Prevention and Medicare costs.
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Cardiovascular Diseases↗
Biomedical subjects
L B Russell
Publications and source records attributed to L B Russell.
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↗
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↗
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↗
Molecular genetic dissection of mouse unconventional myosin-VA: head region mutations.
The mouse dilute (d) locus encodes unconventional myosin-VA (MyoVA). Mice carrying null alleles of dilute have a lightened coat color and die from a neurological disorder resembling ataxia and opisthotonus within three weeks of birth. Immunological and ultrastructural studies suggest that MyoVA is involved in the transport of melanosomes in melanocytes and smooth endoplasmic reticulum in cerebellar Purkinje cells. In studies described here, we have used an RT-PCR-based sequencing approach to identify the mutations responsible for 17 viable dilute alleles that vary in their effects on coat color and the nervous system. Seven of these mutations mapped to the MyoVA motor domain and are reported here. Crystallographic modeling and mutant expression studies were used to predict how these mutations might affect motor domain function and to attempt to correlate these effects with the mutant phenotype.
Alleles↗
Molecular genetic dissection of mouse unconventional myosin-VA: tail region mutations.
We used an RT-PCR-based sequencing approach to identify the mutations responsible for 17 viable dilute alleles, a mouse-coat-color locus encoding unconventional myosin-VA. Ten of the mutations mapped to the MyoVA tail and are reported here. These mutations represent the first extensive collection of tail mutations reported for any unconventional mammalian myosin. They identify sequences important for tail function and identify domains potentially involved in cargo binding and/or proper folding of the MyoVA tail. Our results also provide support for the notion that different myosin tail isoforms produced by alternative splicing encode important cell-type-specific functions.
Animals↗
Biomedical risk factors for hospital admission in older adults.
OBJECTIVES: This study examines the influence of risk factors such as cigarette smoking, blood pressure, serum cholesterol, or chronic illness on frequency of hospital admission in a population-based sample. METHODS: Data from the National Health and Nutrition Examination Survey I Epidemiologic Followup Study for 6,461 adults aged 45 years and older were used to assess the influence of risk factors measured by interview, physical examination, and laboratory tests on frequency of hospital admission over a 12- to 16-year follow-up period. Cox proportional hazard regressions were estimated separately for men and women and for ages 45 to 64 years and 65 years and older. SUDAAN software was used to correct for clustering, stratification, unequal weighting, and multiple observations per respondent. RESULTS: Risk of hospitalization was higher for current but not former smokers (relative risk [RR] = 1.17-1.34 for different age-sex groups; P < 0.01), higher blood pressure (RR = 1.25-1.28 for ages 45-64; RR = 1.07-1.15 for ages 65 and older; P < 0.01), and lower serum albumin (RR = 1.08-1.14; P < 0.01). Diabetes, lung conditions, heart attack, and ulcer each were associated with higher risk in at least three of the four age-sex groups, as was arthritis among the middle-aged (45-64 years). Serum cholesterol was not associated with hospitalization. CONCLUSIONS: Chronic conditions with high morbidity as well as many factors associated with mortality are associated with a higher frequency of hospitalization.
Age Factors↗
Modeling all-cause mortality: projections of the impact of smoking cessation based on the NHEFS. NHANES I Epidemiologic Follow-up Study.
OBJECTIVES: A model that relates clinical risk factors to subsequent mortality was used to simulate the impact of smoking cessation. METHODS: Survivor functions derived from multivariate hazard regressions fitted to data from the first National Health and Nutrition Examination Survey (NHANES I) Epidemiologic Followup Study, a longitudinal survey of a representative sample of US adults, were used to project deaths from all causes. RESULTS: Validation tests showed that the hazard regressions agreed with the risk relationships reported by others, that projected deaths for baseline risk factors closely matched observed mortality, and that the projections attributed deaths to the appropriate levels of important risk factors. Projections of the impact of smoking cessation showed that the number of cumulative deaths would be 15% lower after 5 years and 11% lower after 20 years. CONCLUSIONS: The model produced realistic projections of the effects of risk factor modification on subsequent mortality in adults, Comparison of the projections for smoking cessation with estimates of the risk attributable to smoking published by the Centers for Disease Control and Prevention suggests that cessation could capture most of the benefit possible from eliminating smoking.
Aged↗
Molecular characterization of four induced alleles at the Ednrb locus.
The piebald locus on mouse chromosome 14 encodes the endothelin-B receptor (EDNRB), a G protein-coupled, seven-transmembrane domain protein, which is required for neural crest-derived melanocyte and enteric neuron development. A spontaneous null allele of Ednrb results in homozygous mice that are predominantly white and die as juveniles from megacolon. To identify the important domains for EDNRB function, four recessive juvenile lethal alleles created by either radiation or chemical mutagens (Ednrb27Pub, Ednrb17FrS, Ednrb1Chlc, and Ednrb3Chlo) were examined at the molecular level. Ednrb27Pub mice harbor a mutation at a critical proline residue in the fifth transmembrane domain of the EDNRB protein. A gross genomic alteration within the Ednrb gene in Ednrb3Chlo results in the production of aberrantly sized transcripts and no authentic Ednrb mRNA. Ednrb17FrS mice exhibited a decreased level of Ednrb mRNA, supporting previous observations that the degree of spotting in piebald mice is dependent on the amount of EDNRB expressed. Finally, no molecular defect was detected in Ednrb1Chlc mice, which produce normal levels of Ednrb mRNA in adult brain, suggesting that the mutation affects important regulatory elements that mediate the expression of the gene during development.
Alleles↗
Assessing the effectiveness of health interventions for cost-effectiveness analysis. Panel on Cost-Effectiveness in Health and Medicine.
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Cost-Benefit Analysis↗
Spectrum of Bmp5 mutations from germline mutagenesis experiments in mice.
Over 40 years of mutagenesis experiments using the mouse specific-locus test have produced a large number of induced germline mutations at seven loci, among them the short ear locus. We have previously shown that the short ear locus encodes bone morphogenetic protein 5 (BMP5), a member of a large family of secreted signaling molecules that play key roles in axis formation, tissue differentiation, mesenchymalepithelial interactions, and skeletal development. Here we examine 24 chemical- and radiation-induced mutations at the short ear locus. Sequence changes in the Bmp5 open reading frame confirm the importance of cysteine residues in the function of TGF beta superfamily members. The spectrum of N-ethyl-N-nitrosourea-induced mutations also provides new information about the basepair, sequence context, and strand specificity of germline mutations in mammals.
Amino Acid Sequence↗
The knowledge base for public health strategies.
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Aged↗
Guidelines for pharmacoeconomic studies. Recommendations from the panel on cost effectiveness in health and medicine. Panel on cost Effectiveness in Health and Medicine.
This article reports the recommendations of the Panel on Cost Effectiveness in Health and Medicine, sponsored by the US Public Health Service, on standardised methods for conducting cost-effectiveness analyses. Although not expressly directed at analyses of pharmaceutical agents, the Panel's recommendations are relevant to pharmacoeconomic studies. The Panel outlines a 'Reference Case' set of methodological practices to improve quality and comparability of analyses. Designed for studies that inform resource-allocation decisions, the Reference Case includes recommendations for study framing and scope, components of the numerator and denominator of cost-effectiveness ratios, discounting, handling uncertainty and reporting. The Reference Case analysis is conducted from the societal perspective, and includes all effects of interventions on resource use and health. Resource use includes 'time' resources, such as for caregiving or undergoing an intervention. The quality-adjusted life-year (QALY) is the common measure of health effect across Reference Case studies. Although the Panel does not endorse a measure for obtaining quality-of-life weights, several recommendations address the QALY. The Panel recommends a 3% discount rate for costs and health effects. Pharmacoeconomic studies have burgeoned in recent years. The Reference Case analysis will improve study quality and usability, and permit comparison of pharmaceuticals with other health interventions.
Cost-Benefit Analysis↗
Comparison of two surveys of hospitalization: the National Hospital Discharge Survey and the NHANES I Epidemiologic Followup Study.
OBJECTIVES: This report compares hospitalization data from the NHANES I Epidemiologic Followup Study (NHEFS) with data from the National Hospital Discharge Survey (NHDS), the benchmark for hospitalization in the United States, for men and women 35 years and older for the period 1971-87. The comparison is intended to help analysts evaluate the validity and generality of analyses based on the NHEFS. METHODS: Hospital stays per 1,000 population and average lengths of stay are compared year by year for each age-sex group and for the entire period. Regression analyses test for differences between the two surveys by age and sex, and for differences in trends over time and the effect of the Medicare program's prospective hospital payment system. RESULTS: Hospital stays per 1,000 population were lower in NHEFS than in NHDS in all age-sex groups at the beginning of the period, but the differences had almost disappeared by 1987. Lengths of stay, although somewhat longer in NHEFS, matched NHDS more closely. Differentials by age and sex were similar in the two surveys for both hospital stays per 1,000 population and length of hospital stay. With its extensive information on baseline risk factors, the NHEFS offers a unique opportunity to study determinants of hospitalization in a representative sample of U.S. adults. The evaluation presented here suggests two points for researchers who want to use the NHEFS. First, including age as a control should largely correct for differences in age distribution between NHEFS and NHDS. Second, a time trend should also be included to capture the effects of several factors that caused the count of stays to be low in the early years of NHEFS followup.
Adult↗
The semidominant Mi(b) mutation identifies a role for the HLH domain in DNA binding in addition to its role in protein dimerization.
The mouse microphthalmia (mi) locus encodes a basic helix-loop-helix-leucine zipper (bHLH-Zip) transcription factor called MITF (microphthalmia transcription factor). Mutations at mi affect the development of several different cell types, including melanocytes, mast cells, osteoclasts and pigmented epithelial cells of the eye. Here we describe the phenotypic and molecular characterization of the semidominant Microphthalmia(brwnish) (Mi(b)) mutation. We show that this mutation primarily affects melanocytes and produces retinal degeneration. The mutation is a G to A transition leading to a Gly244Glu substitution in helix 2 of the HLH dimerization domain. This location is surprising since other semidominant mi mutations characterized to date have been shown to affect DNA binding or transcriptional activation domains of MITF and act as dominant negatives, while mutations that affect MITF dimerization are inherited recessively. Gel retardation assays showed that while the mutant MITF(Mi-b) protein retains its dimerization potential, it is defective in its ability to bind DNA. Computer modeling suggested that the Gly244Glu mutation might disrupt DNA binding by interfering with productive docking of the protein dimer onto DNA. The Mi(b) mutation therefore appears to dissociate a DNA recognition function of the HLH domain from its role in protein dimerization.
Animals↗
Spontaneous mutations recovered as mosaics in the mouse specific-locus test.
The specific-locus test (SLT) detects new mutants among mice heterozygous for seven recessive visible markers. Spontaneous mutations can be manifested not only as singleton whole-body mutants in controls (for which we report new data), but as mosaics-either visible (manifesting mottled coat color) in the scored generation (G2) or masked, among the wild-type parental generation (G1). Masked G1 mosaics reveal themselves by producing clusters of whole-body mutants in G2. We provide evidence that most, if not all, mosaics detected in the SLT (both radiation and control progenies) result from a single-strand spontaneous mutation subsequent to the last premeiotic mitosis and before the first postmeiotic one of a parental genome-the "perigametic interval." Such events in the genomes of the G1 and Gzero results, respectively, in visible and masked 50:50 mosaics. Per cell cycle, the spontaneous mutation rate in the perigametic interval is much higher than that in pregamete mitotic divisions. A clearly different locus spectrum further supports the hypothesis of different origin, and casts further doubt on the validity of the doubling-dose risk-estimation method. Because mosaics cannot have arisen in mitotic germ cells, and are not induced by radiation exposure in the perigametic interval, they should not be included in calculations of radiation-induced germ-line mutation rates. For per-generation calculations, inclusion of mosaics yields a spontaneous frequency 1.7 times that calculated from singletons alone for mutations contributed by males; including both sexes, the multiple is 2.2.
Animals↗
Chlorambucil and bleomycin induce mutations in the specific-locus test in female mice.
Specific-locus studies have shown chlorambucil (CHL) and bleomycin (BLE) to be mutagenic in mouse oocytes, almost doubling the number of chemicals previously known to induce mutations in females. The overall CHL-induced mutation rate in oocytes is, however, one order of magnitude below that for male meiotic and postmeiotic stages, and only 1/50 that for early spermatids. For BLE, no specific-locus data for males are available for comparison, but the chemical had earlier been found negative for dominant-lethal induction in males. Both BLE and CHL were significantly mutagenic only in mature and maturing oocytes. In keeping with an earlier report, BLE produced a high incidence of dominant lethals in these stages. CHL failed to induce dominant lethals, indicating that for mature and maturing oocytes, in contrast with results for males, sensitivity to dominant-lethal mutations is not a prerequisite for induction of specific-locus mutations. Exposure of immature oocytes to either BLE or CHL produced neither dominant lethals nor significant induction of specific-locus mutations; however, CHL gave evidence of killing immature oocytes. By contrast, BLE, which has been considered a radiomimetic chemical, does not appear to kill immature oocytes and thus differs markedly from radiation exposures equivalent for dominant-lethal induction. Therefore, the failure to recover specific-locus mutations cannot be ascribed to cell selection resulting from oocyte killing, as has sometimes been done for radiation. Adding results on the nature of the CHL- and BLE-induced mutations to prior information, the estimated minimum proportion of large DNA lesions induced in oocytes by chemicals becomes 35.3%, significantly different from the corresponding figure (approximately 70%) for radiations. For chemical treatments, the oocyte proportion is highly significantly above the 3.6% induced in spermatogonia, but only on the borderline of statistically significant difference from that induced in postspermatogonial stages.
Animals↗
Recommendations of the Panel on Cost-effectiveness in Health and Medicine.
OBJECTIVE: To develop consensus-based recommendations for the conduct of cost-effectiveness analysis (CEA). This article, the second in a 3-part series, describes the basis for recommendations constituting the reference case analysis, the set of practices developed to guide CEAs that inform societal resource allocation decisions, and the content of these recommendations. PARTICIPANTS: The Panel on Cost-Effectiveness in Health and Medicine, a nonfederal panel with expertise in CEA, clinical medicine, ethics, and health outcomes measurement, was convened by the US Public Health Service (PHS). EVIDENCE: The panel reviewed the theoretical foundations of CEA, current practices, and alternative methods used in analyses. Recommendations were developed on the basis of theory where possible, but tempered by ethical and pragmatic considerations, as well as the needs of users. CONSENSUS PROCESS: The panel developed recommendations through 2 1/2 years of discussions. Comments on preliminary drafts prepared by panel working groups were solicited from federal government methodologists, health agency officials, and academic methodologists. CONCLUSIONS: The panel's methodological recommendations address (1) components belonging in the numerator and denominator of a cost-effectiveness (C/E) ratio; (2) measuring resource use in the numerator of a C/E ratio; (3) valuing health consequences in the denominator of a C/E ratio; (4) estimating effectiveness of interventions; (5) incorporating time preference and discounting; and (6) handling uncertainty. Recommendations are subject to the ¿rule of reason,¿ balancing the burden engendered by a practice with its importance to a study. If researchers follow a standard set of methods in CEA, the quality and comparability of studies, and their ultimate utility, can be much improved.
Cost-Benefit Analysis↗