PubMed · 4206474
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J L Betz, P R Brown, M J Smyth, P H Clarke. 1974-02-01. Evolution in action.. https://doi.org/10.1038/247261a0
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BACKGROUND AND OBJECTIVE: Cytochrome-P450-dependent liver function can be measured with the 13C-methacetin breath test (MBT). This has heretofore been done with the use of a mass-spectrometer. This study was undertaken to evaluate the MBT (NDIRS) done with the isotope-selective nondispersive infrared spectrometer. PATIENTS AND METHODS: 20 healthy volunteers (ten women, ten men, aged 22-76 years) and 16 patients (ten women, six men, aged 48-71 years) with histologically confirmed liver cirrhosis (Child-Pugh stage A [n = 7], B [n = 5] or C [n = 4]) were given 13C-methacetin in 100 ml of tea after a 12-hour fasting period. Breath tests were performed before the test drink and 5, 10, 15, 20, 30, 40, 50, 60, 80, 100, 120, 150 and 180 min thereafter. The ratio of 13C to 12C was determined, as delta (/1000), and from it the maximal percentage rate (PDRmax) calculated, as well as the cumulative rate (cPDRmax) after 30, 60, 120 and 180 min (Median and 5th and 95th percentiles). RESULTS: For patients with liver cirrhosis there were significantly lower values for cPDRmax and cPDR after 30, 60, 120 and 180 min than in the healthy subjects (P < 0.002): PDR [%]/h: 3.9 (0.7-15.9) vs. 36.5 (23.1-50.0); cDPR 30 min [%]: 1.1 (-0.2-6.0) vs. 12.4 (7.6-17.1); cDPR 3 h [%]: 9.8 (-2.3-27.5) vs. 36.0 (29.9-45.1). There were significant differences among the patients, depending on their Child-Pugh staging. CONCLUSION: The MBT with the cost-effective NDIRS can reliably and noninvasively distinguish between healthy subjects and patients with liver cirrhosis. The test is therefore suitable for the quantitative analysis of liver functions.
The three-dimensional structure, dynamics, and binding modes of representative kappa-opioid agonists of the arylacetamide class (U50, 488; U69,593; U62,066; CI-977; ICI199,441; ICI197,067; BRL52,537; and BRL52,656) have been investigated using molecular modeling techniques. Systematic exploration of the conformational space of the ligand combined with molecular dynamics (MD) simulations in water revealed consistent conformational preferences for all the kappa-agonists in this series. The results were further compared with available X-ray and 1D- and 2D-NMR data to identify potential "lead" conformers for molecular docking. Ligand binding modes were initially determined using automated docking of two of the ligands (U50,488 and BRL52,537) to the kappa-opioid receptor. Extrapolation of the predicted binding mode to other members in this ligand series revealed similar docking preferences, with each ligand docked along the receptor helical axis. The binding modes were further refined using MD simulations of the receptor-ligand complexes. The results show a that salt bridge is formed between the amino proton of the ligands and the carboxylate group of Asp138 in TM3. This interaction most likely serves as a key anchoring point for the agonist association. Additional ligand contacts were noted with kappa-specific residues Ile294, Leu295, and Ala298, which may, in part, explain the kappa-selectivity in this series. In comparing the arylacetamides with opiate-based ligands, no evidence was found to link these classes through a common binding motif (except for the ion pair). The binding site model was also applied to explain the enantiomeric preference of U50,488 and to provide insight to the mu/kappa-selectivity of representative ligands in this series. Overall, the results provide a structure-based rationale for ligand recognition that is consistent both with site-directed mutagenesis experiments and structure-function relationship data.
The efficiency of pretreatment of aqueous soil extracts using a cation-exchange resin has been investigated by gas chromatographic-mass spectrometric (GC-MS) determination of nerve agent hydrolysis products after tert.-butyldimethylsilyl (TBDMS) derivatization. An aqueous solution containing methylphosphonic acid (MPA) and its monoalkyl esters, ethyl methylphosphonic acid, isopropyl methylphosphonic acid and pinacolyl methylphosphonic acid, was dried, and these phosphonic acids were derivatized with N-methyl-N-(tert.-butyldimethylsilyl)trifluoro-acetamide and analyzed by GC-MS. The yields of TBDMS derivatives were significantly decreased by the addition of calcium and magnesium ions to an aqueous solution (approximately 0.5 mM) before derivatization. The extent of lowered yields was related to the hydrophilicity of phosphonic acids. MPA and its monoalkyl esters were spiked into soil samples (sand, alluvial soil and volcanic ash soil), extracted with distilled water, dried, silylated and applied to GC-MS. The yields of TBDMS derivatives of monoalkyl esters from soil samples were low (3-42%) and MPA derivative was scarcely detected (yield: < 0.7%). By desalting the aqueous soil extract by passage through a strong cation-exchange resin, the yields of TBDMS derivatives of monoalkyl esters were significantly improved (12-69%) and MPA derivative was detected (yield: 2-36%). The extent of improved yields was related to the concentrations of divalent metal cations in aqueous soil extracts. In combination with desalting by the cation-exchange resin, GC-MS after TBDMS derivatization enables detection of nerve agent hydrolysis products in soils at sub-ppm (0.2 microgram/g) concentrations.