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Biomedical subjects

C L Brown

Publications and source records attributed to C L Brown.

At least 109 records · Page 6Linked to original sources
PubMed1986

The benzodiazepine receptor ligand, methyl beta-carboline-3-carboxylate, is both sedative and proconvulsant in chicks.

Certain pharmacological properties of methyl beta-carboline-3-carboxylate (beta-CCM), a benzodiazepine receptor ligand, have been investigated in chicks. Although beta-CCM has been established previously as an "inverse agonist" of benzodiazepine receptors in rodents, having effects opposite to those of benzodiazepines in a variety of tests, in chicks this compound had a different pharmacological profile. Firstly, in contrast to the overt convulsant action of beta-CCM in other species, beta-CCM (0.05-40 mg/kg) did not produce convulsions by itself in chicks, but it was only proconvulsant. Secondly and most surprisingly, beta-CCM, like diazepam, produced in chicks a sedation which could be blocked by the benzodiazepine receptor antagonist Ro 15-1788. Thus it appears that beta-CCM can function both as an agonist and as an inverse agonist in this animal.

Animals↗
PubMed1985

Photoperiodic regulation of thyroid responsiveness to TSH in Fundulus heteroclitus.

Treatment of the killifish, Fundulus heteroclitus, with ovine thyrotropin (oTSH) produced elevations in serum thyroxin (T4) that varied seasonally with a strong inverse correlation to environmental photoperiod (P less than 0.001). At 20 degrees C, oTSH (0.2 IU) increased serum T4 to levels ranging from 1.5 micrograms/100 ml in midsummer to 7.5 micrograms/100 ml in midwinter despite relatively stable resting levels throughout the two years of study. Similar rates of clearance of T4 in summer and winter suggest that an alteration in thyroid response to oTSH accounts for this change. The serum T4 response to oTSH is both photoperiod- and temperature-dependent. In laboratory studies, fish exposed to a short artificial photoperiod (LD 8:16) for one month responded to oTSH with T4 levels about twice as high as those in fish exposed to long days (LD 14:10). On the other hand the T4 response to oTSH was sharply reduced at 5 degrees C from that seen at 20 degrees C. This suggests that, in nature, seasonal changes in photoperiod and temperature have opposite effects on thyroidal responsiveness to TSH. Overall, the annual variation in the T4 response to oTSH appears to be driven by photoperiod, inasmuch as the alterations preceded major temperature changes in the wild and can be shown to occur at constant temperature in captivity. Photoperiodic induction of changes in thyroid sensitivity may aid in the maintenance of basal T4 levels under changing thermal conditions.

Animals↗
PubMed1985

Photoperiod-dependent negative feedback effects of thyroid hormones in Fundulus heteroclitus.

In Fundulus heteroclitus, an annual cycle in the response of the thyroid to ovine thyroid-stimulating hormone (oTSH) is characterized by maximal thyroxin (T4) secretion in mid-winter and minimal T4 secretion in summer. Four daily injections of oTSH, given in winter caused serum T4 to plateau at elevated levels for several days, while in summer fish similar treatment resulted in far more fluctuating titers of serum T4; maximum levels were similar in both groups. The difference in sustenance rather than magnitude of Peak T4 led to an examination of the negative feedback effects of thyroid hormones as they might relate to these seasonal changes. Radioiodine uptake by thyroid follicles served as a simple, but effective bioassay for endogenous TSH. Fish collected in summer were more sensitive to negative feedback of T3 than those collected in winter; feedback effects of T4 in the two groups were not significantly different. The effects of specific photoperiods on negative feedback sensitivity to T3 and T4 were also tested. Exposure of winter fish for one month to long days (LD 14:10) enhanced the degree of reduction of iodine uptake caused by T4 in the aquarium water (10 micrograms/100 ml). Negative feedback in short-day (LD 8:16) winter fish was not demonstrated. It is concluded that long days increase and short days diminish the negative feedback sensitivity of the hypothalamus-pituitary axis to thyroid hormones in F. heteroclitus. Such photoperiodically induced changes may act to aid in the year-round maintenance of T4 levels necessary for seasonal adaptation and survival.

Animals↗
PubMed1985

Functional specificity of gonadotropin and thyrotropin in Fundulus heteroclitus.

Gonadotropic hormones (GTHs) and thyrotropic hormones (TSHs) reportedly bear close evolutionary and structural relationships, and the thyroid appears to be active in reproduction in some fish species. We tested the sensitivity of the thyroid of Fundulus heteroclitus to glycoprotein hormones from mammalian and piscine sources. Six mammalian glycoprotein hormones, including four gonadotropins and two thyrotropins, produced dose-dependent elevations in serum thyroxin. A release of endogenous gonadotropins was elicited by injecting GnRH. This resulted in gonadal stimulation, with no alteration in circulating thyroxin levels and the rate of radioiodine uptake. We also treated fish with partially purified salmon gonadotropin (SG-G100). The gonadotropic actions of this extract were confirmed by steroid elevations, and again T4 and 125I uptake remained at resting levels. The lack of response of the thyroid gland to fish gonadotropins suggests that TSH receptors in Fundulus heteroclitus can differentiate between endogenous thyrotropin and gonadotropin(s), even though most heterologous glycoprotein hormones are thyrotropic.

Animals↗
PubMed1985

Follicular carcinoma.

The workshop participants agreed on the following points regarding follicular carcinoma: Follicular carcinoma should be divided into two groups according to its degree of invasion: encapsulated and widely invasive. Patients in the first group only occasionally develop distant metastases, whereas in the second group the prognosis is much poorer. In encapsulated follicular tumors, high cellularity and nuclear atypia should not be used as criteria of malignancy; this diagnosis should be based on the presence of vascular or capsular invasion. Only tumor thrombi occurring in vessels in or outside the capsule should be regarded as indicative of vascular invasion. Capsular invasion should be diagnosed only if penetration of the whole capsule is seen. We agree that some tumor islands within the capsule may represent true tumor invasion, but we believe that some others may be due to capsular infoldings or tangential sectioning. Whenever tumor tissue within the capsule is seen, additional tissue blocks from the capsular area should be processed in a search for capsular penetration or vascular invasion. The degree of differentiation in follicular carcinoma does not correlate to the course of disease as clearly as the degree of invasion, although the so-called insular or poorly differentiated, subtype seems to have a poorer prognosis. Thyroid carcinomas composed of large eosinophilic cells (Hürthle cell carcinomas) usually show follicular differentiation and are therefore included in the category of follicular carcinoma. The same diagnostic criteria of malignancy that apply for other follicular tumors should be used when evaluating these tumors. Although follicular carcinomas often show foci of clear cells, tumors composed solely of clear cells are rare. Most pure clear-cell tumors in the thyroid represent metastatic tumors, usually from the kidney. In the distinction of follicular carcinoma from papillary carcinoma, all differential diagnostic criteria should be used. However, in some cases, the diagnosis can be based on one criterion only, mainly the presence of widespread ground-glass nuclei or abundant neoplastic papillae in papillary carcinoma. The presence of occasional papillae in encapsulated tumors composed of large eosinophilic cells is not sufficient for the diagnosis of papillary carcinoma if the other microscopic features of this tumor are lacking.

Adenocarcinoma↗
PubMed1984

Modification of pyrazoloquinolinone affinity by GABA predicts efficacy at the benzodiazepine receptor.

A series of pyrazoloquinolinones CGS 9896, CGS 9895 and CGS 8216 have been reported to exhibit agonist, partial agonist and antagonist properties, respectively, at the benzodiazepine receptor. We have examined the effects of these compounds and of diazepam on pentylenetetrazole seizure thresholds in mice and found CGS 9896 to be a partial agonist and CGS 8216 a weak inverse agonist in this respect; CGS 9895 was essentially devoid of efficacy. In the presence of 100 microM GABA and 150 mM NaCl, the affinity of CGS 9896 for the benzodiazepine receptor at 37 degrees C was significantly increased whereas the affinity of CGS 8216 was similarly decreased and that of CGS 9895 was unchanged. The effect of GABA on the affinity of these ligands for the benzodiazepine receptor at 37 degrees C was thus predictive of the pharmacological efficacy which we observed.

Animals↗
PubMed1984

A new DNA-dependent ATPase from Escherichia coli. Purification and characterization of ATPase IV.

A new DNA-dependent ATPase named ATPase IV has been purified to apparent homogeneity from Escherichia coli as a by-product of DNA polymerase III purification. The enzyme has a specific activity of 360 mumol of ATP hydrolyzed per min/mg of protein. The purified enzyme exists as monomer with a molecular weight of 81,000. It sediments in a glycerol gradient as a single species of 4.5 S. The enzyme has considerable activity at 0 degree C and has a Q10 of 3.8. In the presence of a DNA effector and magnesium ion, the enzyme will hydrolyze ATP, dATP, GTP, or dGTP to a nucleoside diphosphate plus orthophosphate with a Km of 0.20, 0.50, 0.60, and 1.30 mM, respectively. The guanine nucleotides, however, are only 25-35% as effective as substrates compared with the adenine nucleotides. ATPase IV shows strong substrate inhibition by ATP, but not dATP, above 0.2 mM. The polynucleotide effector requirement can be satisfied by either single-stranded or double-stranded DNA. The enzyme binds the effector very tightly with a Km of 3 X 10(-8) M (nucleotide) for G4 DNA. The enzyme is inhibited by E. coli single-stranded DNA-binding protein, a variety of ATP analogues and N-ethylmaleimide. The relationship of ATPase IV to DNA polymerase III holoenzyme is discussed.

Adenosine Triphosphatases↗
PubMed1984

Photoaffinity labelling of the benzodiazepine receptor compromises the recognition site but not its effector mechanism.

When subjected to ultraviolet light flunitrazepam could be irreversibly attached to brain membrane preparations such that the affinity of the benzodiazepine receptor for certain ligands, such as diazepam, becomes markedly reduced. However, the apparent affinity for diazepam is increased by the addition of gamma-aminobutyric acid and sodium chloride, to the same extent in this membrane preparation as in membranes not so pretreated. This observation suggests that photoaffinity labelling of the benzodiazepine receptor with flunitrazepam modifies the recognition characteristics of the receptor but not its effector mechanism.

Affinity Labels↗
PubMed1984

Kinetics of [3H]Ro 15-1788 binding to membrane-bound rat brain benzodiazepine receptors.

Ro 15-1788 is thought to interact specifically with the benzodiazepine receptor population in the mammalian CNS as an antagonist. We have compared the kinetics of interaction of this ligand with the benzodiazepine agonist flunitrazepam in the rat cerebellum. The association of [3H]Ro 15-1788 with the benzodiazepine receptor in this brain region is monoexponential, and the dissociation, initiated either by dilution or by displacement with a number of different ligands, also obeys simple monoexponential kinetics. There is no evidence of cooperative interactions with this ligand, and its dissociation is unaffected by the presence of 100 microM gamma-aminobutyric acid and/or 150 mM sodium chloride. In contrast, the dissociation of the agonist [3H]flunitrazepam is biphasic, and the possible interpretation of this data in terms of agonist-induced conformational change is discussed. Evidence is also presented that the mechanism of interaction of Ro 15-1788 with the benzodiazepine receptor population in hippocampal membranes is distinct from that found in the cerebellum.

Animals↗
PubMed1983

Photoaffinity labelling of the benzodiazepine receptor cannot be used to predict ligand efficacy.

Irreversible attachment of flunitrazepam to brain membranes occurs on exposure to UV light, resulting in a loss of the number of binding sites detected by saturation binding of [3H]flunitrazepam, but not of [3H]ethyl-beta-carboline-3-carboxylate (beta CCE). Changes in the affinity of ligands for the benzodiazepine receptor produced by photoaffinity labelling, as indicated by the relative IC50 values for the displacement of [3H]beta CCE in photoaffinity labelled versus control membranes, appear to be related to their chemical structure rather than to their pharmacological profile.

Animals↗
PubMed1983

Cell cycle regulation of ribonucleoside diphosphate reductase activity in permeable mouse L cells and in extracts.

Ribonucleoside diphosphate reductase (EC1.17.4.1) was previously characterized in exponentially growing mouse L cells selectively permeabilized to small molecules by treatment with dextran sulfate (Kucera and Paulus, 1982b). This characterization has now been extended to cells in specific phases of the cell cycle and in transition between cell cycle phases, with activity studied both in situ (permeabilized cells) and in cell extracts. Cells at various stages in the cell cycle were obtained by unit-gravity sedimentation employing a commercially available reorienting chamber device, by G1 arrest induced by isoleucine limitation, and by metaphase arrest induced by Colcemid. G1 cells from both cycling and noncycling populations had negligible levels of ribonucleotide reductase activity as measured by CDP reduction both in situ and in extracts. When G1 arrested cells were allowed to progress to S phase, ribonucleotide reductase activity increased in parallel with [3H]thymidine incorporation into DNA. Ribonucleotide reductase activity in extracts increased at a somewhat greater rate than in situ activity. S phase ribonucleotide reductase activity measured in situ resembled the previously characterized activity in exponentially growing cells with respect to an absolute dependence on ATP or its analogs as positive allosteric effector, sensitivity to the negative allosteric effector dATP, and low susceptibility to stimulation by NADPH, dithiothreitol, and FeCl3. Disruption of permeabilized cells caused reductase activity to become highly dependent on the presence of both dithiothreitol and FeCl3. As synchronized cultures progressed from S into G2/M phase, no significant change in ribonucleotide reductase activity was seen. On the other hand, when cells that had been arrested in metaphase by Colcemid were allowed to resume cell cycle traversal by removing the drug, in situ ribonucleotide reductase activity decreased by 75% within 2.5 h. This decrease seemed to be a late mitotic event, since it was not correlated with the percentage of cells entering G1 phase. The cause of a subsequent slight increase of in situ ribonucleotide reductase activity is not clear. Parallel measurements of ribonucleotide reductase activity in cell extracts indicated also an initial decline accompanied by increasing dependence on added dithiols and FeCl3, followed by complete activity loss. Our results suggest a cell cycle pattern of ribonucleotide reductase activity that involves negligible levels in G1 phase, a progressive increase of activity upon entry into S phase paralleling overall DNA synthesis, continued retention of significant ribonucleotide reductase activity well into the metaphase period of mitosis, and a very rapid decline in activity during the later phases of mitosis. The periods of increase and decrease of ribonucleotide reductase activity were accompanied by modulation of the properties of the enzyme as indicated by differential changes in enzyme activity measured in situ and in extracts.

Animals↗
PubMed1983

Prolactin--thyroid interaction in Fundulus heteroclitus.

Injections of adult Fundulus heteroclitus with 0.2 IU of oTSH over 4 days caused an increase in serum T4, with no effect on serum T3. Administration of 12 IU of oPRL in conjunction with the same dosage of TSH prevented the TSH-induced rise in T4, without affecting serum T3 levels. The failure of TSH to cause T4 levels to rise in the presence of PRL may result from either inhibition of release or acceleration of metabolic clearance of T4. We therefore conducted three experiments to examine potential effects of PRL on the kinetics of peripheral clearance of thyroid hormones. 125I T4 was cleared from serum in a biphasic pattern that was unaltered by PRL. Clearance of labeled T3 followed a similar pattern that was also not influenced by PRL treatment. Generation of labeled T3 by deiodination of a dose of 125I T4 was quantified over a 24-h period. Again, PRL-treated fish showed no significant differences. Since PRL is without effects on thyroid hormone clearance patterns or deiodination rate, we conclude that PRL prevents TSH-induced increases in serum T4 in this species by directly affecting thyroid function.

Animals↗
PubMed1983

Experience with the 'Triple Test' in pancreatic disease.

The results of the secretin-pancreozymin test, duodenal aspirate cytology and hypotonic duodenography (the Triple Test), performed during a single duodenal intubation in patients with pancreatic or ampullary carcinoma, chronic pancreatitis and non-pancreatic disease were analysed retrospectively. Thirty-five of 36 carcinoma patients and all 11 chronic pancreatitis patients had an abnormal result. One hundred and sixteen of 170 non-pancreatic disease patients had a normal result. It would appear that the Triple Test (TT) may be a useful screening test for pancreatic disease.

Cholecystokinin↗