bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of a Functional Epitope in Plasminogen Activator Inhibitor-1, not Localized in the Reactive Center Loop
Authors: Debrock Sophie , Declerck Paul 
Published: March 2018

SummaryPlasminogen activator inhibitor-1 (PAI-1) is unique among the ser-pins because of its conformational flexibility. Previously, we have characterized monoclonal antibodies that neutralize PAI-1 activity by switching the active, inhibitory pathway into the non-inhibitory substrate pathway (10). Here, we report the identification of the epitopes for two of these antibodies, i.e. MA-55F4C12 and MA-33H1 and apply this information to explain their functional effects.Using a random PAI-1 epitope library (11), phages displaying specific PAI-1 fragments were isolated after selective screening for binding onto the respective antibodies. Competition experiments with PAI-1 demonstrated that selected phages react with the antigen-binding site of the antibodies. Comparison of the sequences of the different overlapping inserts, encoding the PAI-1 epitope, with the PAI-1 cDNA sequence revealed that both epitopes, even though not identical, are located between amino acids Glu128 and Ala156 in the PAI-1 molecule. Analysis within the three-dimensional structure of PAI-1 showed that these residues completely cover helix F, which is localized close to the major β-sheet A. This localization provides a rational basis for explaining the mechanism of PAI-1 inactivation by both antibodies: upon binding of these antibodies to PAI-1, a stabilizing effect is induced on helix F resulting in a decrease of the kinetics of insertion of the reactive site loop into β-sheet A during interaction with the target proteinase. This forms the molecular basis for the observed functional effects of these antibodies and fully explains why PAI-1, in the presence of these antibodies, has lost its inhibitory properties but remains succeptible to cleavage by its target proteinases. The identification and localization of these functionally important epitopes opens new perspectives for the development of pharmacological agents with PAI-1 modulating properties.
Inhibition of Fibrinogen Binding and Surface Recruitment of GpIIb/IIIa as Dose-Dependent Effects of the RGD-Mimetic MK-852
Authors: Wittig Kathrin , Rothe Gregor , Schmitz Gerd 
Published: March 2018

SummaryConformational activation of platelet GpIIb/IIIa which is coupled to increased affinity for binding of soluble fibrinogen is an important step in platelet aggregation. Antibodies, peptides, and small molecules which antagonise fibrinogen binding, therefore, have been developed as a new class of potent anti-aggregatory compounds. The binding of these artificial ligands, however, similar to fibrinogen binding may also stimulate platelet adhesion and degranulation. Therefore, in this study effects of MK-852, a cyclic hexapeptide based on the RGD-template, on the platelet phenotype were analysed by whole blood flow cytometry. MK-852 already in the nanomolar range completely inhibited the surface binding of fibrinogen to ADP or TRAP-6 stimulated platelets. In the micromolar range, MK-852 induced an up to four-fold increase of GpIIb/IIIa surface expression in the absence of increased P-selectin expression. In conclusion our results suggest that the selective surface recruitment of GpIIb/IIIa may be a side effect of exposure to RGD-analogues which occurs at concentrations well above inhibition of fibrinogen binding.
Assessment of Thrombin Inhibitor Efficacy in a Novel Rabbit Model of Simultaneous Arterial and Venous Thrombosis
Authors: Lewis Sidney , Lehman Dale , Gardell Stephen , Motzel Sherri , Lynch Joseph , Lyle Elizabeth Marsh 
Published: March 2018

SummaryThe importance of thrombin in arterial and venous thrombosis renders thrombin inhibition an important therapeutic target. Identification of novel inhibitors requires an appropriate animal model. We modified a previously reported rat arterial thrombosis model to allow simultaneous assessment of the arterial and venous antithrombotic efficacies of heparin, hirudin, hirulog, a novel thrombin inhibitor H-(N-Me-D-Phe)-Pro-L-trans-4-aminocyclohexyl-Gly-[CO-CO]-NHCH3 (L-370,518) and the factor Xa inhibitor tick anticoagulant peptide in rabbits. Thrombosis was induced through application of 70% ferric chloride to the femoral artery and jugular vein. Incidence of occlusion, thrombus weight, aPTT and plasma inhibitor concentrations were determined. Heparin was efficacious in preventing arterial and venous occlusive thrombosis but at a dose that profoundly elevated aPTT. On a molar dosing basis, the approximate order of potency of the thrombin and factor Xa inhibitors was similar in artery and vein: hirudin>tick anticoagulant peptide>hirulog≥L-370,518. Data suggested that compounds tended to be more potent in preventing venous thrombosis than arterial. This thrombin-dependent model is an economical and efficient approach to arterial and venous antithrombotic efficacy screening that eliminates variabilities encountered when multiple model/multiple animal strategies are employed.
Thrombin-like Enzymes from Snake Venoms: An Updated Inventory
Authors: Pirkle Hubert 
Published: March 2018

SummaryAs in the previous inventory (93), the term “thrombin-like”, continues to mean direct “fibrinogen-clotting”. The present tabulation adds 32 publications to the earlier one and focuses mainly on biochemical properties. Broader treatment of these enzymes, such as medical and other biological applications, can be found in a number of review articles and chapters (9, 69, 90, 110, 118).
A Mutation in the Thrombomodulin Gene, 127G to A Coding for Ala25Thr, and the Risk of Myocardial Infarction in Men
Authors: Doggen Carine , Kunz Gabriella , Rosendaal Frits , Vos Hans , Stubbs Peter , Cats Volkert Manger , Ireland Helen , Lane David 
Published: March 2018

SummaryThrombomodulin is an endothelial cell surface receptor that transforms the procoagulant thrombin into an anticoagulant. A mutation in the thrombomodulin gene is a potential risk factor for venous and arterial thrombosis.We screened a region within the coding sequence of the thrombomodulin gene by single-strand conformation polymorphism analysis (SSCP) in a pilot study of 104 patients with myocardial infarction and 104 age, sex and race matched controls. We identified a 127G to A mutation in the gene, which predicts an Ala25Thr substitution, in 2 out of 104 patients (1 man and 1 woman) with myocardial infarction but in no controls. We assessed the risk of myocardial infarction associated with the mutation in a larger “Study of Myocardial Infarctions Leiden” (SMILE). Among 560 men with a first myocardial infarction before the age of 70, 12 were carriers of the Ala25Thr substitution. In a control group of 646 men, frequency-matched for age, seven were carriers of the Ala25Thr substitution. The allelic frequencies were 1.07% among patients and 0.54% among controls suggesting risk associated with the mutation [odds ratio (OR) 2.0, 95% confidence interval (CI) 0.8-5.1]. In patients aged below 50, the predicted risk was almost seven times increased (OR 6.5, CI 0.8-54.2). In the presence of additional risk factors, such as smoking and a metabolic risk factor, the predicted risk increased to 9-fold (OR 8.8, CI 1.8-42.2) and 4-fold (OR 4.4, CI 0.9-21.3), respectively.While not conclusive, these results strongly suggest that the Ala25Thr substitution is a risk factor for myocardial infarction, especially in young men, and when in the presence of additional risk factors.
Associations of Fibrinogen, Factor VII and PAI-1 with Baseline Findings among 10,500 Male Participants in a Prospective Study of Myocardial Infarction
Authors: Aillaud Marie-Francoise , Amouyel Philippe , Evans Alun , Luc Gérald , Ferrières Jean , Arveiler Dominique , Juhan-Vague Irène , Scarabin Pierre-Yves 
Published: March 2018

SummaryThe contribution of coagulation factors and fibrinolytic variables to the development of ischaemic arterial disease is still not clearly established. The PRIME study is a prospective cohort study of myocardial infarction in men aged 50-59 years and recruited from three MONICA field centers in France (Lille, Strasbourg and Toulouse) and the center in Northern Ireland (Belfast). Baseline examination included measurement of plasma fibrinogen, factor VII, and PAI-1 activity in over 10,500 participants. We investigated the associations of these haemo-static variables with cardiovascular risk factors, prevalent atherosclerotic disease and geographical area. Fibrinogen level increased with age, smoking, waist-to-hip ratio, LDL-cholesterol, and it decreased with educational level, leisure physical activity, alcohol intake and HDL-cholesterol. Factor VII activity increased with body mass index, waist-to-hip ratio, triglycerides, HDL- and LDL-cholesterol. PAI-1 activity increased with body mass index, waist-to-hip ratio, triglycerides, alcohol intake, smoking, and decreased with leisure physical activity. PAI-1 level was higher in diabetic subjects than in subjects without diabetes. Cardiovascular risk factors explained 8%, 9%, and 26% of the total variance in fibrinogen, factor VII, and PAI-1, respectively. Compared with participants without prevalent cardiovascular disease, those with previous myocardial infarction (n = 280), angina pectoris (n = 230), or peripheral vascular disease (n = 19) had significantly higher levels of fibrinogen, but those with stroke (n = 67) had not. PAI-1 activity showed a similar pattern of association. The odds ratio for cardiovascular disease associated with a rise of a one standard deviation in fibrinogen and PAI-1 was 1.31 (95% confidence interval: 1.20 to 1.42, p <0.001) and 1.38 (95% confidence interval: 1.27 to 1.49, p <0.001), respectively. After adjustment for cardiovascular risk factors, these associations were attenuated but remained highly significant. There was no significant association between factor VII activity and prevalent cardiovascular disease. Fibrinogen level and, to a lesser extent, factor VII and PAI-1 activity were higher in Northern Ireland than France after adjustment for the main cardiovascular risk factors. These geographical variations are consistent with the 2 to 3-fold higher incidence of myocardial infarction in Northern Ireland than France. Our results provide further epidemiological evidence for a possible role of fibrinogen and PAI-1 in the pathogenesis of coronary heart disease.
FVIII Coagulant Activity and Antigen in Subjects with Ischaemic Heart Disease
Authors: Grant Peter , Rice Gillian 
Published: March 2018

SummaryRaised factor VIII coagulant activity has been associated with Ischaemic Heart Disease and Myocardial Infarction (MI). We measured FVIII:C and FVIII:Ag levels in 288 white European patients characterised for extent of atheroma by coronary angiography and for a history of MI by WHO criteria, and 313 white European healthy controls. FVIII:Ag levels were higher in patients than controls after adjustment for confounding variables (1.17 IU/ml patients, 1.03 IU/ml controls [p <0.0005]), whereas FVIII:C levels were lower in patients (1.26 IU/ml patients, 1.45 IU/ml controls [p < 0.0005]). FVIII:Ag levels were higher in patients with MI and with angiographic evidence of atheroma than controls. FVIII:Ag levels but not FVIII:C levels were a significant independent risk factor for MI in multivariate analysis (Odds Ratio 2.40 [1.35-4.27] [p = 0.003]). No association of FVIII:Ag or FVIII:C levels and presence or extent of atheroma was found in multivariate analysis. In conclusion, this study found an independent association of FVIII:Ag but not FVIII:C with MI.
Measurement of Active Coagulation Factors in Autoplex®-T with Colorimetric Active Site-Specific Assay Technology
Authors: Bergstrom Jennifer , Vreker Rene De , Bray Gordon , Gomperts Edward , Baker Don , Kingdon Henry , Mann Kenneth , Hartshorn Jeanette , Jenny Richard , Lundblad Roger 
Published: March 2018

SummaryAutoplex® -T is a partially activated prothrombin complex concentrate used primarily for the treatment of patients expressing factor VIII inhibitors. While Autoplex® -T has a demonstrated record of clinical effectiveness, the procoagulant composition of this material has not been reported. This absence of composition data is a reflection of the lack of techniques appropriate for accurately measuring an individual protease such as factor IXa in complex mixtures of similar proteases. The development of Colorimetric Active Site-Specific ImmunoAssay technology (CASSIA) has permitted the accurate analysis of the coagulant enzymes present in Autoplex® -T. Ten lots of Autoplex® -T were reacted with both biotinylated phenylalanylprolylarginine chloromethylketone and biotinylated glutamylglycylarginine chloromethylketone. Only activated forms of the clotting factors present in Autoplex® -T react with the peptide chloromethylketones and were thus separated from the other proteins present in Autoplex® -T by adsorption onto streptavidin. The individual proteins bound to streptavidin were then detected with specific antibodies. Mean results from the analysis of ten lots of Autoplex® -T (mean values) are as follows: factor XIa, 5.9 nM or 0.8 μg/ml; factor Xa, 46.5 nM or 2.1 μg/ml; factor IXa, 177.8 nM or 11.7 μg/ml; factor VIIa, 68.6 nM or 3.3 μg/ml and factor IIa, 5.3 nM or 0.2 μg/ml. These results are discussed with respect to the mechanism of action of Autoplex® -T in the treatment of factor VIII inhibitor patients.
The Protein C System – How Complex Is it?
Authors: Marlar Richard 
Published: March 2018

SummarySince the initial discovery of activated protein C (APC) and protein C (PC), subsequent findings have demonstrated that the protein C anti-thrombotic mechanism (anticoagulant and profibrinolytic) is very complex and convoluted, involving a multitude of other proteins and interactions with cell surfaces (1, 2). The PC system may be as complex as the coagulation scheme and other defense mechanisms. In recent years, investigations into ancillary functions of the PC system have identified interactions with some of these defense mechanisms in particular the inflammatory response (1, 3). Investigation of this highly complex system is no simple task.The number of proteins directly or indirectly involved in the PC system is growing, with several playing dual roles in the presence or absence of cells (1-5). Because of its complexity, the PC system can be broken down into functional subsets: cell-surface activation of protein C, the anticoagulant mechanism, the long-recognized but poorly-understood fibrinolytic response, and the shutdown mechanisms of the PC system. In the analysis of in vitro mechanisms of the PC pathway, care must be taken in the final interpretation of and application to the in vivo activities. We must weigh the importance of the apparent “minor” interactions with the perceived “major” roles these proteins play (5, 6). Any cursory review of these functions delineates the complexity of the system as a whole. The complex nature of the PC system reinforces how important good research is to the realization of our understanding of this functioning system. Because of the complexity of the system, the following questions must be meticulously addressed: What is the importance of each of the interactions? And what is the physiological role of these seemingly “minor” interactions of components in the regulation of the PC system?
Das Down-Syndrom als Risikofaktor für einen komplizierten Verlauf bei RSV-Infektion
Authors: Hoffmann P. , Wagner A. , Jung A.-M. , Rohrer T. , Gortner L. , Simon A. 
Published: March 2018

ZusammenfassungKinder mit Down-Syndrom haben einen nicht abschließend charakterisierten humoralen und zellulären Immundefekt mit unterschiedlicher klinischer Ausprägung, der in den ersten Lebensjahren das Risiko von Atemwegsinfektionen deutlich erhöht. Einige Publikationen beschreiben das Down-Syndrom (auch ohne Frühgeburtlichkeit oder einen hämodynamisch relevanten angeborenen Herzfehler) als unabhängigen Risikofaktor für einen komplizierten Verlauf der RSV-Infektion. Dieser Beitrag stellt die aktuell verfügbaren Informationen aus der Literatur zusammen, die nahelegen, dass Kinder mit Down-Syndrom wahrscheinlich im ersten Lebensjahr von einer Prophylaxe mit Palivizumab profitieren. Die Zahl der für eine randomisierte Prüfung dieser Fragestellung erforderlichen Probanden überstiege die Zahl der in Deutschland pro Jahr geborenen Kinder mit Down-Syndrom (ein Dilemma für Mediziner, die Kinder mit seltenen Erkrankungen oder angeborenen Syndromen behandeln).
Rückfälligkeit bei Jugendlichen und Heranwachsenden nach Entlassung aus der Entziehungsmaßregel
Authors: Schläfke D. , Fegert J. M. , Maaß C. 
Published: March 2018

ZusammenfassungJugendliche und Heranwachsende nehmen aufgrund ihres jungen Alters eine besondere Stellung im deutschen Strafrechtssystem ein. Vor allem im Maßregelvollzug muss die spezielle Behandlungsbedürftigkeit der Jugendlichen beachtet werden. Ob die Therapie erfolgreich war lässt sich unter anderem durch eine Analyse des Legalbewährungsverlaufs nach Entlassung überprüfen. In der Klinik für Forensische Psychiatrie Rostock, in der Patienten nach § 64 StGB untergebracht sind, wurde zu diesem Zweck eine umfangreiche Rückfalluntersuchung initiiert. Im Folgenden wurden Bundeszentralregisterauszüge für 76 Jugendliche und Heranwachsende im Alter von 15 bis 21 Jahren analysiert, die zwischen 2001 und 2012 entlassen wurden. Die allgemeine Rückfallquote lag bei 65,8%, wobei 38% aller rückfällig gewordenen Patienten innerhalb der ersten sechs Monate nach Entlassung die Tat begingen. Junge Patienten, deren Behandlung nicht erfolgreich abgeschlossen wurde, stellen zudem eine besondere Risikogruppe dar. In der Gruppe der 15-bis 21-Jährigen wurden Therapieabbrecher signifikant häufiger rückfällig als regulär entlassene Patienten. Diese Unterschiede konnten in keiner anderen Altersgruppe beobachtet werden.
Telemedizin im Neurologischen Hintergrunddienst
Authors: Janssen F. , Lang R. , Awadallah M. , Alhalabi A. , Lunkenheimer J. , Stark D. , Scibor M. , Handschu R. 
Published: March 2018

ZusammenfassungTelemedizin hat sich innerhalb der klinischen Neurologie vor allem in der Schlaganfallversorgung entwickelt. Zur Nutzung in der allgemeinen Neurologie existieren nur wenige Arbeiten. Im Projekt Telemedizin im Neurologischen Hintergrunddienst (TelNHI) wird die im Schlaganfallnetzwerk mit Telemedizin in Nordbayern (STENO) bewährte Technik genutzt, um im Hintergrunddienst einer neurologischen Akutklinik Fälle mit neurologischen Akutproblemen mittels audiovisueller Fernuntersuchung zu beurteilen. Bislang wurden 62 Patienten untersucht. Die ersten Erfahrungen zeigen, dass eine audiovisuelle Fernuntersuchung auch im neurologischen Hintergrunddienst helfen kann, die Qualität zu verbessern und die Belastung des Personals zu verringern. Allerdings deutet sich in verschiedenen Diagnosegruppen ein unterschiedlich ausgeprägter Nutzen an. In weiteren Projektstufen müssen Untersuchungsalgorithmen für die Diagnosegruppen entwickelt und der Nutzen und Risiken telemedizinischer Anwendungen für den fachärztlichen Hintergrunddienst in weiteren Studien untersucht werden.
Leitlinie zur Diagnostik, Therapie und Prophylaxe von Cluster-Kopfschmerz, anderen trigeminoautonomen Kopfschmerzen, schlafgebundenem Kopfschmerz und idiopathisch stechenden Kopfschmerzen
Authors: Evers S. , Brössner G. , Jürgens T. , Gantenbein A. R. , Malzacher V. , Straube A. , May A. 
Published: March 2018

ZusammenfassungNach der 2013 überarbeiteten IHS-Klassifikation werden der episodische und chronische Cluster-Kopfschmerz, die episodisch und chronisch paroxysmale Hemikranie und SUNCT-Syndrom (short-lasting unilateral neuralgiform headache with conjunctival injection and tearing) und das SUNA-Syndrom (short-lasting unilateral neuralgiform headache with autonomic symptoms) sowie die Hemicrania continua unter dem Begriff trigemino-autonome Kopfschmerzen (TAK) zusammengefasst. Sie unterscheiden sich in Dauer, Frequenz und Rhythmik der Schmerzattacken. Autonome Begleitsymptome wie ipsilaterale Lakrimation, konjunktivale Injektion, Rhinorrhoe, nasale Kongestion, Gesichtsschwitzen, Völlegefühl im Ohr und Lidschwellung treten mehr oder weniger stark ausgeprägt auf. Ein wesentliches weiteres Unterscheidungsmerkmal liegt in dem unterschiedlichen Ansprechen auf Indometacin: Der Cluster-Kopfschmerz und das SUNCT- und SUNA-Syndrom sprechen nicht auf Indometacin an, bei den anderen TAK ist Indometacin per definitionem effektiv. Grundsätzlich unterteilt sich die Therapie der TAK in eine Akuttherapie und eine medikamentöse Prophylaxe. Aufgrund der relativen Kürze der Attacken ist bei der paroxysmalen Hemicranie und beim SUNCT/SUNA-Syndrom keine Akuttherapie möglich, beim Cluster-Kopfschmerz sind orale Substanzen in der Regel nicht ausreichend rasch wirksam. Das größte Augenmerk der Therapie liegt daher stets auf der Prophylaxe. Die Therapie der TAK erfordert eine individuell auf den Patienten zugeschnittene Kombination der verschiedenen Therapieoptionen. Obwohl ausreichend gute, vergleichende Studien rar sind, kann in der Praxis in der Mehrzahl der Fälle eine positive Beeinflussung der Schmerzattacken erreicht werden. Nur in seltenen Fällen ist eine invasive Therapie nötig. Die Therapieempfehlungen stützen sich, soweit möglich, auf Kriterien der evidenzbasierten Medizin (EBM).
Morbus Wilson
Authors: Voss H. 
Published: March 2018

ZusammenfassungMorbus Wilson ist eine autosomal-rezessive Erkrankung, bei der es durch Mutationen des ATP7B-Gens zu einer Störung des Kupferstoffwechsels kommt. Eine verminderte biliäre Kupferausscheidung und massive Kupferablagerungen insbesondere in Leber und Gehirn sind die Folge. Klinisch manifestiert sich der M. Wilson klassischerweise als (akute) hepatische Form im Kindes- und Jugendalter oder im jungen Erwachsenenalter mit extrapyramidalmotorischen oder psychiatrischen Symptomen. Unklare Bewegungsstörungen, insbesondere in Kombination mit (sub)klinischer Leberfunktionsstörung sollten aber auch in höherem Alter an den M. Wilson denken lassen. Unbehandelt kommt es zu schwerer Behinderung und Tod. Rechtzeitig erkannt, kann die Symptomprogredienz zumeist gestoppt und eine Rückbildung der Symptome erreicht werden. Der Einsatz von Chelatbildnern führt zu einer renalen Kupferausscheidung, mit Zinksalzen wird die Resorption von Kupfer im Darm gehemmt. Eine Lebertransplantation ist bei schweren hepatischen Verläufen sinnvoll und wird auch bei anders nicht zu kontrollierenden neurologischen Verlaufsformen diskutiert.
Komplikationen einer ADS-Behandlung im Erwachsenenalter
Authors: Grön G. , Kahn N. , Brummer D. , Kölle M. A. 
Published: March 2018

ZusammenfassungAufmerksamkeitsdefizit-/-Hyperaktivitäts-Störungen (ADS/ADHS) im Erwachsenenalter können medikamentös mit Stimulanzien oder mit noradrenerg-/dopaminerg wirksamen Nichtstimulanzien behandelt werden. Wir berichten den Fall eines 22-jährigen Patienten mit einer ADS, der mit Bupropion behandelt worden war. Hierunter hatte der Patient einen komplex-fokalen Anfall erlitten, woraufhin die Therapie abgebrochen worden war. Auslösende Faktoren des Anfalls waren am ehesten eine nicht beabsichtigte Bupropionüberdosierung sowie möglicherweise eine links-temporal gelegene Arachnoidalzyste. Nach sorgfältiger Nutzen-Risiko-Bewertung wurde eine Behandlung mit Methylphenidat begonnen, von welcher der Patient deutlich profitierte. Weitere unerwünschte therapieassoziierte Ereignisse blieben aus. Der Fall verdeutlicht die Bedeutung der hirnorganischen Diagnostik bei ADS/ADHS im Erwachsenenalter sowie die Effizienz der Therapie mit Methylphenidat im Vergleich zu Nichtstimulanzien, auch in Risikokonstellationen.