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

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

Dinitrogen Activation in the Gas Phase: Spectroscopic Characterization of C–N Coupling in the V₃C⁺ + N₂ Reaction

We report on cluster-mediated C–N bond formation in the gas phase using N2 as a nitrogen source. The V3C+ + N2 reaction is studied by a combination of ion-trap mass spectrometry with infrared photodissociation (IRPD) spectroscopy and complemented by electronic structure calculations. The proposed reaction mechanism is spectroscopically validated by identifying the structures of the reactant and product ions. V3C+ exhibits a pyramidal structure of C1 symmetry. N2 activation is initiated by adsorption in an end-on fashion at a vanadium site, followed by spontaneous cleavage of the N≡N triple bond and subsequent C−N coupling. The IRPD spectrum of the metal nitride product [NV3(C=N)]+ exhibits characteristic C=N double bond (1530 cm-1) and V-N single bond (770, 541 and 522 cm-1) stretching bands

Wirkungsweise alter und neuer Antikoagulanzien

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 bieten. = Atrial fibrillation, venous thromboembolism, and valvular heart disease are the most common indications for treatment with anticoagulants. Regarding the high incidence of these diseases, it can be assumed that about 1% of the population takes oral anticoagulants. Approximately one third of the patients hospitalized in a surgical clinic receive vitamin K antagonists. Hence, general practitioners and specialists in hospitals as well as in private practice are constantly faced with different options of anticoagulatory treatment. In numerous situations, inhibitors of coagulation exhibit a substantial benefit. However, this is only achieved by accepting an increased risk of bleeding. To walk the tightrope between too much and insufficient anticoagulatory action is an important challenge in clinical practice. Knowledge of the mechanisms underlying pharmacological anticoagulation is crucial in order to evaluate the indications for and efficiently manage anticoagulant therapy. Ideally, the aim of an adequate anticoagulation should be to guarantee sufficient hemostasis in combination with simultaneous prevention of thrombus formation. This article intends to provide an overview of the coagulation system and established as well as novel pharmacological targets

Acute maternal oxidant exposure causes susceptibility of the fetal brain to inflammation and oxidative stress

Background Maternal exposure to environmental stressors poses a risk to fetal development. Oxidative stress (OS), microglia activation, and inflammation are three tightly linked mechanisms that emerge as a causal factor of neurodevelopmental anomalies associated with prenatal ethanol exposure. Antioxidants such as glutathione (GSH) and CuZnSOD are perturbed, and their manipulation provides evidence for neuroprotection. However, the cellular and molecular effects of GSH alteration in utero on fetal microglia activation and inflammation remain elusive. Methods Ethanol (EtOH) (2.5 g/kg) was administered to pregnant mice at gestational days 16–17. One hour prior to ethanol treatment, N-acetylcysteine (NAC) and L-buthionine sulfoximine (BSO) were administered to modulate glutathione (GSH) content in fetal and maternal brain. Twenty-four hours following ethanol exposure, GSH content and OS in brain tissues were analyzed. Cytokines and chemokines were selected based on their association with distinctive microglia phenotype M1-like (IL-1β, IFN γ, IL-6, CCL3, CCL4, CCL-7, CCL9,) or M2-like (TGF-β, IL-4, IL-10, CCL2, CCL22, CXCL10, Arg1, Chi1, CCR2 and CXCR2) and measured in the brain by qRT-PCR and ELISA. In addition, Western blot and confocal microscopy techniques in conjunction with EOC13.31 cells exposed to similar ethanol-induced oxidative stress and redox conditions were used to determine the underlying mechanism of microglia activation associated with the observed phenotypic changes. Results We show that a single episode of mild to moderate OS in the last trimester of gestation causes GSH depletion, increased protein and lipid peroxidation and inflammatory responses inclined towards a M1-like microglial phenotype (IL-1β, IFN-γ) in fetal brain tissue observed at 6–24 h post exposure. Maternal brain is resistant to many of these marked changes. Using EOC 13.31 cells, we show that GSH homeostasis in microglia is crucial to restore its anti-inflammatory state and modulate inflammation. Microglia under oxidative stress maintain a predominantly M1 activation state. Additionally, GSH depletion prevents the appearance of the M2-like phenotype, while enhancing morphological changes associated with a M1-like phenotype. This observation is also validated by an increased expression of inflammatory signatures (IL-1β, IFN-γ, IL-6, CCL9, CXCR2). In contrast, conserving intracellular GSH concentrations eliminates OS which precludes the nuclear translocation and more importantly the phosphorylation of the NFkB p105 subunit. These cells show significantly more pronounced elongations, ramifications, and the enhanced expression of M2-like microglial phenotype markers (IL-10, IL-4, TGF-β, CXCL10, CCL22, Chi, Arg, and CCR2). Conclusions Taken together, our data show that maintaining GSH homeostasis is not only important for quenching OS in the developing fetal brain, but equally critical to enhance M2 like microglia phenotype, thus suppressing inflammatory responses elicited by environmental stressors

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

The unacknowledged legacy

This paper presents a critical discussion of the treatment of mimetic art, and particularly poetry and the theatre, in the work of the Athenian philosopher Plato (427-347 BC). It centres on Plato's discussion of the corrupting powers of the arts in the Republic, and the implications that his fierce attack on poetry and theatre have for his construction of the ideal polity. The legacy of Platonic ideas in later elaborations of the corrupting power of the arts is discussed. Furthermore, the paper investigates the relationship between current debates on cultural policy and the Platonic idea that the transformative powers of the arts ought to be harnessed by the state to promote a just society. The conclusion thus reached is that “instrumental cultural policy”, rather then being a modern invention, was in fact first theorized precisely in Plato's Republic

Gas phase vibrational spectroscopy of cold (TiO2)−n (n = 3–8) clusters

We report infrared photodissociation (IRPD) spectra for the D2-tagged titanium oxide cluster anions (TiO2)−n with n = 3–8 in the spectral region from 450 to 1200 cm−1. The IRPD spectra are interpreted with the aid of harmonic spectra from BP86/6-311+G* density functional theory calculations of energetically low-lying isomers. We conclusively assign the IRPD spectra of the n = 3 and n = 6 clusters to global minimum energy structures with Cs and C2 symmetry, respectively. The vibrational spectra of the n = 4 and n = 7 clusters can be attributed to contributions of at most two low-lying structures. While our calculations indicate that the n = 5 and n = 8 clusters have many more low-lying isomers than the other clusters, the dominant contributions to their spectra can be assigned to the lowest energy structures. Through comparison between the calculated and experimental spectra, we can draw conclusions about the size-dependent evolution of the properties of (TiO2)−n clusters, and on their potential utility as model systems for catalysis on a bulk TiO2 surface