Short- and long-term prognosis after coronary artery bypass grafting in relation to smoking habits

A study was conducted to determine the conditions needed to achieve the equilibrium concentration for the epimerization of d-lysergic acid diethylamide (LSD) to iso-LSD. The reaction was followed by integration of the C-9 resonance of LSD and iso-LSD by proton nuclear magnetic resonance (NMR). The C-9 resonance of LSD and iso-LSD appear as singlets at 6.35 and 6.27 ppm respectively. Starting with pure LSD, the conversion to iso-LSD is attained at temperatures above 37 degrees C and pH levels over 7.0. At a pH of 7.0 or higher, the LSD/iso-LSD ratio of 9:1 is achieved after one week at 45 degrees C or two weeks at 37 degrees C. Starting with iso-LSD, the conversion to LSD requires more vigorous conditions. The 9:1 LSD/iso-LSD ratio is attained only after 6 weeks at a temperature of 45 degrees C and a pH of 9.7. At lower pH levels, the reaction proceeds more slowly. The 9:1 LSD/iso-LSD ratio is achieved whether the starting material is LSD or iso-LSD and therefore represents an equilibrium concentration (K = 9). In addition, the more vigorous conditions needed to achieve equilibrium of iso-LSD to LSD demonstrate the difficulty in extraction of the epimerizable proton of iso-LSD. This study is the first to quantitate the epimerization of LSD by NMR techniques and establishes the conditions needed to induce epimerization in solution.     

Mesocosm study of Mytilus edulis larvae and postlarvae, including the settlement phase, exposed to a gradient of tributyltin

In a mesocosm study, the effects of a gradient of tributylin (TBT) (nominal TBT concentrations of 0.3, 2.3, 18.5, 146, and 1150 ng Sn liter-1) on Mytilus edulis larvae and postlarvae, including the settlement phase, were investigated over 15 days. Effects of TBT on mortality, growth measured as increase in shell length, shell dimensions, and settlement were evaluated. In general, mortality was high in all mesocosms including the control; during the first 24 h of the experiment, mortality was 63% at the highest TBT concentration (26% in the control). An LC50 (24 h) of 254 ng Sn liter-1 was estimated. The mortality rate of larvae/postlarvae increased 40% at 18.5 ng Sn liter-1 (0.41 day-1) compared with the control (0.30 day-1). For postlarvae, the growth rate decreased with increasing TBT concentration. The mean shell length at 2.3 ng Sn liter-1 was significantly reduced in comparison to the control on Day 15. Then EC10 (15 days) for shell growth was estimated to be 5.4 ng Sn liter-1. This is the lowest effect concentration ever reported in the literature. For postlarvae, shell dimensions in terms of shell length-shell width relations were affected by TBT at 1150 ng Sn liter-1, because the reduced growth led to the failure of adult mussels to secret a dissochonch shell. During the first days of exposure, the settlement monitored on polyethylene settling strips was stimulated by TBT, after which the settlement decreased due to the high mortality. Only a small portion of the population survived to the end of the test period. By comparison of the biotic conditions (in terms of larval abundance and particle concentration reflecting larval food) in the control mesocosm with those in the cove where the experiment was conducted, it was concluded that the mesocosm had successfully simulated the field conditions.     

Multiple human cytochromes contribute to biotransformation of dextromethorphan in-vitro: role of CYP2C9, CYP2C19, CYP2D6, and CYP3A

Cytochromes mediating the biotransformation of dextromethorphan to dextrorphan and 3-methoxymorphinan, its principal metabolites in man, have been studied by use of liver microsomes and microsomes containing individual cytochromes expressed by cDNA-transfected human lymphoblastoid cells. In-vitro formation of dextrorphan from dextromethorphan by liver microsomes was mediated principally by a high-affinity enzyme (Km (substrate concentration producing maximum reaction velocity) 3-13 microM). Formation of dextrorphan from 25 microM dextromethorphan was strongly inhibited by quinidine (IC50 (concentration resulting in 50% inhibition) = 0.37 microM); inhibition by sulphaphenazole was approximately 18% and omeprazole and ketoconazole had minimal effect. Dextrorphan was formed from dextromethorphan by microsomes from cDNA-transfected lymphoblastoid cells expressing CYP2C9, -2C19, and -2D6 but not by those expressing CYP1A2, -2E1 or -3A4. Despite the low in-vivo abundance of CYP2D6, this cytochrome was identified as the dominant enzyme mediating dextrorphan formation at substrate concentrations below 10 microM. Formation of 3-methoxy-morphinan from dextromethorphan in liver microsomes proceeded with a mean Km of 259 microM. For formation of 3-methoxymorphinan from 25 microM dextromethorphan the IC50 for ketoconazole was 1.15 microM; sulphaphenazole, omeprazole and quinidine had little effect. 3-Methoxymorphinan was formed by microsomes from cDNA-transfected lymphoblastoid cells expressing CYP2C9, -2C19, -2D6, and -3A4, but not by those expressing CYP1A2 or -2E1. CYP2C19 had the highest affinity (Km = 49 microM) whereas CYP3A4 had the lowest (Km = 1155 microM). Relative abundances of the four cytochromes were determined in liver microsomes by use of the relative activity factor approach. After adjustment for relative abundance, CYP3A4 was identified as the dominant enzyme mediating 3-methoxymorphinan formation from dextromethorphan, although CYP2C9 and -2C19 were estimated to contribute to 3-methoxymorphinan formation, particularly at low substrate concentrations. Although formation of dextrorphan from dextromethorphan appears to be sufficiently specific to be used as an in-vitro or in-vivo index reaction for profiling of CYP2D6 activity, the findings raise questions about the specificity of 3-methoxymorphinan formation as an index of CYP3A activity.     

Enhancement of 5-aminolaevulinic acid-induced photodynamic therapy in normal rat colon using hydroxypyridinone iron-chelating agents

Currently, the clinical use of 5-aminolaevulinic acid (ALA)-induced protoporphyrin IX (PPIX) for photodynamic therapy (PDT) is limited by the maximum tolerated oral ALA dose (60 mg kg(-1)). This study investigates whether hydroxypyridinone iron-chelating agents can be used to enhance the tissue levels of PPIX, without increasing the administered dose of ALA. Quantitative charge-coupled device (CCD) fluorescence microscopy was employed to study PPIX fluorescence pharmacokinetics in the colon of normal Wistar rats. The iron chelator, CP94, when administered with ALA was found to produce double the PPIX fluorescence in the colonic mucosa, compared with the same dose of ALA given alone and to be more effective than the other iron chelator studied, CP20. Microspectrofluorimetric studies demonstrated that PPIX was the predominant porphyrin species present. PDT studies conducted on the colonic mucosa showed that the simultaneous administration of 100 mg kg(-1) CP94 i.v. and 50 mg kg(-1) ALA i.v. produced an area of necrosis three times larger than similar parameters without the iron-chelating agent with the same light dose. It is possible, therefore, to increase the amount of necrosis produced by ALA-induced PDT substantially, without increasing the administered dose of ALA, through the simultaneous administration of the iron-chelating agent, CP94.     

Crystal structure of a murine alpha-class glutathione S-transferase involved in cellular defense against oxidative stress

STATEMENT OF PROBLEM: The electric alloy brazed joints of removable partial denture alloys have failed frequently after routine usage. PURPOSE: A technique providing higher joint strengths was investigated. This investigation compared the tensile strengths of electric-brazed and laser-welded joints for a cobalt-chromium removable partial denture alloy. MATERIAL AND METHODS: Twenty-four cobalt-chromium standard tensile testing rods were prepared and divided into three groups of eight. All specimens in the control group (group 1) were left in the as-cast condition. Groups 2 and 3 were the test specimens, which were sectioned at the center of the rod. Eight specimens were joined by using electric brazing, and the remaining specimens were joined by using laser welding. After joining, each joint was ground to a uniform diameter, then tested to tensile failure on an Instron universal testing machine. Failure loads were recorded and fracture stress calculated. Statistical analysis was applied. RESULTS: The student-Newman-Keuls test showed a highly significant difference between the joint strengths of the as-cast control specimens, the electric-brazed and laser-welded joints. CONCLUSIONS: The tensile strengths of the as-cast joints were higher than those for the laser-welded joints, and both were higher than the electric-brazed joint strengths.