Search PubMed⌕ Search

Biomedical subjects

L R Williams

Publications and source records attributed to L R Williams.

At least 37 records · Page 2Linked to original sources
PubMed1997

Stochastic completion fields; a neural model of illusory contour shape and salience.

We describe an algorithm- and representation-level theory of illusory contour shape and salience. Unlike previous theories, our model is derived from a single assumption: that the prior probability distribution of boundary completion shape can be modeled by a random walk in a lattice whose points are positions and orientations in the image plane (i.e., the space that one can reasonably assume is represented by neurons of the mammalian visual cortex). Our model does not employ numerical relaxation or other explicit minimization, but instead relies on the fact that the probability that a particle following a random walk will pass through a given position and orientation on a path joining two boundary fragments can be computed directly as the product of two vector-field convolutions. We show that for the random walk we define, the maximum likelihood paths are curves of least energy, that is, on average, random walks follow paths commonly assumed to model the shape of illusory contours. A computer model is demonstrated on numerous illusory contour stimuli from the literature.

Algorithms↗
PubMed1997

Regional distribution of iron, transferrin, ferritin, and oxidatively-modified proteins in young and aged Fischer 344 rat brains.

Iron dysregulation in the brain is thought to contribute to the oxidative damage seen in neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. A role for iron in the oxidative stress thought to contribute to normal ageing is less certain. To better characterize the role of iron in normal ageing, the concentrations of iron, transferrin, ferritin, and protein carbonyl groups are measured in nine separate regions of Fischer 344 rats. The largest (approximately 30%) age-related increases in brain iron concentration are seen in the temporal cortex, medial septum, and cerebellum. Ferritin concentration in these same brain regions increases 50 to 250% with age, while protein carbonyl concentration is only -27 to +4%, of young rats. These results indicate that an increase in the major iron-binding protein ferritin compensates for any age-related increase in iron concentration, and suggest that the increased ferritin is cytoprotective, serving to prevent the accumulation of protein carbonyl groups (a principal product of metal-catalysed oxidation of proteins).

Aging↗
PubMed1997

Identification of superoxide dismutase activity in Borrelia burgdorferi.

Infective and noninfective strains of Borrelia burgdorferi, along with Borrelia afzelii and Borrelia garinii, possessed a single iron-containing superoxide dismutase (SOD). None of the Lyme disease spirochetes tested possessed catalase or peroxidase activities. The borrelial SOD was not inducible by growth with increased oxygen concentrations and thus appeared to be produced constitutively.

Borrelia burgdorferi Group↗
PubMed1996

Brain-derived neurotrophic factor, but not neurotrophin-3, prevents ischaemia-induced neuronal cell death in organotypic rat hippocampal slice cultures.

We have investigated the neuroprotective actions of neurotrophins in a model of ischaemia using slice cultures. Ischaemia was induced in organotypic hippocampal cultures by simultaneous oxygen and glucose deprivation. Cell death was assessed 24 h later by propidium iodide fluorescence. Pre- but not post-ischaemic addition of brain-derived neurotrophic factor (BDNF) produced a concentration-dependent reduction in neuronal damage. Neurotrophin-3 was not neuroprotective. These data suggest that BDNF may form part of an endogenous neuroprotective mechanism.

Animals↗
PubMed1996

Evidence for DNA fragmentation in the CNS of aged Fischer-344 rats.

The aged central nervous system (CNS) is characterized by a loss of neurons. Apoptosis has been reported to be responsible for neuronal death during development and may also be involved in some age-related neurodegenerative diseases of the CNS. No evidence is currently available as to whether apoptosis is also responsible for the loss of neurons associated with physiological aging. In this study, we have found fragmented DNA, a characteristic trait of cells undergoing apoptosis, in the hippocampus and, to a minor extent, in the frontal cortex and basal forebrain of aged (24-month-old) Fisher-344 rats, but not in the cerebellum. These data represent important evidence to support the idea that apoptosis may be associated with the neuronal death observed during normal aging.

Aging↗
PubMed1996

Cyclophosphamide is neuroprotective in a gerbil model of transient severe focal cerebral ischemia: correlation with effects of tirilazad mesylate (U-74006F).

Using a gerbil model of severe, temporary focal ischemia (3 h unilateral carotid occlusion), preliminary experiments identified an involvement of neutrophils in the reperfusion injury to the ischemic hemisphere. The present experiments were designed to (1) quantitate the temporal accumulation of neutrophils in the gerbil model, (2) determine if cyclophosphamide-induced neutropenia provided cytoprotection to the ischemic hemisphere, and (3) attempt to correlate the cytoprotective efficacy of tirilazad mesylate with possible effects on postischemic neutrophil accumulation. Following 3 h of unilateral carotid occlusion, animals were collected at increasing times of reperfusion and the CA1 region of the hippocampus and the lateral cortex were assessed for postischemic neuronal damage using a semiquantitative index (N.D.I.) of 0 (no damage) to 4 (>75% neuronal loss). The extent of neutrophil accumulation was determined by counting intensely cytochrome oxidase-positive cells. Minimal neuronal death was evident after 2 h of reperfusion, mean N.D.I. = 0.36. However, between 2 and 4 h of reperfusion, neuronal death did not increase. By 6 h of reperfusion, the neuronal death began to proceed at an accelerated rate, N.D.I. = 0.78. By 12 h, the N.D.I. reached 3.20. The accelerated neuronal death coincided with parenchymal invasion of neutrophils. Cyclophosphamide administration delayed neuronal death in the hippocampus, but exhibited a more sustained protective effect in the lateral cortex. Administration of tirilazad mesylate also resulted in a significant reduction in neutrophil accumulation and significant neuronal protection in both brain areas. Thus, in this gerbil model of transient, but prolonged focal cerebral ischemia, neutrophils appear to play an active role in the reperfusion injury to brain tissue. Our experiments confirm the previously demonstrated neuroprotective efficacy of tirilazad mesylate in this model and provide evidence for a similar protective effect of cyclophosphamide. Although other effects of this antioxidant are also thought to contribute to the overall efficacy, the data are consistent with the hypothesis that one mechanism by which tirilazad acts involves limiting the ability of neutrophils to participate in the reperfusion phase of ischemic cerebral injury.

Animals↗
PubMed1996

Glial cell line-derived neurotrophic factor sustains axotomized basal forebrain cholinergic neurons in vivo: dose-response comparison to nerve growth factor and brain-derived neurotrophic factor.

Glial cell line-derived neurotrophic factor (GDNF) was infused continuously for 2 weeks into the ventricles of male Wistar rats that had received a unilateral knife transection of the fimbria/fornix. In vehicle-treated, control animals, there was a 70% loss of choline acetyltransferase (ChAT)-positive and a 60% loss of p75-positive neurons in the septum/diagonal band ipsilateral to the axotomy as identified by immunohistochemistry, with no loss in ChAT biochemical activity. GDNF treatment at 10 micrograms/day completely prevented the loss of p75-positive neurons, significantly reduced the loss of ChAT-positive neurons to 40% of normal, and stimulated ChAT biochemical activity to 40% more than normal in an axotomy-dependent manner. GDNF is 1 order of magnitude less potent than NGF but, unlike NGF, had little or no effect on normal, uninjured neurons. GDNF was 1 order of magnitude more potent than BDNF, and BDNF had no effect on ChAT biochemical activity. GDNF and NGF inhibited weight gain, whereas BDNF induced significant weight loss and death at the dosage of 100 micrograms/day.

Animals↗
PubMed1995

Painful keratoderma and photophobia: hallmarks of tyrosinemia type II.

Tyrosinemia type II (Richner-Hanhart syndrome), which is caused by a deficiency of hepatic tyrosine aminotransferase, results in elevated plasma and urinary tyrosine concentrations. We describe a young boy who was seen at 6 months of age with red eyes, photophobia, and eye pain that were not suspected to be caused by tyrosinemia II until painful plantar keratoderma developed at 2 1/2 years of age. Treatment with a diet low in tyrosine and phenylalanine reversed the manifestations of the disease.

Amino Acid Metabolism, Inborn Errors↗
PubMed1995

A proposed blood circulation model for Reference Man.

As part of the revision of the Reference Man model of the International Commission on Radiological Protection (ICRP), we have reviewed and reanalyzed available data on blood flow and in previous publications have proposed reference values for total and regional blood volumes, total cardiac output, and the distribution of cardiac output. In this paper we unify these proposed features of the revised Reference Man within the framework of a dynamic blood circulation model and show how the model can be used to predict the distribution of decays of short-lived radionuclides after injection or absorption into blood. The total blood volume is partitioned into the blood contents of 24 separate organs or tissues, right heart chambers, left heart chambers, pulmonary circulation, arterial outflow to the systemic tissues (aorta and large arteries), and venous return from the systemic tissues (large veins). As a compromise between physical reality and computational simplicity, the circulation of blood is viewed as a system of first-order transfers between blood pools, but outflow from any given pool is delayed during the first pass of material through the circulation with the delay time depending on the mean transit time across the pool. The model can be used to predict the movement and gradual dispersal of a bolus of material in the circulation after intravascular injection. In contrast to the treatment of the circulation in ICRP Publication 53, Radiation Dose to Patients from Radiopharmaceuticals, the present model allows consideration of incomplete, tissue-dependent extraction of material during passage through the circulation and return of material from tissues to plasma.

Adult↗
PubMed1995

Oxidative stress, age-related neurodegeneration, and the potential for neurotrophic treatment.

Amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease are major human neurodegenerative disorders, the etiologies for which remain unknown. Although a unique subset of neurons is particularly affected in each of the three diseases, they have several intriguing overlapping similarities. Evidence is reviewed supporting the hypothesis that these diseases result from an inability to protect against accumulated damage by free radicals due to oxidative stress. If oxidative stress underlies or exacerbates the etiology of these diseases, then agents that effectively attenuate brain tissue lipid peroxidation or otherwise limit free radical damage may hold promise for the treatment of these neurodegenerative diseases. Although antioxidant chemical supplementation may provide effective therapy, the most effective therapy for neurodegenerative diseases may be treatment with specific neurotrophic, survival-promoting proteins. For example, brain-derived neurotrophic factor promotes survival of spinal motor neurons and mesencephalic dopaminergic neurons. One mechanism through which these proteins may exert their protection may be by stimulating endogenous defenses against oxidative stress and damage by free radicals. This hypothesis is being tested in several laboratories and provides exciting direction both for basic neurobiological research and therapeutic drug discovery.

Aging↗
PubMed1995

Nerve growth factor facilitates cholinergic neurotransmission between nucleus basalis and the amygdala in rat: an electrophysiological analysis.

Treatment of rats in vivo with NGF promotes the survival and enhances the neurotransmitter phenotype of basal forebrain cholinergic neurons. We showed recently (Williams et al., 1993) that NGF-induced stimulations of the cholinergic markers ChAT and high-affinity choline uptake are reflected in an enhanced synthesis and release of ACh in terminals fields of basal forebrain cholinergic neurons. The objective of the present study was to determine whether such effects translate into an enhancement in neurotransmission between nucleus basalis neurons and postsynaptic target cells, and therefore are likely to be of physiological significance. Changes in cholinergic neurotransmission after NGF were assessed by comparing the ability of cholinergic pathway activation, produced by electrical stimulation of nucleus basalis or the external capsule, to elicit intracellularly recorded muscarinic responses in basolateral amygdaloid (BLA) neurons in ventral forebrain slice preparations from NGF-treated and control Fischer 344 adult rats. Chronic infusion of NGF for 3 weeks (1.2 micrograms/d, i.c.v.) increased the likelihood of eliciting cholinergic slow depolarizations (slow EPSP) via stimulation of cholinergic pathways in the slice. In addition, the frequency-response curves for generation of the cholinergic slow EPSP by nucleus basalis or external capsule stimulation were shifted approximately twofold to the left and the EF50 values significantly reduced in neurons from NGF-treated slices, compared to those in preparations from vehicle-treated or untreated controls. Treatment with NGF also resulted in a leftward shift in the frequency-response curve for cholinergic pathway-induced blockade of the slow afterhyperpolarization, without change in the maximal inhibitory effect. The NGF-induced enhancement in cholinergic synaptic effectiveness was not accompanied by alterations in the resting membrane properties or intrinsic excitability of BLA pyramidal neurons. Nor did treatment with NGF affect their chemosensitivity or responsiveness to direct postsynaptic applications of the cholinergic carbachol. We conclude from these results that chronic administration of exogenous NGF can facilitate neurotransmission within basal forebrain cholinergic projections in normal adult brain, presumably as a consequence of its ability to stimulate presynaptic mechanisms involved in synthesis and/or release of ACh.

Amygdala↗
PubMed1994

Role of neurotrophins in cholinergic-neurone function in the adult and aged CNS.

Cholinergic neurones in the CNS undergo complex changes during normal aging. In recent years, considerable attention has focussed on the neurotrophins and, in particular, nerve growth factor, as potential maintenance factor for cholinergic-neurone function, and as therapeutic agents for use in a variety of neurodegenerative disorders including Alzheimer's disease. While brain cholinergic neurones from the neonate to the aged respond to nerve growth factor with enhanced expression of transmitter phenotype, there appears to be an age-related, region-specific decline in responsiveness. This age-related decrement in neurotrophin action might play a role in dysfunction of cholinergic neurones, and cognitive loss, and could limit the use of these factors as therapeutic agents.

Aging↗
PubMed1994

Transcellular permeability of chlorpromazine demonstrating the roles of protein binding and membrane partitioning.

Transcellular permeability of the neuroleptic-anesthetic chlorpromazine (CPZ) was examined using a cell type (MDCK) that forms a confluent monolayer of polarized cells resulting in distinct apical (AP) and basolateral (BL) membrane domains separated by tight junctions. Because CPZ is membrane interactive, transmonolayer flux was analyzed as two kinetic events: cell uptake from the AP donor solution and efflux into the BL side receiver. Using the rate of cell uptake in the presence of different concentrations of BSA, an intrinsic cell partition coefficient of 3700 +/- 130 and an operational dissociation binding constant of 0.4 +/- 0.05 mM were calculated. In contrast to uptake, efflux of CPZ from either the AP or the BL side of the cell monolayer was approximately 10(4)-fold slower and was dependent upon the avidity of CPZ for the protein acceptor in the receiver solution. These results emphasized the importance of simultaneously measuring disappearance of a lipophilic molecule from the donor solution and its appearance in the receiver and demonstrated how interactions with proteins on either side of the cellular barrier influence permeability. Appearance kinetics showed that the composition of the receiving environment is critical to model a particular in vivo situation and implied that the intrinsic permeability of membrane-interactive molecules in vitro does not necessarily predict penetration beyond the initial cellular barrier in vivo.

Animals↗
PubMed1994

Rapid-fire pistol shooting as a dynamic problem.

The kinetic aspects of the aiming phase of a pistol-shooting task were examined in the light of the previous finding of relative timing invariance in the shooting phase of the same task. A single highly skilled marksman executed a total of 45 trials over three timing conditions in a normal competition setting. Data from a tri-axial accelerometer fixed to the pistol were used to produce phase plane trajectories of the movement in each of the three timing conditions. These trajectories showed marked consistency across timing conditions which indicated that the marksman applied a single kinetic solution to his motor problem.

Attention↗
PubMed1994

Rapid screening of the antimicrobial activity of extracts and natural products.

A spectrophotometric method has been developed for the rapid measurement of the antimicrobial activity of natural products, including crude extracts or pure materials. The assay depends on the measurement of non-specific esterase activity using fluorescein diacetate (FDA) hydrolysis in broth cultures of microbes after they have been treated with test compounds. The assay is accurate, reproducible and economical in both time and materials. The speed and economy of the method make it suitable for the rapid screening of many samples and the bioassay directed purification of antimicrobial substances. The assay can also be used with a wide variety of micro-organisms since most micro-organisms are FDA positive. Applications are described in the fields of marine natural products chemistry and essential oils research.

Fluoresceins↗
PubMed1993

Hippocampal choline acetyltransferase activity correlates with spatial learning in aged rats.

Age-related cognitive deficits in both humans and experimental animals appear to relate to dysfunction of basal forebrain cholinergic neuron systems. The present study assessed spatial learning performance in a water maze task as a function of choline acetyltransferase and high-affinity choline uptake specific activity (the two phenotypic markers for cholinergic neurons) in frontal cortex, hippocampus and striatum of aged male Fischer-344 rats. We observed that increased hippocampal choline acetyltransferase activity was related to better performance on the water maze task, and that, of the individual measures, hippocampal choline acetyltransferase activity was the best predictor of behavioral performance in the spatial learning task.

Aging↗