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Biomedical subjects

L S Wilkinson

Publications and source records attributed to L S Wilkinson.

At least 19 recordsLinked to original sources
PubMed2005

Increasing the diagnosis of multifocal primary breast cancer by the use of bilateral whole-breast ultrasound.

AIM: The aim of this study was to evaluate the contribution of bilateral whole-breast ultrasound (BBUS) to the diagnosis and management of women with newly diagnosed breast cancer. METHODS: Over a period of 6 months, 102 women presenting with breast cancer underwent BBUS. Data were collected on clinical findings, radiology, histology and surgical outcome. These women were compared with a control group of 124 women presenting over a similar 6-month period 1 year previously, who had undergone targeted breast ultrasound. RESULTS: Multicentric/multifocal tumours were demonstrated in 35 (34%) of the 102 participants and in 18 (15%) of the 124 controls, a statistically significant difference (Fisher's exact test, p = 0.001). Multiple tumours were diagnosed preoperatively in 18% of the study population compared with 8% of the controls, and BBUS identified invasive multifocal/multicentric tumours in significantly more women in the study population (11 versus 1 control) (Fisher's exact test, p = 0.019). Contralateral cancer was diagnosed in 4 women in the study population and none in the control population (Fisher's exact test, p = 0.040). Surgical review showed that the surgical management changed significantly in 8% (95% confidence interval 4 to 14%) of cases in the study population following BBUS. The increase in the number of women undergoing benign biopsies in the study population (10 versus 5 controls) was not statistically significant (Fisher's exact test, p = 0.11). CONCLUSION: BBUS increased the preoperative diagnosis of multiple tumours in women presenting with primary breast cancer, resulting in a management change in 8% of cases.

Adult↗
PubMed2004

Effects of acute and chronic buspirone on impulsive choice and efflux of 5-HT and dopamine in hippocampus, nucleus accumbens and prefrontal cortex.

RATIONALE: Reduced central serotonin (5-HT) activity has been associated with impulsive choice behaviour, but there is no consensus about the precise nature of these effects. Behavioural and neurochemical effects of 5-HT(1A) agonists such as buspirone depend critically on the dose and the duration of treatment. We thus undertook a parametric study of the effects of acute and chronic buspirone on the performance on a test of delayed gratification, as well as on the efflux of serotonin and dopamine (DA) in cortical and subcortical regions in rats. OBJECTIVES: Three experiments examined (i) the effects of acute buspirone on impulsive choice and how such effects were modified by prior chronic exposure to buspirone; (ii) the effects of chronic buspirone on impulsive choice; (iii) the effects on impulsive choice of a selective 5-HT(1A) antagonist, WAY-100635 tested alone and in combination with buspirone; (iv) the effects of chronic and acute buspirone on 5-HT and DA efflux in anaesthetised rats. METHODS: In experiment 1, rats previously trained on the delayed gratification task were tested with acute buspirone (0.5, 1 and 2 mg/kg). The same rats were then treated with chronic buspirone (1 mg/kg/day) over the next 65 days, and the effects of acute buspirone (1 mg/kg) re-determined at 20, 45 and 65 days of chronic treatment. In experiment 2, two groups of rats trained on the delayed gratification task were treated either with saline or buspirone (1 mg/kg/day) continually for 65 days before being tested with acute buspirone (1 mg/kg), WAY-100635 (0.08 mg/kg), or a combination of the two drugs. In experiment 3, rats received the same regimen of buspirone dosing as in experiment 2, before receiving in-vivo microdialysis for 5-HT and DA in the ventral hippocampus, nucleus accumbens and medial prefrontal cortex. RESULTS: Acute buspirone dose dependently increased the choice for the small, immediate reinforcer (impulsive choice) but the effects of 1 mg/kg were reversed on chronic administration of buspirone. This increased choice of the large, delayed reinforcer, which was not accompanied by any changes in baseline (non-drugged) performance, was blocked by the 5-HT(1A) receptor antagonist WAY-100635. The chronic buspirone regimen did not alter buspirone-evoked reductions in 5-HT efflux in hippocampus but did lead to a differential effect of acute buspirone in medial prefrontal cortex, with the chronic buspirone and saline groups exhibiting decreases and increases in efflux, respectively. There were no systematic changes in DA efflux under any condition. CONCLUSIONS: These findings show that the effects of acute buspirone on impulsive choice are reversed following chronic treatment and are mediated by 5-HT(1A) receptors, and suggest, in addition, that the behavioural effects may involve changes in 5-HT functioning in medial prefrontal cortex.

Analysis of Variance↗
PubMed2001

Learning, remembering and applying an arbitrary non-matching to position rule in mice.

We describe maze-based behavioural methodologies to assay aspects of arbitrary rule learning in mice. The methods allow for rapid acquisition of a non-matching to position (NMTP) rule that is relatively uninfluenced by innate behavioural strategies, and which give rise to stable baseline performance. Use of the NMTP rule under baseline conditions did not appear to be influenced by extra-maze cues nor intra-maze cues based on olfactory information. Hence the information used to guide performance at test was probably a visual and/or a kinaesthetic representation of the sample. Whatever the precise nature of the trace, its availability to guide behaviour was degraded by introducing delays between sample and test run components of the task. The characteristics of the so-called "forgetting curve" produced did not seem to be influenced by mediating strategies, whereby performance could be maintained following a delay by use of persistent olfactory cues or rehearsal of the correct response using body position, suggesting that, to some degree the degraded performance following delays was indexing effects on short term memory processes. We then went on to obtain behavioural indices that may be of use in dissociating, within-subjects, between learning the basic NMTP rule and being able to apply it in a choice situation, using single and simultaneous discrimination conditions, respectively. The data are discussed in terms of the utility of the behavioural methods to assay different psychological functions underlying the ability to learn, remember and apply non-matching to position rules in mice and their particular use in examining age-related deficits in cognitive functioning.

Animals↗
PubMed2001

Mice with very low expression of the vesicular monoamine transporter 2 gene survive into adulthood: potential mouse model for parkinsonism.

We have created a transgenic mouse with a hypomorphic allele of the vesicular monoamine transporter 2 (Vmat2) gene by gene targeting. These mice (KA1) have profound changes in monoamine metabolism and function and survive into adulthood. Specifically, these animals express very low levels of VMAT2, an endogenous protein which sequesters monoamines intracellularly into vesicles, a process that, in addition to being important in normal transmission, may also act to keep intracellular levels of the monoamine neurotransmitters below potentially toxic thresholds. Homozygous mice show large reductions in brain tissue monoamines, motor impairments, enhanced sensitivity to dopamine agonism, and changes in the chemical neuroanatomy of the striatum that are consistent with alterations in the balance of the striatonigral (direct) and striatopallidal (indirect) pathways. The VMAT2-deficient KA1 mice are also more vulnerable to the neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in terms of nigral dopamine cell death. We suggest that the mice may be of value in examining, long term, the insidious damaging consequences of abnormal intracellular handling of monoamines. On the basis of our current findings, the mice are likely to prove of immediate interest to aspects of the symptomatology of parkinsonism. They may also, however, be of use in probing other aspects of monoaminergic function and dysfunction in the brain, the latter making important contributions to the pathogenesis of schizophrenia and addiction.

Animals↗
PubMed2001

Imprinted genes and mental dysfunction.

There is a rapidly accumulating body of evidence from family, adoption and twin studies suggestive of a genetic component to many common mental disorders. In some cases, the transmission of abnormalities has been shown to be dependent upon the sex of the parent from whom they are inherited. Such 'parent-of-origin effects' may be explained by a number of genetic mechanisms, one of which is 'genomic imprinting'. In imprinted genes one allele is silenced according to its parental origin. This in turn means that imprinted traits are passed down the maternal or paternal line, in contrast to the more frequent Mendelian mode of inheritance that is indifferent to the parental origin of the allele. In the present review, we survey the evidence for the influence of imprinted genes on a number of mental disorders, ranging from explicit imprinted conditions, where in some cases abnormalities have been mapped to particular gene candidates, to examples where the evidence for parent-of-origin effects is less strong. We also consider, briefly, the wider implications of imprinted effects on mental dysfunction, in particular with respect to evolutionary pressures on mammalian brain development and function.

Angelman Syndrome↗
PubMed2000

The effect of dopamine depletion from the caudate nucleus of the common marmoset (Callithrix jacchus) on tests of prefrontal cognitive function.

This study examined the effects of depletion of dopamine from the caudate nucleus of the common marmoset (Callithrix jacchus), on tasks sensitive to prefrontal damage (attentional set-shifting and spatial delayed response). There was a marked impairment in performance on the spatial delayed response task, but performance on the attentional set-shifting task was relatively preserved except for an impairment in re-engagement of a previously relevant perceptual dimension. This pattern of impairment is distinct from that seen after excitotoxic lesions of the prefrontal cortex and in patients with Parkinson's disease. Though it is not possible to identify specific cognitive functions that are independent of dopaminergic modulation of the caudate nucleus, due to the partial nature of the lesion, the results do provide insight into those cognitive processes that appear most dependent on caudate dopamine.

Animals↗
PubMed1999

Maternal deprivation of neonatal rats produces enduring changes in dopamine function.

Isolation-rearing of weanling rats produces a syndrome of behavioral and neurochemical effects that are indicative of enhanced ventrostriatal dopamine function observed in adulthood. By contrast, maternal deprivation of neonatal rats decreases behavioral responses to dopamine agonists when tested in adults, which may indicate the opposite situation. However, in the present study it is reported that in vivo microdialysis of the nucleus accumbens (NAC) revealed enhanced release of dopamine (DA) in response to both d-amphetamine and high K+ perfusate in maternally deprived subjects. Thus, behavioral responses to d-amphetamine are diminished in maternally deprived rats despite apparent increases in presynaptic dopaminergic function in the NAC.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1999

Forebrain serotonin depletion facilitates the acquisition and performance of a conditional visual discrimination task in rats.

Three experiments examined the effects of depleting forebrain 5-hydroxytryptamine (5-HT) on the acquisition and performance of an operant conditional discrimination in the visual modality. In the first experiment, rats with 5-HT lesions induced by infusing the neurotoxin 5,7-dihydroxytryptamine intracerebroventricularly acquired the conditional visual discrimination more rapidly than the sham-operated controls. Following acquisition, a series of manipulations of the task parameters tested the effects of the lesion on cognitive, sensory and motivational aspects of performance. In experiment two, the performance of rats that had acquired the task to asymptote before receiving lesions was assessed. The performance of this second group of serotonin-lesioned rats was similar to that of the pre-acquisition lesioned group following all but one manipulation of the task parameters. When the rate of stimulus presentations was increased, rats with forebrain 5-HT depletions were protected from the disruptive effects on performance seen in the sham-operated controls. This latter finding was also observed in a third experiment, in which the infusion of the 5-HT1A receptor partial agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT), directly into the dorsal raphe nucleus improved the performance of unlesioned rats following an increase in the rate of stimulus presentations. The results are discussed in terms of the behavioural, neurochemical and neuroanatomical specificity of serotonin function in appetitive learning and the implications for general theories of the function of serotoninergic processes in cognition.

Animals↗
PubMed1999

Visuospatial attentional functioning in mice: interactions between cholinergic manipulations and genotype.

Attentional functioning in mice was assessed in an analogue of the five-choice serial reaction time task in which the requirement was to detect brief visual stimuli presented across five spatial locations. Two hybrid strains of mice were assessed; F1 C57Bl/6xDBA/2 and C57Bl/6x129sv. Both strains acquired the task to high levels of performance with, in particular, no problems due to premature responding. At performance, systematic manipulation of the task parameters indicated a pattern of effects consistent with the task, taxing aspects of visuospatial attention. There were some differential effects of task manipulations at baseline across strain. However, the pattern of effects suggested these were likely to be the result of effects on factors other than attentional functioning per se, such as behavioural reactivity and inhibition. There was evidence in both strains of specific, centrally mediated effects of scopolamine on attentional functioning, with the C57Bl/6xDBA/2 hybrid showing greater sensitivity to the drug manipulation. Specific effects on discriminative accuracy were observed at doses of 0.02 and 0.2 mg/kg scopolamine. At the 2 mg/kg dose, large reductions in accuracy were associated with large effects on other measures, including omissions and response latencies, suggestive of nonspecific effects on task performance. These data indicate, for the first time, the utility of operant methods in assessing visuospatial attentional functioning in mice. They confirm the importance of cholinergic mechanisms in attentional processes across species, and suggest interactions between cholinergic mechanisms and genotype in the expression of attentional phenotypes.

Animals↗
PubMed1998

Isolation rearing in rats: pre- and postsynaptic changes in striatal dopaminergic systems.

Isolation rearing of rats produces a behavioral syndrome indicative of altered dopamine (DA) function in the nucleus accumbens (NAC). The present experiments extend these findings by investigating: (a) interactions between isolation rearing and repeated handling/testing on presynaptic DA function in the NAC using in vivo microdialysis: (b) the dose-response curve for the effects of d-amphetamine, and the responses elicited by high potassium, using in vivo microdialysis, and (c) postsynaptic function in isolates as indexed by DA receptor-linked cAMP production. Experiment 1 showed that both isolation rearing and repeated handling/testing had effects on monoamine function in the NAC. However, while both manipulations enhanced DA release evoked by d-amphetamine, only isolated rats had elevated basal DA levels. Opposite neurochemical changes were observed with respect to the serotonin metabolite 5-HIAA, isolates having lower, and repeatedly handled/tested animals having higher, extracellular levels. Experiment 2 provided evidence for enhanced d-amphetamine-evoked DA release in isolated animals, while potassium-evoked DA release was reduced. Experiment 3 provided evidence that the isolation rearing induced changes in presynaptic DA function were accompanied by postsynaptic changes. Specifically, the inhibitory influence of the D2 receptor on D1 receptor-stimulated cAMP production was attenuated in ventral striatal slices taken from isolates, suggesting a functional downregulation of D2 receptors.

Animals↗
PubMed1998

Dissociations in dopamine release in medial prefrontal cortex and ventral striatum during the acquisition and extinction of classical aversive conditioning in the rat.

Dual perfusion in vivo brain microdialysis was used to monitor extracellular levels of dopamine in the medial prefrontal cortex and ventral striatum during the acquisition and extinction of a classical aversive conditioning paradigm in rats. The main finding was a dissociation in the pattern of release in the two brain areas. The first stimulus-footshock pairing elicited large increases in cortical dopamine over baseline levels that were much greater than the increases elicited by different stimuli of equivalent salience that were unpaired with footshock. In contrast, dopamine levels in ventral striatum were unchanged under these conditions. Over the next two pairings, there was a decline in the cortical response and an increase in the response in ventral striatum. The first presentation of the aversive conditioned stimulus in a separate context elicited the largest response in ventral striatum. Post-conditioning, the cortical response to the conditioned stimulus was smaller than that elicited by the initial stimulus-footshock pairing and was equivalent in magnitude to that elicited by stimuli unpaired with footshock. Over the final two conditioned stimuli presentations, in the absence of the footshock reinforcer (extinction), responses declined in both brain areas. Simultaneous monitoring of behaviour indicated that the neurochemical events were accompanied by effective aversive learning, as indexed by conditioned freezing responses. The data are discussed in terms of the hypothesis that medial prefrontal cortex is especially engaged during novel circumstances which may, potentially, require new learning, whilst ventral striatal dopamine more closely follows the expression of conditioned responding during learning and extinction.

Animals↗
PubMed1997

Defining the use of gadolinium enhanced MRI in the assessment of the postoperative lumbar spine.

A retrospective study of case notes and magnetic resonance imaging (MRI) examinations was performed to assess the value of gadolinium enhanced MRI in the investigation of persistent back pain following lumbar spine surgery in patients who have not had a discectomy for disc herniation. Gadolinium enhancement is commonly used during MRI of patients with persistent back pain following surgery and epidural scar is frequently identified in patients who have had a previous discectomy. However the value of gadolinium enhancement in patients without previous discectomy had not been addressed. One hundred sets of case notes were examined and 24 patients with an accurate history of previous lumbar spine surgery without discectomy were identified. The nature of surgery and the MRI findings were correlated in these patients. Epidural enhancement was identified at seven sites in six patients (engorged epidural venous plexus, three; enhancement adjacent to degenerate discs, two; enhancement adjacent to facets, two). In no case was epidural scarring involving nerve roots identified. We conclude that routine gadolinium enhancement is unnecessary in patients without a history of discectomy for disc herniation.

Aged↗
PubMed1997

The effects of isolation-rearing of rats on behavioural responses to food and environmental novelty.

Isolation-reared rats exhibited enhanced behavioural responses to novelty, but only some aspects of such behavior was affected. In Experiment 1, environmental neophobia was enhanced but food neophobia was diminished in isolation-reared rats compared to socially reared rats. However, in Experiment 2, when subjects were not handled extensively prior to testing, no differences in behavioural responses to environmental or food novelty in an open-field were observed between rearing groups. The difference between these experiments was hypothesized to be the result of ceiling effects produced by increased anxiety or arousal in experiment 2 in which the animals had not been extensively handled. In summary, in these experiments anticipatory responses to novelty were alterred by isolation-rearing but the behavioural expression of this increased sensitivity was determined by intrinsic aversive/rewarding or arousing qualities of novel environments and novel foods.

Animals↗
PubMed1997

The effects of isolation-rearing on sucrose consumption in rats.

Three experiments examined the hypothesis that social isolation of weanling rats potentiates hedonic processes by examining the consumption of sucrose solutions. In the first experiment no differences in consumption were found between socially reared rats and isolation-reared rats allowed to consume sucrose in a familiar test apparatus. In a second experiment socially-reared rats and isolation-reared rats were food and water deprived. Again, no differences in consumption were found. In a third experiment socially reared and isolation-reared rats were allowed to consume sucrose presented in either an ascending or descending order of concentration. When given sucrose in an ascending order of presentation isolation-reared rats consumed significantly more sucrose than socially reared rats. This suggests that isolation-rearing increased the effects of positive contrast, and is consistent with other observations of increased incentive motivation in isolates.

Animals↗
PubMed1997

The effects of isolation-rearing on preference by rats for a novel environment.

In the previous paper isolation-reared rats exhibited enhanced environmental neophobia under some conditions in an open-field. However, previous work has shown that isolation-reared rats have greater preferences for a novel environment in a dimly lit enclosed box. The hypothesis examined in the present experiments was that manipulation of the intrinsic aversive qualities of such an environment, by altering lighting conditions, could reverse the preference which isolation-reared rats exhibit for a novel chamber. When preference for a novel chamber was examined in a non-aversive environment in Experiment 1, isolation-reared rats exhibited a preference for a novel environment which was enhanced compared to social controls. When tested under more aversive white light conditions in Experiment 2, no differences in novelty preference were observed between isolation-reared and socially reared rats. Thus, the increased sensitivity to novel environments by isolation-reared rats appears to be critically dependent on the arousing or aversive properties of the testing conditions.

Animals↗
PubMed1997

Contrasting effects of excitotoxic lesions of the prefrontal cortex on the behavioural response to D-amphetamine and presynaptic and postsynaptic measures of striatal dopamine function in monkeys.

The effects of excitotoxic lesions of the prefrontal cortex on behavioural, neurochemical and molecular indices of dopamine function in the caudate nucleus were studied in the marmoset. The lesion, which encompassed both the lateral and orbital regions of prefrontal cortex, made the animals more sensitive to the performance disrupting effects of the dopamine releasing drug, D-amphetamine, in a variation of the object retrieval task. Specifically, following drug administration, the lesioned marmosets were less able to gain access to food reward in the minimum number of responses. Analysis of the nature of the errors suggested that the deficit was not due to inhibition of a prepotent response as the lesioned monkeys were just as likely to make a detour reach to the unopened side of the box as a direct "line-of-sight" reach into the unopened front of the box. Rather, the data indicated a general disorganization of behaviour. The enhanced behavioural responsiveness to manipulations increasing presynaptic dopamine function was accompanied by neurochemical changes indicating a reduced responsiveness, as revealed by in vivo microdialysis. Thus, in lesioned animals, whilst there were no effects on baseline levels of extracellular dopamine in dorsolateral caudate, evoked release, both to systemic D-amphetamine and to a local depolarizing pulse of potassium ions, was attenuated. These opposite effects of the prefrontal cortex lesion on behavioural and neurochemical indices of striatal dopamine function occurred in the absence of any changes in striatal dopamine receptors of the D1 and D2 subtype, as determined both by radioligand binding assays and measurements of messenger RNA using in situ hydridization techniques. These data provide further insight into the interactions between prefrontal cortex and striatal dopamine function in the non-human primate. In particular, when taken in the light of our previous studies they indicate that following prefrontal manipulations, concurrence between behavioural and neurochemical indices of striatal dopamine function depends, critically, on the behavioural task. These findings are discussed with respect to the growing body of evidence implicating abnormalities in frontostriatal neurotransmission in complex disorders such as schizophrenia.

Analysis of Variance↗
PubMed1997

The nature of interactions involving prefrontal and striatal dopamine systems.

A number of converging lines of evidence from work in rodents suggest that dopamine (DA) function in the prefrontal cortex (PFC) and striatal terminal fields may be linked, possibly in an 'inverse' manner, whereby a change in prefrontal dopamine transmission in one direction occasions an opposite change in dopamine function in striatal territories. The present article considers the possible functional importance of this concept in the light of recent neuroanatomical data and new data from our own laboratory indicating that, at the neurochemical level, the basic finding of an inverse relationship between dopamine function in prefrontal and striatal regions also holds good in the non-human primate. The main conclusion is that the simple idea of an inverse relationship between prefrontal and striatal dopamine systems emphasizing presynaptic release mechanisms is unlikely to underlie, solely, the full repertoire of functional interactions. Whilst there is evidence consistent with dynamic interactions between prefrontal and striatal dopamine release under some circumstances, specifically, during the early phases of aversive learning, a complete account of possible interactions between prefrontal and striatal dopamine systems requires consideration of additional factors. Such factors include: (1) the precise nature of the psychological function investigated, (2) the possibility of acute, localized changes in striatal postsynaptic function secondary to changes in presynaptic function and (3) the possibility of manipulations of prefrontal cortex leading to adaptive changes in striatal function, at a diffuse, neural systems level.

Animals↗