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Biomedical subjects

W L Russell

Publications and source records attributed to W L Russell.

At least 73 records · Page 4Linked to original sources
PubMed1982

Dose--response curve for ethylnitrosourea-induced specific-locus mutations in mouse spermatogonia.

The extreme mutagenic effectiveness of N-ethyl-N-nitrosourea in the mouse has permitted the accumulation of the most extensive dose--response data yet obtained for chemical induction of specific-locus mutations in spermatogonia. In the lower portion of the curve, below a dose of 100 mg/kg, the data fall statistically significantly below a maximum likelihood fit to a straight line. Independent evidence indicates that, over this dose range, ethylnitrosourea reaches the testis in amounts directly proportional to the injected dose. It is concluded that, despite the mutagenic effectiveness of ethylnitrosourea, the spermatogonia are apparently capable of repairing at least a major part of the mutational damage when the repair process is not swamped by a high dose. This finding is important both in basic studied on the mutagenic action of chemicals in mammals and in risk estimation.

Animals↗
PubMed1982

Effect of dose fractionation on the ethylnitrosourea induction of specific-locus mutations in mouse spermatogonia.

As measured by specific-locus mutations in mouse spermatogonia, fractionating a dose of 100 mg of ethylnitrosourea per kg of body weight into doses of 10 mg/kg injected intraperitoneally at weekly intervals greatly reduces the mutation frequency compared with that from a single dose of 100 mg/kg. Because there is independent evidence that the doses of 10 and 100 mg/kg reach the germ cells in amounts directly proportional to the injected dose, the lower mutational response with the fractionated dose is attributed to repair. The induced mutation rate expected from a single 10-mg/kg dose (on the assumption that this would be 1/10th the rate observed after 10 such doses) would be only 75% of the spontaneous mutation rate. Mouse spermatogonia apparently have an efficient repair system that is effective even against a potent mutagen.

Alleles↗
PubMed1982

Specific-locus mutation frequencies in mouse stem-cell spermatogonia at very low radiation dose rates.

Experiments were undertaken to augment the information on the lowest radiation dose rates feasible for scoring transmitted induced mutations detected by the specific-locus method in the mouse. This is the type of information most suitable for estimating genetic hazards of radiation in man. The results also aid in resolving conflicting possibilities about the relationship between mutation frequency and radiation dose rate at low dose rates. There was no statistically significant difference between mutation frequencies obtained in spermatogonia with 300 R (1 R = 2.6 x 10(-4) coulombs/kg) of gamma radiation at two different dose rates, 0.005 and 0.0007 R/min, or between either of these frequencies and data obtained earlier at dose rates of 0.8 R/min and below. This supports the view in an earlier publication by one of us (W.L.R.) that, at approximately 0.8 R/min and below, mutation frequency is independent of dose rate. Because this independence is now shown to extend over the more than 1000-fold range from 0.8 to 0.0007 R/min, it seems likely that it would hold at still lower dose rates, perhaps even to the much lower dose rates encountered in most human exposures.

Age Factors↗
PubMed1982

Mutation frequencies in male mice and the estimation of genetic hazards of radiation in men.

Estimation of the genetic hazards of ionizing radiation in men is based largely on the frequency of transmitted specific-locus mutations induced in mouse spermatogonial stem cells at low radiation dose rates. The publication of new data on this subject has permitted a fresh review of all the information available. The data continue to show no discrepancy from the interpretation that, although mutation frequency decreases markedly as dose rate is decreased from 90 to 0.8 R/min (1 R = 2.6 x 10(-4) coulombs/kg) there seems to be no further change below 0.8 R/min over the range from that dose rate of 0.0007 R/min. Simple mathematical models are used to compute: (a) a maximum likelihood estimate of the induced mutation frequency at the low dose rates, and (b) a maximum likelihood estimate of the ratio of this to the mutation frequency at high dose rates in the range of 72 to 90 R/min. In the application of these results to the estimation of genetic hazards of radiation in man, the former value can be used to calculate a doubling dose--i.e, the dose of radiation that induces a mutation frequency equal to the spontaneous frequency. The doubling dose based on the low-dose-rate data compiled here is 110 R. The ratio of the mutation frequency at low dose rate to that at high dose rate is useful when it becomes necessary to extrapolate from experimental determinations, or from human data, at high dose rates to the expected risk at low dose rates. The ratio derived from the present analysis is 0.33.

Animals↗
PubMed1982

Therapeutic substitution practices in short-term hospitals.

Hospital policies concerning the automatic interchange of therapeutically equivalent drugs were examined. A questionnaire was sent to the chief pharmacists at 6326 shot-term hospitals throughout the United States. The survey items solicited demographic data and formulary policies on generic and therapeutic substitution. A total of 2437 (39%) usable questionnaires were returned. Approximately 40% of the hospitals reported that their formulary system allows the stocking of a single product to represent a given therapeutic category. A total of 751 hospitals reported that their formulary system allows automatic dispensing of the therapeutically equivalent drug product without contacting the physician for permission. Therapeutic substitution was found particularly prevalent in federally owned hospitals. There were regional variations in the existence of therapeutic substitution. Factors that appeared to be associated with therapeutic substitution were: drug use review activity, medical school affiliation, existence of a formulary system, perceptions of favorable view by the state board of pharmacy, and favorable perception of the savings generated through bid purchasing. Reasons for not engaging in therapeutic substitution included the following: (1) would not be accepted by the physicians, (2) interferes with physicians' right to select the drug, (3) unnecessary risk of civil liability, (4) violation of laws, and (5) expected benefits do not justify the cost. Most respondents thought that physicians are usually aware of therapeutic substitutions that occur. Although they were a minority, a large percent of the respondents had a formulary system that allowed automatic interchange of generically inequivalent products within a therapeutic class of drugs. The influence of therapeutic substitution on drug therapy outcomes and cost savings need to be evaluated.

Drug Prescriptions↗
PubMed1981

Aortoiliac occlusive disease: factors influencing survival and function following reconstructive operation over a twenty-five-year period.

During a period of slightly over 25 years, 949 new patients with aortoiliac atherosclerotic occlusive disease--409 (43%) with associated distal disease--were submitted to various reconstructive operations for claudication in 719 and rest ischemic problems in 230 patients. The ages ranged from 21 to 91 years with a medial age of 59. Men outnumbered women 2.5 to 1. Associated diseases were present in 695 (75%); heart disease and diabetes were most common. The mortality rate from operation--50% of which was from heart disease--8% in first 5 years and 3% during the last 15 years. Good function, i.e., restoration of femoral pulses, leg salvage, and relief of symptoms, was achieved in 95% of cases early after treatment. Early results were best in patients with claudication and those without associated distal disease. The long-term survival rates were significant--50%, 30%, and 15% at 10, 15, and 20 years, respectively--and successful function was maintained in survivors in 79%, 70%, and 56% at the same intervals. Amputation was performed in only 23 (3%) patients with claudication and 33 (14%) with rest ischemia during the period of study. Survival, functional results, and incidence of amputation varied with the numerous factors described in detail herein.

Adult↗
PubMed1981

State regulatory positions concerning therapeutic substitutions in hospitals.

State regulatory agencies were surveyed to determine their views concerning hospital policies that allow therapeutic substitution. A questionnaire consisting of 10 close-ended questions was sent to the executive secretary of each board of pharmacy in the 50 states and District of Columbia. Agencies were contacted by telephone in four weeks if they did not respond. Of the 51 jurisdictions surveyed, 34 answered all of the questions, 13 answered some, and 4 did not respond. None of the 13 partial respondents expressed their views concerning the legality of therapeutic substitution in the institutional setting. Fifteen agencies indicated they would view this practice as illegal, 17 said it is in accordance with policies established by the P & T committee and therefore not subject to state or federal regulation, and two agencies gave qualified responses. Seven agencies indicated enforcement procedures would be initiated if they were to learn that therapeutic substitution was being practiced in a hospital within their jurisdiction. Three states were uncertain about what action would likely be taken, 23 indicated no action would be taken, and two gave qualified responses. All 39 agencies responding to the question indicated they had never taken action against the practice of a formulary system that allows therapeutic substitution. Few state laws address the practice of therapeutic substitution, and opinions of regulatory agencies vary. Moreover, the opinions rendered have not been tested in the courts.

Government Agencies↗
PubMed1981

Therapeutic substitution and the hospital formulary system.

Physicians consent and statutory regulations relating to therapeutic substitution are discussed. Some hospitals have adopted policies allowing the interchange of a chemically inequivalent product deemed therapeutically identical by the P & T committee. In the absence of statutory regulation, hospital pharmacists usually refer to (1) the physician's agreement to abide by hospital bylaws (including the formulary system) when joining the hospital staff, or (2) prescription blanks and order sheets preprinted with the statement "substitution permitted unless otherwise indicated" as the legal authority for therapeutic substitution. Only two states have addressed the legality of therapeutic substitution. An opinion of the Oregon Attorney General and a Washington state statute both authorize therapeutic substitution under certain circumstances if the prescriber has given prior consent. Neither of the states specifies, however, whether the agreement of prescribers to abide by hospital bylaws constitutes authorization of therapeutic substitution. It is proposed that state boards of pharmacy and state legislatures draft laws that address therapeutic substitution and specify acceptable methods of consent.

Formularies, Hospital as Topic↗
PubMed1980

Cimetidine-induced mental status changes: case report and literature review.

An apparent case of psychosis induced by cimetidine is reported. A 61-year-old Caucasian woman was hospitalized with chief complaints of left-sided paresthesias, headache, and vertigo. She had a history of hyperparathyroidism, thyroid insufficiency, and chronic but stable renal insufficiency. Admitting laboratory data indicated possible hepatic compromise. On day 16 of hospitalization, cimetidine (300 mg q 6 hr p.o.) was begun because of a falling hematocrit and guaiac-positive stools. Within 24 hours after cimetidine therapy was begun, the patient was confused, tearful, and disoriented. This confusional state continued during treatment with cimetidine, and was refractory to antipsychotic therapy. On day 5 of cimetidine therapy, the patient experienced visual and auditory hallucinations, and both cimetidine and antipsychotic drugs were discontinued. The patient was noted to be alert and oriented 24 hours later. A review of the literature revealed 30 cases of apparent cimetidine-induced CNS changes. Patients experiencing such reactions were typically elderly with compromised renal or hepatic failure, or both. Future studies on this topic should focus on predisposing patient factors and serum or cerebrospinal fluid concentrations of cimetidine associated with the symptomology.

Adult↗
PubMed1979

Doxycycline in the prevention of hepatic dysfunction: an evaluation of its use following jejunoileal bypass in humans.

A prospective randomized study was carried out to evaluate doxycycline hyclate in the prevention of hepatic dysfunction following jejunoileal bypass for morbid obesity. Forty-five patients were entered into the study and were observed for a year or more. Patients received either 100 mg of doxycycline hyclate twice daily on postoperative days 5 through 10 and then 100 mg daily for six weeks, or no drug. At six weeks, 12 weeks, and 12 months after the operation, biochemical levels were measured. After one year all patients had a liver biopsy. Doxycycline, in the regimen, was not demonstrated to be of value in the prevention of hepatic dysfunction in these patients. A lack of correlation was demonstrated between the biochemical definition of hepatic dysfunction and liver histopathology.

Adolescent↗
PubMed1979

Specific-locus test shows ethylnitrosourea to be the most potent mutagen in the mouse.

Use of the specific-locus test to measure the frequency of transmitted gene mutations induced in mouse spermatogonia has shown ethylnitrosourea to be by far the most potent mutagen yet discovered in the mouse. The dose used, 250 mg/kg, gave a mutation rate 5 times as high as had been obtained with 600 R, the most effective acute dose of x-rays. Compared to procarbazine, heretofore the most mutagenic chemical known in the mouse, ethylnitrosourea proved to be 15 times more mutagenic than the peak effect obtained with the most effective dose of procarbazine. Because of its high mutagenicity, ethylnitrosourea can serve as a model compound in exploring the effect of such factors as dose response, dose fractionation, sex, and cell stage on the mutagenic action of a chemical. Ethylnitrosourea is clearly the mutagen of choice for the production of any kind of desired new gene mutations in the mouse.

Alleles↗
PubMed1979

Analysis of the albino-locus region of the mouse. I. Origin and viability.

Numerous specific-locus experiments designed to test the mutagenic effect of external radiation have yielded, in over 3,600,000 animals observed, altogether 119 presumed mutations involving the c locus. Of these, 55 were viable and albino (cav), 13 were viable and of various intermediate pigment types (cxv), four were subvital (cas and cxs), seven were neonatally lethal albinos (cal), 28 prenatally lethal albinos (cal); 12 died untested. All of the prenatally lethal and at least one of the neonatally lethal c-locus mutations (cal classes) are probably deficiencies that we have analyzed extensively in other experiments. Since absence of the locus mimics albino in phenotype, the intermediates (cxv and cxs groups) probably resulted from intragenic changes. The class of viable albino mutants (cav) might include, in addition to intragenic changes, some extremely small deficiencies. --The effects on viability of c-locus lethals (cal's) in heterozygous condition are not drastic enough to be perceived in stocks of mixed genetic background except in the case of the two longest known deficiencies and a few others. --Analysis of the relation between radiation treatment and type of c-locus mutants obtained shows that the relative frequency of viable mutations, for each germ-cell type, is greater for low-LET than for neutron irradiation; however, the difference for any individual cell type is not significant. The majority (66.7%) of mutations derived from X- or gamma-ray irradiated spermatogonia are viable, and the proportion of "intermediates" among these viables is similar to that among presumed spontaneous c-locus mutations. No significant dose-rate effect on the proportion of lethals could be demonstrated within the set of mutants induced by low-LET irradiation of spermatogonia. Although sets from other germ-cell stages are too small for statistical tests, the results for oocytes are similar, as far as they go. Furthermore, most of the c-locus mutations induced in spermatogonia, even by high-dose-rate X-ray or gamma irradiation, are of a type most likely to result from single-tract events (62% cxv, cxs, and cav; plus 16% presumed deficiencies not involving the closest marker). These results support the view that most of the reduction in mutation frequency at low dose rates is not due to a change in relative proportion of two-track and one-track ionizing events.

Animals↗
PubMed1979

Comments on mutagenesis risk estimation.

Several hypotheses and concepts have tended to oversimplify the problem of mutagenesis and can be misleading when used for genetic risk estimation. These include: (1) the hypothesis that radiation-induced mutation frequency depends primarily on the DNA content per haploid genome, (2) the extension of this concept to chemical mutagenesis, (3) the view that, since "DNA is DNA," mutational effects can be expected to be qualitatively similar in all organisms, (4) the REC unit, and (5) the view that mutation rates from chronic irradiation can be theoretically and accurately predicted from acute irradiation data. Therefore, direct determination of frequencies of transmitted mutations in mammals continues to be important for risk estimation, and the specific-locus method in mice is shown to be not as expensive as is commonly supposed for many of the chemical testing requirements.

Animals↗
PubMed1978

Confirmation of a computer-derived nomogram to predict gentamicin serum concentrations in postsurgical patients.

The applicability of a previously reported nomogram to predict serum gentamicin levels in postsurgical patients was investigated. Seventeen patients accounting for 20 courses of gentamicin were studied. A total of 72 peak serum gentamicin levels were measured by a microbiological assay and compared with predicted serum levels determined by the dosing nomogram. Eighty-five percent of the measured peak gentamicin serum levels agreed with nomogram-predicted levels. This figure was reduced to 65% when certain unforeseen factors (i.e., patient interference with intravenous lines, dosage miscalculation and extra routes of gentamicin elimination) were identified. The nomogram is a particularly useful tool for the clinician to whom serum gentamicin levels are unavailable and who needs a method to predict serum gentamicin concentration based upon a given dosage.

Adult↗
PubMed1977

The role of mammals in the future of chemical mutagenesis research.

Radiation genetics has demonstrated that mutagenesis is a complex process affected by many factors. The ABCW hypothesis, that mutation frequency per rad over a wide range of organisms, from microbes to man, is linearly related to DNA content, ignores the fact that, within the mouse alone, different cell stages exhibit a range of mutation rates greater than that listed for the whole evolutionary tree. Also ignored are the findings that the important effects of dose rate and some other factors in the mouse were not predictable even from Drosophila. A much greater maze of complexities has already been found in chemical mutagenesis. This is illustrated even by the results obtained from testing of a single drug. Thus, it is clear that the attempt to extend the ABCW hypothesis to chemicals will be of little, if any, predictive value. Similarly, such concepts as the REC (roentgen-equivalent-chemical), designed to express the mutagenic risk from a chemical by a single unit quantitatively related to radiation damage, are defeated by the extreme qualitative differences in response. Unifying theories and simple non-mammalian tests that reliably predict the results in mammals cannot be expected to materialize until much more information has been collected on transmitted mutations induced in mammalian germ cells.

Alkylating Agents↗
PubMed1977

Mutation frequencies in female mice and the estimation of genetic hazards of radiation in women.

The female germ cell stage of primary importance in radiation genetic hazards is the immature, arrested oocyte. In the mouse, this stage has a near zero or zero sensitivity to mutation induction by radiation. However, the application of these mouse results to women has been questioned on the ground that the mouse arrested oocytes are highly sensitive to killing by radiation, while the human cells are not; and, furthermore, that the mature and maturing oocytes in the mouse, which are resistant to killing, are sensitive to mutation induction. The present results have a 2-fold bearing on this problem. First, a more detailed analysis of oocyte-stage sensitivity to killing and mutation induction shows that there is no consistent correlation, either negative or positive, between the two. This indicates that the sensitivity to cell killing of the mouse immature oocyte may not be sufficient reason to prevent its use in predicting the mutational response of the human immature oocyte. Second, if the much more cautious assumption is made that the human arrested oocyte might be as mutationally sensitive as the most sensitive of all oocyte stages in the mouse, namely the maturing and mature ones, then the present data on the duration of these stages permit more accurate estimates than were heretofore possible on the mutational response of these stages to chronic irradiation.

Animals↗