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41.
A simple method to improve the accuracy of non-invasive ultrasound in selecting TIA patients for cerebral angiography. 总被引:2,自引:2,他引:0 下载免费PDF全文
P Humphrey P Sandercock J Slattery 《Journal of neurology, neurosurgery, and psychiatry》1990,53(11):966-971
A prospective study is reported of the ability of B mode ultrasound imaging and continuous wave Doppler flow studies to detect different degrees of stenosis of the extracranial internal carotid artery (ICA) in 186 arteries in 99 patients with transient ischaemic attacks (TIA) and minor ischaemic stroke. A simple mathematical equation has been developed which combines the image and flow data to provide a single predictor of the degree of angiographic stenosis which has advantages over either ultrasonic modality used alone. The sensitivity and specificity of the predictive model in the detection of stenosis greater than or equal to 25% was 73% and 98%, of stenosis greater than or equal to 50% was 90% and 93%, of stenosis greater than or equal to 75%, 65% and 99% and occlusion 100% and 94% respectively. The principal clinical value of ultrasound screening is to spare patients with "non-significant" stenosis the risk of unnecessary angiography. Thus a simple measure of the Duplex screening tests' performance is the proportion of all strokes occurring as a complication of angiography that are avoided by changing the investigation policy from "angiograms for all carotid TIA and minor ischaemic stroke patients" to "angiograms for all patients with abnormal ultrasound results". If Duplex scanning were used to select patients most likely to have a significant abnormality on angiography, depending on the degree of stenosis to be detected, 52-85% of angiographic strokes might be avoided. If the predictive equation were used 62-88% of angiographic strokes might be avoided. 相似文献
42.
H Lauder L A Sellers T -P D Fan W Feniuk P P A Humphrey 《British journal of pharmacology》1997,122(4):663
- The aim of the present study was to determine the effect of somatostatin (SRIF) on mitogen-induced regeneration of rat aortic vascular smooth muscle cells (VSMC) and for comparison Chinese hamster ovary (CHO)-K1 cells expressing human recombinant sst5 receptors (CHOsst5), following partial denudation of a confluent cell monolayer. Regeneration was assessed by measuring areas of recovery into the denuded area and by counting total cell numbers.
- In VSMC, SRIF (0.1 nM–1 μM) had no effect on the basal levels of regeneration but caused a concentration-dependent inhibition (pIC50 8.0–8.6) of the stimulated regeneration induced by sub-maximal concentrations of basic fibroblast growth factor (bFGF, 10 ng ml−1), platelet-derived growth factor-BB (PDGF, 5 ng ml−1) or endothelin-1 (ET-1, 100 nM). SRIF (pIC50 8.8) also inhibited bFGF-induced regeneration of CHOsst5 cells.
- In VSMC, the inhibitory action of SRIF on the regeneration induced by bFGF (10 ng ml−1) was due to an anti-proliferative effect, rather than an effect on cell migration, as SRIF (0.1 nM–1 μM) abolished bFGF-induced increases in total cell numbers. The bFGF-induced increase in cell numbers was also abolished by actinomycin D (0.1 μg ml−1).
- The sst5 receptor-selective agonist, L-362,855 (pIC50 10.5), was about 100 times more potent than SRIF at inhibiting bFGF-induced regeneration of both VSMC and CHOsst5 cells whilst the sst2 receptor-selective agonist, BIM-23027 (pIC50 6.8), was approximately 20 times weaker than SRIF.
- The sst5 receptor antagonist, BIM-23056 (100 nM), antagonized SRIF-induced inhibition of bFGF-induced regeneration in both VSMC and CHOsst5 cells (estimated pKB values 8.8 and 8.3, respectively).
- SRIF-induced inhibition of bFGF-induced regeneration of VSMC and CHOsst5 cells was abolished by pretreating cells with pertussis toxin (100 ng ml−1) for 20 h.
- These findings suggest that SRIF-induced inhibition of the proliferation of rat aortic VSMC is mediated via activation of receptors which are similar to human sst5 receptors. Furthermore this inhibitory effect is transduced via pertussis toxin-sensitive Gi/Go proteins.
43.
A study was conducted to evaluate patient response to patient controlled analgesia (PCA) devices. All patients were interviewed for this concurrent study. A survey was also taken with the nursing staff for their assessments regarding PCA therapy and comparison of outcomes between morphine and meperidine use. Our goal was to see what improvements could be made in pain management and patient therapy wherever possible. 相似文献
44.
D. J. Trezise A. D. Michel C. B. A. Grahames B. S. Khakh A. Surprenant P. P. A. Humphrey 《Naunyn-Schmiedeberg's archives of pharmacology》1995,351(6):603-609
The effects of the putative selective P2X purinoceptor agonist, ,-methylene-l-adenosine 5-triphosphate (me-l-ATP), were determined at rat neuronal and smooth muscle P2X purinoceptors.Me-l-ATP had no effect on the extracellularly recorded membrane potential of the rat isolated vagus nerve preparation at concentrations up to 300 M. In contrast, the archetypal P2X purinoceptor agonist, , methylene ATP (meATP;1–100 M), produced concentration-related depolarisation responses with a mean EC50 value of 10.8 M. The depolarising effects of meATP were not attenuated by me-l-ATP (100 M). In voltage clamp experiments on single nodose ganglion neurones, ATP (100 M), but not me-l.-ATP (1–300 M), evoked rapid ( < 20 ms onset) inward currents when applied using a concentration-clamp method. In receptor binding studies to rat brain membranes, me-d-ATP and meATP competed with high affinity for [3H]Lx meATP binding sites, with mean pIC50 values of 7.7 and 8.3, respectively. However, me-l-ATP possessed low affinity for these sites and competed only at concentrations in excess of 10 M (mean pIC50 value 4.1).In prostatic segments of the rat vas deferens, me-l-ATP (1–100 M) and meATP (0.3–100 M) each produced concentration-related contractile responses with mean EC50 values of 17.1 and 3.6 M, respectively. Me-l-ATP (1–10 M) evoked fast inward currents in freshly dispersed vas deferens smooth muscle cells, indicative of an action at ligand-gated ion channels. Binding sites in vas deferens membranes labelled using 1 nM [3H]meATP exhibited high affinity for me-l-ATP, meATP and me-d-ATP with mean PIC50 values of 7.7, 8.4 and 7.3, respectively.These results indicate that me-l-ATP exhibits neither agonist nor antagonist properties at P2X purinoceptors on rat vagal neurones and possesses only very low affinity for [3H]meATP binding sites in rat brain. In contrast, me-l-ATP is a potent, high affinity agonist at smooth muscle P2X purinoceptors of the rat vas deferens. This selective agonist action of me-l-ATP suggests that P2X purinoceptors in smooth muscle and neurones are different and represent distinct P2X purinoceptor subtypes. 相似文献
45.
Somatostatin receptors mediating inhibition of basal and stimulated electrogenic ion transport in rat isolated distal colonic mucosa 总被引:4,自引:0,他引:4
E. S. McKeen W. Feniuk P. P. A. Humphrey 《Naunyn-Schmiedeberg's archives of pharmacology》1995,352(4):402-411
The aim of this study was to examine the potencies of several recently identified selective somatostatin (SRIF)-receptor ligands as inhibitors of electrogenic ion transport in the rat distal colonic mucosa with the view to identifying the SRIF receptor type involved. Under basal conditions, cumulative administration of SRIF and SRIF2g decreased short circuit current (SCC), a measure of electrogenic ion transport, with EC50 values of 4 nM and 9 nM respectively. The peptidase inhibitors, phosphoramidon (1 M) and amastatin (10 M), had no effect on the potencies of either SRIF or SRIF28. The inhibitory action of SRIF on basal SCC was suppressed by piretanide and diphenylamine-2-carboxylate, compatible with the assumption that the Na+K+2Cl– co-transporter and Cl– channels, respectively, may be involved in this antisecretory action of SRIF. Tetrodotoxin (1 M) had no effect on the antisecretory action of SRIF, suggesting that the process was not neuronally mediated.All of the SRIF analogues examined, with the exception of BIM-23056, maximally inhibited basal SCC to a similar extent as SRIF. Seglitide and octreotide were both more potent antisecretory agents than SRIF (respective EC50 values, 0.4 nM and 1.5 nM) suggesting that this effect was mediated by a receptor belonging to the SRIF1 receptor group. The most distinguishing feature of the rank order of agonist potencies was the high potency of the selective sst2 receptor ligand, BIM-23027 (EC50, value 0.32 nM), the weaker potency exhibited by the selective sst5 receptor ligand, L-362855 (EC50 value 21 nM), and the lack of agonist activity displayed by the selective sst3 receptor ligand, BIM-23056 (EC50 value > 1000 nM). This profile is comparable with that observed in binding studies on the recombinant sst2 receptor.Forskolin-stimulated secretion was suppressed by SRIF analogues with the rank order of agonist potencies BIM-23027 > SRIF > L-362855 > BIM-23056 which resembled that exibited under basal conditions. However, the absolute potencies of these agonists were lower (respective EC50 values 2 nM, 14 nM, 38 nM and > 1000 nM) whilst the magnitude of inhibition was about three fold greater. BIM-23027 and SRIF (both 30 nM) also inhibited carbachol-stimulated increases in basal SCC by 60–70%, while a similar concentration of L-362855 inhibited these responses by 11 %. BIM-23056 (1 M) had no effect on carbachol-simulated secretion. Radioligand binding studies on rat colonic mucosal membranes using [125I]-Tyr11-SRIF suggested heterogeneity of SRIF binding sites. Thus, SRIF and SRIF28 competed for binding (IC50 values, 0.32 and 0.63 nM, respectively) with Hill slopes less than unity; while seglitide and BIM-23027 both maximally displaced only 30–40% of specific binding with apparent high affinity (respective pIC50 values, 10.1 nM and 10.0).In conclusion, SRIF decreases basal as well as both cAMP and Ca2+-dependent Cl– secretion in rat colonic mucosa. The rank order of agonist potencies suggests that receptors resembling the recombinant sst2 receptor mediate inhibition of basal and forskolin-stimulated secretion. Radioligand binding studies suggest that BIM-23027 interacts with a sub-population of [125I]Tyr11-SRIF binding sites in rat colonic mucosal membranes which probably correspond to the receptors mediating the antisecretory effects described here. 相似文献
46.
The nature of error detection as manifested by the error-related negativity was examined in both a Sternberg memory search task and a visual search task. Both tasks were performed in conditions with consistent or varied stimulus-response mapping and loads of three or six letters. After subjects were trained extensively in all conditions, they performed the tasks throughout the night without sleeping. The data suggest that the effectiveness of error detection decreases over time because of a decrease in the quality of perceptual processing. Error detection also suffers when performance requires more search-related resources. In both cases, the representation of the correct response is compromised. These results indicate that error detection depends on the same perceptual and cognitive processes that are required for correct performance. 相似文献
47.
Michel AD Chessell IP Humphrey PP 《Naunyn-Schmiedeberg's archives of pharmacology》1999,359(2):102-109
The actions of monovalent and divalent ions on the P2X7 receptor have been assessed by measuring their effect on responses to the P2 receptor agonist, 2’- and 3’-O-(4-benzoyl-benzoyl)-ATP (DbATP), in HEK293 cells expressing the human recombinant P2X7 receptor. In these cells, DbATP increased the cellular accumulation of the DNA binding, fluorescent dye, YO-PRO-1. The potency
of DbATP to elicit this effect was decreased by both calcium and magnesium ions. In addition, when the pH was increased above
8 or reduced below 6.5, the potency of DbATP was less than obtained at pH 7.5. Monovalent ions also affected the P2X7 receptor such that the potency of DbATP was 19-fold higher in NaCl-free buffer containing 280 mM sucrose (pEC50=6.48) than in 140 mM NaCl containing buffer (pEC50=5.19). Monovalent cations differentially affected the potency of DbATP. Thus, when the chloride concentration was maintained
at 140 mM, pEC50 values for DbATP were 6.14, 5.87 and 5.19 when the counter cation was 140 mM choline, potassium or sodium, respectively.
Monovalent anions also differentially affected the potency of DbATP and in the presence of 140 mM sodium ions, pEC50 values for DbATP were 6.14, 6.07, 5.19 and 4.53, respectively, when the counter anion was 140 mM aspartate, glutamate, chloride
or iodide. The inhibitory effect of monovalent anions on P2X7 receptor function was also observed in electrophysiological studies. Thus in sodium glutamate containing buffer the potency
of DbATP (pEC50=5.55) was approximately 22-fold higher than in NaCl containing buffer (pEC50=4.20). This study has demonstrated that P2X7 receptor function can be markedly affected by a wide range of ions and that physiological concentrations of sodium and chloride
ions, as well as divalent cations, contribute to the low potency of ATP as an agonist at this receptor.
Received: 27 July 1998 / Accepted: 18 November 1998 相似文献
48.
Humphrey GH Shapiro MA Randinitis EJ Guttendorf RJ Brodfuehrer JI 《Journal of clinical pharmacology》1999,39(11):1143-1150
The pharmacokinetics of R-clinafloxacin and S-clinafloxacin enantiomers of the broad-spectrum fluoroquinolone antibiotic, clinafloxacin, were characterized in selected volunteer subjects and patients after the administration of oral and intravenous doses of racemic drug. The absorption of each enantiomer was rapid and nearly complete after a single, oral 400 mg racemic dose. The mean (+/- SD) bioavailability of R-clinafloxacin was 87.5% +/- 4.8% compared to 86.2% +/- 5.8% for S-clinafloxacin. The mean Cmax of each enantiomer was 1.19 micrograms/mL, with plasma concentrations of each enantiomer remaining above 0.1 microgram/mL for at least 12 hours. No notable differences in the disposition of R-clinafloxacin and S-clinafloxacin were observed. After a single 400 mg intravenous dose of racemic drug, mean (+/- SD) t1/2 was 5.6 +/- 0.3 hours and 5.7 +/- 0.4 hours, plasma Cl was 329 +/- 49 mL/min and 314 +/- 45 mL/min, and Vdss was 138 +/- 18 L and 134 +/- 16 L for R- and S-clinafloxacin, respectively. Two healthy volunteers each received a single 400 mg oral dose of racemic clinafloxacin (alone) and with oral administration of 1 gm probenecid separated by a 1-week washout period between treatments. With probenecid coadministration, the increase in AUC0-infinity was 75% and 83% for R-clinafloxacin and was 71% and 75% for S-clinafloxacin in each subject, respectively. Probenecid increased the total exposure (AUC) of both R-clinafloxacin and S-clinafloxacin, although it had no stereo-selective effects on the disposition of either enantiomer. The antimicrobial potency of the isomers was also evaluated. In vitro susceptibility testing showed that the two compounds were comparable in their inhibitory activities, as all MICs were within twofold for each organism tested. These results demonstrate that in addition to their similar antimicrobial potency, R- and S-clinafloxacin have nearly identical disposition characteristics and are eliminated by similar mechanisms that display no apparent enantioselectivity in man. 相似文献
49.
R W Humphrey K M Wyvill B Y Nguyen L E Shay D R Kohler S M Steinberg T Ueno T Fukasawa M Shintani H Hayashi H Mitsuya R Yarchoan 《Antiviral research》1999,41(1):21-33
The pharmacokinetics, toxicity, and activity of KNI-272, a transition state inhibitor of HIV-1 protease, was assessed in a phase I trial. After an initial phase in which the pharmacokinetics were assessed, 37 patients with AIDS or symptomatic HIV infection and 100-400 CD4 cells/mm3 were entered in an escalating dose study. KNI-272 was administered four times daily for up to 12 weeks. Oral bioavailability ranged from 22 to 55% and was not appreciably different in the fasting and post-prandial state. The dose limiting toxicity was hepatic transaminase elevation; this could be reduced by escalating the dose over 4 weeks. When administered this way, the maximum tolerated oral dose was 40 mg/kg per day. At the highest two tolerated doses (26.4 and 40 mg/kg per day), there was some evidence of an anti-HIV effect with median decreases of 0.2-0.3 log10 copies/ml plasma HIV RNA; these decreases persisted through 7-8 weeks of treatment. There was an upward trend in the CD4 count at the 40 mg/kg per day dose but not at other doses. Additional studies focused on approaches to improve the therapeutic index of KNI-272 may be warranted. 相似文献
50.
Esophagogastrectomy for adenocarcinoma of the cardia. Ten years' experience and current approach. 总被引:4,自引:2,他引:2 下载免费PDF全文
During a 10-year period, 94 surgical resections for adenocarcinoma of the cardia (75 "curative" and 19 palliative) were performed using three primary approaches: Group I (46 curative, 14 palliative), esophagogastrectomy performed through a left thoracotomy or left thoraco-abdominal incision; Group II (17 curative, 4 palliative), resection done through two separate incisions (abdominal and thoracic) with delayed reconstruction between two and three months later; and Group III (12 curative, 1 palliative), resection, also through abdominal and thoracic incisions, with simultaneous reconstruction. Operative mortality in the 75 procedures done for cure was 19.5%, 18%, and 8.3% in Groups I, II, and III, respectively. Microscopic residual tumor at the line of resection was 56%, 12%, and 8%. Free margins less than 3 cm had the same local recurrence rate (21%, 6%, and 8%) within 18 months as did margins with residual microscopic tumor. The length of time from operation to first regular meal was 12, 110, and 7 days, respectively. Wide resection with subtotal esophagectomy and simultaneous reconstruction is advocated. 相似文献