Biomedical subjects
W L Russell
Publications and source records attributed to W L Russell.
Radiation-induced mutations at mouse hemoglobin loci.
In experiments designed to detect new mutations affecting hemoglobin, we irradiated the male or female parent in reciprocal crosses of two mouse strains that differ in alleles at the hemoglobin (Hba, Hbb) loci as well as at five other specific loci. Offspring were analyzed for hemoglobin properties (electrophoretic pattern, solubility, crystal pattern), serum albumin differences, erythrocyte lysis, reticulocyte count, and external appearance. Five hemoglobin variants were found among the mutants. In three, the genetic contribution from the irradiated father was not expressed with regard to the alpha-chain; one carried a tandem deuplication (the first known case in the mouse) involving Hbb; and one probably resulted from double nondisjunction of chromosome 7. The finding that major chromosome aberrations can mimic hemoglobin mutations indicates the need, in similar experiments, to follow F1 screening with thorough cytogenetic analysis. The variants in which there is nonexpression of the alpha chain may be the result of small deficiencies or of faults in transcription or translation. Mutation rates based on these three variants are not out of line with earlier specific-locus results, although confidence limits are still wide.
Stercoraceous ulcer.
Seven cases of stercoraceous ulcer are presented and discussed; six occurred in the colon and one in the terminal ileum. The six colon ulcers perforated; the ulceration of the ileum presented as obstruction without perforation. The mean age was 48. Five patients had chronic constipation, and alkali and clay ingestion were implicated. There was an interesting lack of a marked febrile and leukemoid response. Three patients survived following exteriorization or resection.
Results of tests for possible transmitted genetic effects of hycanthone in mammals.
Extensive tests to detect transmitted genetic effects of hycanthone in mammals have been made to provide the most pertinent information for estimating a possible mutagenic hazard of this compound. The tests include dominant lethal studies in males and females, X chromosome loss study in offspring of treated females, and a search for deficiencies and gene mutations in the offspring of treated males whose germ cells were exposed in spermatogonial and postspermatogonial stages. In most tests, no genetic effect of hycanthone was observed even at dosages much higher than the clinical level. In the few cases where the results are possibly or definitely positive, there is none where the magnitude of the effect estimated, with maximizing assumptions, at the clinical level reaches as high as 10% of the spontaneous mutation rate or 10% of the frequency in controls.
Effects of dose on the induction of dominant-lethal mutations and heritable translocations with ethyl methanesulfonate in male mice.
Genetic damage by ethyl methanesulfonate (EMS) in male mice was measured at doses ranging from 50 to 300 mg/kg with dominant-lethal mutations and reciprocal translocations as endpoints. No appreciable increase in dominant-lethal mutations was detected following a dose of 100 mg/kg. Dominant lethals induced by EMS were convincingly detected only after a dose of 150 mg/kg, but in the translocation experiment an increase in the genetic effect was detectable at the 50 mg/kg dose. It is likely that dominant lethals had also been induced at the 50 and 100 mg/kg doses, but were not detected due to the relative insensitivity of the dominant..lethal procedure. Thus, for detection of low levels of EMS-induced chromosome breakage, translocations are a much more reliable endpoint than are dominant-lethal mutations. A procedure for large-scale screening of induced translocations is described.-The dominant-lethal dose-response curve, plotted on the basis of living embryos as a percentage of the control value, is clearly not linear as it is markedly concave downward. Similarly, the translocation dose-response curve showed a more rapid increase in the number of translocations with dose than would be expected on the basis of dose-square kinetics. It is clear for both of these endpoints that the effectiveness of EMS in inducing chromosome breakage is proportionately much lower at low doses.
Symposium No. 3: Radiation genetics. Introduction by the Chairman. Future research in mouse radiation genetics.
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Radiation and chemical mutagenesis and repair in mice.
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Effect of the interval between irradiation and conception on mutation frequency in female mice.
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DEPENDENCE OF MUTATION FREQUENCY ON RADIATION DOSE RATE IN FEMALE MICE.
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EXCEPTIONAL INHERITANCE OF A SEX-LINKED GENE IN THE MOUSE EXPLAINED ON THE BASIS THAT THE X/O SEX-CHROMOSOME CONSTITUTION IS FEMALE.
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RADIATION-INDUCED MUTATION RATES IN FEMALE MICE.
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SHORTENING OF LIFE IN THE OFFSPRING OF MALE MICE EXPOSED TO NEUTRON RADIATION FROM AN ATOMIC BOMB.
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Pure Strain Mice Born to Hybrid Mothers Following Ovarian Transplantation.
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Strain and sex variations in the sensitivity of mice to dominant-lethal induction with ethyl methanesulfonate.
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Cost of acid peptic disorders in a managed-care organization.
The purpose of this study was to determine the cost of managing ambulatory patients with symptoms of acid peptic disorders in a managed-care organization under actual clinical conditions. Study data were collected in a large independent practice association model health maintenance organization in Gainesville, Florida, from prescription records maintained in a computerized database and from patient medical records. Patients had to be started on a histamine2-receptor antagonist (H2RA) or the proton pump inhibitor omeprazole between 1992 and 1994. A total of 113 patients qualified for inclusion in the study; 57 received H2RAs, 27 received omeprazole, and 29 received combination therapy. The costs of procedures, physician visits, and drug therapy were considered in the economic evaluation. Costs were evaluated using two methods: the capitation total cost (CTC) and the fee-for-service total cost (FSTC). The mean CTC and FSTC for managing a patient with acid peptic symptoms for 6 months were $382 +/- 356 (range, $14 to $1820) and $456 +/- 368 (range, $52 to $1925), respectively. Drug costs represented 52% of the total FSTC and 62% of the total CTC. Drug costs were followed by the costs for encounters with primary care physicians, endoscopy, referral to specialists, and upper gastrointestinal (UGI) tract procedures. Documented outcomes were available for 85 patients. Compared with patients receiving H2RAs (n = 41), patients receiving omeprazole (n = 18) had significantly lower FSTCs ($317 +/- 219 compared with $423 +/- 307, respectively); diagnostic testing costs (for endoscopy, $0 compared with $44 +/- 119, respectively; for UGI procedures, $22 +/- 42 compared with $55 +/- 54, respectively); physician encounter costs ($66 +/- 40 compared with $86 +/- 38, respectively); and referral to specialist costs ($0 compared with $18 +/- 60, respectively). Patients receiving omeprazole also had more positive clinical outcomes than patients receiving H2RAs (78% compared with 49%, respectively), resulting in a more favorable cost of producing a successful outcome compared with patients receiving an H2RA. The cost of success was $407 for patients treated with omeprazole compared with $869 for patients treated with H2RAs. The findings of this analysis conducted under actual clinical conditions support findings of randomized clinical trials showing the cost-effectiveness of proton pump inhibitors.
Accuracy of serum gentamicin concentration predictions generated by a personal-computer software system.
Predictions of serum gentamicin concentration and half-life, using a personal-computer software system (SIMKIN [simulated kinetics]), were compared for accuracy as increasing amounts of patient-specific data were supplied to the computer. Data for a two-year period were collected for patients of a hospital's pharmacokinetic consultation service; the study group included adults who had at least one serum concentration for which time of last gentamicin dose was recorded. Input variables were age, weight, height, sex, serum creatinine concentration, concomitant drugs and diseases, gentamicin dosage, time of infusion, dosing interval, number of doses on each regimen, and time and reported value of all serum gentamicin concentrations. Individualized dosing regimens were calculated on the basis of literature estimates, and half-life and serum concentrations were then estimated for these regimens and compared with actual values. One or two measured serum concentrations were then added to the input data. The computer-estimated half-lives (obtained from single-point or two-point analysis in different dosage intervals) were compared with the half-lives determined from actual serum concentration data. Gentamicin serum concentrations were similarly compared. The computer's ability to predict subsequent serum concentrations improved in sequence for literature-averaged prediction and single-point and multipoint analysis. Accuracy of predicting whether peak concentrations were therapeutic or subtherapeutic and whether trough concentrations were toxic also improved as more patient-specific data were input. SIMKIN appropriately evaluated demographic and laboratory data and adequately predicted gentamicin half-lives and serum concentrations.
Conversion from intravenous aminophylline to sustained-release theophylline: computer simulation versus in vivo results.
The accuracy of computer-predicted theophylline serum concentrations compared with actual serum concentrations in patients whose drug therapy was being converted from aminophylline infusions to an oral sustained-release theophylline product (Theo-Dur) was measured. The SIMKIN computer program was used to simulate theophylline serum-concentration curves in nine patients receiving an initial dose of sustained-release theophylline at the time their maintenance aminophylline infusions were discontinued. The sustained-release theophylline doses were calculated using individual patient theophylline clearance values to produce mean theophylline serum concentrations in the normal therapeutic range. Pharmacokinetic variables used in the SIMKIN program were derived from individual patients' serum concentrations and average literature values. Theophylline serum concentrations were measured before the initial dose of the sustained-release product and periodically for 12 hours. Mean SIMKIN-predicted serum theophylline concentrations were within 10% of actual measurements 39% of the time, but data from individual patients varied considerably. Two patients had prolonged absorption lag times that could not be explained. Computer-simulation programs using population-based pharmacokinetic variables to predict theophylline serum concentrations must be tested against in vivo measurements to verify their accuracy.