Recombinant human activated protein C resets thrombin generation in patients with severe sepsis – a case control study

INTRODUCTION: Recombinant human activated protein C (rhAPC) is the first drug for which a reduction of mortality in severe sepsis has been demonstrated. However, the mechanism by which this reduction in mortality is achieved is still not clearly defined. The aim of the present study was to evaluate the dynamics of the anticoagulant, anti-inflammatory and pro-fibrinolytic action of rhAPC in patients with severe sepsis, by comparing rhAPC-treated patients with case controls. METHODS: In this prospectively designed multicenter case control study, 12 patients who were participating in the ENHANCE study, an open-label study of rhAPC in severe sepsis, were treated intravenously with rhAPC at a constant rate of 24 μg/kg/h for a total of 96 h. Twelve controls with severe sepsis matching the inclusion criteria received standard therapy. The treatment was started within 48 h after the onset of organ failure. Blood samples were taken before the start of the infusion and at 4, 8, 24, 48, 96 and 168 h, for determination of parameters of coagulation and inflammation. RESULTS: Sepsis-induced thrombin generation as measured by thrombin-antithrombin complexes and prothrombin fragment F1+2, was reset by rhAPC within the first 8 h of infusion. The administration of rhAPC did not influence parameters of fibrinolysis and inflammation. There was no difference in outcome or occurrence of serious adverse events between the treatment group and the control group. CONCLUSION: Sepsis-induced thrombin generation in severely septic patients is reset by rhAPC within the first 8 h of infusion without influencing parameters of fibrinolysis and inflammation

The effects of continuous venovenous hemofiltration on coagulation activation

INTRODUCTION: The mechanism of coagulation activation during continuous venovenous hemofiltration (CVVH) has not yet been elucidated. Insight into the mechanism(s) of hemostatic activation within the extracorporeal circuit could result in a more rational approach to anticoagulation. The aim of the present study was to investigate whether CVVH using cellulose triacetate filters causes activation of the contact factor pathway or of the tissue factor pathway of coagulation. In contrast to previous studies, CVVH was performed without anticoagulation. METHODS: Ten critically ill patients were studied prior to the start of CVVH and at 5, 15 and 30 minutes and 1, 2, 3 and 6 hours thereafter, for measurement of prothrombin fragment F1+2, soluble tissue factor, activated factor VII, tissue factor pathway inhibitor, kallikrein–C1-inhibitor and activated factor XII–C1-inhibitor complexes, tissue-type plasminogen activator, plasminogen activator inhibitor type I, plasmin–antiplasmin complexes, protein C and antithrombin. RESULTS: During the study period the prothrombin fragment F1+2 levels increased significantly in four patients (defined as group A) and did not change in six patients (defined as group B). Group A also showed a rapid increase in transmembrane pressure, indicating clotting within the filter. At baseline, the activated partial thromboplastin time, the prothrombin time and the kallikrein–C1-inhibitor complex and activated factor XII–C1-inhibitor complex levels were significantly higher in group B, whereas the platelet count was significantly lower in group B. For the other studied markers the differences between group A and group B at baseline were not statistically significant. During CVVH the difference in the time course between group A and group B was not statistically significant for the markers of the tissue factor system (soluble tissue factor, activated factor VII and tissue factor pathway inhibitor), for the markers of the contact system (kallikrein–C1-inhibitor and activated factor XII–C1-inhibitor complexes) and for the markers of the fibrinolytic system (plasmin–antiplasmin complexes, tissue-type plasminogen activator and plasminogen activator inhibitor type I). CONCLUSION: Early thrombin generation was detected in a minority of intensive care patients receiving CVVH without anticoagulation. Systemic concentrations of markers of the tissue factor system and of the contact system did not change during CVVH. To elucidate the mechanism of clot formation during CVVH we suggest that future studies are needed that investigate the activation of coagulation directly at the site of the filter. Early coagulation during CVVH may be related to lower baseline levels of markers of contact activation

Design of the DIRECT-project: interventions to increase job resources and recovery opportunities to improve job-related health, well-being, and performance outcomes in nursing homes

Background Because of high demands at work, nurses are at high risk for occupational burnout and physical complaints. The presence of job resources (such as job autonomy or social support) and recovery opportunities could counteract the adverse effect of high job demands. However, it is still unclear how job resources and recovery opportunities can be translated into effective workplace interventions aiming to improve employee health, well-being, and performance-related outcomes. The aim of the current research project is developing and implementing interventions to optimize job resources and recovery opportunities, which may lead to improved health, well-being and performance of nurses. Methods/design The DIRECT-project (DIsc Risk Evaluating Controlled Trial) is a longitudinal, quasi-experimental field study. Nursing home staff of 4 intervention wards and 4 comparison wards will be involved. Based on the results of a base-line survey, interventions will be implemented to optimize job resources and recovery opportunities. After 12 and 24 month the effect of the interventions will be investigated with follow-up surveys. Additionally, a process evaluation will be conducted to map factors that either stimulated or hindered successful implementation as well as the effectiveness of the interventions. Discussion The DIRECT-project fulfils a strong need for intervention research in the field of work, stress, performance, and health. The results could reveal (1) how interventions can be tailored to optimize job resources and recovery opportunities, in order to counteract job demands, and (2) what the effects of these interventions will be on health, well-being, and performance of nursing staff

Cross-cultural adaptation and validation of the VISA-A questionnaire for German-speaking Achilles tendinopathy patients

<p>Abstract</p> <p>Background</p> <p>Achilles tendinopathy is the predominant overuse injury in runners. To further investigate this overload injury in transverse and longitudinal studies a valid, responsive and reliable outcome measure is demanded. Most questionnaires have been developed for English-speaking populations. This is also true for the VISA-A score, so far representing the only valid, reliable, and disease specific questionnaire for Achilles tendinopathy. To internationally compare research results, to perform multinational studies or to exclude bias originating from subpopulations speaking different languages within one country an equivalent instrument is demanded in different languages. The aim of this study was therefore to cross-cultural adapt and validate the VISA-A questionnaire for German-speaking Achilles tendinopathy patients.</p> <p>Methods</p> <p>According to the "guidelines for the process of cross-cultural adaptation of self-report measures" the VISA-A score was cross-culturally adapted into German (VISA-A-G) using six steps: Translation, synthesis, back translation, expert committee review, pretesting (n = 77), and appraisal of the adaptation process by an advisory committee determining the adequacy of the cross-cultural adaptation. The resulting VISA-A-G was then subjected to an analysis of reliability, validity, and internal consistency in 30 Achilles tendinopathy patients and 79 asymptomatic people. Concurrent validity was tested against a generic tendon grading system (Percy and Conochie) and against a classification system for the effect of pain on athletic performance (Curwin and Stanish).</p> <p>Results</p> <p>The "advisory committee" determined the VISA-A-G questionnaire as been translated "acceptable". The VISA-A-G questionnaire showed moderate to excellent test-retest reliability (ICC = 0.60 to 0.97). Concurrent validity showed good coherence when correlated with the grading system of Curwin and Stanish (rho = -0.95) and for the Percy and Conochie grade of severity (rho 0.95). Internal consistency (Cronbach's alpha) for the total VISA-A-G scores of the patients was calculated to be 0.737.</p> <p>Conclusion</p> <p>The VISA-A questionnaire was successfully cross-cultural adapted and validated for use in German speaking populations. The psychometric properties of the VISA-A-G questionnaire are similar to those of the original English version. It therefore can be recommended as a sufficiently robust tool for future measuring clinical severity of Achilles tendinopathy in German speaking patients.</p

Adenosine A2A receptor modulation of hippocampal CA3-CA1 synapse plasticity during associative learning in behaving mice

© 2009 Nature Publishing Group All rights reservedPrevious in vitro studies have characterized the electrophysiological and molecular signaling pathways of adenosine tonic modulation on long-lasting synaptic plasticity events, particularly for hippocampal long-term potentiation(LTP). However, it remains to be elucidated whether the long-term changes produced by endogenous adenosine in the efficiency of synapses are related to those required for learning and memory formation. Our goal was to understand how endogenous activation of adenosine excitatory A2A receptors modulates the associative learning evolution in conscious behaving mice. We have studied here the effects of the application of a highly selective A2A receptor antagonist, SCH58261, upon a well-known associative learning paradigm - classical eyeblink conditioning. We used a trace paradigm, with a tone as the conditioned stimulus (CS) and an electric shock presented to the supraorbital nerve as the unconditioned stimulus(US). A single electrical pulse was presented to the Schaffer collateral–commissural pathway to evoke field EPSPs (fEPSPs) in the pyramidal CA1 area during the CS–US interval. In vehicle-injected animals, there was a progressive increase in the percentage of conditioning responses (CRs) and in the slope of fEPSPs through conditioning sessions, an effect that was completely prevented (and lost) in SCH58261 (0.5 mg/kg, i.p.)-injected animals. Moreover, experimentally evoked LTP was impaired in SCH58261- injected mice. In conclusion, the endogenous activation of adenosine A2A receptors plays a pivotal effect on the associative learning process and its relevant hippocampal circuits, including activity-dependent changes at the CA3-CA1 synapse.This study was supported by grants from the Spanish Ministry of Education and Research (BFU2005-01024 and BFU2005-02512), Spanish Junta de Andalucía (BIO-122 and CVI-02487), and the Fundación Conocimiento y Cultura of the Pablo de Olavide University (Seville, Spain).B. Fontinha was in receipt of a studentship from a project grant (POCI/SAU-NEU/56332/2004) supported by Fundação para a Ciência e Tecnologia (FCT, Portugal), and of an STSM from Cost B30 concerted action of the EU

Evaluation of the ADOS Revised Algorithm: The Applicability in 558 Dutch Children and Adolescents

The revised ADOS algorithms, proposed by Gotham et al. (J Autism Dev Disord 37:613–627, 2007), were investigated in an independent sample of 558 Dutch children (modules 1, 2 and 3). The revised algorithms lead to better balanced sensitivity and specificity for modules 2 and 3, without losing efficiency of the classification. Including the restricted repetitive behaviour domain in the algorithm contributes to a clinical ASD classification in modules 2 and 3. For module 1, the results indicate less improvement, probably due to the low-functioning population. In most groups, the advantages of the revised algorithms are achieved without losing the strength of the original algorithm