Seema S. Kengeri

Assessment of recreational physical activity during pregnancy in epidemiologic studies of birthweight and length of gestation: methodologic aspects.

ABSTRACT In 2002, the American College of Obstetricians and Gynecologists revised their 1994 guidelines to recommend that pregnant women without medical or obstetric complications follow exercise guidelines for nonpregnant women. In spite of these guidelines, the optimal dose of recreational physical activity (i.e., total volume of energy expenditure, and specific frequency, duration and intensity) for a pregnant woman remains to be determined. Identification of this dose has been hampered by the complexity of assessing recreational physical activity in general, and particularly during pregnancy, a demanding period characterized by changing physiology. Therefore, we reviewed the measurement methods in the epidemiologic studies that examined the association between recreational physical activity and two specific pregnancy outcomes of primary public health importance, birthweight and length of gestation. From a review of the medical literature, we identified 20 published journal articles between 1966 and 2005. Study designs, participants, and physical activity assessment measures varied widely across studies. The majority of these studies did not consistently assess type, frequency, intensity, and duration of activity and did not measure these variables during each trimester of pregnancy. Because the effect of recreational physical activity on birth outcomes is likely to be modest, measurement must be highly accurate to minimize the possibility that an effect will not be observed because of measurement error. Recommendations are made for the future assessment of recreational physical activity in epidemiologic studies of these major birth outcomes.

Defining the Optimal Selenium Dose for Prostate Cancer Risk Reduction: Insights from the U-Shaped Relationship between Selenium Status, DNA Damage, and Apoptosis

Our work in dogs has revealed a U-shaped dose response between selenium status and prostatic DNA damage that remarkably parallels the relationship between dietary selenium and prostate cancer risk in men, suggesting that more selenium is not necessarily better. Herein, we extend this canine work to show that the selenium dose that minimizes prostatic DNA damage also maximizes apoptosis—a cancer-suppressing death switch used by prostatic epithelial cells. These provocative findings suggest a new line of thinking about how selenium can reduce cancer risk. Mid-range selenium status (.67–.92 ppm in toenails) favors a process we call “homeostatic housecleaning”—an upregulated apoptosis that preferentially purges damaged prostatic cells. Also, the U-shaped relationship provides valuable insight into stratifying individuals as selenium-responsive or selenium-refractory, based upon the likelihood of reducing their cancer risk by additional selenium. By studying elderly dogs, the only non-human animal model of spontaneous prostate cancer, we have established a robust experimental approach bridging the gap between laboratory and human studies that can help to define the optimal doses of cancer preventives for large-scale human trials. Moreover, our observations bring much needed clarity to the null results of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) and set a new research priority: testing whether men with low, suboptimal selenium levels less than 0.8 ppm in toenails can achieve cancer risk reduction through daily supplementation.

Exploring mechanisms of sex differences in longevity: lifetime ovary exposure and exceptional longevity in dogs

To move closer to understanding the mechanistic underpinnings of sex differences in human longevity, we studied pet dogs to determine whether lifetime duration of ovary exposure was associated with exceptional longevity. This hypothesis was tested by collecting and analyzing lifetime medical histories, age at death, and cause of death for a cohort of canine ‘centenarians’– exceptionally long‐lived Rottweiler dogs that lived more than 30% longer than average life expectancy for the breed. Sex and lifetime ovary exposure in the oldest‐old Rottweilers (age at death, ≥ 13 years) were compared to a cohort of Rottweilers that had usual longevity (age at death, 8.0–10.8 years). Like women, female dogs were more likely than males to achieve exceptional longevity (OR, 95% CI = 2.0, 1.2–3.3; P = 0.006). However, removal of ovaries during the first 4 years of life erased the female survival advantage. In females, a strong positive association between ovaries and longevity persisted in multivariate analysis that considered other factors, such as height, body weight, and mother with exceptional longevity. A beneficial effect of ovaries on longevity in females could not be attributed to resistance against a particular disease or major cause of death. Our results document in dogs a female sex advantage for achieving exceptional longevity and show that lifetime ovary exposure, a factor not previously evaluated in women, is associated with exceptional longevity. This work introduces a conceptual framework for designing additional studies in pet dogs to define the ovary‐sensitive biological processes that promote healthy human longevity.

Noninvasive Prediction of Prostatic DNA Damage by Oxidative Stress Challenge of Peripheral Blood Lymphocytes

To move closer to the goal of individualized risk prediction for prostate cancer, we used an in vivo canine model to evaluate whether the susceptibility of peripheral blood lymphocytes (PBLs) to oxidative stress-induced DNA damage could identify those individuals with the highest prostatic DNA damage. This hypothesis was tested in a population of 69 elderly male beagle dogs after they had completed a 7-month randomized feeding trial to achieve the broad range of dietary selenium status observed in U.S. men. The alkaline Comet assay was used to directly compare the extent of DNA damage in PBLs with prostatic DNA damage in each dog. Using stepwise logistic regression, the sensitivity of PBLs to oxidative stress challenge with hydrogen peroxide (H2O2) predicted dogs in the highest tertile of prostatic DNA damage. Dogs with PBLs highly sensitive to H2O2 were 7.6 times [95% confidence interval (95% CI), 1.5-38.3] more likely to have high prostatic DNA damage than those in the H2O2-resistant group. This risk stratification was observed in multivariate analysis that considered other factors that might influence DNA damage, such as age, toenail selenium concentration, and serum testosterone concentration. Our data show that the sensitivity of PBLs to oxidative stress challenge, but not endogenous DNA damage in PBLs, provides a noninvasive surrogate marker for prostatic DNA damage. These findings lend support to the concept that oxidative stress contributes to genotoxic damage, and that oxidative stress challenge may stratify men for prostate cancer risk. (Cancer Epidemiol Biomarkers Prev 2007;16(9):1906–10)

Reevaluation of predictive factors for complete recovery in dogs with nonambulatory tetraparesis secondary to cervical disk herniation.

The vast majority of dogs with cervical disk herniation experience cervical pain and only mild motor deficits; therefore, not much is known about the factors that predict recovery in dogs with nonambulatory tetraparesis (NAT) secondary to cervical disk herniation. In this retrospective study, we tested the hypothesis that two previously reported prognostic factors, site of disk herniation and severity of neurological deficits, are useful predictors of complete recovery. Overall, 20 (62%) of 32 dogs with cervical disk herniation-associated NAT had complete recovery. Site of disk herniation was not a significant predictor of complete recovery; dogs with high cervical lesions (C2 to C3, C3 to C4) did not have a higher likelihood of complete recovery than other dogs. Likewise, severity of neurological deficits (i.e., intact voluntary motor function versus absent voluntary motor function) was not a significant predictor of complete recovery. Using stepwise logistic regression, two significant predictors of complete recovery were identified. Small dogs (delta15 kg body weight) were six times more likely to achieve complete recovery than larger dogs. Dogs that regained the ability to walk within 96 hours after surgery were seven times more likely to completely recover than dogs not walking 96 hours after surgery. We conclude that neither the site of disk herniation nor severity of neurological deficits assists the clinician in predicting postoperative outcome in dogs with cervical disk herniation-associated NAT. Reliable preoperative predictors of complete recovery are needed to advance current diagnostic and treatment protocols to improve overall prognosis.

Life course analysis of the impact of mammary cancer and pyometra on age-anchored life expectancy in female Rottweilers: Implications for envisioning ovary conservation as a strategy to promote healthy longevity in pet dogs

Mammary cancer and pyometra are important health hazards associated with ovary conservation in pet dogs. Early ovariohysterectomy may reduce the incidence of these two diseases, but an estimate of the extent to which the development of mammary cancer or pyometra adversely influences overall longevity is missing. As a first step toward addressing this knowledge gap, the results of a historical cohort study of Rottweilers that lived in North America are reported. Questionnaires completed by owners and veterinarians were used to obtain lifetime health and medical information on 242 female Rottweilers, including years of lifetime ovary exposure, age at death, and cause of death. To determine the extent to which longevity was shortened in females that developed these ovary-associated diseases, age-anchored life expectancy-defined as the median number of remaining years until death for females alive at specified ages during the life course-and years of life lost, a measure of premature mortality, were estimated. Mammary carcinoma was diagnosed in 19 (7.9%) females; median age at diagnosis was 8.5 years; case fatality was 37%. Pyometra was diagnosed in 16 (6.6%) females; median age at diagnosis was 5.4 years; case fatality was 7%. Median lifetime ovary exposure for the study population was 4.3 years. Although risk for developing both diseases increased with longer ovary exposure, longer ovary exposure (≥4.3 years) was also associated with an overall longevity advantage-a 33% decrease in mortality, living 17 months longer than females with shorter ovary exposure (P=0.002). Analysis of age-anchored life expectancy showed that at no time points during the life course was the current or future diagnosis of mammary carcinoma or pyometra associated with shortened survival compared to females who never developed these conditions. This lack of longevity disadvantage is an expected result for diseases with late-onset, moderate (<50%) case fatality (mammary carcinoma) or low (<10%) case fatality (pyometra). These findings fail to support the notion that a strategy, such as elective ovariohysterectomy, implemented to reduce the incidence of mammary carcinoma and pyometra will beneficially impact overall longevity. It follows that future efforts to find and implement effective longevity-promoting interventions should look beyond reducing the incidence of a particular disease to considering trade-offs.