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C Shea

Publications and source records attributed to C Shea.

At least 37 records · Page 2Linked to original sources
PubMed1996

[18F]haloperidol binding in baboon brain in vivo.

The binding of [18F]haloperidol to dopamine D2 and to sigma recognition sites in baboon brain was examined using positron emission tomography (PET). Studies were performed at baseline and after treatment with either haloperidol (to evaluate saturability), (+)-butaclamol (which has specificity for dopamine D2 receptors) or (-)-butaclamol (which has specificity for sigma sites). Binding was widespread. Treatment with (-)-butaclamol had no effect, whereas (+)-butaclamol selectively reduced the uptake in striatum. Haloperidol increased the clearance rate from all brain regions. These results indicate that the binding profile of [18F]haloperidol does not permit the selective examination of either dopamine D2 or sigma sites using PET.

Animals↗
PubMed1996

Decreases in dopamine receptors but not in dopamine transporters in alcoholics.

It has been hypothesized that ethanol's actions on the dopamine (DA) system may participate in addiction. The purpose of this study was to evaluate the DA system in the brain of alcoholics. We evaluated 10 alcoholics and 17 nonalcoholics using positron emission tomography and [11C]raclopride to measure DA D2 receptors. In addition, in 5 of the alcoholics and 16 of the nonalcoholics, we also measured DA transporters with [11C]d-threo methylphenidate. The ratio of the distribution volumes in striatum to that in cerebellum, which corresponds to Bmax/Kd + 1, was used as model parameter of DA D2 receptor and transporter availability. Dopamine D2 receptor availability (Bmax/Kd) was significantly lower in alcoholics (2.1 +/- 0.5) than in nonalcoholics (2.7 +/- 0.6) (p < 0.05) and was not correlated with days since last alcohol use. Alcoholics showed DA transporter values similar to those in nonalcoholics. The ratio of DA D2 receptor to transporter availability was significantly higher in nonalcoholics (1.4 +/- 0.1) than in alcoholics (1.1 +/- 0.1) (p < 0.005). Alcoholics showed significant reductions in D2 receptors (postsynaptic marker) but not in DA transporter availability (presynaptic marker) when compared with nonalcoholics. Because D2 receptors in striatum are mainly localized in gamma-aminobutyric acid (GABA) cells these results provide evidence of GABAergic involvement in the dopaminergic abnormalities seen in alcoholics.

Adult↗
PubMed1995

Plasma input function determination for PET using a commercial laboratory robot.

A commercial laboratory robot system (Zymate PyTechnology II Laboratory Automation System) was interfaced to standard and custom laboratory equipment and programmed to perform rapid radiochemical assays necessary for plasma input function determination in quantitative PET studies in humans and baboons. A Zymark XP robot arm was used to carry out two assays: (1) the determination of total plasma radioactivity concentrations in a series of small-volume whole blood samples and (2) the determination of unchanged (parent) radiotracer in plasma using only solid phase extraction methods. Steady state robotic throughput for determination of total plasma radioactivity in whole blood samples (0.350 mL) is 14.3 samples/h, which includes automated centrifugation, pipetting, weighing and radioactivity counting. Robotic throughput for the assay of parent radiotracer in plasma is 4-6 samples/h depending on the radiotracer. Percents of total radioactivities present as parent radiotracers at 60 min, postinjection of 25 +/- 5.0 (N = 25), 26 +/- 6.8 (N = 68), 13 +/- 4.4 (N = 30), 32 +/- 7.2 (N = 18), 16 +/- 4.9 (N = 20), were obtained for carbon-11 labeled benztropine, raclopride, methylphenidate, SR 46349B (trans, 4-[(3Z)3-(2-dimethylamino-ethyl) oxyimino-3 (2-fluorophenyl)propen-1-yl]phenol), and cocaine respectively in baboon plasma and 84 +/- 6.4 (N = 9), 18 +/- 11 (N = 10), 74 +/- 5.7 (N = 118) and 16 +/- 3.7 (N = 18) for carbon-11 labeled benztropine, deprenyl, raclopride, and methylphenidate respectively in human plasma. The automated system has been used for more than 4 years for all plasma analyses for 7 different C-11 labeled compounds used routinely in our laboratory. The robotic radiotracer assay runs unattended and includes automated cleanup procedures that eliminates all human contact with plasma-contaminated containers.

Animals↗
PubMed1995

Mechanistic positron emission tomography studies of 6-[18F]fluorodopamine in living baboon heart: selective imaging and control of radiotracer metabolism using the deuterium isotope effect.

Mechanistic positron emission tomography (PET) studies using the deuterium isotope effect and specific pharmacological intervention were undertaken to examine the behavior of 6-[18F]fluorodopamine (6-[18F]-FDA; 1) and (-)-6-[18F]fluoronorepinephrine [(-)-6-[18F]FNE; 2] in the baboon heart. Two regiospecifically deuterated derivatives of 6-[18F]FDA [alpha,alpha-D2 (3) and beta,beta-D2 (4)] were used to assess the contributions of monoamine oxidase (MAO) and dopamine beta-hydroxylase, respectively, to the clearance kinetics of 6-[18F]FDA. Compound 3 showed a reduced rate of clearance, consistent with MAO-catalyzed cleavage of the alpha C-D bond, whereas compound 4 showed no change, indicating that cleavage of the beta C-D bond is not a rate-limiting step. Pretreatment with pargyline, an MAO inhibitor, also decreased the rate of clearance. Desipramine and tomoxetine [norepinephrine (NE) uptake inhibitors], but not GBR-12909 (a dopamine uptake inhibitor), blocked the uptake of both (-)-6-[18F]FNE and 6-[18F]FDA, with (-)-6-[18F]FNE showing a higher degree of blockade. Chiral HPLC demonstrated that 6-[18F]FDA is stereoselectively converted to (-)-6-[18F]FNE in vivo in the rat heart. These studies demonstrate that (a) the more rapid clearance of 6-[18F]FDA relative to (-)-6-[18F]FNE can be largely accounted for by metabolism by MAO; (b) selective deuterium substitution can be used to protect a radiotracer from metabolism in vivo and to favor a particular pathway; (c) 6-[18F]FDA and (-)-6-[18F]FNE share the NE transporter; (d) 6-[18F]FDA is stereoselectively converted to (-)-6-[18F]FNE in vivo; and (e) the profile of radioactivity in the heart for 6-[18F]FDA is complex, probably including labeled metabolites as well as neuronal and nonneuronal uptake.

Animals↗
PubMed1995

Analysis of the cost of training residents in a community health center.

BACKGROUND: Currently one federal program funds community health centers (CHCs) to provide services in underserved communities, and a second supports development of primary care teaching programs. Teaching CHCs respond to both program's goals, but their development is hindered by restrictive regulations of the two programs and lack of information regarding cost. METHOD: Spreadsheet software was used to develop a model that allocates cost components of a CHC-based residency. Productivity and staffing data from a teaching CHC program were used to estimate the cost of training and its sensitivity to selected variables. Data from 1992 through 1994 were collected from the family practice residency sponsored by the Brown University School of Medicine, the Memorial Hospital of Rhode Island, and the Blackstone Valley Community Health Center. RESULTS: An educational supplement of $13.21 per visit would be required for the program to be cost-neutral relative to staff. The cost of outpatient training for a resident averaged $13,935 per year. Residents would "break even" if they saw patients at 19% above the average rate recommended by the residency review committee. If staff physicians instead of residents had provided the patient care, the CHC would have saved $6,171 per resident. Additional savings from improved physician recruiting and decreased turnover would increase the value of the program to the CHC. Cost was most sensitive to resident productivity, precepting arrangements, nursing staff support, and staff turnover. CONCLUSION: Developing graduate medical education programs in CHCs can be a cost-effective way of increasing the pool of appropriately trained primary care physicians and increasing health care access for underserved populations. If teaching CHCs are to expand, provisions will need to be made for adequate reimbursement of their costs.

Community Health Centers↗
PubMed1994

PET studies of cocaine inhibition of myocardial norepinephrine uptake.

Positron emission tomography (PET), [11C]cocaine, and (-)-6-[18F]fluoronorepinephrine [(-)-6-[18F]NE] were used to determine the extent to which the binding of labeled cocaine in the baboon heart represents binding to the norepinephrine transporter and to characterize the functional consequences of cocaine administration on the norepinephrine transporter. Peak heart binding of [11C]cocaine was high (0.038-0.055%/g) and clearance was rapid (t1/2 from peak: 2.5-9 min) for both tracer doses and a pharmacological dose. The binding of a tracer dose of labeled cocaine could not be inhibited by desipramine, tomoxetine, cocaine, nomifensine, or benztropine. The behavior of a pharmacological dose of [11C]cocaine could not be distinguished from a tracer dose and also could not be inhibited by tomoxetine. However, pretreatment with cocaine profoundly inhibited norepinephrine uptake as assessed by (-)-6-[18F]NE. Recovery was slow with only 48% of the baseline (-)-6-[18F]NE uptake being recovered by 78 minutes after cocaine administration. [11C]Benzoylecgonine, a vasoactive metabolite of cocaine, showed negligible retention in heart. The results of this study (i.e., the rapid clearance of cocaine from the heart, the inability to inhibit cocaine binding with desipramine and tomoxetine, and its relatively long-lasting effects on norepinephrine uptake) reinforce the need to understand the link between cocaine pharmacokinetics and norepinephrine transporter function and its relationship to cardiotoxicity.

Animals↗
PubMed1994

Slow recovery of human brain MAO B after L-deprenyl (Selegeline) withdrawal.

L-Deprenyl (Selegeline) is an enzyme-activated irreversible inhibitor of monoamine oxidase B (MAO B; EC 1.4.3.4). It is used to treat Parkinson's disease at a dose of 5 mg twice a day. Since enzyme inhibition is irreversible, the recovery of functional enzyme activity after withdrawal from L-deprenyl requires the synthesis of new enzyme. We have measured a 40 day half-time for brain MAO B synthesis in Parkinson's disease and in normal subjects after withdrawal from L-deprenyl. This is the first measurement of the synthesis rate of a specific protein in the living human brain. L-Deprenyl is currently used by 50,000 patients with Parkinson's disease in the United States and its use is expected to increase with reports that it may be beneficial in Alzheimer's disease. The slow turnover of brain MAO B suggests that the current clinical dose of L-deprenyl may be excessive and that the clinical efficacy of reduced dosing should be evaluated. Such an evaluation may have mechanistic importance as well as an impact on reducing the side effects and the costs arising from excessive drug use.

Aged↗
PubMed1993

Monoamine oxidase B (MAO B) inhibitor therapy in Parkinson's disease: the degree and reversibility of human brain MAO B inhibition by Ro 19 6327.

The possibility of slowing the progression of Parkinson's disease (PD) with inhibitors of monoamine oxidase B (MAO B) has stimulated the development of new MAO B inhibitor drugs. Ro 19 6327 is a highly selective inhibitor of MAO B currently under clinical investigation. We used positron emission tomography (PET) and the MAO B tracer [11C]L-deprenyl to determine the degree and reversibility of human brain MAO B inhibition by Ro 19 6327 in six early Parkinson's disease patients who were treated with different doses of Ro 19 6327 (25 mg [n = 3], 50 mg [n = 2], and 100 mg [n = 1]; 0.34 to 1.4 mg/kg) every 12 hours for 1 week. Each patient had three PET scans to assess baseline MAO B activity, degree of trough inhibition, and reversibility. A control group of four elderly normal subjects was scanned twice to assess reproducibility of repeated measures. Four of the patients showed reduction of MAO B concentration to 1% to 7% of baseline on doses of 0.43 mg/kg or greater, and the remaining two at 0.34 mg/kg showed significant but incomplete inhibition (10% to 21% of baseline in the global region and in the thalamus, basal ganglia, and mesencephalon). Thus, 0.4 mg/kg or greater of Ro 19 6327 given every 12 hours is the minimum dose necessary to provide > 90% inhibition of brain MAO B in patients with early PD. Brain MAO B activity returned to baseline values by 36 hours after drug discontinuation.

Aged↗
PubMed1993

Synthesis and PET studies of fluorine-18-BMY 14802: a potential antipsychotic drug.

BMY 14802 is a compound containing fluorine developed as a potential antipsychotic drug. It has a moderate affinity for the sigma binding site and a very low affinity for dopamine D2 receptors and has been predicted to have antipsychotic properties without the side effect potential of existing drugs. To assess the brain uptake, pharmacokinetics, stereoselectivity and binding properties of this potential antipsychotic drug, enantiomerically pure samples of (-) and (+)-[18F]BMY 14802 were examined in a baboon with PET. A tissue distribution with racemic labeled BMY 14802 was also carried out in mice. Radiochemical yields of 15% at the end of bombardment (EOB) for the racemic mixture, and 5% for each enantiomer with a specific activity of 2-5 Ci/mumol at EOB were obtained. In baboons, [18F]BMY 14802 cleared rapidly from the plasma and the glucuronidated [18F]BMY 14802 appeared. Radioactivity peaked (0.04-0.07% dose/cc) in all areas of the brain examined at about 5 min postinjection. It then rapidly cleared to about 30% of peak value by 20 min postinjection and to less than 10% of peak by 60 min postinjection in all regions. A similar rapid clearance from brain was also observed in mice. Pretreatment with unlabeled BMY 14802 (7 mg/kg), did not produce the expected reductions in distribution volume and clearance halftimes consistent with receptor binding. Although the rapid kinetics of [18F]BMY 14802 made it difficult to resolve the processes of transport and binding of the labeled drug, the lack of regional distribution consistent with the known distribution of sigma binding sites as well as the lack of stereoselectivity suggest that the behavior of BMY 14802 in the brain is dominated by its transport properties in tissue rather than its binding to sigma sites. Moreover, its rapid clearance from brain may be a limiting factor in its use as an antipsychotic drug.

Animals↗
PubMed1993

Reproducibility of repeated measures of carbon-11-raclopride binding in the human brain.

Carbon-11-raclopride has been successfully utilized with PET to assess changes in endogenous dopamine concentration after pharmacological intervention in the living baboon brain. For similar studies to be done in humans, measurements of 11C-raclopride with no intervention need to be reproducible. In order to test the reproducibility (test-retest) of 11C-raclopride binding in the human brain, we performed repeated studies on two different days. Studies were done in five normal controls with no pharmacological intervention. Time-activity (%dose/cc) curves for 11C-raclopride in the basal ganglia (BG) and cerebellum (CBL) were highly reproducible with an average difference in peak uptake for repeated studies in the same individual of 4%. The BG to CBL ratio for the average activity concentration between 30 and 60 min showed differences that ranged from -7% to 8% between the repeated studies. Graphical analysis to obtain the distribution volume revealed intrasubject values that ranged from -9% to 7% for the ratio of the distribution volume in BG to that in CBL. These studies demonstrate that in order to use 11C-raclopride to measure an individual's change in relative dopamine concentration secondary to pharmacological or behavioral intervention, a change in striatal 11C-raclopride binding in excess of 10% is required.

Adult↗
PubMed1992

Ion chromatographic analysis of high specific activity 18FDG preparations and detection of the chemical impurity 2-deoxy-2-chloro-D-glucose.

Because of the widespread use of 2-deoxy-2-[18F]fluoro-D-glucose (FDG) prepared by the "Julich" method or its variants it was decided necessary to determine the major chemical impurities present in the final product. An analytical system for quantifying FDG was developed using pulsed amperometry after separation by high-performance anion exchange chromatography. With this system a heretofore unidentified impurity, 2-deoxy-2-chloro-D-glucose (C1DG, ca 20-2000 micrograms; typically < 100 micrograms), was found in our preparation and in those from other laboratories using the "Julich" method. C1DG arises from Cl- ion displacement during the labeling procedure where Cl- ion comes from several sources, and Cl- ion displacement from the HCl used in the hydrolysis step. FDG mass was present in the same preparations at a level of ca 1-40 micrograms. Other major chemical constituents were glucose (ca 1-6 mg) and mannose (ca 10-18 micrograms). Glycerol, arising from sterilizing filters, was also detected in most preparations. Although C1DG is a chemical impurity which has not been detected previously in nca FDG preparations, its biochemical and pharmacological properties are similar to FDG and 2-deoxy-D-glucose. Thus it is unlikely that the presence of small quantities of C1DG found in typical FDG preparations (ca 100 micrograms) would have adverse pharmacological or toxicological consequences that would limit continued application of this radiopharmaceutical in basic and clinical studies.

Chromatography, Ion Exchange↗
PubMed1991

Radiochemical and chemical quality-assurance methods for [13N]-ammonia made from a small volume H2(16)O target.

HPLC and TLC systems were sought for routine assurance of [13N]NH3 for human PET studies. An ion chromatograph with conductivity and radioactivity detection was used to confirm that [13N]NO2- and [13N]NO3- were the major 13N species formed by the 16O(p, alpha)13N reaction in a small volume (0.5 mL) water target irradiated with protons (24 MeV), and that Devarda's alloy reduction and distillation in an apparatus constructed of disposable components and requiring no external heating gave radiochemically and radionuclidically pure [13N]NH3. Merck polyethylene-backed TLC plates were developed in the upper phase of the solvent mixture: H2O/acetone/propionic acid (6:4:2, v/v) saturated with NaCl. The Rf of [13N]NH3 was 0.6. HPLC was conducted with a 25 X 0.46 cm column with 2 mL/min CH3CN/10 mM aqueous sodium 1-octanesulfonate (1:2, v/v). [13N]NH3 eluted at 3.5 min.

Ammonia↗
PubMed1991

Comparison of the adhesion properties of Deleya marina and the exopolysaccharide-defective mutant strain DMR.

Deleya marina 219 (ATCC 25374) produces large quantities of an acidic exopolysaccharide and characteristically forms mucoid colonies and large aggregates of cells. The exopolysaccharide of wild-type D. marina cells appears to occur as both film and fibrils in electron micrographs. The organization of exopolymeric material was indicative of structural heterogeneity. A spontaneous rough-colony mutant defective in exopolysaccharide, D. marina DMR, has been isolated. The absence of exopolymer corresponds to a nonmucoid, nonaggregating, adhesion-altered phenotype. In microplate adhesion assays, wild-type cells grown at 19 or 25 degrees C attached to hydrophilic surfaces but not to a hydrophobic surface. In contrast, mutant cells exhibited a significantly reduced level of attachment to hydrophilic surfaces and increased adhesion to a hydrophobic surface.

Bacteria↗
PubMed1991

Personality and socialization correlates of vicarious emotional responding.

The relations of personality and family characteristics to adults' negative vicarious emotional responses to sympathy and distress films were examined. Ss reported more sympathy and less personal distress and exhibited less skin conductance as well as heart rate deceleration when viewing a sympathy-evoking film. Dispositional emotional intensity and fantasy empathy were associated with greater self-reported emotional responding and higher skin conductance. Dispositional perspective taking and personal distress were positively and negatively correlated, respectively, with reported vicarious responding to the sympathy film when Ss were administered instructions to imagine the emotions of those in the films. Family cohesiveness was associated with reported sympathy and sadness in reaction to the sympathy film, whereas the expression of negative subordinate and positive emotional states in the home of origin was associated with women's reported responsivity.

Adult↗
PubMed1990

Architectural organization in the interphase nucleus of the protozoan Trypanosoma brucei: location of telomeres and mini-chromosomes.

We studied the spatial organization of chromatin in the interphase G1, S and G2 nucleus of the protozoan Trypanosoma brucei, applying in situ hybridization with conventional fluorescence and confocal scanning optical microscopy. The majority of the trypanosome telomere GGGTTA repeats from different chromosomes were found clustered together, either extending in a network through the nuclear interior or localized at the nuclear periphery. The population of one hundred mini-chromosomes was often asymmetrically located: either clustered in a narrow band in close association with the nuclear envelope or distributed into several clusters that segregated into roughly one half of the nucleus. The nuclear organization may undergo modifications during the cell cycle and development. We conclude that non-random spatial positioning of DNA exists in the nucleus of this protozoan. Finding a high level of structural organization in the interphase nucleus of T.brucei is an important first step towards understanding chromosome structure and functioning and its role in the control of gene expression.

Animals↗