely inhibited activation of platelets induced by r-TF. The effect of APC on r-TF-mediated platelet activation was concentration-dependent in the range of 0.5 to 20 μg/ml showing an increase in CD-62 expression at lower concentrations. In citrated and APC-anticoagulated blood the generation of thrombin was studied after IA and EA. At 10 and 20 μg/ml APC effectively prevented blood clotting which rapidly occurred especially after EA. The amount of thrombin generated via the extrinsic pathway was reduced by APC whereas after IA F1+2 levels measured in the presence of APC were still strongly increased. These results indicate that small amounts of thrombin generated by r-TF are sufficient to activate platelets as well as blood coagulation. APC exerts strong concentration-dependent anticoagulant actions and effectively prevents activation of platelets. © 1997 Elsevier Science Ltd

The development of specific inhibitors of blood coagulation enzymes has led to a number of new anticoagulant/antithrombotic agents that could be useful for prophylaxis and/or treatment of thromboembolic disorders. Because thrombin is the central bioregulatory enzyme in hemostasis, blocking of the active site of the enzyme by a fast reaction with an inhibitor may effectively prevent intravascular coagulation as well as other important biological effects of thrombin. For the direct inactivation of thrombin, several classes of compounds have been developed and characterized in vitro and in vivo as potential antithrombotic agents including naturally occurring as well as synthetic thrombin inhibitors such as hirudin, hirulog, arginine (argatroban), and benzamidine (NAPAP) derivatives as well as tripeptide-type inhibitors (efegatran, D-Phe-Pro-Arg-CH2Cl, boroarginine derivatives). Experimental findings suggest that directly acting thrombin inhibitors may be effective in a wide range of arterial and venous thrombotic events. The important role of factor Xa in the coagulation cascade at the stage of the conversion of extrinsic and intrinsic pathways and the amplification of its procoagulant action by prothrombinase complex formation makes factor Xa a promising target also for antithrombotic drugs. Experimental studies on highly effective and selective factor Xa inhibitors (antistasin, tick anticoagulant peptide, yagin, DX-9065a) showed that inhibition of coagulation at a relatively early stage is a very effective way for the prevention of thrombotic processes. Furthermore, it is assumed that factor Xa inhibitors selectively inhibit thrombus formation without compromising hemostasis. In conclusion, both thrombin and factor Xa inhibitors are promising drugs for the management of thrombotic disorders. However, besides the strong inhibitory potency against the target enzyme, other pharmacological aspects such as pharmacodynamics, pharmacokinetics, and toxic side effects must be included in the evaluation of the potential usefulness of thrombin and factor Xa inhibitors for clinical indications. Key Words: Anticoagulants—Antithrombotics—Factor Xa inhibitors—Thrombin inhibitors.

In an in vitro study the effect of various thrombin inhibitors (argatroban, efegatran, DuP 714, recombinant hirudin and PEG-hirudin) on platelet activation in whole blood was investigated. Blood was drawn from normal human volunteers using the double syringe technique without use of a tourniquet to avoid autoaggregation of platelets. Blood was anticoagulated with either argatroban, efegatran, DuP 714, hirudin or PEG-hirudin at final concentrations of 10 micrograms/ml. Blood samples were then incubated at 37 degrees C either with saline, r-tissue factor, arachidonic acid, adenosine diphosphate or collagen. At definite times (1, 2.5, 5, 10 min) aliquots were taken and after various steps of fixative procedure the percentage of platelet activation was measured using fluorescent monoclonal antibodies to platelet surface receptors GPIIIa (CD-61) and P-selectin (CD-62). Flow cytometric analysis showed a platelet activation after all agonists used. All thrombin inhibitors studied caused a nearly complete inhibition of r-tissue factor-mediated platelet activation. In contrast, after activation with the other agonists an increased percent CD-62 expression was found with a maximum after 2.5 to 5 min. The results show that in whole blood thrombin inhibitors are effective in preventing platelet activation induced by r-tissue factor. The formation of active serine proteases including thrombin may be effectively inhibited by these agents. The observations further suggest that while thrombin inhibitors may control serine proteases, these agents do not inhibit the activation of platelets mediated by other agonists.

Using a fast kinetic centrifugal analyzer, the inhibitory effects of glycosylated and unglycosylated full-length and truncated forms of TFPI on protease generation were studied in fibrinogen-deficient human plasma after extrinsic (EA) or intrinsic (IA) activation of coagulation. When the assay system was supplemented with increasing amounts of the TFPI variants the generation of both thrombin and factor Xa was inhibited in a concentration-dependent manner. Clear differences in the effectiveness of the TFPI variants were found. After EA, the unglycosylated full-length TFPI was most effective followed by the glycosylated full-length form. The C-terminal truncated TFPI showed the lowest inhibitory activity in this system. However, its efficiency increased several fold when coagulation was activated via the intrinsic pathway. Comparing the IC50 values after IA, the truncated TFPI was more effective than the unglycosylated full-length form and nearly as effective as the glycosylated full-length TFPI. After both EA and IA the thrombin generation inhibition by TFPI variants was more pronounced than the inhibition of factor Xa generation. The results show that chemical modifications of the TFPI structure can result in changes of TFPI's inhibitory properties to activated clotting factors leading to differences in protease generation inhibition.

Les MNT à très haute résolution spatiale sont désormais accessibles pour des secteurs fortement disséqués comme les badlands. Ces représentations numériques de l’altimétrie sous une forme spatialisée sont porteuses d’utilisations multiples et nouvelles pour la connaissance, le suivi et la modélisation des zones érodées. Nous explorons ici des MNT à très haute résolution spatiale, c’est à dire avec des résolutions de quelques centimètres à quelques mètres et avec des qualités de restitution en Z (altitude) meilleures que le mètre. Après une brève présentation des techniques d’acquisition de ces MNT à partir d’images stéréoscopiques ou du Lidar et des précisions qui leur sont associées, on rappelle quelles sont les transformées de l’altitude utiles pour la morphologie. Afin de montrer quelques-unes des possibilités qu’ouvrent ces nouvelles données, diverses applications, menées sur les petits bassins versants marneux de l’Observatoire de Recherche et d’Expérimentation de Draix (Alpes, France), sont détaillées. Elles ont trait, d’abord, à l’extraction du réseau des talwegs à partir de MNT à 2 m (et de MNT dégradés à 4, 8, 20 mètres) et au calcul de sa dimension fractale pour les résolutions à 2 m et 8 m ; puis au repérage automatique de ravines sur critères morphologiques simples afin d’aider à la localisation d’aménagements anti-érosifs. On montre enfin les potentialités des topographies précises par Lidar terrestre pour repérer d’étroites rigoles, suivre leur évolution, ou établir des bilans d’érosion sur versant alors qu’une précision d’ordre centimétrique est requise. Very high resolution DEMs are now available in highly dissected areas such as badlands. These spatial digital elevation data offer new means for erosion processes knowledge, for monitoring and for modeling eroded landforms. We intend here to present DEMs with “Very High Spatial Resolution” i.e. with pixel size of about one meter or less and a Z accuracy better than one meter. The capabilities of these new data acquisition techniques can stimulate new developments in geomorphologic research. After a short description of different techniques of DEMs generation from stereo images and LiDAR with their related accuracy, we recall some of the different mathematical transforms of elevation that represent useful parameters in geomorphology. In order to expose some of the capabilities of these new data, we present several case studies conducted in the marly watersheds of the Draix Research Environmental Observatory (ORE), part of the French Alps. These case studies concern the thalweg network extraction and its complexity analysis using DEM at 2 meters resolution (and others at 4, 8 and 20 meters resolution). The paper also deals with the automatic extraction of gullies according to a series of morphologic criteria, which can be useful for the management of projects for reducing erosion. Finally, Terrestrial Laser Scanning proves to be extremely valuable when high accuracy topographic measurements are needed for identifying rill network initiation and evolution on elementary slopes and for erosion balance assessment.

The generation of thrombin in citrated, r-hirudinized and heparinized whole blood (final concentrations 10, 25, 50 μg/ml) was studied in the presence or absence of various activators. Whole blood from healthy volunteers was activated either by glass or dextran sulfate (contact activation; CA) as well as by thromboplastin/calcium chloride (extrinsic activation; EA) and by ellagic acid/cephaloplastin/calcium chloride (intrinsic activation; IA) and incubated 10 (CA, EA, IA) and 30 (CA) min at 37 °C. After the incubation period plasma levels of prothrombin fragment 1+2 (F1+2) and thrombin-antithrombin III complex (TAT) were measured utilizing ELISA methodology. After EA or IA no blood clotting occurred in all r-hirudinized samples and in heparinized blood at the highest concentration used. Despite inhibition of clotting F1+2 levels were increased both in r-hirudinized and in heparinized blood. However, in blood anticoagulated with heparin F1+2 levels after EA, IA and especially after CA were markedly lower than in r-hirudinized blood. Furthermore, in r-hirudinized blood an increase of TAT levels was found. The enhancement of F1+2 and TAT levels by r-hirudin was concentration-dependent and was lower in the higher r-hirudin concentration. The results indicate that in r-hirudinized whole blood significant amounts of thrombin can be generated which may elicit thrombin-mediated feedback mechanisms.

ZusammenfassungDie vorliegende Arbeit gibt einen Überblick über den gegenwärtigen Kenntnisstand zum pharmakokinetischen Verhalten sowie zur antikoagulatorischen und antithrombotischen Wirksamkeit von rekombinantem Hirudin.Tierexperimentelle sowie erste klinisch-pharmakologische Studien zeigten, daß dieser Wirkstoff mit einer biologischen Halbwertszeit von etwa 1 h eliminiert wird, wobei die renale Exkretion von Hirudin in aktiver Form der vorherrschende Weg ist. Entsprechend seiner hohen inhibitorischen Aktivität und Spezifität gegenüber Thrombin ruft Hirudin konzentrationsabhängige antikoagulatorische Wirkungen hervor, die sich mit Hilfe gebräuchlicher Gerinnungstests (Thrombinzeit, aktivierte partielle Thromboplastinzeit, Thromboplastinzeit) nachweisen lassen. Die ausgezeichnete antithrombotische Wirksamkeit des Thrombinhemmstoffs wurde in verschiedenen tierexperimentellen Thrombosemodellen dargestellt. Hirudin verhindert bereits in sehr niedrigen Dosierungen die Bildung venöser Thromben sowie eine Mikrothrombosierung der Lunge. In höheren Dosen ist der Wirkstoff ebenfalls bei arteriellen Thrombosen oder Thrombosierungen an artefiziellen Oberflächen sowie bei der Verhinderung einer arteriellen Reokklusion nach Angioplastie oder Thrombolyse wirksam.Aus den dargelegten Untersuchungen wird die Schlußfolgerung gezogen, daß dieser hochwirksame Thrombininhibitor Bedeutung zur Prophylaxe und Therapie verschiedener thromboembolischer Erkrankungen erlangen könnte.

Museumsfachleute beobachten die zunehmende Bedeutung von publikumsorientierten Ausstellungen kritisch. Sie befürchten, dass der Bildungsauftrag zu Gunsten von Oberflächenreizen aufgegeben wird. Die Studie blickt einerseits kritisch-diagnostisch auf die gegenwärtige Ausstellungskultur. Besucherorientierte Konzepte mit narrativen, künstlerischen sowie partizipativen Ansätzen werden vorgestellt und diskutiert. Darüber hinaus thematisiert das Buch mit einer praktisch-produktiven Intention kommunikative Dimensionen musealer Präsentationen. Eine exemplarische Ausstellungsanalyse konkretisiert die theoretischen Überlegungen in der Praxis.

The Kunitz-type proteinase inhibitor, tissue factor pathway inhibitor (TFPI), is the only endogenous inhibitor of the tissue factor (TF)-mediated coagulation pathway that plays a dominant role in normal haemostasis. TFPI exerts its action by binding to factor Xa (FXa) forming a TFPI-FXa complex that then, in a second step, binds and effectively inhibits the TF-factor VIIa (FVIIa) complex. Both full-length TFPI and chemically modified forms (e.g., truncated, glycosylated or phosphorylated TFPI variants) exert various pharmacological effects. The anticoagulant and antiplatelet actions of TFPI, its potency in inhibiting thrombin and FXa generation, as well as its favourable antithrombotic effectiveness seen in different animal models of venous and arterial thrombosis make this inhibitor a promising agent that could be potentially useful in several clinical indications. The inhibitory action of TFPI is accelerated by heparin. Heparin, as well as low molecular weight heparin (LMWH) derivatives, release TFPI from the vascular endothelium, an effect which seems to contribute mainly to the antithrombotic effectiveness of these drugs. The clinical relevance of TFPI is still undefined. Based on the beneficial actions in animal studies, as well as on the results obtained in first clinical investigations, TFPI is expected to be effective in the treatment of various diseases, such as disseminated intravascular coagulation, sepsis, coronary syndromes, stroke and acute respiratory distress syndrome (ARD). Further clinical trials should clarify the role of TFPI and more importantly define its potential usefulness as a prophylactic and/or therapeutic agent.

Activation of the 5-lipoxygenase (5-LO) pathway leads to the biosynthesis of proinflammatory leukotriene lipid mediators. Genetic studies have associated 5-LO and its accessory protein, 5-LO-activating protein, with cardiovascular disease, myocardial infarction and stroke. Here we show that 5-LO-positive macrophages localize to the adventitia of diseased mouse and human arteries in areas of neoangiogenesis and that these cells constitute a main component of aortic aneurysms induced by an atherogenic diet containing cholate in mice deficient in apolipoprotein E. 5-LO deficiency markedly attenuates the formation of these aneurysms and is associated with reduced matrix metalloproteinase-2 activity and diminished plasma macrophage inflammatory protein-1alpha (MIP-1alpha; also called CCL3), but only minimally affects the formation of lipid-rich lesions. The leukotriene LTD(4) strongly stimulates expression of MIP-1alpha in macrophages and MIP-2 (also called CXCL2) in endothelial cells. These data link the 5-LO pathway to hyperlipidemia-dependent inflammation of the arterial wall and to pathogenesis of aortic aneurysms through a potential chemokine intermediary route.

DX-9065a is a Factor Xa inhibitor under development by Daiichi as an anticoagulant for the potential treatment of cardiovascular indications, including thrombosis and angina. By March 1996, DX-9065a had entered phase I trials in Japan and Europe, and by November 1998, it was in phase II trials in Japan. In February 2003, phase II trials for the prevention of myocardial infarction in patients with unstable angina pectoris were ongoing in Japan, Europe and the US.