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Published ahead of print April 15, 2016

The objective of this study was to evaluate the corrosion behavior of Ti-29Nb-13Ta-4.6Zr alloy (TNTZ) with immersion in an acidic saline solution containing fluoride by investigating change in color and the surface structure of the oxide film. With immersion in fluoride-containing solution, TNTZ showed a less marked change in color than commercially pure titanium (TI), and a smaller decrease in glossiness. The outermost surface was covered with oxides from its constituent elements at before and after immersion in solution with or without fluoride. When immersed in fluoride-containing solution, the film consisted of larger niobium and tantalum oxides than that before or after immersion in solution without fluoride. In summary, TNTZ showed superior resistance to discoloration to TI after immersion in fluoride-containing solution. The results suggest that the subsequent increase in niobium and tantalum fractions in the oxide film in TNTZ improves resistance to corrosion.

When titanium and titanium alloys are used in prosthodontic devices, exposure to the oral environment may result in discoloration or corrosion. This phenomenon may be due to fluoride, found in prophylactic agents, or peroxide, which is either produced by inflammatory cells or present in denture cleaning agents. The aims of this study were to clarify the process of discoloration or corrosion of titanium in an oral environment, and investigate the reaction of surface titanium oxide to fluoride and hydrogen peroxide by analysis of electrochemical behavior and X-ray photoelectron spectroscopy. Surface oxide film on commercially pure titanium (CP-Ti) in fluoride-containing solution was dissolved and corroded. In the peroxide-containing solution, a gradual development and thickening of the surface oxide film with subsequent discoloration of the titanium was observed

Objective: This study evaluated the influence of laser irradiation with a high pulse repetition rate on dentin bonding. Background Data: Although resin bonding to erbium:yttrium-aluminium-garnet (Er:YAG) laserirradiated dentin has frequently been investigated, the effects of a high pulse repetition rate have not yet been sufficiently investigated. Methods: Four groups treated under different laser conditions were evaluated in this study: 100 mJ/pulse–10 pulses per second [pps], 50 mJ/pulse–20 pps, 33 mJ/pulse–30 pps, and the unlased condition as a control. The total energy used to irradiate each group was adjusted to 1.0 W. After bovine dentin specimens were irradiated by an Er:YAG laser, acid conditioners (10% citric acid/3% ferric chloride) were applied to the lased surface. Thereafter, a PMMA rod was bonded to the lased dentin using 4- META/MMA-TBB resin, and mini-dumbbell-shaped specimens were prepared. These specimens were then tested under tensile mode and fractured surfaces were observed under scanning electron microscopy (SEM). Results: The bond strength of the unlased control was significantly higher than those of the three lased groups. Among the three lased groups, irradiation with higher output energy and lower pulse repetition rate tended to affect the higher bond strength. Upon SEM observation of the fractured surface, the lased groups showed the mixture of failure in the hybrid layer in almost part. There was no significant difference among the three lased groups. Conclusion: It can be concluded from the results of this study that a higher pulse repetition rate is not effective for resin bonding to laser-irradiated dentin.

A thermoelectric module, which consists of rectangular‐fin elements and has a simple structure suitable for micro fabrication, was newly proposed for a micro‐ to milli‐scale thermoelectric power generator. A unit model was introduced to examine the basic characteristics of thermoelectric power generation with rectangular‐fin elements. Theoretical descriptions of the power density and conversion efficiency were given by solving one‐dimensional heat and current flows inside the elements. Then, it was found that there exist optimum aspect ratios of the elements to achieve maximum power density and conversion efficiency. Power density becomes larger if the module is downsized with a similarity in shape, while conversion efficiency remains constant, i.e., smaller devices show better performance. Finally, comparative analysis with a standard pi‐type module was conducted to emphasize the superiority of the proposed module in micro systems, when convective heat transfer resistance is taken into account. © 2006 Wiley Periodicals, Inc. Heat Trans Asian Res, 35(3): 224–244, 2006; Published online in Wiley InterScience (). DOI 10.1002/htj.20108

Purpose: To examine whether inhibition of P-glycoprotein (P-gp) activity by quinidine affects the central nervous system toxicity of lidocaine and racemic bupivacaine (bupivacaine). Methods: Forty male Sprague-Dawley rats were randomly divided into four groups (n = 10). Fifteen minutes following administration of 15 mg·kg−1of quinidine (QL and QB groups) or saline (L and B groups), lidocaine (L and QL groups, 4 mg·kg−1·min−1) or bupivacaine (B and QB groups, 1 mg·kg−1·min−1) was infused until convulsions occurred. Concentrations of lidocaine and its primary metabolite, monoethylglycinexylidide (MEGX) and bupivacaine in plasma and in the brain at the onset of convulsions were measured by high-performance liquid chromatography. Results: There were no differences in the dose of lidocaine required to induce convulsions between the L and QL groups. There were no differences in the concentrations of total (L = 17.2 ± 3.5, QL = 16.6 ± 2.6 μg·mL−1) or unbound lidocaine (L = 7.8 ± 2.5, QL = 7.3 ± 2.3 μg·mL−1), total (L = 1.2 ± 0.5, QL = 1.3 ± 0.7 μg·mL−1) or unbound MEGX (L = 0.9 ± 0.5, QL = 0.8 ± 0.4 μg·mL−1) in plasma, total lidocaine or MEGX in the brain at the onset of convulsions between the L and QL groups. The dose of bupivacaine required to induce convulsions was comparable in the B and QB groups. At the onset of convulsions, plasma concentrations of both total (B = 4.9 ± 1.1, QB = 4.0 ± 0.6 μg·mL−1, P = 0.03) and unbound bupivacaine (B = 1.4 ± 0.6, QB = 0.9 ± 0.2 μg·mL−1, P = 0.02) were significantly lower in the QB group than in the B group. There were no differences in concentration of total bupivacaine in the brain between the B and QB groups. Conclusion: These results suggest that quinidine inhibited P-gp activity, resulting in increased brain/plasma concentration ratio of bupivacaine, but not of lidocaine, and decreased the threshold of plasma concentration for bupivacaine-induced convulsions.

Abstract: Because dental implants contact many different tissues, the implant material must have optimum surface compatibility with the host bone tissue, subepithelial connective tissue, and epithelial tissue. In addition, dental implant surfaces exposed to the oral cavity must remain plaque-free. Such materials can be created under well-controlled conditions by modifying the surfaces of metals that contact those tissues. “Tissue-compatible implants,” which are compatible with all host tissues, must integrate with bone tissue, easily form hemidesmosomes, and prevent bacterial adhesion. This research was aimed at developing such tissue-compatible implants by modifying titanium surfaces using a dry process for closely adhering to the titanium substrate and ensuring good wear resistance. The process includes ion beam dynamic mixing (thin calcium phosphates), ion implantation (Ca+, N+, F+), titania spraying, ion plating (TiN, alumina), and ion beam mixing (Ag, Sn, Zn, Pt) with Ar+. At the bone tissue/implant interface, a thin calcium phosphate coating and rapid heating with infrared radiation were effective in controlling the dissolution without cracking the coating. This thin calcium phosphate coating may directly promote osteogenisis, but it may also enable immobilization of functional proteins or drugs. At the oral fluid/implant interface, an alumina coating and F+ implantation were responsible for inhibiting the adhesion of microbial plaque. In conclusion, dry-process surface modification is useful in controlling the physicochemical nature of surfaces, including the surface energy and the surface electrical charge, and in developing tissue-compatible implants.

We applied dynamic light scattering technique on the model system of hen egg lysozyme in salt-free aqueous ethanol solution to study the mechanism of denaturation and aggregation of protein. At low ethanol concentration [0–63% (v/v)], the fast relaxation mode was observed, which was caused by lysozyme molecules in the solution interacting with each other with strong repulsive electrostatic force. At 45 and 63% (v/v) ethanol, the slow relaxation mode was also observed, which showed translational diffusive nature, similar to that observed in salt-free polyelectrolyte solution. At 72 or 81% (v/v) ethanol, the slow mode disappeared, leaving only the fast mode. However, the mutual diffusion coefficients obtained from the fast mode at 72 and 81% (v/v) ethanol decreased by about one order of magnitude compared with those from the fast mode at 0–63% (v/v). The reported alcohol-induced conformational transformation of lysozyme molecules at >60% (v/v) ethanol from their native structure to an α-helix-rich structure might cause such drastic decrease in the mutual diffusion coefficients. At the highest ethanol concentration of 90% (v/v), the slow mode reappeared, and its relaxation rate was decreasing with elapsed time, which is possibly due to the growth of aggregates of lysozyme molecules. X-ray diffraction results suggested that the intermolecular β-sheet formation caused the aggregation. Thus, our results indicated that the change in molecular structure of lysozyme closely relates to the diffusion of molecules and their aggregation. © 2001 John Wiley & Sons, Inc. Biopolymers 59: 370–379, 2001

Methadone and levo-α-acetylmethadol (LAAM) are opioid agonists used for analgesia and preventing opiate withdrawal. Methadone is sequentially N-demethylated to the inactive metabolites 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenylpyraline (EMDP). LAAM is essentially a prodrug that undergoes bioactivation via sequentialN-demethylation tolevo-α-acetyl-N-normethadol (nor-LAAM) andlevo-α-acetyl-N,N-dinormethadol (dinor-LAAM). Methadone and LAAM are metabolized by CYP3A4 in human liver. Since they are administered orally, and CYP3A4 is expressed in human intestine, we tested the hypotheses that human intestine can metabolize methadone and LAAM, and evaluated the participation of CYP3A4. Intestinal microsomal methadone N-demethylation exhibited hyperbolic noncooperative kinetics and biphasic Eadie-Hofstee plots. Using a dual-enzyme Michaelis-Menten model,Kmvalues were 11 and 1200 μM for EDDP and 23 and 930 μM for EMDP formation, respectively. CYP3A4 inhibitors (troleandomycin and ketoconazole) inhibited EDDP and EMDP formation by >70%. Methadone N-demethylation by CYP3A4 showed biphasic Eadie-Hofstee plots without evidence of positive cooperativity; Kmvalues were 10 and 1100 μM for EDDP and 20 and 1000 μM for EMDP formation. Intestinal microsomal LAAM and nor-LAAM N-demethylation also exhibited hyperbolic kinetics and biphasic Eadie-Hofstee plots.Kmvalues were 21 and 980 μM for nor-LAAM from LAAM and 18 and 1200 μM for dinor-LAAM from nor-LAAM. Troleandomycin and ketoconazole inhibitedN-demethylation by >70%. LAAM and nor-LAAM metabolism by CYP3A4 showed biphasic Eadie-Hofstee plots without evidence of positive cooperativity; Kmvalues were 8 and 1300 μM, 6 and 950 μM, respectively. Predicted in vivo intestinal extraction of methadone and LAAM is 21 and 33%, respectively. We conclude that methadone, LAAM, and nor-LAAM are metabolized by human intestinal microsomes; CYP3A4 is the predominant cytochrome P450 isoform; CYP3A4-catalyzed methadone, LAAM, and nor-LAAM metabolism is characterized by noncooperative, multisite kinetics; and intestinal metabolism may contribute to presystemic methadone inactivation and LAAM bioactivation.

levo-α-Acetylmethadol (LAAM) is a long-acting opioid agonist prodrug used for preventing opiate withdrawal. LAAM undergoes bioactivation via sequential N-demethylation to nor-LAAM and dinor-LAAM, which are more potent and longer-acting than LAAM. This study examined LAAM and nor-LAAM metabolism using human liver microsomes, cDNA-expressed CYP, CYP isoform-selective chemical inhibitors, and monoclonal antibody to determine kinetic parameters for predicting in vivo drug interactions, involvement of constitutive CYP isoforms, and mechanistic aspects of sequentialN-demethylation. N-Demethylation of LAAM and nor-LAAM by human liver microsomes exhibited biphasic Eadie-Hofstee plots. Using a dual-enzyme Michaelis-Menten model,Kmvalues were 19 and 600 μM for nor-LAAM and 4 and 450 μM for dinor-LAAM formation, respectively. LAAM and nor-LAAM metabolism was inhibited by the CYP3A4-selective inhibitors troleandomycin, erythromycin, ketoconazole, and midazolam. Of the cDNA-expressed isoforms examined, CYP2B6 and 3A4 had the highest activity toward LAAM and nor-LAAM at both low (2 μM) and high (250 μM) substrate concentrations. N-Demethylation of LAAM and nor-LAAM by expressed CYP3A4 was unusual, with hyperbolic velocity curves and Eadie-Hofstee plots and without evidence of positive cooperativity. Using a two-site model, Kmvalues were 6 and 0.2 μM, 1250 and 530 μM, respectively. Monoclonal antibody against CYP2B6 inhibited CYP2B6-catalyzed but not microsomal LAAM or nor-LAAM metabolism, whereas troleandomycin inhibited metabolism in all microsomes studied. The ratio [dinor-LAAM/(nor-LAAM plus dinor-LAAM)] with microsomes and CYP3A4 decreased with increasing LAAM concentration, suggesting most dinor-LAAM is formed from released nor-LAAM that subsequently reassociates with CYP3A4. Based on these results, we conclude that LAAM and nor-LAAM are predominantly metabolized by CYP3A4 in human liver microsomes, and CYP3A4 exhibits unusual multisite kinetics.

The amino acid sequence of the coat protein (CP) of a tobacco necrosis virus (TNV) strain, Toyama isolate, was determined by a combination of peptide and cDNA sequencing. The deduced sequence of 276 residues was compared with CPs of other TNV isolates and other plant virus isolates of Tombusviridae. It showed the highest similarity to the TNV Nebraska isolate with 92% identity and moderate similarity to the TNV strain A with 51% identity, confirming the previous serological analysis. It also showed overall similarity with CPs of mostly genera Necrovirus and Sobemovirus, and partial similarity with CPs of genera Tombusvirus and Carmovirus. Among 13 CPs that showed overall similarity, there were 10 completely conserved residues. These included three residues that participate in Ca2+ligation at the interfaces of virion subunits in TNV crystal structure, suggesting that similar metal binding occur in the viruses of genera Necrovirus and Sobemovirus.

The influence of surface modifications to titanium on the initial adherence of Porphyromonas gingivalisATCC33277 and Actinobacillus actinomycetemcomitansATCC43718 was evaluated. Surface modifications were performed with dry processes including ion implantation Ca, N, F, oxidation anode oxidation, titania spraying, ion plating TiN, alumina, and ion beam mixing Ag, Sn, Zn, Pt with Aron polished pure titanium plates. Comparatively large amounts of P. gingivalisand A. actinomycetemcomitansadhered to polished titanium plates. The degree of P. gingivalisadhesion showed a positive correlation with surface energy and the amount of calciumion adsorption. Adherence of both P. gingivalisand A. actinomycetemcomitansincreased on calciumimplanted surfaces compared with polished titanium surfaces, whereas adherence of P. gingivaliswas remarkably decreased on aluminacoated surfaces. These findings indicate that titanium implants exposed to the oral cavity require surface modification to inhibit the adherence of oral bacteria, and that surface modification with a dry process is useful in controlling the adhesion of oral bacteria as well as ensuring resistance against wear.© 2000 John Wiley & Sons, Inc. J Biomed Mater Res, 52, 388–394, 2000.

The crystal structure of tobacco necrosis virus (TNV) has been determined by real-space averaging with 5-fold non-crystallographic symmetry, and refined to R=25.3 % for diffraction data to 2.25 Å resolution. A total of 180 subunits form a T=3 virus shell with a diameter of about 280 Å and a small protrusion at the 5-fold axis. In 276 amino acid residues, the respective amino terminal 86, 87 and 56 residues of the A, B and C subunits are disordered. No density for the RNA was found. The subunits have a “jelly roll” β-barrel structure, as have the structures of the subunits of other spherical viruses. The tertiary and quaternary structures of TNV are, in particular, similar to those of southern bean mosaic virus, although they are classified in different groups. Invisible residues 1 to 56 with a high level of basic residues are considered to be located inside the particle. Sequence comparison of the coat proteins of several TNV strains showed that the sequences of the disordered segment diverge considerably as compared with those of the ordered segment, consistent with a small tertiary structural constraint being imposed on the N-terminal segment. Basic residues are localized on the subunit interfaces or inner surface of the capsid. Positive charges of the basic residues facing the interior, as well as those of the N-terminal segment, may neutralize the negative charge of the RNA inside. Five calcium ions per icosahedral asymmetric unit are located at the subunit interfaces; three are close to the exterior surface, the other two away from it. The environments of the first three are similar, and those of the other two sites are similar. These calcium ions are assumed to be responsible for the stabilization/transition of the quaternary structure of the shell. Three peptide segments ordered only in the C subunits are clustered around each 3-fold (quasi-6-fold) axis forming a β-annulus, and may lead to quasi-equivalent interactions for the organization of the T=3 shell. Copyright 2000 Academic Press

The three‐dimensional structures of the deoxy‐ and carbonmonoxyhaemoglobin (Hb) from Dasyatis akajei, a stingray, have been determined at 1.6 and 1.9 Å resolution, respectively. This is one of the most distantly related vertebrate Hbs to human HbA. Both structures resemble the respective forms of HbA, indicating that the α2β2‐type tetramer and the mode of the quaternary structure change are common to Hbs of jawed vertebrates. Larger deviations between D. akajeiHb and human HbA are observed in various parts of the molecule, even in the Eand Fhelices. Significant mutations and/or conformational changes are also observed around the haems, in the C‐terminal region of the β subunit, in the α1β2interface and in the organic phosphate‐binding site of HbA. Despite these structural differences, the oxygen affinity, haem–haem interaction, Bohr effect and organic phosphate effect of D. akajeiHb are all only moderately reduced. Compared with human HbA, the overall r.m.s. deviation of main‐chain atoms in the helical regions of bony fish Hbs is smaller than that of D. akajeiHb.

Objective: To examine the effect of propofol on the pharmacokinetics of midazolam in vivo and to elucidate the mechanism of the pharmacokinetic changes of midazolam by propofol with the use of human liver microsomes and recombinant CYP3A4.Methods: In an in vivo, double-blind randomized study, 24 patients received 0.2 mg/kg midazolam and either 2 mg/kg propofol (propofol group) or placebo (placebo group) for induction of anesthesia. In the propofol group, continuous infusion of propofol at 9 mg/kg/h was started immediately after the bolus infusion of propofol and was maintained for an hour. In the placebo group the same dose of soybean emulsion as a placebo was given and infused intravenously for an hour instead of propofol. In an in vitro study the effect of propofol on the metabolism of midazolam was studied with human liver microsomes and recombinant CYP3A4.Results: In the propofol group the mean clearance of midazolam was decreased by 37% (P = .005) and the mean elimination half-life was prolonged by 61% (P = .04) compared with the placebo group. The mean plasma concentrations of 1′-hydroxymidazolam were lower in the propofol group than in the placebo group at 5, 10, 15, 20, and 30 minutes after midazolam was administered (P < .05). The mean (±SD) Michaelis-Menten constant for midazolam 1′-hydroxylation by human liver microsomes was 5.6 ± 3.3 μmol/L. The formation of 1′-hydroxymidazolam was competitively inhibited by propofol, and the mean inhibition constant was 56.7 ± 16.6 μmol/L. The mean Michaelis-Menten constant and mean inhibition constant values for midazolam 1′-hydroxylation by recombinant CYP3A4 were 4.0 μmol/L and 61.0 μmol/L, respectively, consistent with the mean values obtained from human liver microsomes.Conclusion: Propofol decreases the clearance of midazolam, and the possible mechanism is the competitive inhibition of hepatic CYP3A4.

To elucidate the effect of cytochrome P450 levels in hepatic microsomes on the metabolism of lidocaine in vivo, we investigated the metabolism of lidocaine in untreated (UT group) and phenobarbital-treated rats (PB group) in vivoand compared the results with those obtained by immunoblotting of rat hepatic microsomes. There were no differences in pharmacokinetic parameters for lidocaine between the UT and PB groups. The plasma concentrations of the N-deethylated metabolite of lidocaine, monoethyl-glycinexylidide (MEGX), in the PB group were significantly higher than those in the UT group. On the other hand, the plasma concentrations of the aromatic ring hydroxylated metabolite of lidocaine, 3-hydroxylidocaine (3-OH LID), were significantly lower in the PB group than in the UT group. When lidocaine metabolism was studied with hepatic microsomes prepared from rats in the UT and PB groups, the rates of formation of MEGX were higher in the microsomes of the PB group than in those of the UT group. The contents of CYP2B1 and 3A2 in rat hepatic microsomes of the PB group measured by immunoblotting were significantly higher than those of the UT group. Strong correlations were found between the area under the plasma concentration vs. time curve for MEGX and specific contents of CYP2B1 and 3A2. These findings suggest that formation of MEGX in vivois dependent on the levels of CYP2B1 or 3A2 in rat liver.

The crystal structure of Arthromyces ramosusperoxidase (ARP) in complex with benzhydroxamic acid (BHA) as determined by X‐ray analysis at 1.6 Å shows unambiguously how BHA binds to ARP. BHA is located in the distal heme pocket. Its functional groups are held by three hydrogen bonds to His56Nϵ, Arg52Nϵ, and Pro154O, but are too far away to interact with the heme iron. The aromatic ring of BHA is positioned at the entrance of the channel to the heme pocket, approximately parallel to the heme group. Most water molecules at the active site of the native enzyme are replaced by BHA, leaving a ligand, probably a water molecule, at the sixth position of the heme. Results are compared with spectroscopic data.

Lidocaine was used for evaluation of hepatic function in a patient undergoing hepatic resection. Preoperatively, half-life of indocyanine green (ICG) was 33 min after intravenous administration. Plasma concentration of the N-dealkylated metabolite of lidocaine, monoethylglycinexylidide (MEGX), was quantitatively determined to evaluate hepatic function. The patient's rate of formation of MEGX at 15 min after administration of lidocaine was within normal limits, at 56 μg/L. These findings suggest that in this patient, hepatic cytochrome P-450IIIA activity was not impaired, but selective impairment of uptake of ICG into hepatocytes or excretion into the bile ducts was present. The rate of formation of MEGX was decreased, and plasma concentration of bilirubin was elevated postsurgically; this could have been the result of decreased cytochrome P-450IIIA activity or decreased hepatic blood flow after hepatic resection. We conclude that the rate of formation of MEGX is a better index of hepatic function than is ICG half-life.

Objective. Finding an optimal soldering system for a titanium prosthesis has become increasingly important with the successful introduction of titanium and titanium alloys to dentistry. This study examined the effect of corrosion on the strength of the soldered joints of pure titanium and Ti6Al4V alloys joined using various solders.

The topotactic reactions between TiO2and barium salts were found and the crystallographic orientation relationships between TiO2and BaTiO3were elucidated as follows.[001]TiO2(R)//[101]BaTiO3and[100]TiO2(R)//[1\bar1\bar1]BaTiO3.[100]TiO2(A)//[100]BaTiO3and[010]TiO2(A)//[010]BaTiO3.