Cyclooxygenase-2 expression is associated with histologic tumor type in canine mammary carcinoma.

Cyclooxygenase-2 (COX-2) is an inducible member of the family of cyclooxygenase enzymes that has been implicated in the genesis of numerous cancers. The role of COX-2 in canine mammary neoplasia remains to be more clearly elucidated. The goal of the study reported here was to determine whether a direct association between levels of COX-2 expression and tumor histologic subtype exists in canine mammary carcinoma. Immunohistochemical analysis was performed using a polyclonal antiprostaglandin G/H synthase 2 IgG COX-2 antibody. Sections from the kidneys of young dogs, which stain positive for COX-2 in the macula densa, served as positive controls. Slides were reviewed by a single pathologist, and were evaluated for COX-2 expression according to previously established scales. Positive-staining tumors were given a COX-2 staining distribution (on the basis of the percentage of positive staining cells in five 400x fields) and intensity score according to previously established scales. The product of the COX-2 staining distribution and intensity scores was calculated to create a COX-2 staining index. COX-2 expression was detected in 28 of 50 (56%) samples evaluated. Anaplastic carcinomas had a significantly higher COX-2 staining distribution, intensity, and index, compared with those for adenocarcinomas (P < 0.0001). The overall percentage of positive tumors (56%) was consistent with that of prior studies. To the authors' knowledge, these results indicate, for the first time, a direct association between COX-2 expression and tumor histologic subtype in canine mammary carcinomas. Future research directed at measuring tumor response in canine mammary carcinoma patients treated with a selective COX-2 inhibitor is indicated.

Assessment of cyclooxygenase-2 expression in canine hemangiosarcoma, histiocytic sarcoma, and mast cell tumor.

To determine whether cyclooxygenase-2 (COX-2) is expressed in canine hemangiosarcoma (HSA), histiocytic sarcoma (HS), and grade-II mast cell tumor (MCT), we performed immunohistochemistry using COX-2 antibodies in the aforementioned tumors. Twenty cases of each tumor type were selected initially from the Laboratory of Pathology archives of cases submitted through the Matthew J. Ryan Veterinary Hospital of the University of Pennsylvania. Immunohistochemistry was performed, using a polyclonal antiprostaglandin endoperoxide synthase immunoglobulin G COX-2 antibody. Sections from the kidneys of young dogs, in which the macula densa stains positive for COX-2, served as positive controls. Slides were reviewed by a single pathologist (M. H. Goldschmidt) and graded for COX-2 expression according to previously established scales. Descriptive data is given for each tumor type. COX-2 expression was identified in 0 of 19 HSA, 1 of 20 HS, and 1 of 17 grade-II MCT. Although COX-2 has been shown to be overexpressed in selected human sarcomas and hematopoeitic tumors, these results indicate that canine HSA, HS, and MCT do not express COX-2 in any appreciable fashion.

Changes in rates of beta-blocker use between 1994 and 1997 among elderly survivors of acute myocardial infarction.

BACKGROUND: Results of recent studies suggest that beta-blockers are underused by elderly acute myocardial infarction (AMI) survivors. The goals of this study were to examine changes in post-AMI beta-blocker use occurring between 1994 and 1997 and to identify factors associated with outpatient use of beta-blockers. METHODS: Patients included 9534 individuals >/=65 years of age who were enrolled in Pennsylvania's Pharmaceutical Assistance Contract for the Elderly (PACE) and who survived AMI between 1994 and 1997. With the use of outpatient prescription claims, beta-blocker usage rates were examined by year, and multivariate logistic regression was used to identify predictors of beta-blocker use. RESULTS: Post-AMI beta-blocker use increased from 39.6% in 1994 to 58.6% in 1997. Controlling for AMI year, individuals who had any prescriptions written by a cardiologist were more likely to use a beta-blocker than individuals who received all prescriptions from noncardiologists (odds ratio 1.52, P =.0001). Elderly patients who did not use beta-blockers tended to have greater severity of illness, non-Q-wave infarctions, atrial fibrillation, and comorbidities such as congestive heart failure, chronic obstructive pulmonary disease, and asthma. Use of calcium channel blockers and diuretics was negatively associated with beta-blocker use, but persons using lipid-lowering agents were more likely to use beta-blockers. CONCLUSIONS: Significant improvements in beta-blocker use by elderly AMI survivors have occurred since 1994. Differences among physician specialties in beta-blocker prescribing appear to remain. Across all prescriber specialties, historic contraindications constitute major factors in the choice of post-AMI therapy. Further efforts should be made to encourage the use of beta-blockers in elderly survivors of AMI, particularly those with heart failure.

Mortality and biomarkers of aging in heterogeneous stock (HS) mice.

A longitudinal study was undertaken to evaluate the relationships among a battery of aging biomarkers and subsequent survival time in 319 genetically heterogenous stock (HS) mice. The biomarker variables chosen were selected from the broad domains of behavior, homeostatic physiology, oxidative defense, and immune function; biomarkers were measured at 45, 90, 360, 630, and 900 days of age. Sex differences were found in the survivor and mortality functions, with a mortality rate crossover occurring at about 525 days and a survival curve crossover at about 750 days of age. Females experienced lower initial mortality but had more sharply increasing mortality with age than did males. Survival analysis using Gompertz parametric models with biomarkers as time-varying covariates yielded significant biomarkers from each domain. Following backward elimination procedures, the final set of independent mortality predictors included headpokes in the File activity apparatus, maximum cord drop time, weight, hematocrit, urine concentration, natural killer cell activity, and concanavalin A response.

Potential environmental effects on adult lipoprotein(a) levels: results from Swedish twins.

Two hundred and ninety four pairs of Swedish twins reared apart and twins reared together were used to evaluate the importance of genetic and environmental influences on lipoprotein(a) (Lp(a)) levels. Lp(a) levels ranged from <10 mg/l to 926 mg/l with 7.9% of the sample having undetectable Lp(a) levels (i.e. <10 mg/l). A substantial genetic component in Lp(a) variation was indicated by a heritability estimate of approximately 90%. No difference in heritability was found across age groups. Quantitative genetic analyses also suggest correlated environmental effects most likely composed of maternal, neonatal and postnatal environmental influences. However, these effects did not reach statistical significance, partly due to a lack of power. Results from analyses of co-twin differences in Lp(a) levels for monozygotic twins indicate that sex hormone use may be of importance for Lp(a) variation in women. There was no evidence of potential influences of alcohol consumption, beta-blocker and diuretic administration on Lp(a) levels in either men or women.

Genetic and environmental influences on blood pressure in elderly twins.

We used 289 pairs of Swedish twins reared apart or together to evaluate the importance of genetic and environmental influences on blood pressure. Unlike other twin and family studies, the adoption/twin design allows a distinction between estimates of the importance of shared rearing environments and genetic effects. Genetic factors were observed to play an important role for individual differences in blood pressure. Model-fitting analyses suggested upper limits of heritability for systolic and diastolic blood pressures in the entire sample of 0.44 and 0.34, respectively. More interestingly, substantial influences of shared family effects accounting for up to 27% of the variation were also revealed. Effects of correlated environment, which might reflect, for example, the intrauterine environment, existed to some extent later in life. The influence of genetic factors tended to decrease across age groups for systolic blood pressure (0.62 in individuals less than 65 years old; 0.12 in those 65 years and older) but not for diastolic blood pressure (0.22 for the middle-aged group; 0.26 for the older group). However, this declining trend for systolic blood pressure did not reach significance (chi 2 = 8.07, df = 4, P = .09).

Genetic and environmental correlations among serum lipids and apolipoproteins in elderly twins reared together and apart.

Genetic and environmental correlations among five serum-lipid measures were examined in the Swedish Adoption/Twin Study of Aging. The sample included 302 twin pairs; 146 of these twin pairs were separated at an early age and were reared apart. The lipid measures examined include total cholesterol, HDL-cholesterol, triglycerides, and apolipoproteins A-I and B. Genetic and environmental correlations were evaluated for two different age groups, formed by dividing the sample at the median. The younger group included individuals 41.8-65.4 years of age at the midpoint of testing, although only 24 individuals were < 50 years of age. The older group included all those > 65.4 years of age, up to age 87 years of age. Substantial genetic correlations were found within each age group, although there is no evidence for a single genetic factor common to all five lipids. The comparison of twins reared together with twins reared apart allowed estimation of the effects of shared rearing environment; however, shared rearing environment only appears to be a significant mediator of the phenotypic correlation between apolipoprotein B and cholesterol in the older group. Examination of the genetic and environmental covariances suggests that the relative contributions of genetic factors are lower in the older group. Nonshared environmental factors are relatively more important mediators of phenotypic correlations among the serum lipids in individuals > 65.4 years of age than they are for the younger group. Sex differences in the mediation of these serum lipids were not as clear.

Genetic and environmental influences on pulmonary function in aging Swedish twins.

BACKGROUND: In addition to their value in assessing pulmonary health and disease, spirometric variables have been shown to be powerful predictors of time until death in aging populations. The sources of variability in these spirometric values are consequently of relevance to basic gerontological research, and also of potential value in clinical application. The objective of this study was to estimate genetic and environmental sources of variance in pulmonary function. METHODS: The study involved 230 Swedish twin pairs (mean age = 64.9 years), of which number 37 monozygotic (MZ) pairs and 72 dizygotic (DZ) pairs had been separated and reared apart. Comparing these groups to the 57 MZ and 64 DZ pairs reared together permits stronger interpretation than that of conventional twin studies. Measures of vital capacity (VC) and forced expiratory volume in one second (FEV1) were residualized for height, age, sex, and tobacco consumption in pack-years. RESULTS: Maximum likelihood analyses of VC and FEV1 gave heritability estimates of .48 and .67, respectively. Age effects were explored both by dividing the sample into two cohorts, respectively above and below 65 years, and by moving interval analysis. In the two-cohort analysis, heritabilities were somewhat higher for the older cohort than the younger cohort for FEV1. The opposite was true for VC: heritability was lower in the older cohort, and there was evidence for a shared rearing environmental effect for this group. Moving interval analysis suggests these differences are gradual rather than saltatory. There were no gender differences in parameter estimates. CONCLUSION: Genetic factors account for between one-half and two-thirds of the variability in pulmonary function. There is a suggestion of age differences in the relative importance of genetic and environmental influences.

Genetic and environmental influences on serum lipid levels in twins.

BACKGROUND: The extent to which serum lipid levels are affected by genetic and environmental factors remains a point of controversy. We examined both genetic and environmental influences on serum lipid levels in twins reared either together or apart who participated in the Swedish Adoption/Twin Study of Aging. METHODS: We studied 302 pairs of twins (mean age, 65.6 years; range, 52 to 86); 146 pairs had been reared apart. We simultaneously compared the twins on the basis of both zygosity and rearing status, which allowed joint estimation of genetic and environmental influences on serum lipid levels. Genetic influence was expressed in terms of heritability, the proportion of the population variation attributable to genetic variation (a value of 1.0 indicates that all of the population variation is attributable to genetic variation). The serum lipids and apolipoproteins measured included total cholesterol, high-density lipoprotein cholesterol, apolipoproteins A-I and B, and triglycerides. RESULTS: Structural-equation analyses revealed substantial heritability for the serum levels of each lipid measured, ranging from 0.28 to 0.78. Comparisons of the twins reared together with those reared apart suggested that the environment of rearing had a substantial impact on the level of total cholesterol (accounting for 0.15 to 0.36 of the total variance). Sharing the same environment appeared to affect the other lipid measures much less, however, than did genetic factors and unique environmental factors not shared by twins. Comparisons of younger with older twins suggested that heritability for apolipoprotein B and triglyceride levels decreased with age. CONCLUSIONS: The effect of genetic factors on the serum levels of some but not all lipids appears to decrease with age. Early rearing environment appears to remain an important factor in relation to levels of total cholesterol later in life, but it has less effect on other serum lipids and apolipoproteins in the elderly.

A longitudinal genetic study of tail tendon fibre break time.

Tail tendon fibre break time (TTFBT), an indicator of collagen cross-linkage, was measured longitudinally in C57BL/6, DBA/2 and B6D2F1 mice, and F2 and backcross genotypes. TTFBT was assessed at 50, 150, 300 and 450 days of age. The distribution of means of these six genotypes suggests substantial genetic influence on this phenotype. Broad sense heritability, as assessed in a classical biometrical analysis, was negligible at 50 and 150 days, but accounted for between 25 and 43% of the variance at 300 to 450 days. The stability and reliability of TTFBT were also examined. Reliability was extremely high for each occasion; stability increased from moderate to substantial levels with increasing age, and may be influenced by heterozygosity.

Individual variability in tail tendon fiber break time in three age cohorts of different strains of mice.

Individual variability in mouse tail tendon fiber denaturation in urea was investigated. Differences in break time between fibers within tendons and between tendon groups were examined. Mean break times for each strain increased with age with the shorter-lived DBA/2 mice exhibiting higher break times within age cohorts than the C57BL/6 animals. Fibers from the two ventral tendon groups had consistently higher break times than those from the two dorsal groups, implying differential rates of collagen maturation between these two areas within the tail. Histological examination revealed conspicuous morphological dorsal/ventral differences in tendon number, proximity to a major blood vessel, and the amount of surrounding muscle tissue. These findings have methodological and experimental design implications for the use of tail tendon break time (TTBT) as a biomarker of aging. Furthermore, they suggest possible physiological mechanisms for differential rates of collagen aging.