The potential use of the discouraging random guessing (DRG) approach in multiple-choice exams in medical education.
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Education, Medical, Undergraduate↗
Biomedical subjects
J E Moulder
Publications and source records attributed to J E Moulder.
Renal toxicity following total-body irradiation and syngeneic bone marrow transplantation.
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Animals↗
Relationship of cell dose and freezing rate to reconstitutive potency in a hematopoietic reconstitution model.
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Animals↗
Renal irradiation and the pharmacology and toxicity of methotrexate and cisplatinum.
We used a rat model to study the effects of renal irradiation on the pharmacology of methotrexate (MTX) and cisplatinum (cis-Pt). Unanesthetized rats were given bilateral kidney irradiation (20 Gy in 9 fractions). At 9 months after irradiation, 3% of the animals had died and survivors showed moderately impaired renal function. At 15 months, 30% of the animals had died and survivors showed severely impaired renal function. Some animals were given i.v. MTX 1 week to 15 months after irradiation. In irradiated rats, the area under the MTX plasma clearance curve equaled that of controls through 6 months, and was significantly above controls from 9 months on. Other animals were given i.p. cis-Pt 1 week to 9 months after irradiation. The acute toxicity of cis-Pt was the same in control and irradiated rats when cis-Pt was given immediately before or after irradiation. Beginning 3 months after irradiation there was a progressive increase in cis-Pt toxicity and a simultaneous decrease in urinary platinum excretion. Irradiated animals that survived cis-Pt treatment showed increased radiation nephritis; the greatest effect occurred when cis-Pt was given 3 months or more after irradiation. MTX and cis-Pt clearance decreased when renal dysfunction was first observed and changes in renal function preceded changes in drug clearance and toxicity.
Animals↗
Effectiveness and biological effects of techniques used to induce hypoxia in solid tumors.
Acute hypoxia is often induced in rodent tumors during studies of the oxygenation or the therapeutic responses of the tumors, either by clamping the blood supply to the tumors or by asphyxiating the hosts with nitrogen. Analyses of data from such experiments generally assume that these processes have no effects other than the induction of hypoxia and that uniform, severe hypoxia is produced throughout the tumors. The studies described in this report test several aspects of these assumptions using BA1112 rat rhabdomyosarcomas and EMT6 mouse mammary tumors. Both clamping and asphyxiation appear to be effective in producing hypoxia in the tumors. Induction of artificial hypoxia for the times necessary for irradiation was not toxic to the tumor cells and generally did not alter the growth of unirradiated tumors. However, the techniques are not without significant effects. Prolonged clamping produced extensive cytotoxicity. Clamping BA1112 tumors for 30 min and removing the clamp just before irradiation altered the tumor cell survival curve and the TCD50. Furthermore, anesthesia and/or restraint (necessary during clamping) have significant effects on tumors and hosts. The data show that the assumptions underlying the use of clamping and N2-asphyxiation to produce hypoxia for short periods in vivo are generally reasonable for BA1112 and EMT6 tumors, but illustrate the necessity for carefully examining the effects and efficacies of the procedures in each tumor/host system.
Animals↗
The immune system in experimental Pseudomonas keratitis. Model and early effects.
A model to study the immune system in Pseudomonas keratitis was developed using defined flora rats (WAG/RijMCW) that have not been exposed to Pseudomonas aeruginosa. One group of rats was made immunocompetent towards P. aeruginosa by intraperitoneal injection of phenol-killed P. aeruginosa while a second group remained naive to this organism. Corneas of both groups were scratched centrally with a 21-g needle, before inoculation with 2 X 10(8) P. aeruginosa organisms. Corneas of control animals were either only scratched or only inoculated with the bacterium. At 18 hr, the naive animals were killed. In naive rat corneas, light and electron microscopy showed bacteria throughout the cornea, polymorphonuclear leukocytes (PMNs) distributed from the limbus towards the center, and little stromal degradation. In contrast, massive corneal degradation was observed in the immunocompetent rats; PMNs were present, but no bacteria were observed free in the stroma. The total acid protease content was higher in the immunocompetent than in the naive rat corneas, a possible reason for the observed difference in corneal degradation. This difference was not due to increased numbers of PMNs since nearly equal numbers of PMNs were counted after enzymatic disaggregation of both types of corneas. Glycogen-induced peritoneal PMNs from both types of rats migrated equally well towards P. aeruginosa culture media and media of corneas incubated with this bacterium. The authors conclude that immune recognition is (1) involved in the corneal host response to P. aeruginosa and (2) required for efficient phagocytosis by PMNs but not their recruitment.
Animals↗
Differential effect of cycloheximide on normal tissue tolerance and tumor control in irradiated rats.
The effect of the protein synthesis inhibitor cycloheximide (CHM) on normal tissue tolerance and tumor control in the rat following single doses of radiation has been studied. We have previously shown that the drug protects against skin damage when administered prior to irradiation of the hind limbs. It does not protect against six-month lethality when given prior to irradiation of the kidneys. In the present studies protection of rat bone marrow as evidenced by 30-day lethality was observed when CHM was given prior to whole-body irradiation. When CHM was given to rats bearing the BA1112 tumor, it had no protective effect on radiocurability. Therapeutically favorable differential protection of rapidly proliferating normal tissue over tumor can be achieved when CHM is administered prior to single radiation doses in the rat. This effect is most likely due to inhibition of protein synthesis and resultant interruption of the cell cycle in proliferating normal tissue. Further studies are required to determine the clinical applicability of CHM.
Animals↗
Development of a rat lung cancer model.
A rat lung cancer model based on intrabronchial instillation of a tumor cell suspension has been developed for use in therapy and toxicity testing. Two tumors were used in this study, a sarcoma and an adenocarcinoma, both of which were of spontaneous origin in the strain of rats used. The inoculated tumor cells implant on the bronchiolar mucosa, forming a detectable single "primary" tumor resembling the spontaneous lung cancers arising in humans. The tumor growth is detectable by use of diagnostic radiographs, weight loss and other "clinical" signs. The tumors appear on chest radiographs 3 to 5 weeks after inoculation, and the implant rate is proportional to the number of tumor cells inoculated. Untreated animals have a median survival (after radiographic detection of the tumor) of 8 days, and die of local complications of tumor growth. When a slow growing transplantable tumor line of lung origin is developed, this model will be used to evaluate radiotherapy and chemotherapy schedules.
Adenocarcinoma↗
Hypoxic fractions of solid tumors: experimental techniques, methods of analysis, and a survey of existing data.
Hypoxic fractions are measured by indirect techniques, which compare the response of tumors to large single doses of radiation given under normal aeration and artificial hypoxia. This paper reviews hypoxic fraction measurements and measurement techniques, giving particular attention to the biological, technical, and statistical aspects of the assays; the implicit assumptions underlying the analyses; and the dependence of the determinations on the assay conditions and the tumor and host characteristics. The three major hypoxic fraction assay techniques (paired survival curve, clamped tumor control, and clamped growth delay) share common biological assumptions. They require that the survival curves of naturally and artificially hypoxic cells have the same slope and intercept. They assume that the majority of the cells are either fully oxic or fully hypoxic. They assume that the methods used to induce artificial hypoxia leave no oxygenated regions and that tumor cells rendered artificially hypoxic are no less viable than cells in normally-aerated tumors. The universal validity of these assumptions is questionable. Each technique uses additional special assumptions and each may measure a different population of hypoxic cells. This paper reviews 92 hypoxic fraction determinations in 42 tumor systems. Radiobiologically hypoxic cells appear to be present in the majority of macroscopic solid rodent tumors. The hypoxic fraction was found to increase as the tumor size increased from microscopic to macroscopic; the dependence of hypoxic fraction on tumor size at macroscopic sizes was less clear. The site of tumor implantation, the use of anesthesia, and certain host characteristics may influence the hypoxic fraction. The hypoxic fraction generally did not depend on the tumor growth rate, transplantation history, or histology. These findings indicate that hypoxic cells are a common feature of solid tumors in rodents and provide no evidence that hypoxic cells should not be present in human tumors.
Anesthesia↗
Tumor-to-tumor variability in the hypoxic fractions of experimental rodent tumors.
Paired determinations of the radiation responses of normally-aerated and artificially hypoxic rodent tumors, performed to measure the hypoxic fractions of the tumors, were obtained from our own laboratories and from the literature. The data were reanalyzed to assess whether the variabilities in the radiation responses of the normally-aerated and artificially hypoxic tumors were similar. If there were large differences in the hypoxic fractions of individual tumors within the experiments, the variability in the data from aerobic tumors would be expected to be greater than the variability in the data from artificially hypoxic tumors (which should all be brought to uniform hypoxia and therefore uniform radioresistance). The analyses revealed the variability to be as great or greater for hypoxic tumors as for normally-aerated tumors. This finding suggests that factors other than tumor-to-tumor differences in oxygenation produce most of the variability in the radiation responses of individual tumors from an experimental tumor line.
Animals↗
Effects of single-dose and fractionated cranial irradiation on rat brain accumulation of methotrexate.
The effects of single-dose and fractionated whole-brain irradiation on brain methotrexate (MTX) has been studied in a rat model. The amount of MTX present in the brain 24 hr after a single i.p. dose (100 mg/kg) was the same wether animals were sham irradiated or given a single dose of 2000 rads 6 or 48 hr prior to the drug (6.9, 8.3, and 6.8 pmol MTX/g, wet weight, respectively). Animals sham irradiated or given 2000 rads in 10 fractions over 11 days and treated with an average dose of 1.2 mg MTX/kg i.p. twice a week for 24 weeks did not differ significantly in their brain MTX concentration (7.9 and 8.3 pmol MTX/g, wet weight, respectively). Chronically MTX-treated animals became folate deficient whether they were irradiated or not (450 and 670 pmol folate/g, wet weight, brain in MTX-treated and control animals). Thus, MTX accumulates in the brain with acute or chronic administration, and this accumulation is not altered by this amount of brain irradiation.
Animals↗
Hypoxic fraction determinations with the BA1112 rat sarcoma: variation within and among assay techniques.
Measurement of the hypoxic fraction in the same tumor system by different assay techniques often gives incompatible results. The hypoxic fraction of the BA1112 sarcoma has been measured by three assay techniques: tumor control and growth delay assays in which the tumors remain in situ after irradiation, and paired survival curve assays in which the tumors are excised after irradiation. The assays were done with and without anesthesia on tumors growing in two different subcutaneous sites. Anesthesia of the hosts produced a statistically significant decrease in the calculated hypoxic fraction in a tumor control assay, but not in a paired survival assay. The excision assays gave consistently higher hypoxic fraction estimates than either the tumor control or growth delay assays. Some of the factors which could produce higher hypoxic fractions in excision assays than in in situ assays are discussed. Interpretation of the results was complicated by disagreements between the growth delay and tumor control assays, and by disparities between replicate determinations. The discrepancies among assays are caused almost entirely by variations in the response of the artificially hypoxic tumors, rather than variations in the response of aerobic tumors. These results indicate that assumptions commonly made when measuring hypoxic fractions may not be valid.
Aerobiosis↗
Effect of cycloheximide on skin and renal radiation tolerance in the rat.
The effect of cycloheximide (CHM) on skin and renal radiation tolerance in the rat has been studied. When administered 24 hr prior to a range of single radiation doses to the hind limbs, the drug protected against skin damage. When administered at intervals of 45 min to 100 hr prior to single-dose irradiation of the kidneys, no protection against renal injury, as manifested by blood pressure, urine creatinine level, and lethality, was observed. CHM-induced alteration in the cell cycle may confer radioprotection to a rapidly proliferating cell renewal system such as the skin and exert no radioprotective action in slowly proliferative tissue such as kidney.
Animals↗
Fatal misonidazole-induced encephalopathy: an RTOG case report.
A case of fatal encephalopathy following administration of misonidazole (MISO) is reported. Anorexia and dehydration preceded signs of encephalopathy after a cumulative dose of 18 g (11 g/m2) of MISO in five weekly doses. Serum MISO levels four hours after weekly administrations were markedly elevated. Postmortem examination revealed focal cortical neuronal necrosis and hemorrhage with focal demyelination. The possible relationship of dehydration or altered drug metabolism to the development of MISO central nervous system toxicity is noted.
Brain Diseases↗
Tumour response endpoints in the BA1112 rat sarcoma.
The rat rhabdomyosarcoma BA1112 has a number of features which make it a useful model for the study of tumour response to radiation therapy. It is a transplantable tumour, isologous to an inbred line of WAG/Rij rats and it elicits no demonstrable host immune response. The tumour grows locally at the implantation site and rarely metastasizes. It is known to contain hypoxic cells which reoxygenate during a prolonged course of fractionated radiation therapy. The growth and radiation response characteristics of the tumour have remained stable for over 15 years. A newly developed in vitro assay for tumour cell clonogenicity greatly facilitates the measurement of radiation dose-response curves and the monitoring of cell response following in vivo treatment. The in vivo response of the tumour to fractionated radiation therapy is analysed in terms of cellular response, reoxygenation and cell proliferation.
Animals↗
Flagellar elongation and shortening in Chlamydomonas. IV. Effects of flagellar detachment, regeneration, and resorption on the induction of flagellar protein synthesis.
Synthesis of new proteins is required to regenerate full length Chlamydomonas flagella after deflagellation. Using gametes, which have a low basal level of protein synthesis, it has been possible to label and detect the synthesis of many flagellar proteins in whole cells. The deflagellation-induced synthesis of the tubulins, dyneins, the flagellar membrane protein, and at least 20 other proteins which co-migrate with proteins in isolated axonemes, can be detected in gamete cytoplasm, and the times of initiation and termination of synthesis for each of the proteins can be studied. The nature of the signal that stimulates the cell to initiate flagellar protein synthesis is unknown. Flagellar regeneration and accompanying pool depletion are not necessary for either the onset or termination of flagellar protein synthesis, because colchicine, which blocks flagellar regeneration, does not change the pattern of proteins synthesized in the cytoplasm after deflagellation or the timing of their synthesis. Moreover, flagellar protein synthesis is stimulated after cells are chemically induced to resorb their flagella, indicating that the act of deflagellation itself is not necessary to stimulate synthesis. Methods were defined for inducing the cells to resorb their flagella by removing Ca++ from the medium and raising the concentration of K+ or Na+. The resorption was reversible and the flagellar components that were resorbed could be re-utilized to assemble flagella in the absence of protein synthesis. This new technique is used in this report to study the control of synthesis and assembly of flagella.
Chlamydomonas↗
Effect of actinomycin D and neoarsphenamine on tumor control and skin tolerance in the rat.
Actinomycin D and neoarsphenamine were tested for their ability to produce therapeutically favorable radiosensitization in the WAG/Rij rat. Acute and late skin reactions and control of the BA1112 rhabdomyosarcoma were examined in drug-treated and untreated animals irradiated in single- and five-fraction schedules. Actinomycin D was found to protect skin and tumors when added 15 minutes before irradiation. Actinomycin D added 2 hours before irradiation in a five-fraction trial produced slight tumor sensitization accompanied by slight skin protection. Neoarsphenamine produced significant tumor sensitization without skin sensitization in one of the single-fraction trials, but had no effect in the five-fraction trials.
Animals↗
Effect of combined metronidazole and DMSO on tumour control and skin tolerance in the rat.
A combination of the radiosensitizer, metronidazole, and the radioprotector, dimethyl sulfoxide (DMSO), was tested for its effects on the radiation tolerance of rat skin and on the radiosensitivity of the BA1112 rhabdomyosarcoma. The simplest interpretation of the effects of the combined treatment is that: metronidazole radiosensitizes BA1112 in one-fraction but not in five-fraction treatments; metronidazole slightly increases the radiosensitivity of skin in one-fraction treatments; metronidazole radiosensitization is independent of the radioprotection produced by DMSO.
Animals↗