[E-Health and reality - what are we facing in patient care?] / E-Health und die Realität ­ was sehen wir heute schon in der Klinik?

The terms e­Health and digitization are core elements of a change in our time. The main drivers of this change - in addition to a dynamic market - are the serious advantages for the healthcare sector in the processing of tasks and requirements. The large amounts of data, the intensively growing medical knowledge, the rapidly advancing technological developments and the goal of a personalized, customized therapy for the patient, make the application absolutely necessary. While e­Health describes the use of information and communication technologies in healthcare, the concept of digitization is associated with the underlying processes of change and innovation. Digital technologies include software and hardware based developments. The term clinical data intelligence describes the property of workability and also characterizes the collaboration of clinically relevant systems with which the medical user works. The hierarchy in digital processing maps the levels from pure data management through clinical decision support to automated process flows and autonomously operating units. The combination of patient data management and clinical decision support proves its value in terms of error reduction, prevention, quality and safety, especially in drug therapy. The aim of this overview is the presentation of the existing reality in medical centers with perspectives derived from the point of view of the medical user.

Long-term antithrombotic protection by in vivo depletion of platelet glycoprotein VI in mice.

Coronary artery thrombosis is often initiated by abrupt disruption of the atherosclerotic plaque and activation of platelets on the subendothelial layers in the disrupted plaque. The extracellular matrix protein collagen is the most thrombogenic constituent of the subendothelial layer; therefore, a selective inhibition of the collagen activation pathway in platelets may provide strong antithrombotic protection while preserving other platelet functions. Here we demonstrate that treatment of mice with a monoclonal antibody against the activating platelet collagen receptor glycoprotein VI (GPVI; JAQ1) results in specific depletion of the receptor from circulating platelets and abolished responses of these cells to collagen and collagen-related peptides (CRPs). JAQ1-treated mice were completely protected for at least 2 wk against lethal thromboembolism induced by infusion of a mixture of collagen (0.8 mg/kg) and epinephrine (60 microg/ml). The tail bleeding times in JAQ1-treated mice were only moderately increased compared with control mice probably because the treatment did not affect platelet activation by other agonists such as adenosine diphosphate or phorbol myristate acetate. These results suggest that GPVI might become a target for long-term prophylaxis of ischemic cardiovascular diseases and provide the first evidence that it is possible to specifically deplete an activating glycoprotein receptor from circulating platelets in vivo.

Identification of critical antigen-specific mechanisms in the development of immune thrombocytopenic purpura in mice.

The pathogenic effects of antiplatelet antibodies were investigated in mice. Monoclonal antibodies (mAbs) of different immunoglobulin G subclass directed against mouse GPIIbIIIa, GPIIIa, GPIbalpha, GPIb-IX, GPV, and CD31 were generated and characterized biochemically. MAbs against GPIb-IX, GPV, CD31, and linear epitopes on GPIIIa had mild and transient effects on platelet counts and induced no spontaneous bleeding. Anti-GPIbalpha mAbs induced profound irreversible thrombocytopenia (< 3% of normal) by Fc-independent mechanisms but only had minor effects on hematocrits. In contrast, injection of intact mAbs, but not F(ab)(2) fragments, against conformational epitopes on GPIIbIIIa, induced irreversible thrombocytopenia, acute systemic reactions, hypothermia, decreased hematocrits, and a paradoxical loss of surface GPIIbIIIa on platelets in vivo, the latter suggesting the formation of platelet-derived microparticles. Blockage of platelet-activating factor receptors inhibited the acute reactions, but not thrombocytopenia, loss of GPIIbIIIa, and decreases in hematocrits. Repeated injections of low doses of anti-GPIIbIIIa antibodies resulted in profound thrombocytopenia and bleeding, whereas no acute systemic reactions were observed. These data strongly suggest that the identity of the target antigen recognized by antiplatelet antibodies determines the mechanisms of platelet destruction and the severity of bleeding in mice, the latter depending on previously unrecognized anti-GPIIbIIIa-specific inflammatory mechanisms.

Expression and function of the mouse collagen receptor glycoprotein VI is strictly dependent on its association with the FcRgamma chain.

Platelet glycoprotein (GP) VI has been proposed as the major collagen receptor for activation of human platelets. Human GPVI belongs to the immunoglobulin superfamily and is noncovalently associated with the FcRgamma chain that is involved in signaling through the receptor. In mice, similar mechanisms seem to exist as platelets from FcRgamma chain-deficient mice do not aggregate in response to collagen. However, the activating collagen receptor on mouse platelets has not been definitively identified. In the current study we examined the function and in vivo expression of GPVI in control and FcRgamma chain-deficient mice with the first monoclonal antibody against GPVI (JAQ1). On wild type platelets, JAQ1 inhibited platelet aggregation induced by collagen but not PMA or thrombin. Cross-linking of bound JAQ1, on the other hand, induced aggregation of wild type but not FcRgamma chain-deficient platelets. JAQ1 stained platelets and megakaryocytes from wild type but not FcRgamma chain-deficient mice. Furthermore, JAQ1 recognized GPVI (approximately 60 kDa) in immunoprecipitation and Western blot experiments with wild type but not FcRgamma chain-deficient platelets. These results strongly suggest that GPVI is the collagen receptor responsible for platelet activation in mice and demonstrate that the association with the FcRgamma chain is critical for its expression and function.

Structural and functional characterization of the mouse von Willebrand factor receptor GPIb-IX with novel monoclonal antibodies.

Five novel monoclonal antibodies (mAbs; p0p 1-5) were used to characterize the structural and functional properties and the in vivo expression of the murine GPIb-IX complex (von Willebrand factor receptor). The molecular weights of the subunits are similar to the human homologs: GPIbalpha (150 kd), GPIbbeta (25 kd), and GPIX (25 kd). Activation of platelets with thrombin or PMA predominantly induced shedding of glycocalicin (GC; 130 kd) but only low levels of receptor internalization. The GC concentration in normal mouse plasma was found to be at least 10 times higher than that described for human plasma (approximately 25 microg/mL versus 1-2 microg/mL). Two additional cleavage sites for unidentified platelet-derived proteases were found on GPIbalpha, as demonstrated by the generation of 3 N-terminal fragments during in vitro incubation of washed platelets (GC, 60 kd, 45 kd). Occupancy of GPIbalpha with p0p mAbs or F(ab)(2)-fragments resulted in aggregate formation in vitro and rapid irreversible thrombocytopenia in vivo, irrespective of the exact binding epitopes of the individual antibodies. GPIb-IX was not detectable immunohistochemically on endothelial cells in the major organs under normal or inflammatory conditions. The authors conclude that the mouse system might become an interesting model for studies on GPIb-IX function and regulation.

The mutagenic activity of unpolymerized resin monomers in Salmonella typhimurium and V79 cells.

Dimethacrylate derivatives are used as monomers to polymerize dental composite materials and for a great variety of other industrial resins. Occupational exposure is likely in various ways because of the many areas of methacrylate application. Here, the mutagenicity of the monomers, bisphenol A-diglycidyl dimethacrylate (Bis-GMA), urethane dimethacrylate (UDMA), triethylene glycol dimethacrylate (TEGDMA), Bisphenol A (BPA), glycidyl methacrylate (GMA), methyl methacrylate (MMA), and 2-hydroxyethyl methacrylate (HEMA) was studied in a bacterial (Ames test) and a mammalian gene mutation assay (V79/HPRT assay). Mutagenicity was determined in different Salmonella typhimurium strains (TA97a, TA98, TA100, TA102) and in V79 cells in the presence and in the absence of a metabolically active microsomal fraction from rat liver (S9). No mutagenic effects were observed with Bis-GMA and UDMA, methyl methacrylate, 2-hydroxyethyl methacrylate and bisphenol A. Glycidyl methacrylate (GMA) was mutagenic in a dose-dependent manner in three Salmonella tester strains. The number of mutants was increased by a factor of 2 to 3 with strains TA97a and TA102 in the absence of S9. Moreover, the numbers of mutants induced in S. typhimurium TA100 were about 8-fold higher than in solvent controls. GMA also induced an increase of mutants in V79 cells in the absence of S9. However, GMA was inactivated by microsomal enzymes. Triethylenglycol dimethacrylate (TEGDMA) was not mutagenic in any S. typhimurium. In contrast, the compound induced a dose-dependent rise in mutant frequencies in V79 cell cultures. It is concluded that TEGDMA acted through a clastogenic mechanism which is not detected by Ames tester strains.