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B C Jones

Publications and source records attributed to B C Jones.

At least 37 records · Page 2Linked to original sources
PubMed1999

Quantitative-trait loci analysis of cocaine-related behaviours and neurochemistry.

We recently conducted a dose-response study of the effects of cocaine on several activity measures in the panel of BxD/Ty recombinant inbred mice. Animals were tested in an automated activity chamber over 2 days with i.p. saline on day 1 and i.p. cocaine on day 2, at one of four doses, 5, 15, 30 or 45 mg kg(-1). The monitor recorded total distance traveled, nosepokes in a holeboard, repeated movements and time spent by an individual in proximity to the centre of the apparatus. Dose-response curves for locomotor activation, i.e. the difference between cocaine and saline scores, showed that for all strains tested, scores increased 5-30 mg kg(-1). With few exceptions, locomotor activity at 45 mg kg(-1) was not significantly higher than that at 30 mg kg(-1). Repeated movement scores showed patterns similar to locomotor activity and nosepokes tended to be progressively inhibited by increasing doses of cocaine. Recombinant inbred strain mean distributions for all behaviours and at all doses exhibited continuous, rather than discrete variation, thus providing evidence of multiple-gene effects on cocaine-related behaviours. Quantitative trait loci (QTL) analysis pointed to several chromosomal locations associated with variations in cocaine-related behaviours and some are either identical or close to QTL reported by others. In separate groups of animals, densities of dopamine D1, and D2 receptors and dopamine uptake transporters were measured in the medial prefrontal cortex, caudate-putamen, nucleus accumbens and ventral midbrain. In all areas, all measures showed distributions consistent with polygenic influence and were associated with QTL. Of particular interest was our finding of a large segment on chromosome 15, which is related to dopamine receptor densities and cocaine-related behaviours.

Animals↗
PubMed1998

Differential effects of stress-induced adrenal function on components of the herpes simplex virus-specific memory cytotoxic T-lymphocyte response.

We have previously demonstrated in a murine model system that psychological stress, applied in the form of physical restraint, suppresses both the activation of splenic-derived, herpes simplex virus (HSV)-specific memory cytotoxic T-lymphocytes (CTLm) to the lytic phenotype and the production of cytokines associated with CTL activation and function. In the studies described herein, we investigated the hypothesis that an adrenal-dependent event is responsible, either in whole or in part, for these observations. While adrenalectomy was shown to abrogate stress-induced suppression of both HSV-specific CTLm activation and the production of IL-6 and IFN-gamma, the reduction in splenic cellularity associated with restraint stress remained, In addition, a role for adrenal function in the regulation of splenic cellularity and IFN-gamma production in non-stressed mice was observed. Together, these results indicate that both adrenal-dependent and adrenal-independent events, operative under both baseline and stress conditions, mediate control of the memory component of the cellular immune response to HSV infection. Overall, these studies provide insight into the mechanisms by which psychological stress modulates immune responsiveness to viral pathogens.

Adrenal Glands↗
PubMed1998

A genetic basis for neuroendocrine-immune interactions.

Psychoneuroimmunology is an exciting, complex field that elucidates interactions among the nervous, endocrine, and immune systems. The contribution of psychosocial factors and behavioral processes to these interactions has been the focus of numerous studies designed to investigate the intricate pathways that are involved in the "mind-body connection." In addition, the effects of this connection on the development and progression of various disease conditions are of considerable interest. Although efforts have been made to identify the cellular and molecular mechanisms underlying these relationships, the impact of genetic makeup on the communication among these systems has yet to be fully realized. The development of sophisticated genetic analytical methods and gene mapping techniques now provide the "tools" to determine the influence of genetics on behavior-neuroendocrine-immune interactions--an area of study that may represent the next frontier in psychoneuroimmunology.

Genes↗
PubMed1998

The effect of age and testosterone on the expression of glial fibrillary acidic protein in the rat cerebellum.

Testosterone reversed the age-related increase in glial fibrillary acidic protein (GFAP) in the male rat cerebellum, a brain region not generally associated with gonadal steroid hormone sensitivity. This supports the hypothesis that a decrease in circulating testosterone contributes to age-related increase in GFAP. These data also suggest that reductions in circulating gonadal steroids during aging could render the brain more susceptible to neurodegeneration and that hormone replacement therapy might have value in neurodegenerative disease intervention.

Aging↗
PubMed1998

Ethanol modulates cocaine-induced behavioral change in inbred mice.

We recently conducted a study of the behavioral effects of combined cocaine and ethanol in genetically defined mice. Male and female C57BL/6 (B6) and DBA/2 (D2) were tested in an automated activity monitor on 2 consecutive days. On day 1, all animals received an IP injection of sterile saline and were placed into the activity monitor for 30 min. Behaviors measured were total distance traveled, stereotypy, nosepokes, and wall-seeking. On day 2, all animals were tested again for 15 min following injection of one of the following: saline, 10% v/v ethanol at 2.0 g kg(-1) or 2.0 g kg(-1) ethanol plus 5, 15, or 30 mg kg(-1) cocaine. Cocaine alone at the same doses was injected into separate groups of animals. For the B6 strain, the overall effect of ethanol was to reduce cocaine-induced locomotor stimulation; no consistent effect of ethanol on cocaine-induced locomotion was observed in D2 mice. Cocaine-induced inhibition of nosepokes in both strains and sexes was partially reversed by ethanol. Ethanol also partially reversed cocaine-elevated stereotypy in both strains and both sexes. In B6 mice, cocaine-increased wall seeking tended to be reversed by coadministration of ethanol, whereas no consistent pattern was observed in the D2s. Results from this study suggest that the several measures affected by cocaine (locomotor activity, stereotypy, exploration, thigmotaxis) were, in turn, differentially affected by concurrent treatment with ethanol. Furthermore, our results point to genetic-based differences in ethanol's effects on cocaine-related behaviors. We address the implications for combined ethanol and cocaine use in humans.

Animals↗
PubMed1998

Distribution and clearance of cocaine in brain is influenced by genetics.

The purpose of this study was to examine the pharmacokinetics of cocaine in two inbred mouse strains, C57BL/6 (B6) and DBA/2 (D2). Male and female mice were administered 30 mg kg(-1) cocaine IP and killed after 5, 15, 30, or 60 minutes postinjection. Brains were removed quickly and assayed for total brain cocaine concentration. Quantification of cocaine was conducted using gas chromatography and mass spectrometry. The results of this study revealed a strain difference in total brain cocaine kinetics. Specifically, we observed that at 5 min onward, B6 mice cleared cocaine from the brain with a t1/2 estimated at 22.3 min, while distribution in D2 mice appeared to be incomplete until 15 min with a subsequent t1/2 estimated at 11.2 min. These results show that despite faster clearance by D2 mice, the prolonged time to distribution in this strain may help explain why D2 mice show initial greater locomotor activation by cocaine, compared to B6s.

Animals↗
PubMed1998

Contribution of sex and genetics to neuroendocrine adaptation to stress in mice.

Male and female C57BL/6 (B6) and DBA/2 (D2) mice were subjected to either acute or 5 days of repeated restraint in ventilated, 50 ml centrifuge tubes. Control animals were not disturbed. The acute restraint animals were killed immediately following 15, 30 or 60 min of restraint and blood collected for corticosterone (CORT) analysis. The results of the acute restraint procedure revealed a strain difference in time to peak CORT in plasma with D2 animals showing an earlier peak. The males of both strains evinced similar maximum response and similar to B6 females; however, the D2 females showed a 2-fold greater CORT response than did the B6 females. Repeated restraint consisted of 5 days of 12 h in the tubes. At the end of 5 days, the animals were weighted and adrenalectomized in preparation for determination of brain corticosteroid receptors. Upon sacrifice, brains, thymus, adrenals and blood were harvested, the last for corticosteroid binding globulin (CBG). Five days of repeated restraint produced body weight loss in both strains, with B6s less affected than D2s. Repeated restraint reduced the mass of the adrenals in the B6s only. Restraint also reduced the mass of the thymus in both strains and sexes, but to a greater extent in the B6s. Plasma CBG densities were also sensitive to restraint, but only in females, showing a restraint-related decrease. Repeated restraint had no effect on hippocampal glucocorticoid or mineralocorticoid receptors; however for the latter, we observed significant strain and sex effects with D2 having higher Bmax than B6 and females having higher Bmax than males. In the pituitary, glucocorticoid receptors (GR) were reduced by repeated restraint in males, but increased in females, especially in the B6. These findings lend preliminary evidence for involvement of sex and genetics as sources of individual differences in bioadaptation to stress.

Adaptation, Physiological↗
PubMed1998

Mapping of provisional quantitative trait loci influencing temporal variation in locomotor activity in the LS x SS recombinant inbred strains.

The finding that stress-induced locomotor activity exhibited a significant strain x time interaction in the LS x SS RI strains prompted examination of QTL influencing this behavior as a function of time. The degree of genetic determination for locomotor activity was 0.26 for the first 5 min and decreased to 0.16 for the last 5 min of a 30-min test but the number of genetic factors stayed relatively constant (three or four) across time. A QTL point analysis revealed a total of 15 QTL, 5-8 per 5-min time block. Few of the QTL were detected across all time points and different combinations of QTL were evident for each time period. Five of the QTL were in common with those reported by other investigators for similar behaviors. The results suggest that locomotor behavior is under a greater degree of genetic control during the initial part of the test but environmental factors become increasingly important as the test progresses. Furthermore, different genetic factors appear to be mediating genetic variation in locomotor behavior at any given time point.

Analysis of Variance↗
PubMed1998

Hemodialysis access graft stenosis: US detection.

PURPOSE: To prospectively evaluate the sensitivity of ultrasonography (US) in diagnosing stenosis of hemodialysis access grafts and their drainage veins in patients clinically suspected of having graft dysfunction. MATERIALS AND METHODS: Thirty-eight patients in whom dysfunction of their hemodialysis access grafts was suspected underwent both Doppler US and angiography. Gray-scale and color US were combined with spectral analysis of the graft, anastomoses, and venous outflow. Flow velocity at anastomoses and suspected stenotic areas was measured. The volume of flow in the graft was also measured. The prospective US criterion for diagnosis of stenosis was a focal twofold or higher elevation of peak systolic velocity (PSV) compared with the PSV immediately upstream. A blinded angiographic evaluation of the graft and drainage veins followed US. Angiographic diagnosis of stenosis required at least 50% narrowing in luminal diameter. US and angiographic results were then compared. RESULTS: Angiography allowed diagnosis of 43 stenoses in 34 patients. US depicted 92% (37 of 40) of these stenoses, with a 94% positive predictive value for any individual patient. Focal 2- to 2.9-times PSV elevation was associated with 75% or greater stenosis. Graft flow volume and resistive index change did not correlate with stenosis. CONCLUSION: US reliably depicts stenoses of hemodialysis access grafts and drainage veins in a clinically selected population when PSV criteria are used.

Adult↗
PubMed1998

Interaction of terfenadine and its primary metabolites with cytochrome P450 2D6.

The substrate structure-activity relationships described for the major human drug-metabolizing cytochrome P450 (P450 or CYP) enzymes suggest that the H1 receptor antagonist terfenadine could interact with CYP2D6 either as a substrate or as an inhibitor, in addition to its known ability to act as a substrate for CYP3A4. Based on this substrate structure-activity relationship, computer modeling studies were undertaken to explore the likely interactions of terfenadine with CYP2D6. An overlay of terfenadine and dextromethorphan, a known substrate of CYP2D6, showed that it was possible to superimpose the site of hydroxylation (t-butyl group) and the nitrogen atom of terfenadine with similar regions in dextromethorphan. These observations were substantiated by the ease of docking of terfenadine into a protein model of CYP2D6. Experimentally, terfenadine inhibited CYP2D6 activity in human liver microsomes with an IC50 of 14-27 microM, depending on the CYP2D6 substrate used. The inhibition of CYP2D6 was further defined by determining the Ki for terfenadine against bufuralol 1'-hydroxylase activity in four human livers. Terfenadine inhibited bufuralol 1'-hydroxylase activity with a Ki of approximately 3.6 microM. The formation of the hydroxylated metabolite (hydroxyterfenadine) in microsomes prepared from human liver and specific P450 cDNA-transfected B lymphoblastoid cells indicated that only CYP2D6 and CYP3A4 were involved in this transformation. As expected, the rate of formation was greatest with CYP3A4 (Vmax = 1257 pmol/min/nmol of P450), with CYP2D6 forming the metabolite at a 6-fold lower rate (Vmax = 206 pmol/min/nmol of P450). The two enzymes had similar KM values (9 and 13 microM, respectively). These data indicate that, as predicted from modeling studies, terfenadine has the structural features necessary for interaction with CYP2D6.

Chromatography, High Pressure Liquid↗
PubMed1997

A second catalytic metal ion in group I ribozyme.

Although only a subset of protein enzymes depend on the presence of a metal ion for their catalytic function, all naturally occurring RNA enzymes require metal ions to stabilize their structure and for catalytic competence. In the self-splicing group I intron from Tetrahymena thermophila, several divalent metals can serve structural roles, but only Mg2+ and Mn2+ promote splice-site cleavage and exon ligation. A study of a ribozyme reaction analogous to 5'-splice-site cleavage by guanosine uncovered the first metal ion with a definitive role in catalysis. Substitution of the 3'-oxygen of the leaving group with sulphur resulted in a metal-specificity switch, indicating an interaction between the leaving group and the metal ion. Here we use 3'-(thioinosylyl)-(3'-->5')-uridine, IspU, as a substrate in a reaction that emulates exon ligation. Activity requires the addition of a thiophilic metal ion (Cd2+ or Mn2+), providing evidence for stabilization of the leaving group by a metal ion in that step of splicing. Based on the principle of microscopic reversibility, this metal ion activates the nucleophilic 3'-hydroxyl of guanosine in the first step of splicing, supporting the model of a two-metal-ion active site.

Animals↗
PubMed1997

Identification of the cytochrome P450 isoforms involved in the O-demethylation of 4-nitroanisole in human liver microsomes.

1. 4-Nitroanisole is O-demethylated to 4-nitrophenol by human liver microsomes. Kinetic studies indicate that this metabolic route is mediated by two cytochrome P450 isoforms, one with a K(m) = 2.1 microM and the other with a K(m) = 220 microM. 2. Chemical inhibition and correlation studies in human liver microsomes indicate that the low K(m) enzyme is CYP2A6 and the high K(m) enzyme is CYP2E1 suggesting that44-nitroanisole is not a general cytochrome P450 substrate. 3. Studies using expressed recombinant cytochrome P450s indicated that all the cytochrome P450s investigated metabolized 4-nitroanisole but CYP2A6 and CYP2E1 produced the highest rates. Kinetic studies with these two isoforms produced a K(m) for CYP2A6 of 9 microM and 54 microM for CYP2E1. 4. The involvement of these two isoforms in the O-demethylation of 4-nitroanisole can be rationalized in terms of a hydrogen bond interaction with the nitro group and the active site of CYP2A6 and a hydrophobic interaction with the active site of CYP2E1.

Adult↗
PubMed1997

Inhibition of replication of hepatitis B virus by cytallene in vitro.

The acyclic cytosine nucleoside analog cytallene [1-(4'-hydroxy-1',2'-butadienyl)cytosine], which has both (+)- and (-)-enantiomers, was evaluated for its anti-hepatitis B virus (HBV) activity in 2.2.15 cells and was found to have potent activity against HBV DNA synthesis. The R-(-)-enantiomer was found to be the more active of the cytallene enantiomers, with a 50% inhibition concentration against HBV synthesis (HBIC50) of 0.08 microM. Its antiviral activity could be reversed by deoxycytidine (dC) and less efficiently by cytidine. Upon removal of the R-(-)-enantiomer from culture medium, the synthesis of HBV DNA could reinitiate, which suggested that the antiviral action is reversible. The R-(-)-enantiomer was also found to be more cytotoxic than the S-(+)-enantiomer. The degree of cytotoxicity varied among the cell lines, with a 50% inhibition of cell growth at greater than 10 microM. The R-(-)-enantiomer had no effect on HBV RNA synthesis and mitochondrial DNA synthesis at a concentration of 10 times or more than the HBIC50. The two enantiomers cannot be deaminated by dC deaminase, and they can be phosphorylated by cytoplasmic dC kinase. The R-(-)-enantiomer of cytallene is the first acyclic cytosine analog with potent inhibitory activity against HBV similar to those of other L-(-)-ddC analogs.

Antiviral Agents↗
PubMed1997

Hypervascular liver metastases: do unenhanced and hepatic arterial phase CT images affect tumor detection?

PURPOSE: To evaluate the relative roles of unenhanced and hepatic arterial phase (HAP) computed tomographic (CT) imaging in the detection of hypervascular liver metastases. MATERIALS AND METHODS: Eighty-four patients with biopsy-proved liver metastases from hypervascular primary tumors other than hepatocellular carcinoma underwent unenhanced and HAP and portal venous phase (PVP) helical CT studies. Three blinded radiologists evaluated each series of images separately for the number, size, and enhancement characteristics of lesions. Sixty-nine patients had follow-up imaging proof of tumor burden. RESULTS: The three readers detected 381-402 lesions on the PVP images and 397-416 lesions on the unenhanced images. Unenhanced images allowed detection of 72%-80% of the lesions seen on PVP images. They detected 94-137 additional lesions on unenhanced but not PVP images. On the HAP images, 375-395 lesions were identified. HAP images allowed detection of 81%-90% of the lesions seen on PVP images. Forty-five to 78 additional lesions were detected on HAP but not on PVP images. In the 69-patient subset, maximal detection of tumor foci occurred in 94% of patients with unenhanced plus PVP images and in 78% with HAP plus PVP images. Unenhanced plus PVP images allowed detection of 96% of the 322 tumors in the subset population. CONCLUSION: Unenhanced plus PVP CT images allow detection of statistically significantly more hypervascular liver metastases than do HAP plus PVP images or imaging only in the PVP.

Contrast Media↗
PubMed1997

Sex and strain influence the effect of ethanol on central monoamines.

OBJECTIVE: We recently investigated the effects of EtOH on the mesolimbic dopamine and serotonin systems in male and female C57BL/6 (B6) and DBA/2J (D2) mice. METHOD: Male and female rodents from the B6 and D2 mouse strains (n = 11 per strain, sex and dose) were used in this study. Doses of EtOH (vs saline) administered were 1.0, 2.0 or 3.0 g/kg. RESULTS: Treatment with saline or EtOH produced both strain- and sex-dependent differences in patterns of monoamine response. For example, D2s exhibited significantly higher overall dopamine (DA) levels than did B6s in the frontal cortex (FC), nucleus accumbens (NA) and caudate-putamen (CP). In the FC, female D2 evinced elevated 5HIAA at 1.0 g/kg. In the NA, D2 females showed dose related increases in levels of DA up to 3.0 g/kg, whereas in the D2 males and in B6 males and females we observed no response. Also in the NA, B6 males showed increases in dihydroxyphenyacetic acid (DOPAC) at 1.0 and 3.0 g/kg. In the CP, B6 males showed higher DA levels than B6 females at the saline, and all EtOH doses. For serotoninergic activity in the CP as well as the NA, EtOH produced a distinctive triphasic response, with the 1.0 and 3.0 g/kg doses of EtOH producing higher levels than saline and 2.0 g/kg of 5HIAA in B6 males than in B6 females. CONCLUSIONS: Our findings indicate strain and sex differences in monoamine response to acute doses of ethanol, and further implicate (via changes in DOPAC) presynaptic mechanisms in the effects of ethanol on dopamine.

Animals↗
PubMed1997

Common quantitative trait loci for alcohol-related behaviors and central nervous system neurotensin measures: hypnotic and hypothermic effects.

Genetic correlations were found between high-affinity neurotensin receptor (NTR(H)) densities and NT-immunoreactivity (NT-ir) levels in specific brain regions and sensitivity to hypnotic and hypothermic effects of ethanol in LSXSS recombinant inbred strains of mice. Simple sequence length polymorphisms were used to identify quantitative trait loci (QTL) influencing hypnotic and hypothermic sensitivity to ethanol, NTR(H) and low-affinity neurotensin receptor densities and NT-ir levels in LSXSS recombinant inbred strains. Common QTL for NTR(H) receptor densities, NT-ir levels and these ethanol actions were identified. One of the QTL (chromosome 2, 80 cM) for NTR(H) density and hypnotic sensitivity is linked to the NTR(H) gene, Ntsr. Also, QTL for NTR(H) density were found in common with confirmed QTL for hypnotic sensitivity on chromosomes 1 (43 cM), 11 (57 cM) and 15 (56 cM) and with an unconfirmed QTL on chromosome 3 (19 cM). Two common QTL for NT-ir levels, but not NTR(H) or low-affinity neurotensin receptor receptors, and ethanol-induced hypothermia were observed on chromosomes 4 (43 cM) and 6 (41 cM). Two common QTL for NT-ir levels and sleep time were identified on chromosomes 3 (19 cM) and 9 (55 cM). Common QTL indicate that genes regulating NT receptor and/or NT-ir expression may be the same as those regulating sensitivity to ethanol.

Alcoholism↗
PubMed1997

Common quantitative trait loci for alcohol-related behaviors and central nervous system neurotensin measures: locomotor activation.

We have analyzed LSXSS recumbinant inbred for ethanol-induced activity using 2.0 g/kg ethanol and a new method we call ethanol activation slope. The ethanol activation slope provides a robust dose-response measure of ethanol activation, independent of both activity after saline and the inhibitory effects of ethanol on locomotor activity. These behavioral data were used in a quantitative trait locus analysis to map chromosomal loci involved in ethanol-induced locomotor activity. We tentatively identified seven loci that mediate the low-dose stimulatory effect of ethanol and six loci involved in locomotion after 2.0 g/kg ethanol. Only one of the loci are in common between the two behaviors. We also compared the behavioral quantitative trait locus to those previously identified that are involved in regulating central nervous system neurotensin levels and neurotensin receptor densities. Six chromosomal regions were identified that regulate at least one central nervous system neurotensin measure and an ethanol-induced locomotor behavior. The identification of loci controlling both central nervous system neurotensin levels or neurotensin receptor densities and ethanol-induced locomotor activity strengthens the proposal that neurotensin regulates, in part, ethanol-induced behaviors and central nervous system sensitivity to ethanol.

Alcoholism↗