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Biomedical subjects

L B Russell

Publications and source records attributed to L B Russell.

At least 19 recordsLinked to original sources
PubMed2001

Preventable smoking and exercise-related hospital admissions. A model based on the NHEFS.

BACKGROUND: The NHANES I Epidemiologic Follow-Up Study (NHEFS), a longitudinal study of a representative sample of U.S. adults, makes it possible for the first time to develop a simulation model relating hospital admissions to baseline clinical risk factors for the general adult population. The model is presented here and used to project the impact on hospital admissions of changes in smoking behavior and sedentary lifestyle. METHODS: Three kinds of projections were calculated for the cohort of adults aged 45 to 74 at baseline: projections of hospital admissions in the absence of the risk factor; projections that reflect a 10-year lag between behavior change and full health benefit; and projections that reflect both lag and incomplete adherence to behavior change. For incomplete adherence we assumed that only 10% of the at-risk population changed their behavior. RESULTS: Tests of the simulation model showed that it agreed with a Cox analysis of the hospital data and accurately projected observed hospital admissions over the study period. The projections showed that eliminating smoking would reduce annual rates of all-cause hospitalization among older adults by 8.9% 20 years after baseline. Eliminating inactivity would reduce them 4.6%. Introducing a lag of 10 years between behavior modification and full benefit delayed the impact on hospitalization rates but the effect at 20 years was the same. When only 10% of the population at risk stopped smoking or became physically active, a percentage that reflects the effectiveness of current interventions, annual hospitalization rates at 20 years fell by 0.9% and 0.5%, respectively. CONCLUSIONS: Substantial reductions in hospital admissions can be achieved by interventions to prevent smoking, help smokers quit, or encourage inactive persons to become active. Improving adherence can markedly improve the impact on hospitalizations. The costs of these efforts would be rewarded not only by better health, but by lower expenditures for hospitalization.

Age Distribution↗
PubMed2001

Molecular and functional mapping of the piebald deletion complex on mouse chromosome 14.

The piebald deletion complex is a set of overlapping chromosomal deficiencies surrounding the endothelin receptor B locus collected during the Oak Ridge specific-locus-test mutagenesis screen. These chromosomal deletions represent an important resource for genetic studies to dissect the functional content of a genomic region, and several developmental defects have been associated with mice homozygous for distinct piebald deletion alleles. We have used molecular markers to order the breakpoints for 20 deletion alleles that span a 15.7-18-cM region of distal mouse chromosome 14. Large deletions covering as much as 11 cM have been identified that will be useful for regionally directed mutagenesis screens to reveal recessive mutations that disrupt development. Deletions identified as having breakpoints positioned within previously described critical regions have been used in complementation studies to further define the functional intervals associated with the developmental defects. This has focused our efforts to isolate genes required for newborn respiration and survival, skeletal patterning and morphogenesis, and central nervous system development.

Alleles↗
PubMed2000

Survival, functional limitations, and self-rated health in the NHANES I Epidemiologic Follow-up Study, 1992. First National Health and Nutrition Examination Survey.

This study examined relative hazards for mortality and functional limitations according to poor self-ratings of health using prospective data from the NHANES I Epidemiologic Follow-up Study, a representative sample of US adults aged 25-74 years that has been followed since the First National Health and Nutrition Examination Survey (NHANES I) was conducted in 1971-1975. Follow-up data were taken from death records and from the 1982 and 1992 reinterviews. Respondents (n = 6,913) provided extensive baseline data through physician examinations, laboratory testing, and self-reports of conditions, symptoms, and risk behaviors. Functional limitations were assessed among survivors in 1982 and 1992. Cox regression models accounting for sample design indicated that baseline self-rated health was associated with a significantly reduced hazard of mortality for males but not for females through 1992; adjusted hazards ratios for excellent health as compared with poor health were 0.52 for males (95% confidence interval: 0.36, 0.73) and 0.80 for females (95% confidence interval: 0.51, 1.23). Self-rated health also predicted 1982 and 1992 functional limitation for both men and women and 1992 function net of 1982 function for men only. Self-rated health contributes unique information to epidemiologic studies that is not captured by standard clinical assessments or self-reported histories, but evidence suggests that the effect may be stronger for men than for women.

Activities of Daily Living↗
PubMed2000

Bleomycin, unlike other male-mouse mutagens, is most effective in spermatogonia, inducing primarily deletions.

Dominant-lethal tests [P.D. Sudman, J.C. Rutledge, J.B. Bishop, W.M. Generoso, Bleomycin: female-specific dominant lethal effects in mice, Mutat. Res. 296 (1992) 205-217] had suggested that Bleomycin sulfate (Blenoxane), BLM, might be a female-specific mutagen. While confirming that BLM is indeed a powerful inducer of dominant-lethal mutations in females that fails to induce such mutations in postspermatogonial stages of males, we have shown in a specific-locus test that BLM is, in fact, mutagenic in males. This mutagenicity, however, is restricted to spermatogonia (stem-cell and differentiating stages), for which the specific-locus mutation rate differed significantly (P<0.008) from the historical control rate. In treated groups, dominant mutations, also, originated only in spermatogonia. With regard to mutation frequencies, this germ-cell-stage pattern is different from that for radiation and for any other chemical studied to date, except ethylnitrosourea (ENU). However, the nature of the spermatogonial specific-locus mutations differentiates BLM from ENU as well, because BLM induced primarily (or, perhaps, exclusively) multilocus deletions. Heretofore, no chemical that induced specific-locus mutations in spermatogonia did not also induce specific-locus as well as dominant-lethal mutations in postspermatogonial stages, making the dominant lethal test, up till now, predictive of male mutagenicity in general. The BLM results now demonstrate that there are chemicals that can induce specific-locus mutations in spermatogonia without testing positive in postspermatogonial stages. Thus, BLM, while not female-specific, is unique, (a) in its germ-cell-stage specificity in males, and (b) in inducing a type of mutation (deletions) that is atypical for the responding germ-cell stages (spermatogonia).

Animals↗
PubMed2000

A mutation in Rab27a causes the vesicle transport defects observed in ashen mice.

The dilute (d), leaden (ln), and ashen (ash) mutations provide a unique model system for studying vesicle transport in mammals. All three mutations produce a lightened coat color because of defects in pigment granule transport. In addition, all three mutations are suppressed by the semidominant dilute-suppressor (dsu), providing genetic evidence that these mutations function in the same or overlapping transport pathways. Previous studies showed that d encodes a major vesicle transport motor, myosin-VA, which is mutated in Griscelli syndrome patients. Here, using positional cloning and bacterial artificial chromosome rescue, we show that ash encodes Rab27a. Rab GTPases represent the largest branch of the p21 Ras superfamily and are recognized as key players in vesicular transport and organelle dynamics in eukaryotic cells. We also show that ash mice have platelet defects resulting in increased bleeding times and a reduction in the number of platelet dense granules. These defects have not been reported for d and ln mice. Collectively, our studies identify Rab27a as a critical gene for organelle-specific protein trafficking in melanocytes and platelets and suggest that Rab27a functions in both MyoVa dependent and independent pathways.

Albinism, Oculocutaneous↗
PubMed2000

Self-tolerance to the murine homologue of a tyrosinase-derived melanoma antigen: implications for tumor immunotherapy.

The human tyrosinase-derived peptide YMDGTMSQV is presented on the surface of human histocompatibility leukocyte antigen (HLA)-A*0201(+) melanomas and has been suggested to be a tumor antigen despite the fact that tyrosinase is also expressed in melanocytes. To gain information about immunoreactivity and self-tolerance to this antigen, we established a model using the murine tyrosinase-derived homologue of this peptide FMDGTMSQV, together with transgenic mice expressing the HLA-A*0201 recombinant molecule AAD. The murine peptide was processed and presented by AAD similarly to its human counterpart. After immunization with recombinant vaccinia virus encoding murine tyrosinase, we detected a robust AAD-restricted cytotoxic T lymphocyte (CTL) response to FMDGTMSQV in AAD transgenic mice in which the entire tyrosinase gene had been deleted by a radiation-induced mutation. A residual response was observed in the AAD(+)tyrosinase(+) mice after activation under certain conditions. At least some of these residual CTLs in AAD(+)tyrosinase(+) mice were of high avidity and induced vitiligo upon adoptive transfer into AAD(+)tyrosinase(+) hosts. Collectively, these data suggest that FMDGTMSQV is naturally processed and presented in vivo, and that this presentation leads to substantial but incomplete self-tolerance. The relevance of this model to an understanding of the human immune response to tyrosinase is discussed.

Amino Acid Sequence↗
PubMed2000

Effect of the topoisomerase-II inhibitor etoposide on meiotic recombination in male mice.

Unlike other chemicals that have been tested in mammalian germ cells, the type-II topoisomerase inhibitor etoposide exhibits significant mutagenicity in primary spermatocytes. Because this is the cell stage during which meiotic recombination normally occurs, and because topoisomerases play a role in recombination, we studied the effect of etoposide on crossing-over in male mice. Exposure to those meiotic prophase stages (probably early to mid-pachytene) during which specific-locus deletion mutations can be induced resulted in decreased crossing-over in the p-Tyr(c) interval of mouse chromosome 7. Accompanying cytological studies with fluorescent antibodies indicated that while there was no detectable effect on the number of recombination nodules (MLH1 foci), there were marked changes in the stage of appearance and localization of RAD51 and RPA proteins. These temporal and spatial protein patterns suggest the formation of multiple lesions in the DNA after MLH1 has already disappeared from spermatocytes. Since etoposide blocks religation of the cut made by type II topoisomerases, repair of DNA damage may result in rejoining of the original DNA strands, undoing the reciprocal exchange that had already occurred and resulting in reduced crossing-over despite a normal frequency of MLH1 foci. Crossing-over could conceivably be affected differentially in different chromosomal regions. If, however, the predominant action of etoposide is to decrease homologous meiotic recombination, the chemical could be expected to increase nondisjunction, an event associated with human genetic risk. Three periods in spermatogenesis respond to etoposide in different ways. Exposure of (a) late differentiating spermatogonia (and, possibly, preleptotene spermatocytes) results in cell death; (b) early- to mid-pachytene induces specific-locus deletions and crossover reduction; and, (c) late pachytene-through-diakinesis leads to genetically unbalanced conceptuses as a result of clastogenic damage.

Animals↗
PubMed2000

Modeling age differences in cost-effectiveness analysis. A review of the literature.

OBJECTIVES: Cost-effectiveness analysts often present cost-effectiveness results by age to help inform decisions about the use of an intervention. Yet it is not known how well studies model the risks and costs associated with age. We reviewed published studies to examine their modeling of age differences. METHODS: MEDLINE searches identified all cost-effectiveness analyses published between 1985 and 1997 that included adults 50 years of age and older, were based on data for developed countries, and compared cost-effectiveness ratios for adults of different ages or for initiation of an intervention at different ages; 36 articles met these criteria. They were reviewed to determine the extent to which they incorporated age-specific data. Studies that justified using the same data for all ages were counted as having varied the data element by age. RESULTS: All studies varied life expectancy by age. Most also varied the incidence/prevalence of the target condition and the case fatality rate. Only 36% varied the effectiveness rate of the intervention by age. Costs were usually assumed constant: 42% of studies varied the cost of treating adverse effects and 17% varied the cost of treating the target condition. Whether a data element was varied did not appear to be related to the pattern of cost-effectiveness ratios by age. CONCLUSIONS: Many studies have not modeled age differences in sufficient detail to ensure that differences in cost-effectiveness ratios by age are accurate and a sound basis for decisions. As cost-effectiveness analysis becomes more widespread, analysts should strive to incorporate more complete age-specific data.

Age Factors↗
PubMed2000

Cost-effectiveness analysis and screening tests for women.

Cost-effectiveness analysis is a method for identifying those medical interventions that are most effective given the resources available. This commentary focuses on the cost effectiveness of screening tests, with particular emphasis on such factors as the frequency and accuracy of the test; the risk of the condition and of adverse effects; the costs of screening, follow-up, and treatment; and the target population. The same test can be much more or less costly per year of life saved, and thus a better or worse use of medical resources, depending on how it is used. Results from cost-effectiveness analyses of a variety of screening interventions important to women (screening for cervical cancer and breast cancer, heart disease, diabetes, and mild thyroid failure) highlight the importance of developing screening protocols wisely so that women will receive the greatest possible benefit from their use.

Breast Neoplasms↗
PubMed1999

Modelling for cost-effectiveness analysis.

A model creates the framework for a cost-effectiveness analysis, allowing decision makers to explore the implications of using an intervention in different ways and under different conditions. To serve its purpose a model must produce accurate predictions and allow for substantial variation in the factors that influence costs and effects. This paper considers three aspects of modelling: validating effectiveness estimates; modelling costs; and the implications of common statistical forms. Validation procedures similar to those for effectiveness estimates are proposed for costs. Modellers need to pay more attention to ensuring that the pathway of events described by a model represents costs as well as it does effects. Modellers can also help improve the epidemiological and clinical research on which cost-effectiveness analyses depend by showing the implications for resource allocation of the statistical forms conventionally used in these fields.

Breast Neoplasms↗
PubMed1999

Significance of the perigametic interval as a major source of spontaneous mutations that result in mosaics.

An earlier analysis showed that a significant percentage of spontaneous specific-locus mutations in mice are recovered as mosaics and that the spontaneous mutation rate per cell cycle is probably higher for those mutations that produce mosaics than for those that produce whole-body mutants. The finding that the average germline composition of the mosaics was approximately 50% supported the suggestion that single-strand DNA alterations during the perigametic interval constitute the major source of spontaneous mosaics. Here, alternative origins of 50% germline mosaicism are examined. Supporting the earlier hypothesis is the finding that spontaneous mutations that are recovered as clusters constitute a different array of types from those giving rise to singletons, and the evidence from interspecies comparisons that a unique component of the life cycle, probably meiosis, makes a major contribution to spontaneous mutations. Biological factors associated with the perigametic interval were examined in an effort to suggest explanations for the observations that 1) the spontaneous mutation rate in that interval is high relative to that characterizing any mitotic cell cycle, 2) the types of mutations appear to be different from those arising during mitotic divisions, and 3) the spontaneous mutation rate for males is higher than that for females. It is concluded that the higher yield from the perigametic interval is consistent with what is known about methylation status in development of both sexes and with repair capacity in the male germline. For both parameters, differences between the sexes during their respective perigametic intervals may be at least partly responsible for the fact that the spontaneous mutation rate of mammalian females is lower than that of males.

Animals↗
PubMed1999

Molecular characterization of radiation- and chemically induced mutations associated with neuromuscular tremors, runting, juvenile lethality, and sperm defects in jdf2 mice.

The juvenile development and fertility-2 (jdf2) locus, also called runty-jerky-sterile (rjs), was originally identified through complementation studies of radiation-induced p-locus mutations. Studies with a series of ethylnitrosourea (ENU)-induced jdf2 alleles later indicated that the pleiotropic effects of these mutations were probably caused by disruption of a single gene. Recent work has demonstrated that the jdf2 phenotype is associated with deletions and point mutations in Herc2, a gene encoding an exceptionally large guanine nucleotide exchange factor protein thought to play a role in vesicular trafficking. Here we describe the molecular characterization of a collection of radiation- and chemically induced jdf2/Herc2 alleles. Ten of the 13 radiation-induced jdf2 alleles we studied are deletions that remove specific portions of the Herc2 coding sequence; DNA rearrangements were also detected in two additional mutations. Our studies also revealed that Herc2 transcripts are rearranged, not expressed, or are present in significantly altered quantities in animals carrying most of the jdf2 mutations we analyzed, including six independent ENU-induced alleles. These data provide new molecular clues regarding the wide range of jdf2 and p phenotypes that are expressed by this collection of recently generated and classical p-region mutations.

Alleles↗
PubMed1999

Is the societal perspective in cost-effectiveness analysis useful for decision makers?

BACKGROUND: The U.S. Public Health Service's Panel on Cost-Effectiveness in Health and Medicine recommends that cost-effectiveness analyses (CEAs) intended to help allocate health resources in the public interest include a reference case analysis, conducted from the perspective of society as a whole. This perspective requires that an analysis measure all health effects and changes in resource use caused by an intervention. VALUE OF SOCIETAL CEAs: Tensions unavoidably arise among the parties to medical decisions--patients, their families and friends, clinicians, and third-party payers. One common approach to handling these tensions is to ignore some of them, to "solve" them by pretending they do not or should not exist. Patients do this when they demand the best care for themselves without regard to the cost to others, payers when they make coverage decisions that shift costs ot others. But by estimating all gains and losses, calculations that reflect the safety, effectiveness, and side effects of an intervention as well as its costs, societal CEAs can help resolve those tensions and provide the basis for decisions that are fair to all parties, an agenda for negotiating such decisions, and information essential for designing compensation and incentives to support them. MAKING BETTER USE OF SOCIETAL CEAs: Use of the societal perspective asks that all parties be aware of and consider the interests of others. Some process or procedure needs to be developed for presenting CEA information to the parties most likely to be affected by decisions, soliciting their views, and negotiating an acceptable decision. This process could be used by government decision makers or by managed care organizations, professional societies, or payers.

Attitude to Health↗
PubMed1999

The cost-effectiveness of autologous transfusion revisited: implications of an increased risk of bacterial infection with allogeneic transfusion.

BACKGROUND: Previous analyses have found autologous transfusion to be very expensive but have not considered avoidance of postoperative bacterial infections as one of its benefits. STUDY DESIGN AND METHODS: A cost-utility analysis using a Markov cohort simulation model compared autologous blood transfusion to allogeneic transfusion in a hypothetical cohort of patients undergoing elective total hip replacement with respect to discounted quality-adjusted life years (QALYs) and health-care system costs. RESULTS: Assuming a base case rate of serious infection of 3.7 percent, a relative risk of infection of 1.85, and additional costs of $12,980 per infection, autologous transfusion has a cost-effectiveness of $2,470 per QALY. If the relative risk of bacterial infection following allogeneic transfusion exceeds 1.1, the cost-effectiveness of autologous transfusion is less than $50,000 per QALY and if the relative risk exceeds 2.4, autologous transfusion is dominant, resulting in both lower costs and greater QALYs. If there were no increased risk of transfusion, the cost-effectiveness of autologous transfusion would be $3,400,000 per QALY. CONCLUSIONS: If there is only a modest increase in the risk of bacterial infection following allogeneic transfusion, autologous transfusion would result in improved outcomes at a cost of less than $50,000 per QALY. Autologous transfusion would be dominant above a relative risk of infection that is within the range of values observed in randomized controlled trials. However, if there is no increased risk of bacterial infection, autologous transfusion would be a very expensive strategy. Until more definitive data are available on the magnitude and costs of this risk, we advise against prematurely closing the debate about the cost-effectiveness of autologous transfusion.

Adult↗
PubMed1998

Unlike other chemicals, etoposide (a topoisomerase-II inhibitor) produces peak mutagenicity in primary spermatocytes of the mouse.

The cancer chemotherapy agent, and topoisomerase-II inhibitor, etoposide (VP-16) produced both recessive mutations at specific loci and dominants at other loci with peak frequencies in primary spermatocytes, a cell type in which the topo-II gene has been shown to be activated. Etoposide thus differs from all other chemicals whose germ-cell-stage specificity has been analyzed. No effects of etoposide exposure of spermatogonial stem cells ( approximately 15, 000 offspring scored) were detectable by either mutagenicity or productivity endpoints. The significant mutagenic response that followed exposure of poststem-cell stages ( approximately 25,000 offspring scored) showed a clear peak, with three of four specific-locus mutants, and three of four dominant mutants conceived during weeks 4 or 5 (days 22-35) post-injection, a period that also encompassed the dominant-lethal peak. For this period, the induced specific-locus rate (with 95% confidence limits) at a weighted-average exposure of 75.1 mg etop/kg was 59.5 (14.6, 170. 9)x10-6/locus. At least 3 of the 4 specific-locus mutations were deletions, paralleling findings with etoposide or analogs in other test systems where a recombinational origin of the deletions has been suggested. Because, unlike other chemicals that induce deletions in male germ cells, etoposide is effective in stages normally associated with recombinational events, it will be of interest to determine whether this chemical can affect meiotic recombination.

Animals↗
PubMed1998

An extensive 3' regulatory region controls expression of Bmp5 in specific anatomical structures of the mouse embryo.

Bone morphogenetic proteins (BMPs) are secreted signaling molecules that control important developmental events in many different organisms. Previous studies have shown that BMPs are expressed at the earliest stages of skeletal development, and are required for formation of specific skeletal features, strongly suggesting that they are endogenous signals used to control formation of skeletal tissue. Despite the importance of BMP signaling in normal development, very little is known about the mechanisms that control the synthesis and distribution of BMP signals in vertebrates. Here, we identify a large array of cis-acting control sequences that lay out expression of the mouse Bmp5 gene in specific skeletal structures and soft tissues. Some of these elements show striking specificity for particular anatomical features within the skeleton, rather than for cartilage and bone in general. These data suggest that the vertebrate skeleton is built from the sum of many independent domains of BMP expression, each of which may be controlled by separate regulatory elements driving expression at specific anatomical locations. Surprisingly, some of the regulatory sequences in the Bmp5 gene map over 270 kb from the Bmp5 promoter, making them among the most distant elements yet identified in studies of eukaryotic gene expression.

Alleles↗
PubMed1998

Differential response of mouse male germ-cell stages to radiation-induced specific-locus and dominant mutations.

In an attempt to provide a systematic assessment of the frequency and nature of mutations induced in successive stages of spermato- and spermiogenesis, X-irradiated male mice were re-mated at weekly intervals, and large samples of progeny, observed from birth onward, were scored and genetically tested for recessive mutations at seven specific loci and for externally recognizable dominant mutations. Productivity findings provided a rough measure of induced dominant-lethal frequencies. A qualitative assessment of specific-locus mutations (which include deletions and other rearrangements) was made on the basis of homozygosity test results, as well as from information derived from more recent complementation studies and molecular analyses. Both recessive and dominant visibles revealed clear distinctions between spermatogonia and postspermatogonial stages. In addition, differences for both of these endpoints, as well as for presumed dominant lethals, were found among various postspermatogonial stages. It may be concluded that radiation produces its maximum rates of genetic damage in germ-cell stages ranging from midpachytene spermatocytes through early spermatids, a pattern unlike any of those that have been defined for chemicals; further, the frequency peaks for radiation are lower and broader. The difference between post-stem-cell stages overall and stem-cell spermatogonia was smaller than is generally found with chemicals, not only with respect to the frequency but also the nature of mutations.

Animals↗