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G E McClearn

Publications and source records attributed to G E McClearn.

139 records · Page 8Linked to original sources
PubMedDate not supplied

Genetic influences on tissue deposition of aluminum in mice.

Aluminum is a known neurotoxin and has been suggested to play a role in the development of Senile Dementia of the Alzheimer's Type. The relationship between aluminum exposure and senile dementia cannot be a simple one, however, as not all exposure results in neurotoxic manifestations. To determine if there are genetic differences in susceptibility to moderate aluminum exposure, 16 mice of five inbred strains were divided into two groups. The control group was fed a purified diet containing all known requirements for mice; the experimental group was fed the same diet supplemented with 260 mg Al/kg diet for 28 d. Analysis of brains, livers, and tibias for aluminum concentrations revealed strain differences in response to dietary treatment. The most notable results occurred in the DBA/2 and C3H/2 strains, with brain aluminum levels higher in the experimental groups. In contrast, A/J, BALB/c, and C57BL/6 strains showed no differences in brain aluminum in response to dietary treatment. These findings suggest that there are genetic differences in the permeability of the blood brain barrier and lend support to the hypothesis that variability in aluminum toxicity may be, in part, genetically determined.

Aluminum↗
PubMedDate not supplied

Genetics and ethanol tolerance.

This paper reviews some of the research on genetic bases of individual differences in ethanol tolerance of mice conducted at the Institute for Behavioral Genetics and at its predecessor laboratory at the University of California, Berkeley. Tolerance is, of course, a complex concept. Theoretical distinctions are made between tachyphylaxis and more slowly acquired tolerance and between dispositional and tissue tolerance. Pragmatically, a variety of measures (such as locomotor activity, sleep time, hypothermia) can be used to define these processes, and the different indices may yield quite different results even when they presumably indicate the same process. It is clear that an understanding of genetic influence in "ethanol tolerance" will require wide sampling of this complex domain. The work described here represents only a beginning, but it may illustrate the general approaches that are available for addressing the issue.

Alcohol Drinking↗
PubMedDate not supplied

Genes as gerontological variables: uniform genotypes.

Genetic conceptualizations and procedures have become integral to the conduct of research across the spectrum of life sciences, including gerontology, even when genetics is not the focus of inquiry. Among the research tools thus provided, one of the most basic is that of inbred strains. A close approximation to genetic uniformity is achieved by a sufficient number of successive generations of matings of relatives, and, once this near-uniformity is attained, the members of an inbred strain constitute a reference group relatively stable over time and available to diverse investigators. Different inbred strains possess different genotypes, so that numerous distinctive reference groups are available. The stability of these groups enhances prospects of replication-testing, and makes possible the focused accumulation of pertinent data. Phenotypic differences among strains identify particular groups that can be most appropriate for particular subsequent research objectives (and also provide ipso facto evidence of genetic influence on the phenotype). The very substantial advantages of the uniform genotypes provided by inbred strains (and by their F1 offspring) are purchased at the cost of limited generalizability of results and constraints on assessment of co-variation among variables. Uniform genotypes are, thus, not a tool for all purposes but must be seen as a powerful basic tool within an abundant genetic tool-kit. Particular research purposes will require use of more than one tool from the kit.

Aging↗
PubMedDate not supplied

Exotic mice as models for aging research: polemic and prospectus by R. Miller et al.

Miller and colleagues present a polemic against uniform genotypes in gerontological research and a paean for genetically heterogeneous populations. Both on simple sampling considerations, and because of selective loss of alleles through inbreeding depression, inbred strains are idiosyncratic, and the lack of genetic variance within strains limits their utility in examining relationships among phenotypes. Heterogeneous stocks, by contrast, are not impaired by inbreeding depression, and the presence of genetic and environmental variance provides for effective assessment of correlations among variables. Those assembled by intermating of inbred strains are replicable in terms of gene pool parameters, even if no individual can ever be replicated, and those derived from wild-trapping may include alleles absent for whatever reason from current laboratory strains. This author concurs that there are limitations on research with uniform genotypes and advantages of heterogeneous populations. However, for specific purposes, the uniformity and stability of inbred strains are extremely valuable attributes, and heterogeneous stocks have their own limitations. Researchers should select the animal model most appropriate for their specific purpose.

Aging↗
PubMedDate not supplied

Genes as gerontological variables: genetically heterogeneous stocks and complex systems.

In gerontological research utilizing animal models, a major general strategy has been the use of uniform genotypes of inbred strains or their F1 hybrids. These animal models provide standard reference groups that are of major importance in establishing a reliable data base on aging phenomena. There are limitations to their usage, however, particularly in respect to descriptions or evaluations of variances or of covariance relationships. For these purposes, genetically heterogeneous stocks have the advantage that phenotypic variance (and covariance) has a genetic as well as an environmental component. The advantages of genetic heterogeneity are best realized when the stock has been systematically derived (usually by intercrossing of inbred strains) and maintained by a mating scheme of sufficient size to minimize inbreeding. Genetically heterogeneous stocks are of particularly high potential value in the study of complex systems. Some examples of their use in a gerontological context are provided.

Aging↗
PubMedDate not supplied

Biogerontologic theories.

Theories of age and aging engage a wide variety of phenomena and levels of explanation. There is a general consensus that aging is a complex process or set of processes, involving many "causal" inputs and manifold consequences. Two general theoretical orientations that explicitly address complexity are sketched here-the differential theory of quantitative genetics and systems theory. Among the suggestions derived are that it may be advantageous to consider aging to be hierarchically organized, with the corollary that subsystems of an organism can have different functional or biological ages, and that several or many indices will be required to provide an adequate characterization of a single individual. Aging probably proceeds by saltation rather than continuously. Uncertainty associated with bifurcations in complex systems, together with individual differences in timing and magnitude of step changes, may constitute fundamental limitations to the predictability across the full life trajectory. Genetic and environmental influences will differ from hierarchical subsystem to subsystem, and may differ within a subsystem across chronological age.

Aging↗
PubMedDate not supplied

Prospects for quantitative trait locus methodology in gerontology.

The remarkable advances in mapping of genomes have made it feasible to search among the hitherto anonymous polygenes of complex systems for loci of intermediate effect size (quantitative trait loci-QTL). Pursuing the strategy of identifying these QTL in complex systems will open the possibility of exploring the genetic architecture and the anatomical, physiological, biochemical, and molecular mechanisms underlying the phenotypes under investigation. One study (Gelman et al., 1988) has pioneered the exploration of QTL in the study of aging. Their engaging results, dealing with age at death as the endpoint measure, portend the power of the search for quantitative trait loci in aging processes.

Aging↗
PubMedDate not supplied

Biomarkers of age and aging.

The escalating interest in research on interventions that may affect aging processes has necessarily focussed attention on the outcome measures. The desirable characteristics of these "biomarker variables" have been widely discussed. This article offers some reflections on validity, reliability, and generalizability of biomarkers. It is argued that our comprehension of aging will evolve iteratively from application of a diversity of biomarker variables. Each of these will have strengths and shortcomings from methodological and measurement points of view. The siren song that a "gold standard" index of aging can be found should be ignored.

Aging↗
PubMedDate not supplied

Genotypic selection provides experimental confirmation for an alcohol consumption quantitative trait locus in mouse.

Quantitative genetic research has produced a wealth of basic information concerning genetic influence on alcohol-related processes. Recent developments in quantitative trait locus (QTL) methodology were promptly applied to the task of individuating polygenes affecting alcohol-related attributes in animal models and a body of reliable data is gradually coming into focus as a result of replication and convergence of evidence from a variety of methods. A key issue in QTL research is the need to distinguish true positive results from the false positive results that are inherent in analytical procedures requiring large numbers of significance tests. One school of thought holds that stringent significance levels should be imposed; another suggests more modest criteria for QTL nomination, with subsequent confirmation trials with independent samples. Recombinant inbred strains and various types of intercrosses have been used in correlational designs, both for nomination and confirmation studies. Alternative experimental procedures include knockout preparations and short-term phenotypic selective breeding. We present here results from a third experimental method-that of marker-based genotypic selection--in evaluation of two nominated QTLs for alcohol acceptance in mice.

Alcohol Drinking↗
PubMedDate not supplied

Genetic and environmental influences for type A-like measures and related traits: a study of twins reared apart and twins reared together.

The relative influences of genetic and environmental factors for Type A-like behaviors and related traits were examined in the Swedish Adoption/Twin Study of Aging. The sample consisted of 99 pairs of monozygotic twins separated at an early age and reared apart, 229 pairs of dizygotic twins reared apart, 160 monozygotic pairs reared together, and 212 dizygotic pairs reared together. The average age of the Swedish Adoption/Twin Study of Aging twins at the time of data collection in 1984 was 58.6 (SD 13.6); 72% of the pairs were over 50 years of age and 60% were female. The Framingham Type A Scale, three descriptors of the Type A behavior pattern (pressure, hard-driving, and ambitious), and measures of hostility and lack of assertiveness were assessed in a mailout questionnaire. Heritability (the proportion of total variance due to genetic effects) was 27%, 28%, 43%, 37%, 20%, and 12%, respectively, for the six measures. The most conservative test of significance indicated significant genetic influence for all but the hostility and assertiveness scales. Sharing the same rearing environment was generally unimportant for twin similarity in the Type A behaviors later in life; however, 20% of the variation in the hostility and assertiveness measures could be attributed to shared family environment. Evidence for the effects of correlated post-rearing environments was found for hostility. Approximately 60% of the variation in each of the measures can be attributed to non-shared environmental experiences unique to the individual.

Arousal↗
PubMedDate not supplied

Effects of ethanol: II. Behavioral sensitivity and acute behavioral tolerance.

Two doses of ethyl alcohol were administered to 48 young male subjects (24 brother-pairs), and placebo doses were administered to five brother-pairs (controls). Dose 1 amount was calculated to result in a peak blood alcohol content (BAC) of 100 mg/100 ml; dose 2 was given when BAC had fallen to one-half the peak BAC resulting from dose 1, in an attempt to raise BAC back to 100 mg/100 ml. Prior to alcohol dosage, baseline measurements were made on a number of behavioral tests. Behavioral performances during metabolism of doses 1 and 2 were compared to baseline performance. Sensitivity to ethanol was indicated by performance decrements on nearly all tests after ethanol dosing. Acute behavioral tolerance to ethanol (ABTE) was indicated for some tests by improved performance after dose 2 compared to performance at a time after dose 1 when BACs were about equivalent. A preliminary search for possible genetic components of sensitivity and ABTE was undertaken by comparing the scores of the brothers.

Adolescent↗
PubMedDate not supplied

Effects of ethanol: I. Acute metabolic tolerance and ethnic differences.

Forty-five young men were given an initial dose of ethanol calculated to achieve a blood alcohol concentration (BAC) of 100 mg of ethanol/100 ml of blood. Using breath analysis, the rates of ethanol clearance were calculated over a period of a few hours. When each individual reached a BAC level exactly one-half (about 50 mg%) that seen at his peak BAC, he was given a second dose of ethanol amounting to 45% of his initial dose, and the clearance rate was again determined. Estimates of absorption time, peak BAC, volume of distribution, clearance rate, and other metabolic parameters were made separately following each dose of ethanol. As intended, there was no significant difference between peak 1 and peak 2; however, there was a significant increase in clearance rate (beta 60) after dose 2. We term this phenomenon acute metabolic tolerance to ethanol ( AMTE ). When the sample was stratified by ethnicity, there was a trend for men of Oriental ancestry to clear the drug at a faster rate than was the case for men of Caucasian or Polynesian ancestry. The data also indicated that prior drinking history may have had an effect on clearance rate, though this differed by ethnicity. Two different methods for estimating volume of distribution (V) were used. The correlation between the separate estimates obtained was poor, and is probably an indication of the need for development of more accurate methods for estimating V.

Adolescent↗