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Objectives 4D flow MRI enables quantitative assessment of helical flow. We sought to generate normal values and elucidate changes of helical flow (duration, volume, length, velocities and rotational direction) and flow jet (displacement, flow angle) as well as wall shear stress (WSS). Methods We assessed the temporal helical existence (THEX), maximum helical volume (HVmax), accumulated helical volume (HVacc), accumulated helical volume length (HVLacc), maximum forward velocity (maxVfor), maximum circumferential velocity (maxVcirc), rotational direction (RD) and maximum wall shear stress (WSS) as reported elsewhere using the software tool Bloodline in 86 healthy volunteers (46 females, mean age 41 ± 13 years). Results WSS decreased by 42.1% and maxVfor by 55.7% across age. There was no link between age and gender regarding the other parameters. Conclusion This study provides age-dependent normal values regarding WSS and maxVfor and age- and gender-independent normal values regarding THEX, HVmax, HVacc, HVLacc, RD and maxVcirc. Key Points • 4D flow provides numerous new parameters; therefore, normal values are mandatory. • Wall shear stress decreases over age. • Maximum helical forward velocity decreases over age.

Mit der Entwicklung von Januskinase (JAK)-Inhibitoren, einer neuen Klasse von „targeted synthetic (ts) disease modifying antirheumatic drugs (DMARDs)“, wurden innovative therapeutische Perspektiven geschaffen. Im Gegensatz zu Biologika, die als Antikorper oder Fusionsprotein ein einzelnes Zytokin extrazellular, einen Zytokinrezeptor oder ein Oberflachenmolekul auf der Zelle blockieren, wirken JAK-Inhibitoren intrazellular und vor allem breiter. Durch Inhibition von Tyrosinkinasen (JAK 1–3, Tyk 2) konnen sie den Signalweg von >50 Zytokinen unterbinden. Die JAK-Inhibitoren erweitern damit die Behandlungsoptionen bei rheumatischen Erkrankungen. Studien zu rheumatischen Erkrankungen bei Erwachsenen und erste Daten bei Kindern und Jugendlichen weisen auf eine im Vergleich zu Biologika gleichwertige oder sogar bessere Effektivitat hin. In aktuell laufenden und zukunftigen Studien wird sich herausstellen, welche „Jakinibs“ die beste Wirkung-Nebenwirkungs-Relation aufweisen. The development of Janus kinase (JAK) inhibitors, a new class of “targeted synthetic (ts) DMARDs”, has opened new perspectives of treatment. Unlike biologics, which are antibodies or fusion proteins that block a single cytokine extracellularly or the corresponding cytokine receptor or a molecule at the cell surface, JAK inhibitors act intracellularly with particularly broader effect. By inhibiting tyrosine kinases (JAK 1–3, Tyk 2), they can stop the signaling pathway of >50 cytokines. JAK inhibitors thus expand treatment options for rheumatic diseases. Studies in rheumatic diseases in adults and initial data in children and adolescents indicate equivalent or even better efficacy compared to biologics. Current and future studies will determine which “Jakinibs” have the best efficacy/side-effect ratio.

The neoplastic stromal cells of giant cell tumor of bone (GCTB) carry a mutation in H3F3A, leading to a mutant histone variant, H3.3-G34W, as a sole recurrent genetic alteration. We show that in patient-derived stromal cells H3.3-G34W is incorporated into the chromatin and associates with massive epigenetic alterations on the DNA methylation, chromatin accessibility and histone modification level, that can be partially recapitulated in an orthogonal cell line system by the introduction of H3.3-G34W. These epigenetic alterations affect mainly heterochromatic and bivalent regions and provide possible explanations for the genomic instability, as well as the osteolytic phenotype of GCTB. The mutation occurs in differentiating mesenchymal stem cells and associates with an impaired osteogenic differentiation. We propose that the observed epigenetic alterations reflect distinct differentiation stages of H3.3 WT and H3.3 MUT stromal cells and add to H3.3-G34W-associated changes., Helmholtz Association, Korean National Cancer Center, Korean National Research Fund, Oxford NIHR BRC, Arthritis Research UK, Projekt DEAL

The neoplastic stromal cells of giant cell tumor of bone (GCTB) carry a mutation in H3F3A, leading to a mutant histone variant, H3.3-G34W, as a sole recurrent genetic alteration. We show that in patient-derived stromal cells H3.3-G34W is incorporated into the chromatin and associates with massive epigenetic alterations on the DNA methylation, chromatin accessibility and histone modification level that can be partially recapitulated in an orthogonal cell line system by the introduction of H3.3-G34W. These epigenetic alterations affect mainly heterochromatic and bivalent regions and provide possible explanations for the genomic instability as well as the osteolytic phenotype of GCTB. The mutation occurs in differentiating mesenchymal stem cells and associates with an impaired osteogenic differentiation. We propose that the observed epigenetic alterations reflect distinct differentiation stages of H3.3 WT and H3.3 MUT stromal cells and add to H3.3-G34W associated changes. Important abbreviations H3.3-G34W, mutated histone variant; H3.3 MUT, stromal cells expressing H3.3-G34W; H3.3 WT, stromal cells expressing wildtype H3.3

Inhibitors of DNA methyltransferases (DNMTis) or histone deacetylases (HDACis) are epigenetic drugs which are investigated since decades. Several have been approved and are applied in the treatment of hematopoietic and lymphatic malignancies, although their mode of action has not been fully understood. Two recent findings improved mechanistic insights: i) activation of human endogenous retroviral elements (HERVs) with concomitant synthesis of double-stranded RNAs (dsRNAs), and ii) massive activation of promoters from long terminal repeats (LTRs) which originated from past HERV invasions. These dsRNAs activate an antiviral response pathway followed by apoptosis. LTR promoter activation leads to synthesis of non-annotated transcripts potentially encoding novel or cryptic proteins. Here, we discuss the current knowledge of the molecular effects exerted by epigenetic drugs with a focus on DNMTis and HDACis. We highlight the role in LTR activation and provide novel data from both in vitro and in vivo epigenetic drug treatment.

Rb–Sr and U–Pb isotopic data for granulite facies rocks, forming textural relics with respect to eclogite facies metamorphism in the Western Gneiss Region (WGR) of Norway, highlight the importance of textures and mineral reaction kinetics for the interpretation of geochronological data. Studied rocks from Bardsholmen, southern WGR, were subjected to granulite facies metamorphism at 955 ± 3 Ma (U–Pb, zircon). Later on, they experienced a subduction-related, kinetically stranded eclogitization ( T > 650 °C at ∼20 kbar) at 404 ± 2 Ma (Rb–Sr multimineral internal isochron data), followed by exhumation through amphibolite facies conditions. Full conversion of granulite to eclogite was restricted to zones of fluid infiltration and deformation. Despite the fact that metamorphic temperatures vastly exceeded the commonly assumed ‘closure temperature’ for Rb–Sr in submillimeter-sized biotite for several Ma during eclogite facies overprint, Sr-isotopic signatures of relic biotite have not been fully reset. Large biotite crystals nearly record their Sveconorwegian (Grenvillian) crystallization age. Sr signatures of other granulite facies phases (feldspar, pyroxenes, amphibole) remained unchanged, with the exception of apatite. The results imply that isotopic signatures much closer correspond to the P , T conditions of formation recorded by a dated phase and its paragenesis, than to a temperature history. In texturally well-equilibrated high-grade rocks which experienced no mineral reactions and remained devoid of free fluids during exhumation, like granulites or eclogites, isotopic resetting during cooling is either kinetically locked, or restricted to sluggish intermineral diffusion which demonstrably does not lead to full isotopic homogenization. In texturally unequilibrated rocks, textural relics are likely to represent isotopic relics. It is shown that for both high-grade rocks and for rocks with textural disequilibria, geologically meaningful isotopic ages based on isochron methods can only be derived from sub-assemblages in isotopic equilibrium, which have to be defined by analysis of all rock-forming minerals. Conventional two-point ‘mica ages’ for such rocks are a priori geochronologically uninterpretable, and valid multimineral isochron ages a priori do not record cooling but instead date recrystallization-inducing processes like fluid–rock interaction.

Rb–Sr multimineral isochron data for metamorphic veins allow to date separate increments of the mineral reaction history of polymetamorphic terranes. Granulite facies rocks of the Lindas nappe, Bergen Arcs, Norway, were subducted and exhumed during the Caledonian orogeny. The rocks show petrographic evidence for two distinct events of local fluid infiltration and vein formation, along fractures and shear zones. The first occurred at eclogite facies (15–21 kbar, 650–750°C) and a later one at amphibolite facies conditions (8–10 kbar, 600°C). The presence of fluids enabled local metamorphic equilibration only near fluid pathways. In fluid-absent domains, preexisting assemblages were metastably preserved. This resulted in a heterogeneity of metamorphic signatures on meter to μm-scales. Well-preserved granulite facies rocks preserve their Proterozoic Rb–Sr mineral ages, as does the U–Pb system of zircon in most lithologies. Six Rb/Sr multimineral isochron ages for eclogite facies veins and their immediate wallrocks date the fluid-induced eclogitization at 429.9 ± 3.5 Ma (2σ, weighted average, MSWD = 0.39). An eclogite facies vein has yielded metamorphic zircon with concordant U–Pb ages of 429 ± 3 Ma, identical to the U–Pb age of 427.4 ± 0.9 Ma for zircon xenocrysts in an amphibolite facies vein. Seven Rb/Sr mineral isochron ages date amphibolite-facies fluid infiltration at 414.2 ± 2.8 Ma (MSWD = 1.5), an age value testifying to residence of the rocks in the deep orogenic crust at temperatures >600°C for nearly 15 Ma. The new data show that Rb–Sr mineral isochron ages effectively date fluid-induced (re)crystallization events rather than stages of cooling. The direct link between isotopic ages and distinct petrographic equilibrium assemblages aids to constrain the evolution of rocks in the P–T-reaction-time space, which is essential for understanding exhumation histories and the internal dynamics of orogens in general.

Structural and metamorphic data from the island of Amorgos (central Aegean Sea) show evidence for the existence of two distinct high-pressure units, the Metabasite Unit and the Basal Conglomerate Unit. These are exposed at the base of a thick marble sequence and overlying flysch deposits. The Metabasite Unit is characterized by a mineral assemblage of blue amphibole, garnet and clinopyroxene, indicating P – T conditions of 500–600 °C and >13 kbar. It is juxtaposed below carpholite-bearing metaconglomerates and quartz-rich micaschists of the Basal Conglomerate Unit, for which metamorphic conditions of 300–450 °C and 10–14 kbar are estimated. The contact between the two units is interpreted as a low-angle detachment fault that accommodated top-to-the-NW sense of motion. The Amorgos succession above the Basal Conglomerate Unit collectively resembles the stratigraphy of external units in the Hellenides and could possibly be correlated with the so-called ‘Basal Unit’, which crops out in a number of tectonic windows throughout the Aegean Sea. This means that the Metabasite Unit in Amorgos could possibly represent the lowermost structural unit in the central Aegean Sea.

Measuring quality of life is increasingly considered as an outcome criterion in clinical studies. In order to assess quality of life, disease specific as well as generic instruments are used. Generic instruments make it possible to compare outcomes among different indications, but for this purpose a test of the factorial validity of the method in each indication is necessary. In this study, the generic short form 12 was administered to a sample survey of 545 patients with inflammatory-rheumatic disease. Patients data from three scientific rehabilitation research projects were pooled for the analysis. First the structure was tested using confirmatory structural equation modeling. In a second step age and gender specific values were calculated and compared to norm data from the German National Health Survey 1998. The questionnaire's structure is acceptable and comparable to international results. Confirmatory analyses support a model allowing covariations of error terms between items of the same subdimensions. The two latent dimension are highly correlated. Crossloadings of items from different subdimension does not improve the model fit significantly. Comparisons with the German norm data shows that the patients are impaired within their physical and mental dimension of subjective health. Higher impairment is evident especially on the physical sumscale. Women show higher impairment in both scales. However no effects of age can be detected. The SF-12 could be used with trust in the study of patients with inflammatory-rheumatic diseases. But physical and mental health can not be seen as independently.

Multimineral Rb/Sr internal isochrons from eclogite facies rocks of the Eclogite Zone (Tauern Window, Eastern Alps) consistently yield an Early Oligocene age of 31.5±0.7 Ma. This age has been obtained both for late-prograde, dehydration-related eclogitic veins, and for rocks variably deformed and recrystallized under eclogite facies conditions (2.0–2.5 GPa, 600°C). Initial Sr-isotopic equilibria among all phases indicate absence of significant post-eclogitic isotope redistribution processes, therefore the ages date eclogite facies assemblage crystallization. Equilibria also prove that no prolonged pre-eclogite facies history is recorded in the rocks. Instead, subduction, prograde mineral reactions, and eclogitization proceeded rapidly. Fast exhumation immediately after eclogitization, with minimum rates >36 mm/a is inferred from a 31.5±0.5 Ma internal mineral isochron age of a post-eclogitic greenschist facies vein assemblage. Such rates equal typical subduction rates. Late Eocene to Early Oligocene subduction of the European continental margin, with subsequent rapid exhumation of high-pressure nappe complexes has previously been recognized only in the Western Alps. The new data signify synchronous continental collision all along the Alpine belt. Our results demonstrate the unique potential of Rb/Sr assemblage ‘system analysis’ for precise dating of both eclogite facies and post-eclogitic events, thus for precisely constraining exhumation rates of deep-seated rocks, and for straightforward linkage of petrologic evidence with isotopic ages.

Lebensqualitat besitzt als Erfolgskriterium therapeutischer Masnahmen hohe Relevanz. Zur ihrer Erfassung werden neben krankheitsspezifischen auch generische Instrumente eingesetzt, die Vergleiche uber verschiedene Indikationen ermoglichen. Hierzu ist es jedoch notwendig, die differentielle faktorielle Validitat des Verfahrens in unterschiedlichen Indikationen nachzuweisen. Mittels Strukturgleichungsmodellierung wurde die Fragebogenstruktur des Short Form 36 in einer Stichprobe von Patienten mit entzundlich-rheumatischen Erkrankungen konfirmatorisch getestet. Zudem wurde die Veranderungssensitivitat des Verfahrens sechs Monate nach einer Rehabilitationsmasnahme ermittelt. Anschliesend wurden alters- und geschlechtsspezifische Kennwerte berechnet und mit Normdaten verglichen. Die SF-36 Daten von 436 Patienten sowie deren Alter und Geschlecht wurden aus zwei Forschungsprojekten im Rahmen einer Sekundaranalyse zusammengefuhrt. Die konfirmatorischen Analysen belegen fur ein Modell mit Mischladungen unter der Annahme korrelierter Hauptdimensionen die beste Gute. Die Veranderungssensitivitat ist bis auf die Subskala Schmerz gering. Der Normdatenvergleich weist darauf hin, dass die Patienten vor allem auf den physischen SF-Subskalen sowohl zu Beginn der Masnahme als auch nach sechs Monaten erheblich beeintrachtigt sind. Manner zeigen dabei uber alle Altersgruppen hinweg eher besseres Befinden als Frauen. Der generische SF-36 ist ausreichend faktoriell valide, so dass aus dieser Perspektive nichts gegen dessen Einsatz bei Patienten mit entzundlich-rheumatischen Erkrankungen spricht. Die Verwendung der (unkorrelierten) SF-Summenskalen als Operationalisierung psychischer bzw. physischer Gesundheit sollte allerdings kritisch hinterfragt werden.

With the enforcement of the German law for psychotherapeutics at the beginning of 1999, the field of psychotherapy detached from a widespread "delegation procedure" through the possibility of first-access for patients to a psychotherapist. In the form of an experiment, Saxony-Anhalt practiced as the only land in the Feral Republic of Germany a modified form of delegation procedure in the legal health insurance since 1992. The most important modification consisted in the possibility of first-access for the patient to the psychotherapist. Using selected results of the investigation in the view of psychotherapy patients and from medical and psychological psychotherapists, the situation after 5 years since introduction of this model in the out-patient, psychotherapeutic care in Saxony-Anhalt will be shown, as well as experience gained from this model.

Molecular medicine is undergoing fundamental changes driving the whole area towards a revolution in modern medicine. The breakthrough was generated the fast-developing technologies in molecular biology since the first draft sequence of the human genome was published. The technological advances enabled the analysis of biological samples from cells and organs to whole organisms in a depth that was not possible before. These technologies are increasingly implemented in the medical and health care system to study diseases and refine diagnostics. As a consequence, the understanding of diseases and the health status of an individual patient is now based on an enormous amount of data that can only be interpreted in the context of the body as a whole. Systems biology as a new field in the life sciences develops new approaches for data integration and interpretation. Systems medicine as a specialized aspect of systems biology combines in an interdisciplinary approach all expertise necessary to decipher the human body in all its complexity. This created new challenges in the area of information and communication technologies to provide the infrastructure and technology needed to cope with the data flood that will accompany the next generation of medicine. The new initiative 'IT Future of Medicine' aims at driving this development even further and integrates not only molecular data (especially genomic information), but also anatomical, physiological, environmental, and lifestyle data in a predictive model approach-the 'virtual patient'-that will allow the clinician or the general practitioner to predict and anticipate the optimal treatment for the individual patient. The application of the virtual patient model will allow truly personalized medicine.

Background Gene Regulatory Networks (GRNs) control the differentiation, specification and function of cells at the genomic level. The levels of interactions within large GRNs are of enormous depth and complexity. Details about many GRNs are emerging, but in most cases it is unknown to what extent they control a given process, i.e. the grade of completeness is uncertain. This uncertainty stems from limited experimental data, which is the main bottleneck for creating detailed dynamical models of cellular processes. Parameter estimation for each node is often infeasible for very large GRNs. We propose a method, based on random parameter estimations through Monte-Carlo simulations to measure completeness grades of GRNs. Results We developed a heuristic to assess the completeness of large GRNs, using ODE simulations under different conditions and randomly sampled parameter sets to detect parameter-invariant effects of perturbations. To test this heuristic, we constructed the first ODE model of the whole sea urchin endomesoderm GRN, one of the best studied large GRNs. We find that nearly 48% of the parameter-invariant effects correspond with experimental data, which is 65% of the expected optimal agreement obtained from a submodel for which kinetic parameters were estimated and used for simulations. Randomized versions of the model reproduce only 23.5% of the experimental data. Conclusion The method described in this paper enables an evaluation of network topologies of GRNs without requiring any parameter values. The benefit of this method is exemplified in the first mathematical analysis of the complete Endomesoderm Network Model. The predictions we provide deliver candidate nodes in the network that are likely to be erroneous or miss unknown connections, which may need additional experiments to improve the network topology. This mathematical model can serve as a scaffold for detailed and more realistic models. We propose that our method can be used to assess a completeness grade of any GRN. This could be especially useful for GRNs involved in human diseases, where often the amount of connectivity is unknown and/or many genes/interactions are missing.

[1] Recent findings for a young (31.5 ± 0.7 Ma) age of high-pressure metamorphism at ∼90 km depths in the Eclogite Zone of the Tauern Window, Eastern Alps, prompt the question about the timing of the structural development of the Tauern Window and its relation to high-pressure metamorphism. We show that all major structures in the Tauern Window, resulting from strong N-S lithospheric shortening and simultaneous minor E-W extension, began developing coevally with high-pressure metamorphism in the Eclogite Zone. Large-scale strike-slip shear zones started to form at ∼32–30 Ma and facilitated the spatial accommodation of simultaneous shortening and extension. At least some of the strike-slip and extensional shear zones operated into the Middle Miocene, either continuously or intermittently, with pronounced activity at ∼21–15 Ma. The considerable exhumation of the Eclogite Zone from ∼90 km depths into the middle crust, and the tectonic development of its framework occurred within only 1–2 Ma after eclogitization. This is evidenced by almost identical ages for eclogite facies metamorphism and for the development of the major structures that bound the Eclogite Zone under blueschist- and greenschist facies metamorphic conditions. We discuss a tectonic model in which considerable transpressional shortening and thickening took place in the present central-southern part of the Tauern Window. We propose that the Tauern Window nucleated here and that most of the regional deformation at ∼32–30 Ma is today found at the periphery of the window and in the adjacent Austroalpine units. Afterward, transpression continued, the window grew to the E, W, and N, and deformation progressed to those parts of the window. Ductile deformation in the present-day surface level ceased at ∼15 Ma.

Novel territory-specific markers from the sea urchin Strongylocentrotus purpuratus have been identified using screens for genes that are differentially expressed in lithium-treated embryos, which form an excess of endomesoderm, and in zinc-treated embryos, in which endomesoderm specification is blocked., Background The genome of the sea urchin Strongylocentrotus purpuratus has recently been sequenced because it is a major model system for the study of gene regulatory networks. Embryonic expression patterns for most genes are unknown, however. Results Using large-scale screens on arrays carrying 50% to 70% of all genes, we identified novel territory-specific markers. Our strategy was based on computational selection of genes that are differentially expressed in lithium-treated embryos, which form excess endomesoderm, and in zinc-treated embryos, in which endomesoderm specification is blocked. Whole-mount in situ hybridization (WISH) analysis of 700 genes indicates that the apical organ region is eliminated in lithium-treated embryos. Conversely, apical and specifically neural markers are expressed more broadly in zinc-treated embryos, whereas endomesoderm signaling is severely reduced. Strikingly, the number of serotonergic neurons is amplified by at least tenfold in zinc-treated embryos. WISH analysis further indicates that there is crosstalk between the Wnt (wingless int), Notch, and fibroblast growth factor signaling pathways in secondary mesoderm cell specification and differentiation, similar to signaling cascades that function during development of presomitic mesoderm in mouse embryogenesis. We provide differential expression data for more than 4,000 genes and WISH patterns of more than 250 genes, and more than 2,400 annotated WISH images. Conclusion Our work provides tissue-specific expression patterns for a large fraction of the sea urchin genes that have not yet been included in existing regulatory networks and await functional integration. Furthermore, we noted neuron-inducing activity of zinc on embryonic development; this is the first observation of such activity in any organism.

Neoplastic progression in patients with chronic ulcerative colitis is characterized by the development of epithelial dysplasia, which is accompanied by genetic alterations. This study determined the time of onset of p53 and Ki-ras mutations as well as DNA aneuploidy during histological progression towards carcinoma. In all, 278 samples of 7 colectomy specimens were analyzed by flow cytometry, histology and single-strand conformation polymorphism analysis. Of the samples, 22% (61/278) were dysplastic and 43% (122/278) aneuploid, while 25% (71/278) showed p53 and 4% (11/278) Ki-ras mutations. The correlation between aneuploid status and p53 mutations varied among the patients. A strong correlation was noticed between histological progression from low-grade dysplasia to carcinoma and p53 mutations as well as DNA aneuploidy. Ki-ras mutations were found in 40% (2/5) of the carcinomatous samples. The correlation between p53 mutations and the histological status of the samples suggest the involvement of this genetic event in the development of colon cancer in patients with ulcerative colitis. In contrast to Ki-ras mutations, the appearance of p53 mutations is an early event. Therefore p53 analysis might be helpful in the classification of indefinite dysplasia and in the identification of patients at risk for cancer development. Further studies are necessary to detect the additional genetic alterations preceding the development of DNA aneuploidy.

During the last decade flexibility has become a key notion of modern life and sciences. Especially for management science dealing with the dynamics of systems, flexibility turns out to be of particular importance. Expressions like flexible manufacturing, flexible workforce, and flexible market behaviour indicate its popularity.

The formation and decomposition of negative molecular ions following low energy electron capture is studied using electron attachment and electron transmission spectroscopy. An analysis of the kinetic energy release of the reaction products is performed in order to obtain information on the intramolecular decomposition dynamics of the transient negative parent ions. Typical results and trends are presented for a number of prototype molecules such as SF 6 , substituted methanes, ethylenes, benzenes and alcohols. In many systems, semiempirical MNDO calculations permit a correlation between the experimentally obtained attachment energies and the virtual molecular orbitals involved, as well as the mechanisms of the subsequent decomposition reactions. Recent results of work on electron attachment to van der Waals' complexes are presented.

Starting from a continuously inspected stochastic dynamic inventory problem the procedure of Brown derives reorderpoint policies being implemented in many software packages. Schneider adapted this procedure to the more realistic periodically inspected problem. Although his method is straight-forward some crucial assumptions have to be imposed. In the present paper these assumptions are investigated analytically and numerically, particularly with respect to regular and sporadic demand, thus giving clear limits as to the validity of the fundamental derivation of Brown/Schneider.

Extending the derivation of Schneider and Tijms/Groenevelt to non-stationary demand the paper determines the reorder point for periodically reviewed stochastic inventory problems. It is shown that after some adaptations the calculations are of the same quality as those for the stationary case.

Nachdem die in der vorliegenden Arbeit zu benutzenden Modelle festgelegt und die flexible Planung als die geeignete Methode zur Ermittlung optimaler und effizienter Losungen beschrieben wurde, konnen wir uns jetzt dem eigentlichen Phanomen der Flexibilitat zuwenden. Flexibilitat kann als die Eigenschaft eines Systems betrachtet werden, die dessen Fahigkeit zur Bewaltigung der Unsicherheit und der Dynamik der Umwelt angibt.

Im Kapitel 5 werden Planungsmodelle entwickelt, mit denen sich auf Modell L basierende Entscheidungsprobleme handhaben lassen. Es geht nun um die Bewaltigung von Entscheidungsproblemen praktischen Umfangs und nicht mehr um eine stark vereinfachte Betrachtung wie in Kapitel 4. Dort stand erstens die prinzipielle Flexibilitatswirkung der Kombination von Eil— und Normalmasnahmen und zweitens die Ermittlung prinzipieller Eigenschaften optimaler Strategien im Vordergrund. Diese Fragen konnten aufgrund der einfacheren Struktur des benutzten Modells LAT2 durch die Anwendung der optimalen flexiblen Planung analysiert werden.

Untersuchungsgegenstand der Kapitel 2 und 3 der vorliegenden Arbeit ist das Phanomen der Flexibilitat, uber die eine Unternehmung oder ein abgegrenzter Unternehmensbereich bei der Erstellung beliebiger betrieblicher Leistungen verfugt. Um betriebliche Flexibilitat definieren und anschliesend einen Flexibilitatskalkul zur Unterstutzung betriebswirtschaftlicher Planungsprozesse entwickeln zu konnen, ist zunachst das Modell des betrieblichen Systems festzulegen, das betrachtet werden soll1. Deshalb wird nun zuerst das in dieser Arbeit benutzte Modell in seiner allgemeinsten Form eingefuhrt — bezeichnet als Modell A — und im weiteren Verlauf der Untersuchungen im Hinblick auf die Klarung bestimmter Fragestellungen jeweils in zweckmasiger Weise spezialisiert.

Gestutzt auf die Theorie der dynamischen Optimierung wird ein Konzept zur Messung der Flexibilitat beliebiger betrieblicher Systeme vorgestellt. Die Flexibilitat eines Systems, mit der man dessen Fahigkeit zur Bewaltigung von Unsicherheit und Dynamik verbindet, ist eng korreliert mit der Fahigkeit des Systems, zu uberleben. Das vorgestellte Flexibilitatsmass kann deshalb zur Unterstutzung strategischer Auswahlentscheidungen uber Systemlayouts eingesetzt werden. Daruber hinaus werden in diesem Buch Probleme der Planung und Steuerung flexibler Potentiale untersucht, die das Verstandnis flexibilitatsorientierter Planung vertiefen. Fur konkrete logistische Fragestellungen aus den Bereichen Materialwirtschaft und Kapazitatsplanung werden hierarchisch strukturierte Entscheidungsmodelle entwickelt, die beispielsweise bezuglich der Optimierung des kombinierten Einsatzes von Routine- und Eilbestellungen bei der Lagerdisposition zu vollig neuen und fur die Praxis wichtigen Ergebnissen fuhren.

Untersucht werden die in den Verfahren von Brown und Schneider zur Ermittlung einer (Bestellpunkt, Bestellgrenzen)-Lagerhaltungspolitik enthaltenen Approximationen.

Der in Kapitel 3 erarbeitete Flexibilitatskalkul wird nun zur Untersuchung der prinzipiellen Flexibilisierungswirkung einer Kombination von Praventiv- und Sanierungsmasnahmen bei der Bewaltigung von Unsicherheit genutzt. Dies wird im Kapitel 4 fur den speziellen Fall der Disposition von Normal — und Eilbestellungen in der Lagerhaltung geschehen. Zu diesem Zweck steht das schon in Abschnitt 2.1.3 formulierte Modell LAT zur Verfugung. Kapitel 4 wirkt deshalb als Bindeglied zwischen den beiden Hauptteilen der vorliegenden Arbeit: Einerseits wird der Flexibilitatskalkul noch einmal an einem etwas aufwendigeren Beispiel verdeutlicht; andererseits wird jetzt die Flexibilitatswirkung einer Kombination von Praventiv- und Sanierungsmasnahmen prinzipiell analysiert.

Um die in dieser Arbeit gewonnen Erkenntnisse zusammenfassen zu konnen, wenden wir uns nach der Analyse speziellerer Modelle in den Kapiteln 4 und 5 nun wieder dem allgemeinen Entscheidungsmodell A zu (vgl. Abschnitt 2.1.1). Eine Zielsetzung dieser Arbeit ist es, Prinzipien einer Planung herauszuarbeiten, mit der Unsicherheit bewaltigt werden kann. Da Planung aber letztlich auf den Modellen basiert, mit denen der Entscheidungstrager die Realitat abbildet, mus der Modellbildungsprozes bei Unsicherheit mit in die Uberlegungen einbezogen werden.

Vor etwa 10 Jahren hat K. Spicher einen Algorithmus zur Lagerdisposition vorgestellt [ZOR (19)1975, B1-B12], der entgegen den ublichen Bestellpunkt-Bestellgrenzen-Verfahren die Einhaltung eines Ziellieferbereitschaftsgrades als zentrale Zielgrose betrachtet. Methodisch stellt der SB-Algorithmus ein Feedback-Verfahren dar, wahrend die ubliche Lagerhaltungstheorie mit Feedforewardheuristiken arbeitet. Von daher ist das Verfahren von Spicher von grundsatzlichem Interesse, so das eine vergleichende Analyse wunschenswert erscheint.