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Biomedical subjects

H Wagner

Publications and source records attributed to H Wagner.

At least 271 records · Page 15Linked to original sources
PubMed1995

Chemotherapy of advanced inoperable non-small cell lung cancer with paclitaxel: a phase II trial.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has demonstrated significant antineoplastic activity against different tumor types, notably ovarian and breast carcinoma. Two phase II trials of 24-hour paclitaxel infusions in chemotherapy-naive patients with stage IIIB or IV non-small cell lung cancer (NSCLC) reported response rates of 21% and 24%. Leukopenia was dose limiting: as many as 62.5% of patients experienced grade 4 leukopenia. We investigated the efficacy and toxicity of a 3-hour paclitaxel infusion in a phase II trial in patients with inoperable stage IIIB or IV NSCLC. The 58 patients treated (41 men and 17 women) had a median age of 59 years (age range, 25 to 75) and a performance status of 0 through 2. Most patients (72.4%) had stage IV NSCLC. Paclitaxel 225 mg/m2 was infused over 3 hours every 3 weeks with standard prophylactic premedication. Of 50 patients evaluable for response, 12 (24%) had partial remission, 26 (52%) had no change, and 12 had disease progression (24%). Hematologic toxicities were mild: only one patient (2%) developed grade 3 or 4 neutropenia, while 29% had grade 1 or 2. Grade 1 or 2 polyneuropathy affected 56% of patients while only one (2%) experienced severe polyneuropathy. Similarly, grade 1 or 2 myalgia/arthralgia was observed in 63.2% of patients, but only 14.3% experienced grade 3 or 4. Nausea and vomiting were infrequent, with 14% of patients experiencing grade 1 or 2 and only 2% experiencing grade 3 or 4. Paclitaxel is thus an active single agent in this patient population, with a 3-hour infusion proving comparably effective to a 24-hour infusion and superior in terms of the incidence of hematologic and nonhematologic toxicity. Further phase II studies with paclitaxel combined with other drugs active against NSCLC are indicated, and phase III studies comparing paclitaxel with standard chemotherapy remain to be completed.

Adenocarcinoma↗
PubMed1995

The integration of natural healing procedures into research and teaching at German universities.

This article describes the activities of the "Münchener Modell," a project for "Integration of Natural Healing Procedures into Research and Teaching" at the Ludwig-Maximilian University in Munich. Its objective is to improve research and teaching of Natural Healing Procedures (NHPs) and to provide the infrastructural and conceptual prerequisites for the establishment of an independent academic institution. In the years 1989 to 1992 the project organized three 1-year pregraduate courses of NHPs for medical students. Parts of the courses have now been integrated in the regular undergraduate education. In 1993 a quality assurance project for postgraduate education was piloted. In a network of clinics using NHPs a comprehensive quality assurance project including observational studies and controlled clinical trials has been implemented and piloted. For evaluating the actual state of knowledge in a transparent way the project performs systematic reviews of published research. Further clinical-experimental research is being done in the area of immunomodulation with natural products.

Complementary Therapies↗
PubMed1994

Application of capillary and free-flow zone electrophoresis and isotachophoresis to the analysis and preparation of the synthetic tetrapeptide fragment of growth hormone-releasing peptide.

The use of high-performance electromigration separation methods, capillary zone electrophoresis (CZE) and capillary isotachophoresis (CITP) and continuous free-flow arrangements of these two separation principles, free-flow zone electrophoresis (FFZE) and free-flow isotachophoresis (FFITP), was investigated in the analysis and purification of the synthetic C-terminal tetrapeptide fragment (H2N-Ala-Trp-D-Phe-Lys.NH2) of the growth hormone-releasing peptide. CZE and CITP were used for microanalysis of peptide preparations after different steps of their purification. The homogeneity of the peptide preparations, including fractions of preparative separations, was quantified by relative zone length (CITP) and/or relative peak height (CZE). In addition, the data obtained by CZE and CITP (electrophoretic and electroosmotic flow migration velocities) were utilized for conversion of micro-scale capillary separations (nano- to picomole level) into the preparative separations realized by FFZE and FFITP with a capacity from tens to hundreds of milligrams per hour.

Amino Acid Sequence↗
PubMed1994

Exogenous superantigens acutely trigger distinct levels of peripheral T cell tolerance/immunosuppression: dose-response relationship.

Ligand-specific immunosuppression requires an understanding of the parameters that control peripheral T cell tolerance. T cell receptor (TcR) transgenic mice offer a clear advantage for studying post-thymic tolerance mechanisms in vivo that are operational in a monoclonal T cell population with preselected antigen specificity. Yet it is unclear whether the rules defined in monoclonal T cells of genetically manipulated mice reflect those operative in clonally diverse peripheral T cells of normal mice. To analyze acute tolerance mechanisms in unselected peripheral T cells, we challenged normal mice with the superantigen staphylococcal enterotoxin B (SEB) and analyzed ligand-reactive V beta 8+ T cells for TcR-triggered tolerance mechanisms such as anergy, TcR down-regulation, or apoptosis. Upon challenge with graded doses of SEB (0.001-10 micrograms) V beta 8+ T cells become anergic within 6-16 h. Importantly, a dosage effect of SEB in regard to the level of anergy induced was observed. Anergy induced by low concentrations of SEB (0.001-0.1 microgram) is transient and is overcome by clonal growth, while higher concentrations of SEB (0.1-10 micrograms) cause long-lasting anergy resistant to cell cycle progression. At high SEB concentrations (1-10 mg) about 50% of the anergic V beta 8+ T cells additionally down-regulate their TcR-CD3 complex, followed by a loss of CD2, CD4, CD8 accessory molecules. In parallel, T cell phenotype-negative but genotypically V beta 8+ T cells are generated. The T cell phenotype-negative cells reacquire their V beta 8+ T cell phenotype upon culture in vitro. In vivo, a subset of V beta 8+ cells, defined by an intermediate stage of TcR down-regulation, i.e. V beta 8lowCD3+ cells, but not T cell phenotype-negative cells are selectively programmed for apoptosis, which occurs within 1 h. These data suggest that SEB triggers distinct tolerance pathways which operate in a hierarchical fashion in clonally diverse ligand-reactive T cells. Specifically, the results illustrate the power of exogenous superantigens to exploit these distinct tolerance pathways, thereby achieving distinct levels of immunosuppression.

Animals↗
PubMed1994

Characterization and toxicological behavior of synthetic amorphous hydrophobic silica.

During almost three decades of experience with hydrophobic silicas, no adverse health effects have been observed in manufacturing and applications with appropriate handling of the materials. The oral LD50 for rodents is > 7.9 g/kg body wt. Fumed or precipitated hydrophobic silicas do not produce inflammation of the skin or mucous membranes. Likewise, acute and chronic oral tests yielded no adverse systemic effects. A limited carcinogenesis study in rats did not induce tumors and the Ames test of a toluene extract was negative. Reproductive or developmental toxicity was not observed. In general, hydrophobic silicas provide a toxicological profile essentially the same as common silicas.

Animals↗
PubMed1994

The immunodominant peptide from listeriolysin in Quil A liposomes vaccinates CD8+ cytolytic T cells and confers protection to infection.

Cytolytic T-cell vaccination with immunodominant MHC class I-restricted peptides contained within Quil A liposomes has been previously demonstrated. In recent years, Quil A has been under consideration for use as an adjuvant in humans. We assessed the possible use of peptide inoculation in the context of Quil A liposomes to be protective in a mouse model. Listeria monocytogenes was used as the challenge pathogen and the previously identified listeriolysin 91-99 peptide as the immunogen. The listeriolysin 91-99 Quil A liposome inoculum showed significant enhancement of survival after challenge with up to 10 times the L. monocytogenes LD50.

Adjuvants, Immunologic↗
PubMed1994

Vaccination with immunodominant peptides encapsulated in Quil A-containing liposomes induces peptide-specific primary CD8+ cytotoxic T cells.

Immunostimulating complexes (ISCOMs), containing lipids, the saponin Quil A, and proteinaceous antigens, have been proven to vaccinate effectively CD8+ cytolytic T cells in vivo. However, conventional ISCOM technology is restricted to hydrophobic proteins or fatty acid-derivatized proteins or peptides. We therefore analysed whether Quil A-containing liposomes are an effective vehicle to shuttle hydrophilic proteins or peptides into the MHC class I pathway of antigen presentation resulting in the in vivo induction of antigen-specific cytolytic T cells (CTL). Liposomes were formed by a lipid dry-down method followed by resuspension with an aqueous solution containing protein/peptide and Quil A and then an extrusion step. Quil A-containing liposomes are an effective means to elicit a CD8+ CTL response to peptide antigen in vivo. CTL could be raised in C57B1/6 mice against ovalbumin (OVA) peptide 257-264 and vesicular stomatitis virus nucleoprotein 52-59, as well as in Balb/c mice against listeriolysin peptide 91-99 and cytomegalovirus pp89 168-176, demonstrating the versatility of this approach. The elicited response was peptide-specific, peptide dose-dependent and Quil A was necessary. Vaccination with liposomes entrapping the whole ovalbumin molecule or an extended (OVA) peptide 254-276 also yielded a CTL responsive to the immunodominant OVA peptide 256-264, implying cellular internalization and correct processing. Thus Quil A-containing liposomes appear to be a versatile vehicle to vaccinate CD8+ T cells in vivo; in addition, they could rapidly enhance the understanding of subunit vaccines and rules of antigen processing and peptide-MHC class I binding.

Adjuvants, Immunologic↗
PubMed1994

Oligoclonality and skewed T cell receptor V beta gene segment expression in in vivo activated human intestinal intraepithelial T lymphocytes.

Intraepithelial intestinal T lymphocytes (IEL) bearing alpha beta or gamma delta T cell receptors (TCR) are positioned to serve as a first line of defense against enteric pathogens. To investigate whether intestinal IEL are subject to antigenic selective forces distinct from that influencing (xp T cells in the peripheral blood (PBL), we performed a comparative analysis of V beta gene segment usage in IEL and PBL of immunologically normal donors by quantitative PCR. Primers for 22 different human TCR V beta gene segments of V beta gene segments families were used to analyze the repertoire of TCR beta chain transcripts in colonic IEL (c-IEL), in corresponding colonic lamina propria lymphocytes (c-LPL), and in peripheral blood lymphocytes. In each of the three individuals examined, a limited number (1-4 out of 22) of TCR V beta families predominated and accounted for more than 50% of the total beta chain transcripts from c-IEL, whereas in PBL and c-LPL a more even distribution of V beta gene families was observed. The dominating V beta gene families were V beta 2, V beta 3, V beta 6, V beta 8 and V beta 14. In one individual, V beta 3 comprised more than 40% of the entire repertoire of c-IEL beta chain transcripts. Sequence analysis of the predominant V beta 3 family in this individual revealed identical sequences in 13 of 17 clones analyzed. Human alpha beta TCR+ c-IEL could not be driven to proliferate or exhibit cytotoxic function in vitro however, PCR analysis for detection of lymphokine mRNA revealed constitutive production of several lymphokines known to exert trophic effects on intestinal epithelial cells and pro-inflammatory activities. Taken together, the striking degree of oligoclonality may indicate that the intraepithelial intestinal immune system is targeted to a limited set of hitherto unknown self- or foreign antigens present in the intestine and orchestrates intramucosal inflammatory and regenerative processes.

Base Sequence↗
PubMed1994

Biologically active triterpene saponins from Bupleurum fruticosum.

Extracts of the root of B. fruticosum L. showed in a biological screening hemolytical activity, hepatoprotective and phagocytosis stimulating effects, and a specific inhibitory activity of leucine aminopeptidase. Further monitoring of the fraction with antihepatotoxic activity led to the isolation of an hepatoprotective saikosaponin identified as buddlejasaponin IV and the new malonylbuddlejasaponin IV, determined as saikogenin F-3-O-[6-O-malonyl-beta-D-glucopyranosyl-(1-->2)-beta-D-glucopyranosyl (1-->3)]-beta-D-fucopyranoside. The structures were elucidated on the basis of the chemical and spectroscopic data.

Animals↗
PubMed1994

Immunologically active polysaccharide from Cetraria islandica.

A new alkali-soluble polysaccharide has been isolated from Iceland moss, Cetraria islandica (L.) Ach., by ethanol fractionation, ion-exchange chromatography, and gel filtration. The mean M(r) was estimated to be 18,000. Sugar and methylation analysis, partial hydrolysis, and 13C-NMR spectroscopy showed the polysaccharide to be a branched galactomannan with a backbone composed of two structural elements; (1-->6)-linked alpha-D-mannopyranosyl and alpha-D-(1-->6)-galactopyranosyl units. The polysaccharide showed pronounced immunostimulating activity in an in vitro phagocytosis assay and in the in in vivo carbon clearance assay.

Carbohydrate Sequence↗
PubMed1994

[The nuclear magnetic tomographic diagnosis of focal lesions of the red bone marrow. The optimization of the acquisition parameters for GE and SE sequences].

Gradient-echo (GE) imaging with repetition times equivalent to those of T1-weighted spin-echo (SE) sequences and echo times for antiphase (opposed) transverse magnetisation have proved to be sensitive for high contrast imaging of focal lesions of red bone marrow. The sensitivity of antiphase GE sequences is due to the chemical shift between water-bound and fat-bound protons which introduces a tissue parameter that is not accessible by SE sequences. Main advantage of these GE sequences is the low signal intensity of intact red marrow and the high signal intensity of tumours and inflammatory lesions which allows, similar to T2-weighted SE sequences, for positive contrast imaging of lesions. In order to evaluate and to optimise the contrast-to-noise ratio (CNR) for red bone marrow and tumour 200 GE and 40 SE sequences with repetition times (TR) between 100 and 900 ms, echo times (TE) between 14 and 21 ms and flip angles (alpha) between 10 and 90 degrees were studied. CNR was measured and optimized regarding TR, TE, and alpha. The results indicate that opposed GE sequences, relatively independent from TR and alpha, are characterized by a high contrast-to-noise ratio. According to their high sensitivity for lesion detection they are suited to replace T2-weighted SE sequences.

Artifacts↗
PubMed1994

Serum cytokine levels in cancer patients treated with different schedules of ultra-low-dose interleukin-2.

Interleukin-2 (IL-2) induces secondary cytokines in vivo that may mediate antitumor effects as well as toxicity. The course and quantity of this in vivo reaction may depend on scheduling of IL-2 due to changes in responsiveness of the respective producer cells. This was evaluated in a phase-Ib study with ultra-low-dose IL-2 at 0.9 and 4.5 MIU/m2 administered once daily subcutaneously either once weekly (4 doses, stratum I), three times a week every other day (9 doses, stratum II), or five times a week every other week (10 doses, stratum III). Twenty-eight patients with advanced cancer were randomly assigned to the six treatment groups. Serum levels of IL-2, secondary cytokines, and soluble receptors were significantly increased after a single dose of 0.9 MIU/m2 s.c. demonstrating systemic efficacy. Baseline levels and native responsiveness were recovered after a 1-week treatment-free interval in stratum I patients with the exception of sCD8 that was still increased although readily inducible at that time. Stratum II patients exhibited a prolonged and possibly continuous elevation of all serum parameters studied. Values did not increase beyond the 2nd week of therapy and even decreased with respect to sCD8 and neopterin. A sequential mode of administration (stratum III) may obviate some of these adaptive mechanisms as evidenced from a progressive increase of neopterin and sCD8 levels after the second treatment cycle, although induction of sTNFRI was saturable under these conditions. Thus, scheduling of IL-2 profoundly affects in vivo responses as evidenced from cytokine and soluble receptor serum levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Influence of stimulus level on acoustic motion-direction sensitivity in barn owl midbrain neurons.

1. Many neurons in the owl's midbrain are able to discriminate by their responses the motion of an acoustic source in one direction, the preferred direction, from the motion of the source in the opposite direction, the null direction. This differential response can be understood by the action of an acoustic motion detector. However, the motion detector would work in an effective way only if the motion direction-sensitive responses of a cell were largely independent of stimulus level. 2. We investigated the level dependence of acoustic motion sensitivity in midbrain neurons with standard extracellular recording techniques. We used an apparent motion paradigm with sounds moving clockwise or counterclockwise in the horizontal plane or stationary sounds for stimulation from free-field speakers. In most cases we added a constant level of background noise to the stimuli having a variable level. Thus we could analyze the responses as a function of the signal-to-noise ratio. 3. Moving and stationary sounds yielded similar response thresholds and similar dynamic ranges. 4. When the background level was changed the response threshold changed accordingly, so that the response threshold always occurred at a constant signal-to-noise ratio independent of background level. 5. The preferred direction of all cells was independent of stimulus level and some 22 percent of the cells showed a directional bias of their response at threshold. In no cell was a change in the preferred direction observed when stimulus level was varied. Typically, however, the motion direction sensitivity, measured by a signed directionality index, was not maximal at threshold. However, the dynamic range, i.e., the range of stimulus levels over which motion direction sensitivity changed, was < or = 20 dB in most cases. Therefore these cells are indeed able to encode motion direction largely independently of stimulus level. 6. We discuss the data within the framework of the acoustic motion detector mentioned above and with respect to earlier reports on acoustic motion sensitivity in the owl and other animals.

Animals↗
PubMed1994

Inhibition of MAO by fractions and constituents of hypericum extract.

The inhibition of monoamine oxidase (MAO) by six fractions from hypericum extract and three characteristic constituents (as pure substances) were analyzed in vitro and ex vivo to study the antidepressive mechanism of action. Rat brain homogenates were used as the in vitro model, while the ex vivo analysis was performed after intraperitoneal application of the test substances to albino rats. Massive inhibition of MAO-A could be shown with the total extract and all fractions only at the concentration of 10(-3) mol/L. At 10(-4) mol/L, one fraction rich in flavonoides showed an inhibition of 39%, and all other fractions demonstrated less than 25% inhibition. Using pure hypericin as well as in all ex vivo experiments, no relevant inhibiting effects could be shown. From the results it can be concluded that the clinically proven antidepressive effect of hypericum extract cannot be explained in terms of MAO inhibition.

Animals↗
PubMed1994

Pharmaceutical quality of hypericum extracts.

Hypericum extracts contain at least ten constituents or groups of components that may contribute to the pharmacological effects. It is not yet possible to correlate the antidepressive mode of action with specific constituents; therefore, the pharmaceutical quality of the extracts was characterized on the basis of typical leading substances and especially the hypericins. For the analysis and improvement of the production procedure, the content of hypericin and pseudohypericin was measured experimentally. The drug material was extracted with different solvents and the yield was analyzed for each kind of solvent, its concentration and extraction temperature. Optimal yields were obtained with 80% methanol at temperatures of 80 degrees C.

Anthracenes↗
PubMed1994

Critical review and meta-analysis of serial agitated dilutions in experimental toxicology.

1. We conducted an overview and quantitative meta-analysis of all experimental literature on the protective effects of serial agitated dilutions (SADs) of toxin preparations. 2. Articles were systematically collected and evaluated for scientific quality using pre-defined methodological criteria and then independently analysed for validity. 3. We found 105 publications exploring the effects of SAD preparations in toxicological systems. 4. The quality of evidence in these studies was low with only 43% achieving one half of the maximum possible quality score and only 31% reported in a fashion that permitted reevaluation of the data. 5. Very few studies were independently replicated using comparable models. 6. Among the high quality studies, positive effects were reported 50% more often than negative effects. 7. Four of 5 outcomes meeting quality and comparability criteria for meta-analysis showed positive effects from SAD preparations. 8. Average percent protection over controls in these preparations was 19.7 (95%Cl 6.2-33.2). 9. Further research with special attention to methodological detail and independent replication should be done.

Animals↗