52-jährige Patientin mit positivem Troponin, Eisenmangelanämie und bekannter Sarkoidose

Zusammenfassung Wir berichten über eine 52-jährige Patientin mit reaktivierter Neurosarkoidose und atypischer glutensensitiver Enteropathie (GE; asymptomatisch, IgA-Antikörper und Histologie positiv). Ein falsch-positiver Nachweis von kardialem Troponin I infolge der IgA-Antikörper führte zunächst zur Verdachtsdiagnose eines akuten Koronarsyndroms. Unter glutenfreier Diät waren die IgA-Antikörper rückläufig und der Troponin-I-Test dann negativ. Die Häufung einer potenziellen GE (nur Antikörpernachweis) bei Patienten mit Sarkoidose wurde beschrieben. Das Zusammentreffen einer atypischen GE und einer Sarkoidose ist selten.     

Modulation of pacemaker activity in sheep cardiac Purkinje fibers by stimulation of β-adrenoceptor subtypes

The electrophysiological effects mediated by ₁- and ₂- in spontaneously active sheep cardiac Purkinje fibers were investigated using the non-selective agonist (–)-isoproterenol (IPN) and the selective agonists (–)-noradrenaline (₁) and procaterol (₂) in the absence and presence of the selective antagonists bisoprolol (₁) and ICI 118,551 (₂).IPN (0.01 mol/l) increased the spontaneous rate by 54% and the slope of diastolic depolarization by 68% of the respective control values. Further, IPN increased the action potential duration at –20 mV (APD –20 mV) from 96 to 154 ms, reduced the APD –70 mV by 17% and the duration of the diastole by 39% and slightly hyperpolarized the maximum diastolic potential. These effects were partially inhibited by ICI 118,551 (0.03 mol/l), diminished by bisoprolol (0.1 mol/l) and almost completely blocked by the combination of both antagonists. Concentration response curves of IPN were influenced by the selective antagonists as follows: ICI 118,551 (0.03 mol/l) shifted the curves to the right by 0.2–0.4 log units and increased the slope factor. Bisoprolol (0.1 mol/l) induced a greater shift to the right by 1.1–1.5 log units. Combination of bisoprolol with ICI 118,551 shifted the curves to the right by 1.5–1.7 log units.Noradrenaline (0.3 mol/l) elicited similar actions as IPN. Bisoprolol (0.1 mol/l) shifted the concentration response curves of noradrenaline to the right by 1.1–1.9 log units. Actions of procaterol (0.1 mol/l) were weak, attained only 15–35% of the maximal effects of IPN and could be blocked by ICI 118,551 (0.03 mol/l).These results show that the increase of pacemaker activity induced by catecholamines in sheep cardiac Purkinje fibers is predominantly mediated by stimulation of ₁. However, contribution of ₂ mediated effects could be demonstrated.Supported by Ministerium für Wissenschaft und Forschung, Nordrhein-Westfalen, Projekt-Nr, 40008786.     

Expression and prognostic roles of integrins and interleukin-1 receptor type I in patients with ductal adenocarcinoma of the pancreas

To Investigate the prognostic indicator, we examined the expression of ₆- and ₅- integrin and interleukin-1 receptor type I (IL-1RI) immunohistochemically, and analyzed the correlation between immunohistochemical findings and clinicopathological factors in pancreatic cancer. In patients with a strongly expressing ₆- integrin subunit or weakly expressing ₅₁-integrin in pancreatic cancer tissues there was a significant association with advanced TNM stage (P = 0.027 and 0.014, respectively), presence of liver metastases (P = 0.032 and 0.002, respectively), and poor prognosis (P = 0.0155 and 0.0056, respectively). In patients with a weakly expressing ₆ integrin subunit or weakly expressing ₅₁-integrin in noncancerous pancreatic tissues there was a significant association with poor prognosis (P = 0.0324 and 0.0396, respectively). Multivariate analysis demonstrated that strong expression of ₆- and weak expression of ₅₁-integrin were found to be independent prognosticators in pancreatic cancer patients. Our present results indicate that ₆₁- and ₅₁-integrin expression can be a significant prognostic indicator in pancreatic cancer.     

Der Urobilinkörperstoffwechsel des Menschen

Zusammenfassung Es wurde eine Mikromethode zur Bestimmung der Serumurobilinkörper und Harnurobilinkörper mit einem Serumbedarf von 5–10 ml entwickelt. Nach Methanolextraktion und Reduktion wurden die Urobilinkörper in Eisessigäther aufgenommen und nach Ehrlich-Reaktion in wäßriger Lösung spektralphotometrische Konzentrationsbestimmungen durchgeführt. Die Serumurobilinkörperkonzentration bei 17 Normalpersonen betrug 2.3±1.7 g%, die methodische Streubreite (2 )±18%, 7 Patienten mit Virushepatitis hatten eine erhöhte Serumkonzentration von 10.6±6.9 g%.Die tageszeitliche Schwankung der Serumurobilinkörperkonzentration (9–19 Uhr) betrug±73% (2 ) des Mittelwertes.

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Summary A micromethod has been developed for the determination of serum and urine urobilinoids, demanding 5–10 ml serum.After methanol-extraction and reduction, the urobilinoids were transferred to aceticacid-ether. After Ehrlich-reaction, concentration was determined in aqueous solution by spectrophotometric measurement.The concentration of serum urobilinoids at 17 normal adults was 2.3±1.7 g%, the methodical 2 -deviation ±18%. At seven patients with virus hepatitis serum concentration was elevated to 10.6±6.9 g%.Changes of concentration of serum urobilinoids at 5 persons during a day (9 a. m. – 19. p. m.) were ±73% (2 ) of average concentration.

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Studie im Rahmen des Assoziationsvertrages Strahlenhämatologie GSF-EURATOM Nr. 031-64-I BIAD.     

The problem of thresholds in chemical carcinogenesis some views on theoretical and practical aspects

Conclusions I have tried to show that the threshold problem for carcinogens is still unsolved and that this unsatisfactory situation creates many problems for the scientific evaluation of the carcinogenesis problem as well as for its regulative aspects. In view of the extremely low acceptance of cancer risks in the general population, which is justified as well as understandable, carcinogenesis research must present new ideas to come nearer to a solution of such problems. More sound data on dose-time-effect curves in the low incidence range of 10-0.1% tumor incidences could indicated whether the established linearity in the higher incidence range might eventually by interrupted. Increase of animal numbers could also increase reliability of carcinogenicity experiments and allow the detection of low-dose effect; the disadvantages of this approach (mega-mouse experiment) however, in regard to cost and space necessary are evident. Increases of the mean life span by optimization of animal husbandry still would be another way of approach. However, no real breakthrough is to be expected here.The most promising approach seems to be the use of other indicators for carcinogenicity instead of tumor formation. Binding studies of carcinogens to biopolymers (Neumann 1980), especially DNA, as well as the determination of preneoplastic, enzyme-deficient islands (Kunz et al. 1978) have been shown to give dose-response curves parallel to the corresponding curves from carcinogenicity studies (Kunz) and extendable over 6 orders of magnitude of doses, without deviation from linearity (Neumann). Additional parameters might be found, which, altogether, might prove to be an important step toward further knowledge in this important field of carcinogenesis research.Oh König, das kann ich dir nicht sagen, und was du frägst, das wirst du nie erfahren R. Wagner, Tristan und IsoldeJournal of Cancer Research and Clinical Oncology publishes in loose succession Editorials and Guest Editorials on actual and/or controversial problems in experimental and clinicial oncology. These contributions represent exclusively the personal opinion of the author. The Editors Die Zeitschrift Journal of Cancer Research and Clinical Oncology bringt in zwangloser Folge Editorials und Guest Editorials zu aktuellen und/oder kontroversen Problemen der experimentellen und klinischen Onkologie. Diese Beiträge geben ausschließlich die persönliche Meinung des Autors wieder.     

Tannin inhibition of protein kinase C in airway epithelium

Tannin, a polydisperse polyphenol extracted from cotton bracts (CBE), has been implicated in the pathogenesis of byssinosis, a lung disease of mill workers. CBE tannin inhibits chloride secretion in airway epithelial cells by means of an unknown mechanism(s). Activation of protein kinase C (PKC) by PMA (phorbol 12-myristate 13-acetate) in airway cells increases chloride secretion. The effect of tannin on this PKC pathway was examined, using canine tracheal epithelium mounted in Ussing chambers. PMA addition (10 nM) to the mucosal bath resulted in a 0.36 ± 0.07 Eq/cm² · h (mean ± SEM, n = 20) increase in short-circuit current (I_sc) and a 0.38 ± 0.17 Eq/cm² · h increase in net chloride secretion (J_net). The inactive 4-phorbol had no effect. Tannin addition to the mucosal bath produced a dose-dependent decrease in I_sc and J_net. In tissues pretreated with 2–50 g/ml tannin, and subsequently stimulated with PMA, tannin inhibited PMA stimulation of chloride secretion beginning at a tannin concentration of 10 g/ml (0.09 ± 0.05 Eq/cm² · h [n = 10] increase in I_sc and 0.08 ± 0.03 Eq/cm² · h increase in J_net with PMA after tannin pretreatment). At 50 g/ml tannin, the stimulatory effect of PMA was completely abolished. The known PKC inhibitor, H-7 (20 M), inhibited PMA stimulation, while chelerythrine (2 M) had not effect on PMA-stimulated I_sc and J_net, and calphostin C was toxic to the airway epithelium. In membrane fragments, 2.5 g/ml tannin inhibited the rate of histone III phosphorylation by PMA from 32.1 ± 4.4 nmol/mg protein per min to 20.1 ± 2.7 nmol/mg protein per min (n = 7). In bovine airway cells, tannin pretreatment (2.5 g/ml) decreased the cytosolic activity of PKC but had no effect on PKC translocation to the membrane. We conclude that tannin inhibits chloride secretion in airway epithelial cells in part by inhibiting PKC.Offprint requests to: Michelle M. Cloutier     

Calcium channel blocker treatment of tumor cells induces alterations in the cytoskeleton,mobility of the integrin αIIbβ3 and tumor-cell-induced platelet aggregation

Summary Calcium channel blockers of the phenylalkylamine (i.e. verapamil), benzothiazepine (i.e. diltiazem) and dihydropyridine (i.e. nifedipine) classes were evaluated for effects on the tumor cell/platelet interactions using Walker 256 carcinosarcoma cells (W256 cells). When W256 cells were pretreated for 15 min with channel blockers at concentrations of 50–200 M, macroscopic tumor-cell-induced platelet aggregation was inhibited (order of potency; nifedipine>diltiazemverapamil). However, ultrastructural analysis revealed limited, focal platelet aggregates associated with tumor cell plasma membranes of verapamil- and diltiazem-treated cells. There was no evidence of platelet activation or platelet association with the tumor cell membrane in cells pretreated with nifedipine. Walker 256 cells possess the integrin _IIb3. Tumor cell _IIb3 was shown to mediate tumor cell/platelet interactions in vitro [Chopra et al. (1988) Cancer Res. 48:3787]. Patching and capping of surface _IIb3 were inhibited by nifedipine>diltiazemverapamil. The degree of inhibition of _IIb3 receptor mobility parallels the inhibition of tumor-cell-induced platelet aggregation. W256 cells are characterized by a well-developed microfilament and intermediate filament network and by the absence of a distinct microtubular network. Calcium channel blockers had no effect on the low polymerization level of tubulin. However, they induced rearrangement of microfilament stress fibers. Intermediate filaments were also rearranged but to varying degrees. The order of effectiveness for alteration of intermediate filament organization was nifedipine>diltiazem while verapamil was ineffective. We propose that the previously reported inhibition of tumor cell/platelet interaction and tumor cell metastasis by calcium channel blockers [Honn et al. (1984) Clin Exp Metastasis 1:61] is due not only to the effects of the Ca²⁺ channel blockers on platelets, but also to their effect on the tumor cell cytoskeleton resulting in an inhibition of the mobility and function of the _IIb3 receptor.Abbreviations CCB calcium channel blocker - _IIb3 platelet glycoprotein IIb/IIIa complex - TCIPA tumor cell induced platelet aggregation - W256 Walker 256 carcinosarcoma This work was supported by Public Health Service grant CA-47115, a grant from Harper Hospital and a grant from the Veterans Administration     

Untersuchungen zur Frage der Heterogenität von Paraproteinen

Zusammenfassung Aus einem bei Ammoniumsulfat-Halbsättigung, gefällten ₊-A-Paraproteins wurde durch freie Elektrophorese aus der absteigenden und aufsteigenden Front je eine Fraktion gewonnen. Die chromatografische Trennung an DEAE-Sephadex A 50 durch schrittweise Elution ergab 4 (absteigende Front) bzw. 3 (aufsteigende Front) immunologisch, und elektrophoretisch einheitliche Fraktionen, die sedimentationsanalytisch untersucht wurden. Es war eine vollständige Trennung der einzelnen Komponenten möglich. Es ergab sich weiterhin, daß die beobachtete Heterogenität des ₊-A-Paraproteins nicht durch Wechselwirkung mit anderen Serumproteinen hervorgerufen sein kann. Die Befunde sind mit der Vorstellung vereinbar, daß es sich bei den Z-Komponenten der Sedimentationsanalyse von ₊-A-Plasmozytomseren z. T. um Aggregate leichterer Komponenten handelt, die in der G-Fraktion wandern. Eine Abhängigkeit der Aggregationsfägkeit des ₊-A-Paraproteins von der Ionenstärke des Milieus wurde bei pH 6 nicht beobachtet.

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Summary Free electrophoresis gave rise to a semi-precipitated ₊-A-paraprotein from a semi-saturated ammonium sulphate solution. Chromatographic separation of DEAE Sephadex A50 gave rise to four decreasing and three increasing steps during immunological and electrophoretically stable fractions, here investigated by analysis of sediment.Complete separation of the individual components was possible and showed that the observed heterogeneity of the ₊-A-paraprotein can be caused by factors other than serum protein. The findings can be represented on the Z-axis of the sedimentary analysis of ₊-A-plasma cytoma serum. When the components are of light weight and wander into the G-fraction, dependancy of the agglutinability of ₊-A-paraprotein on the ionic concentration of the environment was not observable at pH 6.

     

The ability of heat stress and metabolic preconditioning to protect primary rat cardiac myocytes

Primary rat cardiocytes were subjected to either thermal preconditioning for 30 min at 43°C or 20 min metabolic preconditioning (10 mM deoxyglucose, 20 mM lactate, pH 6.5). Eighteen hours later cells were analysed either for hsp 70i expression or subjected to a subsequent lethal heat stress or simulated ischaemia (10 mM deoxyglucose, 20 mM lactate, 0.75 mM sodium dithionite, 12 mM potassium chloride, pH 6.5) for 2 hours and assessed for survival by trypan blue exclusion.Hsp 70i was induced over 100 fold by thermal preconditioning and 30 fold by metabolic preconditioning (p<0.001, p<0.05), hsp 90 was induced 2.71 fold and 2.24 fold (p<0.001, p<0.001) by thermal and metabolic preconditioning respectively, while hsp 60 was not induced by either treatment. Preconditioned cultures had improved survival against subsequent lethal heat stress or simulated ischaemia: Thermal preconditioning reduced death from 69.22% to 52.46% upon subsequent lethal heat stress and from 49.13% to 36.66% upon subsequent lethal simulated ischaemia. Metabolic preconditioning reduced cell death from 51.29% to 33.8% against subsequent lethal heat stress, and from 69.09% to 55.61% upon subsequent lethal simulated ischaemia. A second marker of cell death, the release of lactate dehydrogenase activity into the culture media, was reduced to 65% and 60% of control values for thermally preconditioned cells subjected to lethal heat or lethal simulated ischaemia respectively. Metabolically preconditioned cells demonstrated lactate dehydrogenase activity of 59% and 51% that of control values, when subjected to lethal heat or lethal simulated ischaemia respectively.Abbreviations hsp heat stress protein - hsp 70i inducible 70 kDa heat stress protein - LDH lactate dehydrogenase - PBS phosphate buffered saline     

Die Beziehungen zwischen Mastopathia chronica cystica und Fibroadenom der Mamma zum Mammacarcinom

Zusammenfassung Sowohl Mastopathia fibrocystica als auch Mamma-Fibroadenom sind morphologisch präcanceröse Gewebsveränderungen, aus denen sich besondere Krebse bilden.Die Brustkrebse können in folgender Weise unterteilt werden: Carcinoma ex fibroadenoma (16,09%), Carcinoma ex mastopathia (37,56%), von Fibroadenom und Mastopathie unabhängige Krebse (46,35%).Es wird aus gutem Grund angenommen, daß die Induktionszeit des Carcinoma ex fibroadenoma ungefähr 20 Jahre ausmacht, die des Carcinoma ex mastopathia ungefähr 8 Jahre beträgt.Zentrum für die Diagnose und Behandlung bösartiger Tumoren, Histopathologische Abteilung     

The efficacy of neuraminidase treatment in studies on red cell aging

Summary An in vitro system was developed to test the propensity of rat erythrocytes (RBC) toward phagocytosis by homologous peritoneal macrophages after in vivo aging or after in vitro surface modification. Old RBC obtained from erythrocyte populations separated into fractions on the basis of their density were found to be phagocytosed to a significantly greater extent than cells obtained from young cell fractions. Neuraminidase treatment of RBC resulted in extensive phagocytosis in comparison to control cells representing the whole population or old cells. Galactose oxidase treatment of neuraminidase treated RBC afforded no protection from uptake by macrophages. In contrast, treatment of RBC with neuraminidase immobilized on Sepharose 4B, leading to removal of up to 25% of the total membrane sialic acid, did not lead to phagocytosis above control values. These results indicate that extreme caution is necessary in the interpretation of experiments in which neuraminidase is utilized to produce simulated aged RBC.     

Mutations in the R-type pyruvate kinase gene and altered enzyme kinetic properties in patients with hemolytic anemia due to pyruvate kinase deficiency

Summary The biochemical properties of erythrocyte pyruvate kinase (PK) together with mutations found in the coding sequence of the R-PK gene in five patients with severe hemolytic anemia due to PK deficiency are described. The enzyme variants were designated PK Mosul (homozygote), PK Bukarest_1,2, PK Hamburg₁, PK Köln₁, and PK Essen (compound heterozygote). PK Mosul showed normal positive cooperative substrate binding, PK Bukarest_1,2 exhibited noncooperative behavior, and PK Hamburg₁ and PK Köln₁ displayed mixed cooperativity, whereas PK Essen was negative cooperative. PK Mosul was found to be homozygous for the mutation 1151 ACG to ATG, resulting in an amino acid substitution 384 Thr to Met. In one allele of PK Bukarest_1,2 a single nucleotide substitution GAG-TAG was found at nucleotide 721, causing a change of 241 Glu to a chain termination codon (PK Bukarest₁). Additionally, in the second allele of this patient a point mutation at position 1594 (CGG-TGG) occurs, changing 532 Arg to Trp (PK Bukarest₂). Direct sequencing showed the heterozygosity of the patient's mother (PK Bukarest₁/normal) at position 721 and of the patient's father (PK Bukarest₂ /normal) at position 1594. A point mutation at position 1529 (CGA-CAA), causing an amino acid substitution 510 Arg-Gln, was identified in PK Hamburg₁ and PK Köln₁. The second mutation in these variants was not detected. In PK Essen no mutation in the coding sequence was found at all. Screening for the mutation at position 1529 in further compound heterozygote patients and in normal subjects of Western European origin showed that this exchange is a common mutation responsible for PK deficiency in this population.Supported by theDeutsche Forschungsgemeinschaft, Grants no. La 527/1 and Ne 416/1.     

Bericht über die 34. Tagung des Arbeitskreises Klinische Immunologie, Frankfurt, 03. bis 04.11.2006

Zusammenfassung Schwerpunktthema der diesjährigen Tagung des Arbeitskreises Klinische Immunologie waren die Autoimmunvaskulitiden. Es wurde die Rolle von innate immunity sowie T- und B-Zellen für autoimmune Entzündungsprozesse und innovativer Therapien bei Autoimmunvaskulitiden diskutiert. Darüber hinaus waren die Rolle endothelialer Mikropartikel, Ghrelin und Leptin, regulatorischer und Effektor-memory-T-Zellen bei ANCA-assozierten Vaskulitiden sowie das letale Midline-Granulom, das intrazelluläre Zytokinprofil bei M. Behçet, Autoantikörperdiagnostik bei rheumatoider Arthritis, Polyarteriitis nodosa mit kranialer Manifestation, ILT 6 als genetischer Risikofaktor bei multipler Sklerose und Sjögren-Syndrom, Alpha-Fodrin-Autoantikörper bei multipler Sklerose, Interferon--Autoantikörper bei atypischer Mykobakteriose und autoreaktive T-Zellen bei murinem Lupus weitere Themen.     

Einsatz von β-Blockern bei kardiovaskulären Erkrankungen und Asthma bronchiale/COPD

Zusammenfassung Zahlreiche groe randomisierte Studien zeigen die signifikante Reduktion der Gesamtmortalität bei Myokardinfarkt und chronischer Herzinsuffizienz unter -Blockertherapie. Patienten mit COPD bzw. Asthma bronchiale und akutem Myokardinfarkt oder chronischer Herzinsuffizienz wird diese lebensverlängernde Therapie allerdings häufig vorenthalten. Dabei profitieren Studien zufolge gerade COPD-Patienten aufgrund ihres hohen kardiovaskulären Risikoprofils von einer solchen Therapie. Aktuelle Metaanalysen belegen zudem die gute klinische Verträglichkeit einer kardioselektiven -Blockertherapie ohne wesentliche Beeinträchtigung der Lungenfunktion. Neuere Arbeiten legen nahe, dass die Mortalitätsreduktion durch eine -Blockertherapie die potenziellen Risiken bei COPD und möglicherweise auch bei leichten Formen des Asthma überwiegt. Kontraindikationen für eine -Blockertherapie sind neben akuten Exazerbationen schwere Formen von COPD, mittelgradig bis schweres Asthma sowie eine Dauertherapie mit -2-Sympatomimetika. Die Therapie mit einem -Blocker sollte nach Abwägung des Nutzen-Risiko-Verhältnisses individuell auf den einzelnen Patienten mit initial niedriger Dosierung eingestellt werden. Dabei sollten vorrangig kardioselektive Substanzen mit nachgewiesenem Mortalitätsbenefit bei Myokardinfarkt und chronischer Herzinsuffizienz gewählt werden.     

Heterophilic interactions between cell adhesion molecule L1 and α<Subscript>v</Subscript> β<Subscript>3</Subscript>-integrin induce HUVEC process extension <Emphasis Type="Italic">in vitro</Emphasis> and angiogenesis <Emphasis Type="Italic">in vivo</Emphasis>

Cell adhesion molecule L1 was implicated in angiogenic processes, tumor formation and metastasis. Here, we provide evidence that the sixth Ig-like domain of L1 (L1Ig6) interacts with _{v 3} to induce process extension of human umbilical vein endothelial cells (HUVECs) in vitro and angiogenesis in vivo. HUVECs formed network-like structures on full-length L1 or L1Ig6 substrates comparable to structures found on matrigel. In the presence of mab _{v 3} or cyclic RGD, apoptosis was induced. In fibrin matrices where L1Ig6 was covalently incorporated, HUVECs formed multicellular and hollow processes through interactions between cell-surface _{v 3} and RGD-sites of matrix-immobilized L1Ig6. No such processes were induced by L1Ig6 having non-functional RDG-sites, or in the presence of mab _{v 3} or cyclic RGD. In those matrices, increased apoptosis was found. Co-immunoprecipitation of L1 or L1Ig6 with _{v 3} suggests close interactions. Furthermore, L1Ig6 stimulated HUVECs showed increased tyrosine phosphorylation of _{v 3} and phosphorylation of MAP kinases (ERK1 and ERK2) but not AKT indicating specific activation of _v and _{v 3} followed by activation of downstream kinases. Application of L1Ig6-modified fibrin matrices on CAMs induced 50–60% increased _v and _v3 protein expression and in vivo angiogenesis indicated by ~50% increased mean vascular length density. The results demonstrate angiogenic potential of L1Ig6 involving ligation and activation of _v3     

Zur Immunologie der Lewis-Antikörper

Zusammenfassung Die Genetik und Serologie des Lewissystems ist trotz vieler Untersuchungen noch nicht restlos geklärt. Während über Transfusionsreaktionen durch Le^a-Antikörper wiederholt berichtet wurde, konnten sichere Beweise für die ursächliche Beteiligung an serologischen Schwangerschaftskomplikationen bisher nicht erbracht werden. Klinisch-scrologische Komplikation durch Le^b-Antikörper sind bislang nicht bekannt geworden.Im Gegensatz zu anderen Erythrozytenantigenen weisen Le-Merkmalsträger diese Antigeneigenschaft nicht nur an den Erythrozyten, sondern auch im Plasma auf. Wie bei den Anti-A-und B-Antikörpern werden auch bei den Le^a-Antikörpern Spontanformen und Immunformen beobachtet. Le^b-Antikörper existieren augenscheinlich nur als spontane Antikörper. Auch andere serologische Verhaltensweisen der Lewisantikörper und-antigene weisen auf die enge Verwandtschaft beider Systeme hin. Ursachen für die sogenannte spontane Antikörperbildung und eine ergänzende Vererbungstheorie werden zur Diskussion gestellt.

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Summary Despite many experiments the genetics and serology of the Lewis-system have not been clarified completely. Whereas transfusion reactions due to Le^a-antibodies have been repeatedly reported it has hitherto not been possible to obtain proof for their causative involvement in serological complications of pregnancy. Hitherto clinico-serological complications due to Le^b-antibodies have not been observed.In contrast to other erythrocyte antigens the Le-characteristic carriers do not only demonstrate this antigen characteristic in erythrocytes but also in the plasma. As is the case with anti-A-and-B-antibodies spontaneous forms and immune forms are also observed with the Le^a-antibodies. Le^b-antibodies apparently only exist as spontaneous antibodies. Other serological reactions of the Lewis-antibodies and-antigens also indicate the close relationship of both systems. The author discusses the causes for the so-called spontaneous antibody-formation and he also discusses a supplemental hereditary theory.

     

Zum Dosisspielraum und zur Streuung der effektiven Wirkdosis im Organismus bei der Krebs-Chemotherapie mit N-Oxyd-Lost

Zusammenfassung Unter verschiedenen Bedingungen wird der Verlauf der Konzentration von N-Oxyd-Lost im Bereich 4–8 · 10^–5 mol l^–1 durch je eine größere Anzahl zeitlich versetzter Bestimmungen mittels 4-(4-nitrobenzyl)pyridin untersucht. Ab pH>6–7 erfolgt ein schneller Anstieg der Konzentrationsabnahme. Bei pH=7,5 beträgt diese ca. 25% in 60 min. 5 Vol.-% Ehrlich-Mäuse-Ascites-Krebszellen (EMAC-Zellen) haben keinen fördernden Einfluß auf die Zersetzung (kein meßbarer Pharmakonverbrauch durch die Krebszellen). Im Blutkreislauf findet ein sehr schneller initialer Abfall der Konzentration (_Ü 2 min) durch Konzentrationsausgleich mit der interstitiellen Flüssigkeit statt, dem sich ein langsameres Absinken der Konzentration (_K 32 min) anschließt. Diese zweite Abklingfunktion ist bedingt durch Konzentrationsverlust innerhalb des Blutplasmas selbst ( _K ^* 55 min) und durch Auswanderung aus dem System Blut—interstitielle Flüssigkeit (_A 76 min). Zur 99,999% igen Abtötung von EMAC-Zellen mit N-Oxyd-Lost ist eine Wirkdosis von rund 9,3·10^–2 mol l^–1 min erforderlich. Abschließend werden Betrachtungen über die Wirkdosis in vivo sowie den Dosisspielraum bei der Chemotherapie mit N-Oxyd-Lost angestellt, wobei sich zeigt, daß solange keine Lost-Anreicherung im Tumor stattfindet, ein echter Dosisspielraum und eine Heilungsmöglichkeit bei resistenteren Tumorarten nicht gegeben ist.

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Summary The course of the N-oxide-mustard concentration in the range from 4 to 8 · 10^–5 mol l^–1 is examined under various conditions, making a great number of successive tests by means of 4-(4-nitrobenzyl) pyridine. At pH>6 to 7 there is a rapid increase in the fall of the concentration. At pH=7.5 it is of the order of 25 per cent in 60 minutes. The presence of 5% (v/v) Ehrlich-miceascites cancer cells (EMAC-cells) has no promoting influence on the disintegration i.e., there is no measurable pharmacon consumption by the tumour cells. There is a very rapid initial concentration decrease (_Ü 2 min) in the circulating blood by means of an equilibration with the interstitial fluid, followed by a slower concentration decrease (_K 32 min). This second decreasing function is due to the concentration loss within the blood plasma itself ( _K ^* 55 min) and to diffusion from the blood-interstitial system (_A 76 min). For a 99.999 per cent killing rate of EMAC-cells by N-oxide-mustard an effective dose of about 9.3·10^–2 mol 1^–1 min is necessary.Finally, consideration is given to the effective dose is in vivo as well as to the range of dosage with chemotherapy with N-oxide-mustard, demonstrating that agenuine dosage range and hope for a cure are not given by the more resistant types of tumor, as long as there is no lost enrichment in the tumour.

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Die beschriebenen Untersuchungen wurden im Rahmen eines Auftrages des Staatssekretariats für Forschung und Technik Berlin durchgeführt. Herrn Druckrey danken wir für wertvolle Hinweise, Herrn Brock für die Zusendung von Mitomen^® und NBP.     

Pharmacological basis for duration of effect: Formoterol and salmeterol versus short-acting β2-adrenoceptor agonists

The mechanisms behind the long duration of bronchodilating action of the ₂-adrenoceptor agonists formoterol and salmeterol are only partially understood. This review compares pharmacological characteristics of long-acting versus short-acting ₂-adrenoceptor agonists in human and animal airways. Based upon the reviewed evidence, it is concluded that for ₂-adrenoceptor agonists, long duration of action may depend upon several factors. Both formoterol and salmeterol display a higher lipophilicity and have a higher affinity, selectivity, and potency than most short-acting agonists at the ₂-adrenoceptor. Of these factors, lipophilicity may prove to be one of the most important ones by determining the amount of drug entering into the cell membrane in the vicinity of the ₂-adrenoceptor. However, the receptor affinity, maximal relaxant effect (efficacy or intrinsic activity), potency, and receptor selectivity may also be of importance in determining how much ₂-adrenoceptor agonist must remain at the receptor for sustained action.     

Granulocyte elastase in assessment of severity of acute pancreatitis

Complexes of granulocyte elastase and ₁-antitrypsin are markers for granulocyte activation. In 75 patients with acute pancreatitis these complexes were immunologically determined daily in plasma during the first week of hospitalization. Patients were classified into three groups: mild pancreatitis (I, 1 complication, N=34), severe pancreatitis (II, 2 complications, N= 29), lethal outcome (III, N=12). Initially, granulocyte elastase (mean±sem) was lower in group I (348±39 g/liter) as compared to groups II (897±183 g/l) and III (799±244 g/liter), P<0.001 for I vs II + III. Initial elastase concentrations >400 g/liter were consistent with a severe or fatal course of the disease but did not distinguish between severe and lethal pancreatitis. In patients with mild or severe disease, mean elastase concentrations decreased continuously during the following days (197±15 g/liter in mild cases, 325±30 g/liter in severe cases at day 7). In patients with lethal disease, however, mean elastase concentrations even increased at day 2 and remained higher than 700 g/liter during the observation period. At days 1 and 2 the predictive value for severe or lethal disease of raised (>400 g/liter) elastase concentrations [positive predictive value (PPV) 82%, negative predictive value (NPV) 81%] was better than that of elevated (>100 mg/liter) C-reactive protein (PPV 73%, NPV 73%), elevated (>4.0 g/liter) ₁-antitrypsin (PPV 59%, NPV 50%), or decreased (<1.5 g/liter) ₂-macroglobulin (PPV 82%, NPV 67%). When the time course of the concentrations of the acute-phase proteins was studied, it was found that rises of granulocyte elastase were followed by elevated C-reactive protein levels after one day, by elevated ₁-antitrypsin levels after two days and by decreased ₂-macroglobulin levels after three to four days. We conclude that granulocyte elastase is a good early marker for the severity of acute pancreatitis. Compared with elevated levels of C-reactive protein and ₁-antitrypsin release of granulocyte elastase reflects an event that precedes acute-phase protein induction.     

Der hypertensive Notfall

Zusammenfassung Krisenhafte Blutdruckanstiege werden an internistischen Notaufnahmen in bis zu 25% der Fälle beobachtet. Dabei handelt es sich zu etwa 75% um eine hypertensive Gefahrensituation (urgency) und bei etwa 25% um einen hypertensiven Notfall (emergency). Bezogen auf die Gesamtbevölkerung sind hypertensive Notfälle jedoch selten (weniger als 1% der behandelten Hypertoniker). Gehen Blutdruckkrisen mit akuten kardialen, vaskulären oder zerebralen Organschädigungen einher, liegt ein hypertensiver Notfall (emergency) vor, der eine umgehende Blutdrucksenkung erfordert. Dabei hängt die Intensität der Blutdrucksenkung von der Art der Endorganschädigung ab: kardiale und vaskuläre Endorganschäden bedürfen einer raschen Blutdrucksenkung und -normalisierung, wohingegen zerebrale Endorganschäden nach Beseitigung der Blutdruckspitzen eher von leicht erhöhten/hochnormalen Blutdruckwerten profitieren. Bei einer hypertensiven Dringlichkeit (urgency) liegen keine Endorganschäden vor, hier reicht eine langsame Absenkung des arteriellen Blutdrucks.