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Biomedical subjects

L B Russell

Publications and source records attributed to L B Russell.

At least 91 records · Page 5Linked to original sources
PubMed1990

Genetic and molecular analysis of chlorambucil-induced germ-line mutations in the mouse.

Eighteen variants recovered from specific locus mutation rate experiments involving the mutagen chlorambucil were subjected to several genetic and molecular analyses. Most mutations were found to be homozygous lethal. Because lethality is often presumptive evidence for multilocus-deletion events, 10 mutations were analyzed by Southern blot analysis with probes at, or closely linked to, several of the specific locus test markers, namely, albino (c), brown (b), and dilute (d). All eight mutations (two c; three b; two d; and one dilute-short ear [Df(d se)]) that arose in post-spermatogonial germ cells were deleted for DNA sequences. No evidence for deletion of two d-se region probes was obtained for the remaining two d mutations that arose in stem-cell spermatogonia. Six of the primary mutants also produced low litter sizes ("semisterility"). Karyotypic analysis has, to date, confirmed the presence of reciprocal translocations in four of the six. The high frequency of deletions and translocations among the mutations induced in post-spermatogonial stages by chlorambucil, combined with its overall high efficiency in inducing mutations in these stages, should make chlorambucil mutagenesis useful for generating experimentally valuable germ-line deletions throughout the mouse genome.

Animals↗
PubMed1990

Molecular and genetic characterization of a radiation-induced structural rearrangement in mouse chromosome 2 causing mutations at the limb deformity and agouti loci.

Molecular characterization of mutations in the mouse, particularly those involving agent-induced major structural alterations, is proving to be useful for correlating the structure and expression of individual genes with their function in the whole organism. Here we present the characterization of a radiation-induced mutation that simultaneously generated distinct alleles of both the limb deformity (ld) and agouti (a) loci, two developmentally important regions of chromosome 2 normally separated by 20 centimorgans. Cytogenetic analysis revealed that an interstitial segment of chromosome 17 (17B- 17C; or, possibly, 17A2-17B) had been translocated into the distal end of chromosome 2, resulting in a smaller-than-normal chromosome 17 (designated 17del) and a larger form of chromosome 2 (designated 2(17). Additionally, a large interstitial segment of the 2(17) chromosome, immediately adjacent and proximal to the insertion site, did not match bands 2E4-2H1 at corresponding positions on a normal chromosome 2. Molecular analysis detected a DNA rearrangement in which a portion of the ld locus was joined to sequences normally tightly linked to the a locus. This result, along with the genetic and cytogenetic data, suggests that the alleles of ld and a in this radiation-induced mutation, designated ldIn2 and ajIn2, were associated with DNA breaks caused by an inversion of an interstitial segment in the 2(17) chromosome.

Abnormalities, Radiation-Induced↗
PubMed1989

Some of the tough decisions required by a national health plan.

The goals of providing coverage for everyone in the United States and controlling the growth in national health expenditures require difficult decisions about what medical services to provide. Currently accepted practices vary enormously in the amount of health they produce for a given expenditure. Studies of the health effects of several major interventions in relation to their costs--Pap smears, mammography, coronary care units, bypass surgery, and cholesterol reduction--indicate the kinds of choices to be made.

Cost-Benefit Analysis↗
PubMed1989

The effect of prospective payment on Medicare expenditures.

Medicare's prospective payment system was introduced in 1983 to slow the growth of expenditures for hospital care, which from the bulk of Medicare costs. Instead of reimbursing hospitals for the actual costs of patient care, the system pays them at fixed rates for each admission. In this study, we estimated the savings to Medicare from the use of prospective payment. We analyzed the expenditure projections published in 10 successive annual reports (1979 to 1988) by the trustees of the federal Hospital Insurance Trust Fund, which pays hospital bills for Medicare beneficiaries. To show the effect of prospective payment, these projections were adjusted to correct for the different assumptions about inflation and admissions made in each report. We also examined trends in expenditures from the Supplementary Medical Insurance Trust Fund, which pays for outpatient services, to see whether the savings in hospital expenses were offset by higher spending for out-of-hospital services. We found that prospective payment has reduced Medicare's hospital costs substantially. Expenditures from the Hospital Insurance Trust Fund for 1990 are expected to be +12 billion less in 1980 dollars, and +18 billion in 1990 dollars, than was expected shortly before prospective payment went into effect--the equivalent of a savings of approximately 20 percent. By contrast, the effect of prospective payment on the supplementary fund has not been great. We conclude that the prospective payment system is having a major impact on Medicare's hospital expenditures and that the savings is not offset by an increase in outpatient expenditures.

Ambulatory Care↗
PubMed1989

Reciprocal relationship between mouse germ-cell mutagenesis and basic genetics: from early beginnings to future opportunities.

The scientific foundations for several mammalian germ-line mutagenesis tests in common use today were laid in the 1930s, 1940s, and early 1950s. Subsequent developments in the field have had multiple objectives: detection of mutagenicity of environmental agents (which has led to the development of numerous methodologies), identification of biological and physical factors that affect mutation yield, analysis of the structural nature of the genetic alterations, and assessment of the organismic effects of various types of mutations. Mutagenesis studies have made numerous contributions to basic genetics by generating mutant types that led to elucidation of sex-determining mechanisms in mammals; formulation of the single-active-, or inactive-, X-chromosome hypothesis; correlation of genetic and cytological maps; discovery of genetic "imprinting" phenomena; study of developmental pathways and cell lineages, etc. Particularly useful are sets of complexly overlapping deletions that have been recovered in radiation mutagenesis studies, propagated in breeding stocks, and genetically analyzed; these have constituted prerequisites for molecular genetic studies aimed at development of the DNA structure-function relationships for important genomic regions. Mutagenesis experiments have also served to identify mutagens that are particularly effective in inducing specific types of genetic lesions desired for basic studies. Reciprocally, basic genetics has contributed to the development of mutagenesis tests and has enhanced the value of the specific-locus test by adding to its quantitative capabilities the capability for qualitatively characterizing the actions of mutagens.

Animals↗
PubMed1989

Functional and structural analyses of mouse genomic regions screened by the morphological specific-locus test.

Genetic analyses of certain classes of mutations recovered in the mouse specific-locus test (SLT) have characterized arrays of deletions, overlapping at the marked loci. Complementation maps, generated for several of the regions, have identified a number of functional units surrounding each marked locus and have ordered the mutations into complementation groups. Molecular entry to all but one of the marked regions has been achieved by (1) identifying proviral integrations in, or close to, the specific loci (d, se, a, c); (2) mapping random anonymous clones from appropriately enriched libraries to the longest deleted segments, then submapping to more limited segments on the basis of complementation and deletion-breakpoint maps (c, p); (3) similarly mapping known clones thought to be located in pertinent chromosomal regions (p, c, d); and (4) cloning specific genes that reside in regions corresponding to the deletions (b, c, p). The molecular analyses have confirmed that genetically-inferred deletions are structural deletions of DNA. The emerging physical maps are concordant with the complementation maps, and in several cases have discriminated among members of a complementation group with respect to breakpoint positions. Deletion-breakpoint-fusion fragments have prove to be highly useful for making large chromosomal jumps to facilitate physical mapping. The recent advances toward correlating physical and functional maps of specific regions of the mouse genome owe much to the existence of arrays of mutations involving loci marked in the SLT. In turn, the characterizations of these regions have made it possible to demonstrate qualitative differences among mutations resulting from different treatments. This new capability for qualitative analysis, which will increase as the molecular studies proceed, further enhances the value of the SLT, which has been extensively used for quantitative studies in germ-cell mutagenesis.

Animals↗
PubMed1989

Chlorambucil effectively induces deletion mutations in mouse germ cells.

The chemotherapeutic agent chlorambucil was found to be more effective than x-rays or any chemical investigated to date in inducing high yields of mouse germ-line mutations that appear to be deletions or other structural changes. Induction of mutations involving seven specific loci was studied after exposures of various male germ-cell stages to chlorambucil at 10-25 mg/kg. A total of 60,750 offspring was scored. Mutation rates in spermatogonial stem cells were not significantly increased over control values; this negative result is not attributable to selective elimination of mutant cells. Mutations were, however, clearly induced in treated post-stem-cell stages, among which marked variations in mutational response were found. Maximum yield occurred after exposure of early spermatids, with approximately 1% of all offspring carrying a specific-locus mutation in the 10 mg/kg group. The stage-response pattern for chlorambucil differs from that of all other chemicals investigated to date in the specific-locus test. Thus far, all but one of the tested mutations induced by chlorambucil in post-stem-cell stages have been proved deletions or other structural changes by genetic, cytogenetic, and/or molecular criteria. Deletion mutations have recently been useful for molecular mapping and for structure-function correlations of genomic regions. For generating presumed large-lesion germ-line mutations at highest frequencies, chlorambucil may be the mutagen of choice.

Animals↗
PubMed1989

Cost-effectiveness of antihypertensive treatment. General considerations.

Cost-effectiveness analysis, a set of methods for estimating the costs and health effects of medical interventions, helps decision makers to compare alternative treatments and to decide which interventions are appropriate in which situations. This article outlines some fundamental principles of cost-effectiveness analysis and discusses the characteristics necessary if alternative therapies are to be more cost-effective than traditional drug treatment for hypertension. The discussion focuses primarily on the newer drugs like angiotensin converting enzyme inhibitors, alpha-adrenergic receptor blockers, and calcium antagonists.

Adrenergic alpha-Antagonists↗
PubMed1989

The albino-deletion complex in the mouse defines genes necessary for development of embryonic and extraembryonic ectoderm.

A detailed embryological analysis has been undertaken on embryos carrying the c4FR60Hd-, c5FR60Hg- or c2YPSj-albino deletions of mouse chromosome 7. Embryos homozygous for the c4FR60Hd deletion are abnormal at day 7.5 of gestation. The extraembryonic ectoderm does not develop, and primitive-streak formation and mesoderm production do not occur. In contrast, extensive development of the extraembryonic ectoderm, as well as mesoderm production, are observed in the c5FR60Hg- and c2YPSj-homozygous embryos. The mesoderm does not, however, organize into somites and the neural axis does not form. The embryos are grossly abnormal by day 8.5 of development. There are two other albino deletions (c6H and c11DSD) that are known to affect the embryo around the time of gastrulation (Niswander et al. 1988), and the lethal phenotype observed for the c4FR60Hd-homozygous embryos is similar to that described for c6H-homozygous embryos, whereas the c5FR60Hg- and c2YPSj-homozygous embryos display a phenotype that is similar to c11DSD-homozygous embryos. A detailed complementation analysis using these five deletions revealed that the c5FR60Hg, c2YPSj and c11DSD deletions could partially complement the phenotype produced by the c4FR60Hd and c6H deletions in any combination. Extensive development of the extraembryonic structures and production of mesoderm occurs in the compound heterozygotes. These results suggest that the distal breakpoints of the c5FR60Hg, c2YPSj and c11DSD deletions lie more proximal than the distal breakpoints of the c4FR60Hd and c6H deletions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Medical technology in the United States. The last decade.

This paper reviews the evolution of U.S. policy toward medical technology in areas such as cost containment, regulation of devices and drugs, and third party reimbursement. In addition the authors chronicle the diffusion of major medical technologies, procedures, and organizational innovations in the United States. Finally, the article provides tentative observations on the effect of recent policy changes and concludes with some recommendations for the future.

Communication↗
PubMed1988

High frequency of mosaic mutants produced by N-ethyl-N-nitrosourea exposure of mouse zygotes.

Mouse zygotes containing one multiple-recessive parental genome (a, b; p cch; d se; s) and the corresponding wild-type alleles in the other were exposed to N-ethyl-N-nitrosourea (ENU) at various stages in vivo. At weaning age, the resulting mice were examined for mutations at the marked loci as well as at others producing externally visible phenotypes. Because of viability problems in one of two reciprocal crosses, the bulk of the mutagenesis data are derived from the cross that detects recessive mutations in the maternal genome. The mutation rate was approximately 8 times higher in groups treated 2.5-3 hr postmating (sperm entry, completion of second meiotic division) than in those injected 5-6 hr postmating (pronuclear formation). In the former more sensitive zygote population, the mutation rate is about an order of magnitude greater than that induced by the same ENU exposure (50 mg/kg) to spermatogonial stem cells. Of 11 mutants recovered, 8 were mosaics. Progeny tests have demonstrated germ-line involvement for most of the mosaics, and the average fraction of the germ line carrying the mutation is close to 50%. The nature of the mutations indicates (i) that the mosaicism results not from misassortment at the first cleavage but from mutation affecting one DNA strand of the maternal chromosome, and (ii) that the mutations are intragenic lesions rather than multilocus deletions, thus resembling ENU-induced mutations in spermatogonia. The finding that mosaicism for presumed point mutations is readily inducible by ENU treatment of zygotes may provide a means of generating genetic materials that can be of use for developmental studies.

Animals↗
PubMed1988

The albino deletion complex and early postimplantation survival in the mouse.

The albino deletion complex in the mouse represents 37 overlapping chromosomal deficiencies that have been arranged into at least twelve complementation groups. Many of the deletions cover regions of chromosome 7 that contain genes necessary for early embryonic development. The work reported here concentrates on two of these deletions (c6H, c11DSD), both of which were known to be lethal around the time of gastrulation when homozygous. A detailed embryological analysis has revealed distinct differences in the lethal phenotype associated with the c6H and c11DSD deletions. c6H homozygous embryos are grossly abnormal at day 7.5 of gestation, whereas c11DSD homozygous embryos appear abnormal at day 8.5 of gestation. There is no development of the extraembryonic ectoderm in c6H homozygotes, whereas extensive development of this tissue type occurs in c11DSD homozygotes. The visceral endoderm is abnormally shaped and the parietal endoderm appears to be overproduced in c6H homozygotes; these structures are not affected in c11DSD homozygotes. The embryonic ectoderm is runted in both types of embryo and it is not possible to obtain homozygous embryo-derived stem-cell lines for either deletion. Mesoderm formation occurs in the c11DSD but not in the c6H homozygotes. The c11DSD deletion chromosome complements the c6H chromosome in that the lethal phenotype of the compound heterozygote is similar to that of the c11DSD homozygote. These results suggest that a gene(s) necessary for normal development of the extraembryonic ectoderm is present in the c11DSD but deficient in the c6H deletion chromosome.

Albinism↗