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Biomedical subjects

J Pratt

Publications and source records attributed to J Pratt.

At least 19 recordsLinked to original sources
PubMed2004

Methyl-beta-D-glucopyranoside in higher plants: accumulation and intracellular localization in Geum montanum L. leaves and in model systems studied by 13C nuclear magnetic resonance.

Using (13)C-NMR, methyl-beta-D-glucopyranoside (MeG) was characterized as a major compound in the leaves of the alpine herb Geum montanum L. MeG continuously accumulated during the life span of G. montanum leaves, and accounted for up to 20% of the soluble carbohydrates in aged overwintering leaves, without being reallocated during senescence. Incubating intact plant tissues, culture cells, and purified organelles with (13)C-labelled substrates showed that MeG was synthesized in the cytosol of cells, directly from glucose and methanol molecules. There was no contribution of the C-1 pathway. MeG was subsequently stored in the vacuole without being re-exported to the cytoplasm. All the dicots tested contained the enzymatic machinery permitting MeG synthesis from methanol and glucose, but the plants accumulating this compound at concentrations higher than 1 micromol g(-1) wet wt were mainly members of the Rosaceae family belonging to the Rosoideae subfamily. It is suggested that the synthesis of MeG may contribute to reduce the accumulation in the cytoplasm of methanol and its derived compounds.

Aging↗
PubMed2001

Delta 9-tetrahydrocannabinol-induced alterations in limbic system glucose use in the rat.

The effects of Delta9-tetrahydrocannabinol (THC) on neural activity in the rat were investigated using [14C]2-deoxyglucose autoradiography to measure local cerebral glucose use. Overall, THC reduced glucose use at 5 mg/kg and slightly increased it at 1 mg/kg. Significant reductions were seen at the higher dose in regions of the hippocampus and limbic system, and in structures associated with sensory and sensorimotor process ing, consistent with the effects of THC on memory, sensory perception and motor control. Glucose use was increased in the shell of the nucleus accumbens at 1 mg/kg but not reduced at 5 mg/kg. This may reflect increases in activity in mesolimbic reward pathways which at the higher dose are mitigated by reduced glutamatergic outflow from the hippocampus.

Analgesics, Non-Narcotic↗
PubMed2001

Synthesis of anticonvulsive AMPA antagonists: 4-oxo-10-substituted-imidaz.

The overstimulation of excitatory amino acid receptors such as the glutamate AMPA receptor has been implicated in the physiopathogenesis of epilepsy as well as in acute and chronic neurodegenerative disorders. An original series of readily water soluble 4-oxo-10-substituted-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-carboxylic acid derivatives was synthesized. The most potent derivative 6a exhibited nanomolar binding affinity (IC50 = 35nM) and antagonist activity (IC50 = 6nM) at ionotropic AMPA receptor. This compound also demonstrated potent anticonvulsant properties in MES in mice and rats with long durations of action with ED50 values in the 1-3 mg/kg dose range following ip and iv administration.

Animals↗
PubMed2001

Bioisosteres of 9-carboxymethyl-4-oxo-imidazo[1,2-a]indeno-[1,2-e]pyrazin-2-carboxylic acid derivatives. Progress towards selective, potent in vivo AMPA antagonists with longer durations of action.

A novel series of 2- and 9-disubstituted heterocyclic-fused 4-oxo-indeno[1,2-e]pyrazin derivatives was synthesized. One of them, the 9-(1H-tetrazol-5-ylmethyl)-4-oxo-5,10-dihydroimidazo[1,2-a]indeno[1,2-e]pyrazin-2-yl phosphonic acid 4i exhibited a strong and a selective binding affinity for the AMPA receptor (IC50 = 13 nM) and demonstrated potent antagonist activity (IC50 = 6nM) at the ionotropic AMPA receptor. This compound also displayed good anticonvulsant properties against electrically-induced convulsions after ip and iv administration with ED50 values between 0.8 and 1 mg/kg. Furthermore, a strong increase in potency was observed when given iv 3 h before test (ED50 = 3.5 instead of 25.6 mg/kg for the corresponding 9-carboxymethyl-2-carboxylic acid analogue). These data confirmed that there is an advantage in replacing the classical carboxy substituents by their bioisosteres such as tetrazole or phosphonic acid groups.

Animals↗
PubMed2001

The effects of onsets and offsets on visual attention.

Two experiments are presented which examine the effect of onset and offset cues on early occurring attentional cueing effects and later occurring inhibition of return (IOR). The first experiment compared the effects of single onset cues, single offset cues, and simultaneous onset and offset cues (at opposite locations) at a 100-ms stimulus-onset-asynchrony (SOA) and IOR at a 900-ms SOA. Whereas the first experiment examined these conditions with choice localization keypress responses, the second experiment used simple detection keypress responses. Both experiments found that onset and offset cues presented in isolation produce early facilitation and late IOR. When onset and offset cues were simultaneously presented, facilitation but not IOR was found with localization responses, while neither facilitation or IOR was found with detection responses. Overall, these findings suggest that offset cues can be treated in the same manner as onset cues by the attentional system, although the onset cues may have priority in orienting attention when targets must be localized in space.

Attention↗
PubMed2001

Responding to feature or location: a re-examination of inhibition of return and facilitation of return.

It was found [Vision Res. 36 (1996) 2125] that reaction times for repeated targets were longer in detection and location discrimination tasks (inhibition of return; IOR) and shorter in color and orientation discrimination tasks (facilitation of return; FOR). The present experiment, using a more detailed analysis, shows that both IOR and FOR can be found in the discrimination tasks. Overall, the results are inconsistent with the notion that IOR and FOR effects reside in separate visual pathways. Rather, the results are accounted for by repetition priming and IOR that occur with specific combinations of target features and task demands.

Analysis of Variance↗
PubMed2001

Attentional set modulates visual areas: an event-related potential study of attentional capture.

The present experiment offers event-related potential evidence suggesting that modulation of neural activity in the visual cortex underlies top-down attentional capture by irrelevant cues. Participants performed a covert visual search task where they identified the unique stimulus in a brief, four-location display. Targets defined uniquely by color or onset were run in separate blocks, encouraging observers to adopt different attentional sets in each block. In Experiment 1, a brief, white, abrupt-onset cue highlighted one of the locations 100 or 200 ms prior to the target display. In Experiment 2, the cue display consisted of three white and one red cues simultaneously presented at the four locations. In both experiments, participants were informed that there was no predictive relation between the location of the cue and that of the target. Reaction times were dependent on the location of the preceding cue (i.e. attention was captured), but only in those blocks where the cue shared the uniquely relevant target feature. Evoked potentials over the right hemisphere were modulated during the attention-capturing blocks just prior to the cue's appearance. Additionally, the N1 wave elicited by the cue was enhanced over occipital regions during the attention-capturing blocks. These findings support the notion that attentional capture with peripheral cues is not simply reflexive but is modulated by top-down processes.

Adolescent↗
PubMed2001

Is position "special" in visual attention? Evidence that top-down processes guide visual selection.

The role of spatial position in selective visual processing has been the source of recent debate. Experiments by Tsal and Lavie (1988) and van der Heijden et al. (1996) have been designed to establish the status of position in visual selection. Tsal and Lavie found that observers tend to select letters from a briefly presented array according to position. Using the same paradigm, van der Heijden et al. found that observers tend to select according to colour, except under conditions of low contrast and unrestricted eye movements. The present study attempted to reconcile these findings by exploring the influence of top-down processes (task instructions) while explicitly controlling for eye movements. Experiment 1 demonstrated there was no inherent selection bias for stimuli similar to those used by van der Heijden et al., suggesting that the tendency to select according to colour found by van der Heijden et al. was due to task demands. Experiment 2 further established the role of top-down factors by replicating the results of van der Heijden et al. with our stimuli. Experiment 3 demonstrated that selection can be switched from colour to position by changing the demands of the task. These results suggest that selection may be accounted for by task demands (e.g., instructions) with no priority access for position information.

Analysis of Variance↗
PubMed2001

British National Lymphoma Investigation: pilot studies of neoadjuvant chemotherapy in clinical stage Ia and IIa Hodgkin's disease.

In order to improve treatment in early Stage IA and IIA Hodgkin's disease, the British National Lymphoma Investigation (BNLI) has evaluated two neoadjuvant chemotherapy regimens with involved field radiotherapy. This article reports the results of the methotrexate, vinblastine and prednisolone (MVP) study in 39 patients and updates the previous report on vinblastine, bleomycin and methotrexate (VBM) in 30 patients. Both studies recruited clinical Stage IA or IIA Hodgkin's disease patients with intermediate risk of relapse into a prospective multicentre Phase II study. They received two cycles of chemotherapy followed by involved field radiotherapy and then four further cycles of chemotherapy. For MVP the 5-year survival is 97% and for VBM it is 93%. The 5-year event-free survival rates are 71% and 87% respectively. The acute pulmonary and haematological toxicity occurring with VBM was not acceptable and therefore the MVP study was performed. There was less toxicity with this regimen although modest acute pulmonary toxicity was still observed. However, in view of the length of treatment with MVP (9 months) and the excellent results reported by the Manchester group, future efforts of the BNLI are to be directed towards a new short course chemotherapy regimen, VAPEC-B (vincristine, doxorubicin, prednisolone, etoposide, cyclophosphamide and bleomycin).

Adolescent↗
PubMed2001

The spatial distribution of inhibition of return.

Inhibition of return (IOR) refers to the finding that response times (RTs) are typically slower for targets at previously attended (cued) locations than for targets at novel (uncued) locations. Although previous research has indicated that IOR may spread beyond a cued location, the present study is the first to examine the spatial distribution of IOR with high spatial resolution over a large portion of the central visual field. This was done by using a typical IOR procedure (cue, delay, target) with 4 cue locations and 441 target locations (each separated by 1 degree of visual angle). The results indicate that IOR spreads beyond the cued location to affect the cued hemifield. However, the cues also produced a gradient of RTs throughout the visual field, with inhibition in the cued hemifield gradually giving way to facilitation in the hemifield opposite the cue.

Adult↗
PubMed2001

Symbolic control of visual attention.

The present study reports four pairs of experiments that examined the role of nonpredictive (i.e., task-irrelevant) symbolic stimuli on attentional orienting. The experiments involved a simple detection task, an inhibition of return (IOR) task, and choice decision tasks both with and without attentional bias. Each pair of experiments included one experiment in which nonpredictive arrows were presented at the central fixation location and another experiment in which nonpredictive direction words (e.g., "up," "down," "left," "right") were presented. The nonpredictive symbolic stimuli affected responses in all experiments, with the words producing greater effects in the detection task and the arrows producing greater effects in the IOR and choice decision tasks. Overall, the present findings indicate that there is a strong connection between the overlearned representations of the meaning of communicative symbols and the reflexive orienting of visual attention.

Adolescent↗
PubMed2001

Examining location-based and object-based components of inhibition of return in static displays.

Tipper and Colleagues (e.g., Jordan & Tipper, 1998; Tipper, Driver, & Weaver, 1991; Tipper, Weaver, Jerreat, & Burak, 1994) have provided support for inhibition of return (IOR) being composed of a location-based and an object-based component. They were able to separate out the effects of location-based and object-based IOR by using complex displays and displays that involved moving the cued object. The present study was designed to further examine the object- and location-based components of IOR in static displays. Three experiments were conducted that looked at the presence or absence of placeholder boxes on IOR. The first experiment was designed to replicate the results of Jordan and Tipper by presenting both objects and no-objects in the same display. In the second experiment, trials were blocked, and in the third experiment trials were presented in a random order. Overall, the results are inconsistent with the notion that independent object-based and location-based IOR components combine to produce the overall IOR effect and that additive effects are realized due to the context in which the trials are presented. We propose that a single inhibitory mechanism can account for the data.

Attention↗
PubMed2001

The effect of the physical characteristics of cues and targets on facilitation and inhibition.

The present experiment was conducted in order to examine the role of cue-target discriminability on early occurring attentional cuing effects and late occurring inhibition of return (IOR). The experiment used a single target stimulus in conjunction with three different cue stimuli. The cues were the same as the target, different in color, shape, and luminance to the target, or did not spatially overlap with the target. At shorter stimulus onset asynchronies (SOAs; 100 and 200 msec), attentional cuing effects were only found with the nonoverlapping cues. However, at longer SOAs (400 and 800 msec), approximately equal IOR effects were found with all three types of cues. The results indicated that the physical characteristics of the cues and targets affected the pattern of reaction times at the shorter SOAs but not at the longer SOAs. The conclusion is that the biphasic pattern of early facilitation and late inhibition following a peripheral cue should not be considered the definitive signature of the peripheral cuing paradigm.

Adult↗
PubMed2001

The effects of occlusion and past experience on the allocation of object-based attention.

There is considerable evidence indicating that cuing a specific portion of an object results in the entire object's being attended to. In the present study, we examined whether previous experience with an object could halt perceptual (i.e., amodal) completion. In Experiment 1, two parallel rectangles were initially displayed, and then the middle portions of these objects were occluded. Attentional cuing effects were found for both discrete portions of the completed rectangles. In the final two experiments, four discrete objects were initially displayed, followed by the same occluder as that used in the first experiment. The appearance of the occluder (500 msec before the cue in Experiment 2,100 msec before the cue in Experiment 3) allowed the four discrete objects to be completed into two rectangles. Attentional cuing effects were found for the completed rectangles in both experiments, indicating that previous experience was not sufficient to halt the amodal completion of objects.

Attention↗
PubMed2001

RPR 119990, a novel alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid antagonist: synthesis, pharmacological properties, and activity in an animal model of amyotrophic lateral sclerosis.

Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonists are of potential interest for the treatment of certain acute and chronic neurodegenerative diseases, including amyotrophic lateral sclerosis. Here, we describe the synthesis and pharmacological properties of 9-carboxymethyl-4-oxo-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-phosphonic acid (RPR 119990). The compound displaced [3H]AMPA from rat cortex membranes with a K(i) of 107 nM. In oocytes expressing human recombinant AMPA receptors, RPR 119990 depressed ion flux with a K(B) of 71 nM. The antagonist properties of this compound were confirmed on rat native AMPA receptors in cerebella granule neurons in culture and in hippocampal slices where it antagonized electrophysiological responses with IC50 values of 50 and 93 nM, respectively. RPR 119990 antagonized hippocampal evoked responses in vivo, demonstrating brain penetration at active concentrations. RPR 119990 is a potent anticonvulsant in the supramaximal electroshock in the mouse with an ED50 of 2.3 mg/kg 1 h post s.c. administration, giving it a workably long action. Pharmacokinetic studies show good passage into the plasma after subcutaneous administration, whereas brain penetration is low but with slow elimination. This compound was found active in a transgenic mouse model of familial amyotrophic lateral sclerosis (SOD1-G93A) where it was able to improve grip muscle strength and glutamate uptake from spinal synaptosomal preparations, and prolong survival with a daily dose of 3 mg/kg s.c.

Amyotrophic Lateral Sclerosis↗
PubMed2000

Synthesis and potent anticonvulsant activities of 4-oxo-imidazo[1,2-a]inden.

The over-stimulation of excitatory amino acid receptors such as the glutamate AMPA receptor has been suggested to be associated with neurodegenerative disorders. Here we describe an original series of readily water soluble 4-oxo-imidazo[1,2-a] indeno[1,2-e]pyrazin-8- and -9-carboxylic (acetic) acid derivatives. One of these compounds, 4f, exhibited nanomolar binding affinity, potent competitive antagonism at the ionotropic AMPA receptor and a long duration of anticonvulsant activity after administration by parenteral route in vivo.

Animals↗
PubMed2000

Riluzole prolongs survival and delays muscle strength deterioration in mice with progressive motor neuronopathy (pmn).

The neuroprotective drug riluzole (Rilutek) is a sodium channel blocker and anti-excitotoxic drug which is marketed for the treatment of amyotrophic lateral sclerosis (ALS). Previous studies have shown that riluzole prolongs survival of transgenic mice harboring the mutated form of Cu,Zn-superoxide dismutase found in familial forms of the human disease. In this study we have examined the effect of treatment with riluzole in mice suffering from progressive motor neuronopathy (pmn), a hereditary autosomal recessive wasting disease which shares some symptoms of ALS. These mutants display hind limb weakness starting during the 3rd week of life and leading to paralysis and death during the 7th week of life. Daily treatment with 8 mg/kg of riluzole by oral route significantly retarded the appearance of paralysis, increased life span and improved motor performance on grip test and electromyographic results in the early stage of the disease. There was no effect of riluzole on weight gain. These data demonstrate that riluzole significantly prolongs life span, retards the onset of paralysis and slows the evolution of functional parameters connected with muscle strength in the pmn mouse model of motor neuron disease.

Animals↗