Demand-driven evolution of IT systems in healthcare--a case study for improving interdisciplinary processes.

OBJECTIVES: To analyze and to optimize interdisciplinary clinical processes, to introduce an IT-supported model for demand-driven system evolution in healthcare, and to demonstrate the feasibility of the approach for a clinical example and to present an evaluation. METHODS: System evolution and change management are viewed as two sides of the same coin, thus formal methods for process analysis and IT system evolution were embedded into a goal-oriented change management model. Based on a process model, a Failure Mode and Effects Analysis (FMEA) and a computer simulation were performed. A tool for rapid application development (RAD) was used to incrementally improve the healthcare information system according to newly arising needs. RESULTS: Each of the formal methods used contributed to the successful reorganization of the interdisciplinary clinical process. An evaluation demonstrated significant improvements. An integrated IT application was implemented to support the optimized process. CONCLUSIONS: Process improvement is feasible and effective when formal methods for process analysis and requirements specification are used in a reasonable and goal-oriented way. It might be necessary to trade off costs and benefits or simplify a given method in the context of a particular project. As the same information is utilized in different tools, it is supposed that the efforts for process analysis, documentation and implementation of adapted applications could be reduced if different tools were integrated and based on a single coherent reference model for description of clinical processes.

Effects of hypertonic saline on expression of human polymorphonuclear leukocyte adhesion molecules.

Hypertonic saline prevents vascular adherence of neutrophils and ameliorates ischemic tissue injury. We hypothesized that hypertonic saline attenuates N-formyl-methionyl-leucyl-phenylalanine (fMLP)-stimulated expression of adhesion molecules on human polymorphonuclear leukocytes (PMNLs). fMLP-stimulated up-regulation of beta2-integrins was diminished by hypertonic saline but not by hypertonic choline chloride-, mannitol-, or sucrose-modified Hanks' buffered salt solution. Shedding of L-selectin was decreased by hypertonic saline and choline chloride but not by hypertonic mannitol or sucrose. When the effects of hypertonic sodium chloride- and choline chloride-modified media were compared, neither solution affected fMLP-receptor binding but both equally inhibited fMLP-stimulated increase in intracellular calcium, ionophore A23187, and phorbol myristate acetate (PMA)-stimulated numerical up-regulation of beta2-integrins. Analysis of mitogen-activated protein (MAP) kinases p38 and p44/42 for phosphorylation revealed that hypertonic solutions did not differ in preventing fMLP-stimulated increases in phospho-p38 and phospho-p44/42. Resting PMNLs shrunk by hypertonic saline increased their volume during incubation and further during chemotactic stimulation. Addition of amiloride further enhanced inhibition of up-regulation of beta2-integrins. No fMLP-stimulated volume changes occurred in PMNLs exposed to hypertonic choline chloride, resulting in significant cell shrinkage. Results suggest a sodium-specific inhibitory effect on up-regulation of beta2-integrins of fMLP-stimulated PMNLs, which is unlikely to be caused by alterations of fMLP receptor binding, decrease in cytosolic calcium, attenuation of calcium or protein kinase C-dependent pathways, suppression of p38- or p44/42 MAP kinase-dependent pathways, or cellular ability to increase or decrease volumes.

tPA of human keratinocytes: contribution to cell surface-associated plasminogen activation and upregulation by retinoic acid.

We tested distinct variants of a human keratinocyte line (HaCaT) for the expression of tissue-type plasminogen activator (tPA)-specific mRNA, as well as cell surface-associated and secreted tPA. Cells of early passages (passage no. 22) only expressed urokinase plasminogen activator (uPA)- but not tPA-specific mRNA. Cells after prolonged culture (passage no. 44) expressed uPA- and tPA-specific mRNA, but did not release tPA in the extracellular space and did not display surface-associated tPA. HaCaT cells transformed with the c-Ha-ras oncogene (HaCaTras) showed both secreted and surface-associated tPA antigen. The secreted and the surface-associated plasminogen activator (PA)-activity of HaCaTras cells were in part inhibitable by anticatalytic anti-tPA antibodies, thus indicating that tPA contributes to extracellular and surface-associated plasminogen activation. Finally, we demonstrate that tPA secretion of HaCaT 44 cells can be induced by retinoic acid, most likely via interaction of retinoic acid with nuclear-associated retinoic acid-receptor(s).

Plasminogen activator inhibitor-2: prognostic relevance in 1012 patients with primary breast cancer.

The antigen levels of urokinase-type plasminogen activator (uPA) and its inhibitor plasminogen activator inhibitor (PAI) 1, as detected in tumor extracts by ELISA, have been reported to be correlated with a poor prognosis in primary breast cancer. In the present study we have characterized a novel PAI-2-specific ELISA, designed to measure PAI-2 antigen levels in tumor cytosols. We determined PAI-2 antigen levels along with those of uPA and PAI-1 in 1012 routinely prepared tumor cytosols of patients with primary breast cancer (median follow-up, 71 months). In the overall population there was no significant association between the level of PAI-2 and prognosis, while in tumors with high uPA values, PAI-2 (test for trend) was associated with a prolonged relapse-free survival, metastasis-free survival, and overall survival (for all analyses, P < 0.02). In Cox's multivariate analysis for relapse-free survival, metastasis-free survival, and overall survival in tumors with high uPA values (including patient's age, menopausal status, lymph node status, tumor size, estrogen and progesterone receptor status, uPA, and PAI-1), PAI-2 either dichotomized or, as a continuous variable, was independently associated with a favorable relapse-free survival, metastasis-free survival, and overall survival. We conclude that the PAI-2-specific ELISA described herein is well suited for the measurement of PAI-2 levels in cytosols routinely prepared for analysis of steroid hormone receptors. We speculate that PAI-2 may serve as an inhibitor for uPA in human primary breast cancers.

Enzyme-linked immunosorbent assays for plasminogen activators.

ELISA procedures are described for the quantitative analysis of the urokinase-type plasminogen activator (uPA) and of the tissue type PA (tPA). The assays were developed to detect the respective type of PA in cell culture supernatants. TPA can be present as a single-chain or a two-chain protein; uPA as pro-uPA, high or low molecular weight uPA, respectively. In addition, both PAs can be complexed with the plasminogen activator inhibitors PAI-I or PAI-2. Monoclonal antibodies specific for uPA or tPA were selected that recognized the distinct molecular forms of the PAs, even in the presence of fetal calf serum, which is a common--relatively ill-defined--ingredient of cell culture media. The test systems were found to be reliable, easy to perform, and to permit the detection of both types of PA in serum-free and serum-containing cell culture supernatants. Finally, the ELISA--in combination with functional tests--were used to analyse the different PA components in culture supernatants of uPA- or tPA-producing cell lines.