bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ser968Thr Mutation within the A3 Domain of Von Willebrand Factor (VWF) in Two Related Patients Leads to a Defective Binding of VWF to Collagen
Authors: Lavergne Jean-Maurice , Juhan-Vague Irène , Obert Bernadette , Cherel Ghislaine , Meyer Dominique , Girma Jean-Pierre , Ribba Anne-Sophie , Loisel Irmine 
Published: March 2018

SummaryWe report the identification of a new mutation of von Willebrand Factor (VWF) gene within exon 30 occurring in two related patients (mother and daughter) with a hemorrhagic syndrome. A T A transvertion at nucleotide 5441 was found changing the serine 968 to threonine of the mature VWF subunit (S1731T of the preproVWF). The Ser968Thr mutation is located within the VWF A3 domain which interacts with type I and III collagens. Both patients were found to be heterozygous for the mutation. The propositus (daughter) exhibited a slightly prolonged bleeding time, levels of VWF:Ag and VWF:RCo at the lower limit of normal, contrasting with normal levels of VIII:C. Her mother exhibited borderline bleeding time and moderately decreased levels of VWF and VIII:C. In both patients multimeric structure of VWF and ristocetin- as well as botrocetin-induced binding of VWF to GPIb were normal; however both patients repeatedly showed decreased binding of VWF to collagen. The Ser968Thr substitution was reproduced by site-directed mutagenesis on the full-length cDNA of VWF. The mutated recombinant VWF (rVWF), T968rVWF, and the hybrid S/T968rVWF were transiently expressed by COS-7 cells. Both rVWF exhibited normal multimeric pattern and normal ristocetin- as well as botrocetin-induced binding to GPIb. T968rVWF showed significantly decreased binding to collagen while the hybrid S/T968rVWF bound to collagen in a similar way to that of the patients’ plasma VWF. Thus, our data demonstrate that the Ser968Thr mutation of the VWF A3 domain is clearly responsible for the abnormal binding of VWF to collagen observed in both patients. The Ser968Thr substitution of the VWF is the first mutation identified in two patients leading to a decreased affinity of VWF for collagen and a normal multimeric structure.
A Barbourin-albumin Fusion Protein that Is Slowly Cleared In Vivo Retains the Ability to Inhibit Platelet Aggregation In Vitro
Authors: Marques Janey , George Jacob , Smith Ian , Bhakta Varsha , Sheffield William 
Published: March 2018

SummaryBarbourin is a 73 amino acid venom protein that inhibits platelet aggregation. Recombinant barbourin (BARH6), rabbit serum albumin (RSAH6), and a barbourin-RSA fusion protein (barbourin-linker-albumin; BLAH6) were secreted from Pichia pastoris yeast, and purified by nickel-chelate affinity chromatography via their C-terminal hexahisti-dine (H6) tags. BARH6 and BLAH6 did not differ in their IC50s for inhibition of platelet aggregation using either human platelets stimulated with thrombin or ADP, or rabbit platelets stimulated with ADP. BARH6 and BLAH6 were also effective in inhibiting platelet aggregation in whole blood, and formed complexes with platelet integrin αIIbβ3. The terminal catabolic half-life of BLAH6 approached that of RSAH6[3.4 ± 0.2 versus 4.0 ± 0.1 days (n = 4 ± SD)], but was substantially increased relative to that of BARH6 [0.15 ± 0.03 days (n = 3 ± SD)]. Our results suggest that fusion to albumin slows the clearance of barbourin in vivo, while preserving its ability to inhibit platelet aggregation.
Adenovirus-mediated Expression of a Truncated PDGFβ Receptor Inhibits Thrombosis and Neointima Formation in an Avian Arterial Injury Model
Authors: Ding Hongliu , Wang Rongqing , Marcel Robin , Fisher Daniel 
Published: March 2018

SummaryPlatelet-derived growth factor (PDGF) is a major mediator of neointima formation after arterial injury. We constructed a recombinant adenovirus, Ad/PDGFtr, that expresses the soluble extracellular domain of the murine PDGFβ receptor (PDGFtr). The expressed PDGFtr was appropriately glycosylated and secreted by chicken vascular smooth muscle cells (SMCs) in vitro. The expressed PDGFtr inhibited human PDGF-BB induced receptor autophosphorylation, and also inhibited PDGF-BB induced cell proliferation without affecting PDGF-AA induced mitogenesis. In vivo transduction of balloon-injured rooster femoral arteries with Ad/PDGFtr resulted in expression and secretion of the glycosylated PDGFtr. The expressed PDGFtr significantly inhibited neointima formation compared with controls. Neointima-associated thrombus was significantly reduced in Ad/PDGFtr transduced arteries compared with controls. Thus, in addition to impacting on SMC proliferation and migration, PDGF-BB plays a role in thrombus formation in response to arterial injury. Growth factor inhibition by localized gene delivery constitutes a powerful approach to intervene in the molecular pathways involved in vascular disease.
Temperamentskonzepte in der Psychopathologie
Authors: Jäger M. 
Published: March 2018

ZusammenfassungDie Temperamentsforschung hat in der Psychopathologie eine lange Tradition. Hier sind beispielsweise die Beiträge von Ernst Kretschmer und Gottfried Ewald zu nennen, welche beide fließende Übergänge zwischen Temperaments- bzw. Persönlichkeitseigenschaften und manifesten psychischen Erkrankungen beschreiben. Allerdings wird von Kretschmer der Temperamentsbegriff deutlich weiter gefasst als dies bei Ewald der Fall ist. Karl Leonhard führte die Konzepte seines Lehrers Ewald weiter aus und bemühte sich, die Zusammenhänge zwischen akzentuierten Temperamentszügen, Persönlichkeitsstörungen und affektiven Psychosen weiter herauszuarbeiten. Demgegenüber konnte beispielsweise Kurt Schneider keine solchen Beziehungen bzw. Übergänge finden. Die hier diskutierten Fragen haben heute nicht an Aktualität verloren und sollten weiterhin Gegenstand empirischer Forschung sein. Hierzu stehen inzwischen standardisierte Instrumente zur Verfügung wie beispielsweise die von Hagop Akiskal entwickelte TEMPS-Skala.
Die klinische Relevanz von Temperament
Authors: Brieger P. 
Published: March 2018

ZusammenfassungNach Akiskal gibt es fünf Temperamente: hyperthym, zyklothym, reizbar, depressiv und ängstlich. Mittels TEMPS-A-Skala können diese bestimmt werden. Anhand eines Fallbeispiels wird die Komplexität dieses Ansatzes dargestellt. Methodische Grenzen dieses Temperamentsbegriffs werden erklärt sowie Ergebnisse aus Genetik, Verlaufsforschung und Forschung zu Komorbidität, die das Konzept unterstützen. Temperament hilft, affektive Störungen besser zu verstehen.
Stellenwert der Disulfiramtherapie heute?
Authors: Grosshans M. , Mutschler J. 
Published: March 2018

ZusammenfassungDisulfiram nimmt in der Suchtmedizin eine besondere, oftmals kontroverse, Rolle ein. Das Medikament ist inzwischen über 60 Jahre für die Behandlung der Alkoholabhängigkeit in vielen Ländern zugelassen. Seit 2011 ist Disulfiram in Deutschland formal allerdings nicht mehr zugelassen, kann aber weiterhin als „Off-lable“-Medikament eingesetzt und über Auslandsapotheken bezogen werden. Dieser Umstand und eine mögliche Ausweitung der Einsatzgebiete machen neben dem Wissen um die therapeutischen Effekte auch fundierte Kenntnisse um Wirkung, Wechselwirkungen, Kontraindikationen und Nebenwirkungen von Disulfiram erforderlich. In der folgenden Übersicht soll eine aktuelle Überblick gegeben werden.
The Pleiotropic Effects of Tissue Factor: a Possible Role for Factor VIIa-induced Intracellular Signalling?
Authors: Peppelenbosch Maikel , Spek Arnold , Versteeg Henri 
Published: March 2018

SummaryTissue factor, a 47 kDa membrane glycoprotein, lies at the basis of the extrinsic pathway of the coagulation cascade. Interaction of TF with factor VIIa results in the formation of fibrin from fibrinogen, thereby inducing the formation of a blood clot. In addition to this well-established role in blood coagulation, TF is associated with various other physiological processes such as sepsis, inflammation, angiogenesis, metastasis and atherosclerosis. The molecular basis of the latter events is slowly emerging. It has become clear that TF-FVIIa interaction elicits a variety of intracellular signalling events that may be implicated in these actions. These events include the sequential activation of Src-like kinases, MAP kinases, small GTPases and calcium signalling. How this progress in the understanding of TF associated signal transduction may generate answers as to the mechanism through which TF exerts it pleiotropic effects will be focus of this review.
Thromboprophylaxis following Caesarean Section
Authors: Thomson A. J. , Conkie J. A. , McCall F. , Walker I. D. , Greer I. A. , Ellison J. 
Published: March 2018

SummaryPharmacological thromboprophylaxis is increasingly being used after caesarean section to prevent venous thromboembolism. Although a variety of low molecular weight heparins (LMWH) have been used no comparative study exists on their effects on the haemostatic system in this situation. Furthermore, their antithrombotic effect may be mediated through effects other than their inhibitory effect on activated factor X. We compared the plasma anti-factor Xa activity, plasma concentration of tissue factor pathway inhibitor (TFPI) and the reduction in plasma thrombin-antithrombin (TAT) complex concentration in 30 women randomised to receive either dalteparin 5,000 IU anti-Xa once daily (n = 10), enoxaparin 4,000 IU anti-Xa once daily (n = 10) or tinzaparin 50 IU/kg anti-Xa (average dose 3,650 anti-Xa units) once daily (n = 10) following caesarean section. Sampling occurred at 0, 1, 3, 6, 12 and 24 h relative to time of dosing. All preparations produced an increase in mean anti-Xa assay (p <0.0001), a reduction in mean TAT (p <0.05) and an increase in mean TFPI concentration (p <0.05). Analysis of variance (ANOVA) revealed a significant difference between the LMWHs in terms of mean anti-factor Xa activity (p <0.005) and reduction in plasma TAT concentration (p <0.005). Post hoc analysis indicated that the anti-Xa values of the groups receiving enoxaparin and dalteparin were significantly higher than those of the group receiving tinzaparin (p <0.05), but not significantly different from each other. Post hoc analysis of the reduction in plasma TAT concentration showed the reduction to be significantly less in the group receiving enoxaparin compared to the dalteparin and tinzaparin groups (p <0.05), which did not differ significantly from each other. There was no significant difference between treatment groups with regard to plasma concentration of TFPI. These findings demonstrate that LMWHs differ in their effects on haemostatic parameters including thrombin generation as assessed by TAT. The increase in TFPI may be an additional mediator of LMWH’s antithrombotic effects. Although these findings demonstrate that LMWHs differ in their haemostatic effects, this does not necessarily infer a clinical difference between these agents.
Identification and Characterization of Two Novel Mutations (Q421K and R123P) in Congenital Factor XII Deficiency
Authors: Kanaji Sachiko , Osaki Koichi , Kuroiwa Mika , Sakaguchi Masao , Mihara Katsuyoshi , Niho Yoshiyuki , Okamura Takashi , Kanaji Taisuke 
Published: March 2018

SummaryThe factor XII genes of two unrelated factor XII-deficient Japanese families were screened, and two novel mutations were identified. A heterozygous mutation (Q421K) was identified in the gene of a cross-reacting material (CRM)-negative patient with reduced FXII activity (entitled Case 1). No mutations were discovered in the other allele. Case 2 was a CRM-negative patient with severe FXII deficiency. In this case, a homozygous mutation (R123P) was discerned. Expression studies in Chinese Hamster Ovary (CHO) cells demonstrated accumulation of mutant Q421K factor XII in the cell, and insufficient secretion, while the R123P mutant showed lower levels of accumulation than wild-type, and no evidence of secretion in culture supernatant. In the presence of proteasome inhibitor, all types of FXII (wild-type, Q421K, R123P) accumulated in the cells. Protease protection experiments using the microsomal fraction of these cell lines demonstrated that while 20% wild-type FXII (total wild-type:100%) and 10% R123P mutant (total R123P-type: 40%) were resistant to treatment with trypsin, 50% Q421K-type FXII (total Q421K-type:130%) remained resistant to digestion. From these results, we conclude that Q421K is less susceptible to proteasome degradation than wild-type, but is unable to exit the ER efficiently, resulting in insufficient secretion phenotype. In contrast, R123P is susceptible to proteasome degradation and is not secreted.
Localization of Blood Coagulation Factors In Situ in Pancreatic Carcinoma
Authors: Rucinska Monika , Zacharski Leo , Kozlowski Leszek , Zimnoch Lech , Piotrowski Zdzislaw , Kudryk Bohdan , Kisiel Walter , Wojtukiewicz Marek 
Published: March 2018

SummaryBlood coagulation is activated commonly in pancreatic carcinoma but the role of the tumor cell in this activation is undefined. Immunohistochemical procedures were applied to fixed sections of 22 cases of resected adenocarcinoma of the pancreas to determine the presence of components of coagulation and fibrinolysis pathways in situ. Tumor cell bodies stained for tissue factor; prothrombin; and factors VII, VIIIc, IX, X, XII, and subunit “a” of factor XIII. Fibrinogen existed throughout the tumor stroma, and tumor cells were surrounded by fibrin. Staining for tissue factor pathway inhibitor, and plasminogen activators was minimal and inconsistent. Plasminogen activator inhibitors -1, -2, and -3 were present in the tumor stroma, and on tumor cells and vascular endothelium. Extravascular coagulation activation exists associated with pancreatic carcinoma cells in situ that is apparently unopposed by naturally occurring inhibitors or the plasminogen activator-plasmin system. We postulate that such local coagulation activation may regulate growth of this malignancy. These findings provide a rationale for testing agents that modulate the blood coagulation/fibrinolytic system (that inhibit tumor growth in other settings) in pancreatic carcinoma.
Hepatic Thrombopoietin mRNA Is Increased in Acute Inflammation
Authors: Fandrey Joachim , Frackowski Urszula , Jelkmann Wolfgang , Wolber Eva-Maria 
Published: March 2018

SummaryThe plasma concentration of thrombopoietin (TPO) in general is inversely related to the mass of platelets and megakaryocytes. However, reactive thrombocytosis of inflammatory disease is accompanied by elevated TPO levels. To investigate whether the rate of TPO mRNA expression is altered during acute inflammation, rats were injected with bacterial lipopolysaccharide (LPS). After 6 h, total RNA from liver and kidney was reverse transcribed and analyzed by competitive PCR for TPO and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). LPS-treated rats showed a significant increase in hepatic TPO mRNA concentration. The ratio of TPO to GAPDH mRNA was 3.5 ± 0.6% in the livers of control rats and 8.3 ± 2.0% in the livers of LPS-treated rats (mean ± SD). Thus, reactive thrombocytosis of inflammatory disease might result from an increase in hepatic TPO production. Since platelets are involved in the immune reaction, reactive thrombocytosis may be a mechanism of host defense.
Identification of Critical Residues on Thrombin Mediating Its Interaction with Fibrin
Authors: Hall Scott , Gibbs Craig , Leung Lawrence 
Published: March 2018

SummaryThrombin binding to fibrin may be important in localizing thrombin to the site of vascular injury. However, fibrin-bound thrombin retains its catalytic activity toward fibrinogen, and may be prothrombotic under certain conditions. A collection of 52 purified thrombin mutants was used to identify those residues mediating the thrombin-fibrin interaction. Comparison of fibrinogen clotting activity with fibrin binding activity identified twenty residues involved in fibrinogen recognition with four of these residues important in fibrin binding (Lys65, His66, Tyr71, Arg73). No mutant was identified with normal clotting activity and deficient fibrin binding, suggesting that these two properties are not readily dissociable. A DNA thrombin aptamer that binds to these residues was able to inhibit the thrombin-fibrin interaction, and displace thrombin that was already bound. Mapping of these fibrin-binding residues on thrombin revealed that they are localized within exosite I, and comprise a subset of the residues important in fibrinogen recognition.
Comparison of the Responses of Global Tests of Coagulation with Molecular Markers of Neutrophil, Endothelial, and Hemostatic System Perturbation in the Baboon Model of E. coli Sepsis
Authors: Wada Hideo , Yamamuro Miho , Inoue Akiko , Shiku Hiroshi , Sakuragawa Nobuo , Redl Heinz , Peer Glenn , Taylor Fletcher 
Published: March 2018

SummaryThis study correlates changes in neutrophilic activity and endothelial injury with markers of hemostatic activity following the infusion of increasing concentrations of E. coli organisms. It focuses on the hemostatic response as a marker of microvascular injury and uses the response to increasing concentrations of E. coli to refine our definition of disseminated intravascular coagulation (DIC) and distinguish between a compensated (non-overt DIC) and uncompensated (overt DIC) response. We observed that the global coagulation tests reflected activation of the hemostatic system in a dose dependent manner (overt DIC) in the early phases (T+2 to 6 h) of the response to increasing concentrations of E. coli, but that they failed to do so in the late phases (T+ 24 to 48 h). We observed that molecular markers, soluble thrombomodulin and elastase, unlike thrombin/antithrombin and plasmin/antiplasmin complexes, remained elevated out to T+24 to 48 h indicating endothelial injury that persists beyond the initial inflammatory insult in compensated as well as uncompensated DIC.
A Novel Function of Extraerythrocytic Hemoglobin
Authors: Ohmura Sayuri , Sugiki Masahiko , Anai Keita , Maruyama Masugi , Yoshida Etsuo 
Published: March 2018

SummaryFollowing wounding, the surrounding fibroblasts migrate towards the clotted blood in the wounded space to form granulation tissue resulting in wound repair. One of the most abundant proteins in the wound is hemoglobin (Hb). The aim of the present study was to examine the effect of Hb on fibroblasts in producing components of the plasminogen-plasmin system which play an important role in wound healing. Human Hb Ao added to cultures of human fibroblasts elicited a dose-dependent increase in fibrinolytic activity. ELISA demonstrated an increased fibrinolytic activity due to increased urokinase-type plasminogen activator (uPA). An increase in tissue-type PA was also detected, while the type-1 PA inhibitor level remained unaffected. Globin showed a similar effect, while hemin and protoporphyrin IX exerted no effect. The influence of Hb was quenched when haptoglobin was added. Although northern blot analysis revealed no difference in uPA transcripts between stimulated and non-stimulated cells, immunopretipitation experiments confirmed an increased uPA synthesis in Hb- and globin-treated cells, suggesting that enhanced expression is achieved through translational regulation. These findings suggest a potential role for globin in modulating cellular functions during the process of wound healing.
Inactivation of Plasminogen Activator Inhibitor-1 Accelerates Thrombolysis of a Platelet-rich Thrombus in Rat Mesenteric Arterioles
Authors: Rupin Alain , Martin Frédéric , Vallez Marie-Odile , Bonhomme Edith , Verbeuren Tony 
Published: March 2018

SummaryTo investigate the role of active plasminogen activator inhibitor 1 (PAI-1) in the evolution of a microthrombus generated in the arteriolar microcirculation, the monoclonal antibody, 33H1F7, which transforms active PAI-1 to a tissue type plasminogen activator (t-PA) substrate, was evaluated in an arteriolar thrombosis model in the rat mesentery. Arterioles (200-300 μm) were stimulated electrically to create an endothelial lesion; ADP was then perfused for 2 min to induce the formation of a platelet-rich thrombus which lysed spontaneously in 140 ± 24 s. Two successive ADP superfusions produced comparable thrombi which lysed in comparable times. Different doses of 33H1F7 were infused to rats for 30 min and the dose which inactivates rapidly and totally active rat PAI-1 (300 μg/kg/min) was selected to be tested on the thrombosis model. Infusion of 33H1F7 beginning 10 min before the ADP application significantly reduced the lysis time in comparison to the control (123 ± 30 s versus 169 ± 33 s, P < 0.05, paired Student’s t-test) and the cumulative thrombus area during the lysis period was decreased by 56 ± 7%. These results demonstrate that inactivation of PAI-1 is able to accelerate lysis of a platelet-rich clot in a mesenteric arteriole of the rat. Thus active PAI-1 most likely participates to the resistance to thrombolysis in the arteriolar microcirculation and its inactivation may shorten ischemic periods after microvascular obstruction such as e.g. during cerebral stroke.
Lokale rt-PA-Lyse bei Paget-von-Schroetter-Syndrom
Authors: Hebgen A. , Daum K. H. , Fervers J. , Ludwig N. 
Published: March 2018

ZusammenfassungEine 39jährige, bislang gesunde Patientin stellte sich mit einer 2 Tage alten lividen und schmerzhaften Schwellung des rechten Armes im Sinne eines Paget-von-Schroetter-Syndroms vor. Nach duplexsonographischer und phlebographischer Diagnosebestätigung führten wir in Anbetracht der ausgeprägten klinischen Symptomatik eine lokale Lysetherapie mit insgesamt 30 mg rt-PA durch und konnten eine vollständige Rekanalisation der Vena axillaris und Vena subclavia erreichen.
Akuttherapie des Schlaganfalls
Authors: Eschenfelder Ch. C. , Zeller J. , Stingele R. 
Published: March 2018

ZusammenfassungDie aktuellen Konzepte zur Behandlung der akuten zerebralen Ischämie sowie der Hirnblutung werden dargestellt. Die Indikationsstellung zur Thrombolyse im Standardfall und in besonderen Situationen, die Anwendung moderner MRT-Diagnostik und differenzialtherapeutische Überlegungen werden dargelegt. Bei der Therapie der Hirnblutung wird auf die Indikationsstellung zur neurochirurgischen Hämatomevakuation eingegangen und die akute hämostatische Therapie besprochen.
Direkte Thrombininhibition in der interventionellen Kardiologie
Authors: Heinze H. , Darius H. 
Published: March 2018

ZusammenfassungDer direkte Thrombininhibitor Bivalirudin wurde im Rahmen der ACUITY-Studie bei 13 819 Patienten mit akutem Nicht-ST-Elevations-Koronarsyndrom prospektiv randomisiert untersucht. Dabei wurden drei antithrombotische Therapieregime im Rahmen eines frühinvasiven Vorgehens verglichen: Heparin plus Glykoprotein-IIb/IIIaRezerptorinhibitor (GPI), Bivalirudin plus GPI und Bivalirudin als Montherapie. Bezogen auf den Endpunkt der ischämischen Ereignisse war Bivalirudin allein vergleichbar mit Heparin plus GPI bei signifikant verringerter Rate von Blutungskomplikationen.