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K Friedrich

Publications and source records attributed to K Friedrich.

At least 55 records · Page 3Linked to original sources
PubMed1996

Biological activity of IL-4 and IL-13 on human endothelial cells: functional evidence that both cytokines act through the same receptor.

The cytokine IL-4 has unique effects on human endothelial cells. It specifically increases expression of vascular cell adhesion molecule (VCAM)-1 promoting adhesion of lymphocytes but not neutrophils, and causes profound effects on the morphology of endothelial monolayers characterized by formation of cell clusters and the appearance of holes in the cultured monolayer. In this study we show that the effects of IL-13 on human umbilical vein endothelial cells (HUVEC) are indistinguishable from those of IL-4. Both cytokines induce the same morphological changes in cultured HUVEC monolayers which are distinct from any other cytokine. In addition, IL-13 and IL-4 stimulate comparable levels of VCAM-1 expression with similar time kinetics, but at doses 10-fold less than those required for B cell activation and proliferation. Using a combination of mutant IL-4 antagonists and mAb to the IL-4R alpha chain (CD124), we show that expression of IL-4R alpha is essential for HUVEC responses to both IL-4 and IL-13, consistent with this receptor subunit being a component of the receptors for both cytokines. In contrast, the common gamma chain (gamma c), which is a component of the classical IL-4 receptor, was not detected on endothelial cells by flow cytometry or immunogold histochemistry. In addition, RT-PCR showed extremely low or absent gamma c mRNA, consistent with the absence of detectable surface protein. These results strongly suggest that the cytokines IL-4 and IL-13 are both important in modulating endothelial cell function, and may act through a single receptor complex on human endothelial cells that includes the IL-4R alpha chain but not the gamma c chain.

Antibodies, Monoclonal↗
PubMed1996

3D electron dose calculation using a Voxel based Monte Carlo algorithm (VMC).

A new model for calculating electron beam dose has been developed. The algorithm is based on a two- or three-dimensional geometry defined by computerized tomography (CT) images. The Monte Carlo technique was used to solve the electron transport equation. However, in contrast to conventional Monte Carlo models (EGS4) several approximations and simplifications in the description of elementary electron processes were introduced reducing in this manner the computational time by a factor of about 35 without significant loss in accuracy. The Monte Carlo computer program does not need any precalculated data. The random access memory required is about 16 Mbytes for a 128(2) X 50 matrix, depending on the resolution of the CT cube. The Voxel Monte Carlo model (VMC) was tested in comparison to calculations by EGS4 and the "Hogstrom algorithm" (MDAH) using several fictive phantoms. In all cases a good coincidence has been found between EGS4 and VMC, especially near tissue inhomogeneities, whereas the MDAH algorithm has produced dose underestimations of up to 40%.

Algorithms↗
PubMed1996

Residential relocation and regional redistribution of the elderly in the USA and Germany.

"This paper reviews some of the principal differences and similarities in the migration and spatial redistribution behavior of the older populations of the USA and of Germany.... The paper is divided into three distinct parts. The paper first reviews actual and prospective redistribution of the older population, with regard to interregional shifts of population as well as to changes in concentration along an urban-rural continuum. Following these macroscopic elements, the paper then moves to a presentation of the results of two ex post facto surveys (one taken in the USA and the other in Germany) of recent older movers in order to compare the motivations expressed for the move and the present degree of satisfaction with it. The concluding section considers the implications of redistribution at both geographic levels and of mover satisfaction in light of political developments as they are presently unfolding in Europe."

Adult↗
PubMed1995

Different human interleukin-4 mutants preferentially activate human or murine common receptor gamma chain.

Interleukin-4 (IL-4) shows species-specific activity due to species-restricted interaction with the IL-4 receptor alpha (IL-4R alpha) chain. The second subunit of a functional IL-4 receptor, the common gamma chain (gamma c), is more promiscuous, since human IL-4 is able to activate IL-4 receptor complexes containing either human or murine common gamma receptor chain (gamma c). We have stably transfected factor-dependent mouse cells of myeloid and lymphoid origin with combinations of human IL-4R alpha and gamma c derivatives. In these cell lines, both human and murine gamma c receptors as well as IL-4R alpha chains from both species are simultaneously expressed. Both versions of gamma c readily form ternary complexes with either human IL-4 and human IL-4R alpha or murine IL-4 and murine IL-4R alpha. Due to distinct ligand-binding properties of human and murine gamma c, the two receptor complexes can be activated preferentially by different mutant variants of human IL-4. The contribution of murine common gamma chain to human IL-4-induced signal transduction is suppressed by an inhibitory antibody directed to the extracellular domain of the mouse gamma c. We present evidence that the two IL-4R complexes functionally interfere with each other and compete for response-limiting signalling components.

Animals↗
PubMed1995

Species-specific agonist/antagonist activities of human interleukin-4 variants suggest distinct ligand binding properties of human and murine common receptor gamma chain.

Interleukin-4 (IL-4) is a pleiotropic cytokine eliciting various responses in target cells upon binding to its receptor. Activation of the IL-4 receptor probably involves interaction of the ligand with both the IL-4 receptor alpha subunit (IL-4R alpha) and the common gamma chain (c gamma). Although human and murine IL-4 receptor alpha chains are specific for IL-4 from the same species, murine c gamma can form a signal-competent complex with human IL-4R alpha (hIL-4R alpha) and human IL-4 (hIL-4). We have generated a hIL-4 responsive murine myeloid cell line (FDC-4G) expressing a chimera comprising the extracellular domain of human IL-4R alpha and the intracellular domain of human granulocyte colony-stimulating factor receptor (hG-CSFR). This hybrid receptor was shown to form a complex with hIL-4 and the murine c gamma-chain. Biological activities of human IL-4 variants on murine FDC-4G cells and on the human erythroleukemic cell line TF-1 displayed a strikingly different pattern. Single amino acid replacements at two different positions in the C-terminal helix of hIL-4, the region of the previously defined "signaling site," lead to an inverse agonist/antagonist behavior of the resulting cytokines in the two cellular systems. From these findings we conclude that upon formation of the activated IL-4 receptor complex murine and human c gamma interact with hIL-4 in a geometrically different fashion.

Amino Acid Sequence↗
PubMed1995

Expression of p53 and bcl-2 in correlation to clinicopathological parameters, hormone receptor status and DNA ploidy in breast cancers.

The expression of p53 and bcl-2 was immunohistochemically investigated in 61 formalin-fixed, paraffin-embedded invasive breast carcinomas. The study was aimed to elucidate the relationship between both markers and the correlation of p53 and bcl-2, respectively, to clinicopathological variables, to hormone receptor status and to DNA-ploidy. Twenty tumors showed a positive reaction with the monoclonal antibody DO-1 against p53 protein. Its immunohistochemical demonstration was significantly correlated with a tumor size larger than 2 cm, a low estrogen receptor status and DNA-aneuploidy. Bcl-2 was demonstrated in 51 breast cancers. Bcl-2 was preferably seen in low grade and hormone receptor positive tumors. We found a negative correlation between the immunoreactive scores of p53 and bcl-2, but in 17 carcinomas a coexpression of both proteins was seen. Cases with this coexpression did not differ significantly from the other tumors in clinicopathological parameters. In eight of these cases more than 10% of the cells were found to be positive for both markers. In four cases we could show many cells to exhibit both markers as it was assessed by an immunofluorescence double labeling technique.

Breast Neoplasms↗
PubMed1995

A potent human interleukin-4 antagonist stimulates the proliferation of murine cells expressing the human interleukin-4 binding chain.

A single-amino-acid substitution mutant form of human interleukin-4 (hIL-4), Y124D.hIL-4, has been described previously as an antagonist of the effects of hIL-4 on various human cells. The murine T-cell leukemic cell line CT.h4S, which expresses the human IL-4 receptor, proliferates in response to both hIL-4 and murine IL-4. Although Y124D.hIL-4 antagonizes the proliferative effects of hIL-4 on human phytohaemagglutinin-stimulated peripheral blood mononuclear cells, Y124D.hIL-4 is a potent stimulator for CT.h4S cells. Molecular modelling studies were performed to investigate the stability of different conformations of residue 124 as well as the efficiency of different molecular mechanics force fields in homology modelling. We suggest that the aspartate substitution alters the C-terminal end of the D-helix in such way that the analogue still binds to the human IL-4 receptor alpha-chain and signals through the murine gamma c-chain. In contrast, the Y124D.hIL-4/IL-4 receptor complex cannot signal through the human gamma c-chain.

Amino Acid Sequence↗
PubMed1995

East German uranium miners (Wismut)--exposure conditions and health consequences.

Underground uranium mining was performed in East Germany after World War II on a large scale. East Germany was the main supplier of uranium for the Soviet Union. This review gives a historical summary and describes the broad spectrum of exposure to potential health hazards and the health consequences. Working conditions were very poor during the postwar years from approximately 1946-1955: there was drilling with air floating and a lack of forced ventilation. Dust levels were very high and there was a significant inhalative incorporation of alpha-radiating substances, mostly from short-lived radon progeny. However, long-lived alpha-radiating substances such as uranium-238 contributed considerably to the radiation dose. There was also exposure to toxic chemicals, such as arsenic (in some mines) or crystalline silica, and a variety of other health hazards. From approximately 1956-1970, mining conditions improved: there was drilling with the addition of water and forced ventilation of the mines. As of approximately 1970, compliance with rules of industrial hygiene and international standards of radiation protection was evident. In 1990, uranium production was generally stopped. To date, more than 5,000 cases of bronchial carcinoma are accepted as compensable occupational diseases and more are expected. The extensive data from Wismut uranium mining could improve our understanding of a complex exposure situation resulting in a variety of health impairments other than lung cancer.

Germany↗
PubMed1995

[The initial results on the radiobiological comparability of continuous LDR irradiation and PDR irradiation using a guinea pig skin animal model].

AIMS: The classic continuous low dose rate (LDR) brachytherapy was very important in such cases with a higher risk of severe especially late radiation reactions. From clinical experiences and radiobiological considerations it is known, that the therapeutic ratio of LDR is higher than HDR. Another way to combine the therapeutic ratio of LDR and the possibility of optimisation is the use of pulse dose rate (PDR) technique. The PDR-technique is a method, which can be compared with continuous LDR-therapy. PDR should have biological effects equivalent to conventional LDR. MATERIAL AND METHODS: We have tried to compare the classic continuous LDR-technique with 2 PDR-regimes by means of the guinea pig skin model. In this test series we involved 20 female animals with an initial weight of 400 to 500 g. We compared radiation reactions of following regimes: 1. Continuous LDR regimen with a cobalt-60 source with an activity of 5.5 mCi 30 Gy in 60 hours. 2. PDR regimen 0.5 Gy hourly, pulse length minimal 10 minutes, 30 Gy in 60 hours with an Ir-192 source with an activity of nearly 40 mCi. 3. PDR-regimen 0.8 Gy hourly with 9 hours night break (10.00 p. m. to 7.00 a. m.). The radiation reaction was controlled by the help of an evaluation table in which the criteria of radiation reaction were classified according to the degree of seriousness. The observation time is now minimal 14 and maximal 24 months. RESULTS: The findings shows a significant coincidence of early and late radiation reactions of the skin fields irradiated with the continuous LDR-technique and fields irradiated with the PDR-technique. There was not a difference of the radiation reactions between PDR-irradiation with and without night break. CONCLUSIONS: Generally it is possible to compare the radiation reactions of PDR-irradiation and the classic continuous LDR-brachytherapy. It is also possible to use a PDR-regimen with a night break of 9 hours. But results must be calculated for each tissue of interest, in our test consequently for guinea pig skin.

Animals↗
PubMed1995

Heterogeneity of the chromatin fine structure in DNA-diploid breast cancer cells.

The chromatin fine structure of Feulgen-stained DNA-diploid tumour cells was studied by means of image cytometry in fine-needle aspiration biopsies of 115 breast cancer patients. The investigation was focused on diploid, several subtypes of polyploid, and aneuploid tumours. Only the clearly separable diploid peaks of these tumours were measured cytometrically by an OPTIMAS-based image analysis system, which led to a set of 93 primary cytometric features in each diploid subpopulation. The results demonstrate that the diploid tumours are clearly different to the diploid compartments of various subtypes of polyploid and aneuploid tumours. Between those diploid subpopulations from polyploid tumours, chromatin structure differences also exist. A higher degree of similarity between polyploid and aneuploid tumours, compared to diploid, became evident. The actual structural differences between the diploid subpopulations indicate both increasing variances within the peak and increasingly coarse and contrasted, irregular chromatin structure with the occurrence of tetraploid, octoploid, and aneuploid DNA-histogram peaks. Therefore, the structural effects of an increasing genomic instability seems not to be restricted to the non-diploid cell populations.

Adenocarcinoma↗
PubMed1994

[Demonstration and possible prognostic value of the nucleolar organizer region (NOR), the microtubule-associated proteins 1A/1B (MAP) and the intermediate filaments vimentin and cytokeratin 19 in invasive ductal breast carcinoma].

We examined the expression of the nucleolar organizer region, the microtubule-associated protein and the intermediate filaments vimentin and cytokeratin 19 and their possible value for prognosis in 51 infiltrating ductal breast carcinomas. We registered the highest NOR counts in pT2/3-tumors, in poorly differentiated breast carcinomas, in tumors with a strong MAP- and vimentin expression (this holds true for vimentin only in pT2/3-tumors). There was a relationship between areas of NOR and the differentiation degree on the one hand and the MAP- and vimentin expression on the other hand. The area of nucleolus increased with the decrease of differentiation and with the increase of vimentin expression, respectively. The expression of cytokeratin 19 showed no homogeneous relations to the traditional prognostic factors as well as to the parameters of the NOR. The area of nucleus had no prognostic value in our study. The value of the NOR is limited by its high variation. The NORs are suitable only as an adjuvant factor for the prognosis. Further studies into MAP and vimentin and their role in the prognosis of infiltrating ductal breast carcinomas appear to be important.

Age Factors↗
PubMed1994

Characterization of wear in composite material orthopaedic implants. Part II: The implant/bone interface.

Carbon fiber/PEEK polymer (C/PEEK) composite materials are being developed for use as orthopaedic implant materials. Wear is an issue of increasing importance in orthopaedic implants; particulate debris generated by the wearing of biomaterials may be a causal factor leading to osteolysis and implant loosening. Therefore, numerical and experimental studies were completed to characterize the wear of C/PEEK composite materials in comparison to current orthopaedic implant materials. Finite element analyses (FEA) of a composite material hip stem implanted in a femur and loaded at 890 N determined that peak contact stresses will occur at the proximal-medial and distal regions of the implant. These contact stresses were found to be below 1.0 MPa over most of the implant surface; however the peak stress in the proximal-medial region was 1.8 MPa and higher still at the distal portion of the stem. In vivo forces result in contact stress values up to 9.0 MPa. The composite implant exhibited 10-40% lower contact stresses in the distal region compared to a titanium-alloy implant of identical design. Composite material wear samples were slid against porous hydroxylapatite (HA) to simulate the stem/bone interface. An identical series of experiments was run for comparison to a current orthopaedic implant material--Ti6A14V titanium alloy. Two domains of motion were studied; a composite ring-on-HA disc large amplitude sliding wear test; and a composite pin-on-HA disc small amplitude fretting regimen. Nominal contact pressures during testing were 1.4 MPa and 7.6 MPa for sliding and fretting tests, respectively. Fretting and sliding abrasive wear tests resulted in the composite material exhibiting a lower wear rate than the titanium-alloy. The magnitude of the difference was greatly dependent on the contact pressures, sliding amplitudes, and counterface material properties.

Alloys↗
PubMed1993

A light stabilizer (Tinuvin 770) that elutes from polypropylene plastic tubes is a potent L-type Ca(2+)-channel blocker.

A pharmacologically active agent was easily extracted by aqueous or organic solvents from laboratory plastic tubes (Falcon Blue Max) and has been chemically identified as bis(2,2,6,6-tetramethyl-4-piperidyl) sebacate. This compound (approximately 12 micrograms per tube approximately 25 nmol) blocked 1,4-dihydropyridine-sensitive 45Ca2+ uptake into GH3 cells with an IC50 value of 3.6 microM, inhibited Sr2+ currents through L-type Ca2+ channels in A7r5 smooth-muscle cells in whole-cell patch-clamp experiments after extracellular application, and affected the high-affinity binding of Ca2+ entry-blocker ligands to a variety of preparations. Bis(2,2,6,6-tetramethyl-4-piperidyl) sebacate is a highly potent (IC50 values < 10 nM) inhibitor at the phenylalkylamine- and benzothiazepine-selective drug-binding domains of the alpha 1 subunit of L-type Ca2+ channels. This compound behaves as a heterotropic allosteric regulator for the 1,4-dihydropyridine-selective domain in purified Ca(2+)-channel preparations from rabbit skeletal muscle. (+)-Tetrandrine stimulation of 1,4-dihydropyridine binding to the membrane-bound L-type Ca2+ channel is inhibited by the compound in a competitive manner (Ki value = 6.8 nM). Bis(2,2,6,6-tetramethyl-4-piperidyl) sebacate is therefore classified as the prototype of another class of L-type Ca(2+)-channel blockers that binds to the alpha 1 subunit at the drug-binding domains selective for (+)-tetrandrine or (+)-cis-diltiazem. This compound is identical to Tinuvin 770, which is used worldwide as a light stabilizer for polyolefins.

Alkaloids↗
PubMed1993

High-yield production of bacteriorhodopsin via expression of a synthetic gene in Escherichia coli.

A gene (bos) coding for bacterioopsin (BO), the apoprotein of bacteriorhodopsin was assembled from chemically synthesized oligonucleotides by a new method of repeated rounds of insertion mutagenesis. The gene sequence was designed for convenient manipulation in future protein engineering experiments. In-frame fusion of bos to the lacZ454 gene allowed high-yield production in Escherichia coli of a beta-Gal454/BO fusion protein, deposited as intracellular inclusion bodies. These were enriched by virtue of their insolubility in 0.5% Triton X-100 and cleaved in aqueous suspension with IgA protease at a specific site provided at the beta-Gal454/BO boundary. Pure BO could be obtained from the mixture of water-insoluble cleavage products by selective extraction into organic solvent. The yield was in the range 30-50 mg pure protein/l culture medium, depending on individual preparation. This material could be used for reconstitution of fully functional bacteriorhodopsin. Taken together, the procedure constitutes a practical basis for the production of genetically engineered bacteriorhodopsins.

Amino Acid Sequence↗
PubMed1993

Properties of bacteriorhodopsin derivatives constructed by insertion of an exogenous epitope into extra-membrane loops.

Bacteriorhodopsin (BR) is folded into a bundle of seven alpha-helices which is embedded in the cellular membrane of Halobacterium salinarium; these helices are connected by short extra-membrane loops, three on the cytoplasmic side and three on the outside. Oligonucleotide-directed insertion or replacement mutagenesis was used to integrate the C-terminal sequence (13 amino acids long) of Sendai virus L-protein individually into each of the six helix-connecting loops. The altered gene products were obtained by expression of the mutant genes in either Escherichia coli or Schizosaccharomyces pombe and were used to reconstitute BR in proteoliposomes. In four cases (altered loops B/C, C/D, D/E or E/F), the mutant BRs were found to be fully functional as judged by light-driven proton pumping and photocycle kinetics. Within the four functional BR variants, recognition of the viral epitope by a monoclonal antibody is restricted to modified loops B/C and E/F. Immunogold staining of S.pombe cells producing either of the two latter BR variants shows that the protein is distributed among various cellular membranes but is not present in mitochondrial membranes. Sequence alteration of loop A/B or F/G resulted in loss of function, most plausibly due to a folding defect of the respective proteins. These results on the one hand document differences in structural importance of the various BR extra-membrane loops and on the other hand open the door to the construction of multifunctional membrane proteins via loop replacement mutagenesis of BR.

Amino Acid Sequence↗
PubMed1992

In vivo labeling of L-type Ca2+ channels by fluorescent dihydropyridines: evidence for a functional, extracellular heparin-binding site.

We have synthesized and characterized fluorescently labeled dihydropyridines (DHPs) as probes for L-type Ca2+ channels. Racemic as well as (+)- and (-)-1,4-dihydro- 2,6-dimethyl-4-(2-trifluoromethylphenyl)-3,5-pyridinecarboxylic acid 2-(aminoethyl)ethyl ester hydrochlorides were coupled to boron dipyrromethane (Bodipy) derivatives. (4,4-Difluoro-5,7-dimethyl-4-bora-3a,4a-diaza)-3- (s-indacene)propionic acid (DMBodipy)-DHP and (4,4-difluoro-7-styryl-4-bora-3a,4a-diaza)-3-(s-indacene+ ++)propionic acid (STBodipy)-DHP have Kd values in the nanomolar range for membrane-bound or partially purified skeletal muscle and for neuronal L-type Ca2+ channels. (-)- and (+)-STBodipy-DHPs block 45Ca2+ uptake through L-type Ca2+ channels into GH3 cells with IC50 values of 14.8 and 562 nM, respectively. The measurement of bound fluorescence after removal of free DMBodipy-DHP with charcoal shows that the probes can substitute for radioactive ligands to study the properties (equilibrium binding, kinetics, allosteric regulation) of partially purified L-type Ca2+ channels from skeletal muscle. L-type Ca2+ channels on GH3 cells were steroselectively visualized by using the optical enantiomers of STBodipy-DHP. Heparin inhibited GH3 cell labeling by (-)-STBodipy-DHP with an IC50 value of 9.7 micrograms/ml and blocked L-type Ca(2+)-channel-mediated 45Ca2+ uptake with an IC50 value of 32 micrograms/ml. These findings argue for an extracellular orientation of the heparin-binding domain of the Ca2+ channel that is coupled to the DHP receptor.

Animals↗
PubMed1991

Calcium channels from Cyprinus carpio skeletal muscle.

The complete amino acid sequence of the L-type calcium channel alpha 1 subunit from the carp (Cyprinus carpio) white skeletal muscle was deduced by cDNA cloning and sequence analysis. The open reading frame encodes 1852 amino acids (Mr 210,060). A 155-amino acid COOH-terminal sequence (after the fourth internal repeat) is evolutionarily preserved (90% homology) and may represent an important functional domain of L-type calcium channels. The photolabeled, membrane-bound, and purified carp alpha 1 subunits have masses of 211 and 190 kDa. The purified channel could not be phosphorylated by cAMP-dependent protein kinase. Two glycoproteins (alpha 2 subunits) are associated with the alpha 1 subunit and change their apparent masses from 235 and 220 kDa to 159 kDa upon reduction of disulfide bonds. Nucleic acid hybridization with alpha 2 cDNA revealed an 8.0-kilobase transcript in carp skeletal muscle. Evidence for a copurification of subunits similar in size to mammalian beta or gamma subunits was not obtained.

Affinity Labels↗