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Biomedical subjects

C Bauer

Publications and source records attributed to C Bauer.

At least 109 records · Page 6Linked to original sources
PubMed1994

Hypoxia and cobalt stimulate lactate dehydrogenase (LDH) activity in vascular smooth muscle cells.

O2 plays a dominant role in the metabolism and viability of cells; changes in O2 supply lead to many physiological responses in the cell. Recent reports have shown that hypoxia induces the transcription of a number of genes, among them those for the glycolytic enzymes. We have investigated signalling events that may lead to enhanced activity of lactate dehydrogenase (LDH) in cultured vascular smooth muscle (VSM) cells derived from rat aorta, grown under hypoxic conditions (1% versus 20% O2). LDH was chosen because this enzyme exhibits one of the largest increases in activity among the glycolytic enzymes after hypoxic stimulation of cells. Hypoxic exposure of VSM cells for 24 h resulted in a 2-fold increase in LDH activity and in a 2.5-fold increase in intracellular cAMP levels. Agents that activate adenylate cyclase, such as forskolin, cholera toxin and 1-methyl-3-isobutylxanthine (IBMX), and thus increase cAMP production, significantly induced LDH activity. Moreover, induction of LDH activity by hypoxia was prevented in the presence of the protein kinase A inhibitor N-[2-(methyl-amino)ethyl]-5-isoquinolinsulphonamide dihydrochloride (H-8), and the cyclooxygenase inhibitor indomethacin. In contrast to the cAMP-stimulating agents, stable cGMP analogues (dibutyryl-cGMP, 8-bromo-cGMP), activators of protein kinase C [12-O-tetradecanoylphorbol-13-acetate (TPA), and 1-oleoyl-2-acetyl-glycerol (OAG), and the calcium ionophore ionomycin did not alter LDH activity in VSM cells kept at 20% O2. A dose-dependent increase in LDH activity was also observed in normoxic cells exposed to cobalt chloride (50-200 microM), indicating that a metal binding protein might be involved in this signalling cascade.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Lack of transport of erythropoietin across the human placenta as studied by an in vitro perfusion system.

The transfer of human recombinant erythropoietin (rhEPO) from the maternal to the fetal side was investigated using the technique of in vitro perfusion of an isolated cotyledon of human placenta, with recirculation of the perfusate (130 ml) in separate closed maternal and fetal circuits. rhEPO (221-512 U), together with [14C]BSA (bovine serum albumin, 44.8 kBq or 2,688,000 dpm), was added to the maternal circuit only. Despite a considerably lower molecular weight of EPO (mol. wt. = 30,400 Da) compared to BSA (mol. wt. = 69,000 Da), no difference was found in their transfer across the placenta from the maternal to the fetal side, which was very low for both macromolecules. The total transfer of rhEPO derived from the concentration measured in the samples taken from the fetal circuit at the end of 4-5 h of perfusion, was in the range of 0.04% of the amount initially added to the maternal compartment. A similar amount of transfer was determined for [14C]BSA (0.04-0.07%, n = 12). In conclusion, by direct determination in a dually in vitro perfused human placental cotyledon, no significant transfer of rhEPO from the maternal to the fetal side could be shown.

Biological Transport↗
PubMed1994

Efficacy of two formulations ('injectable' and 'pour on') of moxidectin against gastrointestinal nematode infections in grazing cattle.

The efficacy of moxidectin, 'injectable' and 'pour on', against gastrointestinal nematodes was determined in cattle in two separate field trials (Trial I in 1990 and Trial II in 1991) with respectively 88 and 94 young grazing cattle of either sex. The efficacy was measured on the basis of the reduction of the egg output and of the evaluation of the results from larval differentiation. Animals in Group MI received 0.2 mg kg-1 body weight (b.w.) moxidectin injectable solution in Trial I on Day 0. Group CI was not given any medication on Day 0, but 0.2 mg kg-1 b.w. ivermectin injectable solution (Ivomec) was applied after 2 weeks to prevent clinical disease. In Trial II, animals in Group MP were treated with pour on moxidectin (0.5 mg kg-1 b.w.) on Day 0. Animals in Group CP serving as controls for Group MP during the first part of the trial received the same formulation at the same dose 2 weeks after treatment of Group MP. When the egg output was compared within treated groups, the egg count reduction was very similar post treatment (p.t.) with both formulations being 96.3% and 96.6% on Day 7 after the application of injectable moxidectin or pour on moxidectin, respectively, and 90.7% and 92.5% on Day 28 p.t. When egg counts of treated and control animals were compared (corrected for the e.p.g. values before treatment) the egg count reduction was 95.4% and 91.5% on Day 7 and 92.9% and 84.8% on Day 14 p.t. with either the injectable or pour on formulation. Pour on moxidectin seemed to be more effective against Ostertagia spp. than against Cooperia spp. Animals treated with injectable moxidectin gained significantly more body weight (4.2 kg per animal) than the controls from Day -7 to Day +14, while no significant difference in weight gain was achieved within 2 weeks after treatment with pour on moxidectin.

Administration, Topical↗
PubMed1994

Lungworm infection in a beagle colony: Filaroides hirthi, a common but not well-known companion.

116 beagle dogs of both sexes were examined for infection with Filaroides hirthi within the framework of several toxicological studies. 98% of the animals demonstrated lung-worm-associated lesions. Most of the macroscopic visible lesions can be subdivided into four groups, representing different histopathological pictures ranging from living worms, different types of granulomatous inflammation to tumorlike lesions. Especially the latter is liable for several misinterpretations in toxicologic studies. This is the first positive evidence of an infection of Beagle dogs with Filaroides hirthi in Germany.

Animals↗
PubMed1994

Hypermutable ligation of plasmid DNA ends in cells from patients with Werner syndrome.

Werner Syndrome is a rare autosomal recessive disorder characterized by an increased cancer risk and by symptoms suggestive of premature aging. Cells from these patients demonstrate a typical pattern of chromosomal instability and a spontaneous hypermutability with a high rate of unusually large deletions. We have studied the in vivo DNA ligation in three lymphoblast cell lines from Werner syndrome patients and three from normal donors. In our host cell ligation assay we transfected linearized plasmid pZ189 and measured the amount of plasmid DNA ends rejoined by these host cells as the ability of the recovered plasmid to transform bacteria. A mutagenesis marker gene close to the ligation site allowed screening for mutations. Subsequent mutation analysis provided information about the accuracy of the ligation process. The cells from Werner syndrome patients were as effective as normal cells in ligating DNA ends. However, mutation analysis revealed that the three Werner syndrome cell lines introduced 2.4-4.6 times more mutations (p < 0.001) than the normal cell lines during ligation of the DNA ends: the mutation rates were 69.4, 97.2, and 58.7%, as compared to 23.6, 21.7, and 24.4% in the normal cell lines. These increased mutation frequencies in plasmids ligated during passage through Werner syndrome cells were mainly due to a significant (p < 0.001) increase in deletions. This error-prone DNA ligation might be responsible for the spontaneous hypermutability and the genomic instability in Werner syndrome cells and related to the apparently accelerated aging and high cancer risk in affected patients.

Cell Line↗
PubMed1994

rh-erythropoietin stimulates immature reticulocyte release in man.

The pharmacodynamics of single intravenous dosing with recombinant human erthropoietin (rhEPO) was investigated in eight healthy volunteers (150 U/kg, n = 2; 300 U/kg, n = 6) with respect to reticulocyte subdivisions (by fluorescence flow cytometry) and serum ferritin over 6.5 d. The present study shows that bolus rhEPO injection produces an immediate release of high and middle fluorescence (immature) reticulocytes with a high RNA content from the marrow into the circulation, whereas the low fluorescence (more mature) reticulocytes were at first not affected. Serum ferritin decreased markedly within 24 h, reaching a nadir 50% of baseline after 120 h (5 d), with no increase in haemoglobin. Our data suggests that rhEPO triggers premature expulsion of immature reticulocytes from the bone marrow into the circulation independent of its effect in stimulating erythropoiesis and that rhEPO has an effect on serum ferritin concentration which in this dynamic situation is dependent not only on the iron stores.

Bone Marrow↗
PubMed1994

Expression of the erb B oncogene in the Morris hepatoma 7777.

Altered expression of protooncogenes/oncogenes is believed to be involved in hepatocarcinogenesis of the chemically induced, transplantable Morris hepatoma 7777. We compared the mRNA expression of c-N-ras and v-erb B mRNA of normal rat liver with that of Morris hepatoma 7777 using Northern blot analysis and in situ hybridization. Northern blot analysis revealed a strong overexpression of the v-erb B related mRNA, while the c-N-ras mRNA was only slightly increased. In situ hybridization using a c-N-ras mRNA probe also showed only a slightly increased number of silver grains in the hepatoma cells compared with normal rat liver. On the other hand, the v-erb B related mRNA was strongly overexpressed in the hepatoma cells, while the connective-tissue capsule, the blood vessels, blood cells and the necrotic foci did not show an elevated v-erb B related gene mRNA expression. Similar results were obtained in liver metastases. The detectable v-erb B hybridization signal was lost by pretreatment with RNase A. We conclude that the c-N-ras gene is of minor importance in the chemically induced, transplantable Morris hepatoma 7777, while the increased expression of the v-erb B related mRNA is due to a selection of ligand-independent tyrosine kinase activity.

Animals↗
PubMed1994

Immunohistochemical and electronmicroscopic effects of a new 2.1 microns Ho:YAG laser on the rat brain.

Using an experimental animal model, the thermal single-pulse lesion derived from a mid-infrared 1.0 Joule 300 microns fibre-conducted Holmium: Yttrium-Aluminum-Garnet (Ho:YAG) laser was examined, with special emphasis on the orientation and depth of the tissue reaction. Performing biparietal craniotomy in Sprague-Dawley rats weighing 250-300 g, both hemispheres were targeted by different radiant exposures from 20 to 140 J/cm2 derived from a 600-800 microsecond single pulse. After survival periods of one to 30 days, the animals were sacrificed and both hemispheres were processed for light- and electronmicroscopic investigations. To resolve the depth and orientation of the tissue reaction regarding the localization of reactive astrocytes, we looked for the expression of glial proteins like glial fibrillary acidic protein (GFAP), Vimentin and S 100 with a three-step biotin-avidin immunoperoxidase method. Neuronal and secondary axonal damage was investigated by labelling Neurofilament and Synaptophysin. The tissue reaction beneath the ablated material, consisting of a vacuolation and coagulation zone resulting from heat diffusion, was further elucidated by localization of the heat shock protein (HSP 72 kilo Dalton). Revealing the extension of reactive astrocytes and the degree of the electronmicroscopically depicted glial oedema, the depth of the tissue damage was estimated to reach about 700 microns beneath laser excision. Since McKenzie predicted the depth of tissue damage beneath CO2 and YAG laser excisions in a theoretical mathematical model, the authors were able to develop a sensitive model for testing new laser systems and as a promising instrument for neurosurgery.

Aluminum↗
PubMed1993

Lack of associations between fetal and maternal serum-erythropoietin at birth.

Erythropoietin (EPO) is known to be the main regulator of erythropoiesis. We wanted to determine whether EPO production during pregnancy takes place independently in the mother and the fetus, and to identify the factors which set the EPO level. Endogenous EPO levels were determined in simultaneous samples from the umbilical vein, the umbilical artery and a maternal vein in 126 mother-child pairs and simultaneously from amniotic fluid (n = 14) in unselected births. Results were related to clinical and biochemical parameters of fetal well-being, mode of delivery, duration of labor, and infant parameters at birth. There was a weak correlation between maternal and fetal log EPO values (umbilical vein: r2 = 0.11; umbilical artery: r2 = 0.08), but a highly significant correlation between log EPO levels in the two umbilical vessels (r2 = 0.91) and between both umbilical blood and amniotic fluid (r2 = 0.41). Maternal EPO levels were lower than fetal levels in 76 cases, higher in 47, and nearly identical in 3. Increased fetal EPO levels were associated with clinical and biochemical indicators of fetal stress. These associations help to explain why EPO concentrations in fetal blood are independent of maternal levels and also indicate that EPO does not cross the placental barrier. These findings are discussed in the light of the animal experimental and in vitro evidence for placental transfer of EPO. Our data, and the work of others, make such a transfer in humans quite unlikely. This observation has therapeutical consequences for the treatment of maternal anemia with recombinant human EPO.

Amniotic Fluid↗
PubMed1993

Control of photosystem genes in Rhodobacter capsulatus.

Two environmental factors, oxygen and high light intensity, are known to repress synthesis of the Rhodobacter capsulatus photosystem. One level of regulation is the control of light harvesting and reaction centre gene expression at the point of transcription initiation. This has recently been shown to involve transcriptional activators which exhibit sequence similarity to members of the 'two-component' class of prokaryotic regulators. An additional level of regulation involves the formation of 'superoperons' that transcriptionally link pigment biosynthesis operons with operons that code for the light harvesting and reaction centre structural genes. A final level of regulation involves the selective degradation of reaction centre mRNA transcripts which influence the stoichiometric synthesis of the light harvesting and reaction centre complexes.

Anaerobiosis↗
PubMed1993

In-vivo assessment of DNA ligation efficiency and fidelity in cells from patients with Fanconi's anemia and other cancer-prone hereditary disorders.

We developed a host cell DNA ligation assay, in which we transfected linearized plasmid pZ189 into human lymphoblasts or fibroblasts in order to assess the efficiency and accuracy of DNA ligation within these host cells. We used cell lines from patients with Fanconi's anemia and other chromosome breakage or instability syndromes (Bloom's syndrome, ataxia telangiectasia, Werner's syndrome). With the Fanconi's anemia lymphoblast line GM8010 we did not find a reduced, but a slightly hypermutable DNA ligation. Mutation analysis revealed a unique 7.9-12.5-fold increase in insertions or complex mutations. With cells from the other chromosome breakage/instability syndromes we also found a hypermutable and/or reduced DNA ligation. An impaired DNA ligation might be a common molecular mechanism of genetic instability in these disorders.

Cell Line↗
PubMed1993

The role of receptor binding in drug discovery.

Radioligand receptor binding has been used extensively to identify and characterize a host of receptors and enzymes targeting virtually every therapeutic area. Many drug discovery programs have been based on the utilization of radioligand receptor binding technology to identify lead compounds which interact with receptors likely to be important in neuronal, immunological, gastrointestinal, and cardiovascular function/dysfunction. There are several obvious advantages to using in vitro receptor binding as a first level screen when compared to in vivo pharmacometric screens. Scientifically, the structure activity data generated in binding assays is a direct reflection of the ligand/receptor interaction minus the complications which result from secondary events, bioavailability, and pharmacodynamic issues. Technically, the binding studies require only a small amount of test compound (< or = 1 mg), while whole animal studies routinely need gram quantities. Similarly, only a small amount of tissue is required, compared with the cost of purchase and maintenance of live animals for in vivo screening. Supply and labor costs are drastically reduced due to the limited volume and test tube based technology of receptor binding. For these reasons receptor binding assays have been utilized with considerable success to discover site specific lead compounds in virtually every therapeutic area.

Animals↗
PubMed1993

Influence of dopaminergic agonists/antagonists on fucose metabolism in the rat brain.

UNLABELLED: Valid indications of a key role for dopaminergic drugs in glycoprotein fucosylation in neuronal tissue in vitro led us to investigate whether the administration of dopaminergic agonists/antagonists influences fucose metabolism in the rat brain in vivo. Three test groups were set up. Group 1 was given L-DOPA (210 mg/l), Group 2 haloperidol (10.5 mg/l) in drinking water, Group 3 served as control. The rats were sacrificed after 8 weeks and enzyme activities in 5 different brain areas were determined concerning the enzymes of the anabolic fucose metabolism: fucokinase, fucose-1-phosphate pyrophosphorylase and fucosyltransferase 1 and 2. Only the specific activity of fucokinase was affected by haloperidol or L-DOPA administration. In the olfactory bulbus, thalamus and cortex, haloperidol decreased fucokinase activity by 21%, 37%, and 39%, respectively (p < 0.05 in each case). No changes were observed in the cerebellum and striatum. Surprisingly, fucokinase activity in the cortex was decreased by L-DOPA (31%, p < 0.05). CONCLUSIONS: Cerebral fucokinase activity is influenced in vivo by dopaminergic drugs in well circumscribed brain areas. Other enzymes of the anabolic fucose metabolism showed no change in activity. It is, therefore, conceivable that these drugs, apart from known mechanisms, exert part of their pharmacological action via a modulation of fucose metabolism.

Animals↗
PubMed1993

Leukocyte-endothelial cell interactions in the liver after hemorrhagic shock in the rat.

Leukocyte-endothelial cell interactions in rat livers were investigated using intravital fluorescence microscopy following hemorrhagic shock (MAP at 40 mm Hg for 60 min) and resuscitation. Thirty minutes after resuscitation, when MAP was higher than 100 mm Hg, sinusoidal perfusion was only slightly reduced (>90% of controls). Firm adhesion of leukocytes increased to 370 +/- 54 leukocytes/mm2 after shock and resuscitation compared to control animals (48 +/- 8/mm2; mean +/- SEM; P < .01). Leukocyte-endothelium adhesion was highest in the portal areas and lowest in midzonal and pericentral regions (relationship:2.0: 1.1:1.0). Pretreatment with dexamethasone (5 mg/kg bw) resulted in a dramatic rise of adherent leukocytes following hemorrhagic shock (920 +/- 62/mm2; P < .001). Pretreatment with ibuprofen (15 mg/kg bw) resulted in a similar increase of adherent leukocytes after hemorrhagic shock (750 +/- 60/mm2; P < .001), while pretreatment with MK 886(10 mg/kg), inhibitor of lipoxygenase pathway, reduced leukocyte adhesion slightly (270 +/- 38/mm2). The results reveal that leukotrienes, e.g., released by activated macrophages, are involved in the regulation of leukocyte adhesion in liver sinusoids following hemorrhagic shock and resuscitation. The negative effect of dexamethasone and ibuprofen on hepatic leukocyte adhesion, however, has to be considered for therapeutic use.

Animals↗
PubMed1992

Inhibitory effect of zinc on stimulated erythropoietin synthesis in HepG2 cells.

The effect of zinc on erythropoietin (EPO) synthesis in HepG2 cells was investigated. The increase in EPO synthesis induced by Co2+ (50 microM), Ni2+ (300 microM) or oxygen (1% O2) was inhibited by the presence of ZnCl2 (50-150 microM) in the tissue-culture medium, whereas basal EPO synthesis was unaffected. The effect was reflected by corresponding changes in the EPO mRNA level. These effects of zinc on EPO synthesis could not be mimicked by CdCl2 (less than or equal to 2 microM). Addition of FeCl3 to the medium appeared to decrease the inhibitory effect of zinc on hypoxia-induced EPO synthesis, implying that zinc may interfere with an iron-dependent step in EPO regulation.

Blotting, Northern↗