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Biomedical subjects

T J Phillips

Publications and source records attributed to T J Phillips.

At least 19 recordsLinked to original sources
PubMed1999

Ontogeny of ethanol-induced locomotor activity and hypothermia differences in selectively bred FAST and SLOW mice.

The replicate lines of selectively bred FAST and SLOW mice differ in locomotor response to 2 g/kg ethanol (EtOH). FAST mice show enhanced locomotion; SLOW mice exhibit no change or locomotor depression. Little is known about the responses of FAST and SLOW mice to EtOH during development. We assessed the locomotor responses of FAST and SLOW mice at postnatal days (P) 10, 15, 30, and 60. A genetically correlated response, EtOH-induced hypothermia, was also investigated. Although all animals demonstrated their respective selection phenotypes in adulthood, developing FAST mice exhibited ethanol stimulation by P15 (replicate 1) or P30 (replicate 2). At these ages, responses of FAST mice differed from those of SLOW. The stimulant response in FAST mice was adult-like at P30. EtOH-induced hypothermia was seen in SLOW mice by P15. These data suggest that sensitivity to the locomotor stimulant effects of EtOH changes during postnatal development, and may mirror developmental profiles for certain neurotransmitter systems.

Aging↗
PubMed1999

Identifying genes for alcohol and drug sensitivity: recent progress and future directions.

New methods for identifying chromosomal regions containing genes that affect murine responses to alcohol and drugs have been used to identify many provisional quantitative trait loci (QTLs) since 1991. By 1998, 24 QTLs had been definitively mapped (P<5x10(-5)) to specific murine chromosomes, which indicates the presence of a relevant gene or genes at each location. The syntenic (homologous) region of the human genome for these genes is often known. For many mapped QTLs, candidate genes with relevant neurobiological function lie within the mapped region. Data that implicate candidate genes for specific responses include studies of knockout animals. Current strategies for gene identification include the use of congenic strains containing QTL regions introduced from another strain. There is increasing emphasis on gene-gene and gene-environment interactions in such studies.

Alcohol Drinking↗
PubMed1999

The long-term effect of an innovative family physician curricular pathway on the specialty and location of graduates of the University of Washington.

PURPOSE: To report the specialty and rural/urban distribution a mean of 19 years after graduation for a cohort of students from a family physician curricular pathway. METHOD: Specialty and location information for medical students who had entered the University of Washington between 1968 and 1973 was obtained from the 1994 Physician Masterfile of the American Medical Association. RESULTS: Of the 239 family physician pathway graduates, 173 (72%) had intended family practice at graduation, and 136 (57%) were family physicians two decades later. The proportions of all graduates in family practice and of graduates serving rural Washington as family physicians had increased over that of a cohort of students who had entered the University of Washington prior to the introduction of the pathway curriculum. These proportions surpassed the goals set at the time the new curriculum was introduced. CONCLUSION: With early identification and support of students interested in family practice, an increased number entered the specialty and were still family physicians in mid-career.

Career Choice↗
PubMed1999

Endoscopy of the navicular bursa: a new technique for the treatment of contaminated and septic bursae.

A technique for evaluation of the navicular bursa using a 4 mm 25 degrees inclined view arthroscope is described. This allows examination of the palmar/plantar surface of the navicular bone, the insertions of the navicular suspensory, T and impar ligaments, the bursal synovium and the dorsal surface of the deep digital flexor tendon. The technique was used in 16 horses with punctures of the navicular bursa. Procedures facilitated by the technique were bursal lavage, removal of pannus, synovial resection and debridement of lesions on the palmar/plantar surface of the bone and in the deep digital flexor tendon. Following treatment, 10 animals were sound and returned to their pre-injury use and 6 animals had persistent lameness; 2 of these were salvaged after neurectomy, 1 was retired for use as a broodmare and 2 were destroyed. In contrast to the 'streetnail' procedure, the reported technique is less invasive and post operative care is simpler. The success rate is also better. Endoscopically guided treatment therefore appears to offer an advantage in the treatment of contaminated or septic navicular bursae.

Animals↗
PubMed1998

Locomotor activity in D2 dopamine receptor-deficient mice is determined by gene dosage, genetic background, and developmental adaptations.

Locomotor activity is a polygenic trait that varies widely among inbred strains of mice (). To characterize the role of D2 dopamine receptors in locomotion, we generated F2 hybrid (129/Sv x C57BL/6) D2 dopamine receptor (D2R)-deficient mice by gene targeting and investigated the contribution of genetic background to open-field activity and rotarod performance. Horizontal activity of D2R-/- mice was approximately half that of drug-naive, strain-matched controls but was significantly greater than haloperidol-treated controls, which were markedly hypokinetic. Wild-type 129/SvEv and C57BL/6 mice with functional D2 receptors had greater interstrain differences in spontaneous activity than those among the F2 hybrid mutants. Incipient congenic strains of D2R-deficient mice demonstrated an orderly gene dosage reduction in locomotion superimposed on both extremes of parental background locomotor activity. In contrast, F2 hybrid D2R-/- mice had impaired motor coordination on the rotarod that was corrected in the congenic C57BL/6 background. Wild-type 129/SvEv mice had the poorest rotarod ability of all groups tested, suggesting that linked substrain 129 alleles, not the absence of D2 receptors per se, were largely responsible for the reduced function of the F2 hybrid D2R-/- and D2R+/- mice. Neurochemical and pharmacological studies revealed unexpectedly normal tissue striatal monoamine levels and no evidence for supersensitive D1, D3, or D4 dopamine receptors in the D2R-/- mice. However, after acute monoamine depletion, akinetic D2R+/- mice had a significantly greater synergistic restoration of locomotion in response to SKF38393 and quinpirole compared with any group of D2R+/+ controls. We conclude that D2R-deficient mice are not a model of Parkinson's disease. Our studies highlight the interaction of multiple genetic factors in the analysis of complex behaviors in gene knock-out mice.

Adaptation, Physiological↗
PubMed1998

Localization of genes mediating acute and sensitized locomotor responses to cocaine in BXD/Ty recombinant inbred mice.

Sensitization to the psychostimulant effects of cocaine has received widespread attention because concomitant changes occur in neurochemical pathways that are part of the brain reward pathway. The current study was undertaken with the purpose of mapping genes determining sensitivity to the acute stimulant and sensitizing effects of cocaine. Sensitivity and sensitization to cocaine (5, 10, and 40 mg/kg) were measured in 25 BXD/Ty recombinant inbred (BXD RI) strains and the progenitor C57BL/6J (B6) and DBA/2J (D2) strains. Quantitative trait locus (QTL) mapping provisionally localized cocaine sensitivity genes to regions on all chromosomes except 6, 11, 17, and X; sensitization QTLs were localized to chromosomes 1-10, 13, 15, 18, 19, and X. Provisional QTLs for locomotion after saline injection in a novel setting were mapped to chromosomes 1, 3-6, 9, 12, 13, 18, and 19 and in a familiar setting to chromosomes 4-7, 9, 13, and 19. There were both common and unique QTL regions across the phenotypes. Evidence for a genetic association between magnitude of acute cocaine response and sensitization was obtained for only the 10 mg/kg dose. Some common QTL regions for cocaine, ethanol, and methamphetamine responses suggest the possibility that these drugs induce stimulant effects or sensitization through some common mechanisms. However, independent mechanisms were also indicated. Many candidate genes reside near the provisional QTLs mapped for cocaine responses, including genes coding a variety of neurotransmitter and hormone receptors. These data, once confirmed, should prove useful for directing investigations of acute and chronic cocaine effects down already suspected and novel avenues.

Animals↗
PubMed1998

Duration of sensitization to the locomotor stimulant effects of ethanol in mice.

Behavioral sensitization to the psychomotor stimulant effects of some drugs can be quite persistent, lasting for weeks to months after cessation of drug exposure. We investigated the duration of sensitization to the locomotor stimulant effects of 2.0 g/kg ethanol (EtOH) and determined whether repeated EtOH administration would lead to alterations in blood EtOH clearance rates. Female mice were injected (IP) daily for up to 10 consecutive days with saline or EtOH. Baseline activity and acute EtOH locomotor responses were evaluated in Omnitech automated activity monitors (10-min test), with horizontal distance traveled as the measure of locomotion. Locomotor activity response to EtOH was reevaluated immediately after the final daily EtOH injection, and at 5-day intervals during which no EtOH was administered. Tail blood samples for determination of blood ethanol concentrations (BECs) were collected from EtOH-treated mice at the end of activity sessions. Sensitization lasted for up to 29 days, and in two of three of the behavioral sensitization studies, repeated EtOH treatment resulted in elevated BECs. There was no significant effect of repeated EtOH exposure on EtOH clearance rate in a study involving no behavioral testing. The demonstration of persistent behavioral sensitization may imply a lasting hypersensitivity of certain neural pathways to EtOH, thus increasing the reinforcing value of EtOH and the probability of relapse to EtOH drinking after abstinence.

Animals↗
PubMed1998

Genes on mouse chromosomes 2 and 9 determine variation in ethanol consumption.

Quantitative trait locus (QTL) mapping efforts in alcohol (ethanol) research are beginning to generate promising data that may ultimately lead to the identification of genes influencing alcohol addiction. Rodents have been extensively utilized to study ethanol's rewarding and aversive effects, and to demonstrate the existence of genetic influences on traits such as free-choice ethanol-consumption, ethanol-conditioned place preference and ethanol-conditioned taste aversion. The purpose of the current investigation was to verify or eliminate from further consideration putative QTLs for free-choice ethanol consumption originally identified in BXD Recombinant Inbred (RI) strains and other informative genetic crosses. B6D2F2 mice were utilized in a verification testing strategy to evaluate the viability of putative ethanol consumption QTLs. When data were combined from BXD RI, B6D2F2 and short-term selected line (STSL) mapping studies, verification was obtained for two QTLs, one on Chromosome (Chr) 9 (proximal-mid) and another on Chr 2 (distal), and suggestive verification was obtained for QTLs on Chrs 2 (proximal), 3, 4, 7, and 15. In addition, the possible genetic association of ethanol consumption with conditioned place preference was evaluated. Genetic correlations were estimated from BXD RI strain means, and QTL maps for these traits were compared to evaluate the possibility of a genetic association. The correlational analysis yielded a trend (r = 0.34, p = 0.09), but no statistically significant results. However, comparisons of QTL mapping results between phenotypes suggested some possible genetic overlap for these traits, both putative measures of ethanol reward. These data suggest that the determinants of these two measures are genetically diverse, but may share some common genetic elements.

Alcohol Drinking↗
PubMed1998

High genetic susceptibility to ethanol withdrawal predicts low ethanol consumption.

C57BL/6J (B6) inbred mice are well known to drink large amounts of alcohol (ethanol) voluntarily and to have only modest ethanol-induced withdrawal under fixed dose conditions. In contrast, DBA/2J (D2) mice are "teetotallers" and exhibit severe ethanol withdrawal. Speculation that an inverse genetic relationship existed between these two traits was substantiated by meta-analysis of existing data collected in multiple genetic models, including large panels of standard and recombinant inbred strains, their crosses, and selectively bred mouse lines. Despite methodological differences among laboratories in measurement of both preference drinking and withdrawal, a nearly universal finding was that genotypes consuming large amounts of 10% ethanol (calculated as g/kg/day) during two-bottle choice preference drinking were genetically predisposed to low withdrawal scores in independent studies after either acute or chronic ethanol treatment. Conversely, low-drinking genotypes had higher withdrawal severity scores. The genetic relationship appears to be strongest in populations derived from B6 and D2, where data from more genotypes (BXD RIs, B6D2F2s, BXD RI F1s, and B6D2F2-derived selectively bred lines) were available for analysis. Gene mapping studies in these populations identified four chromosome regions [on Chromosomes (Chrs) 1, 2, 4, and 15] where genes might potentially influence both traits. Among genotypes with greater genetic diversity (for example, a panel of standard inbred strains or selectively bred lines), the relationship was less pronounced. Thus, reduced susceptibility to the development of high alcohol use may be supported by increased genetic susceptibility to ethanol withdrawal symptoms.

Alcohol Drinking↗
PubMed1998

MK-801 potentiates ethanol's effects on locomotor activity in mice.

FAST vs. SLOW selected mouse lines and C57BL/6J (B6) vs. DBA/2J (D2) inbred strains differ in their sensitivities to ethanol's locomotor stimulant effects, and provide two unique sets of genetic animal models to study neurophysiological substrates of this behavior. To determine whether NMDA receptor function mediates sensitivity to ethanol's stimulant effects, we assessed the effects of the noncompetitive NMDA antagonist, MK-801, on locomotor activity of naive and ethanol-treated FAST, SLOW, B6, and D2 mice. MK-801 (0.01-0.5 mg/kg, I.P.) had biphasic effects in all genotypes, with stimulation at moderate doses and decreased activation at the highest dose. FAST mice were more activated by MK-801 than SLOW mice, suggesting that selection differentially altered NMDA receptor function between the lines. B6 and D2 mice did not differ in locomotor responses following MK-801 administration. Stimulant doses of MK-801 decreased or blocked ethanol-stimulated locomotor activity in FAST and D2 mice, and potentiated the locomotor depressant actions of ethanol in SLOW and B6 mice. Potentiation of ethanol's activating properties was observed in one treatment group in D2 mice. These data suggest that NMDA receptors modulate ethanol's stimulant properties, by a more significant involvement in expression of ethanol's locomotor depressant properties.

Aging↗
PubMed1998

Pressure ulcers.

Pressure ulcers are localized areas of tissue necrosis that result from unrelieved pressure. They are graded or staged according to the degree of tissue damage observed. The main etiologic factors include pressure, shearing forces, friction, and moisture. The clinical course may be complicated by several conditions including infection, sepsis, osteomyelitis, fistulas, and carcinoma. Preventive measures in persons at risk can significantly reduce the incidence of pressure ulcers. Successful management should address the four etiologic factors as well as the general condition of the patient.

Humans↗
PubMed1998

Once-daily tazarotene gel versus twice-daily fluocinonide cream in the treatment of plaque psoriasis.

BACKGROUND: A new class of topical receptor-selective acetylenic retinoids, the first of which is tazarotene, has been developed. OBJECTIVE: Our purpose was to compare the safety, efficacy, and duration of therapeutic effect of 12 weeks of once-daily tazarotene 0.1% and 0.05% gel with that of twice-daily fluocinonide 0.05% cream in the treatment of patients with plaque psoriasis. METHODS: Three hundred forty-eight patients with plaque psoriasis were enrolled and 275 patients completed a multicenter, investigator-masked, randomized, parallel-group clinical trial. RESULTS: Both tazarotene gels were as effective as fluocinonide in reducing plaque elevation after 1 week of treatment, and tazarotene 0.1% gel was similar to fluocinonide in reducing scaling of trunk/limb lesions at all study weeks except week 4. Tazarotene 0. 1% gel was similar to fluocinonide in reducing scaling of knee/elbow lesions at weeks 8 and 12. Fluocinonide had a significantly greater effect on erythema than tazarotene at weeks 2 through 8. However, treatments were not significantly different at week 12, and tazarotene demonstrated significantly better maintenance of therapeutic effect after cessation of therapy. CONCLUSION: Tazarotene 0.1% and 0.05% gels were safe and effective in the treatment of mild-to-moderate plaque psoriasis.

Administration, Cutaneous↗
PubMed1998

Alcohol preference and sensitivity are markedly reduced in mice lacking dopamine D2 receptors.

Although dopaminergic transmission has been strongly implicated in alcohol self-administration, the involvement of specific dopamine receptor subtypes has not been well established. We studied the ethanol preference and sensitivity of D2-receptor-deficient mice to directly evaluate whether dopamine D2 receptors contribute to alcohol (ethanol) consumption. We report a marked aversion to ethanol in these mice, relative to the high preference and consumption exhibited by wild-type littermates. Sensitivity to ethanol-induced locomotor impairment was also reduced in these mutant mice, although they showed a normal locomotor depressant response to the dopamine D1 antagonist SCH-23390. These data demonstrate that dopamine signaling via D2 receptors is an essential component of the molecular pathway determining ethanol self-administration and sensitivity.

Alcohol Drinking↗
PubMed1998

Expression of c-fos and c-Ha-ras proto-oncogenes is induced in human chronic wounds.

BACKGROUND: It is known that chronic wounds such as leg ulcers have an increased risk of malignant transformation, mainly to squamous cell carcinoma (reviewed in Reference 1). OBJECTIVES: To better understand the molecular changes responsible for this increased risk of malignant transformation, we examined the expression of c-fos and c-Ha-ras, proto-oncogenes known to be involved in cellular proliferation and transformation, in chronic wounds. RESULTS: The level of both c-fos and c-Ha-ras mRNAs, determined by in situ hybridization, were heavily induced in the basal layer of epidermis in chronic wounds when compared to normal skin and acute wounds, (originated from the edge of wounds created by Moh's surgery). Expression of both proto-oncogenes was not detected in the dermis of any groups. CONCLUSIONS: These results suggest that elevated expression of proto-oncogenes may be partly responsible for the increase susceptibility of chronic wounds to malignant transformation.

Aged↗
PubMed1998

Compression therapy.

BACKGROUND: Compression therapy is the standard care for venous insufficiency ulcers. It reverses some of the underlying pathologies and restores a functional calf pump unit. OBJECTIVES: To review the pathophysiology of venous ulcers and the different types of compression devices available. RESULTS: The choice of a compression device should be individualized and tailored to the need of the patient. It should be applied by skilled nurses or physicians. CONCLUSION: Compression therapy continues to constitute the standard therapy for venous insufficiency ulcers.

Bandages↗
PubMed1998

Effect of chronic wound fluid on fibroblasts.

This study examines how the microenvironment created by fluid in chronic wounds influences the growth of dermal fibroblasts. Newborn fibroblasts, which are known to grow rapidly, were used as a model system to explore how chronic wound fluid affects the growth of regenerative fibroblasts. Wound fluid was collected from patients with chronic venous leg ulcers (duration longer than two months). The biological properties of this fluid were then further characterised to elucidate its molecular effects on cell growth. Results indicate that chronic wound fluid dramatically inhibited the growth of newborn dermal fibroblasts. This growth inhibitory effect was variable among donors, reversible and heat-sensitive. The inhibitory effect was due not to cytotoxicity or impaired plating efficiency of these cells, but to specific interference with the cell cycle. Chronic wound fluid arrested newborn fibroblast growth by preventing entry into the S-phase, or DNA synthesis-phase, of the cell cycle. In contrast to its effects on newborn fibroblasts, chronic wound fluid either stimulated or had a minimal effect on fibroblasts which had been cultured from the edge of chronic venous leg ulcers and healthy tissue on the upper thigh in the same patient. This may partially account for the impaired healing seen in chronic venous leg ulcers.

Adult↗
PubMed1998

Quantitative trait loci affecting peak bone mineral density in mice.

Peak bone mass is a major determinant of risk of osteoporotic fracture. Family and twin studies have found a strong genetic component to the determination of bone mineral density (BMD). However, BMD is a complex trait whose expression is confounded by environmental influences and polygenic inheritance. The number, locations, and effects of the individual genes contributing to natural variation in this trait are all unknown. Experimental animal models provide a means to circumvent complicating environmental factors, and the development of dense genetic maps based on molecular markers now provides opportunities to resolve quantitative genetic variation into individual regions of the genome influencing a given trait (quantitative trait loci, QTL). To begin to identify the heritable determinants of BMD, we have examined genetically distinct laboratory mouse strains raised under strict environmental control. Mouse whole-body bone mineral content by dual-energy X-ray absorptiometry (DXA) correlated strongly with skeletal calcium content by ashing, and peak whole-body BMD by DXA in female mice occurred at approximately 80-90 days of age. We therefore determined mean body weight and peak whole body BMD values in 12-week-old female mice from a panel of 24 recombinant inbred (RI) BXD strains, derived from a cross between C57BL/6 and DBA/2 progenitors. The distribution of body weight and BMD values among the strains clearly indicated the presence of strong genetic influences on both of these traits, with an estimated narrow sense heritability of 60% and 35%, respectively. The patterns of differences in body weight and peak whole body BMD in the BXD strains were then integrated with a large database of genetic markers previously defined in the RI BXD strains to generate chromosome map sites for QTL. After correction for redundancy among the significant correlations, QTL analysis of the BXD RI strain series provisionally identified 10 chromosomal sites linked to peak bone mass development in the female. Several of the identified sites map near genes encoding hormones, structural proteins, and cell surface receptors that are intricately involved in skeletal homeostasis. Four QTL for body weight were also identified. One of these loci was also strongly linked to inherited variation in BMD. This finding suggests that body weight and peak BMD may be influenced by linked genes or perhaps by common genes with pleiotropic effects. Our phenotyping in the RI BXD strains has allowed us to map a number of specific genetic loci strongly related to the acquisition of peak BMD. Confirmation of these findings will likely result in the understanding of which genes control skeletal health.

Absorptiometry, Photon↗