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L B Russell

Publications and source records attributed to L B Russell.

At least 127 records · Page 7Linked to original sources
PubMed1984

The economics of prevention.

A review of cost-effectiveness studies of prevention supports two conclusions: (1) few prevention programs, if any, reduce medical expenditures; (2) even when prevention costs less per person than acute care, its medical costs per unit of health benefit can be as great or greater. So that future studies will allow comparisons over a wider range of medical choices, the paper proposes some steps toward the greater standardization of cost-effectiveness analyses of medical care.

Cost-Benefit Analysis↗
PubMed1984

Computed tomography analysis of the canine brain: effects of hemibrain X irradiation.

Radiation damage induced by megavoltage X irradiation in normal brain tissue can manifest as one of several pathologic processes depending upon the time of brain examination after irradiation. Serial quantitative computed tomography (QCT) analyses were used to study the development of radiation damage in the normal canine brain. Tissue density, volume of low density areas, magnitude and volume of contrast uptake, and ventricular volume were measured following hemibrain irradiation and were correlated with histopathology. Low density areas correlated with edema, demyelination, axonal swelling, and necrosis and appeared 3-4 months after irradiation. Large regions of contrast enhancement (coagulation necrosis and associated vascular changes) appeared 5-6 months after irradiation. Results from this study demonstrated that the pathologic changes induced in the dog brain after single doses of X rays were similar to the changes observed in nonhuman primates and man after exposure to radiation.

Animals↗
PubMed1983

Synaptonemal complex analysis of X-7 translocations in male mice: R2 and R6 quadrivalents.

Synaptonemal complexes of surface-spread spermatocytes of mice heterozygous for reciprocal translocations R2 or R6 between the X-chromosome and chromosome 7 were examined by light and electron microscopy (EM). Measurements of the lengths of all chromosome axes involved in the translocation configurations and of the extent of synapsis were used to calculate the position of the break points of the two translocations. The breaks for R2 were determined to be at 62% of the 7 as measured from the centromere, and at 27% of the X. Quadrivalents were formed almost exclusively. The break points for R6 were calculated to be at 30% of the 7 as measured from the centromere, and at 75% of the X. Although in R6 the break in the X lies within the potential pairing region of the sex chromosomes, univalent Ys were rarely observed (6%). The EM sample of 76 nuclei contained: 42% quadrivalents, 52% heteromorphic bivalents, 4% trivalent plus Y univalent, and 2% X7-7 bivalent plus two univalents (7X and Y). Nonhomologous synapsis occurred in the quadrivalents of both R2 and R6. In R6 nonhomologous synapsis of the X portion of the 7X with the 7 involved up to 14% of the length of the 7. Methods are discussed for determining the position of the break points in the presence of nonhomologous synapsis. It is proposed that the high percentage of bivalents is due to premature desynapsis of the 7X from the 7 and that the X portion of the 7X axis confers its property of premature desynapsis on that portion of the 7 to which it is attached.

Animals↗
PubMed1982

Supermutagenicity of ethylnitrosourea in the mouse spot test: comparisons with methylnitrosourea and ethylnitrosourethane.

The effects of the 3 related compounds ethylnitrosourea (ENU), methylnitrosourea (MNU), and ethylnitrosourethane (NEC) were studied in the mouse spot test. ENU induces a large number of recessive spots (RS) and, due to its low toxicity, can be applied at relatively high doses. This combination of properties makes it the most efficient spot-test mutagen, as shown in a comparison with 16 other chemicals, even though, on the basis of molarity, it is not the most potent one. The ENU mutation frequency in cells at risk, calculated per locus, per unit of applied dose, is roughly similar for melanocyte precursors (in the spot test) and spermatogonial stem cells (in the specific-locus test). MNU which, due to its high embryotoxicity, could be tested only at a low dose, is clearly mutagenic, and dose extrapolations indicate it to be more potent than ENU. NEC, though it could be tested at higher molarities than ENU, is only weakly mutagenic. The spot test, in addition to mutational data, also yields information on cytotoxicity (white midventral spots), embryotoxicity, and teratogenicity. The toxicity and teratogenicity findings parallel earlier results in the rat. For all endpoints studied. ENU is more effective than NEC. Relative to MNU, ENU is less toxic, less teratogenic, and less mutagenic in the spot test; but it is much more carcinogenic (transplacentally) and more mutagenic in spermatogonia. We propose that MNU is more effective in inducing gross chromosomal damage than is ENU, while ENU induces relatively more gene mutations. The spot test scores both types of mutational damage, while mostly the latter type is recovered from spermatogonia.

Animals↗
PubMed1982

Mammalian mutagenesis: future directions.

Future research in mammalian germ-line mutagenesis will benefit from the reciprocal relationship that can exist between the production of mutations and their analysis. Thus, mutagenesis experiments supply altered genes, and thereby tools for basic studies; while, in turn, information on gene structure and function helps in understanding mechanisms of mutagenesis. The nature of genetic alterations recovered in specific-locus tests is illustrated by an account of the analysis of 112 radiation-induced mutations involving the c locus on chromosome 7. Using phenotypic characterizations of various kinds, deficiency mapping with nearby markers, and complementation studies, the mutants could be classed into 13 groups, and 8 functional units could be identified in the c-locus region. Twelve different deficiencies overlapping at c range in length from less than 2 to 6-11 cM. Using the deficiencies, as well as a tandem duplication that involves the c region, and several T(X;7)'s in which c is inactivated in a mosaic fashion, it is possible to generate gene doses from 0 to 3, in steps of 0.5, not only for c but also for other genes included in various deficiencies. Cis and trans configurations can also be compared. This array of genetic materials is now being used for the isolation of DNA sequences from genetically-defined regions. Results from analyses of mutations can contribute answers to some of the pragmatic questions in germ-line mutagenesis and risk assessment. Areas in which contributions may be expected are: the relative roles of intracellular conditions (e.g., nature of chromatin, presence of repair enzymes) and secondary circumstances (e.g., selection) in determining the quantity and quality of transmitted mutations; the validity of quantitative extrapolations, such as projections to low doses and calculations of doubling dose; and the relation between measures of mutation rate and projections of phenotypic damage.

Alleles↗
PubMed1982

Synaptonemal complex analysis of X-7 translocations in male mice. I. R3 and R5 quadrivalents.

The synaptonemal complexes of surface-spread spermatocytes of mice heterozygous for one of two reciprocal translations (R3 and R5) between the X and chromosome 7 have been examined by light and electron microscopy (EM). The break points of R3 were determined to be at 70% of chromosome 7, as measured from the centromere, and at 22% of the X. Translocation quadrivalents were formed almost exclusively. The break points of R5 were at 21% of chromosome 7 as measured from the centromere, and at 83% of the X. There was little indication that the break in the X interfered with sex-chromosome synapsis between the 7X and Y. Univalent Y's were not observed in R3, and only seldom observed (8-14%) in R5. However, in contrast to R3, R5 formed quadrivalents relatively rarely (20% in the EM study of 100 nuclei), and heteromorphic bivalents of 7X-Y and X7-7 quite frequently (72%). Possible causes of this high bivalent frequency are discussed. Light-microscope (LM) analysis alone was found to be inadequate for interpreting synaptic configurations (quadrivalents vs. bivalents) in R5. The LM analysis was further complicated by the occurrence of nonhomologous synapsis in the heteromorphic bivalents of R5, a phenomenon easily recognized and interpreted in the EM portion of the study.

Animals↗
PubMed1982

Analysis of the albino-locus region of the mouse: IV. Characterization of 34 deficiencies.

Thirty-four independent nonviable c-locus mutations (types cal, albino lethal and cas, albino subvital), derived from radiation experiments, were tested for involvement of nearby markers tp, Mod-2, sh-1, and Hbb: 10, 22, and 2 involved, respectively, none of these markers, Mod-2 alone, and Mod-2 plus sh-1. When classified on this basis, as well as according to developmental stage at which homozygotes die, and by limited complementation results, the 34 independent mutations fell into 12 groups. From results of a full-scale complementation grid of all 435 possible crosses among 30 of the mutations, we were able to postulate an alignment of eight functional units by which the 12 groups fit a linear pattern. Abnormal phenotypes utilized in the complementation study were deaths at various stages of prenatal or postnatal development, body weight, and reduction or absence of various enzymes. Some of these phenotypes can be separated by complementation e.g., there is no evidence that mitochondrial malic enzyme influences survival at any age); others cannot thus be separated (e.g., glucose-6-phosphatase deficiency and neonatal death).--We conclude that all of the nonviable albino mutations are deficiencies overlapping at c, and ranging in size from less than 2cM to 6-11 cM. The characterization of this array of deficiencies should provide useful tools for gene-dosage studies, recombinant-DNA fine-structure analyses, etc. Since many of the combinations of lethals produce viable albino animals that resemble the standard c/c type, we conclude (a) that the c locus contains no sites essential for survival, and (b) that viable nonalbino c-locus mutations (cxv) are the result of mutations within the c cistron. Viable albinos (cav, the majority of radiation-induced c-locus mutations) may be intracistronic mutations or very small deficiencies.

Albinism↗
PubMed1981

Synaptonemal complex analysis of mouse chromosomal rearrangements. I. Cytogenetic observations on a tandem duplication.

Electron microscopy of surface-spread spermatocytes from mice heterozygous for a tandem duplication shows the heteromorphic synaptonemal complex (SC) to comprise two lateral elements of unequal length, the longer of which is buckled out in a characteristic loop, representing the unsynapsed portion of the duplication. The loop is a regular feature of late zygotene-early pachytene nuclei; it is longest at these early stages, but, through equalization of the two axes as a consequence of synaptic adjustment, it is replaced by a normal appearing SC at late pachytene. Because equalization, as indicated by a decrease in the percent difference between axes, may begin shortly after completion of synapsis, estimates of duplication segment length are restricted to a sample selected for least adjustment. --Although the mean position of the loop is constant at various pachytene substages, individual positions vary widely from cell to cell, consistent with the behavior expected of a duplication, but not of a deletion or an inversion. The length of the segment that is duplicated is estimated to be 22% of the normal chromosome, the midpoint of the segment is mapped at 0.61 of the chromosome distal to the kinetochore, and the ends of the segment are mapped at 0.50 to 0.72. Measurements of G-banded mitotic chromosomes give comparable values: duplication length, 24%; midpoint, 0.60, and segment ends, 0.48 and 0.71. This agreement constitutes further validation of the SC/spreading method for detecting and analyzing chromosomal rearrangements at pachytene and substantiates the fidelity with which the axes and SCs represent the behavior of chromosomes in synapsis.

Animals↗
PubMed1981

The mouse specific-locus test with agents other than radiations: interpretation of data and recommendations for future work.

The mouse specific-locus test with visible markers (SLT) has been the only extensively used method for detecting and quantifying the induction of heritable point mutations (intragenic changes and small deficiencies) in mammals. Mutations are detected in first-generation offspring; and scoring is simple, objective, and rapid. Different germ-cell stages can be sampled, including those of greatest pertinence for genetic risk assessment. The differential probability of involving the various loci of the marked set makes the method capable of detecting qualitative (as well as quantitative) differences between the actions of mutagens. Control SLT frequencies for males reported by 4 sets of investigators are in excellent agreement and were summed as a "historical control" (801406 observations) for use in our calculations. Experimental results were classified as positive, negative, or inconclusive based upon a multiple-decision procedure produced by the testing of the following 2 hypotheses: (1) the mutation frequency (induced + spontaneous) of treated mice is not higher than the spontaneous mutation frequency, and (2) the induced mutation frequency of treated mice is no less than 4 times the historical-control mutation frequency. Each hypothesis was tested at the 5% significance level. Because of the low mutation frequency in a very large control, the SLT is capable of yielding positive results in relatively small samples. We reviewed 58 publications, SLT results have been reported for 25 chemical agents, of which 17 (representing 21 chemical classes) gave results that were positive or negative by our criteria. The frequency of positive agents was 6 of 14, 5 of 5, and 0 of 1 conclusively tested, respectively, in spermatogonia, post-spermatogonial stages, and unspecified male germ cells. Depending on the chemical used, post-spermatogonial stages can be of greater, less, or equal sensitivity relative to spermatogonia. The SLT was strongly positive for some chemicals that are not mutagenic (or only weakly so) in lower systems, and there are several examples of the reverse situation. Factors which presumably operated to cause these differences (e.g., metabolism, transport, repair in germ cells) are likely also to operate for transmitted point mutations in man.

Animals↗
PubMed1981

Use of the mouse spot test in chemical mutagenesis: interpretation of past data and recommendations for future work.

The mouse spot test, developed 23 years ago, is an in vivo assay capable of detecting genetic effects of several kinds, including intragenic mutations, minute deficiencies, deletions (through breakage or nondisjunction) of various amounts of chromosomal material, and somatic crossing-over. The method involves exposing embryos that are heterozygous for a number of coat-color markers to the test agent, and, 3 weeks later, looking for clones of mutant cells, i.e., spots of color expressing the recessive marker in an otherwise black fur. Spots having other causes may also be induced, specifically white midventral spots due to cytotoxic effects, and certain spots resulting from misdifferentiation. Spot-test results have, to date, been reported from 7 laboratories. Because the control results for any one cross and solvent were found to be reasonably consistent between the laboratories, we pooled these to develop a "historical" control with which experimental results for the same cross and solvent were compared. Experimental results were classified as positive, negative, or inconclusive on the basis of a multiple-decision procedure produced by the testing of the following 2 hypotheses: (1) the mutation frequency (induced + spontaneous) in treated mice is not higher than the mutation frequency in the appropriate pooled control, and (2) the induced mutation frequency of the treated mice is no less than 4 times as high as the observed mutation frequency in the appropriate pooled control. Each hypothesis was tested at the 5% significance level. To date, 30 substances have been employed in the spot test, including 3 that are solvents for some of the others. Of the remaining 27 (26 compounds and 1 mixture), 16 were positive, 6 negative, and 5 inconclusive. The 26 compounds fell into 27 chemical classifications (using a system provided for use by the GENE-TOX program). The inadequacies in the design and reporting of some past experiments indicate a need for a carefully specified protocol. When properly done, the spot test will fulfill a useful role in mutagenicity testing programs because (1) it is an in vivo mammalian assay, (2) it detects genetic effects of many kinds, and (3) it is relatively rapid. Since the test appears well suited to the identification of potent mutagens, its main value should be in screening large numbers of substances and singling out the potentially worst offenders to be further studied in germ-line mutagenesis tests.

Animals↗
PubMed1981

Deletions in the alpha-globin gene complex in alpha-thalassemic mice.

Three induced, heritable mutations in the mouse cause alpha-thalassemias. The adult alpha-globin genes on each mutant chromosome are no longer expressed. Embryos heterozygous for one normal and any of the three mutant chromosomes also seem to be deficient in embryonic alpha-globin-like x-globin, suggesting that the x-globin gene is nearby and also inactivated. A normal genetic polymorphism for a specific EcoRI site in or around the mouse alpha-globin gene complex has been used here to show that each of the three mutated chromosomes has a deletion that includes the segment of a 12-kilobase EcoRI band which normally carries one of the two adult alpha-globin genes. The deletion of the comparable part of the second alpha-globin gene site is also inferred. Nonetheless, a 4.7-kilobase EcoRI segment which carries a characterized alpha-globin-like pseudogene is still present in each mutant. These mutations were recovered after triethylenemelamine or x-ray treatments.

Animals↗
PubMed1981

Three mouse models of human thalassemia.

Three types of mice with globin gene mutations, called 352HB, 27HB, and Hbath-J, appear to be true animal models of human thalassemia. Expression of the alpha-globin genes in three stocks of mice, each one heterozygous for one of the alpha-globin mutations, was examined at the polypeptide, RNA, and DNA levels. alpha-Globin polypeptide chains, relative to beta-globin chains in heterozygous thalassemic mice, are present at approximately 80% of normal. The ratios of alpha-globin to beta-globin RNA sequences are also 75-80% of normal, exactly reflecting the alpha-globin to beta-globin chain ratios. In the case of mutant 352HB, at least one alpha-globin gene is deleted. Thalassemic mouse erythroid cells appear to compensate partially for the loss of half of their alpha-globin genes.

Animals↗
PubMed1981

An aging population and the use of medical care.

This paper projects the use of medical care forward and backward, from 1950 to 2050, to show the importance of the changing age structure of the population for this sector of the economy. The results indicate that institutional care will consume a growing share of the medical care budget in the next century. If rates of use by age and sex remain at current levels, the aging of the population will push days of hospital care to 1621 per 1000 population in 2040, the peak year for hospital use, compared with 1241 per 1000 in 1975. Residents in nursing homes are projected to number 12.8 per 1000 population in 2050, almost two-and-one-half times the 5.4 per 1000 of 1975. Outpatient visits to doctors and visits to dentists are largely unaffected by age structure.

Adolescent↗
PubMed1981

Policies toward medical technology: an international review.

Rapidly rising medical care costs have become an important political issue in industrialized countries during the past decade. Attempts to control the growth in expenditures have focused on the contribution of medical technology to costs. All industrialized countries have begun to experiment with the kinds of mechanisms necessary to effect changes in development, diffusion, and use of medical technologies. This paper describes government policies toward: 1) research and development, 2) evaluation, 3) safety and efficacy regulation, and 4) investment in and use of medical technologies. To clarify how these policies work in practice, policies toward CT scanners, renal dialysis, and coronary bypass surgery are examined. Rapid changes in policies and laws in different countries are attempts to find effective policy mechanisms, but also reflect the difficulties of choosing a realistic policy objective. Until recently, most countries have focused on promoting the development and adoption of new technologies, or increasing the efficiency of their production and use. A few governments have begun to question and test the benefits of medical technologies as an aid to decision making. Finally, with the growing realization that every kind of care that is beneficial cannot be provided, some countries have begun to consider limiting the diffusion of technologies to a level that strikes a balance between the benefits to be gained and the costs of achieving them.

Coronary Artery Bypass↗
PubMed1980

Whole-mammal mutagenicity tests: evaluation of five methods.

Transmitted genetic changes in mammals can be used to study all of the main endpoints of mutagenesis: point mutations, chromosome breakage, with or without rearrangement, and chromosome nondisjunction. Four methods most commonly employed in whole-mammal germ-line mutagenicity tests as well as an in vivo somatic prescreen, are summarized. Genetic basis, historical background, description of the test, limitations, and strengths are presented for each of the five systems. The specific-locus test using visible markers is the most reliable and practical method for detecting heritable point mutations, including small deficiencies, and does not require very large numbers of animals for risk extrapolations, if a relatively high dose can be administered without killing germ cells. For the detection of chromosome-breakage events, dominant lethals are useful to determine relative sensitivities of different germ-cell stages of the male, but the heritable-translocation test is more sensitive when the exposed cells are male meiotic and postmeiotic stages. Chromosome breakage events in the female are best revealed through a sex-chromosome loss test, which utilizes genetically marked X chromosomes. The same method can also be employed to detect nondisjunction in either sex. The in vivo somatic mutation test is useful as a prescreen for both point mutations and losses of chromosomal material. The reliability and efficiency of whole-mammal mutagenicity tests must be considered in two contexts: in the assessment of mutagenicity per se (as this applies to genetic changes transmitted to future generations), and in the use of mutagenicity as a possible indicator of carcinogenicity. In the former context, the whole-mammal tests are irreplaceable because they provide the closest practicable approach to the metabolic pathways existing in man, and because there is no array of lower-system tests that can predict the complexity of the response of the different mammalian germ-cell stages (which differ greatly with respect both to their absolute and their relative sensitivities to the induction of various genetic endpoints). In the second context, i.e., the use of mutagenicity as a screen for carcinogenicity in the exposed individual, most of the whole-mammal tests are of more limited utility, because they require several weeks or months for completion. Of the methods discussed, the spot test appears most suitable, because it provides a relatively rapid in vivo system capable of detecting both gene mutations and chromosomal changes of various kinds in somatic cells, including some that have been suggested to be involved in tumor promotion.

Animals↗