Memoirs of a bookseller.
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Book Industry↗
Biomedical subjects
R W Foster
Publications and source records attributed to R W Foster.
Computer-assisted learning lessons in drug disposition and pharmacokinetics.
A suite of 18 computer-assisted learning (C.A.L.) lessons has been developed in drug disposition covering processes, concepts and techniques, and pharmacokinetics. Development of lesions and implementation (using CDC's PLATO Programmerless Courseware Development authoring language (Advanced Tutorial Model) for delivery on IBM-PC clones (some also using NPL's Microtext on BBC model B microcomputers) and evaluation by questionnaire proceeded in stages. Staff assessed the authoring system and library lessons for their potential usefulness. Students assessed the importance to their own learning of the features that good quality C.A.L. lessons should display. Finally, our lessons were assessed by students for the presence of these features, comparison with other forms of presentation, their teaching performance, and integration into the curriculum. The use of a programmerless authoring language allowed the authors to concentrate on lesson subject content. The students appreciated the ability to go at their own pace and that their active involvement was required. Lessons scored well in relation to private reading and lectures but less well in comparison with practical work and tutorials. Appropriate integration of C.A.L. into the curriculum was found to be important. Evaluation by questionnaire at each stage of development was valuable.
Computer-Assisted Instruction↗
Spasmogen action in guinea-pig isolated trachealis: involvement of membrane K+-channels and the consequences of K+-channel blockade.
1. Acetylcholine (ACh), histamine, prostaglandin E2 and potassium chloride (KCl) each evoked concentration-dependent spasm of guinea-pig isolated trachealis treated with indomethacin (2.8 microM). 2. Neither tetraethylammonium (TEA; 0.1-10 mM) nor procaine (0.1-10 mM) potentiated these spasmogens. Indeed, procaine (10 mM) depressed the log concentration-effect curves of all the spasmogens while TEA (1-10 mM) caused some depression of the log concentration-effect curve of prostaglandin E2. 3. Intracellular electrophysiological recording was performed in trachealis bathed by normal Krebs solution or by Krebs solution containing 2.8 microM indomethacin. In either medium the majority of trachealis cells exhibited spontaneous electrical slow waves while some cells were electrically quiescent. In either medium the spasmogenic effects of ACh (1 mM) and histamine (0.2 mM) were accompanied by depolarization and abolition of slow wave discharge. In many cases the record of membrane potential subsequently exhibited noise which incorporated fast, hyperpolarizing transients. 4. In the absence and presence of indomethacin, TEA (10 mM) and procaine (5 mM) markedly reduced the membrane noise and hyperpolarizing transients evoked by ACh or histamine without augmenting the evoked tension. 5. It is concluded that slow wave discharge does not depend on prostaglandin synthesis. The membrane noise and hyperpolarizing transients evoked by ACh and histamine represent the opening of membrane K+-channels. While such K+-channel opening may offset spasmogen-induced depolarization it does not moderate the evoked tension.
Animals↗
The relaxant and spasmogenic effects of some xanthine derivatives acting on guinea-pig isolated trachealis muscle.
1. Caffeine (10 mM)-induced relaxation of guinea-pig isolated trachealis was attenuated and converted to a small spasmogenic response on cooling to 22 degrees C. The relaxant response was restored on rewarming to 37 degrees C and was abolished by indomethacin (2.8 microM). Cooling to 22 degrees C in the presence of indomethacin revealed spasmogenic responses to caffeine which were abolished on rewarming to 37 degrees C. 2. Trachealis treated with indomethacin (2.8 microM) was repeatedly dosed with acetylcholine (ACh, 10 microM). Caffeine (1 or 10 mM), added as each ACh-induced spasm reached equilibrium, transiently augmented but then suppressed the spasm. On cooling from 37 degrees C to 12 degrees C, the increment in spasm evoked by caffeine increased relative to the spasm evoked by ACh. 3. Trachealis treated with indomethacin (2.8 microM) was repeatedly dosed with caffeine (10 mM). At 37 degrees C caffeine had little effect but it caused spasm when the tissue was cooled to 32 degrees C. Spasm amplitude increased as cooling progressed to 12 degrees C. Similar results were obtained with caffeine (1 mM). 4. At 37 degrees C, caffeine, enprofylline, 1,3,7,9-tetramethylxanthinium (TMX), theobromine, theophylline, xanthine and forskolin each caused concentration-dependent suppression of tracheal tone. Among the xanthine derivatives the rank order of potency was enprofylline greater than theophylline greater than caffeine greater than theobromine greater than xanthine greater than TMX. 5. In trachealis treated with indomethacin (2.8 microM) and maintained at 12 degrees C, the xanthines each caused concentration-dependent spasm. The rank order of potency was theobromine greater than or equal to theophylline greater than or equal to caffeine greater than or equal to enprofylline greater than xanthine greater than TMX. Forskolin was devoid of spasmogenic activity. 6. Trachealis treated with indomethacin (2.8 microM) and maintained at 12 degrees C, was repeatedly dosed with either caffeine (10 mM) or potassium chloride (KCl, 40 mM). Caffeine-induced spasm was attenuated in a Ca2+-free medium containing EGTA (2 mM), modestly at first but subsequently more profoundly. KCl did not evoke spasm at 12 degrees C but at 37 degrees C the KCl-induced spasm was virtually abolished at its first trail in the Ca2+-free, EGTA-containing medium. 7. It is concluded that caffeine, other alkylated xanthines and xanthine itself share a spasmogenic action in guinea-pig isolated trachealis which is best observed when the tissue is treated with indomethacin (2.8 microM) and maintained at 12 degrees C. The spasmogenic action represents the release of Ca2+ from intracellular sites of sequestration and may not depend on the intracellular accumulation of cyclic AMP. The rank order of spasmogenic potency of the xanthine derivatives differs markedly from their rank order of potency in suppressing the spontaneous tone of the trachealis observed at 370C. Since, at 12 degrees C, TMX is spasmogenic at concentrations identical to those causing relaxation at 37 degrees C, it is likely that TMX penetrates the cell. The relaxant effects of TMX do not, therefore, indicate that methylxanthine-induced relaxation is mediated by a receptor located on the external surface of the cell.
Acetylcholine↗
Professionals earn Master's and maintain careers at same time.
To accommodate professionals who wish to further their education while meeting their career and family responsibilities, the University of Colorado at Denver and the Western Network for Education in Health Administration designed the Executive Program in Health Administration. A major portion of the program instruction is done through computer conferencing and both residential and nonresidential course work, with students attending on-campus classes for 11 weeks over a 25-month period. On completion of the Executive Program, students earn the master's of science and health administration degree. The students are assigned course work and tested by computer, which they use to talk with professors and form study groups with one another.
Colorado↗
The relationship between electrophysiological and mechanical events in airways smooth muscle.
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Animals↗
K+-channel opening as a mechanism for relaxing airways smooth muscle.
The properties and physiological roles of K+-channels in the plasmalemma of airways smooth muscle are currently being clarified by the use of techniques such as patch-clamp recording. K+-channel activity plays an important role in determining both the resting membrane potential and the electrical excitability of the airways smooth muscle cell. Established bronchodilators such as agonists at beta-adrenoceptors and methylxanthines may provide K+-channel opening but this is not crucial for their relaxant action. The actions of other smooth muscle relaxants such as BRL 34915 and pinacidil (Fig.) may more closely depend on their ability to open K+-channels and such agents are currently being examined to determine whether they protect against bronchoconstrictor challenge in vivo or have beneficial effects in asthma.
Animals↗
Influence of some variables in the Triton X-100 method of skinning the plasmalemmal membrane from guinea pig trachealis muscle.
Electron microscopy showed that the process of skinning guinea pig trachaelis muscle using Triton X-100 destroys the plasma membranes and causes some retraction of the myofibrils toward the center of the cells. Seven days represents an optimal period for the low temperature storage of the skinned fibers. Increasing the imposed tension from 0.25 to 1.0 g reduces the size of the maximal response to Ca2+. Some sensitization of the skinned fibers to Ca2+ follows the construction of the initial Ca2+ log concentration-response curve. Exogenous calmodulin is not essential for Ca2+-induced tension development and, at 20 degrees C, does not potentiate Ca2+. Useful economy can be achieved without compromising Ca2+ sensitivity or responsiveness by using ATP (a component of the relaxing solution) of purity 99% rather than of 99-100%.
Adenosine Triphosphate↗
Inhibitory responses to nicotine and transmural stimulation in hyoscine-treated guinea-pig isolated trachealis: an electrical and mechanical study.
Guinea-pig isolated trachealis muscle treated with hyoscine (1 microM) exhibited mechanical tone which could be suppressed by transmural stimulation and, in a concentration-dependent manner, by nicotine (10-1000 microM). Hexamethonium (500 microM) did not itself cause tone changes, antagonized effects of nicotine but did not antagonize those of isoprenaline. Tetrodotoxin (0.3 microM) did not itself cause tone changes, did not modify the action of isoprenaline but antagonized the effects of nicotine and very markedly reduced responses to transmural electrical stimulation. Guanethidine (50 microM) did not itself cause tone changes, potentiated the action of isoprenaline, antagonized effects of nicotine and reduced responses to transmural electrical stimulation. Propranolol (1 microM) did not itself cause tone changes, antagonized effects of both isoprenaline and nicotine and reduced responses to transmural electrical stimulation. Propranolol (10 microM) caused greater antagonism of isoprenaline but did not further antagonize nicotine or further reduce responses to electrical stimulation. Intracellular electrophysiological recording from hyoscine-treated trachealis showed that 10 microM nicotine caused little or no mechanical or electrical change. Higher concentrations (100 microM and 1 mM) evoked relaxation which was often though not invariably accompanied by transient hyperpolarization and transient inhibition of electrical slow waves in the impaled cell. Hexamethonium (500 microM), tetrodotoxin (0.3 microM), guanethidine (50 microM) and propranolol (1 microM) each suppressed the electrical or mechanical changes evoked by nicotine (100 microM). However, nicotine (1 mM) tested in the presence of propranolol (1 microM), caused relaxation which could be accompanied by slow wave suppression but not by change in resting membrane potential. Transmural stimulation of hyoscine-treated trachea with single pulses of supramaximal voltage and 0.5 ms duration evoked neither relaxation nor membrane potential changes. Stimulation with similar pulses in trains of 5 s duration evoked relaxation which was dependent on pulse frequency. In many cells this relaxation was not accompanied by membrane potential change. In other cells suppression of slow waves occurred. At high pulse frequencies (greater than 16 Hz) this was generally accompanied by membrane hyperpolarization. In tissue treated with hyoscine and propranolol (both 1 microM), transmural stimulation with pulse trains as described above always evoked relaxation but no membrane potential changes were observed. 10 It is concluded that nicotine and transmural stimulation can excite intramural noradrenergic nerves in guinea-pig trachea and thereby evoke relaxation. The membrane potential changes (slow wave suppression and hyperpolarization) are similar to those evoked by the administration of agonists at beta-adrenoceptors. Nicotine and transmural stimulation also excite non-adrenergic non-cholinergic inhibitory (NANCI) nerves. The relaxation evoked by the NANCI neurotransmitter is accompanied by little, if any, membrane potential change.
Animals↗
Differentiation of calcium antagonists with respect to their effects in normal and skinned taenia caeci preparations.
In taenia preparations, depolarized by a K+-rich medium, Ca2+ caused contraction and cinnarizine (0.4-100 microM), trifluoperazine (2-100 microM) and verapamil (0.02-10 microM) caused concentration-dependent antagonism of Ca2+, displacing the Ca2+ log concentration-effect curve to the right and depressing the maximal response. Equieffective (IC75) antispasmogenic concentrations were selected. The antispasmogenic effects of verapamil were readily offset by removing the drug from the bathing fluid but those of the other drugs were not. The calcium antagonists (antispasmogenic IC75) were then tested for spasmolytic activity in tissues generating tension in response to the EC80 of Ca2+. Verapamil was more effective in producing spasmolysis than cinnarazine or trifluoperazine. In skinned taenia preparations, verapamil (100 microM) did not inhibit Ca2+-induced contractions. High concentrations of cinnarizine (100 microM) and trifluoperazine (100 microM) inhibited Ca2+-induced activation of the contractile proteins. However, antispasmogenic IC75s from intact taenia were not able to produce this effect on skinned preparations. It is concluded that there are differences between calcium antagonists. The action of verapamil on intact taenia is mainly exerted on the plasma membrane. Cinnarizine and trifluoperazine act both on the plasma membrane and upon the intracellular contractile machinery.
Animals↗
Electrophysiologic behavior of normal and sensitized airway smooth muscle.
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Animals↗
Chemical irritant algesia assessed using the human blister base.
The chemical irritants o-chlorobenzylidene malononitrile (CS), n-nonanoylvanillylamine (VAN) and dibenzoxazepine (CR) and several of its derivatives have been assayed using the human blister base. The relative potencies found by this method, CR greater than VAN greater than CS, conflicted with those found in non-human test systems but the rank order of potency of CS and CR reflected that reported in tests on the human eye and tongue. Data derived from humans thus appear to be of importance when assessing irritant potency. Interactions between CS, CR, VAN, capsaicin and bradykinin were investigated to discover any common pathways of irritant activity. Self-desensitization developed on repeated application of all agents to the blister base and selective cross-desensitization also occurred.
Blister↗
The relaxant action of nicorandil in guinea-pig isolated trachealis.
Nicorandil (1-1000 mumol l-1) caused concentration-dependent relaxation of guinea-pig isolated trachealis. Propranolol (1 mumol l-1) did not modify the relaxant action of nicorandil but antagonized isoprenaline. Among K+-channel inhibitors tested, apamin (0.1 mumol l-1) and procaine (5 mmol l-1) did not modify the relaxant action of nicorandil. In contrast, tetraethylammonium (TEA, 8 mmol l-1) caused five fold antagonism. Trachealis exposed to K+-rich (120 mmol l-1) Krebs solution developed near-maximal tension. Nicorandil relaxed the K+-depolarized tissue though its concentration-effect curve was shifted markedly to the right. In tissues in which tone was induced by histamine, methylene blue (100 mumol l-1) antagonized nicorandil and sodium nitroprusside but did not modify the relaxant action of aminophylline. Intracellular electrophysiological recording showed that nicorandil (1 mumol l-1) could evoke some relaxation in the absence of electrical changes. Higher concentrations (10-1000 mumol l-1) reduced the amplitude and frequency of spontaneous electrical slow waves. Nicorandil also caused concentration-dependent hyperpolarization and relaxation. When the hyperpolarization was sufficiently pronounced slow wave activity was abolished. TEA (8 mmol l-1) induced slow waves which were surmounted by a spike potential. TEA slightly reduced the maximal hyperpolarization induced by nicorandil and increased the time required for nicorandil to abolish slow wave discharge. Procaine (5 mmol l-1) induced slow waves of relatively low frequency. Sometimes these were surmounted by a spike potential Procaine markedly reduced the hyperpolarization induced by nicorandil and increased the time required for abolition of slow waves. In studies of the efflux of 86Rb+ from muscle-rich strips of trachea, nicorandil (1000 mumol l-1) increased the efflux rate constant, whereas isoprenaline (1 mumol l-1) was without effect. It is concluded that nicorandil-induced relaxation does not involve the activation of beta-adrenoceptors but is partly attributable to the formation of nitric oxide from the nitrate moiety in its molecular structure. Nicorandil can evoke relaxation in the absence of membrane potential change but towards the upper end of its effective concentration range, nicorandil increases membrane K+ conductance and thereby evokes hyperpolarization of trachealis cells. The K+ channels opened by nicorandil are permeable to 86Rb, insensitive to apamin and TEA but may be inhibited by procaine.
Aminophylline↗
Mechanical and electrical aspects of the relaxant action of aminophylline in guinea-pig isolated trachealis.
Aminophylline (1-1000 mumol l-1) suppressed the spontaneous tone of guinea-pig isolated trachealis in a concentration-dependent manner. In Krebs solution containing acetylcholine (1 mmol l-1), histamine (200 mumol l-1) or K+ (120 mmol l-1) isolated trachealis muscle developed near-maximal tension. The log concentration-effect curve for aminophylline was shifted 20 fold, 3 fold and 4 fold to the right, respectively, in the presence of these spasmogens. Three K+-channel inhibitors were tested: tetraethylammonium (TEA, 8 mmol l-1) did not modify the action of aminophylline, procaine (5 mmol l-1) shifted the log concentration-effect curve for aminophylline 2 fold to the left and 4-aminopyridine (5 mmol l-1) shifted the curve 2.5 fold to the right. Intracellular electrophysiological recording showed that aminophylline 10 mumol l-1 could cause relaxation in the absence of electrical changes. Higher concentrations of aminophylline (100-1000 mumol l-1) suppressed spontaneous slow waves and hyperpolarized the trachealis cells. In the presence of procaine (5 mmol l-1) or TEA (8 mmol l-1), the hyperpolarization induced by aminophylline (1000 mumol l-1) was significantly reduced but its relaxant effect was unchanged. In trachealis skinned of its plasma membranes, tension development induced by Ca2+ (20 mumol l-1) was unaffected either by aminophylline (1000 mumol l-1) or by isoprenaline (1 mumol l-1). In studies of the efflux of 86Rb+ from muscle-rich strips of trachea, aminophylline (100-1000 mumol l-1) was without effect whereas nicorandil (100 and 1000 mumol l-1) increased the efflux rate constant. It is concluded that aminophylline does not directly reduce the sensitivity of the contractile proteins to cytosolic Ca2+. In low concentration (1-10 mumol l-1) its relaxant action is not accompanied by membrane potential change but towards the upper end of its effective concentration range, aminophylline evokes hyperpolarization. This hyperpolarization may involve the opening of K+-channels which are inhibited by procaine and (to a lesser extent) by TEA. These K+-channels may be impermeable to 86Rb+.
Acetylcholine↗
Electrical and mechanical effects of BRL34915 in guinea-pig isolated trachealis.
BRL34915 (0.1-10 microM) suppressed the spontaneous tone of guinea-pig isolated trachealis in a concentration-dependent manner. BRL34915 was not antagonized by propranolol (1 microM). In trachea where spontaneous tone was suppressed by indomethacin (2.8 microM) but subsequently restored to the same level with acetylcholine or histamine, the relaxant potency of BRL34915 was reduced. In Krebs solution containing K+ (120 mM), isolated trachealis muscle developed near-maximal tension. The relaxant effects of BRL34915 were virtually abolished in this medium. Concentration-effect curves for KCl, acetylcholine and histamine were constructed in tissues treated with indomethacin (2.8 microM). BRL34915 (10 microM) depressed the foot of the concentration-effect curve for KCl and caused minor rightward shifts in the concentration-effect curves of acetylcholine and histamine. Four K+-channel inhibitors were tested. Apamin (0.1 microM) did not modify the action of BRL34915. Tetraethylammonium (8 mM) had little effect but procaine (5 mM) and 4-aminopyridine (5 mM) each significantly inhibited the relaxant action of BRL34915. Intracellular electrophysiological recording showed that BRL34915 (0.1 microM) caused very minor relaxation and little, if any, electrical change. Higher concentrations (1-10 microM) evoked relaxation, suppression of spontaneous electrical slow waves and marked hyperpolarization of the trachealis cells. In the presence of TEA (8 mM) or procaine (5 mM) the hyperpolarization induced by BRL34915 was significantly reduced. In trachealis skinned of its plasma membranes, tension development induced by Ca2+ (20 microM) was unaffected either by BRL34915 (10 microM) or by nicorandil (1 mM). In studies of the efflux of 86Rb+ from muscle-rich strips of trachea, BRL34915 (1 and 10 microM) increased the efflux rate constant. It is concluded that BRL34915 evokes relaxation of the trachealis by a mechanism that involves neither beta-adrenoceptor activation nor direct reduction of the sensitivity of the intracellular contractile machinery to cytosolic free Ca2+. The action of BRL34915 may depend on the opening of K+ channels in the plasma membrane which are permeable to 86Rb+. The opening of these channels, or the effects of their opening, may be reduced by K+-channel inhibitors such as 4-aminopyridine, procaine and TEA but not by apamin.
Acetylcholine↗
Cost-shifting under cost reimbursement and prospective payment.
Cost-shifting is seen as a three-way phenomenon involving hospital interests as well as those of government and private patients. Without economies of scale, private patients are indifferent to government policies unless underpayment leads to hospital bankruptcy. In the presence of economies of scale, private patients benefit from reductions in government payment under either cost reimbursement or prospective payment. Their interest in a shift to prospective payment depends upon the hospital's location on its cost curve. Hospitals benefit from increases in payment rates in all cases, but benefit from a shift to prospective payment only if operating in a region of declining average costs. The conventional view of cost-shifting is inconsistent with profit maximization and may be inappropriate for many voluntary hospitals as well.
Cost Allocation↗
Absence of gallium-67 avidity in diffuse pulmonary calcification.
Diffuse pulmonary uptake by bone-seeking radiopharmaceuticals has been reported previously but, in the same patient, would pulmonary uptake of Ga-67 citrate yield clinically meaningful results? A patient with hypercalcemia and renal failure in whom bone scintigraphy demonstrated striking diffuse bilateral pulmonary uptake, but subsequent gallium imaging demonstrated no evidence of pulmonary uptake greater than body background, is discussed. We conclude that pulmonary uptake of gallium cannot be attributed to calcium deposition and should carry the same clinical significance in regard to inflammatory and malignant lesions as would be assigned to patients without pulmonary calcific deposits.
Adult↗
The effects of the dihydropyridine Bay K 8644 in guinea-pig isolated trachealis.
In trachea bathed by Krebs solution containing indomethacin 0.8 mumol l-1, Bay K 8644 (0.01-1 mumol l-1) evoked mild spasm. Peak tension was achieved after 10 min and was generally less than 20% of an acetylcholine (ACh) maximum. The effect of Bay K 8644 was not potentiated by addition of 2.5 mmol l-1 potassium chloride (KCl) to the Krebs solution. Bay K 8644 (1 mumol l-1) caused a small potentiation of KCl and tetraethylammonium (TEA). In contrast it did not modify the actions of ACh or histamine. Bay K 8644 (1 mumol l-1) caused a small potentiation of the effect of calcium chloride (CaCl2) tested in trachea bathed by a K+-rich, Ca2+-free, MOPS-buffered physiological salt solution. Organic inhibitors of calcium influx such as nifedipine (0.1 mumol l-1), verapamil (1 mumol l-1) or diltiazem (10 mumol l-1) each caused marked depression of concentration-effect curves to KCl. Bay K 8644 (0.01-1 mumol l-1) provided concentration-dependent protection against this effect in all three cases. Estimation of calcium influx by the lanthanum technique revealed that Bay K 8644 (1 mumol l-1) was able to promote the cellular influx of Ca2+. Intracellular electrophysiological recording showed that Bay K 8644 (1 mumol l-1) caused no change in the resting membrane potential of trachealis cells and no change in the properties of the spontaneous electrical slow waves. However, Bay K 8644 was able to delay the slow wave suppression evoked by 1 mumol l-1 nifedipine. The ability of Bay K 8644 to promote Ca2+ influx and its ability to protect against the effects of several structurally-unrelated inhibitors of Ca2+ influx are consistent with Bay K 8644 acting as an agonist at the dihydropyridine receptor associated with the voltage-operated Ca2+ channel (VOC) of trachealis muscle. By this action it potentiates those spasmogens (KCl, TEA) which act by permitting Ca2+ influx through VOCs. In contrast it has no effect on those spasmogens (ACh, histamine) which principally act to liberate Ca2+ from intracellular sites of sequestration.
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗