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Biomedical subjects

T J Phillips

Publications and source records attributed to T J Phillips.

At least 145 records · Page 8Linked to original sources
PubMed1991

Genetic analyses of the biphasic nature of the alcohol dose-response curve.

Ethanol (ETOH)-induced locomotor activation and depression were studied in 23 genotypes of mice. This included a diallel cross of four inbred strains tested with a range of ETOH doses from 0 to 2.75 g/kg. The diversity in shapes of the biphasic ETOH dose-response curves was both qualitative and quantitative, and additive gene action characterized the genetic control of the dose-response curve. Small dominance effects were typically directional in the direction of more activation, or resistance to sedation. No evidence was found for maternal effects, sex linkage, or epistasis. Sex differences were seen in the increased susceptibility of male mice to locomotor sedation at higher ETOH doses. In the diallel cross, there was no correlation between the degree of activation produced by low ETOH doses and sedation produced by higher doses. This indicates that while considerable genetic influences exist for both activational and sedative domains of ETOH effects, these genetic influences are relatively independent.

Adult↗
PubMed1991

Use of recombinant inbred strains to assess vulnerability to drug abuse at the genetic level.

The use of Recombinant Inbred mouse Strains (RIS) to derive information about the complexity of the genetic architecture underlying various traits is increasing in popularity. Behaviors measured to index sensitivity to drug effects and vulnerability to drug abuse are considered here. Potential uses of RIS are identification of major gene effects, mapping of traits to particular chromosomal sites, determining genetic correlations between characters, and identifying behaviorally extreme genotypes. This approach has led to identification of a major gene moderating alcohol acceptance in mice and has revealed a more complex polygenic system influencing morphine consumption.

Alcohol Drinking↗
PubMed1991

Locomotor activity response to chronic ethanol treatment in selectively bred FAST and SLOW mice.

FAST and SLOW mice were selectively bred for differential sensitivity to the acute locomotor stimulant effects of alcohol. On average, FAST mice are stimulated by low alcohol doses, while SLOW mice are depressed or unaffected. We report here that, with chronic treatment, SLOW mice develop tolerance to an acute depressant effect, and subsequently exhibit a stimulant response. No evidence was obtained for tolerance to alcohol's stimulant effects during chronic exposure of FAST mice. However, evidence for the development of a sensitized response was found. If locomotor stimulation reflects reinforcement, and models the alcohol-induced euphoria reported by man, perhaps the absence of tolerance development to reinforcing effects provide a strong impetus for the development of alcoholism.

Alcoholism↗
PubMed1991

Cultured epidermal allografts as biological wound dressings.

Recent advances in cell culture technology permit the generation of large stratified epithelial sheets appropriate for wound coverage. Autografts (sheets prepared from the patient's own skin) have proven life-saving in the treatment of large third-degree burns and have been successfully employed in the management of chronic ulcers. Allografts (sheets prepared from the skin of an unrelated donor) have also been used. In our experience, cultured allografts derived from neonatal foreskin provide a potent stimulus to healing in a variety of partial thickness wounds. Their application is a simple outpatient procedure which involves no discomfort for the patient. In contrast to autografting, no biopsy is necessary and use of cultured allogenic cells permits immediate grafts availability and possibility of stockpiling and preserving grafts for future use. Preparation of epithelial sheets suitable for grafting is also faster and easier with newborn than with adult donor cells. Newborn allografts have caused rapid healing of most previously refractory ulcers with long-term results comparable to those obtained with conventional split thickness grafting. We postulate that cultured allografts act by providing a temporary wound covering while releasing multiple cytokines that synergistically promote permanent reepitheliazation by previously quiescent host keratinocytes then stimulated to divide and migrate. Whether allografts are immunologically rejected in a clinically undetectable reaction or simply replaced stochastically by host keratinocytes is presently unknown.

Biological Dressings↗
PubMed1990

Response to selection for sensitivity to ethanol hypothermia: genetic analyses.

Selective breeding has been used to produce lines of mice differing in sensitivity to the hypothermic effects of ethanol (EtOH). Two genetically independent HOT (insensitive) and two COLD (sensitive) lines are maintained along with two nonselected control (CON) lines. The breeding program is currently in selected generation 14, and HOT and COLD mice differ by about 4 degrees C in selected hypothermic response. Estimates of heritability indicate that approximately 20% of the variance in EtOH-induced hypothermic response in mice is of additive genetic origin. Inbreeding has increased at a rate of about 1.7% per generation and no fertility problems have been detected as a result of selection. Projects designed to evaluate apparent correlated responses to selection are discussed.

Animals↗
PubMed1990

Distinctions among sedative, disinhibitory, and ataxic properties of ethanol in inbred and selectively bred mice.

Three different domains of behavioral action of ethanol (ETOH) were examined in a battery of seven inbred strains and in the selectively bred Long-Sleep (LS) and Short-Sleep (SS) mice. Sedative effects were examined with the loss of the righting reflex test at 3.8 g/kg. The variation among inbred strains was only half the size of the difference between LS and SS mice which were selectively bred for extremes in this phenotype; such a result is expected for phenotypes controlled polygenically. Blood ETOH levels at waking from the narcosis also showed a range of differences among the inbred strains that was less than the LS/SS difference. Ataxia was measured with the grid test, and the inbred strains fell into two groups, resembling the highly ataxic LS line, and the less ataxic SS line. Biphasic effects of ETOH on locomotor activity were strongly genotype dependent. Variation in degree of activation/disinhibition produced by doses up to 1.5 g/kg (IP) ranged from no activation, in the C57BL/6Abg strain which was larger than that seen for SS mice. The patterns of strain differences for both ataxia and activation were highly different from the duration of loss of righting reflex measure, suggesting multiple independent genetically based "sensitivities" to ETOH.

Animals↗
PubMed1990

Cultured epidermal autografts and allografts: a study of differentiation and allograft survival.

Cultured epidermal sheets were examined before and at various times after grafting on skin ulcer beds. Before grafting, the sheet consisted of four to five layers of keratinocytes with incomplete differentiation. Ten days after grafting, graft recipient sites showed compact hyperkeratosis, a normal-appearing epidermis, and a flat dermoepidermal junction. At 6 months, the stratum corneum had a basket-weave appearance but the dermoepidermal junction remained flat. Monoclonal antibodies to keratins 14 and 10 showed normal basal and suprabasal localization, respectively. Electron microscopy showed a normal basement membrane with anchoring fibrils. LH7:2, a monoclonal antibody that binds to the type VII collagen molecule, stained the dermoepidermal junction in all biopsy specimens. AE-1, an antibody that stains suprabasal cells in hyperproliferative skin, was expressed suprabasally for up to 12 weeks after healing (16 weeks after grafting), but expression was confined to the basal layer at 18 weeks after healing (6 months after grafting). Anti-involucrin staining was found in the deeper layers of the epidermis up to 12 weeks after healing (16 weeks after grafting) but had receded to a normal distribution in upper spinous and granular layers at 18 weeks (6 months after grafting). Overall, the histologic patterns observed in recipient sites during the first 4 months after grafting resembled those observed for 10 to 14 days in newly healed epidermis and in hyperproliferative states such as psoriasis. In four sex-mismatched graft sites, specimens were reacted with a biotinylated probe to the Y chromosome by in situ hybridization. Lack of Y chromosome-positive cells suggested that host keratinocytes had replaced the allografts. Multilocus DNA analysis in one patient confirmed this observation. Our data suggest that an altered state of epithelial maturation persists for several months after culture grafting, with restoration of the normal pattern by 6 months. No differences were detected between autografted and allografted sites.

Cells, Cultured↗
PubMed1990

Improvement of oncology education at the University of Washington School of Medicine, 1984-1988.

In 1984, performance on the National Board of Medical Examiners (NBME) examination by medical students from the University of Washington School of Medicine was significantly lower in clinical oncology, pathology, surgery, and oncology-related subjects than was their performance in other subjects (p = .002) and inversely proportional to the degree of oncology-relatedness of the material examined. Moreover, their performance on oncology-related questions was significantly lower than the national average (p less than .001). The curriculum committee thus initiated a review of the oncology content in the curriculum of the school of medicine and implemented a two-year plan in 1984-1986 to improve the perceived deficiencies. During the year the two-year intervention was completed, reevaluation demonstrated evidence that substantial improvement had occurred in oncology performance by the students, relative to their performance in non-oncology subjects (p less than .05) and to the national average. Performance on the non-oncology items was unchanged. The authors conclude that oncology education and performance of the students was significantly improved within two years, after instituting the short-term plan to enhance cancer education in the medical school, the improvement in oncology did not occur at the expense of a reduction in performance in non-oncology subjects, and the improved performance in oncology by the students enhanced their overall performance on the NBME examination.

Academic Medical Centers↗
PubMed1990

Estimation of genetic correlation: interpretation of experiments using selectively bred and inbred animals.

There is increasing interest in determining the extent to which multiple characters related to drug sensitivity are influenced by common genes. The principal method for testing for the existence of such genetic correlations has been examination of pairs of mouse or rat lines selectively bred for sensitivity or resistance to a single behavioral effect of a drug. When a pair of selected lines is found to differ significantly on some trait other than the one on which they were selected, it is commonly concluded that significant genetic correlation between the traits exists, implying the action of a common set of genes on the two responses. In addition, results from comparisons of lines of animals selected for trait X and tested for trait Y may be compared with results from lines selected for trait Y and tested for trait X. As the number of correlated responses in selected lines increases, it becomes more important to adhere to sensible, consensual guidelines for interpreting such line differences. The principles underlying phenotypic and genotypic correlational analyses with selected lines are discussed. A scheme is presented to allow standardization across laboratories of inferences about the relative strength of genetic association from experiments with selected lines. Statistical and practical experimental issues are addressed. Estimates of genetic correlations may also be derived from the correlation of mean trait values across a panel of inbred strains. Existing data have sometimes found estimates of genetic correlations made with one approach to be inconsistent with those estimated in other ways. Possible reasons for this are discussed. Finally, the relationship between phenotypic correlations and genetic correlations is discussed. Phenotypic and genetic correlations for a pair of traits may differ widely, and may even be opposite in sign. Both are characteristic of the population from which they are sampled. Phenotypic correlations estimated within selected lines may change over time, as the additive genetic variance in the selected trait is exhausted. A specific example of this phenomenon is given.

Alcoholic Intoxication↗
PubMed1990

Cultured epidermal grafts in the treatment of leg ulcers.

Cultured epidermal grafts offer a major advance in the treatment of burns and other disabling skin wounds in which there are few other available treatments. Cultured allografts offer immediate availability, obviating skin biopsies. Theoretically, they could be grown in advance, cryopreserved, and stored in skin banks. They provide rapid coverage of wounds and produce prompt relief of pain and healing that continues for many weeks after the graft has been applied. Their mechanism of action has not been elucidated, but it seems likely that the allografted cells do not survive permanently and are gradually replaced by host epithelial cells. Release of growth factors by cultured allografts may contribute significantly to their wound healing properties. Whatever their mechanism of action, they promote rapid epithelialization at least in small chronic wounds. Especially for the elderly patient with nonhealing ulcers, they offer an alternative treatment option that is simple, painless, and noninvasive.

Biological Dressings↗
PubMed1989

Selected mouse lines, alcohol and behavior.

The technique of selective breeding has been employed to develop a number of mouse lines differing in genetic sensitivity to specific effects of ethanol. Genetic animal models for sensitivity to the hypnotic, thermoregulatory, excitatory, and dependence-producing effects of alcohol have been developed. These genetic animal models have been utilized in numerous studies to assess the bases for those genetic differences, and to determine the specific neurochemical and neurophysiological bases for ethanol's actions. Work with these lines has challenged some long-held beliefs about ethanol's mechanisms of action. For example, lines genetically sensitive to one effect of ethanol are not necessarily sensitive to others, which demonstrates that no single set of genes modulates all ethanol effects. LS mice, selected for sensitivity to ethanol anesthesia, are not similarly sensitive to all anesthetic drugs, which demonstrates that all such drugs cannot have a common mechanism of action. On the other hand, WSP mice, genetically susceptible to the development of severe ethanol withdrawal, show a similar predisposition to diazepam and phenobarbital withdrawal, which suggests that there may be a common set of genes underlying drug dependencies. Studies with these models have also revealed important new directions for future mechanism-oriented research. Several studies implicate brain gamma-aminobutyric acid and dopamine systems as potentially important mediators of susceptibility to alcohol intoxication. The stability of the genetic animal models across laboratories and generations will continue to increase their power as analytic tools.

Animals↗
PubMed1989

Genotype-dependent effects of GABAergic agents on sedative properties of ethanol.

Two lines of mice, selectively bred for differential sensitivity to the soporific effects of ethanol (ETOH), were administered GABAergic drugs in an effort to evaluate a role for GABA in ETOH sensitivity. ETOH sensitive Long-Sleep mice (LS) showed potentiated ETOH sedation when administered bicuculline, muscimol and aminooxyacetic acid (AOAA). ETOH-insensitive SS mice exhibited reduced ETOH sedation in the presence of the antagonists, bicuculline and picrotoxin, and potentiated sedation in the presence of muscimol and AOAA. These changes in narcosis duration were interpreted as central effects, since blood ethanol levels at waking from ETOH sedation varied with GABAergic drug treatment. Picrotoxin antagonized pentobarbital-induced narcosis in both lines, but to a greater extent in SS mice. These and other experiments with a genetically heterogeneous stock suggest GABA involvement in genotype-dependent ETOH sensitivity, but do not support a simple role of GABA receptor involvement.

Animals↗
PubMed1989

Convulsant properties of GABA antagonists and anticonvulsant properties of ethanol in selectively bred long- and short-sleep mice.

The convulsant potency of bicuculline, a GABA antagonist, was shown to be greater in Short-Sleep (SS) mice than in Long-Sleep (LS) mice. LS mice, selectively bred for lengthy ethanol-induced narcosis, had longer latencies to myoclonus and clonus following administration of bicuculline and picrotoxin than did ethanol-resistant SS mice. SS mice were also more susceptible to pentylenetetrazol-induced myoclonus, but not clonus. F1 hybrids showed bicuculline seizure sensitivity intermediate to the two parent lines. Ethanol weakly inhibited bicuculline-induced myoclonus in both LS and SS mice. Clonus was clearly antagonized by ethanol in both lines, but to a similar degree. These data provide evidence for a GABAergic role in genotype-dependent sensitivity to ethanol.

Animals↗