[Epidemiology and surgical treatment of pancreatic cancer in the State of Brandenburg : Analysis of 5418 cases]. / Epidemiologie und operative Behandlung des Pankreaskarzinoms im Flächenland Brandenburg : Analyse von 5418 Fällen.

BACKGROUND: Pancreatic cancer is the second most frequent cause of death among all forms of cancer in Germany with more than 19,000 deaths per year. The evaluation of the nationwide clinical cancer register aims to depict the reality of treatment and to improve the quality of treatment in the future by targeted analyses. METHOD: The data from the clinical cancer register of Brandenburg-Berlin for the diagnosis years 2001-2017 were analyzed with respect to the treatment of pancreatic cancer. Data from patients resident in the State of Brandenburg were evaluated with respect to epidemiological and therapeutic parameters. RESULTS: A total of 5418 patients with pancreatic cancer were documented in the register from 2001 to 2017 and 49.6% of the patients were diagnosed as having the Union for International Cancer Control (UICC) stage IV. A pancreas resection was carried out in 26.4% of the cases. In cases of cancer of the head of the pancreas the most frequent procedure was a pylorus-preserving resection with 51.8% and a pancreatectomy was carried out in 9.4%. The R0 resection rate of all pancreatic cancers in the period from 2014 to 2017 was 61.9%. After R0 resection the 5­year survival was 19%. Relevant multivariate survival factors were age, UICC stage and the residual (R) tumor classification. The case numbers per hospital had no influence on the absolute survival of patients operated on in the State of Brandenburg. CONCLUSION: The treatment reality in the State of Brandenburg for patients with pancreatic cancer corresponds to the results of international publications with respect to the key performance indicators investigated. A qualitative internationally comparable treatment of these patients is also possible in nonmetropolitan regions.

[Coagulation analysis in transplantation patients]. / Gerinnungsanalyse bei Transplantations-patienten. Pitfalls am Beispiel der Lebertransplantation.

In patients post organ transplantation, the underlying disorder necessitating the transplantation, as well as the transplantation itself, can both mask pre-existing haemostatic abnormalities or lead to them. Since the liver is the main production site for coagulation factors, orthotopic liver transplantation predestinates for acquiring or losing a genetically determined coagulation defect. In coagulation diagnostics, this may lead to a discrepancy between functional plasma tests and molecular biologic findings if these are gathered from nucleated cells of the peripheral blood, as is the standard. Due to the rareness of most defects and the lack of consequences in case of diagnosis of a more common coagulation disorder, no general screening before or after transplantation is required. Underlying diseases leading to liver transplantation as well as the actual transplantation must be considered when interpreting the findings.

[Therapeutic modulation of coagulation in sepsis]. / Gerinnungstherapeutische Ansätze bei Sepsis.

Based on the increasing knowledge of defects in haemostasis in patients with sepsis as well as on the non-conclusive results of studies which tried to increase the prognosis by modulating cytokine response of the patients, in the last years the impact of therapeutic modulation of coagulation in sepsis has been investigated. In contrast to the results of phase III studies with the coagulation inhibitors antithrombin and tissue factor pathway inhibitor recombinant human activated protein C (rhAPC) resulted in a significant reduction in mortality for the whole study population. Data analyses showed, that treatment with rhAPC was clinically beneficial especially in patient groups who showed a high mortality in the placebo arm. Inhibition of thrombus formation due to the therapy with natural coagulation inhibitors resulted in an increase of sepsis-imminent haemorrhage, which became significant in some studies. Treatment with antithrombin and heparin resulted in a considerable increase in bleeding complications and on the other hand, may have antagonized the expected effect of antithrombin on the patient's prognosis. Some results suggesting beneficial effects of heparin on patient prognosis in the placebo arms and on the other hand negative effects of heparin in the verum arms -- especially with antithrombin or tissue factor pathway inhibitor -- let to a controversial discussion of the risk/benefit relation of heparin, given in prophylactic doses to patients with severe sepsis. Whereas the impact and optimal application of heparin to patients with severe sepsis needs to be clarified study results with rhAPC resulted in the approval of this therapy and the implementation in the guidelines of the treatment of patients with severe sepsis.

[Thrombophilia--diagnostic steps and therapeutic consequences after deep vein thrombosis]. / Thrombophilie--Diagnostische Schritte und therapeutische Konsequenzen nach tiefer Venenthrombose.

SUMMARY: In developed countries there is an age dependent increasing incidence of deep vein thrombosis. Hereditary thrombophilia is usually suspected by the clinical constellation and anamnestic informations. For economical reasons usually laboratory testing should be avoided if the results will not change directly the therapeutic process. But for hereditary defects consequences for the patient in future and for relatives should be taken into account especially as more selective strategies for prophylaxis and treatment have to be expected by increasing information in that field of research. As deficiencies of anticoagulant proteins (PC, PS, AT) have an impact on anticoagulant treatment, the indication for testing should not be held too strict. Time point for diagnostic procedures should be early after a thromboembolic event as negative results exclude hereditary defects definitely which allows the planning of the aimed treatment duration. After first onset of deep vein thrombosis, even in presence of hereditary coagulation defects the duration of anticoagulation usually depends on the clinical and anamnestic signs for a thrombophilic tendency of the individual patient. First publications suggest the need for prolonged anticoagulation of carriers with combined defects, showing an elevated rate of re-thrombosis after the first thromboembolic event, when anticoagulation is stopped. Every ongoing anticoagulation should be checked repeatedly in the sense of a risk -benefit evaluation even for patients with a thrombophilic tendency and should be adapted to actual publications.

[Secondary osteoporosis induced by anticoagulants?]. / Sekundäre Osteoporose durch Antikoagulantien?

Generalized osteoporosis is a result of different causes and pathogenic mechanisms, which often combine forces to become clinically relevant. Among the different exogenic factors, drugs play an important role, frequently in connection with other factors such as immobilization or pregnancy. It has been suggested that anticoagulation therapy with heparins or coumarins may induce osteoporotic changes or enhance the development of osteoporosis for other reasons. According to in vitro experiments, preclinical trials, and clinical investigations, it seems reasonable to assume that heparins induce increased bone loss in a time- and dose-related manner. Low-molecular-weight heparins most likely have less effect on bone turnover when compared to unfractionated heparin. Oral anticoagulation therapy with vitamin K-antagonists is believed to have a weak effect on induction of osteoporosis, but clinical studies are contradictory. In spite of the fact that a relevant effect of these drugs on the induction of osteoporosis is questionable, it must be taken into consideration that anticoagulant drugs may enhance the negative effects on bone density of other risk factors capable of inducing osteoporosis such as immobilization, pregnancy, or endocrinological disorders.

The functional unit of interphotoreceptor retinoid-binding protein (IRBP)--purification, characterization and preliminary crystallographic analysis.

To define the relationship between the structure and function of interphotoreceptor retinoid-binding protein (IRBP) we seek to prepare crystals of IRBP suitable for X-ray crystallographic analysis. As recent studies suggest that each of IRBPs four homologous regions or modules possess ligand-binding activity, we here explore the feasibility of preparing crystals from an individual module. Xenopus laevis IRBP, which has a similar four-module structure as that of mammalian and avian IRBPs, was selected for these studies in view of the advantage of the Xenopus retina for cellular and transgenic approaches. In the present study we focused on the second module of Xenopus IRBP. This module was expressed as a thioredoxin/histidine-patch fusion protein to promote its soluble expression in Escherichia coli and subsequent purification. The ligand-binding properties of the fusion protein were determined by fluorescence spectroscopy. For the preparation of crystals, the module was enzymatically separated from the fusion tag. Crystals of the native and selenomethionine derivatized module were prepared by vapor diffusion in hanging drops. Module II of IRBP binds 1.57 +/- 0.041 and 1.49 +/- 0.15 equivalents of at all- trans retinol and 9-(9-anthroyloxy) stearic acid, respectively, with KDs in the 0.1 microM range. Crystals of this module had an elongated rectangular beam-like morphology. A complete dataset of a frozen selenomethionine crystal extending to 1.85 A resolution was collected. Focusing on the individual modules will likely provide an effective strategy to correlate biochemical and structural data to define the functional domains of IRBP. The quality and resolution of the data obtained suggests that it will be possible in the near future to solve the X-ray crystal structure of the IRBP modules.

Purification, crystallization and preliminary crystallographic analysis of bovine cytosolic brain-type creatine kinase.

Creatine kinase (E.C. 2.3.7.2) is an important enzyme in energy metabolism which catalyzes the reversible transfer of a phosphoryl group between phosphocreatine and ADP to give ATP. Large quantities of a brain-type creatine kinase have been isolated from bovine photoreceptor cells and crystals suitable for X-ray diffraction analysis have been obtained by hanging-drop vapor diffusion. Crystals grow as tetragonal bipyramids in space group P43212 with cell dimensions a = b = 96.49, c = 108.42 A and diffract to at least 2.7 A resolution.

Phosducin induces a structural change in transducin beta gamma.

BACKGROUND: Phosducin binds tightly to the beta gamma subunits (Gt beta gamma) of the heterotrimeric G protein transducin, preventing Gt beta gamma reassociation with Gt alpha-GDP and thereby inhibiting the G-protein cycle. Phosducin-like proteins appear to be widely distributed and may play important roles in regulating many heterotrimeric G-protein signaling pathways. RESULTS: The 2.8 A crystal structure of a complex of bovine retinal phosducin with Gt beta gamma shows how the two domains of phosducin cover one side and the top of the seven-bladed beta propeller of Gt beta gamma. The binding of phosducin induces a distinct structural change in the beta propeller of Gt beta gamma, such that a small cavity opens up between blades 6 and 7. Electron density in this cavity has been assigned to the farnesyl moiety of the gamma subunit. CONCLUSIONS: beta gamma subunits of heterotrimeric G proteins can exist in two distinct conformations. In the R (relaxed) state, corresponding to the structure of the free beta gamma or the structure of beta gamma in the alpha beta gamma heterotrimer, the hydrophobic farnesyl moiety of the gamma subunit is exposed, thereby mediating membrane association. In the T (tense) state, as observed in the phosducin-Gt beta gamma structure, the farnesyl moiety of the gamma subunit is effectively buried in the cavity formed between blades 6 and 7 of the beta subunit. Binding of phosducin to Gt beta gamma induces the formation of this cavity, resulting in a switch from the R to the T conformation. This sequesters beta gamma from the membrane to the cytosol and turns off the signal-transduction cascade. Regulation of this membrane association/dissociation switch of Gt beta gamma by phosducin may be a general mechanism for attenuation of G protein coupled signal transduction cascades.