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Biomedical subjects

J A Gray

Publications and source records attributed to J A Gray.

At least 37 records · Page 2Linked to original sources
PubMed2001

Diffusion-weighted magnetic resonance imaging detects early neuropathology following four vessel occlusion ischemia in the rat.

Early neuropathology following a prolonged duration of four-vessel occlusion (4 VO) ischemia in the rat was charted using magnetic resonance imaging (MRI). Animals received either 30 minutes of 4 VO (N = 6) or sham operation (N = 6) prior to in vivo assessment. Proton density and T(2) and combined T(2)/diffusion-weighted (T(2)/DW) MRI were performed at 6, 24, and 72 hours postocclusion. T(2)/DW imaging was the most effective sequence for delineating between injured and intact tissues, indicating neuropathology in the dorsolateral striatum at 24 hours and in the CA1/CA2 subfields of the hippocampus at 72 hours following ischemia. Apparent diffusion coefficient values were significantly reduced in the striatum (P = 0.03) and hippocampus (P = 0.005) at 24 and 72 hours, respectively. This is the first report, to our knowledge, of T(2)/DW imaging detecting lesions following 4 VO in accord with the known temporal evolution of ischemic brain damage.

Animals↗
PubMed2001

Lack of consistent behavioural effects of Maudsley reactive and non-reactive rats in a number of animal tests of anxiety and activity.

RATIONALE: A number of previous studies have reported that the Maudsley reactive (MR/Har) and non-reactive (MNRA/Har) strains of rats show behavioural and physiological differences consistent with the hypothesis that these strains differ in emotionality and could therefore be considered a model of trait anxiety in humans. OBJECTIVES: We sought to confirm this observation by determining their behaviour in various animal models of conditioned and unconditioned fear. METHODS: Both strains were evaluated in the open field (OF), conditioned avoidance (CA), elevated plus maze (EPM) and fear-potentiated startle (FPS) tests. In the OF the behaviour of both strains was consistent with previous results showing that reactive rats had significantly higher levels of defecation and lower levels of activity than the non-reactive rats. However, there were no significant strain differences in CA responses or in the time spent on the open arms of the EPM. In addition, the full benzodiazepine receptor agonist, chlordiazepoxide, induced quantitatively similar effects in both strains of rats. In the FPS test, MNRA/Hars had a higher baseline level of startle and fear potentiation than the MR/Har rats. CONCLUSIONS: These data show that the behaviour of MR/Har and MNRA/Har rats in some models of conditioned and unconditioned fear is inconsistent with that predicted by their behaviour in the OF test, suggesting that they are not a model of trait fear.

Animals↗
PubMed2001

Startle response during smoking and 24 h after withdrawal predicts successful smoking cessation.

RATIONALE: The startle response is thought to reflect changes in attentional processes in humans. The startle response shows a number of forms of plasticity, of which prepulse inhibition (PPI) refers to the attenuation of the startle response to a strong sensory stimulus (pulse), when such a pulse is preceded by a stimulus of lower intensity (prepulse). Recent studies have shown that nicotine modulates startle and PPI of the startle reflex in humans and animals. The present study examined individual differences in cognitive benefits obtained from smoking as indexed by startle response and PPI. OBJECTIVES: We investigated, using a within-subjects design, the effects of cigarette smoking via a comparison of baseline and withdrawal measures of startle and PPI in 18 subjects wishing to quit cigarette smoking. The relapse of five of these subjects enabled a between-group comparison of these measures with the successful quitters. METHODS: Startle and PPI were measured on three separate occasions: before quitting, 24 h after quitting and 1 month after quitting. RESULTS: The presence of a high startle response amplitude while subjects were still engaged in their normal smoking patterns (baseline) and the occurrence of a significant drop of startle amplitude in withdrawal relative to baseline factors were found to be predictive of an individual's ability to quit smoking. Changes in PPI were found to reflect these changes in startle amplitude. CONCLUSIONS: The observed response patterns are discussed in terms of individual differences in commitment to quitting and self-dosing to manipulate attentional mechanisms as measured by the acoustic startle response. Furthermore, it is suggested that these specific response profiles may be predictive of the ability to quit smoking.

Adult↗
PubMed2001

Evidence-based screening in the United Kingdom.

OBJECTIVE: To review the assessment of screening in the United Kingdom, focusing on three methods: mammography for breast cancer, screening for prostate cancer, and routine use of ultrasound in pregnancy. METHOD: To review policy documents and published papers dealing with prevention and screening in the United Kingdom. RESULTS: Indicate that the United Kingdom has an active policy concerning the assessment of screening methods. Generally speaking, this assessment policy is part of the national program for health technology assessment (HTA). The government has given HTA an important place within health care in the United Kingdom, and prevention and screening is no exception to this general rule. The assessment of screening is now implemented through the National Screening Committee, established in 1997. The three issues reviewed in this paper have all been assessed within the context of the Department of Health. In the case of mammography, the assessment was done more than 10 years ago and was followed by a rational implementation of a national screening program for breast cancer. In the case of prostate cancer screening, two systematic reviews have concluded that screening should not be carried out. In general, this recommendation has been accepted in the United Kingdom. Use of ultrasound in pregnancy has been assessed by the National Screening Committee. This complex technology is difficult to assess, and the screening procedure is deeply embedded in clinical practice in the United Kingdom, so assessment has not had much impact on the frequency of screening. CONCLUSION: HTA and the assessment of screening are well established in the United Kingdom. Policy is generally based on the assessments done, and practice generally follows the results of assessment. Assessment of screening is expected to become increasingly important in the United Kingdom during the next years.

Breast Neoplasms↗
PubMed2001

Herbicidal properties of the thaxtomin group of phytotoxins.

The thaxtomins are a group of phytotoxins generated by the bacterium Streptomyces scabies (the main causal organism of potato common scab). Available members of the group were assessed for herbicidal activity by a variety of standard tests. Test results indicated that thaxtomin A, the predominant member, was also the most physiologically active. Injury symptoms in most instances were similar to those caused by known cellulose biosynthetic inhibitors such as dichlobenil and isoxaben. Although test results indicated that the thaxtomins had many of the biological properties desirable in a commercial herbicide, they nevertheless lacked the systemic phytotoxicity critical to deliver reliable weed control at low rates.

Bacterial Toxins↗
PubMed2001

Biochemical markers of bone metabolism in growing thoroughbreds: a longitudinal study.

This study describes longitudinal changes in serum levels of biochemical markers of bone cell activity in a group of 24 thoroughbred foals from birth to 18 months of age. The markers of bone formation included the type I collagen carboxy-terminal propeptide (PICP), the bone-specific isoenzyme of alkaline phosphatase (BAP), and osteocalcin (OC). Levels of the cross-linked telopeptide of type I collagen (ICTP), a marker of bone resorption, and the N-terminal propeptide of type III collagen (PNIIIP), a marker of soft tissue turnover, were also measured. Levels of all markers fell significantly between birth and 18 months of age (70-80 per cent); this decrease being most marked between 0 and 6 months. However, a transient increase in levels of the markers then occurred between 6 and 14 months of age. The timing of this increase was specific for each parameter. ICTP and OC concentrations increased between October and December. PICP concentrations increased between December and April whereas the increase in PIIINP was coincident with the peak in weight gain between April and June. Changes in BAP concentration were less distinct at this time. Season was shown to have significant effects on the biochemical markers independent from the effect of age. Concentrations of all markers decreased with increasing body weight and at any given age heavier horses had lower marker levels. These results show that biochemical markers of bone cell activity and soft tissue turnover follow characteristic patterns of change in growing thoroughbreds influenced by age, season and bodyweight. The demonstration that the reference ranges for the biochemical markers change from month to month means that single samples from individuals are of little value for monitoring bone cell activity in growing thoroughbreds.

Alkaline Phosphatase↗
PubMed2001

Cell-type specific effects of endocytosis inhibitors on 5-hydroxytryptamine(2A) receptor desensitization and resensitization reveal an arrestin-, GRK2-, and GRK5-independent mode of regulation in human embryonic kidney 293 cells.

The effect of endocytosis inhibitors on 5-hydroxytryptamine(2A) (5-HT(2A)) receptor desensitization and resensitization was examined in transiently transfected human embryonic kidney (HEK) 293 cells and in C6 glioma cells that endogenously express 5-HT(2A) receptors. In HEK-293 cells, 5-HT(2A) receptor desensitization was unaffected by cotransfection with a dominant-negative mutant of dynamin (DynK44A), a truncation mutant of arrestin-2 [Arr2(319-418)], or by two well-characterized chemical inhibitors of endocytosis: concanavalin A (conA) and phenylarsine oxide (PAO). In contrast, beta 2-adrenergic receptor desensitization was significantly potentiated by each of these treatments in HEK-293 cells. In C6 glioma cells, however, DynK44A, Arr2(319-418), conA, and PAO each resulted in the potentiation of 5-HT(2A) and beta-adrenergic receptor desensitization. The cell-type-specific effect of Arr2(319-418) on 5-HT(2A) receptor desensitization was not related to the level of GRK2 or GRK5 expression. Interestingly, although beta 2-adrenergic receptor resensitization was potently blocked by cotransfection with DynK44A, 5-HT(2A) receptor resensitization was enhanced, suggesting the existence of a novel cell-surface mechanism for 5-HT(2A) receptor resensitization in HEK-293 cells. In addition, Arr2(319-418) had no effect on 5-HT(2A) receptor resensitization in HEK-293 cells, although it attenuated the resensitization of the beta 2-adrenergic receptor. However, in C6 glioma cells, both DynK44A and Arr2(319-418) significantly reduced 5-HT(2A) receptor resensitization. Taken together, these results provide the first convincing evidence of cell-type-specific roles for endocytosis inhibitors in regulating GPCR activity. Additionally, these results imply that novel GRK and arrestin-independent mechanisms of 5-HT(2A) receptor desensitization and resensitization exist in HEK-293 cells.

Animals↗
PubMed2001

What is the role of clinical ethics support in the era of e-medicine?

The internet is becoming increasingly important in health care practice. The number of health-related web sites is rising exponentially as people seek health-related information and services to supplement traditional sources, such as their local doctor, friends, or family. The development of e-medicine poses important ethical challenges, both for health professionals and for those who provide clinical ethics support for them. This paper describes some of these challenges and explores some of the ways in which those who provide clinical ethics support might respond creatively to them. By offering ways of responding to such challenges, both electronically and face-to-face, the providers of clinical ethics support can show themselves to be an indispensable part of good quality health care provision.

Access to Information↗
PubMed2001

Enhanced startle reactions to acoustic stimuli in patients with obsessive-compulsive disorder.

OBJECTIVE: Anxiety states induced experimentally or occurring naturally potentiate the startle reflex elicited by sudden sensory stimuli in both animals and human beings. The authors investigated whether patients with obsessive-compulsive disorder (OCD) show exaggerated startle reactions to acoustic probes, especially during negative-affect-toned stimuli, compared with healthy subjects. METHOD: Ten patients with OCD and 10 age- and sex-matched comparison subjects were shown a series of film clips. Two of the film clips had positive valence, two had negative valence, and two had relatively neutral valence. The subjects' eyeblink startle response was measured in reaction to startle-eliciting stimuli presented three times binaurally during each film clip. RESULTS: Patients with OCD produced larger startle reflexes and shorter latencies to onset of startle response than the comparison subjects over the entire session. CONCLUSIONS: Patients with OCD were excessively responsive to startle-eliciting stimuli. This effect may be associated with the development or maintenance of OCD.

Acoustic Stimulation↗
PubMed2001

The relationship between prepulse detection and prepulse inhibition of the acoustic startle reflex.

Prepulse inhibition (PPI) of the startle reflex is defined as the attenuation of the startle response to a startling stimulus (pulse), when such a stimulus is briefly preceded by a stimulus of subthreshold intensity (prepulse). PPI is thought to be neither learned nor due to conscious response inhibition, as it occurs at stimulus onset asynchronies (SOAs) too short to enable the activation of a volitional response. The present study explored the latter of these assertions by investigating (a) the degree to which human subjects are able to detect prepulses at SOAs of 30, 60 and 120 ms, and (b) whether such detection is related to inhibition. Startle eyeblink reflex and detection were measured in 39 participants subjected to an acoustic startle paradigm. Results revealed a significant trend in prepulse detection according to SOA, with highest detection rates at the 120-ms SOA (75%). However, trials on which detection occurred did not differ from trials without detection on measures of startle inhibition. This suggests that PPI is independent of awareness of the prepulse.

Acoustic Stimulation↗
PubMed2000

The dynamin-dependent, arrestin-independent internalization of 5-hydroxytryptamine 2A (5-HT2A) serotonin receptors reveals differential sorting of arrestins and 5-HT2A receptors during endocytosis.

5-Hydroxytryptamine 2A (5-HT2A) receptors, a major site of action of clozapine and other atypical antipsychotic medications, are, paradoxically, internalized in vitro and in vivo by antagonists and agonists. The mechanisms responsible for this paradoxical regulation of 5-HT2A receptors are unknown. In this study, the arrestin and dynamin dependences of agonist- and antagonist-mediated internalization were investigated in live cells using green fluorescent protein (GFP)-tagged 5-HT2A receptors (SR2-GFP). Preliminary experiments indicated that GFP tagging of 5-HT2A receptors had no effect on either the binding affinities of several ligands or agonist efficacy. Likewise, both the native receptor and SR2-GFP were internalized via endosomes in vitro. Experiments with a dynamin dominant-negative mutant (dynamin K44A) demonstrated that both agonist- and antagonist-induced internalization were dynamin-dependent. By contrast, both the agonist- and antagonist-induced internalization of SR2-GFP were insensitive to three different arrestin (Arr) dominant-negative mutants (Arr-2 V53D, Arr-2-(319-418), and Arr-3-(284-409)). Interestingly, 5-HT2A receptor activation by agonists, but not antagonists, induced greater Arr-3 than Arr-2 translocation to the plasma membrane. Importantly, the agonist-induced internalization of 5-HT2A receptors was accompanied by differential sorting of Arr-2, Arr-3, and 5-HT2A receptors into distinct plasma membrane and intracellular compartments. The agonist-induced redistribution of Arr-2 and Arr-3 into intracellular vesicles and plasma membrane compartments distinct from those involved in 5-HT2A receptor internalization implies novel roles for Arr-2 and Arr-3 independent of 5-HT2A receptor internalization and desensitization.

Animals↗
PubMed2000

Activation of the retrohippocampal region in the rat causes dopamine release in the nucleus accumbens: disruption by fornix section.

There is a well-described projection from the retrohippocampus (subiculum and entorhinal cortex) to the nucleus accumbens that is involved in the control of psychomotor behaviour, and is implicated in the aetiology of schizophrenia. Cortical abnormalities are widely reported in the brains of schizophrenic patients, but it is unclear whether they are the cause or consequence of those changes in subcortical systems that are treated with neuroleptic drugs. We have, therefore, conducted a series of microdialysis experiments in anaesthetized rats to determine whether infusion of the excitotoxin, N-methyl-D-aspartate, into the retrohippocampus increases mesolimbic dopamine release. We found a clear and reproducible increase in extracellular dopamine in the nucleus accumbens following N-methyl-D-aspartate (2.5 microg), that was abolished when we sectioned the fimbria-fornix. Furthermore, inhibition of gamma-aminobutyric acid receptors following retrohippocampus administration of bicuculline (4 microg), also increased dopamine in the nucleus accumbens. The dopamine response to bicuculline was accompanied by an increase in dopamine metabolism, was long lasting, and also reduced by fornix section.The response to both N-methyl-D-aspartate and bicuculline depends on the integrity of the projection from the retrohippocampus to the nucleus accumbens. The results provide an underlying mechanism whereby a primary insult in the temporal cortex, caused by excessive N-methyl-D-aspartate receptor stimulation, can produce a hyperdopaminergic state. In addition, an increase in subiculo-accumbens activity evoked by bicuculline may also explain why patients with limbic epilepsy can develop a psychosis.

Animals↗
PubMed2000

Functional reconstruction of the hippocampus: fetal versus conditionally immortal neuroepithelial stem cell grafts.

Late fetal CA1 hippocampal grafts and stem cell grafts from the conditionally immortal MHP36 clonal line derived from the H-2Kb-tsA58 transgenic mouse neuroepithelium both improved spatial deficits in rats with ischaemic CA1 damage induced by four-vessel occlusion (4VO). However, the distribution of fetal and MHP36 grafts differed. Fetal cells lodged in clumps around the implant sites and along the corpus callosum, whilst MHP36 grafts infiltrated the area of CA1 ischaemic damage, achieving apparent architectural reconstruction of the hippocampus. The migration of MHP36 cells is damage-dependent. Few cells were found in intact brain; after 15 min of 4VO cells repopulated only the discrete area of CA1 cell loss, whereas with more extensive damage after 30 min occlusion cells migrated to all hippocampal fields and to cortex. A higher proportion of grafted MHP36 cells differentiated into neurons in the host CA1 field than grafts of striatal or cortical expanded cell populations. Cortical population grafts were as effective as MHP36 grafts in improving water maze learning, whereas striatal or ventral mesencephalic cells were ineffective, indicating a degree of stem cell specificity. The efficacy of MHP36 cells extends to primates. In marmosets with profound impairments in conditional discrimination tasks after lesions of the CA1 field, MHP36 cells improved performance as effectively as fetal grafts and migrated evenly through the CA1 field, in contrast to clustered fetal cells. These findings suggest that MHP36 stem cell grafts are as effective as fetal grafts in functional repair of hippocampal damage, and that their preference for areas of cell loss and adoption of appropriate morphologies is consistent with a point-to-point repair mechanism.

Animals↗
PubMed2000

Cytodiagnosis of bronchogenic carcinoma and neuroendocrine tumor of the lung by transthoracic fine-needle aspiration.

To evaluate our experience with the cytodiagnosis of primary lung cancers by transthoracic fine-needle aspiration (TFNA), 106 bronchogenic carcinomas (BC) and 6 neuroendocrine tumors of the lung (NTL) with adequate needle aspirates were reviewed. The cytodiagnostic accuracy rates of BCs were 75.5%, 72%, 100%, 53%, and 50% for bronchogenic adenocarcinomas, squamous-cell carcinomas, small-cell carcinomas, large-cell carcinomas, and mixed carcinomas, respectively. Of the 6 NTLs, 4 typical carcinoid tumors (CT) were correctly diagnosed, 1 atypical CT was wrongly identified as small-cell carcinoma, and 1 large-cell NTL was mistaken for an adenocarcinoma.

Adult↗
PubMed2000

Anxiolytic action on the behavioural inhibition system implies multiple types of arousal contribute to anxiety.

According to "The Neuropsychology of Anxiety" [Gray, J.A., 1982, The Neuropsychology of Anxiety: An Enquiry into the Functions of the Septo-hippocampal System, Oxford University Press, Oxford; Gray, J.A., McNaughton, N., 2000, The Neuropsychology of Anxiety: An Enquiry into the Functions of the Septo-hippocampal System, 2nd ed., Oxford University Press, Oxford], anxiolytic drugs of all types act on a behavioural inhibition system, the most important neural component of which is the septo-hippocampal system. Anxiolytics affect septo-hippocampal function by impairing the subcortical control of hippocampal "theta" activity - the principle response of the septo-hippocampal system to arousal. Our recent experiments show that there are multiple systems controlling theta activity and that anxiolytics act on several, but not all, of these systems. This pattern of results implies that there are many different types of arousal, only some of which appear to contribute to the generation of anxiety in normal subjects and to the etiology of pathological anxiety.

Amygdala↗
PubMed2000

Conditionally immortal neuroepithelial stem cell grafts reverse age-associated memory impairments in rats.

In order to investigate the effects of stem cell grafts on water maze deficits in aged (22-month-old) rats, three groups of aged rats, assigned by pre-training latency scores to unimpaired, impaired control and impaired grafted groups, were compared with young (five-month-old) controls, six to eight weeks after implantation of cells from the conditionally immortal Maudsley hippocampal stem cell line, clone 36 (MHP36 stem cell line), in the cortex, striatum and hippocampus. Grafted rats were substantially superior to their matched impaired aged controls, and learned to find the platform as rapidly as unimpaired aged rats, although young controls were more efficient than all aged groups in several measures of spatial search during training. On the probe trial, however, aged rats with grafts showed significantly better recall of the precise position of the platform than any other group, including young controls, possibly indicating some perseveration. A further comparison found that groups of unimpaired and moderately impaired aged rats showed far less improvement from water maze pre-training to acquisition phases than young controls, indicative of progressive deficits over time. Histological investigation showed that beta-galactosidase-positive MHP36 cells migrated widely from the implantation sites to infiltrate the striatal matrix, all hippocampal fields and areas of the cortex. Grafted cells showed both astrocytic and neuronal morphologies, with cells of pyramidal and granular appearance in appropriate hippocampal strata.Taken together, these results indicate that neuroepithelial stem cell grafts extensively colonize the aged rat brain and substantially reverse progressive cognitive decline associated with ageing.

Aging↗
PubMed2000

Modulation of latent inhibition in the rat by altered dopamine transmission in the nucleus accumbens at the time of conditioning.

Latent inhibition describes a process by which pre-exposure of a stimulus without consequence retards the learning of subsequent conditioned associations with that stimulus. It is well established that latent inhibition in rats is impaired by increased dopamine function and potentiated by reduced dopamine function. Previous evidence has suggested that these effects are modulated via the meso-accumbens dopamine projections. We have now undertaken three experiments to examine this issue directly, especially in the light of one study in which latent inhibition was reported to be unaffected by direct injection of amphetamine into the accumbens. Latent inhibition was studied using the effect of pre-exposure of a tone stimulus on the subsequent formation of a conditioned emotional response to the tone. 6-Hydroxydopamine-induced lesions of dopamine terminals in the nucleus accumbens resulted in potentiation of latent inhibition. Bilateral local injections of the dopamine antagonist haloperidol into the nucleus accumbens (0.5 microg/side) before conditioning also potentiated latent inhibition. Moreover, such injections were able to reverse the disruptive effect of systemic amphetamine (1mg/kg, i.p.) on latent inhibition. Bilateral local injection of amphetamine (5 microg/side) into the nucleus accumbens before conditioning was able to disrupt latent inhibition, provided that it was preceded by a systemic injection of amphetamine (1mg/kg) 24h earlier.We conclude that the attenuation of latent inhibition by increased dopamine function in the nucleus accumbens is brought about by impulse-dependent release of the neurotransmitter occurring at the time of conditioning. The previously reported failure to disrupt latent inhibition with intra-accumbens amphetamine is probably due to impulse-independent release of dopamine. The implications of these conclusions for theories linking disrupted latent inhibition to the attentional deficits in schizophrenia, and to the dopamine theory of this disorder, are discussed.

Amphetamine↗