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Myeloperoxidase (MPO) is a cationic heme enzyme stored in neutrophilic polymorphonuclear leukocytes (PMNs) that has recently been implicated in inflammatory cell signaling and tissue damage. Although PMNs play a critical role in both innate immunity and vascular thrombosis, no previous study has systematically investigated the effect of MPO on blood coagulation. Here, we show that PMN-derived MPO inhibits the procoagulant activity (PCA) of lipidated recombinant human tissue factor (rhTF) in a time- and concentration-dependent manner that involves, but is not entirely dependent on the enzyme's catalytic activity. Similarly, MPO together with its substrate, H2O2, inhibited the PCA of plasma microvesicles isolated from lipopolysaccharide (LPS)-stimulated whole blood, an effect additive to that of a function blocking TF antibody. Treatment of whole blood with LPS or phorbol-myristate-acetate dramatically increased MPO plasma levels, and co-incubation with 4-ABAH, a specific MPO inhibitor, significantly enhanced the PCA in plasma supernatants. MPO and MPO/H2O2 also inhibited the PCA of activated platelets and purified phospholipids (PLs), suggesting that modulation of negatively charged PLs, i.e., phosphatidylserine, rather than direct interference with the TF/FVIIa initiation complex was involved. Consistently, pretreatment of activated platelets with MPO or MPO/H2O2 attenuated the subsequent binding of lactadherin, which specifically recognizes procoagulant PS on cell membranes. Finally, endogenously released MPO regulated the PCA of THP1 cells in an autocrine manner dependent on the binding to CD11b/CD18 integrins. Collectively, these findings indicate that MPO is a negative regulator of PL-dependent coagulation and suggest a more complex role of activated PMNs in haemostasis and thrombosis.

Characteristic features of disseminated intravascular coagulation (DIC) are the opposing risks of bleeding (due to consumptive coagulopathy and hyperfibrinolysis) and organ failure (due to widespread microvascular thromboses). The purpose of anticoagulation in DIC is to attenuate excessive thrombin generation and fibrin deposition. While heparins have been shown to be beneficial in this context, the safety and efficacy of direct oral anticoagulants have not yet been sufficiently addressed. Here, we report two patients in whom chronic DIC was stabilized upon administration of apixaban: an elderly male with aortic dissection presenting with significant mucocutaneous bleeding and a younger female with Klippel-Trénaunay-Weber syndrome presenting with multiple superficial vein thromboses (SVTs). In addition to an improvement in DIC parameters, both patients benefited clinically with resolution of bleeding symptoms and prevention of further SVTs, respectively. Oral apixaban thus showed promising safety and efficacy in the management of DIC caused by vascular abnormalities; still further investigations are needed to support these findings.Zu den charakteristischen Komplikationen der disseminierten intravasalen Gerinnung (

This paper describes a user study on the interaction with an in-vehicle information system (IVIS). The motivation for conducting this research was to investigate the subjectively and objectively measured impact of using a single- or multi-modal IVIS while driving. A hierarchical, list-based menu was presented using a windshield projection (head-up display), auditory display and a combination of both interfaces. The users were asked to navigate a vehicle in a driving simulator and simultaneously perform a set of tasks of varying complexity. The experiment showed that the interaction with visual and audio-visual head-up displays is faster and more efficient than with the audio-only display. All the interfaces had a similar impact on the overall driving performance. There was no significant difference between the visual only and audio-visual displays in terms of their efficiency and safety; however, the majority of test subjects clearly preferred to use the multi-modal interface while driving.

This article investigates the effect of various design parameters of auditory information display on user performance in two basic information retrieval tasks. We conducted a user test with 22 participants in which sets of sound samples were presented. In the first task, the test participants were asked to detect a given sample among a set of samples. In the second task, the test participants were asked to estimate the relative number of instances of a given sample in two sets of samples. We found that the stimulus onset asynchrony (SOA) of the sound samples had a significant effect on user performance in both tasks. For the sample detection task, the average error rate was about 10% with an SOA of 100 ms. For the numerosity estimation task, an SOA of at least 200 ms was necessary to yield average error rates lower than 30%. Other parameters, including the samples' sound type (synthesized speech or earcons) and spatial quality (multichannel loudspeaker or diotic headphone playback), had no substantial effect on user performance. These results suggest that diotic, or indeed monophonic, playback with appropriately chosen SOA may be sufficient in practical applications for users to perform the given information retrieval tasks, if information about the sample location is not relevant. If location information was provided through spatial playback of the samples, test subjects were able to simultaneously detect and localize a sample with reasonable accuracy. © 2013 ACM. Refereed/Peer-reviewed

Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder that may cause life-threatening hemorrhages in patients with plasma cell dyscrasias (PCDs). Early diagnosis and treatment require a thorough understanding of its underlying pathophysiology. Two patients with IgG MGUS presented with dramatically decreased plasma von Willebrand factor (VWF) and a severe type-1 pattern on multimer analysis. A prompt response to intravenous immunoglobulins (IVIG), but not to VWF/FVIII, was consistent with accelerated immunologic clearance of plasma VWF. Another IgG MGUS patient showed a type-2 pattern and a less pronounced response to IVIG, suggesting that additional mechanism(s) contributed to AVWS evolution. In a patient with Waldenstrom's macroglobulinemia and severe depletion of plasma VWF, multimer analysis indicated association of the IgM paraprotein with VWF before, but not after plasmapheresis, resulting in destruction of the agarose gel and a characteristically distorted band structure of VWF multimers. A type-2 pattern with highly abnormal VWF triplets and laboratory evidence of excessive fibrinolytic activity suggested that plasmin-mediated VWF degradation contributed to AVWS in a patient with multiple myeloma (MM) and AL amyloidosis. Finally, in a patient with IgG MM, maximally prolonged PFA-100® closure times and a specific defect in ristocetin-induced platelet agglutination, both of which resolved after remission induction, indicated interference of the paraprotein with VWF binding to platelet GPIb. Importantly, in none of the six patients, circulating autoantibodies to VWF were detected by a specific in-house ELISA. In summary, when evaluating PCD patients with severe bleeding symptoms, AVWS due to various pathogenic mechanisms should be considered.

TPS2596Background: TO (CetuGEX) is a second-generation anti-EGFR antibody that specifically binds to EGFR and acts as a competitive antagonist at the ligand binding site. GAT (PankoMab-GEX) is a no...

This paper describes a user study on interaction with a mobile device installed in a driving simulator. Two new auditory interfaces were proposed and their effectiveness and efficiency were compared to a standard visual interface. Both auditory interfaces consisted of spatialized auditory cues representing individual items in the hierarchical structure of the menu. In the first auditory interface all items of the current level of the menu were played simultaneously. In the second auditory interface only one item was played at a time. The visual interface was shown on a small in-vehicle LCD screen on the dashboard. In all three cases, a custom-made interaction device (a scrolling wheel and two buttons) attached to the steering wheel was used for controlling the interface. The driving performance, task completion times, perceived workload and overall user satisfaction were evaluated. The experiment proved that both auditory interfaces were effective to use in a mobile environment, but were not faster than the visual interface. In the case of shorter tasks, e.g. changing the active profile or deleting an image, the task completion times were comparable for all interfaces; however, both the driving performance was significantly better and the perceived workload was lower when using the auditory interfaces. The test subjects also reported a high overall satisfaction with the auditory interfaces. The latter were labelled as easier to use, more satisfying and more adequate for performing the required tasks than the visual interface. The results of the survey are not surprising as there is a stronger competition for the visual attention between the visual interface and the primary task (driving the car) than in the case of using the auditory interface. So although both types of interfaces were proven to be effective, the visual interface was less efficient as it strongly distracted the user from performing the primary task. Refereed/Peer-reviewed

Background In acute myeloid leukemia (AML), disseminated intravascular coagulation (DIC) contributes to morbidity and mortality, but the underlying pathomechanisms remain incompletely understood. Methods We conducted a prospective study on 69 patients with newly diagnosed AML to further define the correlates of systemic coagulation activation in this hematological malignancy. Tissue factor procoagulant activity (TF PCA) of isolated peripheral blood mononuclear cells (PBMCs) and TF expression by circulating microparticles (MPs) were assessed by single-stage clotting and thrombin generation assay, respectively. Soluble plasma TF antigen and secretion of vascular endothelial growth factor (VEGF) by cultured PBMCs were measured by ELISA. Cell-free plasma DNA was quantified by staining with a fluorescent dye. Result TF PCA of PBMCs was significantly increased in AML patients as compared to healthy controls. Furthermore, TF PCA was significantly associated with decompensated DIC at presentation, as defined by a plasma fibrinogen level of ≤1 g/L (n = 11). In addition to TF PCA and circulating blasts, serum lactate dehydrogenase, a surrogate marker for leukemic cell turnover, correlated with plasma D-Dimer in the total patient cohort and was significantly increased in DIC patients, suggesting a role for myeloblast apoptosis/necrosis in activation of the TF-dependent coagulation pathway. Consistently, TF-bearing plasma MPs were more frequently detected and levels of soluble TF antigen were significantly higher in DIC vs. non-DIC patients. No association was found between TF PCA expression and VEGF secretion by isolated PBMCs, but significantly increased levels of cell-free plasma DNA pointed to a contribution of the intrinsic contact pathway to systemic coagulation activation in the total patient cohort and in patients with lower TF PCA expression. While PBMC-associated TF PCA had no effect on long-term survival, DIC occurrence at presentation increased the risk of early mortality. Conclusion In newly diagnosed AML, TF expression by PBMCs and shedding of TF-bearing plasma MPs are central to the pathogenesis of DIC, but additional pathways, such as DNA liberation, may contribute to systemic coagulation activation.

In this paper we present a system that allows to "touch", grab and manipulate sounds in mid-air. Further, arbitrary objects can seem to emit sound. We use spatial sound reproduction for sound rendering and computer vision for tracking. Using our approach, sounds can be heard from anywhere in the room and always appear to originate from the same (possibly moving) position, regardless of the listener's position. We demonstrate that direct "touch" interaction with sound is an interesting alternative to indirect interaction mediated through controllers or visual interfaces. We show that sound localization is surprisingly accurate (11.5 cm), even in the presence of distractors. We propose to leverage the ventriloquist effect to further increase localization accuracy. Finally, we demonstrate how affordances of real objects can create synergies of auditory and visual feedback. As an application of the system, we built a spatial music mixing room.

Graphical user interfaces for mobile devices have several drawbacks in mobile situations. In this paper, we present Foogue, an eyes-free interface that utilizes spatial audio and gesture input. Foogue does not require visual attention and hence does not divert visual attention from the task at hand. Foogue has two modes, which are designed to fit the usage patterns of mobile users. For user input we designed a gesture language build of a limited number of simple but also easy to differentiate gesture elements.

Nowadays, mobile devices provide new possibilities for gesture interaction due to the large range of embedded sensors they have and their physical form factor. In addition, auditory interfaces can now be more easily supported through advanced mobile computing capabilities. Although different types of gesture techniques have been proposed for handheld devices, there is still little knowledge about the acceptability and use of some of these techniques, especially in the context of an auditory interface. In this paper, we propose a novel approach to the problem by studying the design space of gestures proposed by end-users for a mobile auditory interface. We discuss the results of this explorative study, in terms of the scope of the gestures proposed, the tangible aspects, and the users' preferences. This study delivers some initial gestures recommendations for eyes-free auditory interfaces.

In this paper we summarize, evaluate, and discuss the effect of movement patterns in a spatial sound space on the perceived amount of simulator sickness, the pleasantness of the experience, and the perceived workload. During our user study nearly 48 percent of all participants showed mild to moderate symptoms of simulator sickness, with a trend towards stronger symptoms for those experiencing left to right movements. We found evidence for predictable left to right movements leading to a perceived unpleasantness that is significantly higher than for unpredictable or no movement at all. However none of the movement patterns had a noticable effect on the perceived cognitive load for simple tasks. We also found some differences in the perception of the sound space between men and women. Women tended to have a stronger dislike for the sound space and found the task to be more difficult. Refereed/Peer-reviewed

In this paper we describe an exploration into the usability of spatial sound and multimodal interaction techniques for a mobile phone conferencing application. We compared traditional keypad based-interaction to that of a newer approach using the phone itself as a device to navigate within a virtual spatial auditory environment. While the traditional keypad interaction proved to be more straightforward to use, there was no significant impact on task completion times or number of interaction movements made between the techniques. Overall, users felt that the spatial audio application supported group awareness while aiding peripheral task monitoring. They also felt it aided the feeling of social connectedness and offered enhanced support for communication. Refereed/Peer-reviewed

In this paper we evaluate the safety of the driver when using an embedded communication device while driving. As a part of our research, four different tasks were preformed with the device in order to evaluate the efficiency and safety of the drivers under three different conditions: one visual and two different auditory conditions. In the visual condition, various menu items were shown on a small LCD screen attached to the dashboard. In the auditory conditions, the same menu items were presented with spatial sounds distributed on a virtual ring around the user's head. The same custom-made interaction device attached to the steering wheel was used in all three conditions, enabling simple and safe interaction with the device while driving. The auditory interface proved to be as fast as the visual one, while at the same time enabling a significantly safer driving and higher satisfaction of the users. The measured workload also appeared to be lower when using the auditory interfaces. Refereed/Peer-reviewed

Acquired hemophilia A (AHA) and acquired von Willebrand Syndrome (AVWS) are both rare bleeding disorders that can be associated with lymphoproliferative or autoimmune diseases. AHA is uniformly caused by inhibitory autoantibodies against coagulation factor VIII (FVIII), while the pathophysiology of AVWS comprises several distinct mechanisms, including reduced synthesis, accelerated clearance, or increased proteolysis. In this regard, autoantibodies to von Willebrand factor (VWF) have been described in patients with systemic lupus erythematosus (SLE) or monoclonal gammopathy. Here, we report the case of a 71-year-old patient with a recent onset of spontaneous mucocutaneous and soft-tissue bleeding due to severely decreased FVIII and VWF. While there was no evidence for monoclonal gammopathy, specific IgG antibodies against both FVIII and VWF were detected. Furthermore, VWF multimer analysis revealed the presence of ultralarge plasma multimers and absence of the typical multimeric triplet structure, a finding consistent with decreased proteolytic processing of massively released, but rapidly cleared VWF. Both FVIII and VWF readily responded to immunosuppressive therapy with prednisolone. Interestingly, clinical and laboratory findings established the diagnosis of “late-onset SLE” in our patient. Thus, about 45 years after the first description of AVWS in a 12-year-old boy with SLE, we present another unusual case of concomitant autoimmune-mediated AHA and AVWS in an elderly SLE patient, which, to the best of our knowledge, has not been reported so far.