Helix movement is coupled to displacement of the second extracellular loop in rhodopsin activation

The second extracellular loop (EL2) of rhodopsin forms a cap over the binding site of its photoreactive 11-cis retinylidene chromophore. A crucial question has been whether EL2 forms a reversible gate that opens upon activation or acts as a rigid barrier. Distance measurements using solid-state 13C NMR spectroscopy between the retinal chromophore and the β4 strand of EL2 show that the loop is displaced from the retinal binding site upon activation, and there is a rearrangement in the hydrogen-bonding networks connecting EL2 with the extracellular ends of transmembrane helices H4, H5 and H6. NMR measurements further reveal that structural changes in EL2 are coupled to the motion of helix H5 and breaking of the ionic lock that regulates activation. These results provide a comprehensive view of how retinal isomerization triggers helix motion and activation in this prototypical G protein-coupled receptor. © 2009 Nature America, Inc. All rights reserved

Evidence of nonlinearity in digoxin pharmacokinetics

Six normal male volunteers received 0.5 mg label doses of digoxin as (a) a bolus intravenous injection over 2 min, (b) a constant rate intravenous infusion over 1 hr, (c) a constant rate intravenous infusion over 3 hr, and (d) a solution in 5% dextrose given orally. Plasma concentrations of digoxin were measured by radioimmunoassay for a 4 day period and urinary excretion for a 6 day period after the single doses. The mean (coefficient of variation) total areas under the plasma concentration-time curves per 0.5 mg of digoxin were (a) 35.55 (14.8%), (b) 30.20 (27.7%), (c) 25.80 (35.5%), and (d) 15.47 (49.9%); the means differed significantly (0.01>p>0.005). The mean (coefficient of variation) total amounts excreted in the urine as a fraction of the dose were (a) 0.689 (6.31%), (b) 0.517 (20.4%), (c) 0.588 (16.8%), and (d) 0.374 (23.4%); the means differed significantly (p<0.001. Both the total clearance and the nonrenal clearance of digoxin differed significantly with the method of intravenous administration. The slower the rate of input of digoxin to the body, the greater were both the total clearance and the nonrenal clearance of the drug, which strongly suggests nonlinear pharmacokinetics .Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45078/1/10928_2005_Article_BF01068079.pd

Soft power and soft disempowerment: Qatar, global sport and football’s 2022 World Cup finals

This paper examines the critical role of global sport within Qatar’s international strategy, most notably through the successful bid to stage the 2022 football World Cup. Our discussion draws particularly on interviews with key stakeholders in the Qatari sport system, as well as fieldwork in Qatar and the analysis of relevant documents and secondary materials. The paper is separated into five main parts. First, we set out our theoretical framework, which draws on the concepts of globalization and soft power; to assist in the analysis of Qatar’s engagement with global sport, we introduce the two further concepts of ‘glocal consciousness’ and ‘soft disempowerment’. Second, we provide the reader with background information on Qatar and Qatari sport. Third, we discuss three key themes that emerged mainly from our interviews on Qatar and global sport: exhibiting Qatar’s supremacies as a microstate; the pursuit of peace, security and integrity; and confronting national health crises. Fourth, we explore issues of soft disempowerment and reputational risk with regard to these three themes and, in particular, critical international comment surrounding Qatar’s hosting of the 2022 World Cup. Fifth, we conclude by arguing that Qatar’s soft disempowerment, although damaging in the short term, leaves the door open for the state to respond in a positive manner, regenerating its soft power capabilities in the process

Pharmacokinetics of tolmetin with and without concomitant administration of antacid in man

The purpose of this study was to determine whether a concomitant single dose of antacid or multiple doses of antacid administered prior to, and with tolmetin, alter the pharmacokinetics of tolmetin when the drug was administered as a commercially available tablet containing tolmetin sodium. The possible effects of the antacid on plasma concentrations and urinary excretion of tolmetin and its major metabolite were evaluated following administration of: (a) tolmetin sodium alone; (b) antacid four time a day for three days prior to a single dose of tolmetin sodium, with continuation of the antacid during the day tolmetin was given; and (c) co-administration of single doses of tolmetin sodium and antacid. The twenty-four subject study was of the crossover type. There were no significant differences among treatment means for: (i) peak plasma concentrations of both tolmetin and metabolite, (ii) AUC 0–8 h and AUC 0-∞ for both tolmetin and metabolite, (iii) time to peak plasma concentration for both tolmetin and metabolite, (iv) plasma concentrations of both tolmetin and the metabolite at all sampling times (except for tolmetin at 2 h), (v) renal clearance of both tolmetin and its metabolite, and (vi) the amount of metabolite excreted in the 0–24 h urine. There were small, but significant, differences among amounts of tolmetin excreted in the 0–24 h urine. Semilogarithmic plots of both tolmetin and metabolite plasma concentrations past the peak concentrations were curved over the entire 8-h observation period; although the elimination half-life of tolmetin has been reported to be about one hour, the half-life most probably exceeds 2.6 h in most subjects. The results of this study indicate a lack of a significant drug-drug interaction between the non-steroidal anti-inflammatory agent, tolmetin sodium, and a commonly used antacid, which is a mixture of magnesium and aluminium hydroxides.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46637/1/228_2004_Article_BF00561061.pd