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Introduction Approximately one third of all patients with cardiogenic shock suffer from acute kidney injury. Percutaneous coronary intervention, intra-aortic balloon pump, and continuous renal replacement therapy (CRRT) require effective antiplatelet therapy and anticoagulation, resulting in a high risk for platelet loss and bleeding events. The reversible platelet glycoprotein IIb/IIIa receptor inhibitor tirofiban was investigated to preserve platelet number and activation in a prospective open-blinded endpoint evaluation study. Methods Forty patients with cardiogenic shock and acute kidney injury requiring CRRT were randomly assigned to two groups receiving unfractioned heparin (UFH) (n = 20) or a combined anticoagulation with UFH and tirofiban (n = 20). The primary endpoint was platelet loss during CRRT. Secondary endpoints were urea reduction, haemofilter life span, bleeding events, and necessity for platelet transfusions. Results In UFH-treated patients, the percentage of platelet-monocyte aggregates significantly increased (P < 0.001) and consecutively platelet cell count significantly decreased (P < 0.001). In contrast, combined treatment with UFH and tirofiban significantly decreased platelet-monocyte aggregates and platelet numbers (P < 0.001). Conclusions This pilot study provides evidence that the use of tirofiban in addition to UFH prevents platelet loss and preserves platelet function in patients with cardiogenic shock and acute kidney injury requiring CRRT. The pathophysiological inhibition of platelet aggregation and platelet-monocyte interaction appears to be causally involved.

A new synthetic strategy for the simple and high yielding preparation of arrays of 2′-amido-2′-deoxyadenosine derivatives ready for biological testing without the need for chromatographic purification is described. Acids are coupled to the Kenner or Ellman safety catch linker, respectively, activated by cyanomethylation and subsequently transferred to the 2′-amino group of 2′-amino-2′-deoxyadenosine.

The attachment of linker molecules to polymer beads used as insoluble supports for organic synthesis is a frequent requirement. Defined immobilization of these linker molecules before loading selected building blocks is crucial for subsequent transformations. Therefore, the control of the linker attachment is a central task. Because the molecular bodies of linkers are not incorporated in the final molecules, they can often be replaced or modified without affecting the structure of the products that are finally released. Consequently, it seems straightforward to look for coloured substitutes to established linker molecules. By using coloured linkers, visual inspection of the beads enables fast property estimation after attachment and monitoring of losses during synthesis. This very simple estimation does not have a validated loading determination, but is a useful element of straightforward and non-destructive reaction control that has general applicability. Here we present a red azo dye as an alternative to the Kenner safety-catch linker.

Die demokratische Verfassung im Deutschen Reiches war jung und ungesichert, als Ende der zwanziger Jahre die Weltwirtschaftskrise die okonomischen Grundlagen des Staates zutiefst erschutterte. Die Wahlerschaft der beiden linken Parteien, der Sozialdemokraten und Kommunisten, erwies sich als weitgehend stabil. Sie betrug bei allen Reichswahlen von 1920 bis 1933 zwischen 33% und 43%. Ebenso ist die Loyalitat der katholischen Zentrumspartei, in Verbindung mit der Bayerischen Volkspartei, und ihrer zwischen 14% und 18% schwankenden Wahlerschaft unbestritten. Nur 1933 erhielten die katholischen und sozialistischen Parteien zusammen weniger als 50% der Stimmen. Der Stimmanteil dieser Parteien scheint von den wirtschaftlichen Entwicklungen weitgehend unbeeinflust geblieben zu sein.

Introduction: Even though bleeding and thromboembolic events are major complications of extracorporeal membrane oxygenation (ECMO), data on the incidence of venous thrombosis (VT) and thromboembolism (VTE) under ECMO are scarce. Aims and objectives: This study analyzes the incidence and predictors of venous thrombosis and thromboembolism in patients treated with ECMO due to respiratory failure. Methods: Retrospective analysis of 102 patients treated on ECMO in our center from 04/2010 to 11/2015. Patients with thromboembolic events prior to admission were excluded. Diagnosis was made by imaging in survivors and postmortem examination in deceased patients. Results: We identified 42 survivors and 21 autopsy cases (mean age 46.0 ± 14.4 years; 37 (58.7%) male). 34 patients (54.0%) underwent ECMO therapy due to ARDS, 29 Patients (46.0%) with chronic organ failure were bridged to lung transplantation. Despite systemic anticoagulation at a mean PTT of 50.6 ± 12.8 s, (VT/VTE 47.0 ± 12.3 s and no VT/VTE 53.63 ± 12.51 s (P = 0.037)), VT and/or VTE were observed in 29 cases (46.1%). The rate of V. cava thrombosis was 15/29 (51.7%). Diagnosis of pulmonary embolism prevailed in deceased patients (5/21 (23.8%) versus 2/42 (4.8%) (P= 0.036). In a multivariable analysis only aPTT and time on ECMO predicted VT/VTE. There was no difference in the incidence of clinically diagnosed VT in ECMO survivors and autopsy findings. Conclusions: Venous thrombosis and thromboembolism following ECMO therapy are frequent and might influence outcome. Quality of anticoagulation and ECMO runtime predicted thromboembolic events. Current aPTT recommendations might be too low.

Combinatorial chemistry with a newly-developed screening procedure using complementary fluorescein- and rhodamine-labelled oligonucleotides (below) has been used to select peptide dsDNA binding ligands. A high structure–affinity relationship of the dsDNA-binding unnatural peptide was observed.

With focus on exploring the structural demands of adenosine triphosphate pockets of different target enzymes, the 3'-amido-3'-deoxyadenosines 1-7 were synthesized. The inhibitory activity of these compounds on a selected cyclin-dependent kinase as model target in anticancer research was evaluated in vitro. A starfish oocyte enzyme based assay revealed a decreased inhibitory activity in comparison to adenosine. Consequently, the introduction of spacefilling lipophilic 3'-amido substituents alters the enzyme inhibition in an unfavorable manner.

A congeneric series of paullones were characterized using a 3-D QSAR with cyclin-dependent kinase 1 (CDK1) inhibition data. A homology model of CDK1-cyclin B was developed from the crystal structure of CDK2-cyclin A, which subsequently served as the basis for the structure-based design. Paullones were docked into the ATP binding site of the CDK1-cylin B models and were optimized with molecular mechanics. Hydropathic analyses of the paullone-CDK1 complexes were performed after the atom types were assigned based on each ligand's electronic properties calculated from quantum mechanics. Hydropathic descriptors formed a significant multiple regression equation that predicts paullone IC50 data. The results indicate that the combination of hydropathic descriptors with molecular mechanics geometries are sufficient to design overt steric and chemical complementarity of the ligands. However, the electronic properties derived from quantum mechanics helped direct synthetic chemistry efforts to produce ligands that promote better charge transfer and strengthen hydrogen bonding as facilitated by resonance stabilization. Compounds with low affinity for CDK1 were poor charge acceptors and made less than ideal hydrogen bonding arrangements with the receptor. These considerations led to the prediction that structures such as 9-cyanopaullone would be considerably more potent than the parent compound, a finding supported by enzyme inhibition data. Also, 9-nitropaullone emerged as a paullone which also had similar potency in enzyme inhibition as well as a favorable anti-proliferative activity profile in living cells.

Introduction Stimulation of beta2-adrenergic receptors (β2-ARs) inhibits tumor necrosis factor-alpha (TNF-α) release in monocytes. In septic shock, endogenous catecholamines induce β2-AR downregulation, leading to an increased TNF-α release. The aims of this study were to analyze the molecular mechanisms of β-adrenergic downregulation and to explore therapeutic interventions with maintained anti-inflammatory efficacy in septic shock using the inhibition of phosphodiesterase 4 (PDE4). Methods We conducted in vitro stimulation of peripheral blood mononuclear cells of healthy volunteers (n = 20) and patients with septic shock (n = 20) with lipopolysaccharide (LPS) or Staphylococcus aureus enterotoxin B (SEB) without or with isoprenaline, forskolin (an activator of adenylate cyclase), or ropipram (an inhibitor of PDE4). We also conducted flow cytometric analysis of Toll-like receptor (TLR) 4 and TLR2 surface expression and intracellular TNF-α production of untreated and stimulated CD14+ monocytes. Protein expression of β-ARs, of G proteins, of adenylate cyclase, and of TLRs was measured by Western blotting. Results Investigations were done by LPS (100 ng/mL) or SEB (10 ng/mL) when TLR4 and TLR2 were maximally expressed. LPS- or SEB-treated CD14+ monocytes of healthy volunteers were able to produce TNF-α. This effect was attenuated by isoprenaline, forskolin, or rolipram in a concentration-dependent manner. In CD14+ monocytes of patients with septic shock, the anti-inflammatory effect of isoprenaline was completely blunted whereas efficacy of forskolin and rolipram was maintained. CD14+ monocytes of healthy volunteers were compared with patients with septic shock: protein expression of β2-ARs was reduced and inhibitory G protein was increased, whereas no changes in adenylate cyclase and stimulatory G protein were found. Conclusions In septic shock, the anti-inflammatory effects of catecholamines are blunted by downregulation of β2-ARs and upregulation of the inhibitory G protein in CD14+ monocytes. Beta-adrenergic downregulation is overcome by inhibitors of PDE4. These results provide a mechanistic rationale for the therapeutic use of selective PDE4 inhibitors in the treatment of septic shock.

Introduction Regional citrate anticoagulation is safe, feasible and increasingly used in critically ill patients on continuous renal replacement therapy (CRRT). However, in patients with hepatic or multi-organ dysfunction, citrate accumulation may lead to an imbalance of calcium homeostasis. The study aimed at evaluating the incidence and prognostic relevance of an increased total to ionized calcium ratio (T/I Ca2+ ratio) and its association to hepatic dysfunction. Methods We performed a prospective observational study on n = 208 critically ill patients with acute kidney injury (AKI) and necessity for CRRT with regional citrate anticoagulation (CRRT-citrate) between September 2009 and September 2011. Critical illness was estimated by Simplified Acute Physiology Score II; hepatic function was measured with indocyanine green plasma disappearance rate. After achieving a steady state of calcium homeostasis patients were classified into tertiles according to the T/I Ca2+ ratio (