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Biomedical subjects

J E Barrett

Publications and source records attributed to J E Barrett.

At least 19 recordsLinked to original sources
PubMed2005

Lecozotan (SRA-333): a selective serotonin 1A receptor antagonist that enhances the stimulated release of glutamate and acetylcholine in the hippocampus and possesses cognitive-enhancing properties.

Recent data has suggested that the 5-hydroxytryptamine (5-HT)(1A) receptor is involved in cognitive processing. A novel 5-HT(1A) receptor antagonist, 4-cyano-N-{2R-[4-(2,3-dihydrobenzo[1,4]-dioxin-5-yl)-piperazin-1-yl]-propyl}-N-pyridin-2-yl-benzamide HCl (lecozotan), which has been characterized in multiple in vitro and in vivo pharmacological assays as a drug to treat cognitive dysfunction, is reported. In vitro binding and intrinsic activity determinations demonstrated that lecozotan is a potent and selective 5-HT(1A) receptor antagonist. Using in vivo microdialysis, lecozotan (0.3 mg/kg s.c.) antagonized the decrease in hippocampal extracellular 5-HT induced by a challenge dose (0.3 mg/kg s.c.) of 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT) and had no effects alone at doses 10-fold higher. Lecozotan significantly potentiated the potassium chloride-stimulated release of glutamate and acetylcholine in the dentate gyrus of the hippocampus. Chronic administration of lecozotan did not induce 5-HT(1A) receptor tolerance or desensitization in a behavioral model indicative of 5-HT(1A) receptor function. In drug discrimination studies, lecozotan (0.01-1 mg/kg i.m.) did not substitute for 8-OH-DPAT and produced a dose-related blockade of the 5-HT(1A) agonist discriminative stimulus cue. In aged rhesus monkeys, lecozotan produced a significant improvement in task performance efficiency at an optimal dose (1 mg/kg p.o.). Learning deficits induced by the glutamatergic antagonist MK-801 [(-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate] (assessed by perceptually complex and visual spatial discrimination) and by specific cholinergic lesions of the hippocampus (assessed by visual spatial discrimination) were reversed by lecozotan (2 mg/kg i.m.) in marmosets. The heterosynaptic nature of the effects of lecozotan imbues this compound with a novel mechanism of action directed at the biochemical pathologies underlying cognitive loss in Alzheimer's disease.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2001

Treatment of dysthymia and minor depression in primary care: a randomized trial in patients aged 18 to 59 years.

OBJECTIVE: The researchers evaluated the effectiveness of paroxetine and Problem-Solving Treatment for Primary Care (PST-PC) for patients with minor depression or dysthymia. STUDY DESIGN: This was an 11-week randomized placebo-controlled trial conducted in primary care practices in 2 communities (Lebanon, NH, and Seattle, Wash). Paroxetine (n=80) or placebo (n=81) therapy was started at 10 mg per day and increased to a maximum 40 mg per day, or PST-PC was provided (n=80). There were 6 scheduled visits for all treatment conditions. POPULATION: A total of 241 primary care patients with minor depression (n=114) or dysthymia (n=127) were included. Of these, 191 patients (79.3%) completed all treatment visits. OUTCOMES: Depressive symptoms were measured using the 20-item Hopkins Depression Scale (HSCL-D-20). Remission was scored on the Hamilton Depression Rating Scale (HDRS) as less than or equal to 6 at 11 weeks. Functional status was measured with the physical health component (PHC) and mental health component (MHC) of the 36-item Medical Outcomes Study Short Form. RESULTS: All treatment conditions showed a significant decline in depressive symptoms over the 11-week period. There were no significant differences between the interventions or by diagnosis. For dysthymia the remission rate for paroxetine (80%) and PST-PC (57%) was significantly higher than for placebo (44%, P=.008). The remission rate was high for minor depression (64%) and similar for each treatment group. For the MHC there were significant outcome differences related to baseline level for paroxetine compared with placebo. For the PHC there were no significant differences between the treatment groups. CONCLUSIONS: For dysthymia, paroxetine and PST-PC improved remission compared with placebo plus nonspecific clinical management. Results varied for the other outcomes measured. For minor depression, the 3 interventions were equally effective; general clinical management (watchful waiting) is an appropriate treatment option.

Adolescent↗
PubMed2000

Effect of pollination and exogenous ethylene on accumulation of ETR1 homologue transcripts during flower petal abscission in geranium (Pelargonium x hortorum L.H. Bailey).

We have isolated two cDNAs from geranium, PhETR1 and PhETR2. The deduced amino acid sequences of PhETR1 anti PhETR2 share 78% and 79% identity with ETR1 from Arabidopsis thaliana respectively. These genes are members of a multigene family and are expressed at moderate levels in leaves, pedicels, sepals, pistils and petals, and at very low levels in roots. PhETR1 and PhETR2 mRNAs are expressed in geranium florets long before they are receptive to pollination and transcript levels remain constant throughout floral development. Message levels of PhETR1 and PhETR2 in pistils and receptacles are unaffected by self-pollination or treatment with 1 micro/l ethylene that induces petal abscission. Our results indicate that the amount of PhETR1 and PHETR2 mRNA is not indicative of the level of sensitivity of geranium florets to ethylene.

Amino Acid Sequence↗
PubMed2000

Conditioning rhinitis in allergic humans.

A classical Pavlovian paradigm pairing an olfactory cue with allergen challenge for a single training trial was used to produce conditioned histamine release and conditioned nasal airflow decrease in seasonal allergic rhinitis sufferers. There was no conditioned increase in subjective symptoms. Histamine release and airflow decrease showed evidence of extinction by a second test trial. A second study comparing the effects of the number of training trials showed that three training trials produced greater histamine release and airflow decrease than a single training trial, suggesting stronger effects with additional training.

Humans↗
PubMed2000

Embryonic quail eye development in microgravity.

The US-Russian joint quail embryo project was designed to study the effects of microgravity on development of Japanese quail embryos incubated aboard Mir. For this part of the project, eyes from embryonic days 14 and 16 (E14 and E16) flight embryos were compared with eyes from several groups of ground-based control embryos. Measurements were recorded for eye weights; eye, corneal, and scleral ring diameters; and numbers of bones in scleral ossicle rings. Transparency of E16 corneas was documented, and immunohistochemical staining was performed to observe corneal innervation. In addition, corneal ultrastructure was observed at the electron microscopic level. Except for corneal diameter of E16 flight embryos, compared with that of one of the sets of controls, results reported here indicate that eye development occurred normally in microgravity. Fixation by cracking the shell and placing the egg in paraformaldehyde solution did not adequately preserve corneal nerves or cellular ultrastructure.

Animals↗
PubMed2000

Characterization of the anxiolytic properties of a novel neuroactive steroid, Co 2-6749 (GMA-839; WAY-141839; 3alpha, 21-dihydroxy-3beta-trifluoromethyl-19-nor-5beta-pregnan-20-one), a selective modulator of gamma-aminobutyric acid(A) receptors.

The purpose of this study was to evaluate the effects of a novel neuroactive steroid, Co 2-6749 (GMA-839; WAY-141839; 3alpha, 21-dihydroxy-3beta-trifluoromethyl-19-nor-5beta-pregnan-20-one), on gamma-aminobutyric acid(A) receptors in vitro and to define its anxiolytic-like effects and side effect profile in vivo. Co 2-6749 fully inhibited [(35)S]t-butylbicyclophosphorothionate binding in rat brain cortical membranes with an IC(50) value of 230 nM and in human gamma-aminobutyric acid(A) receptor subunit combinations of alpha1beta2gamma2L, alpha2beta2gamma2L, alpha3beta2gamma2L, alpha4beta3gamma2L, alpha5beta2gamma2L, and alpha6beta3gamma2L receptors (IC(50) values of 200, 200, 96, 2300, 210, and 2000 nM). Rats were trained in a Geller-Seifter operant conflict paradigm. Co 2-6749 caused a dose-related increase in punished responding with a minimum effective dose of 1.6 mg/kg, p.o., a wide therapeutic index relative to a decrease in unpunished responding and relative to ataxia, and no tolerance. Additionally, ethanol caused less than a 2-fold shift to the left in the dose-response function of Co 2-6749 in the rotorod procedure in rats. In a pigeon conflict paradigm, punished responding was maximally increased to 784% of vehicle control by 30 mg/kg, p.o., with a 2-h duration and no effect on unpunished responding at this dose. Similarly, punished responding in squirrel monkeys was maximally increased to 1774% of control by 10 mg/kg, p.o., with no effect on unpunished responding at this dose. With robust anxiolytic-like activity across species, a large separation between anxiolytic-like effects and sedation/ataxia, a minimal interaction with ethanol, a lack of tolerance, and apparent oral bioavailability, Co 2-6749 makes an ideal candidate for development as a novel anxiolytic drug.

Alprazolam↗
PubMed2000

Pharmacological characterization of the discriminative stimulus effects of the potassium channel blocker 4-aminopyridine in rats.

The discriminative stimulus (DS) effects of 4-aminopyridine (4-AP) were evaluated in 36 male Sprague-Dawley rats that were trained to discriminate 4-AP from saline in a standard two-lever food reinforced drug discrimination procedure. 4-AP along with its structural analogs 3-aminopyridine (3-AP), 2-aminopyridine (2-AP), and 2,3-diaminopyridine (2,3-DIAP) produced dose-dependent increases in the percentage of responses on the 4-AP-associated lever with full substitution at one or more doses. 2,6-Diaminopyridine (2, 6-DIAP) and 3,4-diaminopyridine (3,4-DIAP) produced dose-dependent increases in the percentage of responses on the 4-AP-associated lever but only partially substituted for 4-AP. Neither 4-dimethylaminopyridine (4-DMAP) nor pyridine substituted for 4-AP. Substitution studies were also conducted with indirect dopamine, norepinephrine, serotonin, and acetylcholine agonists, and gamma-aminobutyric acid A (GABA(A)) agonists and antagonists. The norepinephrine reuptake inhibitor tomoxetine, but not nisoxetine or imipramine, produced dose-dependent increases in the percentage of responses on the 4-AP-associated lever and partially substituted for 4-AP. In addition, antagonism studies were conducted using indirect dopamine, norepinephrine, serotonin, acetylcholine antagonists, and GABA(A) agonists as pretreatments to the training dose of 4-AP. The benzodiazepine agonists chlordiazepoxide and diazepam dose dependently attenuated the DS effects of 4-AP. The present results demonstrate that the K-channel blocker 4-AP can be trained as a DS in rats and the DS effects of 4-AP are likely mediated through blockade of voltage-dependent K-channels. The results also demonstrate a novel interaction between benzodiazepines and K-channels.

4-Aminopyridine↗
PubMed2000

The relationship of aging and dysthymia in primary care.

The authors compared symptomatic and functional characteristics between older (age > or =60; n=91) and younger (age 18-59; n=125) primary care patients with dysthymia. Three of six significantly different depression symptoms were of moderate-to-large effect size, with the older group having a lower proportion reporting the symptom. The older group had a worse physical health function score but a better mental health function score. There appears to be a core of symptoms and functional impairment that generalizes across the age span. There are also significant age differences. Growing older appears to have an impact on the nature of what it means to have dysthymia.

Adult↗
PubMed1999

The pharmacokinetics of lamivudine phosphorylation in peripheral blood mononuclear cells from patients infected with HIV-1.

OBJECTIVE: To assess the pharmacokinetics of lamivudine phosphorylation in peripheral blood mononuclear cells (PBMC) from patients infected with HIV-1. DESIGN: Single-center, open-label, randomized, two-period, cross-over study in 10 asymptomatic, antiretroviral-experienced, HIV-1-infected patients who had a CD4+ lymphocyte count of 200-500 x 10(6)/l and had received combination treatment with lamivudine 150 mg twice a day plus zidovudine 600 mg a day (divided into two or three doses) for > or = 16 weeks prior to study entry. METHODS: Patients were randomly assigned to receive lamivudine 150 mg twice a day or lamivudine 300 mg twice a day for 14 days, with at least a 48-h washout period between treatments. Serial blood samples were collected over 36 h for determination of lamivudine serum concentrations using liquid chromatography/mass spectrometry and intracellular phosphate PBMC concentrations using high performance liquid chromatography/radioimmunoassay methods. Pharmacokinetic parameters were calculated based on lamivudine and lamivudine anabolite concentration-time data. RESULTS: Intracellular pharmacokinetic parameters were highly variable between patients (coefficient of variations approximately 50%). The two regimens produced lamivudine-total phosphate (totP) values of a similar magnitude. Although the 300-mg regimen tended to produce higher lamivudine-monophosphate (MP) and -triphosphate (TP) values, differences from values produced by the 150-mg regimen were not statistically significant. As lamivudine diphosphate (DP) was the predominant anabolite, accounting for 50-55% of lamivudine-totP (compared with 30-35% for lamivudine-MP and 15-20% for lamivudine-TP), the conversion of lamivudine-DP to lamivudine-TP can be regarded as the rate-limiting step. The median lamivudine-TP intracellular half-life (t1/2) for the 150-mg and 300-mg regimens did not differ significantly (15.3 and 16.1 h, respectively). Serum lamivudine pharmacokinetic parameters were consistent with those observed in previous studies in HIV-1-infected patients. No apparent linear relationships were observed between lamivudine intracellular anabolite and serum data. CONCLUSIONS: The intracellular pharmacokinetics of lamivudine phosphorylation in PBMC from asymptomatic HIV-1-infected patients are highly variable and do not differ statistically between the 150- and 300-mg twice a day regimens. The variations in intracellular lamivudine-TP concentrations following these two lamivudine dosage regimens are unlikely to result in differences in clinical effect. This was confirmed by the results of a large phase III study in HIV-1-infected patients which showed no differences in HIV-1 RNA or CD4+ lymphocyte counts between the 150- and 300-mg lamivudine regimens in combination with zidovudine.

Anti-HIV Agents↗
PubMed1999

Pretreatment methods to improve nerve immunostaining in corneas from long-term fixed embryonic quail eyes.

Pretreatment methods were used to improve neurofilament immunostaining in corneas from embryonic day 16 Japanese quail corneas that had been stored in fixative solution for several months. A sequential combination of the following three pretreatments: brief microwave heating in saline, followed by extraction with sodium dodecyl sulfate (SDS) at 37 degrees C, followed by digestion with hyaluronidase at 37 degrees C, produced significantly increased antibody staining of corneal neurofilament proteins, compared with embryonic corneas subjected to no prior pretreatments or to single or two-step protocols. After applying the sequence of all three pretreatments, darkest nerve staining and increased numbers of fine branches were observed, together with lower background staining. Thus, the result of applying the three-step pretreatment sequence is better than that of applying any of its component single pretreatments or even combinations of any two of them. These findings therefore suggest that each of these three pretreatments causes a unique effect, beneficial to immunostaining of neurofilament proteins, and that their individual effects are independent and additive. In addition to embryonic corneas, the three-step procedure also may be useful for immunostaining of nerves in other very delicate, highly-hydrated tissues containing an abundance of extracellular matrix.

Animals↗
PubMed1999

Tyrosine 146 of thymidylate synthase assists proton abstraction from the 5-position of 2'-deoxyuridine 5'-monophosphate.

Tyr 146 of TS has been proposed to assist in the removal of the proton from the 5-carbon of the pyrimidine in a steady-state intermediate [Hyatt, D. C., Maley, F., and Montfort, W. R. (1997) Biochemistry 36, 4585-4594]. We prepared a replacement set of mutations at position 146 of L. casei TS. The kcat and kcat/Km values of 15 mutants studied were significantly lower than wild-type TS. There was no effect on the Km of dUMP, and only moderate effects on the Km of the cofactor. We concluded that Y146 is not directly involved in substrate binding, but contributes significantly to catalysis. We also examined the Y146 mutants as catalysts for cofactor-independent dehalogenation of BrdUMP, a reaction which simulates early steps of the normal pathway up to and including enzyme-nucleotide covalent adduct formation. Many mutants had activity comparable to the wild-type enzyme, and we concluded that the effects of Tyr 146 mutations occur after the initial covalent adduct is formed. A covalent steady-state intermediate-containing enzyme, dUMP, and cofactor accumulated with Tyr 146 mutants, and could be isolated by SDS-PAGE. The complex was kinetically competent as an intermediate in dTMP formation. Using Y146D and F, it was shown that removal of the C-5 proton from the covalent intermediate was defective. We conclude that in the wild-type enzyme Tyr 146 assists in proton removal from the covalent intermediate. Mutants containing fluorinated tyrosines at position 146 showed an inverse linear correlation of activity versus acidity, again indicating that the basicity of the phenolic oxygen plays an important catalytic role. Speculations of how the poorly basic phenol group might assist proton removal are made in which Tyr 146 acts as a proton conduit to N5 of the cofactor or as a cohort of a water molecule serving as the direct general base catalyst.

Binding Sites↗
PubMed1999

Root formation in ethylene-insensitive plants.

Experiments with ethylene-insensitive tomato (Lycopersicon esculentum) and petunia (Petunia x hybrida) plants were conducted to determine if normal or adventitious root formation is affected by ethylene insensitivity. Ethylene-insensitive Never ripe (NR) tomato plants produced more below-ground root mass but fewer above-ground adventitious roots than wild-type Pearson plants. Applied auxin (indole-3-butyric acid) increased adventitious root formation on vegetative stem cuttings of wild-type plants but had little or no effect on rooting of NR plants. Reduced adventitious root formation was also observed in ethylene-insensitive transgenic petunia plants. Applied 1-aminocyclopropane-1-carboxylic acid increased adventitious root formation on vegetative stem cuttings from NR and wild-type plants, but NR cuttings produced fewer adventitious roots than wild-type cuttings. These data suggest that the promotive effect of auxin on adventitious rooting is influenced by ethylene responsiveness. Seedling root growth of tomato in response to mechanical impedance was also influenced by ethylene sensitivity. Ninety-six percent of wild-type seedlings germinated and grown on sand for 7 d grew normal roots into the medium, whereas 47% of NR seedlings displayed elongated tap-roots, shortened hypocotyls, and did not penetrate the medium. These data indicate that ethylene has a critical role in various responses of roots to environmental stimuli.

Ethylenes↗
PubMed1999

Improving the recognition and management of depression: is there a role for physician education?

BACKGROUND: Many patients who visit primary care physicians suffer from depression, but physicians may miss the diagnosis or undertreat these patients. Improving physicians' communication skills pertaining to diagnosing and managing depression may lead to better outcomes. METHODS: We performed a randomized controlled trial involving 49 primary care physicians to determine the effect of the Depression Education Program on their knowledge of depression and their behavior toward depressed patients. After randomization, physicians in the intervention group completed the Depression Education Program, which consists of 2 4-hour interactive workshops that combine lectures, discussion, audiotape review, and role-playing. Between sessions, physicians audiotaped an interview with one of their patients. Two to 6 weeks following the intervention program, physicians completed a knowledge test and received office visits from 2 unannounced people acting as standardized patients with major depression. These "patients" completed a checklist and scales. Logistic and linear regression were used to control for sex, specialty, and suspicion that the patient was a standardized patient. RESULTS: For both standardized patients, more intervention physicians than control physicians asked about stresses at home, and they also scored higher on the Participatory Decision-Making scale. During the office visits of one of the standardized patients, more intervention physicians asked about at least 5 criteria for major depression (82% and 38%, P = .006), discussed the possibility of depression (96% and 65%, P = .049), scheduled a return visit within 2 weeks (67% and 33%, P = .004), and scored higher than control physicians on the Patient Satisfaction scale (40.3 and 35.5, P = .014). CONCLUSIONS: The Depression Education Program changed physicians' behavior and may be an important component in the efforts to improve the care of depressed patients.

Communication↗
PubMed1998

Protective effects of cruciferous seed meals and hulls against colon cancer in mice.

Protective effects of diets containing cruciferous seed meals or hulls against chemically-induced colon tumors were examined in male CF1 mice. When commercial crambe meal, autolyzed crambe meal, crambe hulls, high glucosinolate rapeseed meal, or canola meal were fed as 12% of the diets of mice injected with 1,2-dimethylhydrazine, 25-80% of the animals developed colon tumors. Animals fed a soybean meal control diet had a 100% tumor rate. Data suggest that cruciferous seed meals may contain a number of compounds that can exert protective effects against tumor formation and growth.

Animals↗
PubMed1998

Alkaline heating of canola and rapeseed meals reduces toxicity for chicks.

A simple method for improving the nutritive quality of canola and high glucosinolate rapeseed meals for monogastric animals (chicks) was developed; the meals were mixed with NaHCO3 and NH4HCO3, then heated in a conventional oven. Chicks fed untreated canola or rapeseed meals gained less weight than those fed a soybean meal diet, whereas chicks fed the alkaline-heated meals had weight gains not significantly different than those fed the soybean diet. The antithyroid effect of the untreated rapeseed meal was reduced by alkaline treatment of the meals, as shown by improved T4 and free T4 levels in chicks fed the processed products. In chicks fed untreated or alkaline-treated canola or alkaline heated rapeseed meal, all thyroid hormone levels were similar to those of birds fed the soybean meal diet. However, heart tissue of chicks fed diets containing rapeseed or canola meals showed muscle fiber degeneration, although relative heart weights were the same in all groups. Liver tissue from most of the chicks in all dietary groups appeared normal or only slightly abnormal. The nutritive value of both rapeseed and canola meals was improved by this simple processing technique.

Animal Feed↗
PubMed1998

An automated learning and memory model in mice: pharmacological and behavioral evaluation of an autoshaped response.

The purpose of the present experiments was to develop and validate pharmacologically an automated, relatively rapid, and reproducible behavioral model of learning and memory using an autoshaping procedure in mice. Nose-poke responses into a recessed area were differentiated by response-dependent reinforcement during two identical consecutive daily sessions. Performance during the first session was considered to be a measure of acquisition and that during the second session a measure of retention. Sensitivity to procedural manipulation, as well as an index of learning under these conditions, was demonstrated, for example, by a decrease in response rate when nose-poke responses did not produce a reinforcer. The sensitivity of the paradigm to pharmacological intervention was examined after drug administration before the first session. Scopolamine (0.1-10.0 mg/kg) had no effect on acquisition but caused a significant dose-related impairment of retention. Dizocilpine (0.01-1.0 mg/kg) impaired both acquisition and retention performance. 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.1-1.0 mg/kg) disrupted behavior in general, but failed to have a selective effect on acquisition or retention. Linopirdine (0.1-1.0 mg/kg) showed only a weak enhancement of acquisition, whereas 4-aminopyridine (4-AP; 0.1-1.0 mg/kg) significantly facilitated acquisition. This paradigm offers the potential for a rapid, objective, and reliable indication of whether a drug will affect the acquisition or retention of a positively reinforced response in mice and could be a useful supplement to existing procedures.

4-Aminopyridine↗