bluuebunny/crossref_metadata_2025_split huggingface dataset:
Risk of Pregnancy-related Venous Thrombosis in Carriers of Severe Inherited Thrombophilia
Authors: Legnani Cristina , Bucciarelli Paolo , Grandone Elvira , De Stefano Valerio , Mannucci Pier Mannuccio , Martinelli Ida 
Published: March 2018

SummaryHomozygous carriers of factor V Leiden have an approximately 80-fold increased risk of venous thrombosis. Also double heterozygous carriers of both the factor V Leiden and the prothrombin gene mutations are at high thrombotic risk. The magnitude of the risk of venous thrombosis in pregnant women with the two severe thrombophilic conditions has not been estimated so far. We performed a multicenter retrospective family study in women with homozygous factor V Leiden, double heterozygous factor V Leiden and the prothrombin gene mutation, and women with normal coagulation. Only relatives of index patients with thrombosis formed the study cohort. Fifteen homozygous and 39 double heterozygous women were compared to 182 women with normal coagulation. Venous thrombosis occurred in 3 of 19, 2 of 50 and 1 of 221 pregnancies, respectively. One thrombotic episode occurred in the third trimester, the remaining 5 in the postpartum. The prevalence of venous thrombosis was 15.8% (95% CI 3.4-39.6) for homozygotes, 4.0% (95% CI 0.5-13.7) for double heterozygotes and 0.5% for women with normal coagulation. The relative risk of pregnancy-related venous thrombosis was 41.3 (95% CI 4.1-419.7) for homozygous and 9.2 (95% CI 0.8-103.2) for double heterozygous carriers. In conclusion, homozygous carriers of factor V Leiden and, to a lesser extent, double heterozygous carriers of factor V Leiden and of the prothrombin mutation have an increased risk of venous thrombosis during pregnancy, particularly high during the postpartum period. On the basis of these findings we recommend that these women receive anticoagulant prophylaxis at least in the postpartum, that should perhaps be extended to the whole pregnancy in homozygous carriers.
Assembly of High Molecular Weight Kininogen and Activation of Prekallikrein on Cell Matrix
Authors: Shariat-Madar Z. , Mahdi F. , Sampaio C. A. M. , Schmaier A. H. , Motta G. 
Published: March 2018

SummaryInvestigations determined if extracellular matrix of endothelial cells (EC) is a platform for HK assembly and PK activation. In buffers containing bovine serum albumin, biotin-HK binding to ECV304 cells or their matrix requires ≥ 50 µM added Zn 2+. Ortho-phenanthroline or a HK domain 5 peptide blocks HK binding. Binding to umbilical vein EC or matrix, but not ECV304 cells or matrix, is mediated by cytokeratin 1. Biotin-HK binds to ECV304 cells or matrix with a Kd
of 15.8 or 9.0 nM and a Bmax
of 2.6 107 or 2.4 107 sites/cell, respectively. PK activation on ECV304 cells or matrix is blocked by antipain or SBTI and corn trypsin inhibitor partially inhibits kallikrein formation. PK activation occurs on ECV304 cells or matrix prepared without serum or in human factor XII deficient serum, indicating that the PK activator is not factor XIIa. EC matrix promotes plasminogen activation after the assembly of HK, PK and pro-urokinase. These studies indicate that matrix of various EC has the ability to assemble HK allowing for PK activation and subsequent activities.Abbreviations: EC: endothelial cells, FXII: factor XII, HK: high molecular weight kininogen, HKa: bradykinin-free HK, PK: plasma prekallikrein, Pro-UK: pro-urokinase, uPAR: urokinase plasminogen activator receptor, tcuPA: twochain urokinase, CK1: cytokeratin 1, SBTI: soybean trypsin inhibitor, HUVEC: human umbilical vein endothelial cell, SDS-PAGE: sodium dodecyl sulfatepolyacrylamide gel electrophoresis, CTI: corn trypsin inhibitor, p-APMSF: p-amidinophenylmethylsulfonylfluoride, EBSS: Earle’s Balanced Salt Solution
Plasmin Proteolysis of Endothelial Cell and Vessel Wall Associated Tissue Factor Pathway Inhibitor
Authors: Stalboerger Paul , Panetta Carmelo , Simari Robert , Caplice Noel 
Published: March 2018

SummaryPlasmin is an important protease that mediates clot fibrinolysis and vessel wall extracellular matrix proteolysis. Recently, in vitro studies have suggested that plasmin can cleave and inactivate recombinant TFPI, a major inhibitor of TF-mediated coagulation. We hypothesized that such an interaction may occur in vascular cells expressing TFPI, or in the vessel wall, with implications for thrombolysis. In a series of experiments, we examined the effects of plasmin on cell surface and extracellular matrix (ECM) associated TFPI in endothelial cells (EC) in culture and on EC and smooth muscle cells (SMC) in the vessel wall. Plasmin (0.2 μM) decreased cell surface and matrix associated TFPI activity in cultured endothelial cells by 77 ± 5 % and 69 ± 6% respectively (p < 0.01). Plasminogen, the proenzyme form of plasmin had no such effect on cell surface TFPI or matrix TFPI. Cell surface TFPI antigen measured by fluorescence activated cell sorter (FACS) was also significantly reduced by plasmin. Proteolysis of conditioned medium TFPI was suggested by loss of a ~45kD TFPI on Western Blot analysis following plasmin treatment. Plasmin also proteolysed a ~45kD TFPI protein in the intact ECM of EC, an effect which was inhibited by preincubation with aprotinin, a plasmin inhibitor. Incubation of similar concentrations of plasmin, with homogenates of normal vessel decreased a ~45kD TFPI immunoreactive band on Western blot analysis. Plasmin also decreased surface TFPI activity on frozen sections of normal vessel as measured by an amidolytic assay. Finally, plasmin treatment of atherosclerotic plaque sections caused complete removal of TFPI immunoreactivity associated with luminal EC and intimal SMC, when compared to control treated plaque (n = 3). Together these data suggest that plasmin proteolyses the majority of EC-associated (surface and matrix) TFPI and may remove TFPI from the luminal surface and intima of the vessel wall. TFPI proteolysis in cultured EC was associated with significant reduction in TFPI anticoagulant activity. These data provide evidence that plasmin degradation of TFPI occurs in vascular cells and in the vessel wall and may have implications for rethrombosis following thrombolysis in vivo.
Transfer, Transition und kontinuierliche Erwachsenenbetreuung von Patienten mit Phenylketonurie (PKU)
Authors: Mütze U. , Rohde C. , Arelin M. , Kirmse S. , Ceglarek U. , Baerwald C. , Beblo S. , Thiele A. G. 
Published: March 2018

ZusammenfassungDurch moderne Screeningmethoden, verbesserte Diagnostik und neue Therapieoptionen steigt die Zahl der langfristig zu betreuenden Patienten mit seltenen angeborenen Stoffwechselerkrankungen stetig an. Im Jahr 2005 wurde am Universitätsklinikum Leipzig eine der ersten deutschen Spezialambulanzen für diese Patienten gegründet und ein Transitionsprogramm etabliert. Vier und zehn Jahre später wurde retrospektiv die Langzeitbetreuung am Beispiel von Patienten mit Phenylketonurie (PKU) im Hinblick auf die metabolische Einstellung, Transitions-, Therapie- und Lebenszufriedenheit und den sozioökonomischen Status untersucht. 96 PKU-Patienten (56 w/40 m) wurden bis 2015 transferiert. 81 % wurden zuletzt noch betreut. Die metabolische Einstellung lag stets im angestrebten Bereich. Über 80 % der Patienten waren mit der Transition und Erwachsenenbetreuung zufrieden. Bei Lebensqualität und gesamtsozioökonomischen Daten gab es keine Unterschiede zur Kontrollpopulation. Unter enger multidisziplinärer Zusammenarbeit der erfahrenen Mitarbeiter aus Pädiatrie und Erwachsenenmedizin gelang eine erfolgreiche Transition bei den meisten Patienten. Zur Vermeidung eines Therapieabbruchs ist die weitere Etablierung spezialisierter Ambulanzen für angeborene Stoffwechselerkrankungen für Kinder und insbesondere Erwachsene dringend notwendig.
Franz Anton Mesmer (1734–1815) als Pionier der Psychotherapie
Authors: Boerner R. J. 
Published: March 2018

ZusammenfassungMesmer bzw. der „Mesmerismus“ haben über Jahrzehnte wichtige Denkanstöße in Medizin, Wissenschaft und Kultur gegeben, die bis heute nachwirken. Dessen Bedeutung für die Psychotherapie wurde jedoch nur partiell zur Kenntnis genommen. Es wird gezeigt, dass durch den „Mesmerismus“ mit dessen geisteswissenschaftlicher Position in der Dialektik von Natur und Geist, mit der Hervorhebung des besonderen Stellenwerts der Persönlichkeit des Therapeuten, der Therapiemethoden mit Suggestion, Meditation und hypnoseähnlichen Interventionen zentrale Themen und Richtungen in der heutigen Psychotherapie (-debatte) angestoßen wurden.
Suchtbehandlung bei komorbid psychischen Krankheiten
Authors: Soyka M. , Aichmüller C. 
Published: March 2018

ZusammenfassungDas Auftreten von komorbiden psychischen Störungen bei Suchterkrankungen ist häufig, dabei sind die Verläufe im Vergleich zu Patienten, die nur eine Diagnose aufweisen, schlechter. Eine effektive Suchttherapie ist nur im Rahmen der Mitbehandlung der psychischen Komorbidität möglich. Integrierte Behandlungskonzepte scheinen dabei von Vorteil zu sein. Die dafür erforderlichen pharmakologischen und psychosozialen Interventionen sind bei den jeweiligen psychischen und Suchterkrankungen teilweise gut untersucht. Die Datenlage bei komorbiden Suchterkrankungen ist kaum evidenzbasiert. Dies liegt unter anderem an der Heterogenität der Studien, aber auch jedoch an der Vielzahl möglicher Komorbiditätsformen. Anhand einer Kasuistik wird das therapeutische Procedere und das Behandlungsangebot der Spezialstation für Abhängigkeitserkrankungen mit komorbiden Störungen der Privatklinik Meiringen dargestellt.
Fluorescence and Cerenkov luminescence imaging
Authors: Schwenck J. , Fuchs K. , Eilenberger S. H. L. , Rolle A.-M. , Castaneda Vega S. , Thaiss W. M. , Maier F. C. 
Published: March 2018

SummaryThis review addresses small animal optical imaging (OI) applications in diverse fields of basic research. In the past, OI has proven to be cost- and time-effective, allows real-time imaging as well as high-throughput analysis and does not imply the usage of ionizing radiation (with the exception of Cerenkov imaging applications). Therefore, this technique is widely spread – not only geographically, but also among very different fields of basic research – and is represented by a large body of publications. Originally used in oncology research, OI is nowadays emerging in further areas like inflammation and infectious disease as well as neurology. Besides fluorescent probe-based contrast, the feasibility of Cerenkov luminescence imaging (CLI) has been recently shown in small animals and thus represents a new route for future applications.Thus, this review will focus on examples for OI applications in inflammation, infectious disease, cell tracking as well as neurology, and provides an overview over CLI.
Optical imaging probes and their potential contribution to radiotracer development
Authors: Hermann S. , Schäfers M. , Höltke C. , Faust A. 
Published: March 2018

SummaryOptical imaging has long been considered a method for histological or microscopic investigations. Over the last 15 years, however, this method was applied for preclinical molecular imaging and, just recently, was also able to show its principal potential for clinical applications (e.g. fluorescence-guided surgery). Reviewing the development and preclinical evaluation of new fluorescent dyes and target-specific dye conjugates, these often show characteristic patterns of their routes of excretion and biodistribution, which could also be interesting for the development and optimization of radiopharmaceuticals. Especially ionic charges show a great influence on biodistribution and netcharge and charge-distribution on a conjugate often determines unspecific binding or background signals in liver, kidney or intestine, and other organs.Learning from fluorescent probe behaviour in vivo and translating this knowledge to radio-pharmaceuticals might be useful to further optimize emerging and existing radiopharmaceuticals with respect to their biodistribution and thereby availability for binding to their targets.
Endothelial Perturbation in Cystic Fibrosis
Authors: Romano Mario , Collura Mirella , Iapichino Luciana , Pardo Francesca , Falco Angela , Chiesa Pierluigi Lelli , Caimi Gregorio , Davì Giovanni 
Published: March 2018

SummaryCystic fibrosis (CF) is characterized by a persistent inflammatory state, which can be secondary to chronic pulmonary infection and may affect vascular endothelium. We measured circulating levels of von Willebrand factor (vWF), tissue-plasminogen activator (t-PA), and P-selectin in 20 CF patients and 20 healthy subjects. vWF, t-PA and P-selectin levels were significantly higher in CF patients. Endothelial perturbation (> 2 SD increase in both vWF and t-PA) was present in 65% of CF patients. These patients displayed lower FEV1 values compared to individuals without endothelial perturbation and an inverse correlation between FEV1 and P-selectin levels was observed. Tumor necrosis factor- (TNF-) and interleukin (IL)-6 levels were also increased in CF patients and significant direct correlations were found between TNF- and vWF, t-PA or P-selectin levels. These results indicate that CF patients exhibit signs of endothelial dysfunction/perturbation, which are likely to be related to a persistent inflammatory state due to chronic pulmonary infection, and may play a role in the progression of this disease.
Compound Heterozygosity of the GPIbα Gene Associated with Bernard-Soulier Syndrome
Authors: Larrucea Susana , Pastor Angela , Butta Nora , Arias-Salgado Elena , Ayuso Matilde , Parrilla Roberto , González-Manchón Consuelo 
Published: March 2018

SummaryWe report the molecular genetic analysis of the Bernard-Soulier syndrome (BSS) phenotype in two related patients showing absence of glycoprotein (GP) Ibα and detectable amounts of GPIX on the platelet surface, and a truncated form of GPIbα in solubilized platelets and plasma. They both were compound heterozygotes for the GPIbα gene: a maternal allele with a T insertion at position 1418 causing a translational frameshift and premature polypeptide termination, and a paternal allele with a T715A substitution changing Cys209 to Ser. Heterozygotes for either one of these mutations were asymptomatic. Transient transfection of cells coexpressing GPIbβ and GPIX failed to detect surface expression of the GPIbα mutants. Cells transfected with [1418insT]GPIbα-cDNA showed a truncated protein of the predicted size in both cell lysate and conditioned medium, indicating the inability of the mutant protein to anchor the plasma membrane. In contrast, transfection of [T715A]GPIbα-cDNA yield a mutated protein barely detectable in the cell lysate and absent in the medium, indicating that the loss of Cys209 renders GPIbα more vulnerable to proteolysis and unable to undergo the normal secretory pathway. Our findings indicate that the additive effects of both mutations are responsible for the BSS phenotype of the patients.
Characterization and Structural Impact of Five Novel PROS1 Mutations in Eleven Protein S-deficient Families
Authors: Andersen Bente Damm , Bisgaard Marie Luise , Lind Bent , Philips Malou , Villoutreix Bruno , Thorsen Sixtus 
Published: March 2018

SummaryHeterozygozity for four novel missense mutations (W108C, W342R, E349K and L485S) and one novel 4 bp deletion (ACdelAAAG affecting codons 632-633) was identified in PROS1 of unrelated thrombosis prone Danish families with protein S type I or III deficiency. The 4 bp deletion results in a frameshift leading to replacement of the coding sequence for the 3 C-terminal amino acids by an abnormal extended sequence that codes for 9 amino acids. The E349K substitution was found in 7 families. Haplotype analysis using 7 microsatellite markers flanking PROS1 was consistent with a common founder for this mutation. The mutations reported here are most likely the cause of the protein S deficiency. Firstly, the four missense mutations cosegre-gate with the abnormal plasma protein S phenotype and lead to the loss of highly conserved amino acids. Secondly, computer analysis of structural models of protein S predicts that the substitutions could affect proper protein folding and/or stability. Analysis of platelet mRNA from subjects with the W108C, E349K, L485S mutation or the 4 bp deletion showed that mutated mRNA was expressed in significant amounts suggesting that mutated molecules are synthesized. Our results are compatible with defective protein folding/unstable molecules, impaired secretion and intracellular degradation of mutated protein, which appear to be the major molecular disease mechanisms for missense mutations and certain other mutations found in genetic disorders.
Experimental Arterial Thrombosis in Genetically or Diet Induced Hyperlipidemia in Rats
Authors: De Curtis Amalia , D’Adamo Maria Cristina , Amore Concetta , Polishchuck Roman , Di Castelnuovo Augusto , Donati Maria Benedetta , Iacoviello Licia 
Published: March 2018

SummaryTo investigate the relationship among lipids, coagulation and thrombosis in the absence of atherosclerosis, spontaneous or dietary-induced hyperlipidemic (FHL) rats were studied. FHL showed higher levels of coagulation factors VII, IX, X, VIII and XII and a shortening of the occlusion time (OT) of an artificial arterial prosthesis as compared with normolipidemic (FNL) animals. Damage of abdominal aorta of FHL was followed by increased fibrin deposition in the vascular intima as compared to FNL. After 5 months of cholesterol-rich diet FNL showed increased cholesterol, triglycerides and factor II, VII, IX, X, XII levels. A significant shortening of the OT and increased fibrin deposition was also observed. Two-month diet withdrawal restored the initial condition. Warfarin treatment, at a dose decreasing vitamin K-dependent factor to levels found in FNL, prolonged the OT and reduced fibrin deposition, without modifying F XII or changing lipid profile. An increase in the activated form of F VII was observed. In contrast, no difference was found in F VII clearance. High lipid levels favour the process of thrombus formation by increasing the activation of vitamin K-dependent coagulation factors. Low-dose warfarin treatment reverts the prothrombotic effect of hyper-lipidemia.
Defect of Heparin Binding in Plasma and Recombinant von Willebrand Factor with Type 2 von Willebrand Disease Mutations
Authors: Rastegar-Lari Ghassem , Ajzenberg Nadine , Ribba Anne-Sophie , Vereycken-Holler Valérie , Legendre Paulette , Villoutreix Bruno , Meyer Dominique , Baruch Dominique 
Published: March 2018

SummaryThe aim of our study was to characterise heparin-binding properties of mutated von Willebrand factor (VWF) in 24 patients plasmas with type 2 von Willebrand disease (VWD), and in 15 recombinant VWF (rVWF) with the corresponding mutations. Binding of mutated rVWF or plasma VWF was compared to that of WT-rVWF or normal pool plasma VWF. Four mutations, at positions C509, V551, R552 and R611 lead to significantly decreased binding to heparin in both plasma and rVWF. Interestingly, whereas these four residues are distant in the primary structure of VWF-A1 domain, they are close to each other in its three-dimensional structure. Structural analysis suggested how folding problems and destabilisation due to these mutations could induce reorganisation of surface regions involved in heparin binding. In contrast, no heparin-binding defect was found associated with different type 2 VWF mutants, at positions G561, E596, I662, R543, R545, V553, R578 or L697.
Crotalin, a vWF and GP Ib Cleaving Metalloproteinase from Venom of Crotalus atrox
Authors: Wu Wen-Bin , Peng Hui-Chin , Huang Tur-Fu 
Published: March 2018

SummaryBinding of von Willebrand factor (vWF) to a variety of extracellular matrix (ECM) components and to platelet glycoprotein (GP) Ib-IX-V complex is important in mediating platelet adhesion and aggregation in the early stage of hemostasis. We previously purified a potent antithrombotic protein, named crotalin, functionally acting as a GP Ib antagonist (1). In this study, we further characterized crotalin as a P-I metalloproteinase with a molecular mass of 25 kDa as determined by gel filtration and two-dimensional SDS-PAGE. Crotalin is a vWF binding and cleaving metalloproteinase. In addition, crotalin cleaved platelet GP Ib as judged by flow cytometry and Western blotting. The multiple effects of crotalin on vWF and platelet GP Ib antagonized ristocetin-, but not collagen and thrombin-induced platelet aggregation, suggesting that its effect is specific. We also found that crotalin auto-proteolytically degraded to ~14 and ~10 kDa fragments in the presence of SDS. Interestingly, both degradation fragments, intact and reduced crotalin were able to bind vWF, suggesting the binding of crotalin to vWF is conformation-independent. In conclusion, the results presented further explain the potent antithrombotic effect of crotalin in vivo. In addition, the multiple effects of crotalin may be used as a tool to determine the binding motifs that are responsible for the vWF-ECMs or vWF-GP Ib interaction.
The Antithrombotic Efficacy of AT-1459, a Novel, Direct Thrombin Inhibitor, in Rat Models of Venous and Arterial Thrombosis
Authors: Yun Chi-ho , Seo Hyoung-sik , Koga Takaki , Dan Takashi , Kim Hak-yeop , Cho Jae-hyung , Koo Bon-am 
Published: March 2018

SummaryThe antithrombotic efficacy of AT-1459, a novel, direct thrombin inhibitor (Ki = 4.9 nM) was evaluated in rat models of venous thrombosis combined with a bleeding time test and arterial thrombosis.After drugs were given by i. v. bolus injection plus a continuous infusion, the ID50 (a dose that exhibits 50% inhibition of thrombus formation over each vehicle group) values of AT-1459, argatroban, and dalteparin were 0.04 mg/kg plus 0.04 mg/kg/h, 0.1 mg/kg plus 0.4 mg/ kg/h, and 13.0 IU/kg plus 26.0 IU/kg/h, respectively, in the venous thrombosis study. The BT2 (a dose that causes 2-fold prolongation of bleeding time over each vehicle group) values of AT-1459, argatroban, and dalteparin were 0.9 mg/kg plus 0.9 mg/kg/h, 1.0 mg/kg plus 0.6 mg/kg/h, and 345.5 IU/kg plus 691.0 IU/kg/h in the rat tail transection model. The ratios of BT2/ID50 of AT-1459, argatroban, and dalteparin were 22.5, 10.0, and 26.6, respectively.In a rat model of arterial thrombosis induced by topical FeCl2 application, intravenous administration of AT-1459, argatroban, and dalteparin improved the vessel patency significantly (P <0.01) at 0.6 mg/kg plus 0.6 mg/kg/h, 0.6 mg/kg plus 2.4 mg/kg/h, and 300 IU/kg plus 600 IU/kg/h, respectively.The oral antithrombotic effect of AT-1459 lasted for 6 after administering 30 mg/kg and improved the vessel patency significantly 1 h after administering the same dose in venous and arterial thrombosis models, respectively, with a rapid onset of action. Warfarin also inhibited thrombus weight and improved the vessel patency significantly after oral administration of 0.3 mg/kg for three consecutive days in the same study. The antithrombotic and hemorrhagic effects of all drugs studied were correlated with plasma concentration or clotting times.These results suggest that AT-1459 may be clinically useful as an orally available antithrombotic agent for the prevention of venous and arterial thrombosis.