Direct Identification of Acetaldehyde Formation and Characterization of the Active Site in the [VPO4].+/C2H4 Couple by Gas‐Phase Vibrational Spectroscopy

The gas‐phase reaction of the heteronuclear oxide cluster [VPO4].+ with C2H4 is studied under multiple collision conditions at 150 K using cryogenic ion‐trap vibrational spectroscopy combined with electronic structure calculations. The exclusive formation of acetaldehyde is directly identified spectroscopically and discussed in the context of the underlying reaction mechanism. In line with computational predictions it is the terminal P=O and not the V=O unit that provides the oxygen atom in the barrier‐free thermal C2H4→CH3CHO conversion. Interestingly, in the course of the reaction, the emerging CH3CHO product undergoes a rather complex intramolecular migration, coordinating eventually to the vanadium center prior to its liberation. Moreover, the spectroscopic structural characterization of neutral C2H4O deserves special mentioning as in most, if not all, ion/molecule reactions, the neutral product is usually only indirectly identified.DFG, 390540038, EXC 2008: UniSysCatDFG, 234149247, SFB 1109: Molekulare Einblicke in Metalloxid-Wasser-Systeme: Strukturelle Evolution, Grenzflächen und AuflösungTU Berlin, Open-Access-Mittel - 201

Wirkungsweise alter und neuer Antikoagulanzien

Zusammenfassung: Die drei häufigsten Indikationen für eine Behandlung mit Hemmern der plasmatischen Gerinnung sind das Vorhofflimmern, die venöse Thromboembolie und valvuläre Kardiopathien. Aufgrund der Häufigkeit dieser Pathologien kann man davon ausgehen, dass rund 1% der Bevölkerung oral antikoaguliert ist. Ungefähr ein Drittel der auf einer chirurgischen Abteilung hospitalisierten Patienten erhält Vitamin-K-Antagonisten. Somit handelt es sich hierbei um eine Behandlungsmodalität, mit der sowohl Grundversorger und Spezialisten in der Praxis als auch Klinikärzte fortwährend konfrontiert sind. Inhibitoren der Gerinnung haben in vielen Situationen einen großen Nutzen gezeigt, welcher allerdings mit einem erhöhten Blutungsrisiko bezahlt sein will. Diese Gratwanderung zwischen einem Zuviel und einem Zuwenig der antikoagulatorischen Wirkung ist eine wichtige Herausforderung in der klinischen Arbeit mit Patienten. Die Kenntnis der der medikamentösen Gerinnungshemmung zugrundeliegenden Mechanismen ist notwendig, um Indikationen für antikoagulatorische Therapien kritisch evaluieren und deren Management effizient steuern zu können. Im Idealfall muss die Sicherstellung einer ausreichenden Hämostase bei gleichzeitiger Vermeidung thrombotischer Ereignisse das Ziel einer adäquaten Gerinnungshemmung sein. Dieser Artikel soll einen Überblick über das Gerinnungssystem und über etablierte, aber auch neue pharmakologische Angriffspunkte biete

Rotation thromboelastometry (ROTEM®) stability and reproducibility over time

Background: Thromboelastometry is a whole blood assay performed to evaluate the viscoelastic properties during blood clot formation and lysis. Rotation thromboelastography (ROTEM®, Pentapharm GmbH, Munich, Germany) has overcome some of the limitations of classic thromboelastography. So far, no clinical validation on reproducibility (inter- and intra-assay variability) and sample stability over time has been published. Methods: To evaluate the pre-analytic aspects, sample stability over time was assessed in 48 patients in eight age groups. Citrated blood was stored at room temperature. Tests measured every 30min from T 0min up to T 120min on two ROTEM® devices were INTEM (ellagic acid activated intrinsic pathway), EXTEM (tissue factor-triggered extrinsic pathway) and FIBTEM (with platelet inhibitor (cytochalasin D) evaluating the contribution of fibrinogen to clot formation). Precision by intra- and inter-assay variability was evaluated at two points of time in 10 volunteers. Finally, reference intervals and effect of age and sex were evaluated. Results: Blood was stable over 120min and no significant differences in ROTEM® results were found. Maximum clot firmness measurements had a coefficient of variation of ≪3% for EXTEM, ≪5% for INTEM and ≪6% for FIBTEM. For clot formation time, the coefficient of variation was ≪4% for EXTEM and ≪3% for INTEM. Coefficient of variation for angle alpha was ≪3% for EXTEM and ≪6% for INTEM. The coefficient of variation for clotting time was ≪15% for both EXTEM and INTEM. Small but significant differences between ROTEM® devices were found for maximum clot firmness in FIBTEM and INTEM as well as clot formation time and alpha angle in INTEM. Conclusions: ROTEM® yields stable results over 120min with a minimal variability on the same ROTEM® device. However, small but significant differences between ROTEM® devices were observed. Analysis should be performed on the same ROTEM® device if small differences are of importance for treatmen

In vitro factor XIII supplementation increases clot firmness in Rotation Thromboelastometry (ROTEM®)

Factor XIII (F XIII) is an essential parameter for final clot stability. The purpose of this study was to determine the impact of the addition of factor (F)XIII on clot stability as assessed by Rotation Thromboelastometry (ROTEM(R)). In 90 intensive care patients ROTEM(R) measurements were performed after in vitro addition of F XIII 0.32 IU, 0.63 IU, 1.25 IU and compared to diluent controls (DC; aqua injectabile) resulting in approximate F XIII concentrations of 150, 300 and 600%. Baseline measurements without any additions were also performed. The following ROTEM(R) parameters were measured in FIBTEM and EXTEM tests: clotting time (CT), clot formation time (CFT), maximum clot firmness (MCF), maximum lysis (ML), maximum clot elasticity (MCE) and a-angle (aA). Additionally, laboratory values for FXIII, fibrinogen (FBG), platelets and haematocrit were contemporaneously determined. In the perioperative patient population mean FBG concentration was elevated at 5.2 g/l and mean FXIII concentration was low at 62%. The addition of FXIII led to a FBG concentration-dependent increase in MCF both in FIBTEM and EXTEM. Mean increases in MCF (FXIII vs. DC) of approximately 7 mm and 6 mm were observed in FIBTEM and EXTEM, respectively. F XIII addition also led to decreased CFT, increased aA, and reduced ML in FIBTEM and EXTEM. In vitro supplementation of FXIII to supraphysiologic levels increases maximum clot firmness, accelerates clot formation and increases clot stability in EXTEM and FIBTEM as assayed by ROTEM(R) in perioperative patients with high fibrinogen and low FXIII levels

Infrared Photodissociation Spectroscopy of C2n+1N− Anions with n = 1 – 5

The gas phase vibrational spectroscopy of cryogenically cooled C2n + 1N− anions with n = 1 − 5 is investigated in the spectral range of the C≡C and C≡N stretching modes (1850–2400 cm–1) by way of infrared photodissociation (IRPD) spectroscopy of messenger-tagged C2n+1N–· mD2 complexes. The IRPD spectra are assigned based on a comparison to previously reported anharmonic and harmonic CCSD(T) vibrational frequencies and intensities. Experimentally determined and predicted anharmonic vibrational transition energies lie within ± 21 cm–1. For the harmonic CCSD(T)/vqz+ vibrational frequencies a scaling factor of 0.9808 is determined, resulting in comparable absolute deviations. The influence of the D2-messenger molecules on the structure and the IRPD spectrum is found to be small. Compared to the results of previous IR matrix isolation studies additional, in particular weaker, IR-active transitions are identified

Usefulness of standard plasma coagulation tests in the management of perioperative coagulopathic bleeding: is there any evidence?

Standard laboratory coagulation tests (SLTs) such as prothrombin time/international normalized ratio or partial thromboplastin time are frequently used to assess coagulopathy and to guide haemostatic interventions. However, this has been challenged by numerous reports, including the current European guidelines for perioperative bleeding management, which question the utility and reliability of SLTs in this setting. Furthermore, the arbitrary definition of coagulopathy (i.e. SLTs are prolonged by more than 1.5-fold) has been questioned. The present study aims to review the evidence for the usefulness of SLTs to assess coagulopathy and to guide bleeding management in the perioperative and massive bleeding setting. Medline was searched for investigations using results of SLTs as a means to determine coagulopathy or to guide bleeding management, and the outcomes (i.e. blood loss, transfusion requirements, mortality) were reported. A total of 11 guidelines for management of massive bleeding or perioperative bleeding and 64 studies investigating the usefulness of SLTs in this setting were identified and were included for final data synthesis. Referenced evidence for the usefulness of SLTs was found in only three prospective trials, investigating a total of 108 patients (whereby microvascular bleeding was a rare finding). Furthermore, no data from randomized controlled trials support the use of SLTs. In contrast, numerous investigations have challenged the reliability of SLTs to assess coagulopathy or guide bleeding management. There is actually no sound evidence from well-designed studies that confirm the usefulness of SLTs for diagnosis of coagulopathy or to guide haemostatic therap

Relative concentrations of haemostatic factors and cytokines in solvent/detergent-treated and fresh-frozen plasma

Background Indications, efficacy, and safety of plasma products are highly debated. We compared the concentrations of haemostatic proteins and cytokines in solvent/detergent-treated plasma (SDP) and fresh-frozen plasma (FFP). Methods Concentrations of the following parameters were measured in 25 SDP and FFP samples: fibrinogen (FBG), factor (F) II, F V, F VII, F VIII, F IX, F X, F XIII, von Willebrand factor (vWF), D-Dimers, ADAMTS-13 protease, tumour necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, IL-8, and IL-10. Results Mean FBG concentrations in SDP and FFP were similar, but in FFP, the range was larger than in SDP (P<0.01). Mean F II, F VII, F VIII, F IX, and F XIII levels did not differ significantly. Higher concentrations of F V (P<0.01), F X (P<0.05), vWF (P<0.01), and ADAMTS-13 (P<0.01) were found in FFP. With the exception of F VIII and F IX, the range of concentrations for all of these factors was smaller (P<0.05) in SDP than in FFP. Concentrations of TNF-α, IL-8, and IL-10 (all P<0.01) were higher in FFP than in SDP, again with a higher variability and thus larger ranges (P<0.01). Conclusions Coagulation factor content is similar for SDP and FFP, with notable exceptions of less F V, vWF, and ADAMTS-13 in SDP. Cytokine concentrations (TNFα, IL-8, and IL-10) were significantly higher in FFP. The clinical relevance of these findings needs to be established in outcome studie

The Social Contract in Epicureanism

Epicurus held that justice came into being when individuals made compacts with one another to secure the benefit that comes from not harming one another. He also distinguished just laws from those that are not just; and he recognized a virtue of justice. This much is well supported by our evidence. There is also much that is controversial. At the very basis, there is disagreement on his conception of justice. There are also basic questions on how compacts are related to the justice of laws, as well as to the virtue of justice. Plato and Aristotle severed compacts from virtue; and some modern thinkers consider the justice of institutions prior to that of individuals. What was Epicurus’ position? This paper will sketch an outline of Epicurus’ theory of justice as a path to the goal of a pleasant life. As Phillip Mitsis (1988) suggested, Epicurus sought to harmonize a contractual view of justice with the virtue of justice. My aim is to investigate further the coherence of this endeavor. As I will argue, Epicurus presents a unitary theory of justice, composed of a number of steps that develop out of each other in a consistent way. As a developmental path, it admits of much variation. By tracing its basic features, I seek to show how Epicurus puts individuals in charge of attaining their goal, pleasure

Infrared Photodissociation Spectroscopy of Mass-Selected Cluster Ions in the Gas Phase

This habilitation thesis describes my research activities at the Institute for Experimental Physics of the Free University Berlin, which I conducted in the group of Prof. Dr. Ludger Wöste in the period from September 1999 until December 2004. These research activities were the central part of, and financed by, the projects Asmis/Wöste of the Dedicated Research Center „Structure, Dynamics und Reactivity of Transition Metal Oxide Aggregates“ (SFB-546) and the Graduate School „Hydrogen Bonding and Hydrogen Transfer" (GK-788) of the German Research Foundation DFG. The central goal of this work was the development of novel experimental methods to characterize the structure of mass-selected gas phase cluster ions (see Chapter A). Infrared spectroscopy (Chapter B) has been a standard method for structural characterization of condensed phase samples for many decades. Its application to gas phase ions poses mainly two experimental challenges. First, the low number densities of ions attainable in the gas phase, roughly less than one million per cubic centimeter, generally prohibit direct absorption measurements. Second, most of the characteristic infrared transitions lie in the fingerprint region (500 to 2000 cm-1 ) of the electromagnetic spectrum, a region which cannot be continuously covered with the required intensity using commercially available infrared radiation sources. To address these problems a novel, mobile tandem mass spectrometer was constructed (Chapter C.1), which allows trapping, cooling, and probing of mass-selected gas phase ions. The infrared photodissociation experiments (Chapter B.1) were performed at the FOM Institute for Plasma Physics Rijnhuizen (Nieuwegein, The Netherlands) using the free electron laser FELIX (Chapter C.2). In these experiments, FELIX is used as a monochromatic “Bunsen burner”, i.e., the ions are irradiated with intense infrared radiation of a specific wavelength. If the wavelength coincides with an infrared transition, the ion is resonantly heated and eventually breaks apart (Chapter B.3). The absorption is detected indirectly by measuring the fragment ion yield, resulting in a high selectivity and sensitivity. The measured infrared spectrum is a “fingerprint” of the molecular structure and its assignment is generally based on a comparison with the simulated spectra of possible candidates. The developed techniques were applied to two research areas. As part of the SFB-546 we were able to measure the infrared spectra of small vanadium oxide ions for the first time and, based on these, characterize their geometric and electronic structure (Chapter D.1). Unexpectedly, we were able to show a correlation between the spectra of a vanadium oxide surface and cluster ion cages of moderate size (~30 atoms). As part of the GK-788 we measured the first infrared spectra of model systems containing strong hydrogen bonds in the spectral region of the shared proton modes (Chapter D.2). The characterization of the spectral signature of the protonated water dimer H₅O₂⁺, also referred to as the „Zundel cation“, was particularly noteworthy. The failure to accurately model this infrared spectrum impressively demonstrates the difficulties of present day electronic structure theory in describing strongly coupled vibrational modes. The experimental work described in this thesis was a team effort and only possible as such. Parts of this work constitute the Ph.D. and Diploma theses of Mathias Brümmer, Sara Fontanella, Oliver Gause, Cristina Kaposta, Gabriele Santambrogio, and Carlos Cibrián-Uhalte

Epicurus\u27 Scientific Method

I argued that Epicurus sought to infer all truths about what cannot be perceived (what is non-apparent , adêlon) by using what is perceived (the phenomena ) as signs of what is non-apparent. This is an empirical method, based on the claim that sensory perception shows what is true. In the case of his basic physical doctrines, Epicurus argued by a reductio ad absurdum that if the negation of the doctrine were true, there would be a conflict with what we perceive. This applies to Epicurus\u27 first two doctrines, that nothing come to be from non-being and that nothing is destroyed into nonbeing , as much as to succeeding doctrines. Contrary to the usual view (which goes back to Aristotle), Epicurus did not take over these claims from Parmenides. Instead, he proved them by opposing Parmenides\u27 conceptualism with the empirical claim that the phenomena are true. I suggest that Epicurus derived this method from the early atomists