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Biomedical subjects

T Meyer

Publications and source records attributed to T Meyer.

At least 181 records · Page 10Linked to original sources
PubMed1999

Synthesis, mode of action, and biological activities of rebeccamycin bromo derivatives.

Bromo analogues of the natural metabolite rebeccamycin with and without a methyl substituent on the imide nitrogen were synthesized. The effects of the drugs on protein kinase C, the binding to DNA, and the effect on topoisomerase I were determined. The drugs' uptake and their antiproliferative activities against P388 leukemia cells sensitive and resistant to camptothecin, their antimicrobial activity against a Gram-positive bacterium (B. cereus), and their anti-HIV-1 activity were measured and compared to those of the chlorinated and dechlorinated analogues. Dibrominated imide 5 shows a remarkable activity against topoisomerase I, affecting both the kinase and DNA cleavage activity of the enzyme. The marked cytotoxic potency of this compound depends essentially on its capacity to inhibit topoisomerase I.

Aminoglycosides↗
PubMed1999

Author errata.

Explore the source record for details and available documents.

Retraction Notice↗
PubMed1999

Estrogen-induced activation of mitogen-activated protein kinase requires mobilization of intracellular calcium.

Estrogens and growth factors such as epidermal growth factor (EGF) act as mitogens promoting cellular proliferation in the breast and in the reproductive tract. Although it was considered originally that these agents manifested their mitogenic actions through separate pathways, there is a growing body of evidence suggesting that the EGF and estrogen-mediated signaling pathways are intertwined. Indeed, it has been demonstrated recently that 17beta-estradiol (E2) can induce a rapid activation of mitogen-activated protein kinase (MAPK) in mammalian cells, an event that is independent of both transcription and protein synthesis. In this study, we have used a pharmacological approach to dissect this novel pathway in MCF-7 breast cancer cells and have determined that in the presence of endogenous estrogen receptor, activation of MAPK by E2 is preceded by a rapid increase in cytosolic calcium. The involvement of intracellular calcium in this process was supported by the finding that the presence of EGTA and Ca2+-free medium did not affect the activation of MAPK by E2 and, additionally, that this response was blocked by the addition of the intracellular calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetate. Cumulatively, these data indicate that the estrogen receptor, in addition to functioning as a transcription factor, is also involved, through a nongenomic mechanism, in the regulation of both intracellular calcium homeostasis and MAPK-signaling pathways. Although nongenomic actions of estrogens have been suggested by numerous studies in the past, the ability to link estradiol and the estrogen receptor to a well defined signaling pathway strongly supports a physiological role for this activity.

Breast Neoplasms↗
PubMed1999

Dynamic control of CaMKII translocation and localization in hippocampal neurons by NMDA receptor stimulation.

Calcium-calmodulin-dependent protein kinase II (CaMKII) is thought to increase synaptic strength by phosphorylating postsynaptic density (PSD) ion channels and signaling proteins. It is shown that N-methyl-D-aspartate (NMDA) receptor stimulation reversibly translocates green fluorescent protein-tagged CaMKII from an F-actin-bound to a PSD-bound state. The translocation time was controlled by the ratio of expressed beta-CaMKII to alpha-CaMKII isoforms. Although F-actin dissociation into the cytosol required autophosphorylation of or calcium-calmodulin binding to beta-CaMKII, PSD translocation required binding of calcium-calmodulin to either the alpha- or beta-CaMKII subunits. Autophosphorylation of CaMKII indirectly prolongs its PSD localization by increasing the calmodulin-binding affinity.

Actins↗
PubMed1999

Inhibition of inducible nitric oxide synthase exacerbates chronic cerebral toxoplasmosis in Toxoplasma gondii-susceptible C57BL/6 mice but does not reactivate the latent disease in T. gondii-resistant BALB/c mice.

Infection of C57BL/6 mice with Toxoplasma gondii leads to progressive and ultimately fatal chronic Toxoplasma encephalitis (TE). Genetic deletion or inhibition of inducible nitric oxide synthase (iNOS) from the beginning of infection increased the number of T. gondii cysts in the brain and markedly reduced the time-to-death in this mouse strain. In the present study, we addressed whether iNOS also contributes to the control of intracerebral parasites in a clinically stable latent infection that develops in T. gondii-resistant BALB/c mice after resolution of the acute phase of TE. iNOS was expressed in the inflammatory cerebral infiltrates of latently infected BALB/c mice, but the number of iNOS+ cells was significantly lower than in the brains of chronically infected T. gondii-susceptible C57BL/6 mice. In BALB/c mice with latent TE (> 30 days of infection), treatment with the iNOS inhibitors L-N6-iminoethyl-lysine or L-nitroarginine-methylester for < or = 40 days did not result in an increase of the intracerebral parasitic load and a reactivation of the disease, despite the presence of iNOS-suppressive inhibitor levels in the brain. However, L-nitroarginine-methylester treatment had remarkably toxic effects and induced a severe wasting syndrome with high mortality. In contrast to BALB/c mice, L-N6-iminoethyl-lysine treatment rapidly exacerbated the already established chronic TE of C57BL/6 mice. Thus, the containment of latent toxoplasms in T. gondii-resistant BALB/c mice is independent of iNOS, whereas the temporary control of intracerebral parasites in T. gondii-susceptible C57BL/6 mice with chronic TE requires iNOS activity.

Administration, Oral↗
PubMed1999

Syntheses and biological activities of rebeccamycin analogues. Introduction of a halogenoacetyl substituent.

In the course of structure-activity relationships on rebeccamycin analogues, a series of compounds bearing a halogenoacetyl substituent were synthesized with the expectation of increasing the interaction with DNA, possibly via covalent reaction with the double helix. Two rebeccamycin analogues bearing an acetyl instead of a bromoacetyl substituent were prepared to gain an insight into the role of the halogen atom. The new compounds show very little effect on protein kinase C and no covalent reaction with DNA was detected. However, the drugs behave as typical topoisomerase I poisons, and they are significantly more toxic toward P388 leukemia cells than to P388/CPT5 cells resistant to camptothecin. The introduction of a bromo- or chloro-acetyl substituent does not affect the capacity of the drug to interfere with topoisomerase I either in vitro or in cells. One of the bromoacetyl derivatives, compound 8, is the most cytotoxic rebeccamycin derivative among the hundred of derivatives we have synthesized to date. In addition, we determined the antimicrobial activities against two Gram-positive bacteria, Bacillus cereus and Streptomyces chartreusis, and against the Gram-negative bacterium Escherichia coli. The effect of the drugs on Candida albicans yeast growth and their anti-HIV-1 activities were also measured.

Aminoglycosides↗
PubMed1999

[Alcoholism: old and new approaches to diagnosis and therapy].

Several different possibilities concerning pharmacotherapy of alcoholism are discussed on the background of new neurobiochemical findings. Contributions to a new understanding of relapse are made and the complexity of the treatment of patients with double diagnosis is explained.

Alcohol Deterrents↗
PubMed1999

Identification of apoptotic cell death in distraction osteogenesis.

The purpose of this experimental work was to investigate whether apoptosis contributes to tissue remodelling during distraction bone healing. In a rabbit model of mandibular distraction osteogenesis, we quantitatively analysed the extent of apoptotic cell death in relation to differently applied mechanical loadings. Apoptotic cells were identified by means of an in situ detection assay for nuclear DNA fragmentation using a modified TUNEL procedure and by electron microscopical examination for typical morphological features of programmed cell death. TUNEL-positive cells were frequently detected in samples distracted at higher strain magnitudes. Ultrastructurally, these apoptotic cells displayed a condensed chromatin and fragmented nuclei, while the continuity of their plasma membranes remained intact. Our results clearly indicated that the discontinuous traction of osteotomized mandibles induced enhanced apoptosis. In contrast to non-distracted samples and mandibles distracted at low strain magnitudes, in which only minimal evidence of apoptotic cell death was detected, the application of hyperphysiological strain magnitudes resulted in an increased apoptosis rate. Thus, mechanical loading seems to be a triggering factor for apoptotic changes in osteoblastic cells. These findings suggest a pathophysiological role of apoptotic cell death in the control of tissue integrity during distraction osteogenesis.

Animals↗
PubMed1999

Antiglutamate therapy of ALS--which is the next step?

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease which was thought to be untreatable for a long time. However, recent evidence in men indicates that antiglutamatergic strategies are the first to have an influence on its pathogenesis and slow down the disease process. Since the effect of the drugs is still small, this progress cannot only be seen as a success of the present but most also be acknowledged as a starting point for the future. How will these future studies look like? They will have to take into account that ALS presumably has a long preclinical period and they will use a number of novel compounds and treatment strategies which have recently been shown to be effective in a transgenic animal model. This also implies that we are likely to use combination therapies and have to try to treat patients early. The latter will be necessarily connected with the demand for a novel clinical attitude to the diagnosis of the disease.

Amyotrophic Lateral Sclerosis↗
PubMed1999

[Cardiovascular and metabolic response to dynamic stress echocardiography by patients with coronary heart disease and healthy probands].

25 patients with coronary heart disease (CHD, 62 +/- 9 years) and 18 subjects free from cardiovascular disease (28 +/- 9 years) were tested on a cycle ergometer using a graded incremental test protocol: a) in the common upright position, b) as dynamic stress echocardiography in a semi-supine position. Whereas no relevant differences could be detected between the two conditions for the healthy subjects concerning heart rate, blood pressure, and rate-pressure product (2 x 3 ANOVA, t-tests with alpha-adjustment), the CHD patients showed both significantly higher heart rates as well as a significantly higher rate-pressure product (50 W: 15,300 +/- 2973 mm Hg/min vs. 13,822 +/- 3042 mm Hg/min; 75 W: 18,028 +/- 3479 mm Hg/min vs. 16,337 +/- 2619 mm Hg/min) on equivalent stages during stress echocardiography if compared to the sitting position. There were no differences for systolic blood pressure in this group; the diastolic values were higher in the sitting position at rest and during 50 W. Lactate concentrations (determined only in the healthy subjects) were significantly higher on all stages during dynamic stress echocardiography. The workload at the individual anaerobic threshold (IAT) was significantly lower. In conclusion, we found a higher metabolic along with a similar cardiovascular strain at equivalent workloads in stress echocardiography compared to upright bicycle ergometry for healthy subjects. However, CHD patients have a higher cardiocirculatory load in the semi-supine position. When investigating these patients with stress echocardiography, higher heart rates of about 8 beats/min have to be expected for equivalent workloads if compared to the upright position.

Adult↗
PubMed1999

Immune reactions to Listeria monocytogenes in the brain.

Listeria monocytogenes (LM) is a common pathogen of cerebral infections. Experimental studies in mice have revealed that epithelial cells of the choroid plexus, ependymal cells, macrophages/microglia, and neurons are the target cells of LM. For the intracerebral pathogenesis of LM cell-to-cell spread via phospholipase C was particularly important. However, phospholipase C-deficient LM were not completely attenuated and, therefore, other virulence factors may also contribute to the intracerebral spread of LM. In general, all mice suffering from cerebral listeriosis rapidly succumbed to the disease. Active systemic immunization prior to intracerebral infection reduced the mortality rate to 40%. The favorable prognosis of immunized mice correlated with a reduced intracerebral bacterial load, an increased recruitment of protective CD4+ and CD8+ T cells as well as an upregulated mRNA production of protective cytokines.

Animals↗
PubMed1999

The effect of magnitude and frequency of interfragmentary strain on the tissue response to distraction osteogenesis.

PURPOSE: Bone regeneration is believed to be partially controlled by the applied local mechanical strain. To test whether the magnitude or frequency of discontinuous traction regulates the tissue response, defined daily strains were applied on mandibular osteotomies using an implanted mechanical distractor. MATERIALS AND METHODS: Unilateral mandibular osteotomies were performed in skeletally immature rabbits (n = 36). and distraction was done by applying 2,000, 20,000, 200,000, or 300,000 microstrains once or 10 times (2,000, 20,000 microstrains) per day, respectively. Sham-operated animals (n = 6), serving as controls, underwent frame application and osteotomy without distraction. At the end of the distraction process, the newly formed tissue was evaluated histomorphometrically by the use of a well-defined scoring system of bone-forming indices. RESULTS: The highest bone-forming indices were detected in the osteotomized, nondistracted group and in samples exposed to a physiologic strain (2,000 microstrains). Application of hyperphysiologic strains (200,000 and 300,000 microstrains) resulted in the formation of fibrous tissue and decreased bone-forming indices. Using Kruskal-Wallis tests, a statistically significant relationship was found between the bone-forming indices and the applied strain magnitudes. Scanning and transmission electron microscopic examinations showed osteoblastic differentiation and early mineral deposition in samples distracted up to 20,000 microstrains, whereas higher strain magnitudes led to the formation of fibroblast-like cells surrounded by collagen fibrils and only slight mineralization. Multiple strain applications (10 cycles/d vs 1 cycle/d) did not alter the histomorphometric indices or ultrastructural morphology significantly but increased the amount of newly formed tissue. CONCLUSIONS: These results suggest that the magnitude and not the frequency of mechanical loading controls the differentiation of bone cells and the subsequent formation of bone tissue.

Analysis of Variance↗
PubMed1999

Titrimetric determination of Cremophor EL in aqueous solutions and biofluids: part 2: ruggedness of the method with respect to biofluids.

A titration method for Cremophor EL, as a multicomponent mixture commonly used as non-ionic emulgent for manufacturing certain parenteralia, was developed for quantitative routine analysis in biofluids. A coated wire electrode is used as the end-point indicator in potentiometric titrations of Cremophor EL with sodium tetraphenylborate. The method tolerates a broad pH range, addition of alkanols and components of drug formulations and is sufficiently rugged. Reliable results are obtained at 20 degrees C. Disturbing ions from biofluid matrices can be masked or complexed by addition of formaldehyde, ethylenediaminetetraacetic acid and sodium fluoride. Sodium hydroxide is used for the required adjustment of the samples to pH 10. Cremophor EL spiked urine samples can be determined directly, whereas the true value of the emulgent content in the case of Cremophor EL spiked plasma samples is achieved by means of a conventional method.

Alcohols↗
PubMed1999

Decreased neuroendocrine responses to meta-chlorophenylpiperazine (m-CPP) but normal responses to ipsapirone in marathon runners.

Several clinical studies suggest antidepressive and anxiolytic effects of regular aerobic exercise. To study the effects of exercise on central serotonergic receptor sensitivity, we performed neuroendocrine challenges using oral doses of meta-chlorophenylpiperazine (m-CPP, 0.4 mg/kg), ipsapirone (0.3 mg/kg) and placebo in 12 marathon runners and 12 healthy controls not practicing regular exercise. After administration of the nonselective serotonergic agonist m-CPP, which exerts a number of well-reproducible effects mainly by means of its action on 5-HT2C receptors, marathon runners showed a significantly reduced cortisol response in comparison to the control group. There was also a statistical trend toward a blunted prolactin response after m-CPP in the athlete group. In contrast, the increase of cortisol and the hypothermia observed after administration of the 5-HT1A agonist ipsapirone were of the same magnitude in both groups. The behavioral response to m-CPP or ipsapirone and the mean maximal increases of plasma adrenaline and noradrenaline did not differ between the marathon and the control group. In conclusion, exercise-induced downregulation of 5-HT2C receptors could play an important role in mediating the anxiolytic and antidepressive effects of exercise.

Adult↗
PubMed1999

Calcification tendency of various biological aortic valves in an experimental animal model.

The present study aimed at investigating the influence of fixation methods on the ultrastructure and calcium content of five different aortic biovalves. Biovalves subcutaneously implanted in Wistar rats for 12 weeks demonstrated significant differences in their calcium contents. Using Scheffe tests, two different groups of biovalves could be distinguished: (i) valves with high calcium content, such as Toronto-SPV (165 +/- 42 mg/g dry tissue) and Intact (193 +/- 36 mg/g dry tissue), and (ii) valves with low calcium content, such as Mosaic (2.7 +/- 1.8 mg/g dry tissue), Freestyle (2.3 +/- 1.1 mg/g dry tissue) and Hancock-II (3.6 +/- 1.2 mg/g dry tissue) (P < 0.05). All biovalves with an ultrastructurally preserved endothelium exhibited a low calcification tendency. The data suggest that if the endothelium is lost as a result of the fixation procedure, then calcification can only be prevented by appropriate anticalcification methods.

Animals↗
PubMed1999

Decreased expression of osteocalcin and osteonectin in relation to high strains and decreased mineralization in mandibular distraction osteogenesis.

In a rabbit model of mandibular distraction osteogenesis, high strains resulted in a substantial reduction in the expression rate of the two osteogenic marker proteins, osteocalcin and osteonectin. In non-distracted samples and mandibles exposed to 2000 microstrains, staining for osteocalcin in the osteotomized area was detected in osteoblasts and diffusely dispersed in the mineralized matrix of the surrounding bone. However, in osteotomized mandibles distracted at strains above physiological levels (200,000 and 300,000 mustrains, respectively) the majority of osteoblast-like cells failed to express immunodetectable amounts of osteocalcin. Similarly, in the extracellular matrix of the distraction area the expression of osteonectin decreased by applying higher strains. Ultrastructural analyses of mandibular samples exposed to hyperphysiological strains revealed that the reduced expression rate of osteocalcin and osteonectin was paralleled by a significant loss of crystal formation, suggesting a functional role of both proteins related to mechanical loading.

Animals↗