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Biomedical subjects

J B Mitchell

Publications and source records attributed to J B Mitchell.

At least 235 records · Page 13Linked to original sources
PubMed1990

Serotonin regulates type II corticosteroid receptor binding in hippocampal cell cultures.

Previous work from our laboratory has shown that early postnatal handling of rat pups permanently increases hippocampal type II, but not type I, corticosteroid receptor binding. Handling also increases hippocampal 5-HT turnover, and the effect of handling on type II corticosteroid receptor binding is blocked by concurrent administration of the 5-HT2 receptor antagonist ketanserin. In view of these findings, the present studies examined the effects of 5-HT on type I ([3H]corticosterone) and type II ([3H]RU 28362) corticosteroid receptor binding in dispersed hippocampal cell cultures derived from animals killed at E19-20 in order to verify that 5-HT can act directly on hippocampal cells to alter corticosteroid receptor binding. Both type I and type II receptors were measurable in cultured hippocampal cells and the apparent affinity (Kd) for [3H]corticosterone (0.4 +/- 0.1 nM) and [3H]RU 28362 (0.8 +/- 0.1 nM) was similar to that from studies with intact animals. 5-HT increased type II, but not type I, corticosteroid receptor binding capacity in a dose-related manner, with the maximal effect (+188%) observed at 10 nM 5-HT and no change in the affinity of the receptor for [3H]RU 28362. The effect of 10 nM 5-HT on [3H]RU 28362 binding required a minimum of 4 d exposure and persisted for at least 7 d following the removal of 5-HT. The effect of 10 nM 5-HT on [3H]RU 28362 binding was completely blocked by the 5-HT2 receptor antagonists ketanserin and mianserin. There were no effects of the 5-HT1a antagonist, BMY 7378, or the 5-HT3 antagonist, MDL 72222.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Pharmacological activity of N-methyl-carbamylcholine, a novel acetylcholine receptor agonist with selectivity for nicotinic receptors.

N-Methyl-carbamylcholine (also called N-methyl-carbachol) is an analogue of the mixed muscarinic-nicotinic acetylcholine receptor agonist, carbachol. Previous studies have provided evidence that radiolabelled N-methyl-carbachol can bind selectively to nicotinic acetylcholine receptors in rat brain. To determine whether N-methyl-carbachol acts as an agonist or an antagonist at nicotine and/or muscarinic receptor sites, the present study examined the pharmacological activity of this compound on some cholinergically innervated tissues. N-Methyl-carbachol, like carbachol, depolarized rat isolated sympathetic ganglia and these effects were inhibited by a nicotinic antagonist, d-tubocurarine, but not by a muscarinic antagonist, atropine. Exposure of rat sympathetic ganglia to N-methyl-carbachol blocked the compound action potential generated in ganglia by stimulation of the pre-ganglionic trunk; this effect of N-methyl-carbachol was likely due to desensitization of the nicotinic response. N-Methyl-carbochol, like carbachol, stimulated the release of [3H]noradrenaline from cultured adrenal medullary cells that had been pre-loaded with [3H]noradrenaline; these effects were largely inhibited by a nicotinic antagonist, mecamylamine, while atropine produced less blockade. N-Methyl-carbachol contracted the frog isolated rectus abdominis muscle and the effect was completely blocked by d-tubocurarine. By contrast, contracture of the rectus abdominis produced by carbachol was partially inhibited by either atropine or d-tubocurarine. N-Methyl-carbachol, like carbachol, contracted the rat isolated ileum and these effects were completely blocked by atropine; however, N-methyl-carbachol was about 42 times less potent than carbachol for this effect. Intravenous injection of N-methyl-carbachol, like nicotine, to the rat produced a transient decrease followed by a more sustained rise in blood pressure while carbachol produced only a sustained decrease in blood pressure. The effects of N-methyl-carbachol and nicotine on blood pressure were blocked by pretreatment of the animal with a nicotinic antagonist, hexamethonium. N-methyl-carbachol, like nicotine, stimulated the release of [3H]dopamine from rat striatal synaptosomes, pre-loaded with [3H]dopamine; release induced by either N-methyl-carbachol or nicotine was inhibited by mecamylamine but not by atropine. In rat cerebral cortical slices pre-loaded with [3H]inositol, carbachol, but not N-methyl-carbachol, stimulated the accumulation of [3H]inositol-1-phosphate, an effect blocked by atropine but not by mecamylamine.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenal Medulla↗
PubMed1989

Free radicals induced by adriamycin-sensitive and adriamycin-resistant cells: a spin-trapping study.

The radicals generated by adriamycin-sensitive (CHO-AB) and adriamycin-resistant (CHO-C5) Chinese hamster ovary cells as well as by adriamycin-sensitive and -resistant human breast cancer cells (MCF7-WT and MCF7-ADR) have been studied with spin-trapping and ESR spectroscopy. During anoxic exposure to adriamycin (ADR) both pairs of cell lines produced the broad ESR singlet characteristic of ADR semiquinone (AQ.). By use of tris(oxalato)chromate (CrOx) as an extracellular line-broadening agent, the distribution of AQ. between the intra- and extracellular compartments was studied. For cell densities of (1-3) X 10(7) cells/mL, CrOx eliminated most, though not all, of the ESR signal, indicating that the AQ. radicals freely diffuse and partition between the intra- and extracellular compartments proportionally to their respective volumes. Similar behavior was exhibited by all four cell lines studied. Upon introduction of oxygen to anoxic cells in the presence of the spin trap 5,5-dimethylpyrroline N-oxide (DMPO), the AQ. signal was replaced by that of the DMPO-OH spin adduct. Metal chelators such as desferrioxamine had no effect on DMPO-OH or AQ. formation. Superoxide dismutase, not catalase, totally eliminated the ESR signal, indicating that DMPO-OH produced by ADR-treated cells originates from superoxide rather than from .OH produced from H2O2. In the presence of CrOx, the DMPO-OH signal was not distinguishable from the background noise, thus excluding any contribution to the signal by intracellular spin adducts.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Effects of castration, steroid replacement, and sexual experience on mesolimbic dopamine and sexual behaviors in the male rat.

The concentrations of dopamine (DA) and a DA metabolite in a terminal field of the mesolimbic DA system, the nucleus accumbens, decreased after castration, an effect that was prevented by treatment with testosterone (T) or estradiol. After castration, DA concentrations were increased in the medial preoptic area, and were unchanged in the caudate-putamen, substantia nigra, and ventral tegmental area. Changes in DA and DA metabolite concentrations in the nucleus accumbens coincided with changes in measures of sexual arousal. Sexual experience did not affect DA concentrations, but did increase DA metabolism in the nucleus accumbens, and also increased the frequency of female-directed behavior in castrated males. These results suggest that T, or its aromatized metabolite, influences the mesolimbic DA system, and that this system is involved in mediating sexual arousability.

Animals↗
PubMed1989

In vitro photodynamic therapy of human lung cancer: investigation of dose-rate effects.

The influence of light dose-rate delivery was studied in human lung adenocarcinoma A549 cells treated with hematoporphyrin derivative (Photofrin II)-based photodynamic therapy. Clonogenic cell survival curves were generated for cells treated for 2 h with 25 micrograms/ml of Photofrin II followed by exposure to light delivered at 0.3, 0.15, 0.075, or 0.0375 milliwatts/cm2. Cellular sensitizer levels, as determined by fluorescence measurements, remained constant over the entire time course of all light exposures. As the dose rate of light delivery was decreased, a significant increase in cell survival was observed at equal light energies (225 mJ/cm2). The enhancement in survival from the highest to the lowest dose rate used was 1.6-fold (at the 50% survival level). These findings may have important clinical implications relating to photodynamic therapy of tumors and may provide a partial explanation for treatment failure.

Adenocarcinoma↗
PubMed1989

Radiation sensitivity of human lung cancer cell lines.

X-Ray survival curves were determined using a panel of 17 human lung cancer cell lines, with emphasis on non-small cell lung cancer (NSCLC). In contrast to classic small cell lung cancer (SCLC) cell lines, NSCLC cell lines were generally less sensitive to radiation as evidenced by higher radiation survival curve extrapolation numbers, surviving fraction values following a 2 Gy dose (SF2) and the mean inactivation dose values (D) values. The spectrum of in vitro radiation responses observed was similar to that expected in clinical practice, although mesothelioma was unexpectedly sensitive in vitro. Differences in radiosensitivity were best distinguished by comparison of SF2 values. Some NSCLC lines were relatively sensitive, and in view of this demonstrable variability in radiation sensitivity, the SF2 value may be useful for in vitro predictive assay testing of clinical specimens.

Adenocarcinoma↗
PubMed1989

Correlation of exposure time, concentration and incorporation of IdUrd in V-79 cells with radiation response.

These experiments were designed to find the minimum concentration at which incorporation of and sensitization by IdUrd (Iododeoxyuridine) would occur and the effect of concentrations from .1 to 100 microM for exposures of 8 to 96 hr in cultured V-79 cells exposed to 137Cs gamma rays at 2 Gy per minute. At 0.1 microM thymidine replacement averaged 1% and the SER ranged from 1.1 to 1.28, significant at the 95% level. The maximum thymidine replacement was 49% after 48 hr exposure to 30 microM yielding an SER of 2.7. SER generally peaked after 72 hr of exposure. This cell line has an 8 hr cycle time in our hands and thus optimal sensitization would occur after 9 cell cycles. These ranges need testing in human cells in culture and in Phase I clinical trials.

Animals↗
PubMed1989

Glutathione modulation in cancer treatment: will it work?

Glutathione (GSH) assumes a pivotal role in numerous cellular functions including bioreductive reactions, maintenance of enzyme activity, amino acid transport, protection from harmful oxidative species, and detoxification of xenobiotics. The importance of GSH in modifying the cellular response to several anti-cancer treatment modalities has become better appreciated with the introduction of agents which can either decrease or elevate GSH levels in cells and tissues. In general, GSH depletion has been demonstrated to further enhance the cytotoxicity of several chemotherapy drugs and nitroimidazole hypoxic cell radiosensitizers. Conversely, GSH elevation affords varying degrees of protection. Whether or not GSH modulating agents will be useful as an adjuvant to selected cancer treatment modalities will depend on whether differential levels of GSH can be achieved in tumor versus normal tissues. Accurate GSH measurements in tumor and normal tissues will be required to adequately use and interpret the results of clinical studies where GSH modulating agents are employed. Precise tumor GSH measurements pose a considerable challenge due to the complicated cellular makeup of tumors.

Antineoplastic Agents↗
PubMed1989

Use of monochlorobimane for glutathione measurements in hamster and human tumor cell lines.

The use of monochlorobimane (MCIB) as a fluorescence label for glutathione (GSH) quantitation was investigated in human tumor cell lines. When MCIB was used with a hamster fibroblast cell line under conditions where GSH was either depleted or elevated, an excellent correlation between bimane-GSH fluorescence and the standard cyclic GSH reductase assay (Tietze's) was accomplished. When the MCIB technique was applied to a human lung adenocarcinoma cell line, little or no GSH labeling was noted even at MCIB levels 10X higher than that used for the hamster line. HPLC analysis suggested that the source of the problem may be the affinity for MCIB to glutathione S-transferase. By using higher dye concentrations and longer staining times, adequate staining was possible. While the MCIB technique may have problems quantitating GSH levels between cell types, the possibility of examining GSH heterogeneity in solid tumor biopsies remains feasible.

Animals↗
PubMed1989

Modification of SR 2508 sensitization in hypoxic V79 cells by manipulation of glutathione levels.

This series of experiments employed the hypoxic cell sensitizer SR 2508 in concentrations ranging from 0.1 to 10 mM and V-79 cells irradiated in air or made hypoxic in glass syringes, then irradiated with 15 MV X rays. Using a series of survival curves measured at the various concentrations, K curves relating sensitizer enhancement ratio (SER) to SR 2508 concentration were calculated with normal GSH levels or with depletion of GSH to 0% using 1 mM buthionine sulfoximine (BSO) or elevation to 200% of normal using 1 mM oxothiazolidine carboxylate (OTZ). Survival curves were fitted by computer, allowing calculation of standard errors for the SER values. The depletion of GSH by BSO sensitized hypoxic and aerated cells significantly and caused more than additive enhancement of SR 2508 sensitization in hypoxic cells. Elevation of GSH with OTZ protects cells irradiated in air or hypoxia and reduces the SER obtained with SR 2508. The results further support the importance of GSH levels in influencing sensitization by nitroimidazoles.

Animals↗
PubMed1989

Evaluation of nitroimidazole hypoxic cell radiosensitizers in a human tumor cell line high in intracellular glutathione.

Five nitroimidazole hypoxic cell radiosensitizers were evaluated in a human lung adenocarcinoma cell line (A549) whose GSH level was 8-fold higher than Chinese hamster V79 cells. One millimolar concentrations of Misonidazole (MISO), SR-2508, RSU-1164, RSU-1172, and Ro-03-8799 sensitized hypoxic A549 cells to radiation, with Ro-03-8799 giving the highest sensitizer enhancement ration (SER) (2.3). However, MISO, SR-2508 and Ro-03-8799 were less effective in this cell line than in V79 cells, presumably due to higher GSH content of the A549 cells. Increased hypoxic radiosensitization was seen with 0.1 mM Ro-03-8799 after GSH depletion by BSO as compared to 0.1 mM Ro-03-8799 alone (SER-1.8 vs 1.3). The combination of GSH depletion and 0.1 mM Ro-03-8799 was considerably more toxic than 0.1 mM or 1.0 mM Ro-03-8799 alone. This sensitivity was much greater than has been observed for SR-2508. These data show that Ro-03-8799 was the most efficient hypoxic cell radiosensitizer in a human tumor cell line considerably higher in GSH than the rodent cell lines often used in hypoxic radiosensitization studies. Thus, Ro-03-8799 may be a more effective hypoxic cell sensitizer in human tumors that are high in GSH.

Cell Line↗
PubMed1989

Effects of reduced training on submaximal and maximal running responses.

The purpose of this investigation was to examine the effects of a reduction in training volume (RT) (8 km/day, 5 days/wk, for 10 days) in five highly trained collegiate distance runners. The subjects were tested midseason (MS) (110 km/wk), after a 10-day taper (80 km/wk) and subsequent championship meet (post-championship, PC), and post RT. PC data represent the runners at their peak performance capacity. Maximal oxygen consumption, maximal heart rate (HR), and time to exhaustion during the max tests, as measured at PC and RT, were not altered. Other parameters were measured for all conditions. No changes were observed in body weight and percent body fat (p greater than 0.05). Submaximal treadmill runs (TR) at 265 and 298 m/min revealed no alterations in VO2 submax, ratings of perceived exertion (RPE), HR and 2-min post-run lactate levels (p greater than 0.05). The HR during a 6-min track run (265 m/min) significantly increased (p less than 0.001) by 10 bts/min with RT vs MS and PC, which may be a result of mechanical or psychological changes. After RT, 1-min recovery HR (HRr) for the track run and 1- and 2-min post-TR were significantly elevated by 16, 12, and 12 bts/min, respectively. It is not apparent what role HRr serves as an indicator of fitness level and performance capability during reduced training. These results suggest that the reduced training program used did not sufficiently diminish nor improve aerobic capacity in highly trained distance runners.

Adult↗
PubMed1989

Radiobiology and clinical application of halogenated pyrimidine radiosensitizers.

Halogenated pyrimidines (HP) represent a unique class of non-hypoxic cell radiosensitizers currently under clinical re-investigation. In order for halogenated pyrimidines to sensitize cells to radiation, they must be incorporated into cellular DNA. In the case of human tumors, which have in general rather long cell cycle times, this may require many days of continuous drug infusion to achieve adequate replacement of the DNA base thymidine with HP. In vitro studies support the relationship between the extent of radiosensitization and the percentage of thymidine replacement. Recent clinical studies evaluating the role of iododeoxyuridine (IdUrd) as a radiation sensitizer in large unresectable sarcomas have been extremely encouraging. To support and expand upon these positive clinical findings more information and research is needed regarding: (1) the mechanism of HP-induced radiosensitization; (2) the percentage of HP thymidine replacement in human tumors achievable and how it relates to treatment outcome; (3) the means of increasing HP incorporation in tumor and minimizing incorporation in normal tissues; (4) a better understanding of optimal timing between HP administration and radiation treatment; and (5) methods to evaluate which tumors are appropriate candidates for HP therapy. While presently limited to use in conventional high dose-rate X-ray therapy, laboratory studies suggest that HP might also be effective in low dose-rate brachytherapy and for selected high LET clinical beams. HPs probably will not be 'general' non-hypoxic cell radiosensitizers for all tumor types, but with appropriate tumor-type/anatomical site selection and refinement in their administration, HPs may prove beneficial in cancer treatment.

Bromodeoxyuridine↗
PubMed1989

Influence of carbohydrate dosage on exercise performance and glycogen metabolism.

This study was undertaken to examine the effects of ingestion of carbohydrate (CHO) solutions of 0 (WP), 6 (CHO-6), 12 (CHO-12), and 18 g CHO/100 ml (CHO-18) on performance and muscle glycogen use. Ten trained cyclists performed five 120-min cycling trials. The first 105 min of each trial was at 70% of maximal O2 consumption (VO2max), and the final 15 min was an all-out performance ride on an isokinetic cycle ergometer equipped to measure total work output. In one of the trials (CHO-12I) the submaximal portion of the ride consisted of seven 15-min rides at 70% of VO2max with a 3-min rest between each ride. Every 15 min the men consumed 8.5 ml.kg-1.h-1 (approximately 150 ml) of one of the four test solutions. Venous blood samples were obtained every 15 min for glucose and insulin. Muscle biopsies were obtained from the vastus lateralis at 0 and 105 min in the WP and the CHO-12 continuous and intermittent trials. Biopsy samples were assayed for glycogen and sectioned and stained for myosin adenosinetriphosphatase and glycogen for single fiber depletion measurements. There were no differences in glycogen use (86.7 +/- 6.0, 75.5 +/- 7.9, and 83.5 +/- 5.5 mmol/kg for the WP, CHO-12C, and CHO-12I, respectively) or depletion patterns between the WP and the two CHO-12 trials. Blood glucose was significantly elevated in both the CHO-12 trials and in the CHO-18 trial compared with the WP trial.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Can price controls induce optimal physician behavior?

Recently, budget-conscious policymakers have shifted their attention to the physician services market and have begun to consider a wide variety of price regulatory schemes for moderating expenditures in this market. In a recent article in this journal, Feldman and Sloan warned that price controls on physician services may cause undesirable declines in service quality, independent of their budgetary ramifications. Our aim in this article is to reconsider the effects of price controls in the broader context of insurance coverage and moral hazard. Our ultimate goal is to assess the benefits of price controls independent of specific assumptions about the controversial issues of demand inducement and income targeting. Using a simple extension of the Feldman/Sloan model, we find that price controls can be and almost certainly are welfare-improving as long as consumers are sufficiently well insured, regardless of where one stands on the inducement issue. The salutary effects of price controls, on the other hand, can be compromised by income-targeting behavior on the part of physicians. We also introduce evidence from Medicare's recent fee freeze to evaluate the possibility of income-targeting behavior empirically. While formal studies of income targeting suggest that its magnitude is small in cross-section, we warn that its effects may be larger over time; this is what our descriptive evidence suggests. We conclude that more dramatic short-term progress on physician fee inflation will require stronger measures, such as putting physicians at risk for consumer expenditures.

Cost Control↗