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Biomedical subjects

R Schön

Publications and source records attributed to R Schön.

At least 19 recordsLinked to original sources
PubMed1997

Preparation of 3-ketodesogestrel metabolites by microbial transformation and chemical synthesis.

Specific microbial reactions were used for the preparation of metabolites of 3-ketodesogestrel (13-ethyl-17 beta-hydroxy-11-methylene-18,19-dinor-17 alpha-pregn-4-en-20-yn-3-one, the active from of the progestagen desogestrel. Clostridium paraputrificum transformed 3-ketodesogestrel (KDG) to the 5 beta-dihydro and tetrahydro metabolites 13-ethyl-17 beta-hydroxy-11-methylene-18,19-dinor-5 beta, 17 alpha-pregnan-20-yn-3-one and 13-ethyl-11-methylene-18,19-dinor-5 beta, 17 alpha-pregnan-20-yne-3 alpha, 17 beta-diol, respectively. The epimeric compound 13-ethyl-11-methylene-18,19-dinor-5 beta, 17 alpha-pregnan-20-yne-3 beta, 17 beta-diol was obtained by chemical reduction of the 3-oxo compound. Mycobacterium smegmatis converted KDG to metabolites of the 5 alpha H-series: 13-ethyl-17 beta-hydroxy-11-methylene-18,19-dinor-5 alpha, 17 alpha-pregnan-20-yn-3-one, 13-ethyl-11-methylene-18,19-dinor-5 alpha, 17 alpha-pregnan-20-yne-3 alpha, 17 beta-diol and 13-ethyl-11-methylene-18,19-dinor-5 alpha, 17 alpha-pregnan-20-yne-3 beta, 17 beta-diol. The ring A-aromatized analog of KDG 13-ethyl-11-methylene-18,19-dinor-17 alpha-pregna-1,3,5(10)-trien-20-yne-3,17 beta-diol was obtained by microbial 1-dehydrogenation with Rhodococcus rhodochrous. Additionally, chemical syntheses of the microbially obtained KDG metabolites listed above were carried out. These included Birch reduction, reduction of KDG with sodium borohydride in aqueous pyridine and in methanol, reduction of KDG with potassium selectride in tetrahydrofuran, and dehydrogenation of KDG with cupric-II bromide in acetonitrile. The problems encountered in chemical syntheses favor the microbial procedures. The compounds were characterized by mass spectra (MS), IR, and circular dichroism (CD). Complete assignments of 1H and 13C chemical shifts were made using homo- and heteronuclear 2-DN-NMR spectroscopy. Chromatographic [gas-liquid chromatography (GLC), high-performance liquid chromatography (HPLC), thin-layer chromatography (TLC)] data of all the prepared KDG metabolites are presented.

Clostridium↗
PubMed1997

Tissue reaction around miniplates used for the fixation of vascularized iliac crest bone grafts.

MATERIAL/METHOD: In six miniature pigs revascularized autologous iliac crest bone grafts were fixed with two 2.0 mm titanium miniplates to a defined defect in the angle of the mandible. Tissue reaction around the implants was examined histologically and histomorphometrically at 2, 4, and 8 weeks after surgery. RESULTS: According to the evaluation of fluorescence microradiography, the cortical and medullary circulation and healing processes of bone in the vicinity of the implanted material were not disturbed after 2 weeks. At 4 weeks after surgery osseous healing occurred at the mandibula/graft interface. The histomorphometric results for the calculated percentage of direct bone/screw contact at 2 weeks were 24% with the grafted bone and 53% with the mandible. Intensive bone formation was observed in all parts of the graft by 4 weeks. The results of direct bone/screw. contact at 4 weeks were 56% and 64% and at 8 weeks 75% and 77% for the grafted and the mandibular bone, respectively. CONCLUSION: With 2.0 mm titanium miniplates used in the animal model, stable osteosynthesis and osseous healing was evident after 8 weeks of surgery. In addition, intensive remodeling of the transplanted bone without signs of creeping substitution was noted, and the bone/screw contact of the miniplate system increased with time.

Animals↗
PubMed1996

Cobalt chromium molybdenum metal combination for modular hip prostheses.

The development of a metal combination for modular hip systems was motivated by the following observations: (1) wear particles from polyethylene acetabular components can lead to a foreign body reaction and late aseptic loosening and (2) well designed all metal hip prostheses had very low wear rates, usually causing no osteolytic problems. The following challenges had to be met: (1) metal alloy with the maximum wear resistance; (2) the optimal clearance (difference in diameter) between 28-mm ball head and acetabular component; and (3) equipping modern, modular hip systems with metal combinations while maintaining compatibility with existing components. The realization of a metal combination consisted of the stable anchoring of a standard metal lining in a polyethylene insert that, combined, is intended to provide adequate load transfer and fit to either the bone cement bed or the titanium shell. The metal lining is manufactured from a carbide containing cobalt chromium molybdenum wrought alloy (Protasul-21WF). From 1988 to 1995, approximately 40,000 metal combinations (Metasul) were implanted. From these, 44 single components, with a maximum time in situ of 5.5 years, were retrieved and examined. The total linear wear rate averaged 2 to 5 micrometers per year per component after the initial conditioning phase. Under these conditions, particle induced late aseptic loosening is not to be expected.

Biomechanical Phenomena↗
PubMed1996

Metal-on-metal articulation for artificial hip joints: laboratory study and clinical results.

As wear is inevitable with artificial joint replacement, it has to be minimized to avoid possible aseptic loosening following osteolysis due to particle-initiated foreign body reaction. Co-Cr-Mo-C alloys have a long history with only minimum wear when articulating with themselves. This investigation shows that the choice of the alloy has an effect on the wear rate of this articulation couple. Tribological studies in a screening device, a pendulum apparatus and a hip joint simulator showed a marked influence of the environment as well as the diameter of the implants with metal-on-metal articulation. A wear-resistant combination with low friction characteristics has been developed by using a wrought Co-Cr-Mo-C alloy and reducing the implant diameter to 28 mm. Clinical wear rates are comparable with laboratory data and demonstrate the potential of the metal-on-metal articulation to solve the problem of wear-induced osteolysis of hip joint endoprostheses.

Bone Cements↗
PubMed1996

Modeling of the three-dimensional structure of the digitalis intercalating matrix in Na+/K(+)-ATPase protodimer.

Based on the knowledge that the digitalis receptor site in Na+/K(+)-ATPase is the interface between two interacting alpha-subunits of the protodimer (alpha beta)2, the present review makes an approach towards modeling the three-dimensional structure of the digitalis intercalating matrix by exploiting the information on: the primary structure and predicted membrane topology of the catalytic alpha-subunit; the determinants of the secondary, tertiary and quaternary structure of the membrane-spanning protein domains; the impact of mutational amino acid substitutions on the affinity of digitalis compounds, and the structural characteristics in potent representatives. The designed model proves its validity by allowing quantitative interpretations of the contributions of distinct amino acid side chains to the special bondings of the three structural elements of digitalis compounds.

Binding Sites↗
PubMed1995

Location and properties of the digitalis receptor site in Na+/K(+)-ATPase.

Since 1985, several research groups have shown that a number of amino acids in the catalytic alpha-subunit of Na+/K(+)-ATPase more or less strongly modulate the affinity of a digitalis compound like ouabain to the enzyme. However, scrutiny of these findings by means of chimeric Na+/K(+)-ATPase constructs and monoclonal antibodies has recently revealed that the modulatory effect of most of these amino acids does not at all result from direct interaction with ouabain, but rather originates from long-range effects on the properties of the digitalis binding matrix. Starting from this knowledge, the present review brings together the various pieces of evidence pointing to the conclusion that the interface between two interacting alpha-subunits in the Na+/K(+)-ATPase protodimer (alpha beta)2 provides the cleft for inhibitory digitalis intercalation.

Sodium-Potassium-Exchanging ATPase↗
PubMed1995

Differentiation between isoforms of Na+/K+-transporting atpase from human and guinea-pig muscle through use of digitalis derivatives as analytical probes.

The aims of the study included: to explore the protein structure basis for the differences in digitalis sensitivity between isoforms of Na/K-ATPase from human and guinea-pig cardiac muscle; to determine the relative significance of the constituents of tripartite digitalis compounds in their inhibitory action on these Na/K-ATPase isoforms; to evaluate the potential significance of the receptor kinetics for pharmacological characteristics. The analytical method has been the recording of the inhibitory interaction of various digitalis derivatives with the Na/K-ATPase isoforms. The protein structure basis for the isoform differences in digitalis susceptibility has been explored by analysing in free-energy plots the kinetics of their inhibitory interaction with 53 digitalis derivatives of grossly different structure. The slope of the regression line and the parameters of the regression equation proved to be similar for the two isoforms in spite of the great difference in their digitalis susceptibilities. This surprising uniformity indicates that a uniform "macroscopic" mechanism underlies the inhibitory effect of the various derivatives on the two isoforms. On the other hand, the differences in the positions of delta G*on and delta G*off values for particular inhibitors relative to the regression line reveal differences in the "microscopic" interaction energy surfaces of the two isoforms. In conclusion, the origin of the isoform distinctions in their susceptibility towards inhibition by various digitalis derivatives is essentially confined to differences in the chemotopology of the digitalis recognition matrix and binding cleft. Specific observations allowed to disentangle the impact of various steroid derivatizations at carbon atoms 3, 17, and diverse other positions on the kinetics of their interaction with the enzyme isoforms. The steroid nucleus of the cardiac glycosides, 5 beta, 14 beta-androstane, proves to be the basal structural element for discrimination of Na/K-ATPase isoforms. This discrimination becomes much enlarged by steroid glycosidation at C3 beta-OH and/or by steroid substitution of C17 beta-H by a lactone ring. The higher inhibitory sensitivity of the human isoform is based either on an increased association rate or a decreased dissociation rate, depending on the nature of derivatization.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1995

Platelet size, fibrinogen and lipoprotein(a) in coronary heart disease.

BACKGROUND: An increase in mean platelet volume has been reported to be associated with arterial thrombosis and myocardial infarction. A larger mean platelet volume has been regarded as an independent risk factor for recurrent myocardial infarction. We therefore investigated whether it is also increased in patients with coronary heart disease examined a few days before cardiac surgery. METHODS: Four hundred and twenty-six patients with coronary heart disease who were waiting for cardiac surgery and 125 healthy individuals were included in the study. Mean platelet volume and other platelet parameters were obtained from a routine blood count procedure using a flow cytometric haematology analyser. RESULTS: Mean platelet volume did not differ significantly between patients and controls; however, as expected from the literature, patients had significantly elevated levels of fibrinogen, cholesterol, triglyceride, apolipoprotein B and apolipoprotein(a). Furthermore, we observed no significant difference in mean platelet volume between patients without myocardial infarction and those who had survived at least one myocardial infarction. CONCLUSION: Our findings suggest that, using a routine laboratory procedure, mean platelet volume cannot be used as a predictive marker for coronary heart disease or myocardial infarction.

Adult↗
PubMed1995

Potential suitability of Na+/K(+)-transporting ATPase in pre-screens for anti-cancer agents.

Twenty-five compounds [digitalis (generic name for cardenolides, bufadienolides and their glycosides) representatives and derivatives, various steroids as well as some customary carcinostatics] have been compared in terms of their potency to suppress the proliferation of Ehrlich mouse ascites carcinoma (EMAC) cells and to inhibit the activity of Na/K-ATPase from EMAC cells and from human cardiac muscle. The inhibitor susceptibilities of the Na/K-ATPase isoforms of EMAC and cardiac muscle are very different, in favour of the cardiac muscle with the digitalis-like acting steroids, whereas they are quite similar with the digitalis-unlike acting compounds. Whereas the K0.5 values for the inhibition of EMAC Na/K-ATPase display the expected dependence on steroid structure, the IC50 values for the suppression of EMAC cell proliferation all lie within a narrow concentration range. With ouabain, the IC50 value for the suppression of proliferation of oestrogen receptor-negative, human mammary carcinoma (MCA) cells is four orders of magnitude higher than the K0.5 value for inhibition of the activity of human cardiac muscle Na/K-ATPase. In contrast to this effectivity order, some synthetic derivatives of digitalis steroids develop primarily antiproliferative potency.

Animals↗
PubMed1994

Sex differences in dehydroepiandrosterone metabolism in the rat: different plasma levels following ingestion of DHEA-supplemented diet and different metabolite patterns in plasma, bile and urine.

Plasma dehydroepiandrosterone (DHEA) and DHEA sulfate levels were determined by an enzyme immunoassay in male and female Sprague-Dawley rats fed a diet containing 0.6% or 0.3% DHEA. A significant difference in DHEA plasma levels was observed in male and female animals. In male rats, total DHEA plasma concentrations were found in the range of 0.4-1.5 microgram/ml (0.6% DHEA chow) and 0.3-0.5 microgram/ml (0.3% DHEA chow). In female animals several times higher DHEA plasma levels were determined: 17.5-33 micrograms/ml (0.6% DHEA chow) and 8.3-14.8 micrograms/ml (0.3% DHEA chow). DHEA was present in rat plasma of both sexes preferably as the sulfate conjugate. Significant sex differences were also found in the DHEA metabolite patterns obtained by TLC separation of extracts from plasma, bile and urine following administration of 3H-DHEA. In female rats, DHEA is present predominantly as the sulfate conjugate in considerable amounts in all materials investigated, whereas in male rats polar metabolites dominate in the patterns.

Animals↗
PubMed1994

The prevalence of poor anticoagulant response to activated protein C (APC resistance) among patients suffering from stroke or venous thrombosis and among healthy subjects.

A poor anticoagulant response to activated protein C (APC) in an activated partial thromboplastin time (aPTT) assay (APC resistance) was recently reported to be a cause of familial thrombophilia. The response to APC was measured in 30 patients suffering from juvenile or recurrent stroke, in 40 patients suffering from venous thromboembolism and in 50 healthy subjects. The prevalence of APC resistance was found to be significantly higher among patients with stroke (20%, P < 0.003) and venous thrombosis (17.5%, P < 0.02) compared with the prevalence of APC resistance among normal controls (2%). In one case of venous thrombosis, the proposita's family (A) could be investigated and in five out of nine investigated members (56%) a poor or borderline response to APC was detected. The family (B) of another APC-resistant patient revealed six subjects with poor coagulation response to APC out of eight family members studied (75%). Measuring protein S activity with an automated calcium-thromboplastin-based protein S activity assay, a significant correlation (P < 0.0001) between the results of this functional protein S assay and APC resistance (represented by the ratio (Rs value) of clotting time with and without addition of activated protein C) was observed. Nine out of 14 patients (64%) with poor APC response showed protein S activities below the normal range. Assessment of protein S activity with a second protein S clotting assay using factor Va as substrate confirmed only 47% of the decreased levels of the thromboplastin-based protein S clotting assay.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Prevalence of factor XII (Hageman factor) deficiency among 426 patients with coronary heart disease awaiting cardiac surgery.

BACKGROUND: Several case reports of myocardial infarction in patients with factor XII deficiency have been published. In the present study we investigated the prevalence of this condition. METHODS: Factor XII activity (one-stage clotting assay), fibrinogen (derived method), and lipoprotein (a) (enzyme-linked immunosorbent assay) were measured in the plasma of 426 consecutive patients with coronary heart disease awaiting cardiac surgery. RESULTS: Among the 426 patients, 44 (10.3%) were found to be moderately deficient in factor XII (factor XII activity 17-50%, antigen 15-57%). The prevalence of factor XII deficiency was significantly higher (P < 0.0001) among patients with coronary heart disease than among 300 healthy blood donors (2.3%). Among coronary heart disease patients with this deficiency, elevated levels of fibrinogen, lipoprotein (a), and blood pressure were no more prevalent than in those without the deficiency; nor were cigarette smoking or a positive family history of thromboembolism more prevalent. CONCLUSIONS: Coronary heart disease patients showed a 10% prevalence of factor XII deficiency. However, the pattern of atherosclerotic risk factors did not differ between patients with or without the deficiency.

Blood Coagulation Tests↗
PubMed1994

Synthesis of a self-contained concept of the molecular mechanism of energy interconversion by H(+)-transporting ATP synthase.

The original aim of the review has been to probe into the validity of the paradigm on the high energy-carrier function of ATP. It seemed to be called into question on the basis of findings with H(+)-transporting ATP synthase suggesting the formation of ATP from ADP and Pi without energy input. Thus, ATP appeared as a low-energy compound. Starting from the current, rich knowledge of the molecular structure and the inviting thinking on the mechanism of H(+)-transporting ATP synthase, we have endeavoured to freshly interpret and integrate the pertinent observations in the light of the comprehensively derived model of the molecular mechanism of energy interconversion by Na+/K(+)-transporting ATPase. In this way, we have uncovered the common mechanistic elements of the two energy-interconverting enzymes. The emerging purpose of the present paper has been the 'synthesis' of a self-contained concept of the molecular mechanism of the interconversion of electrochemical and chemical Gibbs energies by H(+)-transporting ATP synthase. The outcome is reflected in the following tentative evaluations. 1. In ATP hydrolysis, the great Gibbs energy change which is observed in solution, is largely conserved by the F1 sector of ATP synthase as mechanical Gibbs energy in the enzyme's protein fabric, so that it can be utilized in the resynthesis of ATP from enzyme-bound ADP and Pi. The plainly measured low Gibbs energy change results from large compensating enthalpy and entropy changes that reflect the underlying changes in protein conformation. 2. In stoichiometric ATP synthesis by F1 sector from ADP and Pi bound to the catalytic centre, their intrinsic binding energy brings about a loss of peptide chain entropy that makes possible an entropy-driven ATP formation. 3. The driving force for ATP synthesis cannot be the high Gibbs energy change on binding of product ATP; the tight ATP-enzyme complex rather is a low Gibbs energy intermediate from which escape is difficult. 4. The catalytic centre exists either in an open state unable to firmly bind the substrate-product couple, or in a closed state protecting formed ATP from facile hydrolysis by ambient water. 5. The cleft closure, induced by binding of Pi and ADP or ATP, does not necessarily need external energy supply, because the cleft closure proceeds from rigid domain rotations which can occur rather spontaneously. In further analogy to adenylate kinase, the driving force of this domain movement presumably comes from the electrostatic interactions between phosphate moieties and arginine side chains in the catalytic centre.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

The prevalence of moderate and severe FXII (Hageman factor) deficiency among the normal population: evaluation of the incidence of FXII deficiency among 300 healthy blood donors.

Factor XII (FXII) deficiency has been reported to be a risk factor for the development of arterial and venous thromboembolism. However, no data are available on the prevalence of FXII deficiency within the normal population. Measuring APTT and FXII activity, seven FXII deficiencies could be detected among 300 healthy blood donors. This corresponds to an incidence of FXII deficiency of 2.3%. On the basis of these data the prevalence of severe and mild FXII deficiency in the normal population can be estimated to be 1.5-3.0%. Assessment of FXII antigen levels revealed, that all seven FXII deficient individuals had FXII antigen levels matching the activity. One presented a severe FXII deficiency (1/300, 0.3%) without detectable FXII activity and an APTT prolongation of more than 120 s. The remaining six FXII deficiencies (6/300, 2.0%) were moderate variations with FXII activities ranging from 20-45% and less prolonged APTTs. Among the 300 healthy donors 16 (5.3%) subjects with prolonged APTTs were identified. Causes for APTT-prolongation were FXII deficiency (7/16), lupus anticoagulant (6/16), mild FVIII deficiency (1/16) and hepatic disorder (1/16). In the remaining sample (1/16) the cause for the prolongation of the APTT remained unexplained. Although 8.7% (26/300) of the donors had a positive family-history of thromboembolism (TE-FHx), none of the FXII deficient subjects were among those with positive TE-FHx.

Adult↗