Strain difference in transgene-induced tumorigenesis and suppressive effect of ionizing radiation

Transgenic expression in medaka of the Xiphophorus oncogene xmrk, under a pigment cell specific mitf promoter, induces hyperpigmentation and pigment cell tumors. In this study, we crossed the Hd-rR and HNI inbred strains because complete genome information is readily available for molecular and genetic analysis. We prepared an Hd-rR (p53^+/−, p53^−/−) and Hd-rR HNI hybrid (p53^+/−) fish-based xmrk model system to study the progression of pigment cells from hyperpigmentation to malignant tumors on different genetic backgrounds. In all strains examined, most of the initial hyperpigmentation occurred in the posterior region. On the Hd-rR background, mitf:xmrk-induced tumorigenesis was less frequent in p53^+/− fish than in p53^−/− fish. The incidence of hyperpigmentation was more frequent in Hd-rR/HNI hybrids than in Hd-rR homozygotes; however, the frequency of malignant tumors was low, which suggested the presence of a tumor suppressor in HNI genetic background fish. The effects on tumorigenesis in xmrk-transgenic immature medaka of a single 1.3 Gy irradiation was assessed by quantifying tumor progression over 4 consecutive months. The results demonstrate that irradiation has a different level of suppressive effect on the frequency of hyperpigmentation in purebred Hd-rR compared with hybrids.     

Histamine H3 receptor-mediated inhibition of noradrenaline release in pig retina discs

Summary Discs of pig retina were preincubated with ³H-noradrenaline, ³H-dopamine or ³H-serotonin and then superfused. Electrical field stimulation increased the outflow of tritium from discs preincubated with ³H-noradrenaline or ³H-dopamine, but no from discs preincubated with ³H-serotonin. The tritium content at the end of superfusion was similar in discs preincubated with ³H-noradrenaline or ³H-dopamine but about tenfold lower in discs preincubated with ³H-serotonin. The tritium content in discs preincubated with ³H-noradrenaline was markedly reduced when desipramine was present during preincubation but was not affected by selective inhibitors of dopamine and serotonin uptake. The tritium content in discs preincubated with 3Hdopamine and ³H-serotonin, in contrast, was reduced or tended to be reduced by a selective dopamine and serotonin uptake inhibitor, respectively.The electrically evoked overflow of tritium from discs preincubated with ³H-noradrenaline was abolished by tetrodotoxin or omission of Ca²⁺. In discs superfused with desipramine, the electrically evoked overflow was enhanced by phentolamine but not affected by histamine. When both desipramine and phentolamine were present in the superfusion medium, histamine inhibited the evoked overflow (pIC₁₅ 6.85). This effect was mimicked by the histamine H₃ receptor agonist R-(–)--methylhistamine as well as by its S-(+)-enantiomer (pIC₁₅ 7.85 and 5.30, respectively) but not by the H₁ receptor agonist 2-(2-thiazolyl)ethylamine and the H₂ receptor agonist dimaprit (each 10 mol/l). The inhibitory effect of histamine was abolished by the H₃ receptor antagonist thioperamide 0.32 mol/l and attenuated by impromidine 3.2 mol/l but not affected by the H₁ receptor antagonist dimetindene 3.2 mol/l and the H₂ receptor antagonist ranitidine 10 mol/l.The results suggest that, in the pig retina, noradrenaline is taken up into, and released from, noradrenergic neurones (most likely vascular postganglionic sympathetic nerve fibres, less probably tissue-specific noradrenergic neurones of the retina) and that noradrenaline release is subject to modulation via H₃ receptors and probably also a-adrenoceptors.Send offprint requests to E. Schlicker at the above address     

Ifosfamide combination chemotherapy in advanced breast cancer

The objective of our clinical studies was to develop an effective combination chemotherapy regimen (CHT) with acceptable side effects, consisting of the two most potent drugs used as single agents in breast cancer. We tested the combination of an anthracycline, epirubicin (A) at 70 mg/m² i.v. on day 1 or (B) at 120 mg/m² i.v. on day 1 with an alkylating drug ifosfamide (IFO), (C) at 2.5 g/m² in an i.v. infusion given over 4 h on days 1–3 or (D) at 5 g/m² in a 24-h i.v. infusion given on day 1. Courses were repeated every 4 weeks. The combinations were given as first-line therapy as follows: CHT (A, C) in six cases and CHT (B, C) in five cases of advanced breast carcinoma, and CHT (B, D) in seven patients with primary inflammatory breast cancer. Due to side effects (e.g., stomatitis, mental disturbances) and applicability, CHT regimen (B, D) was preferred. Responses (12/18) occurred 1–3 cycles earlier than those previously achieved using the conventional epirubicin/cyclophosphamide CHT. We conclude that 5 g/m² IFO given i.v. over 24 h with uroprotection (mesna) in a two-drug regimen is an effective dose with tolerable toxicity. Alopecia was seen in all cases. However, according to our experience, myelotoxicity is the dose-limiting factor for both of these drugs.Presented at the Satellite Symposium Ifosfamide in Gynecological Tumors of the 5th European Conference on Clinical Oncology and Cancer Nursing, London, September 3–7, 1989     

Thermoresponsive Reversible Unimer Micelles of Amphiphilic Fluorinated Copolymers

Amphiphilic fluorinated copolymers PEGMAx-co-FAy and TEGMAx-co-FAy are prepared by activators regenerated by electron transfer atom transfer radical polymerization (ARGET-ATRP). All polymers present a reversible thermoresponsive lower critical solution temperature-type behavior, and a cloud point temperature (T_c) in the range of 30–60 °C strictly dependent on the length of the oxyethylene side chain, the content of the hydrophobic counits, and the concentration of the solution. Combined small angle X-ray scattering (SAXS) and dynamic light scattering measurements are used to study the self-assembly behavior in water, organic solvents (tetrahydrofuran [THF] and dimethylformamide [DMF]), and a fluorinated solvent (hexafluorobenzene [HFB]). SAXS confirms the formation of compact-globular single-chain self-folded unimer micelles in water below T_c, which generally presents small hydrodynamic diameters (D_h ≤ 8 nm) as a result of the folding of the hydrophobic perfluorohexylethyl acrylate counits. The copolymers are also able to form reverse unimer micelle in HFB. The copolymers are not able to self-assemble in unimer micelles in THF or DMF solutions, in which they adopt conventional random coil conformations.     

Characterization of recast Nafion films by small- and wide-angle X-ray scattering

Room temperature recast Nafion

1 General formula:

films, prepared under different humidities in the curing atmosphere, were characterized by small- and wide-angle X-ray scattering (SAXS and WAXS). SAXS reveals that the humidity influences the size of the ionic clusters in these polymer films. It was found that the number and size of ionic clusters increases with increasing relative humidity. WAXS indicates the presence of locally ordered regions of the backbone polymer. These results allow a qualitative understanding of the electrochemical behaviour of Nafion recast films cured at different humidities, as described in the literature.     

Oxidative reactions in the tear fluid of patients suffering from dry eyes

Purpose: To evaluate whether products of oxidative and inflammatory reactions are detectable in the tear fluid of patients suffering from dry eyes. Methods: The tear fluid of 217 patients (397 eyes) was sampled. Criteria for grouping of the patients were (1) basic secretion test (sicca l: BST = 0–5 mm, n = 78 eyes; sicca 2: BST = 6–10 mm, n = 109 eyes) and (2) subjective symptoms (normal BST, burning, foreign body sensations, tearing, dryness of the eyes: n = 78 eyes). One group of healthy patients (normal BST, n = 132 eyes) served as controls. Lipid peroxide levels and myeloperoxidase activity, as parameters for oxidative tissue damage and inflammatory activity, were determined in the tear fluid. Those patients whose consent could be obtained were subjected to the rose bengal test (sicca 1: 56 eyes; sicca 2: 97 eyes; subjective symptoms: 44 eyes; controls: 49 eyes). The correlation between BST and rose bengal test results was calculated. Results: Lipid peroxides were significantly (P < 0.05) higher in the groups sicca 1 and subjective symptoms than in healthy controls, as was the inflammatory activity in groups sicca 1, sicca 2 and subjective symptoms. Additionally, the inflammatory activity in the group sicca 1 was significantly (P < 0.05) higher than in the groups sicca 2 and subjective symptoms. No evidence of a significant correlation between BST and rose bengal test results was observed. Conclusions: Both oxidative tissue damage and polymorphonuclear leukocytes indicating an oxidative potential occur in the tear film of patients suffering from dry eyes. These reactions lead to severe damage of the involved tissue. Free radicals and inflammation may be involved in the pathogenesis or in the self-propagation of the disease.     

Conditioning hypoxia causes protection against ischemia in the CA 1-region of hippocampal slices

PURPOSE: At present the mechanisms of ischemic or hypoxic tolerance are not fully understood at the cellular level. METHODS: In order to further characterize the effects of conditioning hypoxia on the synaptic transmission in the hippocampal area CA1, rats were exposed to a moderate normobaric hypoxia for 8 h. Transverse hippocampal slices were prepared 1, 7 or 14 days after this conditioning hypoxia and evoked field potentials were recorded in the CA 1 region upon stimulation of the Schaffer collaterals before, during and up to 4 h after ischemia in vitro (hypoxia and reduced glucose). RESULTS and CONCLUSIONS: The time to disappearance of the evoked potential during ischemia was significantly prolonged after seven, but not after one or 14 days in slices taken from conditioned animals. In addition the input/output (I/O) curves of evoked potentials were not altered 4 h after the ischemia. In contrast, the time to disappearance of the evoked potentials was shorter and the I/O curves were diminished in slices from control animals. Possible mechanisms of the protective effect are discussed.     

An indirect method for the estimation of osteoporotic fractures from injury and fracture profiles

Summary Study objective was to develop a valid epidemiological method for the estimation of osteoporotic fracture risk, using administrative databases and accounting for variable baseline risks of injury. Design is the secondary analysis of inpatient and outpatient utilization data. A baseline injury risk was estimated by the incidence of primary utilization of medical services for soft tissue injuries (ICD-9 diagnostic codes 910–929), and the risk profile was compared after normalization with the overall primary utilization rate for fractures (ICD-9 diagnostic codes 800–829). The setting is a county with approximately 100,000 inhabitants in the former East Germany. Participants were all inhabitants of the county who had a physician contact (inpatient or outpatient) during 1987–1988, as well as hospital inpatients for all of Germany in 1989. The number of fractures increased with age, especially in women, when compared to the number of fractures expected from the incidence of soft tissue injury. Similar patterns were identified in hospitalization data from East and West Germany. Estimating the prevalence of osteoporosis directly from certain osteoporotic fracture types associated with higher age is potentially biased, since it neglects the underlying risk of injury. Our model distinguished the osteoporotic fracture risk as the excess risk over an expected injury-related fracture risk for a given age and sex, and may allow a more valid quantification of osteoporotic fractures in different populations.

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Zusammenfassung Studienziel war die Entwicklung einer validen Methode zur Abschätzung des osteoporotischen Frakturrisikos unter Verwendung administrativer Daten und unter Berücksichtigung eines variablen Hintergrundrisikos für Unfälle. Studiendesign ist die sekundäre Analyse von Daten zur stationären und ambulanten Inanspruchnahme. Das Hintergrundrisiko für Unfälle wurde aus der Inzidenz der primären Inanspruchnahme der medizinischen Versorgung für Weichteilverletzungen (ICD-9 Kodierungen 910–929) geschätzt, und das Risikoprofil nach Normalisierung mit der allgemeinen primären Inanspruchnahme wegen Frakturen (ICD-9 Kodierungen 800–829) verglichen. Studienort war ein Landkreis mit etwa 100 000 Einwohnern in der ehemaligen DDR. Studienteilnehmer waren alle Einwohner des Kreises, welche 1987–1988 einen ambulanten oder stationären Arztkontakt hatten, sowie Krankenhausfälle in beiden deutschen Staaten im Jahr 1989. Die Anzahl der Knochenbrüche nahm mit dem Lebensalter zu, vor allem bei Frauen, verglichen mit der Anzahl, welche aus der Inzidenz der Weichteilverletzungen zu erwarten gewesen wäre. Ein ähnliches Muster war bei den Krankenhausfällen in Ost- und Westdeutschland zu beobachten. Die direkte Schätzung der Prävalenz der Osteoporose aus bestimmten osteoporotischen Frakturtypen, welche mit dem höheren Lebensalter verbunden sind, enthält potentiell einen systematischen Fehler, da ein Hintergrundrisiko für Unfälle vernachlässigt wird. Unser Modell identifiziert ein osteoporotisches Frakturrisiko als überschiessendes Risiko über ein nach Alter und Geschlecht zu erwartendes unfallbedingtes Frakturrisiko, und erlaubt potentiell eine validere Quantifizierung osteoporotischer Frakturen in verschiedenen Populationen.

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Résumé L'objective de la recherche était le développement d'une méthode valide pour l'estimation du risque d'une fracture ostéoporotique, utilisant données administratives et tenant compte des risques basales variables concernant les accidents. Le désigne de l'étude est l'analyse secondaire des données hospitalières et ambulatoires. Le risque basale des accidents fut estimé par l'incidence de l'utilisation première des services médicaux pour des blessures non-skeletals (ICD-9 codes 910–929) et cette risque fut comparé après normalisation avec la rate d'utilisation pour des fractures (ICD-9 codes 800–829). La recherche se concentrait sur un département de l'Allemagne de l'Est avec a peu près 100000 habitants. Les participants étaient tous les habitants du département qui avaient un contact avec un médecin (a l'hôpital ou ambulatoire) pendant les années 1987–1988, ainsi que tous les cas hospitalisés dans toute l'Allemagne en 1989. Le nombre de fractures augmentait avec l'âge, en particulier parmi les femmes, comparé avec le nombre attendu de l'incidence des blessures. Des profils de risque pareils ont pu être observés parmi les cas hospitalisés de l'Allemagne de l'Ouest et de l'Est. L'estimation directe de la prévalence de l'ostéoporose a la base de certains types «ostéoporotiques» des fractures, associés avec le troisième âge, peut être incorrecte, parce qu'il néglige le risque basale pour les accidents. Notre modèle distingue le risque ostéoporotique de fracture comme un risque plus haut que le risque de l'accident attendu pour un certain âge et gendre, et permet une quantification plus valide des fractures ostéoporotiques parmi des populations différentes.