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Biomedical subjects

B C Jones

Publications and source records attributed to B C Jones.

At least 73 records · Page 4Linked to original sources
PubMed1994

Comprehensive health care reform: an imperative.

A public relations marketing strategy is essential to the consensus building for the enactment of health care reform legislation. As Governor of Kentucky, the author reflects on the complex legislative experience that he went through in his state, while attempting to enact a health care reform bill similar to President Clinton's proposal. This article draws the parallel in the politics of health reform between the political reality of an individual state, as compared to the one operating on the national scene.

Evaluation Studies as Topic↗
PubMed1993

Inhibitor-induced conformational change in cytochrome P-450CAM.

The X-ray crystal structures of cytochrome P-450CAM complexed with both enantiomers of a chiral, multifunctional inhibitor have been refined to R-factors of 21.0% [(+)-enantiomer] and 19.6% [(-)-enantiomer] at approximately 2.1-A resolution. Binding of either enantiomer, both considerably larger than the natural substrate camphor, results in similar, dramatic structural changes in the enzyme. In contrast to all previous P-450CAM crystallographic structures, the Tyr96 side chain is not pointing "down" toward the heme but is rather directed "up" into the proposed substrate access channel. This conformational change is accompanied by the displacement of the Phe193 side chain out into the solvent at the enzyme surface. These changes are consistent with the assignment of this region of the enzyme as the access channel [Poulos et al. (1986) Biochemistry 25, 5314-5322] and suggest that several aromatic residues lining the channel may be involved in substrate recognition and channeling to the active site. The cation usually observed coordinated to the Tyr96 carbonyl oxygen is missing in the presence of the (+)-enantiomer but is present with the (-)-enantiomer. The Phe87 side chain, located near the inhibitor binding site, adopts different orientations depending upon which enantiomer is bound. Finally, electron density reveals that although the inhibitor enantiomers were dichlorinated as provided, when bound to P-450CAM the chlorine atoms are present at only 0-20% occupancy, probably reflecting selective binding of impurities in the samples. Coordinates of these inhibited P-450CAM complexes have been deposited in the Brookhaven Protein Data Bank [Bernstein et al. (1977) J. Mol. Biol. 112, 535-542].

Binding Sites↗
PubMed1993

Genetic correlations among ethanol-related behaviors and neurotensin receptors in long sleep (LS) x short sleep (SS) recombinant inbred strains of mice.

Studies were designed to examine the hypothesis that genetic based differences in sensitivity to several behavioral effects of ethanol are mediated, in part, by shared genes and that some of ethanol's actions are mediated by brain neurotensinergic processes. In these studies we have used recombinant inbred (RI) strains of mice derived from Long Sleep (LS/Ibg) and Short Sleep (SS/Ibg) lines of mice. The LS and SS mice were selectively bred to differ in hypnotic sensitivity but also differ in hypothermia and locomotor effects of ethanol. Therefore LS x SS RI strains were used to answer the question whether there are shared genetic influences on these diverse ethanol actions. Moreover, since the LS and SS mice were found to differ in neurotensin (NT) receptor densities in various brain regions, the LS x SS RI strains were used to determine associations between NT receptor densities and ethanol actions. The results showed a significant genetic correlation (r = .38) between hypnotic sensitivity and low-dose locomotor effects of ethanol and indicated multigenetic influences, with estimates of seven, four and three genes being responsible for mediating differences in hypnotic, hypothermic, and locomotor effects of ethanol, respectively. The findings are consistent with one or more genes having pleiotropic effects on these ethanol actions.

Alcohol Drinking↗
PubMed1993

Strain and housing affect cocaine self-selection and open-field locomotor activity in mice.

We recently conducted an experiment to investigate the possible cooperation between genetic makeup and differential housing on cocaine self-administration in male and female C57BL/6J and DBA/2J mice. Cocaine self-selection was measured in a two-choice test with one choice being cocaine-HCl solution of 40 mg% in tap water and the other choice being plain tap water. Housing conditions began at weaning (21-23 days of age) and consisted of group housed (GH) with 2-3 mice per cage, and isolated housed (IH) with 1 mouse per cage. The results of this study revealed overall strain, sex and housing differences, with C57BL/6Js consuming more cocaine solution than DBA/2J subjects, females consuming more cocaine solution than males, and group housed consuming more than isolate housed subjects. In a second study, the effect of differential housing on open-field locomotor activity was investigated. Testing was conducted on two consecutive days, with subjects receiving an IP injection of saline on day 1, and 15 mg/kg cocaine HCl on day 2. Four behaviors were recorded, including: total distance, nosepokes, stereotypy, and margin time. Overall, the results revealed significant strain differences for stereotypy and nosepokes, and males were found to be more activated by cocaine than females. Additionally, DBA males tended to be differentially affected by housing condition, with IH showing suppressed locomotor activity as compared to GH subjects. Last, significant strain by housing interactions occurred in nosepokes and stereotypy time.

Animals↗
PubMed1993

Pharmacogenetics of cocaine: I. Locomotor activity and self-selection.

We investigated the effects of cocaine on multiple activity measures and cocaine self-selection in C57BL/6Ibg and DBA/2Ibg mice. Male mice were tested in an automated activity monitor at three doses of cocaine, 5, 15 and 30 mg kg-1. Activity measures included locomotion, rearings, stereotyped movements and wall-seeking. Testing was conducted on 2 days with saline injection, i.p. on day one and cocaine i.p. injected on day two. We also tested other mice of both strains for cocaine ingestion in a two-choice test, pairing tap water with 40 mg% cocaine HCl in tap water. Two separate groups of mice received 15 or 30 mg kg-1 of cocaine i.p., killed at 5 min and brain cocaine levels were determined by HPLC. Cocaine produced dose-related increases in locomotion in both strains, with a delay in initial activation noticed at 30 mg kg-1 in C57s but not in DBAs. In DBAs, cocaine suppressed rearings and increased stereotyped movements while having no consistent effect on either behaviour in C57s. At all doses, cocaine produced moderate increases in proximity to the wall in DBAs and 30 mg kg-1 produced pronounced wall-seeking in C57s. At 15 and 30 mg kg-1 DBAs tended to have higher levels of cocaine in whole brain than did C57s. Finally, C57s consumed significantly more cocaine than did the DBAs.

Animals↗
PubMed1993

Pharmacogenetics of cocaine: II. Mesocorticolimbic and striatal dopamine and cocaine receptors in C57BL and DBA mice.

Studies were conducted to determine whether genetic differences in behavioural effects of cocaine in C57BL/6 and DBA/2 mice might be mediated by strain differences in dopamine and serotonin transporters and dopamine D1 and D2 receptors in specific brain regions. Binding characteristics of [3H]CFT, a cocaine analogue, in the presence of either GBR12909, a dopamine uptake blocker or fluoxetine, a serotonin uptake blocker and binding of [3H]-paroxetine, a specific serotonin uptake receptor antagonist, were evaluated. We observed regional differences in [3H]CFT binding parameters in the presence of GBR12909 or fluoxetine, but no strain differences by brain region were observed. There were no differences in [3H]paroxetine binding characteristics between corresponding brain regions from C57BL and DBA/2 mice. The D1 antagonist, [3H]SCH23390 and the D2 ligands [3H]sulpiride or [125I]epidepride were used to determine dopamine receptor characteristics. Regional differences were found in [3H]SCH23390 and [3H]sulpiride, with higher affinities and lower densities in frontal cortex compared to striatum; with no differences in [3H]SCH23390 binding in corresponding tissues from C57BL and DBA/2 brains. There were strain-related differences in [3H]sulpiride and in [3H]epidepride binding in striatal membranes with higher densities in C57BL than in DBA/2. Our findings suggest striatal D2 receptor differences are possibly involved in genetic differences in cocaine-related behaviours.

Animals↗
PubMed1993

Iron in the brain.

The location and function of iron in the central nervous system are reviewed with particular emphasis on human biology. Iron is distributed to different cell types in the brain in a heterogeneous fashion through the action of transferrin, transferrin receptors, and the metabolic needs of those cells. The function of this iron and its storage is documented in states of growth and development as well as during pathological states associated with aging. The information relating this biology to current observations of attention deficits in iron-deficient humans is also reviewed.

Adult↗
PubMed1993

Synovial sarcoma: MR imaging findings in 34 patients.

OBJECTIVE: MR imaging is considered the procedure of choice for detecting and staging soft-tissue tumors. Its ability to show differences between benign and malignant soft-tissue tumors and its usefulness in suggesting a specific histologic diagnosis remain controversial. We studied the MR features of synovial sarcoma in 34 patients to determine if these tumors have specific MR findings that can be used to suggest the diagnosis. MATERIALS AND METHODS: MR imaging studies of 34 patients with synovial sarcoma were collected from two institutions and studied to determine the following characteristics of the tumor: size, shape, location, signal intensity and homogeneity, margin definition, presence of hemorrhage, and relationships to adjacent structures. These findings were then correlated with pathologic findings. RESULTS: The tumors tended to be deep, large (85% were > or = 5 cm in diameter), and located in the extremities with epicenters close to joints (63% within 7 cm of a joint). The lesions were usually inhomogeneous on T2-weighted images (82%) and clearly delineated from surrounding tissues (91%). Forty-four percent had high signal consistent with hemorrhage on both T1- and T2-weighted images. Fluid-fluid levels, best visualized on T2-weighted images, were present in 18% of patients. Thirty-five percent of the lesions had areas that were hyper-, iso-, and hypointense relative to fat on T2-weighted images, constituting a triple signal intensity. The tumors frequently involved adjacent bone, with 71% invading, eroding, or touching bone. No association of pathologic subtypes with specific imaging findings was noted. CONCLUSION: Our results show a spectrum of MR imaging findings in synovial sarcoma. Nevertheless, the results suggest that synovial sarcoma should be considered when MR images show a relatively well-defined but inhomogeneous hemorrhagic lesion near a joint and in contact with bone. Fluid-fluid levels and areas hyper-, hypo-, and isointense relative to fat (triple signal) on T2-weighted sequences support the diagnosis.

Adolescent↗
PubMed1992

Speculations on the substrate structure-activity relationship (SSAR) of cytochrome P450 enzymes.

This brief review attempts to define the SSAR of two families of cytochrome P450. With P4502D catalytic competence is achieved by tight ionic binding which gives the enzyme high regioselectivity. In contrast P4503A achieves catalytic competence by a flexible binding site relying on hydrophobic forces that allow chemically vulnerable sites to be the principal sites of metabolism. In general, the different binding mechanism should be reflected in the enzyme, such that substrates of P4502D should have lower Km values than substrates of P4503A. Thus, routes of metabolism catalysed by P4502D may be saturated at substrate concentrations lower than routes catalysed by P4503A. The apparent differences between P4502D and P4503A in terms of substrate specificity bring into question what relationships govern other families of cytochrome P450. Our analysis of data suggests that the other principal form involved, generally, in the metabolism of pharmaceuticals in humans is P4502C9 (possibly 2C8 and 2C10). The enzyme is responsible for the metabolism of phenytoin, tolbutamide, tienilic acid [4], naproxen, ibuprofen, diclofenac [38], the 7-hydroxylation of S-warfarin [39] and the 7-hydroxylation of delta 1-tetrahydrocannabinol [40]. These compounds all have areas of strong hydrogen bond [4] forming potential (Fig. 8), all distanced 5-10A from the site of metabolism. Moreover the carboxylic acid function of naproxen, ibuprofen and diclofenac (pKa 4.5) and the sulfonylurea of tolbutamide (pKa 5.4) render the compounds ionized at physiological pH. The ionised group is positioned 7-11A from the site of metabolism. It is likely, therefore, that hydrogen bonding and possibly ion-pair interactions play a major role in determining the SSAR of the P4502C isoenzymes. These interactions would suggest that the P4502C enzymes are analogous to P4502D rather than P4503A. In this regard it is noteworthy that P4502C9 is selectively and potently inhibited by sulfaphenazole (IC50 of 0.6 microM), a compound that is structurally related (Fig. 8) to the substrates in terms of potential hydrogen bonding regions [4, 41]. Simplistically we suggest that the SSAR of the various P450 enzymes ranges from the highly selective enzymes dealing with endogenous substrates, through the enzymes metabolising exogenous substrates with narrow substrate structure requirements such as P4502D to P4503A with its broad substrate structure range. It would seem logical that animals and humans would evolve such combinations of isoenzymes to deal with the vast array of exogenous xenobiotics.

Cytochrome P-450 Enzyme System↗
PubMed1992

Paradoxical effects of nitrous oxide on human memory.

Using the method of adjusted learning, subjects learned number-noun pairs while breathing either placebo or 30% nitrous oxide. Subjects breathing nitrous oxide required more acquisition trials to attain a learning criterion than did subjects breathing placebo. Two weeks later, half of the subjects from each group were administered either placebo or nitrous oxide and were asked to recall the noun that had accompanied each number cue. Results showed that: 1) nitrous oxide inhalation can decrease the accessibility of to-be-recalled material and 2) nitrous oxide administered during the acquisition of material can paradoxically improved the recall of that material 2 weeks later. The additional number of acquisition trials subjects received during nitrous oxide inhalation could potentially account for this paradoxical enhancement of delayed recall; however, correlational analyses suggest this was not the case. No evidence for any state-dependent effects of nitrous oxide on cued recall were found.

Adolescent↗
PubMed1992

Chronic ethanol consumption produces genotype-dependent tolerance to ethanol in LS/Ibg and SS/Ibg mice.

It is well known that chronic ethanol administration produces tolerance to the sedative-hypnotic and hypothermic effects as well as low-dose locomotor inhibitory effects of ethanol. We report herein characterization of a convenient method of producing genotype-dependent functional tolerance to ethanol-induced locomotor inhibition. Mice, LS/Ibg (LS) and SS/Ibg (SS), which differ markedly in acute effects of ethanol on locomotor activity, hypothermia, and hypnotic sensitivity, were required to consume solutions of ethanol in water as the sole source of liquid. Mice were provided lab chow ad lib. and the following regimen of ethanol in water, v/v: 10% for 4 days, 15% for 4 days, 20% for 7 days, followed by 15% for periods longer than 2 weeks. Control animals received water only or were pair-fed sucrose (isocaloric with ethanol) solutions plus lab chow; both control and ethanol-consuming (15 g ethanol/kg/24 h) mice maintained similar body weights for up to 4 weeks. Blood ethanol concentrations from 10-200 mg% were obtained during a 12 L:12 D cycle. At 6 h following withdrawal, LS and SS mice showed differential dose-dependent tolerance to locomotor inhibitory effects of ethanol. However, low-dose locomotor activation was unaltered in either line of mice, and results indicate that an apparent sensitization in SS mice is secondary to development of tolerance to locomotor inhibition. Maximum tolerance to locomotor inhibition was observed after 2 weeks of chronic ethanol consumption, with responses returning to control values within 1-2 weeks after withdrawal. Rates of acquisition of tolerance were similar in LS and SS mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Cocaine actions, brain levels and receptors in selected lines of mice.

The effects of cocaine (15 mg/kg IP) versus IP saline on open-field behaviors were evaluated using a crossover design in long-sleep (LS) and short-sleep (SS) mice. Under treatment order 1, mice received saline injection on day 1 followed 24 h later by cocaine (saline-cocaine, S-C). Under treatment order 2, animals received cocaine on day 1 and saline on day 2 (cocaine-saline, C-S). Immediately following injection, animals were placed into an automated open-field apparatus with behavioral samples taken at 5-min intervals for 30 min. The behaviors measured were distance traveled, stereotypy and time spent in proximity to the margins of the test apparatus (thigmotaxis). Cocaine increased locomotor activity in both lines of mice, with S-C producing more pronounced initial activation than C-S in LS mice. Compared to S-C, C-S also increased thigmotaxis, an effect more pronounced in SS mice. In a separate experiment, brain cocaine levels were measured in brains of adapted and nonadapted LS and SS mice 5 min following injection of 15 mg/kg cocaine. Regardless of order, SS mice had significantly higher brain cocaine levels than did LS mice. Mazindol and cocaine binding studies in the forebrain indicated higher Bmax values for both ligands in LS compared to SS mice. The results of this study indicate that genetically based differences in cocaine receptors as well as treatment order contribute to behavioral actions of cocaine.

Animals↗
PubMed1991

Regional characterization of brain neurotensin receptor subtypes in LS and SS mice.

Neurotensin (NT) receptor subtypes were investigated in nine brain regions from long sleep (LS) and short sleep (SS) mice that were selectively bred for differences in sensitivity to ethanol. Differences in NT receptor densities may mediate, in part, genetically selected differences in ethanol sensitivity between the two lines of mice. The use of [3H] NT at concentrations from 0.02 to 20 nM yielded biphasic binding isotherms as revealed by Scatchard analysis. Membranes from LS ventral midbrain yielded dissociation constants (KD values) of 0.34 and 3.85 nM for the high (NTH) and low (NTL) affinity components, respectively. SS membranes displayed similar KD values, however the maximum number of binding sites (Bmax) for both receptor subtypes were significantly greater in SS than in LS membranes (46.7 vs. 71.5 fmol/mg protein for NTH and 170.2 vs. 208.2 fmol/mg protein for NTL). Using levocabastine, and H1 antagonist with selectivity for NTL, characterization of NTH and NTL binding in nine brain regions was performed. In general, membranes from each brain region of SS mice had higher densities than LS for both receptor subtypes. Significant differences for the total density of receptors and NTL were found in entorhinal cortex, nucleus accumbens, hippocampus, and ventral midbrain. The only region to differ in NTH was the ventral midbrain. Competition experiments using various NT fragments to compete for NTH binding showed the C-terminal amino acids to be essential for binding. The order of potency was NT1-13 = NT8-13 greater than Neuromedin N greater than NT1-8 = NT1-11.

Alcohol Drinking↗
PubMed1991

Metabolism in the rat of a model xenobiotic plant metabolite S-benzyl-N-malonyl-L-cysteine.

1. The metabolism of a model xenobiotic plant metabolite S-benzyl-N-malonyl-L-cysteine (BMC) administered to rat at 10 mg/kg has been studied using a combination of radio-t.l.c. and h.p.l.c. 2. The major route of excretion for the administered 14C was via the urine (79% in 3 days). 3. The major metabolite was hippuric acid. The extent of biotransformation of BMC indicated the lability of the N-malonyl bond whose hydrolytic removal initiated a metabolic sequence which involved the action of C-S lyase to produce benzyl thiol. 4. A comparison of the findings from this study with those from experiments with N-acetyl-S-benzyl-L-cysteine and S-benzyl-L-cysteine is made to support the metabolic pathway proposed.

Animals↗
PubMed1990

Isolate housing alters ethanol sensitivity in long-sleep and short-sleep mice.

Beginning at 45 days of age, male long-sleep (LS) and short-sleep (SS) mice were placed into individual cages for 21-22 days. Control animals were group-housed for the same amount of time. At 65-66 days of age, animals were given anesthetic doses of ethanol, IP. Measures taken were sleep time, body temperature at 30 and 60 minutes postinjection and blood ethanol content (BEC) at regain of righting response. Compared to the same measures in group-housed animals, sleep times and hypothermia were attenuated in isolate-housed LS and SS mice. Isolate housing resulted in a 15% increase, compared to levels observed in group-housed animals, in BEC at regain of righting in LS; there was no significant difference in BEC in SS mice. The results indicated an isolation-related decrease in sensitivity to the anesthetic effects of ethanol in LS; the effect of isolation in SS may be an increased clearance rate of ethanol.

Animals↗
PubMed1990

Low doses of ethanol reduce neurotensin levels in discrete brain regions from LS/Ibg and SS/Ibg mice.

Studies were designed to examine the previously proposed hypothesis that some of the pharmacological actions of ethanol are mediated by neurotensinergic processes. Neurotensin-immunoreactivity (NT-ir) was extracted from various brain regions and shown by high performance liquid chromatography to possess the same retention time as authentic bovine NT1-13. The highest levels of NT-ir were observed in the hypothalamus with intermediate levels in the midbrain and striatum and lowest levels in the frontal cortex. Levels of NT-ir were higher in hypothalamus and midbrain from long-sleep (LS) than from short-sleep (SS) mice. Ethanol, in vivo, produced a dose-dependent decrease in NT-ir in several brain regions; low doses, 1.5 to 3.0 g/kg, but not high doses, 4.1 g/kg, of ethanol significantly decreased NT-ir in hypothalamus, midbrain, and striatum of LS and SS mice. Levels of NT-ir in the frontal cortex were not altered by ethanol administration. Ethanol-induced decreases in NT-ir were of rapid onset with a maximum decrease in 5 min after intraperitoneal (i.p.) injection, and they were of long duration with levels remaining depressed for 4 hr. These findings show that subhypnotic, intoxicating doses of ethanol enhance NT release, in vivo, and support the hypothesis that some of ethanol's actions are mediated by neurotensinergic systems.

Animals↗