Effect of Cimetidine and other antihistaminics on the elimination of aminopyrine,phenacetin and caffein

Cimetidine is widely prescribed for the treatment of peptic ulcer disease and has recently been shown to inhibit the metabolism of warfarin, antipyrine and diazepam. To further examine this phenomenon we investigated the effect of various doses of cimetidine and other related drugs on ¹⁴C-aminopyrine, ¹⁴C-phenacetin and ¹⁴C-caffeine breath tests. Cimetidine caused a dose-related inhibition of the metabolism of aminopyrine and caffeine but had no effect on the phenacetin breath test. Metiamide, H₁-antihistamines, phenothiazines and local anesthetics also inhibited the aminopyrine breath test. Cyproheptadine had no effect on either phenacetin or caffeine elimination. This study demonstrates a complex drug-drug interaction which may have widespread clinical implications.     

Transitions: Homo erectus and the Acheulian: the Ethiopian sites of Gadeb and the Middle Awash

Significant differences in activity-site patterning and artifact composition at Middle Pleistocene localities in Ethiopia's high plains and Afar Rift are indications of both single-episode, small-site residues from small groups and multi-purpose, multiple occupation sites from which larger, temporary groupings might be inferred. Reconstructions of palaeo-environments and geography show that large assemblages relate to relatively stable topography, such as stream channels or lake margins, while small assemblages are more common in deltaic situations of rapid sedimentation and burial in the Rift that preclude possibility of reoccupation. A model for Acheulian socio-economic behaviour within the drier African savanna, based (in part) on chimpanzee behaviour in open savanna habitats, is proposed. This takes the form of organization into relatively extensive territories, each with several more closed-vegetation core areas, of limited extent close to permanent water, surrounded by more extensive areas of drier, open savanna, regularly exploited and patrolled by small groups. Movement from one core area to another was rapid and made together as a group, to minimize danger from large predators and competition from other hominid groups.     

Genetics of NAD metabolism in Salmonella typhimurium and cloning of the nadA and pnuC loci.

The nadA and pnuC loci of S. typhimurium were cloned and found to reside within a 2.2-kilobase region. Two-dimensional O'Farrell gel electrophoresis of the proteins produced after chloramphenicol amplification and subsequent release from chloramphenicol inhibition revealed NadA and PnuC to be 43,000- and 25,000-molecular-weight proteins, respectively. The data indicated that nadA and pnuC represent two distinct genes.     

On-Chip Endothelial Inflammatory Phenotyping

Atherogenesis is potentiated by metabolic abnormalities that contribute to a heightened state of systemic inflammation resulting in endothelial dysfunction. However, early functional changes in endothelium that signify an individual''s level of risk are not directly assessed clinically to help guide therapeutic strategy. Moreover, the regulation of inflammation by local hemodynamics contributes to the non-random spatial distribution of atherosclerosis, but the mechanisms are difficult to delineate in vivo. We describe a lab-on-a-chip based approach to quantitatively assay metabolic perturbation of inflammatory events in human endothelial cells (EC) and monocytes under precise flow conditions. Standard methods of soft lithography are used to microfabricate vascular mimetic microfluidic chambers (VMMC), which are bound directly to cultured EC monolayers.¹ These devices have the advantage of using small volumes of reagents while providing a platform for directly imaging the inflammatory events at the membrane of EC exposed to a well-defined shear field. We have successfully applied these devices to investigate cytokine-,² lipid-^{3, 4} and RAGE-induced⁵ inflammation in human aortic EC (HAEC). Here we document the use of the VMMC to assay monocytic cell (THP-1) rolling and arrest on HAEC monolayers that are conditioned under differential shear characteristics and activated by the inflammatory cytokine TNF-α. Studies such as these are providing mechanistic insight into atherosusceptibility under metabolic risk factors.     

Identification of selenocysteine in glutathione peroxidase by mass spectroscopy

A convenient procedure was developed for identifying selenocysteine in selenoproteins by mass spectroscopy, based on formation of the 2,4-dinitrophenyl (DNP) derivative. Pure ovine erythrocyte glutathione peroxidase was reduced with sodium borohydride and reacted with 1-fluoro-2,4-dinitrobenzene at neutral pH under anaerobic conditions in 4 M guanidine. The inactivated enzyme was hydrolyzed with 6 N HCl for 20 h at 110 degrees C under anaerobic conditions. Following extraction of the hydrolysate with benzene, Se-(2,4-dinitrophenyl)selenocysteine in the aqueous phase was separated from non-DNP-amino acids by gel-filtration chromatography and then separated from other water-soluble DNP-amino acids by reversed-phase high-performance liquid chromatography. The Se-(2,4-dinitrophenyl)selenocysteine was converted to Se-methyl-N-(2,4-dinitrophenyl)selenocysteine by the addition of sodium barbital to induce an intramolecular Se leads to N shift (Smiles rearrangement) under anaerobic conditions, in the presence of methyl iodide to trap the liberated selenol group. Following esterification of the product's carboxyl group with methanol and hydrochloric acid, it was subjected to direct probe mass spectroscopy and identified as the methyl ester of Se-methyl-N-(2,4-dinitrophenyl)selenocysteine. This procedure allows selenocysteine to be isolated quite easily as a readily identifiable derivative and has permitted the first identification of a seleno amino acid in a protein by mass spectroscopy.