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Biomedical subjects

J M Walker

Publications and source records attributed to J M Walker.

At least 73 records · Page 4Linked to original sources
PubMed1997

Endogenous cannabinoids as an aversive or counter-rewarding system in the rat.

Human use of marijuana (Cannabis sativa) is widely assumed to have rewarding properties, a notion supported by its widespread recreational use. However, no study has clearly demonstrated such effects in animal models. The purpose of this study was to test for the presumed rewarding effect of cannabinoids using a conditioned place preference paradigm. The results showed that animals failed to develop place conditioning at a low dose (1.5 mg/kg) and developed a place aversion at a high dose (15 mg/kg) of the active principle in marijuana, delta 9-tetrahydrocannabinol (delta 9-THC), a finding consistent with most previous studies. Moreover, the administration of the cannabinoid antagonist SR141716A induced a conditioned place preference at both a low (0.5 mg/kg) and a high (5 mg/kg) dose. In summary, cannabinoid antagonism produced place preference while cannabinoid agonism induced place aversion. These results suggest that endogenous cannabinoids serve normally to suppress reward or to induce aversion.

Animals↗
PubMed1997

Acute ischaemia: a dynamic influence on QT dispersion.

BACKGROUND: The aim of this study was to test the hypothesis that acute myocardial ischaemia increases QT dispersion measured from the 12-lead electrocardiogram. METHODS: Incremental atrial pacing was used to induce myocardial ischaemia in 18 patients with coronary artery disease and QT dispersion was measured. Six patients with normal coronary arteries served as the control group. FINDINGS: All the patients with coronary artery disease developed angina and/or ST depression accompanied by marked increases in QT dispersion (mean increase 38 ms, 95% CI 30 to 45 ms, p < 0.001). In contrast, in the six patients with normal coronary arteries who remained without symptoms and without ST changes, there was no significant change in QT dispersion in response to pacing. Baseline QT dispersion did not distinguish those patients with coronary artery disease from those with normal coronary arteries (44 ms [95% Cl 39-49 ms] vs 40 ms [25-55 ms]), respectively. INTERPRETATION: These results demonstrate that myocardial ischaemia induced by incremental atrial pacing in patients with coronary artery disease causes an acute increase in QT dispersion. Such "inducible" QT dispersion may prove more useful than resting QT dispersion in assessing the individual risk of arrhythmic events in patients with coronary artery disease.

Arrhythmias, Cardiac↗
PubMed1997

The effect of evisceration on visible contamination and the microbiological profile of fresh broiler chicken carcasses using the Nu-Tech Evisceration System or the conventional Streamlined Inspection System.

Experiments were conducted to determine the effect of evisceration on visible contamination and the microbiological profile of fresh broiler chicken carcasses using the Nu-Tech System or the Streamlined Inspection System (SIS). Visible contamination was evaluated on the inside cavity and outside surface of 1,000 and 7,825 carcasses from Plants A and B, respectively, during 5 d of processing. For the microbiological study, in five separate trials, 80 broiler carcasses were collected each day from two processing plants (A and B). Two groups of 20 carcasses each were collected immediately prior to entering the Nu-Tech eviscerator, bagged separately, and 20 were labeled as NT1 and 20 as SIS1. The third group of 20 carcasses was collected immediately after the cropper on the Nu-Tech line and labeled NT2. For the fourth group, 20 carcasses were aseptically transferred from the Nu-Tech line just prior to evisceration, placed on the SIS line prior to evisceration, allowed to be eviscerated by the SIS eviscerator, collected immediately after the cropper, and labeled SIS2. Whole carcass rinses were conducted and aerobic plate counts (APC), total coliform counts (TC), total Escherichia coli counts (TEC), aerobic mesophilic impedance detection times (DT), and coliform impedance detection times (CDT) were determined within 30 h of collection. The Nu-Tech System was superior to SIS with regard to visible carcass contamination. For Plant A, evisceration using the Nu-Tech System or SIS did not significantly affect APC, TC, or TEC; however, evisceration using the Nu-Tech System resulted in an increase in DT and CDT (indicating a reduction in bacteria); whereas evisceration using SIS resulted in no significant decrease in bacterial levels. For Plant B, evisceration using the Nu-Tech resulted in lower APC, TC, TEC, and higher DT and CDT (indicating a reduction in bacteria); whereas evisceration using SIS resulted in no significant decrease in bacterial levels. Evisceration using the Nu-Tech System was at least equal to or in some cases better than SIS with regard to APC, TC, TEC, DT, and CDT.

Abattoirs↗
PubMed1997

Changes in the male voice at puberty.

The changes in the male voice in relation to the biological characteristics of puberty were assessed longitudinally in 26 boys. Speaking and singing fundamental frequencies were analysed in relation to the Tanner staging of puberty, saliva testosterone levels, and the Cooksey classification of voice analysis. There were abrupt changes in voice characteristics between Tanner stages G3 and G4 and more gradually from stages C3 to C5 of Cooksey. Although testosterone concentrations were not predictive of the changes, there was a correlation with testis volume. Voice fundamental frequencies were seen to change abruptly in late puberty, in contrast with previous studies. There is a good correlation between the Tanner and Cooksey methods of classification during male puberty.

Adolescent↗
PubMed1997

Role of the subthalamic nucleus in cannabinoid actions in the substantia nigra of the rat.

The effect of cannabinoids on the excitatory input to the substantia nigra reticulata (SNr) from the subthalamic nucleus was explored. For this purpose a knife cut was performed rostral to the subthalamic nucleus to isolate the subthalamic nucleus and the SNr from the striatum, a major source of cannabinoid receptors to the SNr. The data showed that the cannabinoid agonist WIN55,212-2 blocked the increase in the firing rate of SNr neurons induced by stimulation of the subthalamic nucleus with bicuculline. Furthermore, the cannabinoid antagonist SR141716A antagonized the effect of the cannabinoid agonist. This study showed that cannabinoids regulate not only the striatonigral pathway, as previously reported, but also the subthalamonigral pathway. The opposite influences of these two inputs to the SNr, inhibitory and excitatory respectively, suggest that endogenous cannabinoids play a major role in the physiological regulation of the SNr.

Analgesics↗
PubMed1996

Suppression of noxious stimulus-evoked activity in the ventral posterolateral nucleus of the thalamus by a cannabinoid agonist: correlation between electrophysiological and antinociceptive effects.

The CNS contains a putative cannabinergic neurotransmitter and an abundance of G-protein-coupled cannabinoid receptors. However, little is known about the function of this novel neurochemical system. Cannabinold agonists produce antinociception in behavioral tests, suggesting the possibility that this system serves in part to modulate pain sensitivity. To explore this possibility, the effects of the cannabinoid agonist WIN 55,212-2 on nociceptive neurons in the ventroposterolateral (VPL) nucleus of the thalamus were examined in urethane-anesthetized rats. After identification of a nociresponsive neuron, a computer-controlled device delivered graded pressure stimuli to the contralateral hindpaw. WIN 55,212-2 (0.0625, 0.125, and 0.25 mg/kg, i.v.) suppressed noxious stimulus-evoked activity of VPL neurons in a dose-dependent and reversible manner. Noxious stimulus-evoked firing was affected more than spontaneous firing. These effects were apparently mediated by cannabinoid receptors, because the cannabinoid receptor-inactive enantiomer of the drug (WIN 55,212-3, 0.25 mg/kg) failed to alter the activity of this population of cells. Administration of morphine (0.5 mg/kg, i.v.) produced effects that were very similar to those produced by the cannabinoid. WIN 55,212-2 (0.25 mg/kg, i.v.) failed to alter the responses of non-nociceptive low-threshold mechanosensitive neurons in the VPL WIN 55,212-2 produced antinociceptive effects with a potency and time course similar to that observed in the electrophysiological experiments, despite the differences in the anesthetic states of the animals used in these experiments. The antinociceptive and electrophysiological effects on VPL neurons outlasted the motor effects of the drug. Furthermore, the changes in nociceptive responding could not be attributed to changes in skin temperature. Taken together, these findings suggest that cannabinoids decrease nociceptive neurotransmission at the level of the thalamus and that one function of endogenous cannabinoids may be to modulate pain sensitivity.

Analgesics↗
PubMed1996

The Arabidopsis thaliana UBC7/13/14 genes encode a family of multiubiquitin chain-forming E2 enzymes.

Covalent modification of proteins by attachment of multiubiquitin chains serves as an essential signal for selective protein degradation in eukaryotes. The specificity of ubiquitin-protein conjugation is controlled in part by a diverse group of ubiquitin-conjugating enzymes (E2s or UBCs). We have previously reported that the product of the wheat TaUBC7 gene recognizes ubiquitin as a substrate for ubiquitination in vitro, catalyzing the condensation of free ubiquitin into multiubiquitin chains linked via lysine 48 (van Nocker, S., and vierstra, R. D. (1991) Proc. Natl. Acad. Sci. U. S. A. 88, 10297-10301). Based on this activity, this E2 may play a central role in the ubiquitin proteolytic pathway by assembling chains in vivo. Here, we describe the cloning and characterization of a three-member gene family from Arabidopsis thaliana (designated AtUBC7/13/14) encoding structural homologs of TaUBC7. Like TaUBC7, recombinant AtUBC7/13/14 proteins formed multiubiquitin chains in vitro. AtUBC7/13/14 mRNAs were found in all tissues examined, and unlike related UBCs from yeast, the levels of mRNA were not elevated by heat stress or cadmium exposure. Transgenic Arabidopsis were engineered to express increased levels of active AtUBC7, for the first time altering the level of an E2 in a higher eukaryote. Plants expressing high levels of AtUBC7 exhibited no phenotypic abnormalities and were not noticeably enriched in multiubiquitinated conjugates. These findings indicate that the in vivo synthesis of multiubiquitin chains is not rate-limited by the abundance of AtUC7 and/or involves other, yet undefined components.

Amino Acid Sequence↗
PubMed1996

Electrophysiological effects of a cannabinoid on neural activity in the globus pallidus.

The globus pallidus contains a dense distribution of cannabinoid receptors and appears to be a site of action of cannabinoids in the production of catalepsy. Single unit electrophysiology was used to explore the role of cannabinoid receptors in the globus pallidus of the rat. Intravenous injections of the potent and selective synthetic cannabinoid (R)-(+)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]-pyrrolo [1,2,3-de]-1,4-benzoxazin-6-yl](1-napthalenyl) methanone (WIN 55,212-2; up to 0.5 mg/kg, i.v.) inhibited the spontaneous firing of neurons in the globus pallidus. In a second set of experiments, WIN 55,212-2 antagonized the inhibition of pallidal firing produced by electrical stimulation of the striatum. The pharmacological specificity of the effects of WIN 55,212-2 on basal and evoked activity in the globus pallidus was demonstrated by the lack of effect of the inactive enantiomer WIN 55,212-3. These results indicate that cannabinoids may produce functionally opposite effects on spontaneous and evoked activity in the globus pallidus: a decrease in spontaneous firing and a decrease in the inhibition of firing produced by the striatopallidal projection.

Action Potentials↗
PubMed1996

Dissociation of the motor effects of (+)-pentazocine from binding to sigma 1 sites.

Radioligand binding and behavioral studies were conducted to determine whether a relationship existed between the motor effects produced by (+)-pentazocine and its binding to sigma sites. Scatchard analyses revealed decreased [3H](+)-pentazocine binding in middle aged rats (5-6 months old) compared to young adult rats (2-3 months old). However, there was no difference between the extent of circling behavior or dystonia produced by microinjection of (+)-pentazocine into the substantia nigra or red nucleus in the older animals compared to the young adult rats. There was also a significant decrease in [3H](+)-pentazocine binding in rats chronically treated with haloperidol. Again, however, despite the reduction in [3H](+)-pentazocine binding, there was no difference between the extent of dystonia produced by unilateral intrarubral microinjection of (+)-pentazocine into animals chronically treated with haloperidol vs. saline. The postural changes produced by (+)-pentazocine could not be attenuated with coadministration of the putative sigma receptor antagonist BD1047 (N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino) ethylamine), or the opiate receptor antagonist naloxone. However, the (+)-opiate, (+)-nordihydrocodeinone, partially attenuated the postural effects of (+)-pentazocine, despite its very low affinity for sigma 1, sigma 2, or opiate receptors. Taken together with previous studies, the results suggest that [3H](+)-pentazocine is a potent and selective probe for sigma 1 binding sites, but the in vivo effects of (+)-pentazocine cannot be fully attributed to actions through these sites. Some of the in vivo effects of (+)-pentazocine appear to involve other binding sites that are not detected under the conditions normally used in in vitro assays.

Aging↗
PubMed1996

Effects of intranigral cannabinoids on rotational behavior in rats: interactions with the dopaminergic system.

The effect of unilateral intranigral cannabinoid receptor stimulation on rotational behavior was explored. The potent cannabinoid agonist CP 55,940 (5 and 10 micrograms/0.5 microliter) induced contralateral turning when microinjected unilaterally into the substantia nigra pars reticulata. In addition, the cannabinoid agonist markedly attenuated the contralateral rotation induced by the dopamine D1 agonist SKF 82958 and completely reversed the ipsilateral rotation induced by the dopamine D2 agonist quinpirole. In both cases, the coadministration of the cannabinoid agonist together with the D1 or D2 agonist induced contralateral rotation. It appears that cannabinoids may exert different effects depending on the state of the ongoing chemical activation of this brain circuitry.

Animals↗
PubMed1996

Synthesis and analysis of the enantiomers of calmidazolium, and a 1H NMR demonstration of a chiral interaction with calmodulin.

Calmidazolium [R24571, 1-[bis(4-chlorophenyl)methyl]-3-[2-(2,4-dichlorophenyl)-2-[(2,4- dichlorophenyl)methoxy]ethyl]-1H-imidazolium chloride] is a potent calmodulin inhibitor. This paper describes the synthesis and properties of the enantiomers of calmidazolium from the enantiomers of miconazole [1(N)-(2-(2,4-dichlorobenzyloxy)-2-(2,4 dichlorophenyl))-ethyl imidazole], prepared from the racemate by chiral preparative scale high performance liquid chromatography. Overlap between ligand and protein resonances in the aromatic region of the 1H NMR spectrum of the calmidazolium-calmodulin complexes has been obviated by preparation of the protein with all of its nine phenylalanine rings deuterated (Phe-d5 calmodulin). This has been accomplished by the overexpression of calmodulin derived from Trypanosoma brucei rhodiesiense in E. coli in a medium supplemented with ring-deuterated phenylalanine. The kinetics of binding of each enantiomer are slow on the 1H NMR time scale as judged by the behaviour of the H2 resonance of Histidine-107, which is clearly visible under the sample conditions used. The aromatic spectral regions of the protein-bound (+) and (-) enantiomers contrast strikingly, reflecting differences in bound environment and/or conformation.

Calmodulin↗
PubMed1996

A comparison of nifedipine once daily (Adalat LA), isosorbide mononitrate once daily, and isosorbide dinitrate twice daily in patients with chronic stable angina.

The efficacy of nifedipine gastrointestinal therapeutic system (GITS), 60-90 mg o.d., isosorbide dinitrate, 40-60 mg b.d., and isosorbide mononitrate slow-release, 50-100 mg o.d. was assessed in a six week double-blind, parallel-group study in patients with stable angina on chronic beta-blocker treatment. Of 339 patients who entered the study, 229 were eligible for the valid case analysis of efficacy and 335 for the safety analysis. Nifedipine GITS was significantly better than isosorbide dinitrate (P < or = 0.025) in prolonging time to 1 mm ST-segment depression, time to maximum ST-segment depression, time to occurrence of angina and total exercise duration, in addition to reducing the number of angina attacks and glyceryl trinitrate consumption after six weeks therapy. Nifedipine GITS was also significantly better than isosorbide mononitrate (P < or = 0.025) in prolonging time to occurrence of angina and time to 1 mm ST-segment depression after six weeks therapy. The incidence of headache was considerably higher in both the isosorbide dinitrate and isosorbide mononitrate groups (40% and 41%, respectively) than in the nifedipine GITS group (9.5%, P < or = 0.001), and was the main reason for withdrawal from the study (isosorbide dinitrate 18/99, isosorbide mononitrate 17/99, nifedipine GITS 2/95). Peripheral oedema was more common in patients treated with nifedipine GITS (12.5%) compared to nitrates (2% in both groups, P < or = 0.01), but resulted in withdrawal of only one patient (treated with nifedipine GITS). This study suggests that the efficacy and tolerability of nifedipine GITS is superior to long acting nitrates as second-line therapy to beta-blockade in the treatment of chronic stable angina.

Adult↗