Search PubMed⌕ Search

Biomedical subjects

J D Smith

Publications and source records attributed to J D Smith.

At least 127 records · Page 7Linked to original sources
PubMed1997

A Bayesian formulation of the Kalman filter applied to the estimation of individual pharmacokinetic parameters.

A general method of Bayesian forecasting employing the dynamic linear model has been adapted to the problem of estimating individual pharmacokinetic parameters. The Bayesian forecasting method incorporates an efficient Kalman filter algorithm for updating pharmacokinetic parameter estimates when further observations are made. The Kalman filter is more general and flexible than other Bayesian methods currently used and simulation studies have demonstrated its practicality for three different pharmacokinetic models. The method serves as the basis for a computer program for general clinical use.

Algorithms↗
PubMed1997

The uncertain response in humans and animals.

There has been no comparative psychological study of uncertainty processes. Accordingly, the present experiments asked whether animals, like humans, escape adaptively when they are uncertain. Human and animal observers were given two primary responses in a visual discrimination task, and the opportunity to escape from some trials into easier ones. In one psychophysical task (using a threshold paradigm), humans escaped selectively the difficult trials that left them uncertain of the stimulus. Two rhesus monkeys (Macaca mulatta) also showed this pattern. In a second psychophysical task (using the method of constant stimuli), some humans showed this pattern but one escaped infrequently and nonoptimally. Monkeys showed equivalent individual differences. The data suggest that escapes by humans and monkeys are interesting cognitive analogs and may reflect controlled decisional processes prompted by the perceptual ambiguity at threshold.

Animals↗
PubMed1997

Food embolus.

A 74 year old man with chronic dysphagia acutely developed nausea, vomiting and fever, followed by abrupt, fatal brainstem stroke. Autopsy revealed an esophagoatrial fistula with multiple food emboli to visceral and cerebral arteries. Review of previous cases indicates that new onset atrial fibrillation or pericardial effusion in patients with chronic esophageal symptoms may herald fistula formation. Early recognition of such fistulas may provide an opportunity to intervene before catastrophic embolization or gastrointestinal hemorrhaging occurs.

Aged↗
PubMed1997

Uncertain responses by humans and rhesus monkeys (Macaca mulatta) in a psychophysical same-different task.

The authors asked whether animals, like humans, use an uncertain response adaptively to escape indeterminate stimulus relations. Humans and monkeys were placed in a same-different task, known to be challenging for animals. Its difficulty was increased further by reducing the size of the stimulus differences, thereby making many same and different trials difficult to tell apart. Monkeys do escape selectively from these threshold trials, even while coping with 7 absolute stimulus levels concurrently. Monkeys even adjust their response strategies on short time scales according to the local task conditions. Signal-detection and optimality analyses confirm the similarity of humans' and animals' performances. Whereas associative interpretations account poorly for these results, an intuitive uncertainty construct does so easily. The authors discuss the cognitive processes that allow uncertainty's adaptive use and recommend further comparative studies of metacognition.

Adult↗
PubMed1997

The emergence of mouse models of atherosclerosis and their relevance to clinical research.

Due to the ability to introduce or mutate genes, the mouse has become the most common experimental animal model for atherosclerosis research. Wildtype mice on a chow diet do not get atherosclerosis. Three ways to induce atherosclerosis in mice are discussed: diet-induced, apoE deficiency-induced, and LDL receptor-deficiency induced. The atherosclerotic lesions in apoE-deficient mice have been well characterized, and they resemble human lesions in their sites of predilection and progression to the fibroproliferative stage. These mouse models of atherosclerosis are being used to identify genes which modify atherosclerosis susceptibility and in the development of antiatherogenic therapies.

Animals↗
PubMed1997

Modulation of statolith mass and grouping in white clover (Trifolium repens) growth in 1-g, microgravity and on the clinostat.

Current models of gravity perception in higher plants focus on the buoyant weight of starch-filled amyloplasts as the initial gravity signal susceptor (statolith). However, no tests have yet determined if statolith mass is regulated to increase or decrease gravity stimulus to the plant. To this end, the root caps of white clover (Trifolium repens) grown in three gravity environments with three different levels of gravity stimulation have been examined: (i) 1-g control with normal static gravistimulation, (ii) on a slow clinostat with constant gravistimulation, and (iii) in the stimulus-free microgravity aboard the Space Shuttle. Seedlings were germinated and grown in the BioServe Fluid Processing Apparatus and root cap structure was examined at both light and electron microscopic levels, including three-dimensional cell reconstruction from serial sections. Quantitative analysis of the electron micrographs demonstrated that the starch content of amyloplasts varied with seedling age but not gravity condition. It was also discovered that, unlike in starch storage amyloplasts, all of the starch granules of statolith amyloplasts were encompassed by a fine filamentous, ribosome-excluding matrix. From light micrographic 3-D cell reconstructions, the absolute volume, number, and positional relationships between amyloplasts showed (i) that individual amyloplast volume increased in microgravity but remained constant in seedlings grown for up to three days on the clinostat, (ii) the number of amyloplasts per cell remained unchanged in microgravity but decreased on the clinostat, and (iii) the three-dimensional positions of amyloplasts were not random. Instead amyloplasts in microgravity were grouped near the cell centers while those from the clinostat appeared more dispersed. Taken together, these observations suggest that changing gravity stimulation can elicit feedback control over statolith mass by changing the size, number, and grouping of amyloplasts. These results support the starch-statolith theory of graviperception in higher plants and add to current models with a new feedback control loop as a mechanism for modulation of statolith responsiveness to inertial acceleration.

Fabaceae↗
PubMed1997

Characterization of the binding of amyloid-beta peptide to cell culture-derived native apolipoprotein E2, E3, and E4 isoforms and to isoforms from human plasma.

The epsilon 4 allele of apolipoprotein E (apoE, protein; APOE, gene) is a major risk factor for Alzheimer's disease (AD). Genetically, the frequency of the epsilon 4 allele is enriched in early-onset sporadic, late-onset familial, and common late-onset sporadic AD. ApoE is found in the extracellular amyloid-beta (A beta) deposits that are characteristic features of AD. In this study, we examined the interaction between A beta and apoE isoforms. The apoE isoforms used in this study were either produced by stably transfected Chinese hamster ovary cells (CHO) or were from human plasma. We report that when similar concentrations of the apoE isoforms were used, native nonpurified apoE3 from recombinant CHO-derived sources bound A beta, but apoE4 did not. In fact, in our system, binding of recombinant apoE4 to A beta was never detectable, even after incubation for 4 days. Furthermore, using the same assay conditions, native apoE2, like apoE3, binds A beta avidly. Furthermore, when human plasma apoE isoforms are tested in A beta binding experiments, apoE3 bound A beta more avidly than apoE4, and a major apoE/A beta complex (the 40-kDa form) was observed with plasma apoE3 but not apoE4. These data extend our understanding of apoE isoform-dependent binding of A beta by associating apoE2 with efficient apoE/A beta complex formation and demonstrate that native apoE3 (whether recombinant or derived from human plasma) forms sodium dodecyl sulfate-stable apoE/A beta complexes more readily than native apoE4. The different A beta-binding properties of native apoE4 versus native apoE3 provide insight into the molecular mechanisms by which the APOE epsilon 4 allele exerts its risk factor effects in AD.

Amyloid beta-Peptides↗
PubMed1997

Allocation of attentional resources during habituation to food cues.

Two experiments were designed to test the hypothesis that habituation to repeated food cues can be inhibited by allocating processing resources to nonfood cues. In two experiments, the salivary response to 10 presentations of lemon yogurt was assessed while subjects engaged in a controlled cognitive search task (demanding attentional resources), an automatic search task (needing fewer attentional resources), or no task. In Experiment 1, the controlled and automatic search tasks differed in the number of memory set items. In Experiment 2, the size of the memory sets was held constant, and individuals were provided practice to stabilize the different search strategies in the task. The automatic search and no task groups habituated to the repeated presentation of food cues in both experiments, but the controlled search group did not. These results support the hypothesis that allocation of attentional resources to external cues can influence the processing of food cues.

Adult↗
PubMed1997

Incidence of contralateral versus ipsilateral neurological signs associated with lateralised Hansen type I disc extrusion.

Asymmetrical neurological signs were noted in 50 dogs presenting with Hansen type I thoracolumbar disc extrusion. Thoracolumbar myelograms and surgical decompression were performed in all cases. Dogs were divided into two groups (acute and chronic) based on the duration of clinical signs prior to presentation to the University of Georgia. Lateralising extradural cord compressive lesions were noted on all myelograms. In the acute group, 35 per cent of the dogs had asymmetrical neurological signs contralateral to the myelographic and surgical lesion, while in the chronic group only 11 per cent had neurological signs contralateral to the lesion. There was found to be no significant difference in frequency of contralateral asymmetrical clinical signs between the two groups (Fischer's exact test; P = 0.095). The high frequency of contralateral signs documents the importance of thoracolumbar myelography for accurate localisation of the disc material before decompressive surgery.

Acute Disease↗
PubMed1997

Cerebral lipid deposition in aged apolipoprotein-E-deficient mice.

To assess the influence of age and diet on cerebral pathology in mice lacking apolipoprotein E (apoE), four male apoE knockout mice (epsilon -/-), and five male wild-type (epsilon +/+) littermate controls were placed on a high-fat/high-cholesterol diet for 7 weeks beginning at 17 months of age. All four aged knockout mice developed xanthomatous lesions in the brain consisting mostly of crystalline cholesterol clefts, lipid globules, and foam cells. Smaller xanthomas were confined mainly to the choroid plexus and ventral fornix in the roof of the third ventricle, occasionally extending subpially along the choroidal fissure and into the adjacent parenchyma. More advanced xanthomas disrupted adjoining neural tissue in the fornix, hippocampus, and dorsal diencephalon; in one case, over 60% of one telencephalic hemisphere, including nearly the entire neocortex, was obliterated by the lesion. No xanthomas were observed in aged wild-type controls fed the high-fat/high-cholesterol diet. Brains from 42 additional animals, fed only conventional chow, were examined; 3 of 15 aged (15- to 23-month-old) apoE knockout mice developed small choroidal xanthomas. In contrast, no lesions were observed in five young (2- to 4-month-old) apoE knockout mice or in any wild-type controls between the ages of 2 and 23 months. Our findings indicate that disorders of lipid metabolism can induce significant pathological changes in the central nervous system of aged apoE knockout mice, particularly those on a high-fat/high-cholesterol diet. It may be fruitful to seek potential interactions between genetic factors and diet in modulating the risk of Alzheimer's disease and other neurodegenerative disorders in aged humans.

Aging↗
PubMed1996

Cyclic AMP induces apolipoprotein E binding activity and promotes cholesterol efflux from a macrophage cell line to apolipoprotein acceptors.

RAW 264 mouse macrophage cells were stably transfected with human apolipoprotein E (apoE) expression vectors. Clonal derivatives were characterized for expression of the human apoE2, apoE3, and apoE4 isoforms. An apoE4-expressing clonal cell line and a non-expressing clonal control cell line were loaded overnight with either [3H]cholesterol or [3H]choline. The cells were washed and incubated for 24 h in serum-free medium with or without the addition of 8-bromo-cyclic AMP (8-Br-cAMP). Only the apoE-secreting cells and only in the presence of 8-Br-cAMP released large amounts of labeled cholesterol or phosphatidylcholine into the medium. Mass analyses of cellular free and esterified cholesterol confirmed the results of the labeling studies; a decrease in cellular cholesterol content was observed in the 8-Br-cAMP-treated apoE-secreting cells, concurrent with an increase in cholesterol found in the medium. FPLC analysis of the medium demonstrated that 8-Br-cAMP treatment of the apoE-secreting cells led to an increased size fraction and amount of a peak of secreted cholesterol which comigrated with apoE. The 8-Br-cAMP-mediated increase in cholesterol efflux was also observed in non-apoE-secreting cells incubated with exogenous apoE or apoAI, and the effect of apoE was saturable. The apoE2, apoE3, and apoE4 isoforms were equally efficient in promoting 8-Br-cAMP-dependent cholesterol efflux. Reductive methylation of apoE abolished its ability to promote 8-Br-cAMP-dependent cholesterol efflux. Brefeldin A and monensin, inhibitors of protein processing through the Golgi, both blocked the 8-Br-cAMP stimulation of cholesterol efflux to exogenous apoE. 8-Br-cAMP induced specific apoE and apoAI binding, but not apoE degradation, by the RAW cells. We present a model wherein cAMP induces a membrane apolipoprotein receptor that does not lead to endocytosis and degradation, but instead promotes the transfer of lipids to apolipoproteins, which can then be released from the cell.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1996

Differential modification of activities of the high-affinity and low-affinity insulin receptors of 3T3-L1 fibroblasts by phosphonolipids in vivo.

The low-affinity and high-affinity forms of the insulin receptor respond differently to modifications of cellular phospholipid content in mouse 3T3-L1 fibroblasts in vivo. When cells are cultured with 2-aminoethylphosphonate the resulting phosphonolipid, which has previously been demonstrated to prevent the insulin-induced differentiation of the fibroblasts into adipocytes [J. D. Smith et al., Biochem. Arch. 8, 339-344 (1992)] results in alterations in both the affinity for insulin and receptor number of the low-affinity receptor while leaving the high-affinity receptor unaffected. That this phospholipid modification induces a specific change in the cellular insulin effect is demonstrated by the lack of alteration in the mobilization of GLUT-4 and glucose transport in the lipid modified cells. The results suggest that this specific cellular phospholipid modification will be useful in dissecting the specific functions of the two forms of the mammalian insulin receptor.

3T3 Cells↗
PubMed1996

Combined hyperlipidemia in transgenic mice overexpressing human apolipoprotein Cl.

We have generated transgenic mice over-expressing human apolipoprotein CI (apo CI) using the native gene joined to the downstream 154-bp liver-specific enhancer that we defined for apo E. Human apo CI (HuCI)-transgenic mice showed elevation of plasma triglycerides (mg/dl) compared to controls in both the fasted (211 +/- 81 vs 123 +/- 52, P = 0.0001) and fed (265 +/- 105 vs 146 +/- 68, P < 0.0001) states. Unlike the human apo CII (HuCII)- and apo CIII (HuCIII)-transgenic mouse models of hypertriglyceridemia, plasma cholesterol was disproportionately elevated (95 +/- 23 vs 73 +/- 23, P = 0.002, fasted and 90 +/- 24 vs 61 +/- 14, P < 0.0001, fed). Lipoprotein fractionation showed increased VLDL and IDL + LDL with an increased cholesterol/triglyceride ratio (0.114 vs 0.065, P = 0.02, in VLDL). The VLDL apo E/apo B ratio was decreased 3.4-fold (P = 0.05) and apo CII and apo CIII decreased in proportion to apo E. Triglyceride and apo B production rates were normal, but clearance rates of VLDL triglycerides and postlipolysis lipoprotein "remnants" were significantly slowed. Plasma apo B was significantly elevated. Unlike HuCII- and HuCIII-transgenic mice, VLDL from HuCI transgenic mice bound heparin-Sepharose, a model for cell-surface glycosaminoglycans, normally. In summary, apo CI overexpression is associated with decreased particulate uptake of apo B-containing lipoproteins, leading to increased levels of several potentially atherogenic species, including cholesterol-enriched VLDL, IDL, and LDL.

Animals↗
PubMed1996

Competition and the canonical ensemble.

Gibbs' canonical ensemble model from equilibrium statistical mechanics furnishes solutions to Eigen's phenomenological rate equations under constant total organization in cases with or without mutability. The evolution of species with mutation under constant total organization reduces to the evolution of substantial virtual species without mutation under the same constant total organization. Application of the canonical ensemble model provides an exact correspondence between thermodynamic and biological parameters. In particular, evolutionary time, as the analog of temperature, emerges as a statistical aggregate of the condition of the evolving system.

Biological Evolution↗