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

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

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

A Switching Mechanism in Doxorubicin Bioactivation Can Be Exploited to Control Doxorubicin Toxicity

Although doxorubicin toxicity in cancer cells is multifactorial, the enzymatic bioactivation of the drug can significantly contribute to its cytotoxicity. Previous research has identified most of the components that comprise the doxorubicin bioactivation network; however, adaptation of the network to changes in doxorubicin treatment or to patient-specific changes in network components is much less understood. To investigate the properties of the coupled reduction/oxidation reactions of the doxorubicin bioactivation network, we analyzed metabolic differences between two patient-derived acute lymphoblastic leukemia (ALL) cell lines exhibiting varied doxorubicin sensitivities. We developed computational models that accurately predicted doxorubicin bioactivation in both ALL cell lines at high and low doxorubicin concentrations. Oxygen-dependent redox cycling promoted superoxide accumulation while NADPH-dependent reductive conversion promoted semiquinone doxorubicin. This fundamental switch in control is observed between doxorubicin sensitive and insensitive ALL cells and between high and low doxorubicin concentrations. We demonstrate that pharmacological intervention strategies can be employed to either enhance or impede doxorubicin cytotoxicity in ALL cells due to the switching that occurs between oxygen-dependent superoxide generation and NADPH-dependent doxorubicin semiquinone formation

Differential Trafficking of Oxidized LDL and Oxidized LDL Immune Complexes in Macrophages: Impact on Oxidative Stress

Oxidized low-density lipoproteins (oxLDL) and oxLDL-containing immune complexes (oxLDL-IC) contribute to formation of lipid-laden macrophages (foam cells). It has been shown that oxLDL-IC are considerably more efficient than oxLDL in induction of foam cell formation, inflammatory cytokines secretion, and cell survival promotion. Whereas oxLDL is taken up by several scavenger receptors, oxLDL-IC are predominantly internalized through the FCgamma receptor I (FCgamma RI). This study examined differences in intracellular trafficking of lipid and apolipoprotein moieties of oxLDL and oxLDL-IC and the impact on oxidative stress.Fluorescently labeled lipid and protein moieties of oxLDL co-localized within endosomal and lysosomal compartments in U937 human monocytic cells. In contrast, the lipid moiety of oxLDL-IC was detected in the endosomal compartment, whereas its apolipoprotein moiety advanced to the lysosomal compartment. Cells treated with oxLDL-IC prior to oxLDL demonstrated co-localization of internalized lipid moieties from both oxLDL and oxLDL-IC in the endosomal compartment. This sequential treatment likely inhibited oxLDL lipid moieties from trafficking to the lysosomal compartment. In RAW 264.7 macrophages, oxLDL-IC but not oxLDL induced GFP-tagged heat shock protein 70 (HSP70) and HSP70B', which co-localized with the lipid moiety of oxLDL-IC in the endosomal compartment. This suggests that HSP70 family members might prevent the degradation of the internalized lipid moiety of oxLDL-IC by delaying its advancement to the lysosome. The data also showed that mitochondrial membrane potential was decreased and generation of reactive oxygen and nitrogen species was increased in U937 cell treated with oxLDL compared to oxLDL-IC.Findings suggest that lipid and apolipoprotein moieties of oxLDL-IC traffic to separate cellular compartments, and that HSP70/70B' might sequester the lipid moiety of oxLDL-IC in the endosomal compartment. This mechanism could ultimately influence macrophage function and survival. Furthermore, oxLDL-IC might regulate the intracellular trafficking of free oxLDL possibly through the induction of HSP70/70B'