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Notes: Zusammenfassung Die Untersuchungen waren von der Frage ausgegangen, ob eine Autosensibilisierung gegen Gewebsbestandteile des menschlichen Zentralnervensystems im Prinzip möglich ist, mit welcher Methode zirkulierende Antikörper gegen Hirnextrakte nachgewiesen werden können, und bei welchen Krankheiten derartige Antikörper gebildet werden. Unter Verwendung der vonOuchterlony angegebenen Technik der Diffusion und Präcipitation im Agargel hatten wir in früheren Untersuchungen festgestellt, daß Seren von Kranken mit Multipler Sklerose, disseminierter Encephalomyelitis und „idiopathischer“ Polyradikuloneuritis (Gulliain-Barre) relativ häufig mit Extrakten aus normalem menschlichen Gehirn (weißer Substanz) eine Präcipitationslinie im Agargel bilden. Die Entstehungsbedingungen dieses Phänomens waren weiter aufzuklären, insbesondere war zu untersuchen, ob das Phänomen durch einen Serum-Eiweißkörper mit bestimmten Eigenschaften hervorgerufen wird. Folgende Ergebnisse wurden festgestellt: 1. Das Präcipitationsphänomen wird durch einen Faktor verursacht, der bei verschiedenen Fällen von Multipler Sklerose in gleicher Weise nachgewiesen werden kann. 2. Der Faktor gehört der Euglobulin-Fraktion an. Er ist in destilliertem Wasser und in neutraler Pufferlösung von geringer Ionenstärke (0,005 M Phosphat) unlöslich. 3. Der Faktor hat die elektrophoretische Beweglichkeit eines schnell wandernden gamma-Globulins. 4. Durch Chromatographie an DEAE-Cellulose kann der Faktor aus größeren Serum-Mengen oder aus Euglobulin präparativ gereinigt und angereichert werden. Der Faktor wird durch Pufferlösungen von hoher Ionenstärke und niedrigem pH-Wert (0,15 bis 0,3 M Phosphat, pH 5,0) aus DEAE-Cellulose eluiert. Der Faktor wird durch Anti-IgM-Seren vom Pferd in typischer Weise präcipitiert, er zeigt Kreuz-Reaktionen mit Anti-IgA- und Anti-IgG-Seren. Gereinigtes Immunglobulin-G (7 S-gamma-Globulin) aus MS-Seren enthält den präcipitierenden Faktor nicht. 5. Der Faktor wird aus größeren Mengen aktiven Serums durch Absorption mit Hirnextrakt vollständig auspräcipitiert. Das gewaschene Immunpräcipitat kann in sauerem Milieu (pH 3,2) dissoziiert werden. Die Immunelektrophorese des dissoziierten Komplexes ergibt ein Protein mit den Eigenschaften eines schnell wandernden gamma-Globulins. Als ein Immunglobulin-M mit Antikörper-Eigenschaften entspricht der Faktor als Protein anderen hochmolekularen Antikörpern der IgM-(19 S)-Klasse, wie z. B. dem Rheumafaktor der primär chronischen Polyarthritis, bestimmten antinucleären Faktoren des Lupus erythematodes visceralis und den Thyreoglobulin-Antikörpern entzündlicher Schilddrüsen-Erkrankungen. Der Faktor in MS-Seren unterscheidet sich jedoch in seiner Antikörper-Eigenschaft von den genannten Faktoren durch die Substratbindung an Hirnextrakt. Er ist mit keinem bisher beschriebenen Faktor identisch. Der Faktor findet sich in Seren von Kranken mit Multipler Sklerose in aktiven Stadien der Entzündung. Nach den vorliegenden Ergebnissen ist es wahrscheinlich, daß der Faktor in einer relativ engen Beziehung zu der entzündlichen Gewebsdestruktion steht.

Notes: [Auszug] T: able 1 Dose-dependent effect of inhibitor on I *HA- and MLC-stimulated hum an lymphocyte s and HeLa cells Inhibitor Lymphocytes Inhibitor Lymphocytes Inhibitor HeLa HeLa (jig/0.2 ml) PHA (3H-Thymidine Mikro) Oig/0.2ml) MLC (3H-Thymidine Mikro) (Hg/0.2 mn 3H-Thymidine ...

Notes: Abstract Modulators for the reversal of multidrug resistance such as R-verapamil and B8509-035, a dihydropyridine, effectively overcome multidrug resistance in vitro and are currently undergoing clinical trial. One problem with their use is the application protocol; the question as to whether they should be given by continuous administration or in sequential doses in combination with the cytotoxic drugs has to be addressed. Therefore, we examined the influence of the exposure time and the sequence of modulator administration on the active transport of the fluorescent dye rhodamine 123 (R123), a substrate for the P-glycoprotein, in the resistant lymphoblastid cell line VCR1000 and the parental nonresistant cell line CCRFCEM. Our results demonstrate the importance of coadministration of R-verapamil and the cytotoxic agent for the modulation of multidrug resistance, whereas the exposure sequence does not seem to be such an essential parameter in the case of B8509-035. This observation should be considered for the further design of clinical studies.

Notes: Abstract Purpose: The alkylating agent cyclophosphamide (CP) is a prodrug that is metabolized to both cytotoxic and inactive compounds. We have previously shown that following dose escalation from conventional-dose (CD) to high-dose (HD) levels; the fraction of the dose cleared by bioactivation is significantly decreased (66% versus 48.5%) in favor of inactivating elimination pathways when the HD is given as a single 1-h infusion. Based on the concept of bioactivating enzyme saturation with increasing doses, we investigated the influence of fractionated application of HD-CP on dose-dependent changes in metabolism. Patients and methods: Plasma concentrations of CP (measured by high-performance liquid chromatography, HPLC) and urinary concentrations of CP and its major metabolites (quantified by [31P]-nuclear magnetic resonance spectroscopy; [31P]-NMR spectroscopy), were determined in four patients with high-risk primary breast cancer who received adjuvant chemotherapy including both CD-CP (500 mg/m2 infused over 1 h) and split HD-CP (50 mg/kg infused over 1 h on each of 2 consecutive days (d): d1 and d2. Results: (Data are given as mean values for CD and d1/d2 of HD, respectively). Systemic clearance (CL) of CP was similar during CD and d1 of HD, but significantly increased on d2 of HD (CL: 83 and 78/115 ml/min; P 〈 0.01 for d1 versus d2). The latter was translated into an increase in formation CL of both active (+16.4 ml/min) and inactive metabolites (+17.6 ml/min) and reflects autoinduction of metabolism. As compared with CD-CP, no statistically significant decrease was observed in the relative contribution of bioactivation CL to overall CL during both days of HD (63% versus 57%/53%). Recovery of intact CP in 24-h urine corresponded to 24%, 29%, 22% of the dose (P 〈 0.05 for d1 versus d2 of HD). Conclusions: Following dose escalation of CP, dividing the high dose over 2 days instead of one single infusion may favorably impact the metabolism of CP in terms of bioactivation. In addition, on day 2 of a split regimen, renal elimination of CP is decreased, which implies that more drug is available for metabolism.

Notes: Abstract Tumor cell resistance to cytotoxic drugs is considered one of the major obstacles to successful chemotherapy. Multidrug resistance (MDR) describes the simultaneous expression of cellular resistance to a wide range of structurally and functionally unrelated drugs. The development of the multidrug resistance phenotype is accompanied by multiple morphological and biochemical changes: (a) increased glutathione levels in the cytoplasm, (b) modified levels of enzymes in the nucleus, particularly topoisomerase II, (c) increased DNA repair capacity and (d) overexpression of the (human)MDR1 gene encoding a transmembrane efflux pump (P-glycoprotein, gp-170), which leads to decreased intracellular accumulation and therefore to resistance to a variety of cytotoxic drugs. In this report we describe a competitive polymerase chain reaction (PCR) assay for the absolute quantification ofMDR1 mRNA. This assay uses a transcript generatedin vitro as an internal standard which is later coamplified together with theMDR1 cDNA. Both cDNAs exhibit the sameMDR1 primer sites but differ in the length of the amplicon. For a second round of amplification we applied nestedMDR1 primers and were successful in improving the sensitivity of this competitive PCR system. This test for characterizing theMDR1 expression offers high sensitivity and specificity and is therefore of great clinical relevance. It should be useful in improving monitoring and design of chemotherapy.

Notes: Quality Management during the Fabrication of Chemical Equipment Made of Special Materials Optimizing a material's resistance to corrosion by the addition of alloying elements up to their solubility limits will make it increasingly difficult to use these frequently unstable alloys for the manufacture of chemical plant. The requirements these materials have to meet in the manufacture of chemical plant in terms of manufacturing technology and quality management, are becoming increasingly stringent. The current situation, for example in the manufacture of domed heads of pressure vessels, forgings, heat exchangers, and filter screens with a high specific surface area as a constituent part of stirred suction filters using advanced metallic materials, is not very satisfactory. Results of fabrication tests necessary for pressure vessel manufacture as well as in-service failures frequently demonstrate insufficient expertise of workshops dealing with high-alloy stainless steels and nickel-based materials. That the in-service failure of compoents clearly leads to considerable costs due to maintenance, delays in supply, and production downtimes. The economic consequences can be substantial. The aim of this paper is to highlight sensitive areas by demonstrating the impact of unintentional and unnoticed fabrication-related changes in welding parameters and to provide information on easily applicable methods of monitoring techniques.