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At least 1,153 records · Page 64Linked to original sources
PubMed2002

Preclinical evaluation of alternative pharmaceutical delivery vehicles for paclitaxel.

New solubilizers, including Sorporol 230, Sorporol 120Ex, Aceporol 345-T, Aceporol 460 and Riciporol 335, as potential new delivery vehicles for paclitaxel were investigated, since recent studies have shown that the paclitaxel delivery vehicle Cremophor EL significantly alters the pharmacokinetics of paclitaxel. Cremophor EL and Tween 80 were used as a reference. As in the case of Cremophor EL, alteration of blood distribution of paclitaxel occurred in the presence of all tested vehicles. Also, no differences in the affinity of paclitaxel for the tested solubilizers was found during equilibrium dialysis experiments. The different vehicles could be distinguished by a different rate of esterase-mediated breakdown, which was correlated with the fatty acid content of the solubilizers. The activation of the complement cascade was less pronounced for all solubilizers, except Riciporol 335, compared to Cremophor EL. The strategies presented here provide the possibility to rapidly screen future candidate delivery vehicles with optimal characteristics for use as a solubilizer in clinical formulations of paclitaxel or other poorly water-soluble drugs.

Antineoplastic Agents, Phytogenic↗
PubMed1996

Synthesis of transferrin-mitomycin C conjugate as a receptor-mediated drug targeting system.

Macromolecular conjugates of mitomycin C (MMC) were synthesized by binding an active ester of glutarylated MMC (MMC-G-OSu) to human holo-transferrin (TF). Water-soluble TF-MMC conjugates (TF-G-MMC) were obtained in a good yield (> 95%) by this method. The MMC content of the conjugate increased (0.82-9.49 MMC/w%) with increasing amounts of MMC-G-OSu added to the conjugation mixture. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis showed no aggregation in these conjugates. 125I-TF-G-MMC was bound specifically to the TF receptor on Sarcoma 180 cells; the measurement of equilibrium binding of the 125I-labeled conjugate resulted in a saturation isotherm. The amount of conjugate specifically bound to the TF receptor decreased as the MMC content of the conjugate increased. However, it was found that the conjugate with an MMC content below 10 mol MMC/mol TF still retains a binding activity of more than half that of TF. Therefore, when an optimal chemical modification was chosen, TF could be used as a tumor specific drug carrier.

Animals↗
PubMed1982

DPN-linked sn-glycerol-3-phosphate dehydrogenase. Cyclopentanoid analogues mimic the active rotameric state of the natural substrate.

Five diastereoisomeric cyclopentane-1,2,3-triol monophosphate analogues of sn-glycerol 3-phosphate have been studied as substrates and inhibitors of sn-glycerol-3-phosphate dehydrogenase (EC 1.1.18) of rabbit skeletal muscle. Of the five analogues, only two were substrates, DL-1,2,3/0-1P (analogue I) and DL-1,2/3-1P (analogue II). The rest were weak competitive inhibitors of the enzyme. Initial rate kinetic studies of the substrate-active analogues analyzed by a rapid equilibrium random-order mechanism showed that Ks (I) = 4.6 +/- 2.6 mM; Ks (II) = 2.2 +/- 0.6 mM compared with Ks (DL-glycerol-3-P) = 2.4 +/- 0.9 mM. Correlation of the structures of the five analogues with their activities indicates that the enzyme requires a syn orientation of the carbon-oxygen bonds about C-2 and C-3 for activity, which is optimized by an anti relationship between the hydroxyl groups at C-1 and C-2 of the cyclopentanetriol monophosphates. These results are used to deduce the conformation of sn-glycerol-3-P as it is bound in the active site of the enzyme.

Binding Sites↗
PubMed1998

Aryl thioglycoside-based affinity purification of exo-acting cellulases.

The influence of ligand-coupling chemistry and mobile-phase composition on the interaction of exo-acting cellulases with an immobilized complementary ligand was investigated. p-Aminophenyl 1-thio-beta-D-cellobioside (APTC) was used as a representative affinity ligand to which exo-acting cellulases (cellobiohydrolases, CBHs) preferentially bind. A "crude" cellulase preparation from the fungus Trichoderma reesei served as an enzyme source. The adsorption properties of the two principal exo-acting CBHs in this preparation, CBH I and CBH II, are shown to be distinctly different under several scenarios. Their relative affinities, based on column elution behavior and partition equilibrium experiments, are shown to be highly dependent on the functional groups employed for ligand coupling, the extent of functional group hydrolysis, the composition of the mobile phase, and the inherent nature of the enzymes. The dependency on the chemistry of the supporting matrix was illustrated using agarose supports containing cyanate ester, N-hydroxy-succinimide, and epoxy functional groups. When compared under apparent optimal conditions, the affinity of CBH II for immobilized APTC was approximately 10-fold that of CBH I. However, selective adsorption of CBH I or CBH II can be achieved by adjusting experimental parameters.

Basidiomycota↗
PubMed1999

Copper-adenine catalyst for O(2) production from H(2)O(2).

In solutions of CuCl2 and adenine copper can be bound to adenine. Two Cu(adenine)(2) complexes [Cu(C(5)H(5)N(5))(2)]2+/Cu(C(5)H(4)N(5))(2)] are in equilibrium with free adenine. Copper-adenine complexes present a catalytic activity (e.g., H(2)O(2) disproportionation into O(2) and water) but depending on complex concentration H(2)O(2) also strongly oxidizes the adenine within the complexes. Raman spectroscopy quantifies copper-adenine complex formation and H(2)O(2) consumption; polarography quantifies O(2) production. As for C(40) catalase, optimal catalytic capacities depend on physiological conditions, such as pH and temperature. The comparative analysis of kinetic parameters shows that the affinity for H(2)O(2) of Cu(adenine)(2) is 37-fold lower than that of C(40) catalase and that the molar activity for O(2) production is 200-fold weaker for Cu(adenine)(2) than for the enzyme. In the 10(-6)-10(-3) M range, the strong decrease of activity with raising complex concentration is explained by aggregation or stacking, which protects Cu(adenine)(2) entities from H(2)O(2) oxidation, but also decreases O(2) production.

Adenine↗
PubMed2000

Purification and in vitro activities of the Bacillus subtilis TnrA transcription factor.

The Bacillus subtilis nitrogen regulatory protein TnrA was purified and its interaction with the nrgAB regulatory region examined. The TnrA protein activates transcription from the nrgAB promoter in vitro. DNase I footprinting and methylation protection experiments demonstrated that TnrA binds to an inverted repeat, upstream of the -35 region of the nrgAB promoter. Gel mobility retardation assays were used to determine the affinity of TnrA for its DNA-binding site. The equilibrium dissociation binding constant for the interaction of TnrA with the nrgAB promoter fragment was 7.7 nM under the conditions used here. Mutations in the TnrA consensus sequence that reduce nrgAB expression in vivo were found to reduce significantly the in vitro affinity for TnrA. An A+T rich region located upstream of the TnrA-binding site was found to be necessary for optimal transcriptional activation. A mutant protein, TnrA(HTH), was constructed in which the putative helix-turn-helix DNA-binding motif was altered by exchanging two arginine residues for alanine residues. The TnrA(HTH) protein was unable to activate the in vivo expression of nrgAB and had an in vitro affinity for the nrgAB promoter that was significantly lower than that of the wild-type protein.

Amino Acid Sequence↗
PubMed1996

On the analysis of CO(2), H(2)- and CO, H(2)-mixtures by water-gas potentiometry with solid electrolyte cells.

The potentiometric analysis of CO(2), H(2) and CO, H(2)O-mixtures using oxide ion-conducting solid electrolytes requires the adjustment of the water-gas equilibrium without side reactions in the high-temperature galvanic cell. Conventional cell designs suitable for the analysis of H(2), H(2)O and CO, CO(2)-mixtures are not applicable due to the insufficient gas residence times in the cells and the insufficient catalytical activity of the platinum electrodes. Solid electrolyte cells have to be modified by integrating of suitable catalysts. Under optimized conditions of gas velocity and cell temperature both gas systems can be analyzed only by measuring the cell tension U (=-emf) and temperature in the favorized temperature range around 813 degrees C. Here systematical errors of the component ratio or the mole fraction were smaller than 6%. Several fundamental requirements for the application of catalysts in solid electrolyte cells for the analysis of reactive water-gas mixtures are pointed out.

Journal Article↗
PubMed1977

Hydrodynamic theory of swimming of flagellated microorganisms.

A theory of the type commonly used in polymer hydrodynamics is developed to calculate swimming properties of flagellated microorganisms. The overall shape of the particle is modeled as an array of spherical beads which act, at the same time, as frictional elements. The fluid velocity field is obtained as a function of the forces acting at each bead through Oseen-type, hydrodynamic interaction tensors. From the force and torque equilibrium conditions, such quantities as swimming velocity, angular velocity, and efficiency can be calculated. Application is made to a spherical body propelled by a helical flagellum. A recent theory by Lighthill, and earlier formulations based on tangential and normal frictional coefficients of a curved cylinder, CT and CN, are analyzed along with our theory. Although all the theories predict similar qualitative characteristics, such as optimal efficiency and the effect of fluid viscosity, they lead to rather different numerical values. In agreement with Lighthill, we found the formalisms based on CN and CT coefficients to be somewhat inaccurate, and head-flagellum interactions are shown to play an important role.

Flagella↗
PubMed2002

Effect of the homogeneity of the column set on the performance of a simulated moving bed unit. II. Experimental study.

Previous studies of the simulated moving bed (SMB) process assume identical characteristics of all the columns incorporated in a given unit. Due to the practical impossibility to manufacture identical columns, numerical applications of the theory to modeling and optimization use for each of the needed column parameter the average value for the entire column set. In this study, the effects of these simplifications on the actual productivity of the SMB process are evaluated by making exact calculations, i.e., by taking the differences in the porosity values into account. We apply a revised set of separation conditions previously introduced and derived from the equilibrium theory. Earlier theoretical results are compared to experimental results obtained in the study of the enantiomeric separation of Tröger's base on Chiralpak AD. Due to the nonLangmuirian character of the adsorption isotherms of these two compounds on the packing material used, the separation area cannot be determined analytically. As an alternative, a reliable numerical algorithm was used to scan a wider region and to define the separation area. The form of this area depends on the applied porosity values. A UV detector and a laser polarimeter located at one node of the SMB monitor on-line the internal concentration profiles. Excellent agreement between the calculated and the experimentally determined concentration profiles was obtained under nonlinear conditions. The influence of column-to-column variations on the performance of the SMB process was found to be more significant under nonlinear than under linear conditions.

Adsorption↗
PubMed1988

Oral carnitine therapy in children with cystinosis and renal Fanconi syndrome.

11 children with either cystinosis or Lowe's syndrome had a reduced content of plasma and muscle carnitine due to renal Fanconi syndrome. After treatment with oral L-carnitine, 100 mg/kg per d divided every 6 h, plasma carnitine concentrations became normal in all subjects within 2 d. Initial plasma free fatty acid concentrations, inversely related to free carnitine concentrations, were reduced after 7-20 mo of carnitine therapy. Muscle lipid accumulation, which varied directly with duration of carnitine deficiency (r = 0.73), improved significantly in three of seven rebiopsied patients after carnitine therapy. One Lowe's syndrome patient achieved a normal muscle carnitine level after therapy. Muscle carnitine levels remained low in all cystinosis patients, even though cystinotic muscle cells in culture took up L-[3H]carnitine normally. The half-life of plasma carnitine for cystinotic children given a single oral dose approximated 6.3 h; 14% of ingested L-carnitine was excreted within 24 h. Studies in a uremic patient with cystinosis showed that her plasma carnitine was in equilibrium with some larger compartment and may have been maintained by release of carnitine from the muscle during dialysis. Because oral L-carnitine corrects plasma carnitine deficiency, lowers plasma free fatty acid concentrations, and reverses muscle lipid accumulation in some patients, its use as therapy in renal Fanconi syndrome should be considered. However, its efficacy in restoring muscle carnitine to normal, and the optimal dosage regimen, have yet to be determined.

Administration, Oral↗
PubMed1989

Characterization of an estrogen-binding protein in the yeast Candida albicans.

An estrogen-binding protein (EBP) has been identified and characterized in the cytosol of the pathogenic yeast Candida albicans. Binding of [3H]estradiol was found to be optimal at pH 7.4 in the presence of 0.3 M KCl and was linearly related to protein concentration. Binding was very rapid, reaching maximal levels in about 30 min, and was reversible with a dissociation rate constant of 13.2 +/- 1.7 x 10(-4) sec-1. EBP binding was destroyed by treatment with proteolytic enzymes and by high temperatures. Scatchard analysis of the [3H]estradiol equilibrium binding data of C. albicans (strain stn-1) yielded an apparent dissociation constant of 12.3 +/- 2.1 nM and a maximal binding capacity of 753 +/- 145 fmol/mg protein. Binding competition experiments showed very high specificity and stereoselectivity of EBP, demonstrating the following order of potency in displacing [3H]estradiol: 17 beta-estradiol greater than estrone greater than estriol greater than 17 alpha-estradiol. Negligible competitive potency was found for other mammalian steroid hormones, diethylstilbestrol, tamoxifen, or fungal hormones. The abundance of EBP was 4- to 10-fold higher during the early logarithmic growth phase of yeast cells than during the stationary phase. The molecular size of EBP, measured by Sephacryl S-200 gel exclusion chromatography, yielded a Stokes radius of approximately 29 A. Sucrose density gradient sedimentation showed a sedimentation coefficient (S2020,W) of 4, with no ionic dependent aggregation of the [3H]estradiol-EBP complex. The apparent mol wt of the EBP is approximately 46,000, with an axial ratio of 1, indicating the symmetrical shape of the molecule. In summary, in addition to the previously described corticosterone-binding protein, a separate high affinity, stereospecific, estrogen-selective binder has been demonstrated in the cytosol of C. albicans.

Candida albicans↗
PubMed1982

DNA-binding protein from HeLa cells that binds preferentially to supercoiled DNA damaged by ultraviolet light or N-acetoxy-N-acetyl-2-aminofluorene.

A DNA-binding protein was partially purified from extracts of HeLa cells by high-speed centrifugation and chromatography on DEAE-cellulose, phosphocellulose and ultraviolet light-irradiated DNA-cellulose columns. It eluted from the phosphocellulose column with 0.375 M potassium phosphate and from the ultraviolet light-irradiated DNA-cellulose column between 0.5 M and 1 M NaCl. The protein binds preferentially to supercoiled PM2 DNA treated with ultraviolet light or N-acetoxy-N-acetyl-2-aminofluorene, as compared to native supercoiled PM2 DNA. The binding is non-cooperative. Nicked or linear forms of PM2 DNA (damaged or untreated) are not efficient substrates, indicating a requirement of DNA supercoiling for DNA binding. The sedimentation coefficient of the protein estimated by glycerol gradient centrifugation is 2.0-2.5 S, corresponding to a molecular weight of about 20000-25000 if the protein is spherical. The binding to DNA irradiated with ultraviolet light or treated with acetoxyacetylaminofluorene is optimal at around 100-200 mM NaCl and is relatively independent of temperature and pH. MgCl2 and MnCl2 at concentrations between 1 and 5 mM do not markedly affect the binding, but it is inhibited by sucrose, ATP and caffeine. The biological significance of the DNA-binding protein remains to be determined. It does not possess significant glycosylase, endonuclease or exonuclease activities. The dissociation equilibrium constant for the binding reaction of the protein to the ultraviolet light or acetoxyacetylaminofluorene-induced binding sites on DNA is estimated to be 4.10(-11) M. There are at least 1.10(5) DNA-binding protein molecules/HeLa cell.

2-Acetylaminofluorene↗
PubMed1991

Prevention of nosocomial aspergillosis.

Unfiltered outside air averages 1-15 pathogenic Aspergillus sp. colony forming units (cfu) m-3 although short-term fluctuations are substantial. Seasonal variation reflects increased spore prevalence during periods of greater availability of non-viable matter. In hospital, airborne spores reflect incomplete filtration, infiltration of outside air and shedding of adherent spores from introduced objects. In highly protected hospital areas supplied with air filtered at high efficiency, where aspergillus cfus may be as low as 0.01 cfu m-3, infiltration and shedding contribute a high fraction of ambient spores. Nosocomial aspergillosis occurs in linear proportion to the mean ambient hospital airborne spore content. An analysis presuming a steady-state dynamic equilibrium is imperfect because repeated sampling produces occasional high counts which violate a Poisson distribution. 'Mini-bursts' arise from disturbance of settled spores in dust, shedding spores from clothes or other subtle sources. These sources are best mitigated by increasing the air change rate. It is most important to protect bone marrow transplant patients, leukaemia and lymphoma patients undergoing intensive, potentially curative therapy. The optimal protective environments include high filtration efficiency, point-of-use filters, protection against infiltration and filter bypass, elimination of in-hospital sources, and high air change rates.

Air Microbiology↗
PubMed2003

Water uptake in the cat flea Ctenocephalides felis (Pulicidae: Siphonaptera).

To counteract water loss due to excretion, cuticular transpiration and respiration, various groups of arthropods have developed mechanisms for active uptake of water vapor from unsaturated air. In this study, active uptake capabilities and water loss rates were examined in the various developmental stages of the cat flea, Ctenocephalides felis. To determine critical equilibrium humidity, the lowest relative humidity at which active water uptake can occur, pre-desiccated immature and adult fleas were placed in a series of humidity regimes ranging from 44 to 93% RH. Active uptake occurred in larval stages at relative humidities above 53% and in pre-pupae at 75-93% RH. Pupae and adults did not demonstrate active uptake at any humidity. Optimal uptake for larvae occurred between 20 and 30 degrees C. When placed over Drierite (<10% RH), larval and adult stages demonstrated a higher rate of water loss than pre-pupal and pupal stages. Active water uptake is necessary to ensure proper development of the larvae of C. felis. Active uptake ceases after the larval-pupal ecdysis and it appears that adults have lost the ability to actively uptake water.

Animals↗
PubMed2003

Control of the sulfide (S2-) concentration for optimal zinc removal by sulfide precipitation in a continuously stirred tank reactor.

Precipitation of Zn2+ with S2- was studied at room temperature in a continuously stirred tank reactor of 0.5l to which solutions of ZnSO4 (800-5800 mgl(-1) Zn2+) and Na2S were supplied. The pH was controlled at 6.5 and S2- concentration in the reactor was controlled at set point values ranging from 3.2x10(-19) to 3.2x10(-4) mgl(-1), making use of an ion-selective S2- electrode. In steady state, the mean particle size of the ZnS precipitate decreased linearly from 22 to 1 microm for S2- levels dropping from 3.2x10(-4) to 3.2x10(-18) mgl(-1). At 3.2x10(-11) mgl(-1) of S2-, the supplies of ZnSO4 and Na2S solutions were stoichiometric for ZnS precipitation. At this S2- level, removal of dissolved zinc was optimal with effluent zinc concentration <0.03 mgl(-1) while ZnS particles formed with a mean geometric diameter of about 10 microm. Below 3.2x10(-11) mgl(-1) of S2- insufficient sulfide was added for complete zinc precipitation. At S2- levels higher than 3.2x10(-11) mgl(-1) the effluent zinc concentration increased due to the formation of soluble zinc sulfide complexes as confirmed by chemical equilibrium model calculations.

Chemical Precipitation↗
PubMed1998

On the importance of public choice in migration models.

"Recent general equilibrium Tiebout models that use single-crossing indifference curves to establish a migration equilibrium incorporate both voting and migration decisions. These models have concentrated on the important question of the existence of an equilibrium, but the incorporation of both voting and migration has important efficiency consequences as well. This paper demonstrates the important effect of the interaction of voting and migration on efficiency conditions by showing that head taxes (which are generally considered to provide efficient migration incentives with constant marginal congestion costs) do not provide incentives for efficient migration decisions unless the public choice mechanism results in optimal public service provision within jurisdictions."

Attitude↗
PubMed2001

Characterization of RNA aptamer binding by the Wilms' tumor suppressor protein WT1.

The interaction of the zinc finger protein WT1 with RNA aptamers has been investigated using a quantitative binding assay, and the results have been compared to those from a previous study of the DNA binding properties of this protein. A recombinant peptide containing the four zinc fingers of WT1 (WT1-ZFP) binds to representatives of three specific families of RNA aptamers with apparent dissociation constants ranging from 13.8 +/- 1.1 to 87.4 +/- 10.4 nM, somewhat higher than the dissociation constant of 4.12 +/- 0.4 nM for binding to DNA. An isoform that contains an insertion of three amino acids between the third and fourth zinc fingers (WT1[+KTS]-ZFP) also binds to these RNAs with slightly reduced affinity (the apparent dissociation constants ranging from 22.8 to 69.8 nM) but does not bind to DNA. The equilibrium binding of WT1-ZFP to the highest-affinity RNA molecule was compared to the equilibrium binding to a consensus DNA molecule as a function of temperature, pH, monovalent salt concentration, and divalent salt concentration. The interaction of WT1-ZFP with both nucleic acids is an entropy-driven process. Binding of WT1-ZFP to RNA has a pH optimum that is narrower than that observed for binding to DNA. Binding of WT1-ZFP to DNA is optimal at 5 mM MgCl(2), while the highest affinity for RNA was observed in the absence of MgCl(2). Binding of WT1 to both nucleic acid ligands is sensitive to increasing monovalent salt concentration, with a greater effect observed for DNA than for RNA. Point mutations in the zinc fingers associated with Denys-Drash syndrome have dramatically different effects on the interaction of WT1-ZFP with DNA, but a consistent and modest effect on the interaction with RNA. The role of RNA sequence and secondary structure in the binding of WT1-ZFP was probed by site-directed mutagenesis. Results indicate that a hairpin loop is a critical structural feature required for protein binding, and that some consensus nucleotides can be substituted provided proper base pairing of the stem of the hairpin loop is maintained.

Base Sequence↗
PubMed2000

The feedback sanction.

The emergency department (ED) is a complex environment. Its equilibrium, or homeostasis, is critically dependent on the continuous action of feedback processes. For any system to function efficiently, it needs to know the outcomes of specific actions in a consistent, reliable, and expeditious way. Historical attitudes and the unique operating characteristics of the ED have combined to impose sanctions on the proper provision of feedback. The following features have been identified as obstructive to optimal feedback operation: incomplete awareness of the significance of the problem, excessive time and work pressures, case infrequency, deficiencies in specialty follow-up, communication failures, deficient reporting systems for near-misses, error, and adverse events, biases in case review processes, shift changeover times, and shiftwork. The result is that clinicians, nurses, and trainees are working in conditions that are suboptimal for the provision of safe care, as well as for learning and job fulfillment. Good feedback is a necessary condition for well-calibrated performance by individuals, and is integral to effective team function. More needs to be known about outcomes for feedback to work efficiently. The critical role of feedback in other aspects of ED function, such as education and human factors engineering, should be emphasized. The current interest in medical error and evolving attitudes toward a new culture of patient safety provide a unique opportunity to examine feedback and the critical role it plays in ED function.

Emergency Medicine↗