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Biomedical subjects

S Stone

Publications and source records attributed to S Stone.

At least 199 records · Page 11Linked to original sources
PubMed1989

The properties of peptidyl diazoethanes and chloroethanes as protease inactivators.

Earlier work has demonstrated the irreversible inactivation of serine and cysteine proteinases by peptides with a C-terminal chloromethyl ketone group. With a C-terminal diazomethyl ketone, on the other hand, peptides become reagents specific for cysteine proteinases. We have now synthesized and examined the properties of reagents with an additional methyl side chain near the reactive grouping with the goal of diminishing side reactions in a cellular environment. Derivatives of neutral amino acids as well as of lysine and arginine have been prepared. The chloroethyl ketones are about 60% less reactive to chemical nucleophiles than the chloromethyl ketones. However, the susceptibilities of the proteases examined varied remarkably. Cathepsins B and L of the papain family of cysteine proteinases were much less susceptible (about 2 orders of magnitude less) to both peptidyl diazoethyl and chloroethyl ketones. In marked contrast, clostripain, a cysteine proteinase of a separate family was decisively more susceptible to chloroethyl ketones. The serine proteinases showed a drop in susceptibility to the chloroethyl ketones generally, and this was similar to the drop in chemical reactivity in proceeding from the chloromethyl to the chloroethyl ketone.

Amino Acid Chloromethyl Ketones↗
PubMed1989

Photoreceptor to horizontal cell synaptic transfer in the Xenopus retina: modulation by dopamine ligands and a circuit model for interactions of rod and cone inputs.

1. In the Xenopus retina, the effects of selective D1 and D2 dopamine ligands on photoreceptor to horizontal cell transfer were studied by intracellular recording from horizontal cell axons. Rod and cone inputs to the horizontal cell were estimated by adjusting the intensities of red and green flashes to elicit equal rod tails. The resultant waveforms were digitized and subtracted, and their difference was taken to reflect solely cone input to the horizontal cell. 2. It was found that both D1 (SKF 38393) and D2 (LY 171555) agonists increased the amplitude and quickened the kinetics of cone-to-horizontal cell transfer; they also depolarized the horizontal cell by 8-10 mV. In contrast, either D1 or D2 agonists reduced the rod input to the horizontal cell without altering its kinetics. 3. Type D2 antagonists reduced and slowed the cone input and hyperpolarized the horizontal cell. D2 antagonists increased the rod input but left its kinetics unchanged. 4. Although both D1 and D2 agonists elicited qualitatively similar effects, the D1 agonist evoked a greater increase in the amplitude and a greater acceleration of the kinetics of the cone input than did the D2 agonist. Moreover, the action of the D1 agonist was blocked by SCH 23390 but not by spiroperidol or metoclopramide, whereas the reverse was true for the D2 agonist. These data indicate that D1 and D2 agonists probably act at different sites. 5. The pharmacologic findings are interpreted to indicate that dopamine ligands act primarily through the cone pathway and that rod-to-horizontal cell transfer is shunted to a variable degree. 6. An equivalent circuit model was developed for a spine-bearing portion of a horizontal cell axon of the Xenopus retina. Anatomic study shows that such spines branch, making contact with both rod and cone photoreceptor bases. Thus there are two conductance pathways in parallel for rod-to-horizontal cell and cone-to-horizontal cell transmission. The model is used to test the hypothesis that mutual shunting in the two pathways can account for the physiological effects observed. 7. The values of the purely resistive elements of the pathway are based on their dimensions. Membrane resistance was taken to be 5,000 omega/cm2 and axial resistance 200 omega/cm. The photoreceptor-to-horizontal cell synaptic battery was taken to be composed of glutamate-sensitive channels, with unitary channel conductance of 6 pS. Channel density was estimated from freeze-fracture data at 5,000 microns-2. A potassium battery and a glycine-sensitive synaptic input from an interplexiform cell were modeled to exist in parallel with the light-sensitive battery. 8. Dopamine was assumed to increase the conductance of the cone-to-horizontal cell synapse, but not to affect the conductance of the rod-to-to-horizontal cell synapse, consistent with physiological measures.(ABSTRACT TRUNCATED AT 400 WORDS)

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1989

Comparison between videotape and personalized patient education for anticoagulant therapy.

To assess the effectiveness of videotape patient education, 22 patients were randomized to receive either videotape or personalized teaching for oral anticoagulant (warfarin) therapy. Both groups scored significantly higher on a questionnaire designed to assess knowledge gained after instruction, with no significant difference between the two groups. Videotape instruction required substantially less nursing time. A second questionnaire assessed patient satisfaction with respect to both methods, which were rated equally effective and worthwhile. Videotape teaching is an effective and well-accepted alternative form of patient education requiring significantly less personnel time.

Administration, Oral↗
PubMed1988

The synthesis and properties of peptidylmethylsulphonium salts with two cationic residues as potential inhibitors of prohormone processing.

Peptidylmethylsulphonium salts incorporating consecutive basic residues at the C-terminus of the peptidyl portion such as -Arg-Arg-, -Arg-Lys-, -Lys-Lys- and -Lys-Arg- were synthesized and examined as proteinase inhibitors. Serine proteinases with a specificity directed towards hydrolysis at cationic residues were found to be unaffected by these derivatives. On the other hand, cysteine proteinases, cathepsin B and, in particular, clostripain were readily inactivated by affinity labelling. The reagents thus are of promise for the study of prohormone processing promoted by cysteine proteinases.

Cathepsin B↗
PubMed1988

Synthesis and properties of peptidyl derivatives of arginylfluoromethanes.

Two peptide derivatives of arginylfluoromethane (Arg-CH2F), namely Bz(benzoyl)-Phe-ArgCH2F and D-Phe-Pro-Arg-CH2F, have been synthesized by extension of available methods, i.e. the Dakin-West reaction [Rasnick (1985) Anal. Biochem. 149, 461-465] or synthesis of a phthaloyl-blocked C-terminal fluoromethane [Rauber, Angliker, Walker & Shaw (1986) Biochem. J. 239, 633-640; Angliker, Wikström, Rauber & Shaw (1987) Biochem. J. 241, 871-875] with subsequent elongation. The guanidino group of arginine was protected as the bis-Cbz (benzyloxycarbonyl) derivative. The products were examined as active-site-directed inhibitors of some trypsin-related serine proteinases as well as a pair of cysteine proteinases. The results extend previous observations that the rate of alkylation of serine proteinases by fluoromethanes may be considerably slower than by chloromethanes. As expected, the amino acid sequence of the inhibitors influenced their relative effectiveness. Thus the rate of inactivation of a number of trypsin-like proteinases by D-Phe-Pro-Arg-CH2F varied by more than two orders of magnitude.

Hydrocarbons, Fluorinated↗
PubMed1988

Morphology and synaptic connections of HRP-filled, axon-bearing horizontal cells in the Xenopus retina.

Axon-bearing horizontal cells of the Xenopus retina were studied by intracellular injection of HRP following physiological characterization. The profile of the cell viewed in whole mount consisted of a round or oval perikaryon about 50 microns in diameter and an axon about 1 mm long which lacked a prominent terminal expansion. The axonal diameter was 0.5-1.0 microns in its proximal third but 2-4 microns in its distal portion. Along its course the axon emitted 25-40 branchlets each 0.2 micron in diameter, up to 10 micron long and terminating in a cluster of two to six synaptic knobs. Electron microscopic examination revealed that both perikaryal dendrites and axon branchlets ended in both rod and cone synaptic bases; cone contacts outnumbered rod contacts by two- to threefold. We were unable to document synapses of presumed interplexiform cells onto identified horizontal cells. Horizontal cell axons are joined in their distal portions by numerous, small (0.2 micron long) gap junctions. Other gap junctions were noted between horizontal cell processes within the synaptic endings of photoreceptors. An hypothesis is advanced whereby the cluster of axon branchlet synaptic knobs permits dynamic interaction of rod and cone synaptic inputs to the horizontal cell.

Animals↗
PubMed1988

Cerebroventricular dilation in spontaneously hypertensive rats (SHRs) is not attenuated by reduction of blood pressure.

In previous studies, we found that spontaneously hypertensive rats (Okamoto-Aoki SHRs) suffer progressive postnatal dilation of the brain ventricles. In the present study we examined intracerebroventricular pressure and blood pressure as possible mechanisms of ventricular dilation in SHRs. We found that intracerebroventricular pressure was not elevated in SHRs. The role of blood pressure was examined in SHRs treated chronically with the antihypertensive drug, captopril, beginning in utero, and in renal hypertensive Sprague-Dawley rats (SDs). Although our experimental treatments produced significant changes in mean arterial pressures, they did not alter brain ventricular size: SDs with experimental hypertension had normal-sized brain ventricles and SHRs with pharmacologically reduced blood pressure had enlarged ventricles. These results suggest that neither increased intraventricular pressure nor high blood pressure is the sole cause of hydrocephalus in SHRs.

Animals↗
PubMed1988

Dopamine modifies the balance of rod and cone inputs to horizontal cells of the Xenopus retina.

Dopamine (greater than or equal to 2 microM) increased the cone input and suppressed the rod input to axon-bearing horizontal cells of the Xenopus retina. Dopamine (10 microM) also depolarized the horizontal cell by about 9 mV. The D2-dopamine antagonists spiperone and metoclopramide had the opposite action to dopamine, whereas the D1-dopamine antagonist SCH 23390 was without effect. None of the agents tested modified the light-evoked responses of rods.

Animals↗
PubMed1988

Synthesis of lysine-containing sulphonium salts and their properties as proteinase inhibitors.

Some sulphonium salts derived from lysine were synthesized with the general structure R-Lys-CH2S+-(alkyl)2. They were examined as inhibitors of the cysteine proteinase clostripain, which has a preference for cleaving peptide bonds at the carboxy group of basic amino acids, and of a number of trypsin-related serine proteinases. Clostripain was irreversibly inactivated by all reagents examined, but in the case of the serine proteinases, depending on the reagent structure, irreversible and reversible inhibitions were observed. These were kinetically characterized.

Cysteine Endopeptidases↗
PubMed1988

Synthesis and properties of Cbz-Phe-Arg-CHN2 (benzyloxycarbonylphenylalanylarginyldiazomethane) as a proteinase inhibitor.

The preparation of peptides terminating in -Arg-CHN2 has been attempted because of their potential value as proteinase inactivators. We have succeeded in one case, converting Cbz-Phe-ArgOH to the diazomethane without blocking the guanidino group. As expected from previous results with such reagents, the new derivative was extremely effective in inactivating a cysteine proteinase specific for cleaving at arginyl bonds, that is, clostripain. However, in contrast with the inertness of serine proteinases to reagents of this type in the cases examined previously, plasma kallikrein was inactivated by Cbz-Phe-Arg-CHN2, although with a considerably lower rate constant than with clostripain. Trypsin, however, was not inactivated, but gradually destroyed the reagent, as had been observed previously with chymotrypsin and Cbz-Phe-CHN2. This has now been re-examined with rho-nitro-Cbz-Ala-Phe-CHN2 and shown to involve a cleavage to rho-nitro-Cbz-Ala-PheOH, probably with liberation of diazomethane.

Cathepsin B↗
PubMed1988

Ranitidine accumulation in patients undergoing chronic hemodialysis.

Ranitidine accumulation was assessed in 20 patients undergoing chronic hemodialysis following oral daily doses of 150 mg ranitidine for 10 days. Serum ranitidine concentrations prior to dialysis were 191 +/- 115 mcg/l and 207 +/- 172 mcg/l for patients dialyzed three and two times per week, respectively. The amount of ranitidine recovered in the dialysate during the final dialysis session of the study was negligible and ranged from 308-3036 mcg, representing less than 3% of the administered dose. Clearance by hemodialysis was 3.0 +/- 1.1 l/hr. Once daily dosing of 150 mg ranitidine does not result in excessive accumulation, and drug loss during hemodialysis is small. These data suggest that supplemental dosing after hemodialysis is not indicated.

Adult↗
PubMed1988

GABA release from Xenopus retina does not correlate with horizontal cell membrane potential.

The relationship between horizontal cell membrane potential and the release of GABA was explored in the retina of Xenopus laevis. The intracellularly recorded membrane potential of horizontal cells was monitored while the retina was exposed to different concentrations of depolarizing agents. The dose-response curves obtained revealed a rise from 5 to 95% maximum depolarization in 0.5-1.5 log unit concentration change. The molar concentrations that elicited a 20 mV depolarization were 40 mM (potassium), 0.8 mM (glutamate), 0.8 mM (glycine), 5 microM (kainate) and 1.3 microM (quisqualate). Autoradiography revealed that radiolabel was accumulated almost exclusively by horizontal cells when isolated retinas were incubated in medium containing 1 microM [3H]GABA. Thus, retinal release of radioactivity was used as a measure of [3H]GABA release from horizontal cells. Endogenous GABA released from retinas was measured using high performance liquid chromatography and was taken to reflect both amacrine and horizontal cell GABA pools. The release of both [3H]GABA and endogenous GABA was stimulated by glutamate, kainate and potassium, but not by glycine or quisqualate. Similar dose-response curves for GABA release and for depolarization were obtained in the case of potassium and kainate but not for glutamate. Potassium-evoked release either of endogenous GABA or [3H]GABA was both calcium- and sodium-dependent, whereas kainate- or glutamate-evoked GABA release was sodium-dependent but calcium-independent. The results indicate that depolarization per se is not necessarily associated with transmitter release in Xenopus retinal horizontal cells. It is suggested that the action of a given neurotransmitter upon the efflux of GABA from horizontal cells may depend on the degree to which it modifies the sodium conductance of the horizontal cell.

Animals↗
PubMed1988

Information strategy for a community unit.

With the implementation of Körner health authorities are having to think seriously about information. The West Lambeth Community Unit decided that it needed a longer-term strategy, and Margaret Hurst and Simon Stone describe how, with the help of the Management Advisory Service, a strategy was evolved through staff participation

Computer Systems↗