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Biomedical subjects

L Müller

Publications and source records attributed to L Müller.

At least 109 records · Page 6Linked to original sources
PubMed1993

High-affinity substance P binding sites of neurokinin-1 receptor type autoradiographically associated with vascular sinuses and high endothelial venules of human lymphoid tissues.

BACKGROUND: Factors that affect leukocyte-endothelial cell interaction in high endothelial postcapillary venules and vascular sinuses of lymphatic tissues indirectly regulate immune function. Studies in sheep demonstrated that acute infusion of substance P (SP) into cannulated popliteal lymph node afferent lymphathics produced a marked and prolonged increase in the output of lymphocytes into nodal efferent lymph. The proposed mechanism is an influence of SP on lymph vascular systems. Such functional importance of the immunoregulatory properties of SP in man is unknown. EXPERIMENTAL DESIGN: The expression and distribution of SP receptors in human lymphoid tissue was investigated using slide-mounted fresh-frozen sections of lymph node, hyperplastic tonsillitis, and spleen for ligand binding and autoradiographic studies. RESULTS: Specific binding of radiolabeled SP to lymph node and tonsils reached a plateau within approximately 40 minutes, being half-maximal at 20 minutes. The specific binding was between 65 and 75% of total binding. In contrast, iodinated neurokinin A under identical incubation conditions, did not significantly associate with the tissues. Neither the SP nor the neurokinin A tracer specifically associated with spleen. Binding specificity of radiolabeled SP was analyzed in binding competition experiments. Synthetic SP, SP (3-11), a selective neurokinin-1 agonist and a neurokinin-1 antagonist competed with the specific binding of SP to lymph node and tonsil sections. The half-maximal inhibition of binding was obtained at a concentration of about 0.5 nmol/liter of SP. The fragment SP (1-4) and selective neurokinin-2 ligands did not compete with the specific binding of SP. Scatchard and nonlinear algorithm analyses revealed two binding sites for SP. For lymph node and tonsil, one site showed a high affinity of about 0.4 nmol/liter and 0.7 nmol/liter and a low capacity for SP, respectively. The second site exhibited a lower affinity of 100 nmol/liter and 50 nmol/liter and a higher capacity for SP in lymph node and tonsil, respectively. Autoradiographic localization of the binding sites shows a very high concentration of silver grains when compared with controls. The reaction occurred mainly over vascular sinuses and high endothelial venules with heterogenous density. Silver grain accumulation was also noticed over the marginal sinuses of the B cell follicles. CONCLUSIONS: The biochemical results indicate the presence of neurokinin-1 receptors in human lymph node and tonsil. We suggest that the neurokinin-1 receptors localized to vascular tissues of lymph node and tonsil mediate the affects of SP on lymphocyte traffic, and we propose that SP plays a regulatory role in lymphocyte homing in man.

Autoradiography↗
PubMed1993

[Lead in drinking water--determination of a new limit value and the problem of lead pipes].

The problem of lead in drinking water with regard to sensitive groups of the general population (e.g. unborn, babies that are not breast-fed, infants and children) is discussed. In respect of children in nurseries, the question regarding the relation of blood-lead levels to neurobehavioural deficits due to lead as well as a theoretical "tolerable" daily intake of lead is discussed. A provisional daily intake of approx. 1.2-1.3 micrograms Pb/kg body weight for children and pregnant women is proposed. For non-pregnant adults a double to three times higher intake may be tolerated (base: high blood pressure). These doses are well three times below the still recognised Provisional Tolerable Weekly Intake of led (PTWI-values, WHO), when related to daily intake. Considering the water consumption as well as the proportionate share of other exposure routes which result in the total lead exposure of risk groups, a toxicologically tolerable level of 10 micrograms Pb/l in drinking water is suggested. A reduction of the actual limiting value in drinking water (40 micrograms Pb/l) is advised. A special problem arises from lead tubes within the water distribution system. Water in stagnation as well as in use in these tubes may have enhanced lead concentrations. Therefore, it is recommended to exchange lead tubes preferentially in areas of sensitive use (e.g. as in the kitchen).

Adult↗
PubMed1992

The clastogenic potential in vitro of pyrrolizidine alkaloids employing hepatocyte metabolism.

Three pyrrolizidine alkaloids (PAs), monocrotaline, retrorsine and isatidine, were tested for their clastogenic activity under different conditions of metabolic activation in vitro. All three compounds exhibited a weak activity when V79 cells were treated at very high concentrations for 18 h in the absence of a metabolizing system. Short-term (2 h) treatment with rat liver S9 mix led to a strong and concentration-dependent increase in chromosomal aberrations for retrorsine. Isatidine was not mutagenic with S9 mix and monocrotaline was positive at high concentrations only. In contrast, a prolonged treatment (18 h) in vitro under activation conditions in the presence of primary hepatocytes led to clear concentration-dependent positive responses for all three PAs investigated. Particularly the results with isatidine demonstrate that in vitro tests using S9 mix for metabolization can generate misleading results. It is not clear whether the results could be attributed to a better activation of the test compounds by intact hepatocytes in comparison to S9 mix or if the fact that only hepatocytes allow a treatment for the whole culture period under activation conditions was more important. Owing to its strong cytotoxicity the exposure to S9 mix is generally limited to 2-4 h, limiting also the exposure of the target cells to a test chemical as well as its metabolites. The results presented show significant differences in mutagenic potency of PAs due to variations in the activation system. This underlines the usefulness of primary hepatocytes, e.g., for the detection of pre-mutagens. The PAs investigated are present in plants which are used for phytotherapeutic medicinal products. They do not contribute to their efficacy and are, therefore, not to be tolerated in amounts that may impose a risk for the user.

Animals↗
PubMed1991

Report of a comparative study of DNA damage and repair assays in primary rat hepatocytes with five coded chemicals.

We report the results of a collaborative study for the detection of chemical-induced DNA damage in primary cultures of rat hepatocytes. The methods include the detection of unscheduled DNA synthesis (UDS) with either autoradiography (5 laboratories) or liquid scintillation counting (2 laboratories) and the assessment of DNA single-strand breaks with the alkaline elution assay (1 laboratory). Interlaboratory standardization was omitted in order to prove the agreement of the assays under routine conditions. Five coded chemicals were tested. For 4 chemicals (2-acetylaminofluorene, thiourea, glycerine and potassium chloride) the UDS data were consistent in all laboratories, thus indicating a high consensus of the test systems applied in the different laboratories. Those 3 chemicals that were not expected to elicit genotoxic activity (thiourea, glycerine, and potassium chloride) yielded negative results in all laboratories. 2-Acetylaminofluorene, a known DNA-damaging agent in hepatocytes, gave strongly positive responses in all laboratories. In contrast, N-nitrosodiphenylamine led to equivocal responses.

2-Acetylaminofluorene↗
PubMed1991

Further investigations on the clastogenicity of paracetamol and acetylsalicylic acid in vitro.

Paracetamol (PCM) and acetylsalicylic acid (ASA), both widely used analgesics, were tested for their clastogenicity in V79 cells in vitro. Rat liver S9 mix and primary rat hepatocytes (PRH) were used as external activation systems. ASA was found to be negative with and without activation system in concentrations up to 10(-2) M. In contrast PCM induced concentration-dependent chromosomal aberrations with and without activation system within the range of 3 x 10(-3) and 10(-2) M. The greatest effects were observed following continuous treatment with PRH activation and without external metabolization. Pulse treatments without external metabolization, with S9 mix and PRH were less effective. The clastogenic potency of PCM seems to be partly independent of metabolic activation. Although clastogenic effects in vitro were observed only in very high concentrations pharmacokinetic data and other published mutagenicity data indicate that there might be a risk for human use. Peak plasma levels of more than 10(-4) M have been reported (Forrest et al., 1982) and 2 groups of investigators (Kocisova et al., 1988; Hongslo et al., 1990) found PCM to be weakly clastogenic in human lymphocytes in vivo in the maximum human therapeutic dose range.

Acetaminophen↗
PubMed1991

The quality of genotoxicity testing of drugs. Experiences of a regulatory agency with new and old compounds.

The state of the art of mutagenicity testing of drugs based upon new entities submitted for registration in the Federal Republic of Germany is reviewed for the period between 1986 and 1989. In the initial phase of registration 50 out of 107 new compounds were tested insufficiently, thus making safety assessment for therapeutic use difficult. The main shortcomings applied to both missing as well as insufficiently performed mutagenicity tests. In some cases indications for a genotoxic activity were obtained due to inadequate testing giving rise to a suspicion of a mutagenic potential which had to be clarified. Upon additional testing during the subsequent phases of the registration procedure almost all insufficiencies and unclarified suspicions could be eliminated. Several examples on this point are discussed. When evaluating data for 'old compounds' regulatory authorities are confronted with considerable problems. This publication gives some practical advice for judging the plausibility and relevance of published data. Two examples (quercetin and malathion) for which published data are summarized, illustrate that even extensive literature data may not be sufficient to draw a definitive conclusion, if the relevance of most of the results is questionable.

Animals↗
PubMed1991

[Long-term results of multimodality therapy of small cell bronchial cancer including surgery].

The results of a prospective Phase II study of a multimodal treatment regimen including surgery of operable stages of small cell lung cancer are reported. Of 45 patients 24 received all parts of the projected treatment. The 5-year survival probability is 56% and 8 patients are still living after more than 60 months. Eleven patients with N2 lymph node metastases receiving the complete therapy have a projected 5-year survival of 60%.

Austria↗
PubMed1991

[Toxicological assessment. A solid basis for preventive health care? Considerations on the preventive character of guidelines for (heavy) metal contamination of children's playgrounds].

The present report discusses the standard limit reference values for metal content of playgrounds, set by the authorities in North-Rhine-Westphalia, Berlin, Hamburg and Bremen. Taking the metals arsenic, lead and cadmium as an example, the causative role of region specific conditions for establishing the limit values for protective measures are described. Essentially, two factors influence the decision: 1. the background concentrations of metals in sand and soils differ between the various states; 2. there is a lack of a uniform concept for the quantitative evaluation of oral intake as a main route of ingestion of metals endangering the health of children on child playgrounds. Due to insufficient data, arbitrary assumptions in respect of intake, relevant age group or playing-time on playgrounds are made. From a toxicological point of view the standard limit values, exceed the span of toxicological tolerance, in an attempt to combine pragmatic and toxicological considerations. However, only few of these values agree with the basic principles of preventive care.

Arsenic↗
PubMed1991

[Indirect traumatic diaphragmatic rupture].

Between 1969 and 1988 51 polytraumatized patients were treated for rupture of the diaphragm due to blunt trauma. In 39 cases the lesion was in the left hemidiaphragm, in 11 cases on the right side and in one case on both sides. Clinical investigation and posterior-anterior chest X-ray were the most important diagnostic procedures. A high percentage of ruptures was only detected intraoperatively during acute laparotomy/thoracotomy. Early or delayed surgery had no influence on the survival of patients. The prognosis depends on the severity of associated injuries, which are the main causes of death in these patients.

Abdominal Injuries↗
PubMed1990

Studies on the efficacy of lipoate and dihydrolipoate in the alteration of cadmium2+ toxicity in isolated hepatocytes.

Lipoate (thioctic acid) is presently used in therapy of a variety of diseases such as liver and neurological disorders. However, nothing is known about the efficacy of lipoate and its reduced form dihydrolipoate in acute cadmium (Cd2+) toxicity which involves severe liver disturbances. Therefore, we investigated the effects of these redox compounds on Cd2(+)-induced injuries in isolated rat hepatocytes. The cells were coincubated with 150 microM Cd2+ and either 1.5-6.0 mM lipoate or 17-89 microM dihydrolipoate for up to 90 min and Cd2+ uptake as well as viability criteria were monitored. Both exposure regimens diminished Cd2+ uptake in correspondence to time and concentration. They also ameliorated Cd2(+)-induced cell deterioration as reflected by the decrease in Cd2(+)-induced membrane damage (leakage of aspartate aminotransferase), by the lessening of the Cd2(+)-stimulated lipid peroxidation (TBA-reactants) and by the increase in Cd2(+)-depleted cellular glutathione (GSH + 2 GSSG). Half-maximal protection was achieved at molar ratios of 9.9 to 19 (lipoate vs. Cd2+) and 0.25 to 0.74 (dihydrolipoate vs. Cd2+), indicating a 19.5 to 50.6 lower protective efficacy of lipoate as compared to dihydrolipoate. Lipoate induced an increase in extracellular acid-soluble thiols different from glutathione. It is suggested that dihydrolipoate primarily protects cells by extracellular chelation of Cd2+, whereas intracellular reduction of lipoate to the dihydro-compound followed by complexation of both intra- and extracellular Cd2+ contributes to the amelioration provided by lipoate.

Animals↗
PubMed1989

Protective effects of DL-alpha-lipoic acid on cadmium-induced deterioration of rat hepatocytes.

The suitability of DL-alpha-lipoic acid (LA) to serve as an antidote in cadmium (Cd) toxicity in rat hepatocytes was investigated. Isolated hepatocytes were exposed to 200 and 450 microM Cd in the presence of 0.2, 1.0 and 5.0 mM LA, respectively. After 30 min of incubation various criteria of cell viability were monitored. Lipoic acid markedly diminished Cd uptake. Concomitantly, Cd-induced membrane injury, as reflected by the leakage of aspartate aminotransferase and sorbitol dehydrogenase (SDH) was decreased. Moreover, LA protected against intracellular toxic responses to Cd, such as a decrease in cellular SDH activity, a decrease in cellular acid soluble thiols, especially in total glutathione, a decrease in cellular urea and an increase in thiobarbituric acid (TBA) reactants, as a measure of lipid peroxidation. Most protective effects were seen in hepatocytes challenged with the lower Cd concentration and coincubated with 5 mM LA. In contrast, at 450 microM Cd even the highest LA concentration applied either did only reverse Cd-effects incompletely (SDH-response, TBA-reactants) or did not protect at all (Cd uptake, enzyme leakage, loss of glutathione). The data indicate that DL-alpha-lipoic acid serves as a protective tool against Cd-induced membrane damage and cell dysfunction in hepatocytes. This stands as long as Cd exposure is low enough to permit interaction with LA prior to interaction with cell structures.

Animals↗
PubMed1989

"Reversible gastric banding" in surgical treatment of morbid obesity--results of animal experiments.

The basic principle of "reversible gastric banding" as a new surgical approach to morbid obesity treatment is the creation of a small fundus reservoir using a silicone cuff which is coiled around the stomach close to the cardia. The extent of obstruction corresponds to the amount of liquid in the cuff which can be varied by puncture of a valve implanted in the subcutis. The reversibility of gastric obstruction is the great advantage of this method as compared to vertical banded gastroplasty or gastric bypass. We studied this method in animal experiments using seven "Göttinger Minipigs". In two animals the objectives of the study were reached, the observed complications, mostly caused by the nature of the test animal, are analyzed and discussed. To our knowledge, this is the first report in the literature on animal experiments in bariatric surgery.

Animals↗
PubMed1989

Mutagenicity testing of doxylamine succinate, an antinauseant drug.

Doxylamine succinate (DA), a compound which was formerly used as an antinauseant during pregnancy, showed no substantial mutagenicity in mouse embryos following transplacental exposure. A small dose-dependent induction of chromosomal aberrations was found in mouse embryos on day 11 of gestation. No induction of sister chromatid exchanges (SCE) was found in embryos on day 11 of gestation. A micronucleus test with fetal blood on day 17 of gestation was negative. Additionally, DA was negative in Chinese hamster bone marrow in vivo (micronuclei) and in human lymphocyte cultures in vitro (SCE).

Animals↗