Spontaneous otoacoustic emission in a pony.
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Animals↗
Biomedical subjects
T J Phillips
Publications and source records attributed to T J Phillips.
Dopamine antagonist effects on locomotor activity in naive and ethanol-treated FAST and SLOW selected lines of mice.
The FAST and SLOW lines of mice are being selectively bred in replicate for differential sensitivities to the locomotor activating effects of ethanol. Whereas FAST-1 and FAST-2 mice are stimulated by 2.0 g/kg ethanol, SLOW-1 and SLOW-2 mice are not stimulated, and are often depressed, by this dose. The dopamine antagonists, SCH-23390 (D1) and raclopride (D2), produced dose-dependent decreases in the locomotor activity of EtOH-naive mice of both lines and replicates; however, FAST and SLOW mice were not differentially sensitive to these effects. The absence of a line difference in activity response to the dopamine antagonists suggests that dopamine receptor function has not been altered by selective breeding for differences in sensitivity to the stimulant effects of ethanol. The ethanol-stimulated activity of FAST-1 and FAST-2 mice was decreased by administration of the dopamine antagonists, haloperidol and raclopride, at doses that had no effect on basal locomotor activity. SCH-23390 decreased ethanol-stimulated activity of FAST-1, but not FAST-2 mice. The ethanol-induced activity changes of SLOW mice were generally unaffected by antagonist administration. These results suggest a role for dopaminergic systems in mediating ethanol-stimulated activity in selectively bred FAST mice. Coadministration of SCH-23390 and raclopride decreased ethanol-induced activation to a greater degree than either drug alone, further suggesting that both D1 and D2 receptor systems contribute to the full expression of the ethanol stimulant response.
Animals↗
Intravenous cocaine self-administration in the C57BL/6J mouse.
Freely behaving C57BL/6J mice with intrajugular catheters were trained to nose-poke for cocaine (0.75 mg/kg per 5-microliters infusion) under a fixed-ratio-10 schedule of reinforcement. Mice were given a choice between two nose-poke holes on opposite sides of the apparatus. Nose-pokes by experimental (O) subjects (operant group) were reinforced on only one side and reinforcer delivery coincided with the onset of a 10-s time-out light stimulus. Drug delivery to control subjects (yoked group) was determined by the behavior of O mice. Nose-poke rate increased in O subjects, whereas yoked subjects did not acquire the nose-poking response. Moreover, nose-poking was selective for the cocaine-paired side in O subjects. When saline infusions were substituted for cocaine (i.e., extinction), nose-poking in O subjects decreased, whereas yoked controls were unaffected. O subjects developed a preference for the drug-associated side of the apparatus during extinction. Overall, these data offer strong evidence of cocaine-directed behavior in the C57BL/6 inbred mouse strain. More generally, these findings support the feasibility of using intravenous self-administration to assess reinforcement in genetically well-defined populations.
Animals↗
Genetic analysis of the corticosterone response to ethanol in BXD recombinant inbred mice.
The genetic control over the corticosterone response to ethanol (EtOH) and its possible relationship to other EtOH-related traits was examined using BXD recombinant inbred (RI) strains derived from an F2 cross of C57BL/6J (B6) and DBA/2J (D2) progenitor strains. Quantitative trait locus (QTL) analysis of corticosterone levels 1 hr following EtOH suggested the influence of a single major gene on this trait. Two loci were predicted to account for 47% of the genetic variance in plasma corticosterone levels 6 hr following EtOH, whereas 3 loci were predicted to account for 78% of the genetic variance in corticosterone levels 7 hr following EtOH. Markers associated with corticosterone levels 7 hr following EtOH and corrected corticosterone levels 6 hr post-EtOH overlapped with ones found to influence acute and chronic EtOH withdrawal severity, suggesting some degree of common genetic determination between these traits. Overall these results indicate that gene action significantly influences stress responsiveness and suggest possible chromosomal locations of these genes.
Alcohol Drinking↗
Effects of acute and repeated ethanol exposures on the locomotor activity of BXD recombinant inbred mice.
Investigations of ethanol's (EtOH's) complex response profile, including locomotor and other effects, are likely to lead to a more in-depth understanding of the constituents of alcohol addiction. Locomotor activity responses to acute and repeated EtOH (2 g/kg, ip) exposures were measured in BXD recombinant inbred (RI) mice and their C57BL/6J (B6) and DBA/2J (D2) progenitors. Both the acute response and the change in initial EtOH response with repeated treatments were strain-dependent. The coefficient of genetic determination was 0.38-0.49 for initial locomotor response to EtOH, and 0.29 for change in response. Changes in response were largely attributable to sensitization of locomotor stimulation. Quantitative trait loci (QTL) analyses identified significant marker associations with basal activity, acute locomotor response, and change in response. Markers were for QTL on several chromosomes, and there was only one case of overlap in marker associations among phenotypes. Acute locomotor response and locomotor sensitization were negatively correlated with 3% EtOH preference drinking data collected in BXD RI strains. Overall, these results demonstrate locomotor sensitization induced by EtOH, suggest independence of genetic determination of locomotor responses to acute and repeated EtOH exposure, and partially support a relationship between reduced sensitivity to the locomotor stimulant/sensitizing effects of EtOH and EtOH consumption.
Alcoholism↗
Bidirectional selective breeding for ethanol effects on locomotor activity: characterization of FAST and SLOW mice through selection generation 35.
Increased recognition of the advantages of genetic animal models has led to heightened interest in their use and development. A replicated bidirectional selective breeding project has produced lines of mice that differ in their locomotor responses to 2.0 g/kg ethanol. FAST-1 and FAST-2 mice are highly stimulated by ethanol (EtOH), whereas SLOW-1 and SLOW-2 mice are either not affected or respond with locomotor depression. Current heritability estimates indicate that approximately 6-8% of the response variance in the FAST lines and 2-10% of the response variance in the SLOW lines is of additive genetic origin. Little systematic response to selection has occurred in recent generations, which implies that the limits of selection have been reached. Analysis of saline activity over 35 generations of selection indicates that baseline activities have not changed during the course of selection in three of the lines, whereas baseline activity of FAST-1 mice has increased slightly. In EtOH dose-response studies (0.5-3.0 g/kg), FAST mice had biphasic dose-response curves, whereas the locomotor activity of SLOW mice was either unaffected or depressed by all doses of EtOH. In addition, FAST mice spent more time in motion, traveled farther per movement, traversed greater distances in the center of the test chamber, and ambulated more quickly than SLOW mice when given EtOH. FAST and SLOW mice differed in EtOH clearance rates; however, the differences were slight relative to the large difference in locomotor response. We encourage the use of FAST and SLOW mice to investigate neurophysiological factors underlying sensitivity to the behavioral effects of EtOH, with a view to further testing of the postulated homology between locomotor stimulant effects and addiction potential of drugs of abuse.
Alcohol Drinking↗
Critical role for glucocorticoid receptors in stress- and ethanol-induced locomotor sensitization.
Locomotor sensitization, the augmentation of the locomotor-activating effects of stimuli with repeated exposure, is being evaluated as a partial model for several phenomena including drug addiction. Alteration of dopaminergic systems has been found in sensitized animals and dopamine neurotransmission appears to be crucial for the expression of sensitized behaviors. However, stress hormones, which are released after exposure to many of the stimuli that produce sensitization, may also be involved in the development of this phenomenon. Corticosterone appears to be important in the development of amphetamine sensitization and glucocorticoid receptors (GR) have been hypothesized to mediate this effect. The purpose of these experiments was first, to determine whether repeated restraint stress sensitizes DBA/2J mice to the activating effect of ethanol (EtOH), and second, to explore the role of GR in stress- and EtOH-induced sensitization with the GR antagonist, RU 38486. This antagonist was administered before restraint or i.p. EtOH (1.5 g/kg) on each of 10 consecutive days of pretreatment. In addition, plasma corticosterone levels were determined at various points throughout the pretreatment period and on test days. The results demonstrated that 10 consecutive days of 2-hr restraint sensitized mice to EtOH's locomotor-stimulating effect. Both stress- and EtOH-induced sensitization were attenuated by administration of RU 38486 during the pretreatment phase.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Histologic evaluation of chronic human wounds treated with hydrocolloid and nonhydrocolloid dressings.
BACKGROUND: Studies of acute surgical wounds in pigs have shown granulomatous tissue reactions induced by hydrocolloid dressings. OBJECTIVE: We examined biopsy specimens from chronic wounds in humans treated with hydrocolloid or nonhydrocolloid dressings to determine whether such reactions occurred. METHODS: A blinded retrospective analysis of 22 chronic ulcer biopsy specimens from 22 patients was performed by two dermatopathologists independently. RESULTS: No differences were seen between hydrocolloid-treated and non-hydrocolloid-treated wounds. Granulation tissue was seen in all specimens. No cavities, eosinophilic inclusions, polarizable material, or multinucleated giant cells were identified. CONCLUSION: There are no significant histologic differences between hydrocolloid-treated and non-hydrocolloid-treated wounds in humans.
Biopsy↗
Genetic determinants of sensitivity to ethanol in inbred mice.
Mice from 15 inbred strains differed in sensitivity to ethanol-induced effects on open-field activity, hypothermia, rotarod ataxia, and anesthesia. Sensitivities to the different behavioral responses were generally uncorrelated. This suggests that the genetic determinants of behavioral sensitivity to one domain of ethanol effects are unrelated to those determining other responses. On the other hand, some variables were genetically related. For example, those strains sensitive to the loss of righting reflex induced by higher doses of ethanol showed reduced activity in the open field at lower doses and were more sensitive to ethanol-induced decreases in rearing. More generally, the pattern of results suggests that genetically influenced sensitivity to ethanol is not a monolithic phenomenon. Rather, it is specific to the particular response variable studied.
Alcoholism↗
Behavioral sensitization to drug stimulant effects in C57BL/6J and DBA/2J inbred mice.
Common features shared by addictive drugs have been difficult to identify. One ubiquitous effect of these drugs is psychomotor stimulation. Further, repeated exposure commonly results in sensitization to drug stimulant effects. This study evaluates sensitization to drugs from several drug classes in C57BL/6J and DBA/2J inbred strain mice. DBA/2J mice showed sensitized responses to ethanol and methamphetamine, whereas C57BL/6J mice developed sensitization to morphine and methamphetamine. Strain susceptibilities to ethanol- and morphine-induced sensitization closely paralleled their sensitivities to the acute stimulant effects of these drugs; this was not the case for methamphetamine. The relative sensitivities of DBA/2J and C57BL/6J mice were not consistent across drugs, suggesting that the stimulant and sensitized responses to these drugs may be mediated by at least partially divergent neural mechanisms.
Animals↗
Chronic cutaneous ulcers: etiology and epidemiology.
The most commonly encountered chronic cutaneous ulcers in the United States are pressure ulcers and leg ulcers; this review is limited to the epidemiology of these ulcers. Chronic leg ulcers are frequently encountered in clinical practice but the extent of the problem is largely unknown. In particular, epidemiologic information within the United States is sadly lacking. Although there are more data available regarding the incidence and prevalence of pressure ulcers in acute and chronic care facilities, national surveys should be considered to obtain more accurate information on their incidence and prevalence. Multicenter studies are necessary to determine the epidemiology and cost of treating pressure ulcers by stage, setting, and other factors. Particular attention should be paid to high-risk groups such as spinal cord injury patients, the elderly, and those who are immobilized or chronically debilitated. Leg ulcers and pressure ulcers probably account for the majority of chronic cutaneous ulcers seen in the United States.
Chronic Disease↗
Localization of genes affecting alcohol drinking in mice.
The genomic map locations of specific genes controlling behaviors can be identified by studying a panel of recombinant inbred (RI) mouse strains. The progenitor C57BL/6J (B6) and DBA/2J (D2) strains, and 19 of the BXD RI strains derived from an F2 cross of these progenitors, were tested for 3% and 10% ethanol (EtOH) intake. The test sequence began with two-bottle free choice between tap water and unsweetened ethanol, and ended with free choice between water and saccharin-sweetened ethanol. Saccharin preference was also measured. Correlational analyses indicated that 59% of the genetic variance in 10% ethanol and sweetened 10% ethanol consumption was held in common, 24% of the genetic variance in saccharin and sweetened 10% ethanol consumption was held in common, and only 7% of the genetic variance in saccharin and unsweetened 10% ethanol consumption was held in common. These percentages for 3% ethanol solutions were 21%, 36%, and 14%. In addition, the severity of handling-induced convulsions during ethanol withdrawal was found to be significantly associated with the amount of ethanol consumed from the sweetened ethanol drinking tubes, suggesting that genetic differences in avidity for ethanol could lead to the development of physical dependence. Quantitative trait loci (QTL) analyses revealed that several genetic markers were associated with ethanol consumption levels, including markers for the D2 dopamine receptor. QTL analyses of saccharin and sweetened ethanol consumption identified the sac locus, thought to determine the ability to detect saccharin. In general, our results suggest that saccharin and ethanol consumption are determined by the actions of multiple genes (QTL), some in common, and suggest specific map locations of several such QTL on the mouse genome.
Alcohol Drinking↗
Ethanol sensitivity of brain NMDA receptors in mice selectively bred for differences in response to the low-dose locomotor stimulant effects of ethanol.
Brain NMDA receptor responses and their sensitivity to ethanol in vitro were determined in replicate lines of FAST and SLOW mice, selectively bred for differences in sensitivity to the locomotor stimulant effects of a low dose of ethanol. L-Glutamate-stimulated increases in the intracellular free calcium concentration (Cai) were determined in microsacs, a cell-free brain membrane preparation, isolated from hippocampus or cerebral cortex. Previous work showed that L-glutamate-stimulated increases in Cai in microsacs are mediated by activation of NMDA receptors. The concentration response for L-glutamate-stimulated increases in Cai did not differ between the lines in either hippocampal or cerebrocortical microsacs. Ethanol produced a concentration-dependent decrease in L-glutamate-stimulated increases in Cai in hippocampal and cerebrocortical microsacs from SLOW mice, but this effect of ethanol was reduced or absent in microsacs isolated from FAST mice. Resting Cai and the ability of a high ethanol concentration to increase resting Cai did not differ between the lines. These results suggest that differences in the sensitivity of brain NMDA receptors to the effects of ethanol determine, at least in part, differences in the locomotor stimulant effects of low doses of ethanol in FAST and SLOW mice. These differences are not due to ethanol effects on resting Cai.
Alcohol Drinking↗
Differences in ethanol sensitivity of brain NMDA receptors of long-sleep and short-sleep mice.
Long-Sleep (LS) and Short-Sleep (SS) mice, selectively bred mice that differ in the duration of anesthesia produced by an acute dose of ethanol, were used to determine the possible association of differing ethanol sensitivity of brain NMDA receptors with differing sensitivity to the anesthetic effects of ethanol in vivo. NMDA receptor-mediated responses were determined by measurement of L-glutamate-stimulated increases in free intracellular calcium concentration (Cai) using the fluorescent indicator for Cai, Indo 1, in microsacs (a cell-free brain membrane vesicle preparation) isolated from hippocampi or cerebral cortices of the two mouse lines. In the absence of added drugs, NMDA responses did not differ between the two lines in hippocampal or cerebrocortical microsacs. However, a high concentration of ethanol (200 mM) inhibited NMDA responses in hippocampal microsacs from LS mice. In contrast, a moderate concentration of ethanol (50 mM) stimulated NMDA responses in hippocampal microsacs isolated from SS mice. In cerebrocortical microsacs, ethanol inhibited NMDA responses in the two lines to an equivalent degree. MK-801, a noncompetitive blocker of NMDA receptors, blocked NMDA responses at lower concentrations in hippocampal microsacs from LS mice than in SS mice, but produced a similar degree of inhibition of NMDA responses in cerebrocortical microsacs from the two lines. A high concentration of ethanol (200 mM) increased resting Cai in hippocampal microsacs from LS mice but not in hippocampal microsacs from SS mice, and increased resting Cai in cerebrocortical microsacs isolated from both lines of mice equally. The small change in resting Cai produced by MK-801 in cerebrocortical microsacs did not differ between the two lines.(ABSTRACT TRUNCATED AT 250 WORDS)
Alcoholic Intoxication↗
Observations on the anatomy and pathology of the palmar intercarpal ligaments in the middle carpal joints of thoroughbred racehorses.
Ten carpi from juvenile Thoroughbred horses were dissected in detail to record the anatomy of the palmar intercarpal ligaments (PICLs). These were found not to be substantially attached to the palmar carpal ligament. The lateral PICL was sited at the convergence of the palmar aspects of the third, fourth, intermediate and ulnar carpal bones and aligned predominantly in a proximodistal direction. The medial PICL had a large origin distally on the lateral aspect of the radial carpal bone (Cr) and attached to third (C3) and second (C2) carpal bones with apparently separate fibre orientations. Fibres between Cr and C3 aligned obliquely from dorsoproximomedial to palmarodistolateral which corresponds to the direction of movement of Cr relative to C3 during carpal extension. Video recordings of arthroscopic evaluations of 67 middle carpal joints of juvenile Thoroughbred horses in race training were reviewed retrospectively and the osteochondral and ligamentous pathology visible in each recorded. Damage to the Cr-C3 part of the medial PICL was present in 47 (70%) joints and, in 6 joints, comprised complete rupture of this branch. A significant (P < 0.001) relationship was found between the presence of remodelling of the dorsodistal margin of Cr and the severity of ligament damage. It is considered that the orientation of fibres of the Cr-C3 branch of the MPICL is consistent with a putative role to alternate forces borne by Cr and C3 during axial loading of the limb and that the injuries of this structure seen in young racehorses may represent a fatigue-type pathology analogous to that seen concurrently in the related osteochondral tissues.
Animals↗
Women in dermatology. Challenges and recommendations.
The total number of women physicians in the United States tripled between 1970 and 1990. Almost 50% of incoming residents in dermatology are women. This article discusses some of the changes, opportunities, and challenges within our profession wrought by these demographic changes. The incorporation of women into all aspects of our specialty is a subject that warrants review, consideration, and creative solutions.
Dermatology↗
Selective breeding for alcohol withdrawal severity.
Mouse lines have been genetically selected to be alcohol Withdrawal Seizure Prone (WSP) or Resistant (WSR). The selection index is the severity of withdrawal handling-induced convulsions seen after removal of mice from chronic exposure to ethanol vapor. Behavioral, pharmacological, and neurochemical results from a replicated bidirectional selection project are reviewed. In reciprocal F1 crosses of the WSP and WSR lines, substantial dominance for resistance to withdrawal was found in both replicated sets of lines. WSP and WSR mice differ principally, and markedly, in traits related to the severity of withdrawal from alcohols and other drugs with depressant properties. This suggests that genes influencing severity of withdrawal from chronic ethanol exposure also pleiotropically influence genetic susceptibility to dependence on other drugs of abuse. However, the results of WSP vs. WSR comparisons for traits related to ethanol sensitivity and tolerance development suggest control in large part by genes different from those influencing withdrawal severity.
Alcohol Withdrawal Delirium↗
Quantitative trait loci (QTL) applications to substances of abuse: physical dependence studies with nitrous oxide and ethanol in BXD mice.
Recombinant inbred (RI) mouse strains were developed primarily as a tool to detect and provisionally map major gene loci--those with effects large enough to cause a bimodal distribution in the trait of interest. This implied that progress toward gene mapping was possible only for gene loci accounting for at least half of the genetic variance. More recently, QTL (quantitative trait loci) approaches have been advanced that do not require bimodal distributions and are thus applicable to a much wider range of phenotypes. They offer the prospect of meaningful progress toward detecting and mapping minor as well as major gene loci affecting any trait of interest, provided there is a significant degree of genetic determination among the RI strains. This paper presents a review of RI gene mapping efforts concerning phenotypes related to drug abuse and presents new data for studies now in progress for nitrous oxide and acute ethanol withdrawal intensity. These two studies exemplify several strengths and limitations of the RI QTL approach.
Alcohol Withdrawal Delirium↗