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Biomedical subjects

D J Williamson

Publications and source records attributed to D J Williamson.

At least 37 records · Page 2Linked to original sources
PubMed1998

Object and action naming in Alzheimer's disease.

We administered measures of object naming and action naming to matched groups of ten patients with Alzheimer's disease (AD) and ten normal control subjects. AD patients were impaired in both object and action naming, with object naming impaired to a significantly greater extent than action naming. This difference remained after controlling for the effects of word frequency. We propose that the pattern of pathological changes in AD impairs both conceptual and lexical retrieval systems for objects but only conceptual systems for actions. The similar patterns of error during the two tasks suggest quantitative rather than qualitative differences in the breakdown of the two abilities.

Aged↗
PubMed1998

Dissociation of sensory-attentional from motor-intentional neglect.

OBJECTIVES: Spatial neglect may result from disruption of sensory-attentional systems that spatially allocate perceptual resources and the motor-intentional systems that direct exploration and action. Previous studies have suggested that the line bisection task is more sensitive to sensory-attentional disorders and the cancellation task to motor-intentional disorders. A new technique was developed that allows the dissociation of sensory-attentional and motor-intentional deficits in both tasks and thereby allows comparison of these tasks. METHODS: Ten patients with right hemispheric injury and hemispatial neglect performed line bisection and cancellation tasks while viewing stimuli on closed circuit TV. Direct view of the exploring hand and the target was precluded; the TV monitor guided performance. The direct condition made the direction of hand movement on the table (workspace) congruent with that on the monitor. Inverting the camera produced the indirect condition wherein the lateral movement in the workspace occurred in the opposite direction on the monitor. RESULTS: On the cancellation task, five patients marked targets in the right workspace in the direct condition but the left workspace in the indirect condition, indicating sensory-attentional neglect. However, four other patients cancelled targets only in the right workspace in both conditions, failing to explore the left workspace, suggesting motor-intentional neglect. A patient who performed ambiguously may have elements of both types of neglect. Only two out of five patients designated as sensory-attentional in cancellation tasks showed sensory neglect on line bisection. The other three patients, as well as patients defined as motor-intentional by cancellation performance, exhibited motor-intentional neglect on line bisection. CONCLUSION: The designation of sensory-attentional versus motor-intentional neglect therefore, in part, depends on task specific demands.

Adult↗
PubMed1998

Brain 5-HT neurotransmission during paroxetine treatment.

BACKGROUND: Animal experimental studies suggest that repeated administration of selective serotonin reuptake inhibitors (SSRIs) produces complex adaptive changes in brain serotonin (5-HT) pathways. The effect of these adaptive changes on different aspects of brain 5-HT neurotransmission and their clinical consequences are not well understood. METHOD: We studied the effect of repeated administration of the SSRI, paroxetine (20 mg daily), on the cortisol responses to the 5-HT precursor, 5-hydroxytryptophan (5-HTP), in healthy subjects and depressed patients. RESULTS: In healthy subjects, following one week of paroxetine treatment there was a large increase in the cortisol response to 5-HTP. This increase had all but disappeared following 3 weeks treatment. In contrast, in depressed patients treated with paroxetine for 8 weeks, the cortisol response to 5-HTP was significantly increased. CONCLUSIONS: SSRI treatment in depressed patients produces a persistent increase in the cortisol response to 5-HTP, a probable measure of neurotransmission at central 5-HT2 receptors. Potentiation of 5-HT2 neurotransmission is unlikely to account for the efficacy of SSRIs in major depression but might underlie their actions in obsessive-compulsive disorder and also perhaps certain of their adverse effects, notably sexual dysfunction.

Adult↗
PubMed1998

Functional imaging: heterogeneity in task strategy and functional anatomy and the case for individual analysis.

To learn more about the functional anatomy of language, the authors used [99mTc]HMPAO single photon emission computed tomography (SPECT) functional imaging to study nonword rhyming, lexical-semantics and syntax. The authors did not find any task-related differences in cerebral blood flow using region-by-region analysis of variance. This led them to examine individual subject's task-related patterns of cerebral blood flow. This analysis revealed regions of interest with little or no change but also regions with changes as great as 30%. There was marked subject-to-subject variability in the pattern of blood flow, which precluded statistically significant results using analysis of variance. An alternative analytic strategy based on numbers of subjects exceeding a minimum threshold task-related change in cerebral blood flow was tested and shows promise in identifying commonalities and differences in individual task-related blood flow patterns. The authors conclude that the complex and difficult to interpret pattern of blood flow changes observed in this study reflect in considerable part the combined effects of variability in task strategy, owing in part to insufficiently constrained task performance, and variability in functional anatomy. The authors also tested the differences in results achieved with simple normalization and analysis of covariance approaches and found them to be insignificant.

Adult↗
PubMed1997

Developmentally-regulated expression of murine K-ras isoforms.

The products (p21) of the three mammalian H-, N- and K-ras genes play important roles in intracellular signal transduction, linking membrane receptor kinases to the nuclear pathway through raf and mitogen activated protein kinase. They are involved in the regulation of proliferation and differentiation, and activating mutations of these genes are commonly associated with human cancers. Two p21 proteins are encoded by the K-ras gene (p21K-rasA and p21K-rasB) due to alternative splicing of the last exon. While the four p21ras proteins are highly homologous, their sequences diverge significantly at the C-termini, to which distinct biochemical and perhaps even functional differences may be ascribed. However, H-, N- and K-rasB appear to be ubiquitously expressed, with little evidence of tissue-specific or developmental regulation. In contrast, we now demonstrate that the expression of K-rasA is strikingly different. K-rasA is induced during differentiation of pluripotent embryonal stem cells in vitro. Its expression during early embryogenesis is limited temporally and spatially in a tissue-specific distribution which is largely maintained as an adult. This suggests a distinct biological role for p21K-rasA.

Alternative Splicing↗
PubMed1997

The novel anti-migraine agent rizatriptan inhibits neurogenic dural vasodilation and extravasation.

These studies in anaesthetised rats showed, using intravital microscopy, that the novel anti-migraine agent, rizatriptan, significantly reduced electrically stimulated dural vasodilation but had no effect on increases in dural vessel diameter produced by exogenous substance P or calcitonin gene-related peptide (CGRP). Rizatriptan also significantly inhibited dural plasma protein extravasation produced by high intensity electrical stimulation of the trigeminal ganglion. We suggest that rizatriptan inhibits the release of sensory neuropeptides from perivascular trigeminal nerves to prevent neurogenic vasodilation and extravasation in the dura mater. These prejunctional inhibitory effects may be involved in the anti-migraine action of rizatriptan.

Analysis of Variance↗
PubMed1997

Effect of paroxetine and nefazodone on 5-HT1A receptor sensitivity.

Animal experimental studies suggest that the therapeutic effect of selective serotonin re-uptake inhibitors (SSRIs) may involve neuroadaptive changes in pre- and post-synaptic serotonin1A (5-HT1A) receptors. We used the endocrine and hypothermic responses to the 5-HT1A receptor agonist, gepirone (20 mg orally), to assess 5-HT1A receptor sensitivity in 37 healthy male volunteers who were studied before and following random double-blind, allocation to treatment with paroxetine, nefazodone or placebo for 17 days. Following antidepressant drug treatment, hypothermic responses to gepirone were markedly decreased by paroxetine but only slightly diminished by nefazodone. Paroxetine also lowered the growth hormone and cortisol responses to gepirone. There was no change in either hypothermic or endocrine response following placebo treatment. Our results suggest that paroxetine treatment produces a striking attenuation of measures of both pre- and post-synaptic 5-HT1A receptor function. Nefazodone appears to decrease the sensitivity of 5-HT1A autoreceptors to some extent and this effect may contribute to its antidepressant activity.

Adult↗
PubMed1997

Tapping, talking and the thalamus: possible influence of the intralaminar nuclei on basal ganglia function.

A patient with a discrete lesion of the left, intralaminar thalamic, nuclei exhibited a paradoxical finding with regard to finger-tapping. Normal subjects typically reduce their tapping rate when performing simultaneous verbal activity. Tapping was impaired in our patient's contralesional hand on baseline trials; however, performing the controlled oral word association (COWA) task, while finger-tapping, normalized her deficit. Subsequent experiments showed that motoric tasks rather than cognitive aspects of the COWA task were critical in potentiating finger-tapping performance. A SPECT study performed at rest revealed focal perfusion asymmetries in motor and premotor cortices. Because the caudal intralaminar nuclei project heavily to the striatum, striatal deafferentiation may account for these asymmetries. These observations provide some insight into the influences of the caudal intralaminar thalamic nuclei on basal ganglia function and the basal ganglia's influence on motor gating.

Adult↗
PubMed1997

Characterization of the P2 receptors in rabbit pulmonary artery.

1. We have identified the P2 receptors mediating vasomotor responses in the rabbit pulmonary artery. 2. Neither ATP nor UTP contracted intact or endothelium-denuded rings. However, both relaxed intact rings of rabbit pulmonary artery that had been preconstricted with phenylephrine (pD2 5.2 and 5.6, respectively). 3. The vasodilator effect of UTP was endothelium-dependent and abolished by the nitric oxide synthase inhibitor NG-nitro-L-arginine (L-NOARG). 4. The vasodilator effect of ATP was only partially inhibited by removal of endothelium or addition of L-NOARG, suggesting an additional direct effect on vascular smooth muscle. 5. The endothelium-dependent vasodilator responses to UTP and ATP were competitively antagonized by suramin. 6. Preconstricted, endothelium-denuded rings were also relaxed by 2-methylthio ATP (pD2 6.6), a P2Y receptor agonist. 7. Ca(2+)-mobilizing P2U receptors were identified on smooth muscle cells on the basis of single cell responses to ATP (pD2 7.8) and UTP (pD2 7.9; 6.7 in the presence of 100 microM suramin). 8. There was no evidence of a Ca(2+)-mobilizing P2Y receptor in these cultured cells. 9. The data suggest the presence of (i) a suramin-sensitive P2U receptor on endothelial cells that induces vasorelaxation through NO release, (ii) a suramin-sensitive P2U receptor on cultured smooth muscle cells that mobilizes Ca2+ but is not coupled to vasomotor responses and (iii) a putative P2Y receptor on vascular smooth muscle cells that induces relaxation via a Ca(2+)-independent signal transduction pathway.

Adenosine Triphosphate↗
PubMed1997

Intravital microscope studies on the effects of neurokinin agonists and calcitonin gene-related peptide on dural vessel diameter in the anaesthetized rat.

This study describes a novel intravital microscope technique for direct measurement of dural blood vessel diameter through a closed cranial window in anaesthetized rats. This technique avoids removal of the skull, which can lead to problems of altered vessel reactivity and brain swelling that are encountered with open cranial window techniques. Substance P and calcitonin gene-related (CGRP) evoked increases in dural vessel diameter, which were abolished by the NK1 receptor antagonist, RP67580 and the CGRP receptor antagonist, human-alpha CGRP(8-37) respectively. Neurokinin A produced increases in dural vessel diameter which were unaffected by the NK2 receptor antagonist SR 48968 but were blocked by RP67580, suggesting that neurokinin A can act through NK1 receptors to produce dural vasodilation in rats. The NK3 receptor agonist, senktide, had no effects on dural vessel diameter. All drugs were administered intravenously. In humans, vasodilation within the meningeal vasculature has been implicated in the pathogenesis of migraine, the present experiments indicate that substance P or neurokinin A (both acting through NK1 receptors) or CGRP may be responsible.

Anesthetics↗
PubMed1997

Sumatriptan inhibits neurogenic vasodilation of dural blood vessels in the anaesthetized rat--intravital microscope studies.

This study used intravital microscopy to measure the diameter of dural arteries in anaesthetized rats. Electrical stimulation of the surface of a closed cranial window produced increases in dural vessel diameter which were blocked by the CGRP receptor antagonist human-alpha CGRP(8-37) but unaffected by the NK1 receptor antagonist RP67580. Sumatriptan (3 and 10 mg kg-1, i.v.) significantly reduced the response to electrical stimulation. In contrast, sumatriptan (3 mg kg-1) had no effects on the response to exogenously administered CGRP. These results indicate that neurokinins play no role in neurogenic vasodilation in this preparation and that neurogenic vasodilation in rat dural vessels is mediated predominantly by CGRP. Furthermore, the data indicate that sumatriptan attenuates neurogenic vasodilation, probably by inhibiting the release of CGRP from perivascular trigeminal nerve endings innervating the dura. These experimental data parallel the clinical findings that CGRP levels are elevated in migraine and normalized, concomitantly with headache relief, by sumatriptan.

Afferent Pathways↗
PubMed1997

Spatial bias: attentional and intentional influence in normal subjects.

Normal subjects often demonstrate a spatial bias on line bisection (LB) and cancellation (CA) tasks. We wanted to learn if horizontal spatial bias found in normal subjects may be dissociable into sensory-attentional (ATT) and motor-intentional (INT) subgroups similar to those described in brain-injured patients with spatial neglect. We studied the influence of ATT and INT factors on the spatial bias observed in normal subjects using a new technique that uncouples the direction of action from the direction of attention. This technique also allowed us to test both LB and CA tasks on the same individuals. Our results show that ATT bias significantly influenced performance on an LB task, whereas performance on a CA task was influenced by biases in both the ATT and INT systems. In addition, the overall bias on these two tasks reflects an interaction between the biases induced by the ATT and INT systems that may be in the same or different directions.

Adult↗
PubMed1997

Resting and stimulated states in functional imaging studies: evidence of differences in attentional and intentional set.

In a [99mTc]-hexamethylpropyleneamine oxime single photon emission computed tomography study of cerebral blood flow (CBF) in a visual activation paradigm (awake, eyes closed versus eyes open viewing a reversing checkerboard pattern), the authors systematically measured previously observed qualitative alterations in frontal blood flow associated with visual stimulation (experiment 1). They confirmed a trend toward reductions in CBF throughout precentral cortex that approached significance in areas 9 and 46, in conjunction with significant increases in CBF in postcentral cortices, including visual association area PO, and areas 3-1-2, 22, and 23. The authors posited that these changes may be related to differences in attentional and intentional state in the eyes-closed and eyes-open conditions. Such differences should be associated with alterations in motor preparedness, leading to changes in response times and to alterations in thalamocortical gating of somatosensory information, which in turn lead to changes in somatosensory-evoked potential amplitudes. In experiment 2, the authors measured simple motor response times to a 1500-Hz tone stimulus and early components of somatosensory-evoked potentials under the same experimental conditions. In the visual stimulation condition, there was a significant increase in the evoked potential amplitude (t = 2.686, p = 0.021), and a significant decrease in response time (t = -2.464, p = 0.031). These observations provided tentative support for their hypothesis. The authors also demonstrated the major effect of normalization assumptions on regional blood flow measurements.

Adolescent↗
PubMed1996

L-733,060, a novel tachykinin NK1 receptor antagonist; effects in [Ca2+]i mobilisation, cardiovascular and dural extravasation assays.

This study investigated the properties of a novel piperidine ether-based tachykinin NK1 receptor antagonist L-733,060, ((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenyl piperidine and its 2R,3R-enantiomer L-733,061 on [Ca2+]i mobilisation in Chinese hamster ovary cells transfected with human tachykinin NK1 receptors, compared to their effects in rodent cardiovascular and neurogenic plasma extravasation assays. Using FURA-2-imaging techniques, L-733,060 inhibited substance P-induced [Ca2+]i mobilisation with an estimated affinity of 0.8 nM whereas L-733,061 (30-300 nM) did not. No significant effects of L-733,060 were observed on mean arterial blood pressure or heart rate in conscious or anaesthetised rats at doses of < 3000 micrograms kg-1 i.v. L-733,060 also stereoselectively inhibited neurogenic plasma extravasation in rat dura produced by electrical stimulation of trigeminal nerves with an ID50 of 212 +/- 19 micrograms kg-1 i.v. Thus, L-733,060 is a novel antagonist of human tachykinin NK1 receptors which stereoselectively inhibits neurogenic plasma extravasation at doses that do not cause adverse cardiovascular effects.

Animals↗
PubMed1996

Acute hemodynamic responses to inhaled nitric oxide in patients with limited scleroderma and isolated pulmonary hypertension.

BACKGROUND: Inhaled nitric oxide (NO) is a selective pulmonary vasodilator that reduces pulmonary vascular resistance (PVR) in patients with primary pulmonary hypertension. Their responses to inhaled NO predict their responses to other vasodilators, such as prostacyclin, and provide an estimate of the "fixed" component of their increased PVR. Some patients with limited cutaneous systemic sclerosis develop isolated pulmonary hypertension with a similar clinical course. Therefore, we have measured the acute hemodynamic response to inhaled NO in such patients. METHODS AND RESULTS: Seven patients were studied during inhalation of increasing concentrations of NO (0 to 80 ppm). Complete hemodynamic data were collected on five patients. They demonstrated a selective, dose-dependent, and rapidly reversible fall in PVR (34%) and mean pulmonary artery pressure (17%). There was a nonsignificant increase in cardiac index but no change in mean arterial pressure or systemic vascular resistance. The mean right atrial pressure fell (27%), but there was no change in pulmonary artery occlusion pressure. Of the seven patients, five responded to inhaled NO ( < or = 40 ppm) with a decrease in total pulmonary resistance of at least 20%. CONCLUSIONS: Inhaled NO is an effective and selective pulmonary vasodilator in a significant number of patients with pulmonary hypertension associated with limited cutaneous systemic sclerosis. It may be useful in determining the potentially reversible contribution to the increased PVR and should be considered for patients with acute pulmonary vascular crisis.

Administration, Inhalation↗
PubMed1996

The effects of paroxetine and nefazodone on sleep: a placebo controlled trial.

We studied the effect of acute (1 day) and subacute (16 days) administration of the new antidepressant, nefazodone (400 mg daily), and the selective serotonin re-uptake inhibitor (SSRI), paroxetine (30 mg daily), on the sleep polysomnogram of 37 healthy volunteers using a random allocation, double-blind, placebo-controlled design. Compared to placebo, paroxetine lowered rapid eye movement (REM) sleep and increased REM latency. In addition, paroxetine increased awakenings and reduced Actual Sleep Time and Sleep Efficiency. In contrast, nefazodone did not alter REM sleep and had little effect on measures of sleep continuity. We conclude that in contrast to typical SSRIs, nefazodone administration has little effect on sleep architecture in healthy volunteers.

Adolescent↗
PubMed1996

5-HT neuroendocrine function in major depression: prolactin and cortisol responses to D-fenfluramine.

We studied the prolactin and cortisol responses to the 5-HT releasing agent, D-fenfluramine in 31 drug-free depressed patients and 29 healthy controls, using a double-blind, placebo-controlled design. There was no difference in either endocrine response between depressives and controls. Examining the sexes separately, or restricting comparisons to patients with melancholic depression, did not lead to any differences between the groups. Our findings suggest that in contrast to other 5-HT neuroendocrine probes such as L-tryptophan and clomipramine, the prolactin response to fenfluramine are not consistently blunted in depressed patients.

Adult↗