Possible coumarin-like mechanism of action for cephalosporins

Summary In three patients treated with cephalosporins (one patient with latamoxef, two patients with cefazedone) vitamin K₁ was injected to investigate whether this was followed by an increase in vitamin K₁ 2,3-epoxide plasma concentrations as compared to controls. Such a rise in K₁-epoxide concentrations in the plasma can be demonstrated following treatment with coumarins. This reflects an inhibition of the vitamin K₁-epoxide reductase in the liver. Coumarins are thought to induce hypoprothrombinaemia by such a mechanism. In all three patients we found a considerable increase in the vitamin K₁-epoxide plasma concentrations following injection of 10 mg vitamin K₁, whereas in normal subjects only traces of K₁-epoxide could be detected (<0.030 µg/ml). The K₁-epoxide concentrations found in our three patients treated with cephalosporins were 0.12, 0.16 and 0.19 µg/ml, respectively. This indicates that latamoxef or cefazedone might reduce clotting factor synthesis by a coumarin-like mechanism of action in these patients. Although the effect of cephalosporins in enhancing vitamin K₁-epoxide plasma concentrations is less than that of coumarins, it might cause severe hypoprothrombinaemia in the presence of latent vitamin K deficiency.Abbreviation PT prothrombin time - TT thrombin time - PTT partial thromboplastin time - PC platelet count - ICU intensive care unit - EEG electroencephalogram - K₁-epoxide vitamin K₁ 2,3-epoxide     

Studies on intracellular transport of secretory proteins in the rat exocrine pancreas

Summary The possible role of microtubules and microfilaments in the secretory process of the rat exocrine pancreas was analysed in vitro using isolated pancreatic lobules. Colchicine and vinblastine as microtubule inhibitors, hexylene glycol as a microtubule stabilizer, and cytochalasin B as a disruptive agent for microfilaments were used in increasing concentrations to test their effects on protein synthesis, intracellular transport, zymogen discharge, and cellular respiration.Colchicine only at 10^–2 M concentrations inhibits protein synthesis, while vinblastine inhibits at 10^–6 and 10^–5 M by 20% and at 10^–4 M by 55%. A similar inhibition is observed with 1.5% concentrations of hexylene glycol while cytochalasine B at 1,5 and 10 g/ml is without effect on protein synthesis. Colchicine and vinblastine have their major effects on intracellular transport both in secretion studies and cell fractionation experiments. Colchicine in concentrations between 10^–3 to 10^–5 M inhibits discharge of newly synthesized proteins by 50%, while vinblastine shows a dose-response relationship of 40% inhibition at 10^–6 M to 90% at 10^–4 M. Discharge of amylase is uniformly reduced by 30% by both colchicine and vinblastine in the whole dose range. The pronounced effect of colchicine and vinblastine is evident in cell fractionation studies: both drugs inhibit the disappearance of protein radioactivity from microsomes and its appearance in zymogen granules; similarly the peak radioactivity in smooth microsomes (Golgi) appears delayed. No differential effect on the secretory process was observed with 1.5% concentrations of hexylene glycol or cytochalasin B at 1.5 and 10 g/ml concentrations. A fines tructural analysis of microtubules and microfilaments in the exocrine pancreatic cell reveals their distribution in all parts of the cytoplasm and in relation to all cell organelles. Both systems (microtubules, microfilaments) seem to be connected, at least in certain areas of the cytoplasm and at the plasma membrane.The reduction of transport efficiency by microtubule inhibitors results in a deposition of secretory material in the cisternal space of the rough endoplasmatic reticulum, which leads to the formation of paracrystals. Colchicine at 10^–3 M concentrations leads to an enlargement of condensing vacuoles in the Golgi complex.A short communication on the same subject was presented at a Symposion on Stimulus-Secretion-Coupling in the Gastro-intestinal Tract, Titisee (May 27–29, 1975).Supported by Deutsche Forschungsgemeinschaft (Ke 113/8).     

Chemotherapy of fish parasites

There are few agents on the market that control fish parasites. These are substances that are mainly used in other hosts; due to the different metabolism of fish, they often have only moderate effects on fish parasites. Therefore, the research and development of fish-specific antiparasitic compounds is needed to avoid the high losses suffered by commercial fish hatcheries. Drugs similar to toltrazuril would perhaps be promising, due to their broad spectrum of efficacy.     

Die sogenannte Impfwut

Zusammenfassung Die im Verlaufe antirabischer Vaccinationen gelegentlich auftretenden paralytischen Komplikationen sind nicht virusbedingt, sondern die Folge einer Antigen-Antikörperreaktion nach Sensibilisierung mit dem organspezifischen Hirnantigen, das in den nicht ätherisierten Tollwutvaccinen enthalten ist. Diesbezüglich von einer Impfwut zu sprechen, erscheint nicht gerechtfertigt. Vielmehr sollte dieser Terminus für die postvaccinalen Komplikationen reserviert bleiben, bei denen der Ausbruch der Erkrankung in direktem Kausalzusammenhang zu dem in einer Vaccine enthaltenen lebenden Virus fixe steht.     

Human acute pancreatitis: Its pathogenesis in the light of immunocytochemical and ultrastructural findings in acinar cells

Summary Human acute pancreatitis results from an autodigestive process frequently associated with alcohol abuse, gall stone disease and shock. Peripancreatic fat necrosis was identified as one of the earliest visible lesions, whereas acinar cell necrosis and haemorrhage were regarded as secondary changes. To examine the alterations in acinar cells in more detail, their enzyme content and fine structural features were studied immunocytochemically using antisera against -amylase, lipase, trypsin, chymotrypsin and pancreatic stone protein, and electronmicroscopically in pancreatic tissues from patients with severe acute pancreatitis. Peripheral acinar cells in the immediate vicinity of fat necrosis were found to be heavily degranulated, while acinar cells at some distance of necrosis fully retained their enzyme content. Other frequent changes of the acinar cells included cuboidal transformation, loss of microvilli, increased occurrence of autophagosomes, and formation of enlarged acinar lumina. As there was no apparent cell membrane leakage or rupture of duct lumina, it is concluded that the acinar cells adjacent to fat necrosis release their granules by undirected basolateral extrusion. The findings thus suggest that one of the basic defects in acute pancreatitis is the uncontrolled release of enzymes from peripheral acinar cells into the interstitial space which, in turn, presumably by the action of lipase, leads to autodigestive fat necrosis.Dedicated to Prof. Dr. G. Seifert on the occasion of his 65th birthdayPresented in part at the Second International Symposium on the Classification of Pancreatitis, Marseille, 1984, and at the Meeting of the European Pancreatic Club, Manchester, 1985     

Beitrag zur regionären Verteilung der Paraty-B-Phagentypen

Zusammenfassung Die Prüfung der Paraty-B-Phagentypen zeigt im Saarland einen hohen Anteil des in Deutschland seltenen Typs Dundee. Ein Vergleich mit den Phagentypen in Frankreich, insbesondere unter Berücksichtigung der departementalen Verteilung, legt es nahe, Über die zweifellos bestehenden engen Verkehrskontakte hinaus ein einheitliches endemisches Vorkommen dieses Typs im Saarland und in Lothringen anzunehmen.     

Assessment of local cellular immunity in lung cancer by bronchoalveolar lavage

Summary Small cell lung cancer (SCLC) is the most malignant of the pulmonary neoplasms and is associated with a poor local cellular immune response. 16 patients with non small cell lung cancer (NSCLC) and 11 patients with SCLC underwent bronchoalveolar lavage (BAL) in the lung which harbored the tumor in order to investigate the lymphocyte surface antigens utilizing the immunoperoxidase technique. Analysis of blood lymphocytes was performed in parallel. 8 patients with previous sarcoidosis in complete remission who underwent BAL and 10 normal blood donors served as controls.Among blood lymphocytes the CD3⁺, CD4⁺ and CD16⁺ cell populations were elevated significantly and the T4/T8 ratio was elevated in NSCLC patients, but only CD16⁺ were augmented in SCLC. Cell populations expressing the activation markers transferrin (TF) receptor, interleukin-2 (IL-2) receptor and the very late antigen VAL-1 were also increased in NSCLC, while SCLC was associated with antigen distributions similar to controls. No differences between the cohorts were seen in the expression of human leukocyte antigen (HLA)-DR. In BAL the population of CD3⁺ and CD4⁺ cells were reduced in SCLC and the T4/T8 ratio was diminished in contrast to controls and NSCLC patients, whereas these two latter groups did not differ from each other. The distribution pattern of CD16, TF receptor and IL-2 receptor in the study groups resembled that of cells of the blood stream, but CD16⁺ natural killer cells were additionally down regulated to control values in SCLC. No differences were seen in the distribution of VLA-1. HLA-DR⁺ cells were clearly elevated in both cancer groups.In general NSCLC was associated with a shift to higher relative numbers of immunocompetent and activated cells. This was most probably attributable to an immune response to neoplastic growth. This shift was largely lacking in SCLC. The analysis of lymphocytes from the periphery of the target organ emerged as a sensitive tool for the study of cellular immunity in lung cancer and showed many similarities to circulating blood cells. However, the analysis of natural killer cells and HLA-DR suggested a dissection of cellular immune response between blood and lung in pulmonary cancer. A depressive interaction between the tumor and the cellular host immune response may contribute to the exceptional malignancy of SCLC.Abbreviations BAL bronchoalveolar lavage - HLA-DR human leukocyte antigen-DR - IL-2 interleukin-2 - NSCLC non small cell lung cancer - SCLC small cell lung cancer - TF transferrin - VLA-1 very late antigen-1     

Vagal mediation of the cholecystokinin satiety effect in rats

Central (intracerebroventricular) and peripheral (intraperitoneal) injections of the octapeptide of cholecystokinin (CCK-8) were compared to determine the most effective route of administration to elicit satiety for food intake in the rat. Subdiaphragmatic bilateral vagotomy and spinal cordotomy (T2-T3) were also performed to investigate the importance of visceral nerves for the satiety effect. CCK-8 suppressed feeding and elicited satiety resting behavior when injected peripherally but it was less effective when injected centrally. The satiety effect of CCK-8 or CCK-33 following peripheral injections was blocked by vagotomy whereas spinal cordotomy had no effect. The results indicate that some component of the vagus is required to mediate the peripherally induced cholecystokinin satiety effect, but the splanchnic nerves are not necessary. The weak effect of CCK-8 following ventricular administration is additional evidence suggesting that cholecystokinin of intestinal origin acts in the periphery rather than directly on the brain to elicit its typically rapid satiety effect in rats.     

Noninvasive measurement of cell volume changes by negative staining

To maintain the intracellular concentration of ions and small molecules on osmotic challenges, nature has developed highly sophisticated transport systems for regulating water and ion content. An ideal measurement technique for volume changes of cells during osmotic challenges has to fulfil two requirements: it has to be osmotically inert, and it should allow online monitoring of cell volume changes. Here, a simple fluorescence microscopy-based approach is presented. Using fluorescein as a negative stain, it is possible to monitor cell volume changes without affecting the functionality of cell membranes and cell osmolarity. Measurement of Madine-Darby canine kidney (MDCK) cells after hypo- and hyperosmotic challenges reveals the main advantages of this approach: besides providing precise and reproducible quantitative data on reversible cell volume changes, the viability of the cells can be assessed directly by the appearance of stain in the cytoplasm. This becomes evident especially after hypo-osmotic challenge of glutaraldehyde-treated cells, which become leaky after fixation, followed by a massive volume change. This new approach represents a very sensitive measurement technique for cell volume changes resulting from water or ion flux, and thus seems to be an ideal tool for studying cell volume regulatory processes.