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B Kuhn

Publications and source records attributed to B Kuhn.

At least 19 recordsLinked to original sources
PubMed2006

Efficacy and immunogenicity of novel erythropoietic agents and conventional rhEPO in rats with renal insufficiency.

Recombinant human erythropoietin (rhEPO) is used to treat anemia in chronic renal insufficiency. Erythropoietin (EPO) immunogenicity can lead to EPO-resistant anemia. Conjugating proteins with polyethylene glycol (PEG) can prolong elimination half-life and diminish protein immunogenicity. We investigated the efficacy of new erythropoietic agents, synthesized by single (Ro 50-3821) and multiple (MIX) integrations of PEG and succinimidyl butanoic acid with rhEPO, in rats with chronic renal insufficiency. Sprague-Dawley rats with surgically induced renal insufficiency received Ro 50-3821 or MIX subcutaneously (s.c.) over 4-12 weeks compared to rhEPO and NaCl. Hemoglobin and antibody levels served as primary efficacy and safety variables. Dosing intervals and dose-response characteristics were investigated. Ro 50-3821 (2.5 microg/kg once weekly) increased hemoglobin levels by 7 g/dl after 4 weeks compared to 1 g/dl in NaCl controls (P<0.05). MIX (2.5 microg/kg once weekly) and rhEPO (0.25 microg/kg three times weekly) increased hemoglobin levels by 3 g/dl. Ro 50-3821 administered for 12 weeks (0.75 microg/kg once weekly) increased hemoglobin levels (from 13 to 19 g/dl) more effectively than rhEPO (0.75 microg/kg once weekly, decline from 13 to 11 g/dl, P<0.05). No antibodies against Ro 50-3821 were detected after 12 weeks of treatment. Antibodies against rhEPO were seen in 69% of animals (P<0.00001). Ro 50-3821 increased hemoglobin levels with once weekly s.c. dosing. Multiple pegylated EPO is less effective. In rats, rhEPO failed to increase hemoglobin levels with once weekly long-term dosing. Antibody formation following rhEPO may explain this finding. Therefore, Ro 50-3821 may provide important clinical advantages compared to unpegylated EPO. It can be administered in longer dosing intervals and has a lower risk of unfavorable immunological responses.

Animals↗
PubMed2002

Pollen movement in declining populations of California Valley oak, Quercus lobata: where have all the fathers gone?

The fragmented populations and reduced population densities that result from human disturbance are issues of growing importance in evolutionary and conservation biology. A key issue is whether remnant individuals become reproductively isolated. California Valley oak (Quercus lobata) is a widely distributed, endemic species in California, increasingly jeopardized by anthropogenic changes in biota and land use. We studied pollen movement in a savannah population of Valley oak at Sedgwick Reserve, Santa Barbara County, to estimate effective number of pollen donors (Nep) and average distance of effective pollen movement (delta). Using twogener, our recently developed hybrid model of paternity and genetic structure treatments that analyses maternal and progeny multilocus genotypes, we found that current Nep = 3.68 individuals. Based on an average adult density of d= 1.19 stems/ha, we assumed a bivariate normal distribution to model current average pollen dispersal distance (delta) and estimated delta= 64.8 m. We then deployed our parameter estimates in spatially explicit models of the Sedgwick population to evaluate the extent to which Nep may have changed, as a consequence of progressive stand thinning between 1944 and 1999. Assuming that pollen dispersal distance has not changed, we estimate Nep was 4.57 individuals in 1944, when stand density was 1.48. Both estimates indicate fewer effective fathers than one might expect for wind-pollinated species and fewer than observed elsewhere. The results presented here provide a basis for further refinements on modelling pollen movement. If the trends continue, then ongoing demographic attrition could further reduce neighbourhood size in Valley oak resulting in increased risk of reproductive failure and genetic isolation.

California↗
PubMed2001

Metabolism of sirolimus and its derivative everolimus by cytochrome P450 3A4: insights from docking, molecular dynamics, and quantum chemical calculations.

A combination of quantum chemical calculations and molecular simulations (DOCKing and molecular dynamics) is used to investigate the metabolism of sirolimus (rapamycin) and its derivative everolimus (SDZ-RAD) by cytochrome P450 3A4. Both molecules are drugs with high immunosuppressive activity. Our calculations yield qualitative predictions of the regiospecificities of the hydroxylations and O-dealkylations occurring in these two substrates which are in good agreement with recent experimental results. An analysis of the modeled enzyme-substrate interactions allows us to rationalize the reduced metabolic activity of the larger substrate everolimus compared to sirolimus. Moreover, our simulations suggest that hydrogen donor functionalities close to the metabolic site are important for anchoring the substrate at the active center of the enzyme. In particular, we predict that replacing one hydroxyl group by a fluorine atom should considerably suppress the major metabolic reaction in sirolimus, 39-O-demethylation.

Algorithms↗
PubMed2001

Elucidating the nature of enzyme catalysis utilizing a new twist on an old methodology: quantum mechanical-free energy calculations on chemical reactions in enzymes and in aqueous solution.

How do enzymes achieve very large rate enhancements compared to corresponding uncatalyzed reactions in solution? We present a computational approach which combines high-level ab initio quantum mechanical calculations with classical free energy calculations to address this question. Our calculations lead to accurate estimates of DeltaG for both trypsin and catechol O-methyltransferase-catalyzed and reference uncatalyzed reactions and give new insights into the nature of enzyme catalysis. The same methodology applied to steps in the catalytic mechanism of citrate synthase further supports the conclusion that one need not invoke special concepts such as "low-barrier hydrogen bonds" or "pK(a) matching" to explain enzyme catalysis.

Catalysis↗
PubMed2000

Binding of a diverse set of ligands to avidin and streptavidin: an accurate quantitative prediction of their relative affinities by a combination of molecular mechanics and continuum solvent models.

We report calculations of free energies of binding, DeltaG(bind), between a diverse set of nine ligands and avidin as well as between a peptide and streptavidin using the recently developed MM/PBSA approach. This method makes use of a molecular dynamics simulation of the ligand-protein complex to generate a thermally averaged ensemble of conformations of the molecules that are involved in the complex formation. Based on this set of structures, a free energy of binding is calculated using molecular mechanical and continuum solvent energies as well as including estimates of the nonpolar solvation free energy and solute entropy. We compare in our simulations different classes of ligands, involving biotin derivatives, the dye 2-(4'-hydroxyazobenzene)benzoic acid (HABA), and a cyclic hexapeptide, which cover a large range of binding free energies from -5 to -20 kcal/mol. Our calculations are able to reproduce experimental DeltaG(bind) values with a very good correlation coefficient of r(2) = 0.92. This agreement is considerably better than the results obtained with an alternate approach, the linear interaction energy approximation, for this system (r(2) = 0.55).

Avidin↗
PubMed2000

Calculating structures and free energies of complex molecules: combining molecular mechanics and continuum models.

A historical perspective on the application of molecular dynamics (MD) to biological macromolecules is presented. Recent developments combining state-of-the-art force fields with continuum solvation calculations have allowed us to reach the fourth era of MD applications in which one can often derive both accurate structure and accurate relative free energies from molecular dynamics trajectories. We illustrate such applications on nucleic acid duplexes, RNA hairpins, protein folding trajectories, and protein-ligand, protein-protein, and protein-nucleic acid interactions.

Base Sequence↗
PubMed2000

Lactonization is the critical first step in the disposition of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor atorvastatin.

In an in vitro study, we compared the cytochrome P450 (CYP)-dependent metabolism and drug interactions of the acid and lactone forms of the 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitor atorvastatin. Metabolism of atorvastatin acid and lactone by human liver microsomes resulted in para-hydroxy and ortho-hydroxy metabolites. Both substrates were metabolized mainly by CYP3A4 and CYP3A5. Atorvastatin lactone had a significantly higher affinity to CYP3A4 than the acid (K(m): para-hydroxy atorvastatin, 25.6 +/- 5.0 microM; para-hydroxy atorvastatin lactone, 1.4 +/- 0.2 microM; ortho-hydroxy atorvastatin, 29.7 +/- 9.4 microM; and ortho-hydroxy atorvastatin lactone, 3.9 +/- 0.2 microM). Compared with atorvastatin acid, CYP-dependent metabolism of atorvastatin lactone to its para-hydroxy metabolite was 83-fold higher [formation CL(int) (V(max)/K(m)): lactone 2949 +/- 3511 versus acid 35.5 +/- 48.1 microl. min(-1). mg(-1)] and to its ortho-hydroxy metabolite was 20-fold higher (CL(int): lactone 923 +/- 965 versus acid 45.8 +/- 59. 1 microl. min(-1). mg(-1)). Atorvastatin lactone inhibited the metabolism of atorvastatin acid by human liver microsomes with an inhibition constant (K(i)) of 0.9 microM while the K(i) for inhibition of atorvastatin by atorvastatin lactone was 90 microM. Binding free energy calculations of atorvastatin acid and atorvastatin lactone complexed with CYP3A4 revealed that the smaller desolvation energy of the neutral lactone compared with the anionic acid is the dominant contribution to the higher binding affinity of the lactone rather than an entropy advantage. Because atorvastatin lactone has a significantly higher metabolic clearance and the lactone is a strong inhibitor of atorvastatin acid metabolism, it can be expected that metabolism of the lactone is the relevant pathway for atorvastatin elimination and drug interactions. We hypothesize that most of the open acid metabolites present in human plasma are generated by interconversion of lactone metabolites.

Atorvastatin↗
PubMed1997

[Heparin-induced thrombocytopenia--a serious complication within the scope of heparin therapy. Follow-up of 7 trauma surgery patients].

Heparin-induced thrombocytopenia type II (HIT-II) is a serious complication in heparin treatment. Because of arterial and/or venous thromboembolism, HIT-II quite often takes a life-threatening course. This article describes the clinical course of seven trauma patients, who developed HIT-II during thromboembolism prophylaxis with unfractionated heparin (UFH, Heparin-Natrium-Nattermann, 250,000 I.E., Rhone-Poulenc Rorer GmbH), given subcutaneously. Thromboembolic complications occurred in 5 out of 7 cases (71.4%). One case took a fatal course (14.3%). UFH was replaced by Orgaran when HIT-II was suspected or diagnosed. There were no more complications. Thrombocyte count increased to normal values within 3 to 9 days. The importance of HIT-II in heparin therapy during in- and outpatient therapy is discussed with reference to the current literature.

Aged↗
PubMed1997

The postnatal development of F-actin in tension fibroblasts of the spiral ligament of the gerbil cochlea.

The tension fibroblasts of the spiral ligament of the mammalian cochlea are thought to create radial tension on the basilar membrane. Their postnatal development was investigated in the gerbil (Meriones unguiculatus) with confocal fluorescence microscopy using phallotoxin as a specific marker for F-actin. In the adult cochlea, tension fibroblasts were restricted to the basal cochlear turn and were arranged in 2-4 rows in the marginal region of the spiral ligament. They contained intensely stained parallel bundles of F-actin. In upper cochlear turns, the marginal region of the spiral ligament was occupied by sparsely distributed, unobtrusively labeled fibrocytes, the bone lining cells. The spiral ligament of young postnatal stages (newborn--6 days after birth (DAB)) lacked F-actin labeling patterns that are characteristic for tension fibroblasts in the adult. Rather, the whole inner surface of the otic capsule throughout all cochlear turns was outlined by cell layers with distinct but diffuse cytoplasmic F-actin label. These cells may represent perichondrial fibrocytes. Around 9 DAB, the perichondrium revealed changes in morphology and F-actin patterns that indicate a further differentiation into tension fibroblasts (basal turn) or bone lining cells (more apical turns). At 12 DAB, around onset of hearing, adult-like bone lining cells were found in the marginal regions of the spiral ligament of upper cochlear turns. In the basal turn, tension fibroblasts were present, but their F-actin cytoskeleton was not fully developed. During the following days, F-actin label increased in tension fibroblasts and reached adult-like configuration at 17 DAB, coinciding with mature hearing characteristics. The role of tension fibroblasts in development of hearing characteristics is discussed.

Actins↗
PubMed1996

The early postnatal development of F-actin patterns in the organ of Corti of the gerbil (Meriones unguiculatus) and the horseshoe bat (Rhinolophus rouxi).

The arrangements of F-actin in hair cells and non-sensory cells were studied in paraformaldehyde-fixed cochleae of horseshoe bats and gerbils in several postnatal stages and in the adult. Phallotoxin-labeled midmodiolar cryostat sections of the organ of Corti were analyzed with confocal fluorescence microscopy. In both species, the arrangement of F-actin in the adult organ of Corti was essentially similar to that described in other mammals; however, both species showed their own species-typical specializations in staining of the Deiters cells. In the gerbil, a distinct baso-apical gradient in morphology and staining properties was found in the upper compartment of the Deiters cells. In the bat, F-actin label within the Deiters cups was most pronounced in the basal cochlear turn and less abundant in the apical turns. During the first postnatal week, the sensory epithelium of the gerbil lacked the tunnel of Corti and the spaces of Nuel. Only the reticular lamina and the surface of the greater epithelial ridge were intensely labeled for F-actin. At 9 days after birth (DAB), when the tunnel of Corti and the inner spiral sulcus were formed, the footplates of Deiters and pillar cells and the apices of pillar cells began to show intense F-actin label. At 12 DAB, corresponding to onset of hearing, F-actin staining was found throughout the supporting cell bodies, but was less intense than in the adult. The specialized upper compartment of the Deiters cells differentiated around 15-20 DAB. In the neonate bat, gross-morphology of the organ of Corti was almost adult-like, but only the reticular lamina and the head- and footplates of pillar cells showed intense F-actin staining. The F-actin cytoskeleton of the Deiters cells bodies was poorly developed. At the onset of hearing (between 3rd and 5th DAB), supporting cells showed only a slight increase of F-actin mainly at mechanically important cell regions, namely the Deiters cups, the contact zone of pillar headplates and the footplates of supporting cells. The most intense increase of F-actin occurred between onset of hearing and 16 DAB. At 16 DAB, the F-actin distribution within the supporting cells was similar to the adult. In both species, there were no clear baso-apical gradients in development of F-actin patterns. It is proposed that F-actin insertion in supporting cells after the onset of hearing contributes to maturation of cochlear function.

Actins↗
PubMed1995

The arrangements of F-actin, tubulin and fodrin in the organ of Corti of the horseshoe bat (Rhinolophus rouxi) and the gerbil (Meriones unguiculatus).

The composition of cytoskeletal elements in hair cells and non-sensory cells was studied in paraformaldehyde fixed cochleae of the horseshoe bat and the gerbil using phallotoxins and antibodies directed against actin, alpha-tubulin and fodrin. In both species, cryostat sections of the organ of Corti were studied using confocal fluorescence microscopy; in the bat, ultrathin sections were investigated using actin-immunoelectron and classical electron microscopy. F-actin was found in stereocilia and cuticular plates of inner and outer hair cells (IHCs and OHCs) of both species. In fixed material from both species, no F-actin staining was detected in the cytoplasm or along the lateral cell membrane of OHCs, whereas in freshly isolated OHCs of the gerbil, a faint F-actin staining was detected along the lateral wall. In the bat, the patterns of F-actin staining were confirmed with actin-immunoelectron microscopy. The alpha-tubulin antibody strongly labeled IHCs of both species. They contained a complex network of microtubules especially in the neck portion. In the bat, OHCs showed no distinct alpha-tubulin reactivity, as would be expected given the scarcity of microtubules observed at the ultrastructural level. In the gerbil, alpha-tubulin reactivity was found throughout the OHC body with highest intensity in the cell apex. In Deiters cells, pillar cells and Boettcher cells of both species, F-actin and microtubules were colocalized at contact zones with the basilar membrane. In Deiters cups, F-actin staining was most pronounced in the basal turn of the bat cochlea. In the gerbil, a distinct baso-apical gradient was found in immunostaining properties and morphology of the Deiters cells. Intense fodrin reactivity was found in the cuticular plates and along the lateral cell membrane of both types of hair cells of the bat. Cytoplasmic fodrin staining was localized within the IHCs of the bat. In the gerbil, intense fodrin staining was only found in cuticular plates of hair cells and staining of the lateral cell membrane of hair cells was faint. A faint fodrin staining was also seen in Deiters cells of both species. The basic arrangement of the cytoskeletal elements in the batś organ of Corti is similar to that of other mammals, however, certain features suggest the presence of subtle differences in micromechanical properties: there is an increased concentration of microtubules in the neck portion of IHCs, an increase in the amount of F-actin within the Deiters cups and a reduced amount of microtubules in the OHCs.

Actins↗
PubMed1994

Increased messenger RNA levels for low-density lipoprotein receptor and 3-hydroxy-3-methylglutaryl coenzyme A reductase in rat liver after long-term ethanol ingestion.

Because long-term alcohol intake leads to severe alterations of cholesterol metabolism resulting in both elevated serum cholesterol levels and increased hepatic concentrations of cholesterol esters, we investigated the effect of long-term ethanol consumption on the hepatic messenger RNA (mRNA) content of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and low-density lipoprotein receptor, two major regulatory factors in cholesterol metabolism, and of apoprotein E. Twenty-four male Sprague-Dawley rats were pair-fed nutritionally adequate liquid diets containing 36% of total calories as either ethanol or isocaloric carbohydrates for 3 wk. In addition, the lipid content of the diets was varied, resulting in 35%, 17.5%, and 8.8% of total calories corresponding to a daily intake of cholesterol of between 1.2 and 6.3 mg/kg body wt. Although increasing dietary cholesterol intake resulted in a significant decrease of hepatic mRNA for low-density lipoprotein receptor and HMG-CoA reductase (p < 0.05), long-term ethanol consumption led to a significant increase of the mRNA for both proteins (p < 0.01), and this increase was predominantly obvious in animals fed a low-cholesterol diet. In contrast, mRNA content of apoprotein E was found to be significantly lower in livers from rats fed ethanol for a prolonged period of time as compared with controls (p < 0.01), and this effect was found to be still present, although less pronounced, after low cholesterol intake.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1992

Specific inhibition of mRNA accumulation for lymphokines in human T cell line Jurkat by mycobacterial lipoarabinomannan antigen.

The immunomodulatory effect of Mycobacterium tuberculosis-derived lipoarabinomannan (LAM) on mitogen/antigen-induced expression of mRNAs for a number of cytokines in human monocytic cell line Mono-Mac-6 and in T cell line Jurkat was investigated. Interestingly, LAM exhibited a down-regulatory effect on the accumulation of mRNAs for IL-2, IL-3, granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-2 receptor alpha (IL-2R alpha) in T cells co-stimulated with phytohaemagglutinin-P (PHA) and 4 beta-phorbol-12-myristyl-13-acetate (PMA). In human Mono-Mac-6 cells. LAM has a weak inhibitory effect on the lipopolysaccharide (LPS)-induced mRNA accumulation for IL-1 beta, a slight stimulatory effect on mRNAs accumulation for IL-8 and tumour necrosis factor-alpha (TNF-alpha), but clearly no effect on mRNA accumulation for intercellular adhesion molecule-1 (ICAM-1). These findings imply that LAM may contribute to the immunologic defects associated with a number of mycobacterial infections by modulating these mediators.

Antigens, Bacterial↗
PubMed1992

Evidence for linkage between the swine L blood group and the loci specifying the receptors mediating adhesion of K88 Escherichia coli pilus antigens.

Brush borders or enterocytes obtained from the small intestine of 248 pedigreed pigs were tested by adhesion assay in vitro with enterotoxigenic Escherichia (E.) coli strains, each expressing one of the three K88 pilus variants K88ab, K88ac and K88ad. All pigs were classified as belonging to one of the four adhesion phenotypes: I--K88ab(-), ac(-), ad(-); II--K88ab(-), ac(-), ad(+); III--K88ab(+), ac(+), ad(-); and IV--K88ab(+), ac(+), ad(+). Serum or red cells were typed for 15 blood group systems: A-O, B, C, D, E, F, G, H, I, J, K, L, M, N and O; for 11 biochemical polymorphisms: PI1, PI2, PO1A, A1BG, GPI, PGD, TF, HPX, ADA, PGM and AMY; the polymorphism at the IGHG1 locus. Linkage analysis was performed between the alleles at the locus (loci) specifying K88 receptors able to bind one or more different serological types of K88 E. coli and alleles for markers at other loci. Linkage was demonstrated between the locus for the L blood group system and the locus (loci) for K88 E. coli receptors (Z = 3.24), adding one locus (loci) to the previously identified linkage group IV (LGIV) [L-SLB]. The maximum likelihood estimate of the recombination fraction (theta) was 0.23. No evidence was found for linkage between any of the other biochemical and immunogenetic markers and the receptor locus (loci) of K88 E. coli.

Animals↗
PubMed1990

IL-3 promotes basophilic differentiation of KU812 cells through high affinity binding sites.

The myeloid precursor cell line KU812 exhibits a constitutive potential to differentiate into basophilic cells. In the present study, the influence of recombinant human (rh)IL-2, rhIL-3, and recombinant human granulocyte-macrophage-CSF on basophilic differentiation of KU812-F cells was studied. Of all cytokines tested, rhIL-3 induced a significant increase in formation of metachromatically granulated cells (from 10% in control cultures up to 30% in cultures supplemented with 100 U/ml of rhIL-3) as well as dose-dependent (1.5- to 3 fold) increase in cellular histamine in KU812-F cell cultures. In addition, KU812-F cells exposed to rhIL-3 bound more IgE antibody than cells cultured in control medium with up to 3.3-fold increases in the mean fluorescence intensity on days 2 and/or 5 compared with control (p less than 0.001). RhIL-3 failed to induce significant changes in expression of the Tac-reactive subunit of the IL-2R (CD25), surface aminopeptidase N (CD13), ICAM-1 Ag (CD54), or CD40 Ag on KU812-F cells. To investigate the mechanism of IL-3 action on KU812-F cells, receptor analyses were performed by using 125I-radiolabeled rhIL-3. Quantitative binding studies and Scatchard plot analyses revealed the presence of a single class of 1910 to 2460 high affinity IL-3-binding sites per KU812-F cell with an apparent dissociation constant of 1.22 to 2.35 x 10(-9) M. Together, these results show that rhIL-3 promotes basophilic differentiation of KU812-F cells through a specific receptor.

Antigens, CD↗
PubMed1990

Moclobemide (Ro 11-1163) versus tranylcypromine in the treatment of endogenous depression.

In this study, moclobemide (100-350 mg daily) was compared with tranylcypromine (10-30 mg daily) in 40 patients with endogenous depression. Treatment was randomly allocated and most patients also received benzodiazepines or mild neuroleptics concomitantly. Improvement on the Hamilton Rating Scale for Depression at the end of treatment was 66% for moclobemide and 41% for tranylcypromine patients. There were 3 suspected tyramine reactions in patients on tranylcypromine. Tolerance was considered good or very good for 95% of moclobemide patients, and for 75% of tranylcypromine patients. No clinically relevant changes in laboratory data were attributed to either of the trial drugs. The results clearly favour moclobemide over tranylcypromine for both efficacy and tolerance in the treatment of endogenous depression.

Antidepressive Agents↗
PubMed1989

Specific binding, internalization, and degradation of human neutrophil activating factor by human polymorphonuclear leukocytes.

The interaction of 125I-labeled recombinant human neutrophil activating factor (NAF) with polymorphonuclear leukocytes (PMN) was studied by means of a radioreceptor assay. The binding was characterized by a rapid transition (t1/2 less than or equal to 1 min) from a pH 3-sensitive state at 4 degrees C to pH 3 resistance at 37 degrees C. This was not caused by internalization of NAF since pH 3-resistant bound iodinated NAF could still be exchanged by an excess of nonlabeled NAF, i.e. was dissociable. Internalized iodinated NAF was processed into trichloroacetic acid-soluble forms. Scatchard transformation of binding isotherms at 4 and 37 degrees C led to nonlinear curves, a finding which is consistent with the expression of two receptor populations, one with high (KD = 11-35 pM) and the other with lower affinity (KD = 640-830 pM) at 4 degrees C. Numbers of the low affinity binding sites were approximately 34,000, and those with high affinity were 5,200/PMN when estimated at 4 degrees C. Binding of iodinated NAF to PMN was specific since it could be competed by an excess of nonlabeled NAF but not by two other activators of PMN function, formylmethionyl-leucyl-phenylalanine or human recombinant granulocyte-macrophage colony-stimulating factor. In addition to human PMN, NAF also bound specifically to two human monocytic cell lines; however, only the low affinity binding site could be detected on these cells.

Binding Sites↗