Clinical trials referral resource. Clinical trials of dolastatin-10.
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Adult↗
Biomedical subjects
J J Wright
Publications and source records attributed to J J Wright.
Alpha rhythm emerges from large-scale networks of realistically coupled multicompartmental model cortical neurons.
Conical pyramidal and stellate neurons were simulated using the GENESIS simulation package. Model neurons were leaky integrate-and-fire and consisted of from four to nine passive compartments. Neurophysiological measurements, based on single-cell recordings and patch-clamp experiments, provided estimations for the simulation of cortical neurons: transmitter-activated conductances, passive membrane time constants and axonal delays. Network connectivity was generated using a previously described probabilistic scheme based on known cortical histology, in which the probability of connections forming between one neuron and another fell off monotonically with increasing inter-cellular separation. Simulations of up to 6400 cortical neurons, approaching the scale of an individual cortical column, confirmed previous findings with smaller networks. Limit-cycle behaviour emerged in the network, in the frequency in the range of the mammalian alpha and beta rhythms (8-20 Hz). Contrary to expectation, near-linear relationships were found between the mean soma membrane potential and and neuronal firing probability. Some of the implications for cortical information processing, in particular the dynamical interactions between the neuronal and larger scales, are discussed.
Alpha Rhythm↗
Dynamics of SCR, EEG, and ERP activity in an oddball paradigm with short interstimulus intervals.
Studies of concurrent central, and autonomic activity using a conventional event-related potential (ERP) oddball paradigms, are considered useful in elucidating the relationship between central and autonomic responses, but the autonomic response tends to overlap. A new method was used to decompose and score overlapping skin conductance responses (SCR). This method enabled examination of dynamic relationships of phasic SCR, prestimulus electroencephalogram (EEG), and ERP to auditory target stimuli in 50 normal adults. SCR amplitude was negatively correlated to EEG and N200 amplitude. The SCR amplitude changes over time exhibited an exponential decline opposite to those of N200, alpha, and beta. All the fitted exponential functions had a time constant of 1-2 min. The findings suggest that a N200 component, active in the auditory sensory discrimination, is concomitant with the SCR. The narrow range of the time constant may provide a clue to the conjoint processes underlying central and autonomic adaptive functions.
Adult↗
Inter-relationships between small, dense low-density lipoprotein (LDL), plasma triacylglycerol and LDL apoprotein B in an atherogenic lipoprotein phenotype in free-living subjects.
A predominance of small, dense low-density lipoprotein (LDL) is a major component of an atherogenic lipoprotein phenotype, and a common, but modifiable, source of increased risk for coronary heart disease in the free-living population. While much of the atherogenicity of small, dense LDL is known to arise from its structural properties, the extent to which an increase in the number of small, dense LDL particles (hyper-apoprotein B) contributes to this risk of coronary heart disease is currently unknown. This study reports a method for the recruitment of free-living individuals with an atherogenic lipoprotein phenotype for a fish-oil intervention trial, and critically evaluates the relationship between LDL particle number and the predominance of small, dense LDL. In this group, volunteers were selected through local general practices on the basis of a moderately raised plasma triacylglycerol (triglyceride) level (>1.5 mmol/l) and a low concentration of high-density-lipoprotein cholesterol (<1.1 mmol/l). The screening of LDL subclasses revealed a predominance of small, dense LDL (LDL subclass pattern B) in 62% of the cohort. As expected, subjects with LDL subclass pattern B were characterized by higher plasma triacylglycerol and lower high-density lipoprotein cholesterol (<1.1 mmol/l) levels and, less predictably, by lower LDL cholesterol and apoprotein B levels (P<0.05; LDL subclass A compared with subclass B). While hyper-apoprotein B was detected in only five subjects, the relative percentage of small, dense LDL-III in subjects with subclass B showed an inverse relationship with LDL apoprotein B (r=-0.57; P<0.001), identifying a subset of individuals with plasma triacylglycerol above 2.5 mmol/l and a low concentration of LDL almost exclusively in a small and dense form. These findings indicate that a predominance of small, dense LDL and hyper-apoprotein B do not always co-exist in free-living groups. Moreover, if coronary risk increases with increasing LDL particle number, these results imply that the risk arising from a predominance of small, dense LDL may actually be reduced in certain cases when plasma triacylglycerol exceeds 2.5 mmol/l.
Adult↗
Steady state visually evoked potential correlates of auditory hallucinations in schizophrenia.
This study attempted to localize regions of brain electrical activity associated with the onset of auditory hallucinations. Changes in Steady State Visually Evoked Potential (SSVEP) topography associated with the onset of spontaneous auditory hallucinations was studied in eight schizophrenic patients. The SSVEP elicited by a spatially uniform sinusoidally varying visual flicker was recorded using a 64-channel electrode helmet. A large and significant decrease in SSVEP latency in the right temporo/parietal region occurred in the second prior to the report of auditory hallucinations. A control task with matching motor movements produced no significant decrease in SSVEP latency in the same right temporo/parietal location. This finding suggests that activity of fine temporal resolution in the neural networks in the right temporo/parietal area may be implicated in the genesis of auditory hallucination, in conformity with certain neuropsychological theories.
Adult↗
Sulfated galactocerebrosides as potential antiinflammatory agents.
Native sulfatides, as well as many sulfated glycolipids, have been shown to avidly bind to the selectin receptors. In vivo, native sulfatides significantly block activity in selectin-dependent inflammatory responses. The fact that nonsulfated galactocerebrosides did not inhibit selectin-mediated adhesion identified a critical role for the anionic sulfate residue. We therefore initiated a program to evaluate the activity of position isomers. This study showed a binding selectivity for the positions 2 and 3 of the sulfate group on the carbohydrate ring as well as enhanced activity for the disulfated analogs. Furthermore, it was discovered that the attachment of lipophilic substituents on the carbohydrate ring was tolerated, consistent with the presence of a lipophilic pocket in the binding activity. This resulted in compounds with a 6-fold increased potency.
Animals↗
Neutrophilia and organomegaly in two patients with cancer.
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Female↗
LINE-I element insertion at the t(11;22) translocation breakpoint of a desmoplastic small round cell tumor.
A t(11;22)(p13;p12) chromosomal translocation, juxtaposing the Wilms' tumor (WT1) and Ewing's sarcoma (EWS) genes, is the cytogenetic hallmark of desmoplastic small round cell tumor (DSRCT), a primitive multiphenotypic sarcoma arising in serosal tissues. Chimeric transcripts generated by this rearrangement encode an aberrant transcription factor that fuses the 5' region of EWS with a 3' WT1 segment. We describe the insertion of a LINE-I DNA mobile genetic element at the genomic breakpoint of a DSRCT chromosomal translocation. A 480 bp heterologous DNA segment with homology to the LINE-I DNA consensus sequence was located between EWS intron 8 and WT1 exon 8 in the productively rearranged allele. Sequence homology corresponded to the LINE-I ORF-2, which encodes a protein with reverse-transcriptase activity. The heterologous inserted fragment was not evident in the germline of normal tissue from the patient, suggesting that transposition occurred in somatic cells, possibly during the process of chromosomal rearrangement. This case represents the first example of LINE-I DNA transposition at the fusion site of a tumor-associated chromosomal rearrangement.
Alleles↗
EEG simulation: variation of spectral envelope, pulse synchrony and approximately 40 Hz oscillation.
Macroscopic EEG travelling wave phenomena and cortical pulse synchronisation effects are related within a single simple simulation. Non-specific activation acts to control the transfer function of the simulated cortex, and thus determines the relative amplitude of macroscopic EEG waves generated by rhythmic inputs. When concurrent asynchronous excitatory inputs to separate, local, cortical sites are introduced, the simulation reproduces both gamma-band (40 Hz) electrocorticogram (ECoG) activity and synchronous oscillation of action potential pulse density at the separate sites. The gamma-band ECoG and pulse synchrony effects depend on different mechanisms: the former upon local excitatory/inhibitory interactions, and the latter on corticocortical interactions. The pattern of synchronous activity depends upon both structural and dynamic aspects of gain, and is sustained by linearised versions of the simulation's state equations. Dynamic properties of the simulation, which are independent of scale, describe both microscopic and macroscopic phenomena, all in accord with physiological findings.
Action Potentials↗
BMS-190394, a selectin inhibitor, prevents rat cutaneous inflammatory reactions.
Selectin binding is the first step in extravasation of leukocytes through the endothelium. Infiltration of leukocytes is a hallmark of an inflammatory response. Blockade of selectin-dependent adhesion, therefore, represents a specific mechanism-based anti-inflammatory strategy. We have used the natural product sulfatide, one of the selectin ligands, as a template to design a novel selectin antagonist. BMS-190394, a structural analog of sulfatide, is an inhibitor of cell binding to P-, E- and L-selectin-Ig fusion proteins. BMS-190394 also inhibits binding mediated by native P-selectin expressed on the surface of activated platelets. Pharmacokinetic analysis of BMS-190394 showed that the compound remained in circulation with a T1/2 of 7 hr, long enough to inhibit the development of an acute inflammatory response. The in vitro activity and pharmacokinetic profile of this selectin-blocking compound led to the determination of its in vivo anti-inflammatory activity. BMS-190394 was a potent inhibitor of the dermal immune complex-induced reverse passive Arthus reaction in rats when delivered by the i.v. or i.p. route. The ED50 of the compound in the reverse passive Arthus reaction compares favorably to that for dexamethasone. BMS-190394 was also an effective inhibitor of the delayed-type hypersensitivity reaction in the rat. Compared with previous reports of the use of antibodies and complex oligosaccharides to inhibit the activity of the selectins, this low-molecular-weight inhibitor of the selectins presents a novel class of anti-inflammatory agents.
Animals↗
Cusum as an aid to early assessment of the surgical trainee.
Tests of knowledge, aptitude and psychomotor skills have been used to assess and select surgical trainees but none of these is reliable in the long term. The industrial quality-control method of the cusum was used to assess performance progress in 17 surgical trainees. Trainees were assessed on their ability to perform, independently, selected surgical operations using the criterion of procedure duration. Cusum profiles were compared with scores from at least four independent assessors using a modified Royal Australasian College of Surgeons' mentor form. The cusum identified all trainees who were considered either satisfactory or less able by their mentors. This objective evaluation was reliable after 25 procedures, whether for appendicectomy or combined with herniorrhaphy and cholecystectomy. Evaluation of surgical performance using the cusum may prove to be a more objective tool for assessing surgical trainees than early impressions or less clinically oriented tests.
Clinical Competence↗
Simulation of electrocortical waves.
We report simulations of the electrocorticogram of the cat and human, based on estimates of fibre range, fibre density, axonal and dendritic delays, and cortical synaptic density. The long-range cortical connections of real cortex were simplified to couplings of symmetric density, decreasing in density with range, on a closed (toroidal) surface. Non-specific cortical activation was modelled as a diffuse global input and specific sensory input as a localised white noise input. Spectral properties of output included peak densities at the frequencies of the major cerebral rhythms, a '1/f' spectral envelope and 'shift to the right' with increasing total power as non-specific activation increased. Steady-state travelling waves with a velocity of 5-7 m/s (human) and < 1 m/s (cat) were produced. Frequency/wavenumber analysis revealed an additional class of activity with wavenumbers independent of temporal frequency. All these findings accord qualitatively and quantitatively with existing physiological results. Global resonant modes were not prominent, but the simulations obey a restricted case of the analytical results of Nunez (1994). Wave/pulse relations resemble the findings of Freeman (1975).
Animals↗
Response of hypercholesterolemic subjects to administration of tocotrienols.
The cholesterol-suppressive actions of Palmvitee and gamma-tocotrienol were assessed in hypercholesterolemic subjects after acclimation to the American Heart Association Step 1 dietary regimen for four and eight weeks, respectively. The four-week dietary regimen alone elicited a 5% decrease (P < 0.05) in the cholesterol level of the 36 subjects. Subjects continuing on the dietary regimen for a second four-week period experienced an additional 2% decrease in their cholesterol levels. Dietary assessments based on unanticipated recalls of 24-h food intake records suggest that significant reductions in energy and fat, predominantly in saturated fat, intakes are responsible. The subjects experienced significant Palmvitee- and gamma-tocotrienol-mediated decreases in cholesterol. The group of subjects acclimated to the dietary regimen for four weeks responded to Palmvitee (a blend of tocols providing 40 mg alpha-tocopherol, 48 mg alpha-tocotrienol, 112 mg gamma-tocotrienol, and 60 mg delta-to-cotrienol/day for four weeks) with a 10% decrease in cholesterol (P < 0.05). Dietary assessments showed no further change in energy and fat intakes. alpha-Tocopherol attenuated the cholesterol-suppressive action of the tocotrienols. The second group of subjects, acclimated to the dietary regimen for eight weeks, received 200 mg gamma-tocotrienol/d for four weeks. The cholesterol-suppressive potency of this alpha-tocopherol-free preparation was calculated to be equivalent to that of the mixture of tocotrienols (220 mg) used in the prior study. Cholesterol levels of the 16 subjects in the second group decreased 13% (P < 0.05) during the four-week trial. Plasma apolipoprotein B and ex vivo generation of thromboxane B2 were similarly responsive to the tocotrienol preparations, whereas neither preparation had an impact on high density lipoprotein cholesterol and apolipoprotein A-1 levels.
Adult↗
Azetidin-2-one derivatives as inhibitors of thrombin.
A series of 3-(3-guanidinopropyl)-azetidin-2-one derivatives was prepared and evaluated as inhibitors of cleavage of synthetic substrates in vitro by the serine proteases thrombin, trypsin and plasmin. The N-unsubstituted, 4-phenethyl derivative 9a demonstrated weak inhibition of these enzymes but acetylation of the beta-lactam N atom afforded 9b, an effective, time-dependent inhibitor of thrombin and a potent inhibitor of plasmin. Variation of the 4-position of the beta-lactam ring was examined in conjunction with different N-substituents to provide a series of potent, time-dependent inhibitors of thrombin. A C-4 substituent was essential for good inhibitory properties and, in general, polar C-4 substituents enhanced the selectivity of inhibition for thrombin compared to plasmin. A trans relationship between the C-4 and C-3 substituents was found to be superior to a cis disposition whilst homologation of the guanidinopropyl side chain to that of a guanidinobutyl moiety reduced activity. Several compounds were effective inhibitors of thrombin-induced clot formation in human plasma in vitro but activity in this assay did not correlate well with inhibition of thrombin-induced cleavage of a synthetic substrate, presumably a consequence of inherent chemical instability and degradation in plasma.
Antithrombins↗
Active site-directed thrombin inhibitors--II. Studies related to arginine/guanidine bioisosteres.
A series of N-arylsulfonylarginine amides was synthesized wherein the guanidine or arginine moiety was isosterically replaced by a number of heterocyclic functionalities. These compounds were evaluated as potential active-site inhibitors of thrombin. Bisamidines 11a-n showed a similar SAR to that of simple arginine compounds. The ex vivo clotting time measurement of 11d after ip dosing showed prolongation of clotting time in rats.
Animals↗
Inhibitors of cholesterol biosynthesis. 2. Hypocholesterolemic and antioxidant activities of benzopyran and tetrahydronaphthalene analogues of the tocotrienols.
Tocotrienols exhibit antioxidant and cholesterol-biosynthesis-inhibitory activities and may be of value as antiatherosclerotic agents. The mechanism of their hypolipidemic action involves posttranscriptional suppression of HMG-CoA reductase (HMGR) in a manner mimicking the action of putative non-sterol feedback inhibitors. The in vitro cholesterol-biosynthesis-inhibitory and HMGR-suppressive activities in HepG2 cells of an expanded series of benzopyran and tetrahydronaphthalene isosteres and the hypocholesterolemic activity of selected compounds assessed in orally dosed chickens are presented. Preliminary antioxidant data of these compounds have been obtained using cyclic voltammetry and Cu-induced LDL oxidation assays. The farnesyl side chain and the methyl/hydroxy substitution pattern of gamma-tocotrienol deliver a high level of HMGR suppression, unsurpassed by synthetic analogues of the present study. In orally dosed chickens, 8-bromotocotrienol (4o), 2-desmethyltocotrienol (4t), and the tetrahydronaphthalene derivative 35 exhibit a greater degree of LDL cholesterol lowering than the natural tocotrienols.
Animals↗
Computer simulation of electrocortical activity at millimetric scale.
We report a simulation of electrocortical wave activity at millimetric scale, during the "desynchronised" state. Asymmetric sigmoid pulse/wave relations, short-range excitatory/inhibitory interactions and long-range excitatory couplings of pools of cortical cells were modelled. Frequency/wave number analysis of cat electrocorticogram was compared with the results of simulation. Local standing waves, with wave numbers from about 0.25/mm to 3.3/mm independent of temporal frequency, appeared in real and simulated ECoG. These arise from interactions of excitatory and inhibitory cells and reciprocal excitation of pyramidal cells. The simulation also exhibits long wave length activity consistent with that of the real ECoG. Serial relay of excitation gives rise to travelling waves with a velocity of about 0.6 m/sec, which approximates earlier experimental estimates based on coherence. Interaction of the local and travelling waves results in group waves with high phase velocities (32 m/sec at 5 Hz, to 0.6 m/sec at 50 Hz). Such group waves have not yet been experimentally identified and would be readily confused with effects of volume conduction. However, the frequency response characteristics of the simulation, along with the group waves, may account for experimental findings of action potential correlation with local field potentials at 40-50 Hz and long-range synchronisation of action potentials.
Animals↗
An MRI study of drying in granular beds of nonporous particles.
MRI is used to study the role of capillary and gravitational forces in controlling mass transport of water during isothermal drying of granular beds of nonporous particles. A new model is presented that shows how capillary and gravitational forces relate to Fickian diffusion driven by a chemical potential gradient. In granular beds, where capillary and gravitational forces dominate, the image profiles give direct information on the dependence of the degree of saturation on capillary suction pressure. The effects of changing particle size and surface tension on the profiles is investigated quantitatively, and it is shown that high capillary pressures create anomalies in the drying profiles.
Algorithms↗