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Biomedical subjects

D L Morgan

Publications and source records attributed to D L Morgan.

At least 127 records · Page 7Linked to original sources
PubMed1993

Critical aspects of initiation, promotion, and progression in multistage epidermal carcinogenesis.

Carcinogenesis in mouse skin can be divided into three distinct stages: initiation, promotion, and progression (malignant conversion). Initiation, induced by a single exposure to a genotoxic carcinogen, can result from a mutation in a single critical gene (e.g., rasHa), apparently in only a few epidermal cells. The change is irreversible. Promotion, resulting in the development of numerous benign tumors (papillomas), is accomplished by the repeated application of a nonmutagenic tumor promoter. The effects of single applications of tumor promoters are reversible since papillomas do not develop after insufficient exposure of initiated skin to promoters or when the interval between individual promoter applications is increased sufficiently. The reversibility of promotion suggests an epigenetic mechanism. Promoter treatment provides an environment that allows the selective clonal expansion of foci of initiated cells. The conversion of squamous papillomas to carcinomas (termed progression or malignant conversion) occurs spontaneously at a low frequency. The rate of progression to malignancy can be significantly increased by treatment of papilloma-bearing mice with certain genotoxic agents. These progressor agents or converting agents are likely to act via a second genetic change in papillomas already bearing the initiating mutation. Progression in the skin is characterized by genetic changes that result in several distinct changes in the levels or activity of structural proteins, growth factors, and proteases. The mechanisms involved in progression are being studied in epidermal cell culture. In order to determine the in vivo phenotype of cultured cells, a grafting system was developed in which the cells were transferred from culture to a prepared skin bed in athymic mice. Introduction of an activated v-fos oncogene into initiated cells bearing an activated rasHa gene produced cells with a carcinoma phenotype, i.e., carcinomas formed when the cells were grafted as part of reconstituted skin. Grafted keratinocytes containing the rasHa gene alone produced papillomas; with v-fos alone, normal skin formed when grafted. The rasHa/fos carcinomas showed changes in differentiation markers characteristic of chemically induced carcinomas. A cell culture assay utilizing cells initiated by the introduction of an activated rasHa oncogene was developed to study progression. After exposure of initiated cells to progressor agents under conditions in which the proliferation of the rasHa-initiated cells was suppressed, proliferating foci developed, with a good correlation of activity in the assay with activity in the progression stage in vivo. The cell culture assay provides a quantitative model to study chemically induced neoplastic progression and may be useful to identify potential progressor agents.

Animals↗
PubMed1993

Cytogenetic studies of rodents exposed to styrene by inhalation.

Female B6C3F1 mice and Fischer 344 rats were exposed to styrene at nominal concentrations of 125, 250 and 500 ppm by inhalation for 6 h per day for 14 consecutive days. One day after the final exposure, murine peripheral blood lymphocytes, spleen and lungs were removed, and the cells were cultured for analysis of chromosomal aberrations, micronucleus induction (using the cytochalasin B-block method) and sister chromatid exchange. Peripheral blood smears were scored for micronucleus induction in normochromatic erythrocytes. For the rats, peripheral blood lymphocytes were cultured for analyses of sister chromatid exchange, chromosomal aberrations and micronuclei in cytochalasin B-induced binucleated cells and were also examined in the single-cell gel assay for analysis of DNA strand breakage under alkaline conditions. Bone-marrow smears were made from femurs of rats for analysis of micronucleus induction in normochromatic erythrocytes. Small but statistically significant concentration-related increases in the frequency of sister chromatid exchange were seen in both mice and rats in all cell types examined. No statistically significant concentration-related increase in chromosomal aberration or micronucleus induction frequencies were observed in either species, and there was no significant increase in DNA strand breakage in peripheral blood lymphocytes from exposed rats. These results indicate that styrene is a weak inducer of sister chromatid exchange in vivo when administration to rodents by inhalation.

Administration, Inhalation↗
PubMed1992

Cytogenetic studies of mice exposed to styrene by inhalation.

The data for the in vivo genotoxicity of styrene (STY) are equivocal. To evaluate the clastogenicity and sister-chromatid exchange (SCE)-inducing potential of STY in vivo under carefully controlled conditions, B6C3F1 female mice were exposed by inhalation for 6 h/day for 14 consecutive days to either 0, 125, 250 or 500 ppm STY. One day after the final exposure, peripheral blood, spleen, and lungs were removed and cells were cultured for the analysis of micronucleus (MN) induction using the cytochalasin B-block method, chromosome breakage, and SCE induction. Peripheral blood smears were also made for scoring MN in erythrocytes. There was a significant concentration-related elevation of SCE frequency in lymphocytes from the spleen and the peripheral blood as well as in cells from the lung. However, no statistically significant concentration-related increases were found in the frequency of chromosome aberrations in the cultured splenocytes or lung cells, and no significant increases in MN frequencies were observed in binucleated splenocytes or normochromatic erythrocytes in peripheral blood smears.

Administration, Inhalation↗
PubMed1992

Intravenous injection of household bleach.

The widespread use of household bleach (5.25% sodium hypochlorite) as a disinfectant by IV drug users may cause an increase in the number of IV injections of this substance. We report the case of a 31-year-old man who injected less than 1 mL of bleach and then experienced transient left-sided chest pain and vomiting. The patient did not have any serious complications. This report is similar to the only other reported case in the medical literature of an IV injection of a small amount of bleach. Based on these two reports, household bleach appears to be safe when used as a disinfectant by IV drug users, but more studies are needed.

Adult↗
PubMed1992

Activity of diverse tumor promoters in a keratinocyte co-culture model of initiated epidermis.

The suppression of focal growth of initiated mouse keratinocytes by co-culture with normal keratinocytes can be overcome by treatment of co-cultures with the phorbol ester tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). This keratinocyte co-culture model was developed as an analog of initiated mouse epidermis to facilitate the study of tumor promotion in cell culture. A number of promoters of TPA-type [those with protein kinase C (PKC) as receptor] were compared to non-TPA-type promoters for activity in the keratinocyte co-culture model. The TPA-type promoters teleocidin and aplysiatoxin show comparable activity to that of TPA. Exposure of co-cultures to oleoyl-2-acetylglycerol, a diacylglycerol activator of PKC, also induces focal outgrowth of initiated cells, suggesting that PKC is likely to be involved in the mechanism of action of these compounds. However, the involvement of alternative pathways (not involving PKC directly) for clonal selection are evident since the non-TPA-type promoters okadaic acid, staurosporine and thapsigargin are also active in the assay. Thus, the keratinocyte co-culture model differs from fibroblast models of normal and neoplastic co-cultures in which only TPA-type promoters are active. In further contrast to certain fibroblast co-cultures, TPA does not inhibit cell-cell communication under conditions that suppress focus formation. Taken together with previous data, we conclude that the keratinocyte co-culture model may have broad application for detecting skin tumor promoters, and may be useful for dissecting the mechanism by which normal epidermal cells suppress the growth of initiated cells.

Animals↗
PubMed1992

Muscle history dependence of responses to stretch of primary and secondary endings of cat soleus muscle spindles.

1. Responses were recorded from both primary and secondary endings of soleus muscle spindles in the anaesthetized cat during slow stretches of the muscle after conditioning contractions at different lengths. 2. After a 5 mm length step and a fusimotor-strength contraction given at the longer length, on return to the initial length the response to a slow test stretch (0.5 mm s-1) showed a change in slope midway through the stretch which was attributed to taking up of slack in intrafusal fibres. 3. The onset of the change in slope during the test stretch depended on the size of the conditioning step. With no conditioning length change, just a fusimotor-strength contraction, there was no slope change and the response consisted of an initial burst followed by a maintained high rate of discharge. 4. Following a conditioning length step, the point of onset of the slope change during the test stretch could be altered by stimulating single identified fusimotor fibres to the spindle. Stimulating some static axons produced large changes in the stretch response while other static axons and dynamic axons had only small effects. 5. Many secondary endings showed a delay in onset of their response to a test stretch, dependent on the size of the preceding conditioning step, signalling the presence of slack in much the same way as the primary endings. Other secondary endings, however, appeared to have stretch responses that were largely independent of muscle conditioning. 6. Muscle history-independent responses of secondary endings were associated with low axonal conduction velocities. It is proposed that secondary endings which remain unaffected by muscle conditioning lie on more distal regions of nuclear chain fibres in the S2-S5 position. Here they are stimulated during both the take-up of slack and the subsequent direct stretch of the intrafusal fibres.

Animals↗
PubMed1992

Predictors of placebo response: a retrospective analysis.

This retrospective evaluation involved 197 patients from independent clinical investigations of four antidepressant medications. Six variables were analyzed for their discriminative utility in predicting placebo response rates: gender; marital status; age; education; duration of illness; and severity of depressive symptomatology, as measured by Hamilton Rating Scale for Depression (HAM-D or HDRS) scores. Men were slightly more responsive to placebo than were women (29.8%, n = 94 vs. 24.3%, n = 103). Married patients demonstrated the highest probability of a positive placebo response (38.15%, n = 76), as compared with widowed/separated/divorced (21.9%, n = 73) or single (16.7%, n = 48) patients. A trend toward an increased probability of placebo response was detected for patients aged 60 and above (35.7%, n = 14). Educational level achieved and duration of illness were not predictive. Severity of illness proved most noteworthy, with the placebo response rate higher in the more mild patients (40.8%, n = 27 vs. 23.4%, n = 77).

Adolescent↗
PubMed1991

Responses of primary endings of cat muscle spindles to locally applied vibration.

Responses of muscle spindles in the cat soleus muscle have been studied during vibration applied locally to the belly of the muscle. Bursts of vibration at 170 Hz and with a peak amplitude of 200 microns were applied to a site at which local pressure initiated impulses from the spindle. The response to vibration depended on the conditioning of the muscle immediately beforehand and the placement of the vibrator. The length at which the vibration was applied was called the test length; this was typically 10 mm less than the muscle's maximum length in the body. After a fusimotor strength contraction at a length 2-5 mm longer than the test length, vibration sensitivity, measured on return to the test length, was low. If the muscle was contracted at a length 2-5 mm shorter than the test length, vibration sensitivity was high. The low vibration sensitivity following conditioning at the longer length was attributed to the development of slack in intrafusal fibres. In the presence of slack, stimulation of some static fusimotor fibres was able to restore vibration sensitivity fully. It is suggested that the vibration sensitivity of passive spindles arises largely in bag2 intrafusal fibres.

Animals↗
PubMed1991

Dermal absorption of neat and aqueous volatile organic chemicals in the Fischer 344 rat.

Quantification of dermal absorption of volatile organic chemicals (VOCs) from aqueous solutions is required to understand the potential health hazards resulting from skin exposure to these chemicals in contaminated water. Male Fischer 344 rats were dermally exposed (3.1-cm2 dorsal skin) to neat, one-third saturated, two-thirds saturated, or saturated aqueous solutions of 14 VOCs for 24 hr. Blood samples were obtained via indwelling jugular catheters during exposure (0, 0.5, 1, 2, 4, 8, 12, and 24 hr), and analyzed for the VOCs by gas chromatography using headspace analysis. Absorption of the neat VOCs in this series of chemicals decreased as water solubility decreased. Peak blood levels of VOCs attained during exposure for 24 hr to neat chemicals were: 1,2-dichloroethane (135.1 micrograms/ml), bromochloromethane (113.3 micrograms/ml), chloroform (51.0 micrograms/ml), benzene (24.2 micrograms/ml), tetrachloroethylene (21.1 micrograms/ml), dibromomethane (18.2 micrograms/ml), trichloroethylene (11.6 micrograms/ml), toluene (9.5 micrograms/ml), xylene (8.8 micrograms/ml), hexane (8.0 micrograms/ml), ethylbenzene (5.6 micrograms/ml), styrene (5.3 micrograms/ml), carbon tetrachloride (5.0 micrograms/ml), and 1,1,1-trichloroethane (3.4 micrograms/ml). Blood levels of 1,2-dichloroethane and benzene continued to increase during the 24-hr exposure to neat chemical, while blood levels of the other neat VOCs peaked within 4 hr and then either decreased or remained about the same for the duration of the exposure. Absorption of VOCs from one-third, two-thirds, or saturated aqueous solutions was rapid, and resulted in depletion of the chemical from the solution although only a small amount of water was absorbed. Blood levels of each VOC were directly related to the exposure concentrations. The rapid appearance of VOCs in the blood from aqueous solutions demonstrates that detectable amounts of VOCs were absorbed during exposure of only about 1% of the skin surface area of the rat.

Animals↗
PubMed1991

A comparison of interfollicular and hair follicle derived cells as targets for the v-rasHa oncogene in mouse skin carcinogenesis.

Methods to isolate and culture intact mouse hair follicles and interfollicular epidermal cells provide a model to test the potential of each to form tumors as a consequence of rasHa gene activation and to determine the risk for progression in the resultant tumors. The v-rasHa oncogene was introduced into intact or dissociated hair follicle cells or interfollicular epidermal cells from newborn mouse skin via a defective retroviral vector. Either immediately after infection or after an additional 6 days of culture, the v-rasHa cells were transferred to nude mice as a skin graft. Both cell populations formed squamous papillomas which were indistinguishable based on morphology and immunocytochemistry. All papillomas expressed epidermal specific markers whether derived from hair follicle or interfollicular cells, and many regressed. After 16 weeks in vivo, 20-30% of the benign skin tumors in all groups converted to malignancy. In addition to papillomas, hair follicle derived populations produced hemangiomas in many animals. None of the groups formed basal cell carcinomas, keratoacanthomas or tumors with characteristics of differentiating hair follicle cells. These studies indicate that ras gene activation can contribute to benign squamous neoplasia originating from several skin-derived cell types. The underlying factors which determine the variable risk for neoplastic progression of skin papillomas after ras gene activation is not simply the origin of the tumor cell from hair follicle or interfollicular epidermis. The activated ras oncogene can also transform skin endothelial cells but does not appear to directly contribute to transformation of the more differentiated cells of the hair follicle.

Animals↗
PubMed1991

Role reversals in the exchange of social support.

We tested the assumption that there is a role reversal in exchanges of social support: that the older one becomes, the less likely one is to send support and more likely one is to receive it. Using data from a community study in Southern California with 513 middle-aged and older respondents, the results show that both support-sending and support-receiving decline with age. The respondents report giving more support than they receive until age 85+. Controls for income and activities of daily living extend the age at which role reversal occurs, and further controls for the number of people in the social network eliminate it. Examining different types of support and different sources of support shows that similar results apply to both affective and instrumental support, but that this pattern applies more to exchanges with family members, as all forms of role reversal are less likely in exchanges with nonfamily.

Activities of Daily Living↗
PubMed1991

Where in the muscle spindle is the resting discharge generated?

This is a report of experiments on muscle spindles of the soleus muscle of the anaesthetized cat. Following a step shortening of the muscle, muscle spindles fall silent. At suitable muscle lengths their discharge may restart several seconds later to gradually recover a maintained rate of discharge. These experiments examine the question of where within the spindle the resumption of a resting discharge may originate. It was found that stimulation of some static fusimotor fibres immediately after the shortening led to early recovery of the resting discharge. Stimulation of dynamic and other static gamma motoneurones had much less effect. Since the dynamic gamma axons innervate almost exclusively the bag1 intrafusal fibre, contraction of this fibre appears to have little influence on the mechanisms responsible for restarting the resting discharge. Bag2 and chain fibres do seem to be involved. For primary endings, the bag2 fibre contraction was especially effective since static axons, which did not evoke 'driving' of the afferent response, and which are thought to predominantly innervate bag2 fibres, did restart the resting discharge. For secondary endings, stimulation of nearly all gamma axons led to an early restart of the resting discharge suggesting that here the nuclear chain fibres were responsible.

Animals↗
PubMed1991

Tension as a function of sarcomere length and velocity of shortening in single skeletal muscle fibres of the frog.

1. Simple measurements of muscle tension at fixed fibre or segment length produce a range of length-tension relationships, depending primarily on the duration of the interval between stimulation onset and tension measurement, in contradiction with the simple predictions of current models. This has been explained by non-uniformity in sarcomere lengths, leading to internal motion and, in turn, to increasing tension because the force-velocity relationship has a much greater slope for slow lengthening than for slow shortening. 2. Previous attempts to reduce the effect of internal motion have been focused on decreasing the initial extent of non-uniformity and measuring tension early in a contraction, when non-uniformities are at a minimum. An alternative approach that has not been attempted previously is to reduce the non-linearity of the force-velocity relationship by avoiding the discontinuity in slope at zero velocity. This is accomplished by imposing overall fibre shortening at velocities sufficient to ensure that all sarcomeres are shortening. 3. When the tension maintained during shortening was measured and plotted against sarcomere length for each release velocity used, linear length-tension relationships resulted that extrapolated to a common sarcomere length intercept. This was true whether the release was applied early in the tetanus or near the end of the 'creep phase' of tension rise. These observations were duplicated by computer simulation using a multisarcomere model of a muscle fibre. 4. These results provide strong support for the view that cross-bridges function as independent force generators and for the explanation of the creep phase of fibre or segment isometric tension as being due to internal motion. The results also imply that the force-velocity relationship scales with sarcomere length without changing shape. 5. Using this novel method for obtaining length-tension relationships, the sarcomere length at which active tension fell to zero was found, by extrapolation, to be 3.65 microns in semitendinosus fibres and 3.53 microns in tibialis anterior fibres from the frog (Rana temporaria).

Animals↗
PubMed1991

Two kinds of resting discharge in cat muscle spindles.

1. The behavior of primary endings of cat soleus muscle spindles was studied during shortening steps carried out at different muscle lengths. 2. Spindles were of two kinds: one, silent spindles, whose afferents fell silent after the shortening, at least over part of the range of lengths tested. The second, spontaneous spindles, resumed firing at all lengths. 3. For silent spindles, the duration of the silent period, measured at lengths where they did recover a resting rate, depended directly on muscle length and became shorter at longer lengths. This is what would be expected if the slack introduced in the spindle by the shortening step was removed more rapidly at longer lengths by the higher passive tension. For spontaneous spindles, on the other hand, the duration of the silent period after the shortening was largely independent of muscle length and depended on the spindle's rate of firing immediately before the shortening. 4. At intermediate lengths the discharge of slack spontaneous spindles remained unaffected by an isometric muscle contraction. It was therefore not possible to produce a pause in the discharge, behavior normally taken as typical of spindles. The discharge could be interrupted by the contraction if this was combined with a large shortening movement. 5. It is proposed that when intrafusal fibers are slackened by a shortening step, the resting discharge in spontaneous spindles is generated by a maintained depolarization of the annulospiral ending resulting from extension of the terminal coils by forces from within the receptor. A shortening contraction compresses the spirals to interrupt the discharge. The sensory endings of silent spindles remain below threshold until the spirals have been opened out sufficiently by external stretch.

Afferent Pathways↗
PubMed1990

Comparative toxicity of ethylene dichloride in F344/N, Sprague-Dawley and Osborne-Mendel rats.

Studies were conducted to compare the toxicity of ethylene dichloride (EDC) in F344/N rats, Sprague-Dawley rats, and Osborne-Mendel rats. Ten rats/sex/group were exposed to EDC in drinking-water at 0, 500, 1000, 2000, 4000 and 8000 ppm for 13 wk. The highest concentration was limited by the maximum solubility of EDC in water (about 9000 ppm). In addition, F344/N rats (10/sex/group) were administered EDC in corn oil by gavage to compare toxicity resulting from bolus administration with that of continuous exposure in drinking-water. Gavage doses of EDC were within the range of total daily doses (in mg/kg body weight/day) resulting from exposure in drinking-water. EDC administered by gavage resulted in greater toxicity to F344/N rats than did administration of similar doses in drinking-water. All males receiving 240 and 480 mg/kg body weight and 9/10 females receiving 300 mg/kg body weight by gavage died before the end of the study. Necrosis of the cerebellum was observed in the brains of 3 males receiving 240 mg/kg body weight and 3 females receiving 300 mg/kg body weight. Hyperplasia and inflammation of the forestomach mucosa were observed in 8 male and 3 female rats that died or were killed in moribund condition. EDC caused minimal toxicity to F344/N, Sprague-Dawley and Osborne-Mendel rats at the drinking-water concentrations used in these studies; only female F344/N rats had EDC-related renal lesions. Based on mortality and EDC-related lesions, the no-effect levels for EDC administered by gavage to F344/N rats were 120 mg/kg body weight for males and 150 mg/kg body weight for females.

Administration, Oral↗
PubMed1990

Cross-bridge cycling theories cannot explain high-speed lengthening behavior in frog muscle.

The Huxley 1957 model of cross-bridge cycling accounts for the shortening force-velocity curve of striated muscle with great precision. For forced lengthening, however, the model diverges from experimental results. This paper examines whether it is possible to bring the model into better agreement with experiments, and if so what must be assumed about the mechanical capabilities of cross-bridges. Of particular interest is how introduction of a maximum allowable cross-bridge strain, as has been suggested by some experiments, affects the predictions of the model. Because some differences in the models are apparent only at high stretch velocities, we acquired new force-velocity data to permit a comparison with experiment. Using whole, isolated frog sartorius muscles at 2 degrees C, we stretched active muscle at speeds up to and exceeding 2 Vmax. Force during stretch was always greater than the peak isometric level, even during the fastest stretches, and was approximately independent of velocity for stretches faster than 0.5 Vmax. Although certain modifications to the model brought it into closer correspondence with the experiments, the accompanying requirements on cross-bridge extensibility were unreasonable. We suggest (both in this paper and the one that follows) that sarcomere inhomogeneities, which have been implicated in such phenomena as "tension creep" and "permanent extra tension," may also play an important role in determining the basic force-velocity characteristics of muscle.

Animals↗
PubMed1990

New insights into the behavior of muscle during active lengthening.

A muscle fiber was modeled as a series-connected string of sarcomeres, using an A. V. Hill type model for each sarcomere and allowing for some random variation in the properties of the sarcomeres. Applying stretches to this model led to the prediction that lengthening of active muscle on or beyond the plateau of the length tension curve will take place very nonuniformly, essentially by rapid, uncontrolled elongation of individual sarcomeres, one at a time, in order from the weakest toward the strongest. Such a "popped" sarcomere, at least in a single fiber, will be stretched to a length where there is no overlap between thick and thin filaments, and the tension is borne by passive components. This prediction allows modeling of many results that have previously been inexplicable, notably the permanent extra tension after stretch on the descending limb of the length tension curve, and the continued rise of tension during a continued stretch.

Animals↗