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Biomedical subjects

J M Olson

Publications and source records attributed to J M Olson.

At least 73 records · Page 4Linked to original sources

Power output of scallop adductor muscle during contractions replicating the in vivo mechanical cycle.

Because measurements on isolated skeletal muscles are often made with limited knowledge of in vivo kinematics, predictions of mechanical performance during natural movements are subject to considerable uncertainties. We used information on the in vivo length cycle and phase of activation of the scallop adductor during swimming at 10 degrees C to design an in vitro contractile regime that replicated the natural cycle. Replicating the in vivo length cycle and stimulation regime resulted in power output during cyclic contractions that matched in vivo performance both qualitatively and quantitatively. When sinusoidal length changes were used instead of the natural length trajectory, the adductor muscle produced a similar average power output (approximately 30 W kg-1 at 1.9 Hz), but the distribution of power throughout the cycles was quite different. We examined the instantaneous force-velocity properties during cyclic contractions and found that the muscle operated on or near its isotonic force-velocity curve for only 30-40% of the time required for shortening. During sinusoidal length cycles, the force-velocity trajectory was quite different. We conclude that during cyclic contractions the isotonic force-velocity curve of skeletal muscle sets an approximate boundary to the force-velocity trajectory, but the shape of this trajectory, and thus the distribution of power output, depends on the pattern of length change.

Animals↗

Robust estimation of gene frequency and association parameters.

Methods based on generalized estimating equations are proposed for estimation and testing of gene frequency and association parameters using family data. In the problems considered, a marginal model is used to estimate the gene frequency and association parameters specified in the marginal distributions of the individuals. These procedures are robust in the sense that consistent estimates of the parameters of interest and their standard errors are obtained even though the marginal model is not fully correctly specified. In addition, the methods are shown to have good efficiency when compared with maximum likelihood methods. Specific procedures for application of the methods to the cases of allele frequency estimation, testing of linkage and Hardy-Weinberg disequilibrium parameters, and testing for marker-disease association are outlined and illustrated with data examples.

Alleles↗

Design and sample-size considerations in the detection of linkage disequilibrium with a disease locus.

The presence of linkage disequilibrium between closely linked loci can aid in the fine mapping of disease loci. We investigate the power of several designs for sampling individuals with different disease genotypes. As expected, haplotype data provide the greatest power for detecting disequilibrium, but, in the absence of parental information to resolve the phase of double heterozygotes, the most powerful design samples only individuals homozygous at the trait locus. For rare diseases, such a scheme is generally not feasible, and we also provide power and sample-size calculations for designs that sample heterozygotes. The results provide information useful in planning disequilibrium studies.

Chromosome Mapping↗

The apolipoprotein E/CI/CII gene cluster and late-onset Alzheimer disease.

The chromosome 19 apolipoprotein E/CI/CII gene cluster was examined for evidence of linkage to a familial Alzheimer disease (FAD) locus. The family groups studied were Volga German (VG), early-onset non-VG (ENVG; mean age at onset < 60 years), and late-onset families. A genetic association was observed between apolipoprotein E (ApoE) allele epsilon 4 and FAD in late-onset families; the epsilon 4 allele frequency was .51 in affected subjects, .37 in at-risk subjects, .11 in spouses, and .19 in unrelated controls. The differences between the epsilon 4 frequencies in affected subjects versus controls and in at-risk subjects versus controls were highly significant (standard normal deviate [ZSND]) = 7.37, P < 10(-9); and ZSND = 4.07, P < .00005, respectively). No association between the epsilon 4 allele and FAD was observed in the ENVG or VG groups. A statistically significant allelic association between epsilon 4 and AD was also observed in a group of unrelated subjects; the epsilon 4 frequency was .26 in affected subjects, versus .19 in controls (ZSND = 2.20, P < .03). Evidence of linkage of ApoE and ApoCII to FAD was examined by maximum-likelihood methods, using three models and assuming autosomal dominant inheritance: (1) age-dependent penetrance, (2) extremely low (1%) penetrance, and (3) age-dependent penetrance corrected for sporadic Alzheimer disease (AD). For ApoCII in late-onset families, results for close linkage were negative, and only small positive lod-score-statistic (Z) values were obtained (model 1, maximum Z[Zmax] = 0.61, recombination fraction [theta] = .30; model 2, Zmax = 0.47, theta = .20). For ApoE in late-onset kindreds, positive Z values were obtained when either allele frequencies from controls (model 1, Zmax = 2.02, theta = .15; model 2, Zmax = 3.42, theta = .05) or allele frequencies from the families (model 1, Zmax = 1.43, theta = .15; model 2, Zmax = 1.70, theta = .05) were used. When linkage disequilibrium was incorporated into the analysis, the Z values increased (model 1, Zmax = 3.17, theta = .23; model 3, Zmax = 1.85, theta = .20). For the ENVG group, results for ApoE and ApoCII were uniformly negative. Affected-pedigree-member analysis gave significant results for the late-onset kindreds, for ApoE (ZSND = 3.003, P = .003) and ApoCII (ZSND = 2.319, P = .016), when control allele frequencies were used but not when allele frequencies were derived from the families.

Adult↗

Cancer in twins of Wilms tumor patients.

We interviewed families of 71 patients registered in the National Wilms Tumor Study and identified as having a twin sibling. Questions concerning zygosity and the occurrence of congenital anomalies and other forms of cancer in the twins were asked. Of the 71 twin pairs, 35 were dizygotic, 31 were monozygotic, and 5 were of unknown zygosity. The only pair concordant for Wilms tumor was dizygotic, leading to a heritability estimate of zero. In a monozygotic pair, one twin was diagnosed with Wilms tumor and the other with medulloblastoma. The estimated relative risk of Wilms tumor and childhood cancer in the co-twin was 250 times and 10 times the population rate, respectively. Four discordant pairs had a family history of Wilms tumor, suggesting that the penetrance of the condition is not complete. Because of the small sample size, caution should be exercised in the interpretation of these results.

Beckwith-Wiedemann Syndrome↗

Linkage between quantitative trait and marker loci: methods using all relative pairs.

Relative-pair methods for detection of linkage between a quantitative trait and a marker locus have been proposed by a number of authors [e.g., Haseman and Elston, Behav Genet 3-19, 1972; Amos and Elston, Genet Epidemiol 349-360, 1989]. However, development of tests of significance that combine information from different types of relative pairs has been hampered by the presence of correlations between relative pairs from the same pedigree. In this paper, the methodology of generalized estimating equations is used to provide an estimate of the robust covariance matrix of the estimates of the set of relative-pair-type-specific regression parameters. Using this matrix, an asymptotically most powerful test of linkage which optimally combines the information contained in the different types of relative pairs is constructed. This test requires optimal weights that depend on unknown values of heritability and recombination fraction to be chosen a priori. However, simulations show that, in the regions of recombination fraction and heritability of practical interest, the power of the test does not depend strongly on the assumptions made when choosing the optimal weights; as a result, weights that depend only on the number of each type of relative pair and the variability of the marker identity-by-descent probabilities work well in practice. In addition, an approximation to the regression model leads to a simple approach to testing linkage in which only a single regression parameter is estimated from data containing different types of relative pairs. The resulting test is slightly less powerful than the test described above, but its computational simplicity and lack of dependence on a priori weighting schemes suggest potential usefulness in large linkage studies.

Epidemiologic Methods↗

Linkage analysis of Alzheimer's disease with methods using relative pairs.

Four relative-pair methods for detecting genetic linkage were applied to familial Alzheimer's disease data. Results obtained using an extended Haseman-Elston test and a weighted rank pairwise correlation test, which both use information from all relative pairs, were consistent with previously published likelihood results and appear to be more powerful than affected sib pair methods.

Alzheimer Disease↗

Diabetes increases excretion of urinary malonaldehyde conjugates in rats.

The effect of streptozotocin-induced diabetes on the urinary excretion of thiobarbituric acid test-positive materials was examined. In diabetic rats, urinary excretion of thiobarbituric acid reactive substances was increased 5-fold over that in nondiabetic animals. High-performance liquid chromatography of urine samples revealed that five of the six fractions previously found to be increased in vitamin E deficiency [Lee, H.-S., Shoeman, D.W., and Csallany, A.S. (1992) Lipids 27, 124-128] were also significantly increased in streptozotocin-induced diabetes. The data suggest that a high level of oxidative stress is induced by uncontrolled diabetes in rats.

Animals↗

Self-esteem and counterfactual thinking.

Two studies examined the relation between self-esteem and counterfactual thinking (consideration of "might-have-been" alternatives to reality). Ss imagined themselves in scenarios with another actor that resulted in either success or failure. Ss then "undid" the outcome by altering events that preceded the outcome. Following success, high self-esteem (HSE) Ss were more likely than low self-esteem (LSE) Ss to mutate their own actions. Following failure, LSE Ss were more likely than HSE Ss to mutate their own actions. Also, the structure of counterfactuals was influenced by outcome valence but not by self-esteem: Subtractive structures (in which antecedents are removed) were elicited by success, whereas additive structures (in which antecedents are added) were elicited by failure. The importance of the self and individual differences in self-esteem to counterfactual thinking is discussed.

Adult↗

Wilms' tumour and parental age: a report from the National Wilms' Tumour Study.

Age distributions of parents at birth of patients registered in the National Wilms' Tumour Study were compared to those of the general population. An increasing incidence of sporadic Wilms' tumour with increasing paternal age was found, with a relative risk of 2.1 of tumour in children of fathers over 55 compared to children of fathers younger than 20. A similar effect for maternal age was found, with a relative risk of 1.4 in children of mothers over 40 compared to children of mothers younger than 20. The maternal age effect was much weaker among patients registered later in the study; in the later, more completely ascertained cohort, paternal age appears to be the major contributor to the parental age effect. Little difference in paternal age distribution was found between patients with bilateral and unilateral tumour and between male and female patients. In contrast, patients with reported associated congenital anomalies, patients with evidence of nephrogenic rests, and patients with early or late age-of-onset of tumour had parents who were, on average, substantially older than the remainder. These findings lend support to the idea that many Wilms' tumours result from new germline mutations. Further, the histologic composition of such tumours may be sufficiently distinct as to provide a valuable diagnostic indicator of the etiology of these tumours.

Adult↗

Testing the Hardy-Weinberg law across strata.

The problem of testing the Hardy-Weinberg law when data are sampled from several populations with different allele frequencies is considered. An odds-ratio representation of disequilibrium is proposed. This ratio is assumed to be constant across strata, an assumption that seems more reasonable than that of previous authors of a constant difference in true and expected (under equilibrium) heterozygote proportions. A score-type test which optimally combines information from the separate strata is then derived using the theory of unbiased estimating equations. Simulations show that the new test has greater power than previously proposed tests when the disequilibrium ratio is constant across strata. The method is applied to glyoxalase genotype data from populations in India.

Alleles↗

Contractile properties of the striated adductor muscle in the bay scallop Argopecten irradians at several temperatures.

The isometric and isotonic contractile properties of the cross-striated adductor muscle of the bay scallop (Argopecten irradians) were measured in vitro at 10, 15 and 20 degrees C. The length at which twitch force was maximal as a function of the closed length in situ (L0/Lcl) averaged 1.38 +/- 0.01 (mean +/- S.E.M.) at 10 degrees C. This length is very close to the typical length at maximum gape during natural swimming at this temperature. Passive force was very low over the range of lengths measured here; at L0, passive force averaged approximately 0.08 N cm-2, or only 0.5% of the corresponding peak twitch force. The mean peak isometric twitch force (Ptw,max) at 10 degrees C was 21.43 +/- 0.68 N cm-2 (S.E.M.), and the ratio of peak twitch force to tetanic force (Ptw,max/P0) averaged 0.89 +/- 0.01. Temperature did not affect either twitch force (Ptw), once fatigue was taken into account, or Ptw,max/P0. In contrast, the time-related properties of twitch contractions (latent period, tL; time to peak tension, tPtw; and time from peak tension to half-relaxation, t50%R) were positively modified by temperature at all temperatures measured (Q10 > 1.8). All three properties were more temperature-sensitive over the range 10-15 degrees C than over the range 15-20 degrees C. The force-velocity relationships of the striated adductor muscle were fitted to the hyperbolic-linear (HYP-LIN) equation. The force-velocity curves of the striated adductor muscle of the scallop were strongly influenced by temperature. Maximal velocity at zero force (Vmax), and therefore maximal power output, increased significantly with temperature. The Q10 over the temperature range 10-15 degrees C (1.42) was significantly lower than that over the range 15-20 degrees C (2.41). The shape of the force-velocity relationship, assessed through comparisons of the power ratio (Wmax/VmaxP0), was not influenced by temperature.

Animals↗

Mechanical performance of scallop adductor muscle during swimming.

Mechanical performance of skeletal muscle has long been the subject of intense interest, but the details of in vivo performance of individual skeletal muscles during normal locomotion remain largely unknown. Performance in vitro has been described with considerable precision under simplified loading conditions. The force production and shortening velocity of most muscles, however, probably change continuously during natural movements. Therefore, modelling in vivo performance on the basis of in vitro contractile properties is subject to large degrees of uncertainty. Designing in vitro experiments that effectively examine the limits of mechanical performance requires increasing knowledge of precisely how muscles are used during normal movements. We report here measurements of the mechanical performance of the adductor muscle in scallops during jet-propulsion swimming. Swimming in scallops is powered solely by the striated portion of the single adductor muscle. Exploiting this simple locomotor morphology with simultaneous high-resolution measurements of pressure and flow rate, we have recorded nearly instantaneous measurements of the performance of a single skeletal muscle during normal locomotion.

Animals↗

Localization of the peripheral-type benzodiazepine binding site to mitochondria of human glioma cells.

Subcellular fractionation was performed on human U251 glioblastoma cultures. In all subcellular fractions, the binding of the peripheral benzodiazepine ligand, [3H]PK 11195, correlated with the specific activity of monoamine oxidase (r = 0.95, p less than 0.001) and succinate dehydrogenase (r = 0.93, p less than 0.001), two mitochondrial enzymes. The specific activity of plasma membrane and nuclear markers correlated poorly with the presence of PK 11195 binding sites. These data support the mitochondrion as the primary location of peripheral-type benzodiazepine binding sites (PBBS) in human glioma cells. Mitochondria-rich preparations were then assayed for [3H]Ro5-4964 binding. Six nM [3H]Ro5-4964 failed to specifically bind to human U251 mitochondria, but bound vigorously to mitochondria from rat C6 glioma. These data indicate that the low affinity of Ro5-4864 for PBBS in human glioma cells compared to those in rat is due to interspecies receptor variation rather than impaired drug transport into human cells.

Alkaline Phosphatase↗

Dietary guar gum halts further renal enlargement in rats with established diabetes.

Guar gum, a dietary fiber known to improve glucose tolerance, was fed to rats with established diabetes to determine its effect on renal enlargement and microalbuminuria. Diabetic rats were fed a modified AIN-76A (basal) diet for 4 wk, at which time half the rats continued to receive the same basal diet (DB-BA group) and half were switched to a 5% guar gum diet (DB-GG group). Nondiabetic rats fed the basal diet served as controls (NRL group). After 8 additional weeks the animals were killed. Glycated hemoglobin, a measure of long-term blood glucose control, was 14.4% in the DB-BA group and 12.4% in the DB-GG group, a statistically significant difference (P < 0.05). Kidney weight of the DB-BA group (3.51 g) was significantly greater than that of the DB-GG group (2.76 g) (P < 0.05). Eight weeks after induction of diabetes, 24-h urinary albumin excretion was highest in the DB-BA group and lowest in the NRL group; excretion in the DB-GG group (4 wk of guar feeding) was intermediate. However, by 12 wk no differences in albumin excretion among the groups were apparent. These results suggest that guar gum may be useful for slowing the progression of diabetic nephropathy and that guar gum deserves further study in this regard.

Albuminuria↗

The amino acid sequence of a major protein component in the light harvesting complex of the green photosynthetic bacterium Chlorobium limicola f. thiosulfatophilum.

A 7.5-kDa protein has been isolated from chlorosomes of Chlorobium limicola f. thiosulfatophilum and the complete primary structure determined by a combination of automatic Edman degradation and plasma desorption mass spectrometry. The 74-residue protein shows great homology to a similar protein of unknown function which has been isolated from Pelodictyon luteolum but otherwise no significant homology to other proteins can be found. The possible role of the protein in the structure and function of the chlorosome is discussed.

Amino Acid Sequence↗

Regulation of glycolysis in the pectoralis muscles of seasonally acclimatized American goldfinches exposed to cold.

Regulation of glycolysis was assessed in winter- and summer-acclimatized goldfinches (Carduelis tristis). We exposed birds to a thermo-neutral temperature (30 degrees C), moderate cold (-15 degrees C), and severe cold (0 degrees C in an atmosphere of 21% O2-79% He), and then measured concentrations of glycogen, glycolytic intermediates, and citrate in the pectoralis muscles. Winter birds used less glycogen when exposed to moderate cold than did summer birds, confirming the carbohydrate sparing noted by Marsh and Dawson [Am. J. Physiol. 242 (Regulatory Integrative Comp. Physiol. 11): R563-R569, 1982]. However, depletion of muscle glycogen did not correlate with thermoregulatory failure in this study. Concentrations of glucose 6-phosphate and fructose 6-phosphate in the pectoralis muscles were approximately 1.9 and 0.3 mumol/g wet mass in birds exposed to thermoneutral temperatures. The levels of these intermediates fell 50-70% under conditions known to enhance flux through glycolysis as indicated by increased glucose turnover and glycogen depletion. This information identifies phosphofructokinase (PFK) as a major regulated step in glycolysis in these highly aerobic skeletal muscles. Winter birds maintained the inhibition of this step under conditions of moderate cold. However, concentrations of citrate, which have been hypothesized to be an important inhibitor of PFK, did not correlate with the observed pattern of inhibition. Therefore, if the enhanced beta-oxidative capacity of winter birds is important in the regulation of glycolysis, a mechanism other than the accumulation of citrate may be involved.

Acclimatization↗

Monte Carlo comparison of preliminary methods for ordering multiple genetic loci.

We carried out a simulation study to compare the power of eight methods for preliminary ordering of multiple genetic loci. Using linkage groups of six loci and a simple pedigree structure, we considered the effects on method performance of locus informativity, interlocus spacing, total distance along the chromosome, and sample size. Method performance was assessed using the mean rank of the true order, the proportion of replicates in which the true order was the best order, and the number of orders that needed to be considered for subsequent multipoint linkage analysis in order to include the true order with high probability. A new method which maximizes the sum of adjacent two-point maximum lod scores divided by the equivalent number of informative meioses and the previously described method which minimizes the sum of adjacent recombination fraction estimates were found to be the best overall locus-ordering methods for the situations considered, although several other methods also performed well.

Chromosome Mapping↗