Amphetamine induced decreases in (18F)-N-methylspiroperidol binding in the baboon brain using positron emission tomography (PET).
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Animals↗
Biomedical subjects
J Logan
Publications and source records attributed to J Logan.
Effects of endogenous dopamine on measures of [18F]N-methylspiroperidol binding in the basal ganglia: comparison of simulations and experimental results from PET studies in baboons.
The effect of endogenous dopamine on PET measures of radioligand binding is important to the measurement of receptor density (or availability) and neurotransmitter interactions in vivo. We recently reported that pretreatment with amphetamine, a drug which stimulates dopamine release, significantly reduced NMS binding in the baboon brain as determined by the product lambda k3 derived from the graphical analysis method for irreversible systems (lambda is the ratio of the forward to reverse plasma to tissue transport constants and k3 is proportional to receptor density) (Dewey et al.: Synapse 7:324-327, 1991). The purpose of this work is twofold: to evaluate the sensitivity and stability of the analysis method used for the NMS data and from simulation studies which include the competitive effects of dopamine on NMS binding to predict the effect of dopamine on the in vivo PET experiment. Using a measured plasma [18F]-NMS input function from a control study in a baboon, simulation data was numerically generated explicitly allowing competition between NMS and dopamine in the calculation. This data was analyzed using the same techniques as used for the experimental data and the results were compared to in vitro calculations. The following conclusions were reached: 1) The effect of dopamine on specific binding was found to be greater in vivo than in vitro because the in vitro equilibrium experiment is controlled only by the relative Kd's of tracer and dopamine while the in vivo experiment also depends upon the halftime of tracer in tissue which is controlled by the tissue-to-plasma transport constant; 2) Experimental evidence from rodent studies (Seeman et al.: Synapse 3:96-97, 1989) and the agreement between PET studies (Wong et al.: Science 234:1558-1563, 1986a) and postmortem human studies (Seeman et al.: Science 225:728-731, 1984) in schizophrenics suggest that NMS is not likely to be affected by normal levels of endogenous dopamine. From the calculations reported here the effective in vivo Kd of dopamine for the NMS binding site would have to be on the order of or greater than 100 nM, assuming a synaptic dopamine concentration of 20 nM, in order that this concentration of dopamine have little effect on NMS binding.
Amphetamine↗
Dose-response effects of glucose, insulin, and glucagon on mouse pre-embryo development.
The diabetic state, as well as elevated culture media glucose level (950 mg D-glucose/dL) per se, significantly retards in vitro development of mouse pre-implantation embryos from a two-cell stage to blastocyst stage; maternal insulin therapy to diabetic mice reverses this impairment. This study was undertaken to assess (1) whether less extreme elevation of the media glucose concentration would also impair development, and (2) whether elevated culture media insulin or glucagon levels would alter development. Two-cell pre-embryos were recovered from B6C3F1 mice that had been stimulated with pregnant mare serum gonadotropin (PMSG) and human chorionic gonadotropin (hGG), mated, and killed 48 hours later. Pre-embryos were observed in culture at 24-hour intervals for a total of 72 hours at four glucose levels: 110 (n = 108), 220 (n = 101), 440 (n = 65), and 950 (n = 106) mg D-glucose/dL. Impairment in progression of development was noted at each time period; compared with development in 110 mg glucose/dL, the distribution of development was significantly different at 24 hours (chi 2 = 60.1, P less than .001), at 48 hours (chi 2 = 36.7, P less than .001), and at 72 hours (chi 2 = 45.1, P less than .001). Rate of development as assessed by ANOVA was also significantly reduced at increasing glucose levels (P less than .0001), with Duncan Multiple Range test demonstrating differences between development at higher glucose levels in the comparison of development in 110 mg/dL versus 440 mg/dL and 950 mg/dL, and at 220 mg/dL versus 950 mg/dL.(ABSTRACT TRUNCATED AT 250 WORDS)
Analysis of Variance↗
A comparison of the brain uptake of N-(cyclopropyl[11C]methyl)norbuprenorphine ([11C]buprenorphine) and N-(cyclopropyl[11C]methyl)nordiprenorphine ([11C]diprenorphine) in baboon using PET.
Buprenorphine and diprenorphine were radiolabeled with 11C and their distributions in the baboon brain were studied using positron emission tomography (PET). Specific binding was demonstrated in the striatum (but not in the cerebellum) by pretreating the baboon with (-)naloxone. The absolute striatal uptakes and time courses were similar for these two radioligands but the ratio of radioactivity in the striatum to cerebellum in the baboon was higher for [11C]diprenorphine than for [11C]buprenorphine. Analysis of baboon plasma indicated that both [11C]diprenorphine and [11C]buprenorphine are rapidly metabolized. Analysis of radioactivity in mouse brain indicated that these two radioligands are stable to metabolic transformation. At 30 min after injection, 86-90% of extracted radioactivity was due to unchanged 11C-labeled radioligands. These results suggest that both [11C]diprenorphine and [11C]buprenorphine may be useful radioligands for studying opioid receptors in humans, although [11C]diprenorphine may be a better radioligand than [11C]buprenorphine for this purpose because of its more rapid clearance from the cerebellum.
Animals↗
Adenovirus E1A protein activates transcription of the E1A gene subsequent to transcription complex formation.
The mechanism of transcriptional activation of the adenovirus E1A and E3 genes by E1A protein during infection was examined by using transcription-competition assays. Infection of HeLa cells with one virus led to inhibition of mRNA accumulation from a superinfecting virus. Synthesis of the E1A 289R protein by the first virus to infect reduced inhibition of transcription of the superinfecting virus, indicating that the E1A 289R protein was limiting for E1A-activated transcription. Infection with an E1A- virus, followed 6 h later by superinfection with a wild-type virus, led to preferential transcriptional activation of the E1A gene of the first virus, suggesting that a host transcription component(s) stably associated with the E1A promoter in the absence of E1A protein and that this complex was the substrate for transcriptional activation by E1A protein. The limiting host transcription component(s) bound to the E1A promoter to form a complex with a half-life greater than 24 h in the absence of E1A 289R protein, as demonstrated in a challenge assay with a large excess of superinfecting virus. In the presence of the E1A 289R protein, the E1A gene of the superinfecting virus was gradually activated with a reduction in E1A mRNA accumulation from the first virus. The kinetics of the activation suggest that this was due to an indirect effect rather than to destabilization of stable transcription complexes by the 289R protein.
Adenovirus Early Proteins↗
Low-dose cyclopenthiazide in the treatment of hypertension: a one-year community-based study.
After an 8-week placebo period, 73 patients whose diastolic blood pressures were between 90 and 110 mmHg were randomly assigned to receive 125 micrograms (low dose) or 500 micrograms of cyclopenthiazide (standard dose) for a period of one year. Blood pressure was measured in the patient's home by the same observer at two-weekly intervals during an 8-week placebo run-in period, every 4 weeks for a further 12 weeks and at 24, 36 and 52 weeks thereafter. Serum potassium, urate, glucose, glycosylated haemoglobin, total and HDL cholesterol, and apolipoproteins were measured at the end of the placebo period and at 4, 8, 24 and 52 weeks of active treatment. Twelve of the 73 patients had an inadequate antihypertensive response--five on the higher dose and seven on the lower dose. One patient receiving 500 micrograms was withdrawn because of adverse effects. In the remaining 60 patients, systolic and diastolic blood pressures were significantly reduced when compared with pretreatment values in both treatment groups throughout the one year period. The decreases in blood pressure were not significantly different from each other (p greater than 0.65). Three patients on 500 micrograms required potassium supplements. Maximum decreases in the serum potassium of 0.52 mmol/l (500 micrograms dose) and 0.14 mmol/l (125 micrograms dose) were observed at 24 weeks of treatment in the remaining 57 patients. The differences between the two doses at this time were statistically significant (p less than 0.05), as were the increases in serum urate observed at 4, 8 and 24 weeks (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Prophylaxis against hepatitis A for travel.
OBJECTIVE: To develop a rational practice policy for prophylaxis against hepatitis A for travellers to high risk areas. DESIGN: 18 Month prospective study of consecutive patients who requested prophylaxis against hepatitis A. SETTING: Inner city general practice. SUBJECTS: 104 Patients aged 15-61 (mean 30) assessed for risk factors for hepatitis A and put into groups depending on predictions from the risk factors of their immunity. MAIN OUTCOME MEASURES AND RESULTS: All patients were screened for antibody to hepatitis A virus. Of 52 patients with no risk factors 47 had no antibody and were thus susceptible to hepatitis A. All 27 patients with major risk factors (having been brought up in an endemic area or with a history of jaundice) were immune. Of 25 patients with minor risk factors (a history of previous travel in high risk areas, drug abuse, having lived in a squat or travelled rough, or having lived with someone who had jaundice) 12 were immune (p less than 0.001, chi 2 test). CONCLUSIONS: All travellers requesting prophylaxis against hepatitis A should be assessed for risk factors for previous exposure to hepatitis A. Those with no risk factors could be immunised with human normal immunoglobulin without screening. The remainder should be tested for hepatitis A antibody and those found to be susceptible should be immunised.
Adolescent↗
Age-related decreases in muscarinic cholinergic receptor binding in the human brain measured with positron emission tomography (PET).
Muscarinic cholinergic M1 and M2 receptors in young and aged adult male volunteers were studied using [N-11C-methyl]-benztropine, a specific muscarinic cholinergic receptor ligand, and high resolution positron emission tomography (PET). A regionally specific pattern of decreased binding was observed in aged volunteers. Using two separate methods of data analysis, thalamic, hippocampal and cerebellar regions showed no decreases in the apparent specific binding of [N-11C-methyl]-benztropine while frontal, parietal, temporal and occipital cortices as well as the corpus striatum showed age related changes in binding that declined (in 82 yrs old subject) to about 50% of the value obtained from the youngest volunteer (19 yrs). These data suggest that regions high in muscarinic receptor density, the corpus striatum and the cortical mantle, show a greater rate of decline than those areas that have a relatively low number of muscarinic receptors. Furthermore, this study demonstrates the usefulness of PET and [N-11C-methyl]-benztropine for assessing age related regional changes in muscarinic cholinergic receptor binding in the living human brain.
Adult↗
Manifestation of diabetes mellitus on mouse follicular and pre-embryo development: effect of hyperglycemia per se.
Animal models of diabetes mellitus during pregnancy have repeatedly suggested that maternal hyperglycemia was teratogenic during organogenesis, and thus may contribute to diabetic teratogenesis. However, little attention has been focused on the effects of hyperglycemia on pre-organogenic development. In this report, we examine the effect of hyperglycemia (950 mg glucose/dL) on the development of mouse pre-embryos in vitro. B6C3F1 mice were superovulated with 5 U pregnant mare serum gonadotropin (PMSG) followed by 5 U human chorionic gonadotropin (hCG) 48 hours later. Two cell pre-embryos were recovered 48 hours later, pooled together, and randomly assigned to different treatment groups. Cultures were performed in HAM's F-10 media (Gibco, Long Island, NY) with 0.1% bovine serum albumin (BSA; Sigma, St. Louis, MO) BSA at 37 degrees C in an atmosphere of 5% CO2, 5% O2, and 90% N2 with 15 to 30 embryos per milliliter of culture fluid. Cultures were viewed daily at 24, 48, and 72 hours after culturing, with recording of the development. Compared with control pre-embryos (n = 216), embryos cultured in elevated glucose levels (950 mg/dL) (n = 226) demonstrated marked growth retardation as assessed both by (1) distribution of developmental stages at each observation point (24 hours, P less than .001; 48 hours, P less than .006; 72 hours, P less than .001); and (2) a difference in the average rank sums indicating a delay in maturation (P less than .005). In a second protocol group, pre-embryos were cultured in an equivalent amount of L-glucose; no impairment in development compared with controls was noted.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Acute effects of ethanol on regional brain glucose metabolism and transport.
To evaluate the effects of ethanol in the human brain, we tested six normal subjects and six alcoholics using positron emission tomography and 2-deoxy-2-[18F]-fluoro-D-glucose (FDG) under baseline conditions and 24 hours later after ethanol administration (1 g/kg). Ethanol inhibited cortical and cerebellar glucose metabolism with relative sparing of the basal ganglia and corpus callosum. This inhibition was more pronounced in the alcoholics than in the controls. Measurement of the constants for glucose transport and utilization showed that decreased glucose metabolism was due to a reduction in glucose phosphorylation and not to a change of glucose transport into the tissue. The pattern of regional metabolic inhibition by alcohol paralleled the distribution of benzodiazepine receptors in the human brain.
Adult↗
Graphical analysis of reversible radioligand binding from time-activity measurements applied to [N-11C-methyl]-(-)-cocaine PET studies in human subjects.
A graphical method of analysis applicable to ligands that bind reversibly to receptors or enzymes requiring the simultaneous measurement of plasma and tissue radioactivities for multiple times after the injection of a radiolabeled tracer is presented. It is shown that there is a time t after which a plot of integral of t0ROI(t')dt'/ROI(t) versus integral of t0Cp(t')dt'/ROI(t) (where ROI and Cp are functions of time describing the variation of tissue radioactivity and plasma radioactivity, respectively) is linear with a slope that corresponds to the steady-state space of the ligand plus the plasma volume,.Vp. For a two-compartment model, the slope is given by lambda + Vp, where lambda is the partition coefficient and the intercept is -1/[kappa 2(1 + Vp/lambda)]. For a three-compartment model, the slope is lambda(1 + Bmax/Kd) + Vp and the intercept is -[1 + Bmax/Kd)/k2 + [koff(1 + Kd/Bmax)]-1) [1 + Vp/lambda(1 + Bmax/Kd)]-1 (where Bmax represents the concentration of ligand binding sites and Kd the equilibrium dissociation constant of the ligand-binding site complex, koff (k4) the ligand-binding site dissociation constant, and k2 is the transfer constant from tissue to plasma). This graphical method provides the ratio Bmax/Kd from the slope for comparison with in vitro measures of the same parameter. It also provides an easy, rapid method for comparison of the reproducibility of repeated measures in a single subject, for longitudinal or drug intervention protocols, or for comparing experimental results between subjects. Although the linearity of this plot holds when ROI/Cp is constant, it can be shown that, for many systems, linearity is effectively reached some time before this. This analysis has been applied to data from [N-methyl-11C]-(-)-cocaine ([11C]cocaine) studies in normal human volunteers and the results are compared to the standard nonlinear least-squares analysis. The calculated value of Bmax/Kd for the high-affinity binding site for cocaine is 0.62 +/- 0.20, in agreement with literature values.
Brain↗
Effects of chronic cocaine abuse on postsynaptic dopamine receptors.
To assess the effects of chronic cocaine intoxication on dopamine receptors in human subjects, the authors evaluated [18F]N-methylspiroperidol binding using positron emission tomography in 10 cocaine abusers and 10 normal control subjects. Cocaine abusers who had been detoxified for 1 week or less showed significantly lower values for uptake of [18F]N-methylspiroperidol in striatum than the normal subjects, whereas the cocaine abusers who had been detoxified for 1 month showed values comparable to those obtained from normal subjects. The authors conclude that postsynaptic dopamine receptor availability decreases with chronic cocaine abuse but may recover after a drug-free interval.
Adult↗
More evidence on women (and men) in the middle.
A recent article by Rosenthal, Matthews and Marshall (1989) focused on two related questions: How typical is Brody's "woman in the middle" and how "normative" is parent care? This research builds on their work by presenting similar analyses for a somewhat larger probability sample of middle-aged women from a U.S. metropolitan area, by presenting parallel analyses for men in the same age groups, and by presenting data on more active measures for an expanded set of roles and role combinations not included in the original article. The four major roles analyzed by Rosenthal et al. (spouse, paid worker, adult child of aging parent, and parent) are found to be typical of those in their forties and early fifties, but each falls off rapidly after that point. Men are almost as likely to experience each of these as are women, and more likely to be married. When measures of more active involvement in these roles are examined, much smaller percentages of women or men are seen participating at any given age, and the combination of full-time work, active parenting, and helping or living with parents is uncommon. It is suggested that the situation described by Brody is not typical of middle-aged women or men in the U.S. today at any given time, but that collection of data on histories of caregiving is needed.
Adult↗
Altered glucose metabolism in microvessels from patients with Alzheimer's disease.
Microvessels isolated from temporal cortex of patients with Alzheimer's disease showed decreased uptake of glucose when compared with vessels from age-matched or young control subjects. This was due to decreased hexokinase activity in the Alzheimer samples, as determined by ion exchange chromatography. This finding was confirmed independently by determination of the phosphorylation constant for hexokinase, K3, using positron emission tomography. The results suggest that Alzheimer's disease may result from a global defect in brain energy metabolism.
Adult↗
Mapping cocaine binding sites in human and baboon brain in vivo.
The first direct measurements of cocaine binding in the brain of normal human volunteers and baboons have been made by using positron emission tomography (PET) and tracer doses of [N-11C-methyl]-(-)-cocaine ([11C]cocaine). Cocaine's binding and release from brain are rapid with the highest regional uptake of carbon-11 occurring in the corpus striatum at 4-10 minutes after intravenous injection of labeled cocaine. This was followed by a clearance to half the peak value at about 25 minutes with the overall time course paralleling the previously documented time course of the euphoria experienced after intravenous cocaine administration. Blockade of the dopamine reuptake sites with nomifensine reduced the striatal but not the cerebellar uptake of [11C]cocaine in baboons indicating that cocaine binding is associated with the dopamine reuptake site in the corpus striatum. A comparison of labeled metabolites of cocaine in human and baboon plasma showed that while cocaine is rapidly metabolized in both species, the profile of labeled metabolites is different, with baboon plasma containing significant amounts of labeled carbon dioxide, and human plasma containing no significant labeled carbon dioxide. These studies demonstrate the feasibility of using [11C]cocaine and PET to map binding sites for cocaine in human brain, to monitor its kinetics, and to characterize its binding mechanism by using appropriate pharmacological challenges.
Adult↗
Effect of norgestrel on development of mouse pre-embryos.
The effect of synthetic progestins found in oral contraceptives has potential implications for developing embryos in women who receive oral contraceptives during early pregnancy. We assessed the effect of the progestin norgestrel on the developing pre-embryo. B3C6F1 mice were given 5 IU PMSG followed by 5 IU hCG 48h later. Studies were performed on pre-embryos recovered and pooled at both 24h (Group A) and 48h (Group B) post hCG. At each time period, they were randomly assigned to control or norgestrel (4.0 ng/ml) treatment. In a third study, pre-embryos collected 24h post hCG were cultured in the absence or presence of 8.0, 80.0, or 800 ng/ml norgestrel. Cultures were performed in Ham's F-10 media with 10% fetal calf serum at 37 degrees C in an atmosphere of 5% CO2, 5% O2 and 90% N2 with 15-30 embryos per 1 ml of culture fluid. At 24h, 48h and 72h post recovery, cultures were viewed, the appearance of embryos noted, and number of blastomeres recorded. Compared to control groups, analysis demonstrated no significant difference in the rate of development of control and norgestrel pre-embryos in any group at any time period (24h, 48h, or 72h post recovery). We conclude that norgestrel at the dose tested has no acute adverse morphological effects on development of mouse pre-embryos. This observation has potential clinical implications with regard to inadvertent use of norgestrel-containing oral contraceptives during early days of pregnancy, as well as consideration of the mechanism of action of norgestrel-containing "morning after" pills.
Animals↗
Gender differences in family support: is there a payoff?
National data for respondents over age 65 revealed that, although women are less likely to be living with a spouse, living arrangements of unmarried women and men are similar. Women live closer to children, receive more phone calls, have marginally more contact but do not receive more mail. Women's receipt of more informal assistance is largely explained by greater need levels, particularly for the unmarried. These findings are discussed in relation to women's roles as family caretaker and kinkeeper at earlier life cycle stages.
Aged↗
Regulation of poly(A) site selection in adenovirus.
We have investigated the mechanisms involved in the early-to-late RNA-processing switch which regulates the mRNA species generated from the adenovirus major late transcription unit (MLTU). In particular, polyadenylation choice mechanisms were characterized by using a reconstructed adenovirus E1A gene as a site for insertion of MLTU poly(A) regulation signals (L1 and L3). Adenovirus constructs containing the variant poly(A) recognition elements were used to compare E1A poly(A) signal utilization with wild-type MLTU (L1 to L5) utilization. In both early and late stages of infection, either polyadenylation site (L1 or L3) is capable of being utilized when presented as the only operational poly(A) site. In an early infection, a virus which contains multiple elements presented in tandem (L13) uses the first poly(A) site, L1, preferentially (ratio of L1 to L3, 8:1) in both E1A and MLTU loci. Transcription termination is not involved in restricting the utilization of the downstream L3 site. In a late infection, when each of the five MLTU poly(A) sites is used, a switch also occurs for the E1AL13 construct, with utilization of both the L1 and L3 poly(A) sites. The switch from early to late was not the result of altered processing factors in the late infection, as demonstrated by superinfecting the E1AL13 construct into cells which had already entered a late stage of infection. The superinfecting virus gave an L1-only phenotype; therefore, a cis mechanism is involved in adenovirus poly(A) regulation.
Adenoviridae↗