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Protein C (PC) deficiency is associated with an increased risk for venous thromboembolism (VTE). In daily practice, exclusion of a hereditary PC deficiency is often based on a single determination of PC activity, by either clotting time–based or mostly chromogenic assay. However, diagnosis of hereditary PC deficiency is challenging due to several laboratory and clinical limitations. We compared the potential of PC activity values measured by either chromogenic or clotting time–based assay to predict a variation in the PROC gene. One hundred one (35%) of 287 patients carried variations within the PROC gene, including 2 previously not published variations. In 20 (20%) patients with identified variation, PC activity, determined by chromogenic assay, was within the reference range. For prediction of an underlying genetic defect determined by chromogenic and clotting time–based assay, sensitivity was 80% versus 99%, specificity 75% versus 18%, positive predictive value 64% versus 39%, and negative predictive value (NPV) 88% versus 97%. The lower NPV of chromogenic versus clotting time–based PC assay can be mainly explained by the presence of PC deficiency type IIb. Following our proposed diagnostic algorithm, additional measurement of PC activity by clotting time–based assay in case of a positive VTE history improves detection of this subtype of PC deficiency. Considering potential therapeutic consequences for primary and especially for secondary VTE prophylaxis, genetic analysis is required not only for confirmation but also for clarification of PC deficiency.

Monitoring of direct thrombin inhibitors (DTIs) in patients with heparin-induced thrombocytopenia (HIT) is primarily performed using the activated partial thromboplastin time (aPTT). This assay is poorly standardized, reagent dependent, and not DTI specific. We compared aPTT, thrombin time (TT), and prothrombin time (PT) to drug levels obtained by the ecarin chromogenic assay (ECA). We analyzed 495 samples of patients with confirmed or suspected HIT on treatment with either argatroban (n = 37) or lepirudin (n = 80). Mean DTI levels ± standard deviation (SD) were 0.41 ± 0.36 µg/mL for argatroban and 0.20 ± 0.21 µg/mL for lepirudin. Results of aPTT were highly variable: 67 ± 22 seconds for argatroban and 55 ± 20 seconds for lepirudin. Significant correlations (P < .01) were found between ECA-based DTI level and TT (argatroban, r = .820 and lepirudin, r = .830), PT (argatroban, r = −.544), and aPTT (lepirudin, r = .572). However, there was no correlation of aPTT with argatroban or PT with lepirudin concentration. Multiple regression analyses revealed that the TT predicted 54% of argatroban and 42% of lepirudin levels, but no significant impact was seen for PT or aPTT. The aPTT-guided monitoring of DTI therapy leads to a high percentage of patients with inaccurate plasma levels, hence resulting to either undertreatment or overtreatment. Knowledge of baseline values prior to DTI therapy and inclusion of clinical settings are essential for dosing DTIs when using aPTT. However, due to several limitations of aPTT, monitoring according to exact plasma concentrations as obtained by specific tests such as ECA may be more appropriate.

Background Argatroban or lepirudin anticoagulation therapy in patients with heparin induced thrombocytopenia (HIT) or HIT suspect is typically monitored using the activated partial thromboplastin time (aPTT). Although aPTT correlates well with plasma levels of argatroban and lepirudin in healthy volunteers, it might not be the method of choice in critically ill patients. However, in-vivo data is lacking for this patient population. Therefore, we studied in vivo whether ROTEM or global clotting times would provide an alternative for monitoring the anticoagulant intensity effects in critically ill patients. Methods This study was part of the double-blind randomized trial “Argatroban versus Lepirudin in critically ill patients (ALicia)”, which compared critically ill patients treated with argatroban or lepirudin. Following institutional review board approval and written informed consent, for this sub-study blood of 35 critically ill patients was analysed. Before as well as 12, 24, 48 and 72 h after initiation of argatroban or lepirudin infusion, blood was analysed for aPTT, aPTT ratios, thrombin time (TT), INTEM CT,INTEM CT ratios, EXTEM CT, EXTEM CT ratios and maximum clot firmness (MCF) and correlated with the corresponding plasma concentrations of the direct thrombin inhibitor. Results To reach a target aPTT of 1.5 to 2 times baseline, median [IQR] plasma concentrations of 0.35 [0.01–1.2] μg/ml argatroban and 0.17 [0.1–0.32] μg/ml lepirudin were required. For both drugs, there was no significant correlation between aPTT and aPTT ratios and plasma concentrations. INTEM CT, INTEM CT ratios, EXTEM CT, EXTEM CT ratios, TT and TT ratios correlated significantly with plasma concentrations of both drugs. Additionally, agreement between argatroban plasma levels and EXTEM CT and EXTEM CT ratios were superior to agreement between argatroban plasma levels and aPTT in the Bland Altman analysis. MCF remained unchanged during therapy with both drugs. Conclusion In critically ill patients, TT and ROTEM parameters may provide better correlation to argatroban and lepirudin plasma concentrations than aPTT. Trial registration ClinicalTrials.gov , NCT00798525 , registered on 25 Nov 2008

Mast cell disease is an epigenetically and genetically determined disease entity with very diverse clinical manifestations in potentially every system and tissue due to inap pro priate release of variable subsets of mast cell mediators together with accumulation of either morphologically normal or altered mast cells. Easy bruising, excessive bleeding, and aberrancies of erythropoiesis can frequently be observed in patients with mast cell disease. A thorough history, including a family history, will guide the appropriate work-up, and laboratory evaluations may provide clues to diagnosis. In recent years, our understanding of the involvement of coagulation and anticoagulant pathways, the fibrinolytic system, and erythropoiesis in the pathophysiology of mast cell disease has increased considerably. This review summarizes current knowledge of the impact of the disturbed hemostatic and erythropoietic balance in patients with mast cell disease and describes options of treatment.

Erlebnispädagogik im deutschen Sprachraum hat sich in den letzten 30 Jahren von einem Schattendasein zu einer anerkannten Methode entwickelt. Diese Entwicklung ist, nach einer längeren Suchbewegung, mit einer anhaltenden Qualitätsentwicklung verbunden. Neben Qualitätsmerkmalen wie Standards und Zertifizierungen ist es vor allem die Arbeit an einem Berufsbild, welche im Zentrum der Arbeit verschiedener Gremien steht. Der Artikel erläutert die Entwicklung der Professionalisierungsansätze, erklärt allgemeine Hintergründe zu Berufsbildern um danach auf das spezifische Berufsbild der Erlebnispädagogik einzugehen. Weiterhin wird der Berufsbildprozess erläutert, welcher in seinen Zielen über das Berufsbild hinaus weitergeht. (DIPF/Orig.).

The phenotypic diagnosis of von Willebrand disease (VWD) is a multistep process with classification dependent on the quantification of von Willebrand factor (VWF) multimeric structure. VWF multimer analysis is a technically challenging, lengthy and non‐standardised assay, usually performed in specialist laboratories. Recently, a new semi‐automated multimer assay, the Hydragel 5 von Willebrand multimers (H5VWM) has become available. This study, performed in two European centres, compared existing in‐house multimer assays to the H5VWM in individuals with and without VWD. Overall agreement of 91.1% was observed in 74 individuals with normal VWF levels, 57 patients grouped as type 1 VWD, 33 type 2A, 16 type 2B, 28 type 2M, 11 type 2N. Patients tested following Desmopressin or VWF concentrate, with thrombotic thrombocytopenic purpura and acquired von Willebrand syndrome were also evaluated. Many of the discrepancies between methods were in patients with genetic mutations linked to more than one type of VWD including p.R1374C/H and p.R1315C. Quantifiable multimer results were available within one working day. Densitometry improved the interpretation of the multimers with slight structural variations that were not apparent by visual inspection of the in‐house method. 5VWM was a rapid, sensitive, standardised assay which used existing technology and could be included as an initial screen of VWF multimers in a VWD diagnostic algorithm in conjunction with traditional multimer analysis.

In diesem Buch wird erstmals die multimodale interdisziplinäre Komplexbehandlung der ANOA (Arbeitsgemeinschaft nicht operativer orthopädischer manualmedizinischer Akutkliniken) umfassend dargestellt. In den ANOA-Kliniken arbeitet ein interdisziplinäres Ärzte-, Psychologen- und Therapeutenteam, um Schmerzerkrankungen des Bewegungssystems multimodal zu diagnostizieren und zu behandeln. Das Therapiekonzept ist ausgerichtet auf die Behandlung akuter Schmerzen und Funktionsstörungen und dem Aufbau medizinischer, psychologischer und sozialer Hilfen zur Bewältigung der Erkrankung und zur Verbesserung der Lebensqualität. Im Zentrum des Buches stehen die Diagnostik (morphologisch, funktionell und psychologisch) sowie die Therapie, für die eigene Behandlungspfade entwickelt wurden. Die Autoren präsentieren strukturelle Voraussetzungen, Team und Teamwork, Behandlungsqualität und Abrechnung und stellen die bisherige wissenschaftliche Datenlage vor.

The complexity of forest structures plays a crucial role in regulating forest ecosystem functions and strongly influences biodiversity. Yet, knowledge of the global patterns and determinants of forest structural complexity remains scarce. Using a stand structural complexity index based on terrestrial laser scanning, we quantify the structural complexity of boreal, temperate, subtropical and tropical primary forests. We find that the global variation of forest structural complexity is largely explained by annual precipitation and precipitation seasonality (R² = 0.89). Using the structural complexity of primary forests as benchmark, we model the potential structural complexity across biomes and present a global map of the potential structural complexity of the earth´s forest ecoregions. Our analyses reveal distinct latitudinal patterns of forest structure and show that hotspots of high structural complexity coincide with hotspots of plant diversity. Considering the mechanistic underpinnings of forest structural complexity, our results suggest spatially contrasting changes of forest structure with climate change within and across biomes. Forest structure depends both on extrinsic factors such as climate and on intrinsic properties such as community composition and diversity. Here, the authors use a dataset of stand structural complexity based on LiDAR measurements to build a global map of structural complexity for primary forests, and find that precipitation variables best explain global patterns of forest structural complexity.

We use a hybrid fluorescence spectroscopic toolkit to monitor T4 Lysozyme (T4L) in action by unraveling the kinetic and dynamic interplay of the conformational states. In particular, by combining single-molecule and ensemble multiparameter fluorescence detection, EPR spectroscopy, mutagenesis, and FRET-positioning and screening, and other biochemical and biophysical tools, we characterize three short-lived conformational states over the ns-ms timescale. The use of 33 FRET-derived distance sets, to screen available T4L structures, reveal that T4L in solution mainly adopts the known open and closed states in exchange at 4 µs. A newly found minor state, undisclosed by, at present, more than 500 crystal structures of T4L and sampled at 230 µs, may be actively involved in the product release step in catalysis. The presented fluorescence spectroscopic toolkit will likely accelerate the development of dynamic structural biology by identifying transient conformational states that are highly abundant in biology and critical in enzymatic reactions. T4 Lysozyme (T4L) is a model protein whose structure is extensively studied. Here the authors combine single-molecule and ensemble FRET measurements, FRET-positioning and screening and EPR spectroscopy to study the structural dynamics of T4L and describe its conformational landscape during the catalytic cycle by an extended Michaelis–Menten mechanism and identify an excited conformational state of the enzyme.