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Biomedical subjects

R K Johnson

Publications and source records attributed to R K Johnson.

At least 217 records · Page 12Linked to original sources
PubMed1981

Effect of maternal dietary energy source on glucose homeostasis, liver glycogen and carcass lipid in the neonatal pig.

Two experiments were conducted to determine the effects of supplementary dietary energy (carbohydrate versus fat) fed to sows during late gestation on energy storage and glucose homeostasis in neonatal pigs. In the first experiment, 28 crossbred sows received one of two dietary treatments that were initiated on day 100 of gestation. The control group was fed daily 1.82 kg of a corn-soybean meal-based diet plus an additional .18 kg of cornstarch. Their counterparts were fed 1.82 kg of a corn-soybean meal diet containing 8% bleachable fancy tallow. The effect of maternal dietary energy source during late gestation on glucose homeostasis was evaluated by fasting pigs from birth (t0), whereas the gestation-lactation effect was evaluated by fasting pigs after they had nursed the sow for 24 hr (t24). Pigs on the tallow treatment responded differently to the t0 fast, as determined by the patterns of plasma glucose (treatment x time, P less than .05) and free fatty acids (treatment x time, P less than .10). The tallow group maintained a slightly higher glucose concentration during the initial 24 hr, after which no difference was observed. Control pigs reached a peak free fatty acid (FFA) concentration by 12 hr, whereas the tallow group reached a maximum by 24 hr, which corresponded with declining glucose concentration. Pigs on the t24 tallow treatment maintained a slightly higher plasma glucose concentration during the initial 24 hr of fasting (12 hr - 68.3 vs 63.2 mg/100 ml; 24 hr - 67.1 vs 56.3 mg/100 ml); however, no significant treatment effect or treatment x time interaction was observed. Pigs on the tallow treatment maintained a higher, although not significantly different, plasma FFA concentration during the fast (144 mueq/liter) than pigs in the control group (126 mueq/liter). In the second experiment, progeny of 12 sows were sacrificed immediately after birth. The respective carcass lipid (percentage) and liver glycogen (milligrams/gram) concentrations for pigs from sows fed the control and tallow diets were 1.48, 229.1 vs 1.50, 234.9. The liver glycogen to body weight ratio (milligrams:gram) was 7.1 and 7.8 for the control and tallow groups, respectively.

Animal Feed↗
PubMed1981

Mechanism of resistance of variants of the Lewis lung carcinoma to N-(phosphonacetyl)-L-aspartic acid.

Variants of the Lewis lung carcinoma were selected for resistance to N-(phosphonacetyl)-L-aspartic acid (PALA) by treatment of tumor-bearing mice with repetitive subcurative doses of PALA. The specific activity of the target enzyme, L-aspartic acid transcarbamylase (ATCase), was measured in the four variants developed. Three had markedly elevated ATCase activities; however, the fourth line, LL/PALA-C, had an ATCase activity identical to that of the parent, PALA-sensitive line (LL/O). One high-ATCase variant, LL/PALA-J, and LL/PALA-C were compared with LL/O in subsequent biochemical studies on the mechanism of resistance to PALA. Enzyme activities in the salvage pathways which phosphorylate pyrimidine nucleosides and deoxynucleosides were found to be similar in all three lines. ATCase in these lines exhibits closely comparable kinetics with its natural substrates as well as with PALA. The time courses of restitution of ATCase after a single therapeutic dose of PALA show that both resistant variants recover full activity more rapidly than the parent. Additionally, inhibition of ATCase 24 hr following graded doses of PALA is lower in the resistant lines. The uptake of [14C]PALA in vitro into cell lines derived from the three Lewis lung carcinomas apparently occurs by passive diffusion and at comparable rates in both sensitive and resistant cells. Analysis of the nucleotide content of tumors reveals comparable spectrums of purine and pyrimidine nucleotide levels in the LL/O and LL/PALA-C lines, whereas the LL/PALA-J line has augmented nucleotide pools. In all three lines, 24 hr after treatment with PALA (400 mg/kg), uridine and cytidine nucleotide levels were substantially diminished (70 to 80%) while adenosine 5'-triphosphate and guanosine 5'-triphosphate levels were elevated (50 to 100%). Estimations of precursor flux through the de novo pyrimidine pathway by measuring orotate and orotidine levels in tumors of mice treated with pyrazofurin (an inhibitor of orotidine-5'-monophosphate decarboxylase) and either 0.9% NaCl solution or PALA shows that PALA treatment eliminates orotate and orotidine accumulation in LL/O but reduces it by only 75 and 50% in LL/PALA-C and LL/PALA-J, respectively. Similarly, PALA treatment (20 microM) of tumor lines in culture provokes a dramatic decrease in the incorporation of NaH14CO3 into pyrimidine intermediates and nucleotides in the LL/O cell line only. Determinations of specific activities of the other enzymes in this pathway reveal that the activity of carbamyl phosphate synthetase II, the rate-limiting step, is elevated 2- to 3-fold in both resistant lines. Since carbamyl phosphate synthetase II exists as a complex with ATCase, the suggestion is made that levels of carbamyl phosphate synthetase II are collaterally important determinants of PALA activity. An augmented pool of carbamyl phosphate in the resistant variants may serve to competitively displace PALA from ATCase, diminish enzyme inhibition, and allow pyrimidine biosynthesis to proceed despite therapy.

Amides↗
PubMed1980

Usefulness and limitations of murine tumor models for the identification of new antitumor agents.

Murine tumor systems that have been employed in the identification of most of the known antitumor agents are reviewed and their usefulness and limitations in the identification of new antitumor agents is discussed. A new antitumor screening program has been initiated by the Division of Cancer Treatment, National Cancer Institute which employs human tumors growing in athymic mice. The questions addressed using this screen and representative data are presented.

Animals↗
PubMed1980

Inheritance of teat number and its relationship to maternal traits in swine.

The relationship of teat number to seven measures of female reproduction was evaluated in the University of Nebraska Gene Pool population. Teat number was recorded for 7,513 pigs, ovulation rate for 2,794 gilts and litter size and weight at birth and weaning (42 days) for 789 gilts. Paternal half-sib and full-sib analyses were used to estimate heritabilities for each trait and to estimate the genetic and phenotypic correlations of teat number with the measures of reproduction. The direct response to selection for ovulation rate and the correlated response in teat number were also evaluated from the regressions of line differences (Select-Control) on generation number (10 generations of selection) and cumulative selection differential for ovulation rate. The paternal half-sib heritabililty for teat number was .32, and the paternal half-sib heritabilities for ovulation rate and the litter traits were similar to previous estimates from this population. Most of the genetic and phenotypic correlations with teat number were negative and all were nonsignificant. The realized heritability for ovulation rate was .46 +/- .10. The regression of response in teat number on generation number number was .08 +/- .03 (P < .10). An estimate of .44 was obtained for the realized genetic correlation of teat number with ovulation rate.

Animals↗
PubMed1980

The relationships between plasma progesterone and lh and the numbers of corpora lutea and embryos in purebred and crossbred gilts.

Relationships between plasma progesterone and luteinizing hormone (LH) and the numbers of corpora lutea and embryos were determined in 133 8-month-old purebred Duroc, Hampshire and Yorkshire gilts and two-breed crosses among the three breeds. The numbers of corpora lutea and normal embryos were determined at slaughter on day 30.8 +/- .2 of pregnancy, and progesterone and LH were quantified in plasma obtained the previous day. Progesterone concentrations in plasma were influenced by sire (P less than .10), breed of dam (P less than .05) and breed of sire x breed of dam (P less than .05). Hampshire gilts had higher concentrations of progesterone in plasma than did Durocs (P less than .05) and Yorkshires (P less than .01). None of the effects in the model was significant for LH. Plasma progesterone and LH had heritability estimates of .48 +/- .41 and .29 +/- .40, respectively. Most genetic and phenotypic correlations of plasma progesterone and LH correlations of plasma progesterone an LH with other traits were small. These data indicate that progesterone concentrations in plasma at 30 days of pregnancy are not a satisfactory predictor of the numbers of corpora lutea and embryos. The differences in plasma progesterone between breeds illustrate the need to consider the breed of gilts when selecting animals for the study of luteal function or physiological factors that may influence progesterone concentrations in plasma.

Animals↗
PubMed1980

Enhancement of antitumor activity of alkylating agents by the radiation sensitizer misonidazole.

The influence of the radiosensitizer misonidazole on the effectiveness of several alkylating agents and cis-platinum against advanced solid murine tumors was investigated. Tumor regrowth delay, frequency of tumor regressions, and animal life span were used to evaluate misonidazole in combination with cyclophosphamide, L-phenylalanine mustard, 1-(2-chloroethyl)-3-trans-4-methylcyclohexyl)-1-nitrosourea, aziridinyl-benzoquinone, and cis-platinum. In the advanced M5076 ovarian carcinoma, misonidazole enhanced the activity of cyclophosphamide, L-phenylalanine mustard, 1-(2-chloroethyl)-3-trans-4-methylcyclohexyl)-1-nitrosourea, and aziridinyl benzoquinone, but not cis-platinum. In early B16 melanoma, misonidazole plus cyclophosphamide was no more effective than cyclophosphamide alone. In advanced Lewis lung carcinoma, misonidazole enhanced the antitumor activity of cyclophosphamide but not 1-(2-chloroethyl)-3-trans-4-methylcyclohexyl)-1-nitrosourea. Misonidazole, at 1000 mg/kg, increased the antitumor effectiveness of L-phenylalanine mustard and cyclophosphamide in M5076 tumors by factors of 2.2 and 1.8, but caused only a 1.2- and 1.3-fold increase in the myelotoxicity of these agents as determined by spleen colony assay of normal bone marrow. Misonidazole also increased the toxicity of cyclophosphamide and L-phenylalanine mustard in non-tumor-bearing mice but to a lesser degree than it enhanced antitumor activity. These results indicate that misonidazole is capable of enhancing the effects not only of ionizing radiation but of alkylating agents as well.

Alkylating Agents↗
PubMed1979

Diabetes mellitus in the juvenile dog: a report of four cases.

In four cases of diabetes mellitus in juvenile dogs, clinical and clinicopathologic findings were similar to those of juvenile onset diabetes mellitus in man. However, histopathologic findings varied from the usual findings in the human disease, and lack of plasma insulin was not proved in the canine cases.

Animals↗
PubMed1979

Median nerve entrapment syndrome in the proximal forearm.

Median nerve compression in the proximal forearm is relatively uncommon. This study reviews 71 cases over a 20 year period. Of the 71 in this series, 51 were treated surgically. The time of onset to definitive treatment ranged from 6 months to 5 years, with an average of 9 months. The ages of patients varied from 15 to 56 years and there were 13 males and 58 females. Past criteria for making the diagnosis are reviewed and an added series of clinical observations is made, including three definitive stress tests. In all cases surgically treated compression of the median nerve has been found at one of three levels, in the following order of frequency: the pronator teres, the flexor superficialis arch, and the lacertus fibrosus. Follow-up has been from 6 months to 19 years and four cases in the series were considered to be failures.

Adolescent↗
PubMed1979

Experimental antitumor activity of aminoanthraquinones.

The activity of a number of substituted alkylaminoanthraquinones was compared in transplanted murine tumor systems including P388 and L1210 leukemias, B16 melanoma, and colon carcinoma 26. The structure-activity relationships among this class of compounds are discussed. Several derivatives had very high antitumor activity in several tumor systems. Two of the most active derivatives, namely, 1,4-bis(2-[(2-hydroxyethyl)amino]ethylamino)-9,10-anthracenedione (bisalkylAAD) and 1,4-dihydroxy-5,8-bis(2-[(2-hydroxyethyl)amino]ethylamino)-9,10-anthracenedione (dihydroxybisalkylAAD), which had curative activity in the above-mentioned tumors, were compared in considerable detail. DihydroxybisalkylAAD showed distinct advantages over bisalkylAAD in several tumor systems and is tenfold more potent with respect to effective dose range. This last difference is important for two reasons. First, these aminoanthraquinones are strong and persistent blue dyes and the administration of lower doses would minimize a potential cosmetic drawback of these compounds. Second and most important, iv administration of dose levels of bisalkylAAD which are within the therapeutic dose range on intermittent dose schedules produced convulsions and immediate death. IV administration of dihydroxybisalkylAAD also caused acute toxicity, but, because of its increased potency relative to antitumor activity and delayed toxicity, this acute toxicity was apparent only at doses well above the therapeutic dose range. All of the aminoanthraquinones evaluated, regardless of their activity as antitumor agents in vivo, proved to be potent inhibitors of DNA and RNA synthesis in vitro and bound strongly to DNA as evidenced by deltaTm values (deltaTm = upward shift in DNA melting temperature). Thus, the strong antitumor activity of aminoanthraquinones would appear to be due to some mechanism other than, or in addition to, DNA binding and inhibition of nucleic acid synthesis.

Animals↗
PubMed1979

Therapy for mouse tumors and human tumor xenografts with the antitumor antibiotic AT-125.

The antimetabolite antibiotic L-(alphaS,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (AT-125) showed significant antitumor activity against L1210 and P388 mouse leukemias and the M5076 mouse ovarian tumor. Depending on the schedule of administration, increases in lifespan of greater than 100% were observed. Activity was observed after ip, oral, or sc inoculation of AT-125 in mice inoculated with L1210 by the ip route. Lewis lung carcinoma and B16 melanoma were not affected by AT-125. The compound was used to treat human tumor xenografts in athymic (nude) mice. The MX-1 mammary tumor regressed when treated with either 8 or 16 mg/kg/day for 10 days, while a dose of 32 mg/kg was toxic. On an every-4-days x 3 schedule there was a marked slowing of MX-1 tumor growth at 50, 100, and 200 mg/kg. The LX-1 lung tumor xenograft growth was slowed significantly by a dose of 32 mg/kg. Growth of colon tumors, CX-1, CX-2, and CX-3, was not affected by AT-125.

Animals↗
PubMed1979

Active efflux of daunorubicin and adriamycin in sensitive and resistant sublines of P388 leukemia.

Significantly decreased uptake and retention of daunorubicin (DAU) and Adriamycin (ADR) have been reported in sublines of P388 leukemia resistant to these anthracyclines. We studied the effects of inhibitors of oxidative phosphorylation on uptake and retention of DAU and ADR in order to characterize the transport process for these anthracyclines and to clarify further the alteration in resistant cells. In glucose-free medium, uptake of DAU and ADR was accelerated by metabolic inhibitors to a greater extent in resistant cells than in sensitive cells. Under these conditions, drug uptake was similar in sensitive and resistant cells. When glucose was added to the incubation medium in the presence of 2,4-dinitrophenol, efflux of DAU from both sensitive and resistant cells was observed. Net efflux of ADR was also observed with the resistant cells, whereas glucose markedly inhibited 2,4-dinitrophenol-stimulated uptake of ADR by the sensitive cells. Furthermore, in sensitive and resistant cells preloaded with ADR and DAU, efflux of the drugs was inhibited by the addition of 2,4-dinitrophenol. These results suggest that there is an active outward transport mechanism for anthracyclines in P388 leukemia cells and that enhanced activity of this efflux process renders cells highly resistant to the cytostatic and cytotoxic effects of ADR and DAU.

Animals↗
PubMed1979

Mechanisms of sensitivity or resistance of murine tumors to N-(phosphonacetyl)-L-aspartate (PALA).

Several biochemical parameters were examined relative to the sensitivity or resistance of representative rodent tumors to N-(phosphonacetyl)-L-aspartate (PALA). The activity of the target enzyme, L-aspartate transcarbamylase (ATCase), was evaluated in homogenates of a spectrum of murine neoplasms. ATCase activity was significantly lower in PALA-sensitive as opposed to PALA-refractory tumors. However, among tumors sensitive to PALA, there was no clearcut relationship between ATCase activity and degree of sensitivity to PALA. Thus, a number of hypotheses were proposed to explain differential sensitivity to PALA in vivo. Enzyme activities in the salvage pathway which phosphorylate pyrimidine nucleosides and deoxynucleosides were found to be greater in refractory tumors. The uptake of PALA, in vitro, though quite slow, was found to be two to eight times greater in two sensitive tumors as compared to the refractory L1210 leukemia. However, in vivo, 24 hours following graduated doses of PALA, nearly identical intratumoral drug concentrations were observed in representative sensitive and refractory tumors. Thus, ultimately, PALA transport would not appear to correlate with differences in drug sensitivity. A number of other biochemical parameters were also found to have no association with sensitivity to PALA in vivo. These included: kinetics of inhibition of ATCase, capacity for restitution of ATCase activity after a dose of PALA, degree of inhibition of ATCase at various doses of PALA, detoxification of PALA by tumor cells, kinetics of uptake of uridine, or catabolism of pyrimidines or pyrimidine nucleosides.

Animals↗
PubMed1979

Effects of local tumor hyperthermia on the growth of solid mouse tumors.

The sensitivity to local tumor hyperthermia (43 degrees, 60 min) of a spectrum of eight different solid mouse tumors (Lewis lung carcinoma, M5076 ovarian carcinoma, colon carcinoma 38, colon carcinoma 26, mammary adenocarcinoma C3HBA, mammary adenocarcinoma 16C, glioma 26, and B16 melanoma) was investigated. A microwave (2.45-GHz) apparatus produced localized heating of the tumors without generation of whole-body hyperthermia. The temperature at the center of the heated tumors was regulated to within +/- 0.1 degrees while the temperature uniformity within the tumor was +/- 0.5 degrees. The local hyperthermia treatments reduced the size and retarded the growth of the treated tumors compared with control values for each of the tumors tested. The faster-growing Lewis lung carcinoma and B16 melanoma were the least responsive to treatment, while the slower-growing colon 38 and M5076 ovarian carcinomas were the most responsive. Multiple treatments resulted in longer grwoth delays and greater tumor growth inhibition than did single treatments. No consistent difference in life span between the control and treated groups was measured, and only five of 188 treated animals were cured.

Animals↗
PubMed1978

In vivo antitumor evaluation of antibiotics. Selected results from the Drug Evaluation Program of the National Cancer Institute, U.S.A.

A summary is given of the in vivo screening results for selected antitumor antibiotics in various stages of the National Cancer Institute drug development program. In addition a brief description of general screening practices of the program is given. After long-term usage of leukemia L1210 as a primary screen, a new screening panel is being initiated with P388 leukemia as a prescreening system. Illustrative data on anguidine, actinomycin D, macromomycin, aclacinomycin, and other fermentation products are shown.

Animals↗