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The treatment of choice for patients infected chronically with HCV is the combination of IFN-alpha and ribavirin. Monotherapy with ribavirin leads to a clinical and histological improvement, but its exact mechanism of action is unknown. Therefore, the effect of ribavirin on synthesis of inflammatory cytokines and on apoptosis in stimulated peripheral blood mononuclear cells (PBMCs) was investigated. PBMCs were isolated from the blood of HCV infected patients and from healthy volunteers. The effect of ribavirin on IFN-gamma and IL-1beta release in the supernatant of unstimulated and phytohemagglutinin (PHA) stimulated PBMCs was investigated by enzyme linked immunosorbent assay (ELISA). The effect on total DNA, RNA, and protein synthesis was analyzed by measurement of 3H-thymidine, 3H-uridine and 3H-leucine incorporation into cellular macromolecules. Ribavirin led to a dose-dependent decrease of the IFN-gamma but an increase of IL-1beta release into the supernatant of PHA-stimulated PBMCs. At the same time, a dose-dependent decrease of total DNA, RNA, and protein synthesis in cultures of PHA-stimulated PBMCs was demonstrated. These effects could be compensated by the addition of equimolar amounts of guanosine. The rate of apoptotic CD45+ and CD14+ cells in PBMCs cultures increased in a dose-dependent manner. Our data suggest that ribavirin administration to chronically HCV-infected patients could lead to a decrease of the synthesis of proinflammatory cytokines (e.g., IFN-gamma) by an inhibition of total DNA-, RNA-, and protein-synthesis and by induction of apoptosis in the cells of the inflammatory infiltrate. Furthermore, ribavirin could influence the synthesis of viral particles in the hepatocytes.

Model-Driven Engineering provides an abstract representation of systems through the use of models and views. For complex systems, however, finding a single model and a single view to represent all relevant information of the system is infeasible. Specialized models for specific subsystems, domains or abstractions are more concise and thus more efficient than monolithic models. Furthermore, different tasks and concerns often require different views on the same model. Sustaining the consistency between different views and models is hard, especially if new models and views are dynamically added.In this paper, we present an approach that supports flexible views that may involve multiple models conforming to different metamodels. The approach is based on Orthographic Software Modeling and synchronizes individual instances using model transformations. These transformations are generated from view type definitions, metamodel correspondence rules and invariants, which are defined in a domain-specific language. We illustrate our approach with an application that combines component-based architectures with objectoriented source code and class diagrams.

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