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Biomedical subjects

M Brenner

Publications and source records attributed to M Brenner.

At least 217 records · Page 12Linked to original sources
PubMed1984

Caffeine blocks activation of cyclic AMP synthesis in Dictyostelium discoideum.

Cyclic AMP (cAMP) appears to play multiple roles in the development of the social ameba Dictyostelium discoideum, serving as the chemoattractant mediating aggregation, and perhaps also regulating gene transcription in both early and late stages of differentiation. Progress in understanding the mechanism of activation of the adenylate cyclase in D. discoideum has been frustrated by the inability to obtain its activation in vitro. Also, the lack of defined cAMP-defective mutants has prevented a causal relationship from being established between cAMP levels and gene expression. As an alternative approach to studying the role of cAMP in D. discoideum development, we have sought a compound which inhibits cAMP synthesis in a reasonably specific manner. Here we identify caffeine as a compound which rapidly and reversibly inhibits cAMP-dependent activation of the adenylate cyclase without affecting either cell viability or intracellular levels of ATP or GTP. Using this drug, we show that cAMP synthesis is not required for the cAMP-stimulated decrease in lightscattering, the increase in cyclic GMP synthesis, or for chemotaxis toward cAMP. Studies of the mechanism of action of caffeine show that the drug does not act by inhibiting a cAMP phosphodiesterase, by inhibiting binding of cAMP to its receptor, by itself binding to a physiological adenosine receptor, or by directly inhibiting the adenylate cyclase. Instead, caffeine blocks the cAMP-dependent activation of the adenylate cyclase. Since similar effects are obtained with the cation ionophore A23187, it is possible that caffeine exerts its effect by altering intracellular calcium distribution.

Adenylyl Cyclases↗
PubMed1984

Synthesis, resolution, absolute stereochemistry, and enantioselectivity of 3',4'-dihydroxynomifensine.

3',4'-Dihydroxynomifensine, 8-amino-1,2,3,4-tetrahydro-4-(3,4-dihydroxyphenyl)-2-methylisoquinoli ne (1a), is an agonist of dopamine receptors in central and peripheral systems. Since this dopamine receptor agonist bears an asymmetric center at position 4, its synthesis and resolution were undertaken as part of a study directed toward determining the mode of interaction of these agents with the receptor(s). The enantiomers of 3',4'-dihydroxynomifensine are of particular interest, as they provide additional probes of present conceptual models of the dopamine receptor(s). Initial attempts to prepare 1a were inefficient or unsuccessful; instead, an isomeric compound, 1,2,4,5-tetra-hydro-2-(3,4-dihydroxyphenyl)-4- methyl-3H-1,4-benzodiazepine (9), was obtained. For this reason, a new route to 3',4'-dihydroxynomifensine was employed. The racemic dimethoxy intermediate 1d, thus obtained, was resolved. Methoxyl cleavage of the isomers of 1d afforded the enantiomers of 1a. Enantiomeric excess of these antipodes or appropriate derivatives was examined by NMR, CD, and HPLC methods. CD analysis suggests an enantiomeric excess greater than 99%. Determination of the absolute configuration of the enantiomers of 1a was determined by single-crystal X-ray diffractometric analysis. Examination of the isomers in several pharmacological test systems revealed a high degree of enantioselectivity. D-1 dopaminergic activity resides almost exclusively in the S enantiomer. The findings of the study have been employed to suggest an accessory binding site on the dopamine receptor(s) that differs from that advanced earlier. This accessory binding site may be specific for the D-1 subpopulation of dopamine receptors.

Adenylyl Cyclases↗
PubMed1984

Tonography software and hardware interface.

A software and hardware interface system was created for an electronic tonography unit, with capabilities for continuous acquisition storage and display on data in both graphic and digital modes. Software was prepared for computation, printout and display of both the facility of outflow coefficient and Po/c values.

Computers↗
PubMed1983

Inhibition of methylprednisolone elimination in the presence of erythromycin therapy.

Methylprednisolone elimination is reduced in the presence of treatment with troleandomycin (TAO), a macrolide antibiotic. To assess whether a similar interaction occurs with a more commonly used and less hepatotoxic macrolide antibiotic, erythromycin, we evaluated methylprednisolone pharmacokinetics before and after a 1 wk course of erythromycin base in nine adolescent patients with chronic asthma. These data were compared to results of studies of the troleandomycin methylprednisolone interaction evaluated in 10 adolescent asthmatic patients. Methylprednisolone clearance and apparent volume of distribution were significantly decreased and mean residence time and half-life significantly increased in the presence of both erythromycin and troleandomycin. The latter caused greater inhibition of methylprednisolone elimination. A nonlinear pattern of methylprednisolone disposition was observed in the presence of concomitant macrolide antibiotic administration. Addition of erythromycin base to methylprednisolone therapy results in inhibition of methylprednisolone elimination and may potentially increase the beneficial and adverse effects of this corticosteroid.

Adolescent↗
PubMed1983

Forskolin does not activate cyclic AMP synthesis in Dictyostelium discoideum in vivo or in vitro.

Cyclic AMP (cAMP) has been postulated to regulate many of the events in the development of the eukaryotic social ameba Dictyostelium discoideum. The various suggested roles of cAMP could be tested were it possible to reversibly elevate cAMP levels in the organism. To this end we examined the effect of forskolin, which activates the adenylate cyclase of many eukaryotic organisms. We found, however, that the drug does not elevate cAMP levels in intact D. discoideum. In addition, it does not stimulate the adenylate cyclase in either its basal state or activated state.

Adenylyl Cyclases↗
PubMed1982

[Long-term results of compression-osteosynthesis with three AO-screws for spongiosa in fractures of the femur-neck (author's transl)].

Between 1969 and 1978 in 42 patients fractures of the femur-neck were treated with three AO-screws for spongiosa (screws with a short thread). Late results in these patients are reported. The interval between operation and follow-up was in average 90 months. In no case pseudarthrosis had developed; the rate of necrosis of the femur head was 23.8%. The method is suitable in selected cases of medial fractures of the femur-neck, type I and II, and in lateral fractures, preferably in younger patients. The results in fractures of type III according to Pauwels show, that in advanced age these fractures should be treated with a partial or total prosthesis, because the rate of necrosis of the femur-head cannot be lowered.

Aged↗
PubMed1982

Steroid-specific and anticonvulsant interaction aspects of troleandomycin-steroid therapy.

Troleandomycin (TAO) is a macrolide antibiotic that has an apparent "steroid-sparing" effect when used in the treatment of severe steroid-dependent asthmatic patients. Recent observations demonstrated the effect of TAO on inhibiting methylprednisolone elimination, possibly contributing to its beneficial effects. Prednisolone and methylprednisolone disposition were studied before and 1 wk after initiation of TAO therapy in three patients. Methylprednisolone elimination was characteristically impaired in the presence of TAO therapy; however, there was no apparent effect on prednisolone elimination. Methylprednisolone elimination was also evaluated before and after initiation of TAO therapy in three patients receiving concomitant anticonvulsant therapy with phenobarbital-1, phenytoin-2. Methylprednisolone clearance before TAO was at least 4 times faster than normal and was probably related to enzyme induction by the anticonvulsant medication. Methylprednisolone clearance was subsequently reduced by approximately 70% in the presence of TAO therapy. The effect of TAO on corticosteroid disposition is steroid-specific and TAO can diminish the effect of certain drugs on the induction of corticosteroid metabolism.

Asthma↗
PubMed1982

Dose- and time-related effect of troleandomycin on methylprednisolone elimination.

Effects of varying doses of troleandomycin (TAO) on methylprednisolone disposition were examined in five steroid-dependent asthmatic patients. The characteristic reduction in methylprednisolone elimination in the presence of TAO after a 40 mg IV methylprednisolone was also present after methylprednisolone doses as low as 4 mg. In patients receiving continuous TAO on an every-other-day basis, inhibition of methylprednisolone elimination was impaired to a greater extent on the "day on" TAO than on the "day off" TAO Methylprednisolone elimination on the day off TAO was still slower than that before TAO, however, TAO on a multiple-dose schedule resulted in greater reduction of methylprednisolone elimination than after a single TAO dose. These results suggest that TAO induces immediate and continued inhibition of methylprednisolone disposition.

Asthma↗
PubMed1981

[Incarcerated Chilaiditi disease. A rare indication for surgery].

Surgery was performed on a rare case of incarcerated Chilaiditi's syndrome, a syndrome that has been known for 10 years. The patient was in the state of ileus with volvulus of the stomach and hepatodiaphragmatic interposition of the stomach, transverse colon, and omentum majus. The patient was at high risk--77 years old and in bad condition due to hyperemesis and abdominal pain. Preoperative intensive care was necessary. During the operation the intestinal structures were repositioned, the diaphragmatic hernia was resected, and the muscular parts were sewn tight. The right position of the liver was reconstructed by sewing the ligaments. Colon resection was inevitable because the colon loop could not be separated and because there was lack of intraabdominal space. For indication of preventive and elective surgery, we propose that the diagnostics be enhanced when Chilaiditi's syndrome is found by chance and is still asymptomatic. These techniques may include a complete radiological examination with contrast medium, intestinal endoscopy, and computer tomography of the thoracoabdominal region.

Aged↗
PubMed1980

Base composition of transfer RNAs from vegetative and developing cells of Dictyostelium discoideum.

In a previous comparison of tRNAs from vegetative and developing cells of Dictyostelium discoideum, displacements of chromatographic peaks were observed for a number of aminoacyl-tRNAs (Palatnik, C.M., Katz, E.R. and Brenner, M. (1977) J. Biol. Chem. 252, 694-703). Since the development peak eluted ahead of the vegetative peak in all but one case, and since levels of amino acid acceptance and tRNA chromatographic profiles were otherwise quite similar, it was suggested that a common change or a very small number of changes in base modification were occurring during development. We have threfore compared tRNAs from both stages with respect particularly to their minor base composition. Of the minor bases which we have analyzed no reproducible differences between the two stages have been detected. Moreover, we have been unable to confirm a recent report (Dingermann, T., Schmidt, W. and Kersten, H. (1977) FEBS Lett. 80, 205-208) that a significant change occurs in the ribothymidine content of tRNA during Dictyostelium discoideum development.

Base Composition↗
PubMed1980

Induction of prostaglandin E release from macrophages by colchicine.

Rat peritoneal macrophages released high amounts of prostaglandin E (PGE) when treated in vitro with 10(-7) to 10(-4) M colchicine. PGE production occurred after a lag period of 4 hr and proceeded at a constant rate for more than 24 hr. Lymphocytes could not be stimulated to PGE release by colchicine. Disaggregation of microtubules appeared to be an essential event, since lumicolchicine was inactive and addition of heavy water (D2O) abolished colchicine-induced PGE formation. Cytochalasin B (5 microgram/ ml) did not interfere with PGE production by colchicine during the initial 12 hr, but thereafter it gave rise to an activity capable of degrading or converting newly synthesized PGE. Although details of the mechanisms by which colchicine in association with disrupted microtubules may induce PGE release remain unclear, these observations suggest that components of the cytoskeleton may efficiently influence the biosynthesis of prostaglandins.

Animals↗