The testing of chemicals in the Syrian hamster embryo (SHE) cell transformation assay for assessment of carcinogenic potential.

The Syrian hamster embryo (SHE) cell transformation assay was used to test 28 chemical substances for their ability to induce morphologically transformed colonies. The purpose was to determine how well the assay method could be transferred from an experienced laboratory by including 18 chemicals previously evaluated and 10 new chemicals. Technical training was obtained in the experienced lab prior to testing. The assay was conducted at pH 6.7, a treatment period of 7 days was used, and single experiments were performed for each chemical. With this limited testing, 78% concordance with rodent bioassay results was obtained, and this high concordance would have increased if small, but statistically negative responses from single trials were overturned by positive data from repeat trials. Similarly, the results were highly concordant (90%) with the experienced lab results; only 2 chemical evaluations were discordant, and the use of repeat experiments would likely have eliminated these apparent disagreements. Thus, with appropriate training, the pH 6.7 SHE assay was successfully and reliably transferred.

In vitro micronucleus assay with Chinese hamster V79 cells - results of a collaborative study with in situ exposure to 26 chemical substances.

A collaborative study with 10 participating laboratories was conducted to evaluate a test protocol for the performance of the in vitro micronucleus (MN) test using the V79 cell line with one treatment and one sampling time only. A total of 26 coded substances were tested in this study for MN-inducing properties. Three substances were tested by all 10 laboratories and 23 substances were tested by three or four laboratories in parallel. Six aneugenic, 7 clastogenic and 6 non-genotoxic chemicals were uniformly recognised as such by all laboratories. Three chemicals were tested uniformly negative by three laboratories although also clastogenic properties have been reported for these substances. Another set of three clastogenic substances showed inconsistent results and one non-clastogenic substance was found to be positive by one out of three laboratories. Within the study, the applicability of the determination of a proliferation index (PI) as an internal cytotoxicity parameter in comparison with the determination of the mitotic index (MI) was also evaluated. Both parameters were found to be useful for the interpretation of the MN test result with regard to the control of cell cycle kinetics and the mode of action for MN induction. The MN test in vitro was found to be easy to perform and its results were mainly in accordance with results from chromosomal aberration tests in vitro.

The use of touch for a patient experiencing laryngospasm.

This article is based on a course work assignment for the Welsh National Board Certificate Level Module in Operating Department Practice (Recovery Branch). The article uses a critical incident reflective approach to explore the issues of using touch in caring for a patient, experiencing laryngospasm following a general anaesthetic. A literature review will explain the mechanisms of laryngospasm and will discuss the use of different forms of touch. Conclusions and recommendations will be drawn from the issues discussed.

Di(isononyl) phthalate (DINP) and di(isodecyl) phthalate (DIDP) are not mutagenic.

Recently there have been reports of liver and kidney tumors in rodents following long-term exposure to di(isononyl) phthalate (DINP). Mechanistic studies suggested that the liver tumors were a consequence of peroxisomal proliferation, whereas the kidney tumors (found only in male rats) were associated with induction of alpha(2u)-globulin. Because both peroxisomal proliferation and alpha(2u)-globulin are considered to be non-genotoxic carcinogenic processes, it seemed appropriate to investigate the genotoxic potential of DINP. Additional studies were also conducted on di(isodecyl) phthalate (DIDP), a structurally related substance that also induces peroxisomal proliferation, although it has not been tested in a carcinogenicity bioassay. The DINP was tested in Salmonella, in vitro cytogenetics and mouse micronucleus assays, whereas DIDP was evaluated in a mouse micronucleus test. All of these tests produced negative results, i.e. neither phthalate was mutagenic in any of the test systems. These data are consistent with results of other published and unpublished genotoxicity tests and provide support for the hypothesis that the liver and kidney tumors induced by DINP were the result of non-genotoxic processes.

Effects of acetylsalicylic acid, paracetamol and caffeine and a combination of these substances on kidney glutathione levels.

Following preliminary tests in which rats proved to be fairly insensitive to the depletory effect of paracetamol (CAS 103-90-2) on kidney glutathione levels, old male mice from a strain exhibiting particular susceptibility to paracetamol were investigated in respect of the comparative effects of paracetamol, acetylsalicylic acid (CAS 50-78-2, ASA) and caffeine (CAS 58-08-2), and a combination of these substances, on kidney glutathione levels. Additionally, the effects of paracetamol and ASA on hepatic glutathione in mice were also measured. When administered separately at oral doses of 150-600 mg/kg both paracetamol and ASA produced dose- and time-dependent depletion of kidney glutathione concentrations in the mice. The effect of ASA at a given dose was weaker than that of paracetamol. Caffeine showed only a very weak and transient depletory effect up to an oral dose of 60 mg/kg. The effects of the combined administration of paracetamol and ASA on kidney glutathione levels were only additive in nature. The administration of caffeine did not increase the reduction in kidney glutathione levels produced by the combination of paracetamol and ASA. The reduction in hepatic glutathione induced in the mice by paracetamol was considerably more pronounced than that observed in the kidneys. ASA, on the other hand, did not affect glutathione in the mouse liver at those doses which had led to a reduction in kidney glutathione levels.

Anti-inflammatory, analgesic, antipyretic and related properties of meloxicam, a new non-steroidal anti-inflammatory agent with favourable gastrointestinal tolerance.

The anti-inflammatory, analgesic and antipyretic properties of the new non-steroidal anti-inflammatory agent, meloxicam, were investigated in a variety of animal models and compared with the properties of piroxicam, diclofenac, indomethacin and several other NSAIDs. With respect to the total effect of a single oral dose, the anti-exudative effect of meloxicam on carrageenan-induced oedema in the rat exceeded that of all the NSAIDs included in the comparison. Additionally, meloxicam showed the greatest potency of all the compounds examined with respect to adjuvant-induced arthritis in the rat, the granuloma pouch model and the cotton pellet test in the rat. Unlike indomethacin, in the carrageenan pleurisy model in the rat, meloxicam caused both a dose-dependent reduction in exudate volume and also inhibition of leucocyte migration. Meloxicam showed a strong and lasting effect on inflammatory pain in the rat. Like other NSAIDs, but unlike dipyrone, meloxicam had no effect in the hot plate and tail clamp tests, which are used to identify weak central analgesic effects. Unlike dipyrone and like indomethacin, meloxicam had no effect in a model of visceral distention pain. In common with other NSAIDs, meloxicam had no influence on the body temperature of normothermic rats in the anti-inflammatory dose range, but did reduce yeast-induced fever in the rat in a dose-dependent manner. Like piroxicam, meloxicam had a uricosuric effect on rats treated with oxonic acid. Low-dose meloxicam inhibited both bradykinin-induced and PAF-induced bronchospasm in the guinea-pig, but had no effect on acetylcholine-induced bronchospasm. Piroxicam had greater ulcerogenic effects in the rat stomach than meloxicam. The therapeutic range of meloxicam in the rat, with regard to inhibition of adjuvant arthritis, was several times greater than that of piroxicam, indomethacin, diclofenac and naproxen.

The abdominal lift: is there any advantage for the critically ill patient?

The use of carbon dioxide to create a cavity for the operation of laparoscopic cholecystectomy leads to serious complications of the cardiovascular system; consequently, patients with ischaemic heart disease can be put at greater risk. For example, on reaching an intra-abdominal pressure of 15mmHg, a fall of about 35% of the static compliance was observed. Upon using the Laparolift, these influences on the respiratory system were not detected, and the rise in systemic vascular resistance usually seen with the CO2-pneumoperitoneum did not occur. From the anaesthetist's viewpoint the Laparolift was helpful in the treatment of patients with serious limitations of cardiac function.

17p anomalies in lymphoid malignancies: diagnostic and prognostic implications.

Eighteen patients with lymphoid malignancies and abnormalities of the short arm of chromosome 17 were evaluated, in order to analyse whether this anomaly was associated with a particular subgroup of lymphoid malignancies. The patients suffered from acute lymphoblastic leukemia, high-grade non-Hodgkin's lymphoma or plasma cell leukemia. No 17p anomaly was found in any patient with chronic lymphocytic leukemia or low-grade non-Hodgkin's lymphoma. In four cases the aberration of the short arm of chromosome 17 was the sole cytogenetic abnormality, in fourteen patients additional chromosomal aberrations were found. Five out of 18 cases were Burkitt's lymphoma/leukemia showing the typical rearrangement of 8q24. In cases with a karyotype evolution the 17p anomaly was always a late event. Concerning the clinical outcome of the patients with abnormalities of the short arm of chromosome 17 eight of nineteen patients died within 90 days after the diagnosis of the 17p anomaly only three were alive at the last follow up (26 months to 40 months after diagnosis of a 17p aberration). Rearrangements of 17p, especially as secondary cytogenetic events, seem to be associated with a poor clinical outcome in lymphoid malignancies.

Correlation of cytogenetic findings with clinical features in 18 patients with inv(3)(q21q26) or t(3;3)(q21;q26).

An inversion in the long arm of chromosome 3--inv(3)(q21q26)--or a translocation between both homologous chromosomes 3--t(3;3)(q21;q26)--is found specifically in myeloid neoplasias characterized by disturbances of thrombopoiesis and megakaryocyte development. Cytogenetic findings were correlated with clinical and hematological data in altogether 18 patients with acute nonlymphocytic leukemia (ANLL) and with inv(3) (13 patients) or t(3;3) (five patients), six of whom were male and 12 who were female. Chromosomal changes in addition to the 3q anomalies were demonstrated in 14 out of 18 patients, predominantly numerical and structural aberrations of chromosome 7 (12 cases) and/or abnormalities of 5q (five cases). Complex karyotype abnormalities were observed in six of 13 patients with inv(3), but in only one of five patients with t(3;3). In ten out of our 18 patients a preceding myelodysplastic syndrome (MDS) and/or exposure to mutagenic/carcinogenic agents had been established. In eight patients the morphology of ANLL blasts was immature (FAB subtype M1); in three patients ANLL-M4, and in two patients each ANLL-M5, M6, and M7 was diagnosed; in one patient with antecedent MDS the leukemic blasts were not classifiable according to the FAB criteria. A disturbed megakaryocyte development, characterized by an excess of micromegakaryocytes was observed in 14 patients, seven of them showed normal or elevated platelet counts as an unusual feature in patients with ANLL. The clinical course and outcome was extremely poor: 15 of 18 patients died within 10 months after the diagnosis of ANLL. Because of their missing response to conventional chemotherapy, patients with inv(3) or t(3;3) have to be estimated as at high risk. The characterization of genes affected by inv(3) or t(3;3) could help to elucidate molecular changes leading to impaired proliferation and differentiation of hematopoietic cells, also of the megakaryocytic lineage. Based on molecular genetic findings new therapeutical approaches could be designed.

1-Methyl-2-pyrrolidinone (NMP) does not induce structural and numerical chromosomal aberrations in vivo.

1-Methyl-2-pyrrolidinone induces aneuploidy in yeast, but only under special treatment conditions. Other genotoxic effects have not been found in vitro, and in vivo no data are available in the literature. Therefore, NMP was investigated in the mouse micronucleus test and the Chinese hamster bone marrow test for structural and numerical chromosomal aberrations. These tests can detect both types of alterations as demonstrated by appropriate positive control substances (cyclophosphamide, vincristine sulfate and benomyl). NMP at single oral doses up to 3800 mg/kg body weight (approximately 80% of the LD50) did not lead to an increase either in micronucleated erythrocytes or in structural or numerical chromosomal aberrations when bone marrow was sampled 16, 24 and 48 h after treatment in the micronucleus test or after 24 and 48 h for karyotype analysis.

[Priorities in polytrauma]. / Prioritäten beim Polytrauma.

Principles of medical action in cases of polytrauma: Immediate concentrated introduction of all measures; simultaneous diagnosis and therapy; ideal management; inspection and palpitation initially adequate; systematic examination from head to foot; choice of a suitable hospital; appropriate scoring. Priority of action (in the hospital): disturbances in vital functions first; puncture/drain valvular pneumothorax and cardiac tamponade; laparatomize intraabdominal bleeding; emergency thoracotomy if severe bleeding persists; laboratory and X-rays; relieve intracranial bleeding; surgery to save vital organs; intensive-care ward.

In vivo screening of glutathione related detoxification products in the early state of drug development.

Glutathione (GSH) adducts and consecutive degradation products thereof are indications of reactive intermediates during drug metabolism. As demonstrated with the analgesic SX-PP 16 (4-amino-3,5-dibromacetanilide), however, interactions of a drug with GSH can be detected by labelling the GSH-stores with labelled cysteine, and consecutive administration of the unlabelled drug even at therapeutic doses. The GSH-adducts are sensitively and specifically traced by HPLC, applying column-switching and a combination of diode-array- and radioactivity detection. This approach seems to be much more sensitive than a classical GSH-depletion study. The structure of the main metabolite of SX-PP 16 (46% of urinary excretion) was elucidated as 3-bromo-4-amino-5-mercapturyl-acetanilid.

[Animal experimental studies on the question of the interaction of paracetamol and acetylsalicylic acid]. / Tierexperimentelle Untersuchungen zur Frage des Zusammenwirkens von Paracetamol und Acetylsalicylsäure.

The mutual effects of acetylsalicylic acid and paracetamol used in combination were studied in rats and mice. The antiexudative effects of acetylsalicylic acid in the edema tests on the hind paw of the rat, the antipyretic activity against yeast-fever of the rat and the analgesic effect on the inflamed hind paw of the rat was potentiated by paracetamol given simultaneously. The biosynthesis of prostaglandins in vitro by an enzyme preparation from bovine seminal vesicles was inhibited by acetylsalicylic acid and paracetamol in additive synergistic mode. The hepatotoxicity of paracetamol in mice measured by an increase of GOT in serum is antagonized by acetylsalicylic acid in dose-dependent manner. The suppression of the hepatotoxicity of paracetamol by acetylsalicylic acid in mice is not the consequence of interaction during absorption. The 3H-content of the liver following an oral dose of 3H-paracetamol is not influenced by acetylsalicylic acid given in combination with paracetamol. The mechanism of interactions between acetylsalicylic acid and paracetamol is discussed.

n-Butyl acrylate: cytogenetic investigations in the bone marrow of Chinese hamsters and rats after 4-day inhalation.

Chinese hamsters and rats were exposed to an average concentration of 817 ppm and 820 ppm n-butyl acrylate (acrylic acid n-butyl ester), respectively for 4 days. In both animal species, the exposure led to distinct signs of toxicity; four of ten male Chinese hamsters died during the exposure period. The chromosome analysis carried out in the bone marrow of the animals after the 4-day inhalation did not indicate any chromosome-damaging effect of n-butyl acrylate. Under the experimental conditions chosen the percentage of metaphases damaged was always in the same range as that of the controls for both Chinese hamsters and rats.

[Age-related problems of wound healing]. / Altersbedingte Probleme der Wundheilung.

A study on wound failures after surgical operations performed at the Dep. of Surgery, Köln-Merheim, revealed an overall rate of 10,8%. 40,3% of all complications were observed in patients aged more than 60 years, which gives a rate of 19,1% for those people. To date this significant increase of wound failures in older individuals is preferently explained by the reduced resistance of the old organism to infections. Our trials with rats as well as numerous publications of other authors on the topic of age-related changes of metabolism prove that the wound healing process is delayed in older individuals. This fact does not consequently lead to complications but the prolonged healing in connection with the repeated change of wound dressing gives an enhanced risk for infections. If special precautions are observed the age of a patient is not a principal contraindication to a great surgical operation today.

Criteria for the standardization of Salmonella mutagenicity tests: results of a collaborative study. II. Studies to investigate the effect of bacterial liquid culture preparation conditions on Salmonella mutagenicity test results.

The influence of various parameters and growth conditions in the "overnight culture" of Salmonella typhimurium strains on mutagenicity test results was investigated. A number of factors were first suspected to be of some importance for the quantitative outcome of the mutagenicity test. None of them, however, was found to influence the results to such a marked extent as to be a major source of variability. Only the brand of nutrient broth used for the propagation of the bacteria proved finally to have a certain effect on the number of (spontaneous and induced) revertant colonies, although no precise and quantitative statements can be made with regard to a possible standardization of this experimental segment in the Salmonella mutagenicity test. The occurrence of such unpredictable but noticeable influences is, however, evidence for the importance of an intralaboratory optimization and standardization of all parts of the test procedure.