Feasibility of collecting tumor samples of breast cancer patients diagnosed up to 50 years ago in the Child Health and Development Studies.

Environmental exposures during pregnancy may increase breast cancer risk for mothers and female offspring. Tumor tissue assays may provide insight regarding the mechanisms. This study assessed the feasibility of obtaining tumor samples and pathology reports from mothers (F0) who were enrolled in the Child Health and Development Studies during pregnancy from 1959 to 1967 and their daughters (F1) who developed breast cancer over more than 50 years of follow-up. Breast cancer cases were identified through linkage to the California Cancer Registry and self-report. Written consent was obtained from 116 F0 and 95 F1 breast cancer survivors to access their pathology reports and tumor blocks. Of those contacted, 62% consented, 13% refused and 24% did not respond. We obtained tissue samples for 57% and pathology reports for 75%, and if diagnosis was made ⩽10 years we obtained tissue samples and pathology reports for 91% and 79%, respectively. Obtaining pathology reports and tumor tissues of two generations is feasible and will support investigation of the relationship between early-life exposures and molecular tumor markers. However, we found that more recent diagnosis increased the accessibility of tumor tissue. We recommend that cohorts request consent for obtaining future tumor tissues at study enrollment and implement real-time tissue collection to enhance success of collecting tumor samples and data.

Maternal weight gain in excess of pregnancy guidelines is related to daughters being overweight 40 years later.

BACKGROUND: Exceeding the Institute of Medicine guidelines for pregnancy weight gain increases childhood and adolescent obesity. However, it is unknown if these effects extend to midlife. OBJECTIVE: We sought to determine if exceeding the Institute of Medicine guidelines for pregnancy weight gain increases risk of overweight/obesity in daughters 40 years later. STUDY DESIGN: This cohort study is based on adult offspring in the Child Health and Development Studies and the Collaborative Perinatal Project pregnancy cohorts originally enrolled in the 1960s. In 2005 through 2008, 1035 daughters in their 40s were recruited to the Early Determinants of Mammographic Density study. We classified maternal pregnancy weight gain as greater than vs less than or equal to the 2009 clinical guidelines. We used logistic regression to compare the odds ratios of daughters being overweight/obese (body mass index [BMI] ≥25) at a mean age of 44 years between mothers who did not gain or gained more than pregnancy weight gain guidelines, accounting for maternal prepregnant BMI, and daughter body size at birth and childhood. We also examined potential family related confounding through a comparison of sisters using generalized estimating equations, clustered on sibling units and adjusted for maternal age and race. RESULTS: Mothers who exceeded guidelines for weight gain in pregnancy were more likely to have daughters who were overweight/obese in their 40s (odds ratio [OR], 3.4; 95% confidence interval {CI}, 2.0-5.7). This magnitude of association translates to a relative risk (RR) increase of 50% (RR = 1.5; 95% CI, 1.3-1.6). The association was of the same magnitude when examining only the siblings whose mother exceeded guidelines in 1 pregnancy and did not exceed the guidelines in the other pregnancy. The association was stronger with increasing maternal prepregnancy BMI (P trend < .001). Compared to mothers with BMI <25 who did not exceed guidelines, the relative risks (RR) for having an overweight/obese adult daughter were 1.3 (95% CI, 1.1-1.7), 1.7 (95% CI, 1.4-2.1) and 1.8 (95% CI, 1.5-2.1), respectively, if mothers exceeded guidelines and their prepregnancy BMI was <25, overweight (BMI 25-<30), or obese (BMI >30). This pattern held irrespective of daughters' weight status at birth, at age 4 years, or at age 20 years. CONCLUSION: Our findings support that obesity prevention before pregnancy and strategies to maintain weight gain during pregnancy within the IOM guidelines might reduce the risk of being overweight in midlife for the offspring.

Exploring the high-dimensional structure of muscle redundancy via subject-specific and generic musculoskeletal models.

Subject-specific and generic musculoskeletal models are the computational instantiation of hypotheses, and stochastic techniques help explore their validity. We present two such examples to explore the hypothesis of muscle redundancy. The first addresses the effect of anatomical variability on static force capabilities for three individual cat hindlimbs, each with seven kinematic degrees of freedom (DoFs) and 31 muscles. We present novel methods to characterize the structure of the 31-dimensional set of feasible muscle activations for static force production in every 3-D direction. We find that task requirements strongly define the set of feasible muscle activations and limb forces, with few differences comparing individual vs. species-average results. Moreover, muscle activity is not smoothly distributed across 3-D directions. The second example explores parameter uncertainty during a flying disc throwing motion by using a generic human arm with five DoFs and 17 muscles to predict muscle fiber velocities. We show that the measured joint kinematics fully constrain the eccentric and concentric fiber velocities of all muscles via their moment arms. Thus muscle activation for limb movements is likely not redundant: there is little, if any, latitude in synchronizing alpha-gamma motoneuron excitation-inhibition for muscles to adhere to the time-critical fiber velocities dictated by joint kinematics. Importantly, several muscles inevitably exhibit fiber velocities higher than thought tenable, even for conservative throwing speeds. These techniques and results, respectively, enable and compel us to continue to revise the classical notion of muscle redundancy for increasingly more realistic models and tasks.

The impact of prenatal parental tobacco smoking on risk of diabetes mellitus in middle-aged women.

Growing evidence indicates that parental smoking is associated with risk of offspring obesity. The purpose of this study was to identify whether parental tobacco smoking during gestation was associated with risk of diabetes mellitus. This is a prospective study of 44- to 54-year-old daughters (n = 1801) born in the Child Health and Development Studies pregnancy cohort between 1959 and 1967. Their mothers resided near Oakland California, were members of the Kaiser Foundation Health Plan and reported parental tobacco smoking during an early pregnancy interview. Daughters reported physician diagnoses of diabetes mellitus and provided blood samples for hemoglobin A1C measurement. Prenatal maternal smoking had a stronger association with daughters' diabetes mellitus risk than prenatal paternal smoking, and the former persisted after adjustment for parental race, diabetes and employment (aRR = 2.4 [95% confidence intervals 1.4-4.1] P < 0.01 and aRR = 1.7 [95% confidence intervals 1.0-3.0] P = 0.05, respectively). Estimates of the effect of parental smoking were unchanged when further adjusted by daughters' birth weight or current body mass index (BMI). Maternal smoking was also significantly associated with self-reported type 2 diabetes diagnosis (2.3 [95% confidence intervals 1.0-5.0] P < 0.05). Having parents who smoked during pregnancy was associated with an increased risk of diabetes mellitus among adult daughters, independent of known risk factors, providing further evidence that prenatal environmental chemical exposures independent of birth weight and current BMI may contribute to adult diabetes mellitus. While other studies seek to confirm our results, caution toward tobacco smoking by or proximal to pregnant women is warranted in diabetes mellitus prevention efforts.

Structure of the set of feasible neural commands for complex motor tasks.

The brain must select its control strategies among an infinite set of possibilities; researchers believe that it must be solving an optimization problem. While this set of feasible solutions is infinite and lies in high dimensions, it is bounded by kinematic, neuromuscular, and anatomical constraints, within which the brain must select optimal solutions. That is, the set of feasible activations is well structured. However, to date there is no method to describe and quantify the structure of these high-dimensional solution spaces. Bounding boxes or dimensionality reduction algorithms do not capture their detailed structure. We present a novel approach based on the well-known Hit-and-Run algorithm in computational geometry to extract the structure of the feasible activations capable of producing 50% of maximal fingertip force in a specific direction. We use a realistic model of a human index finger with 7 muscles, and 4 DOFs. For a given static force vector at the endpoint, the feasible activation space is a 3D convex polytope, embedded in the 7D unit cube. It is known that explicitly computing the volume of this polytope can become too computationally complex in many instances. However, our algorithm was able to sample 1,000,000 uniform at random points from the feasible activation space. The computed distribution of activation across muscles sheds light onto the structure of these solution spaces-rather than simply exploring their maximal and minimal values. Although this paper presents a 7 dimensional case of the index finger, our methods extend to systems with at least 40 muscles. This will allow our motor control community to understand the distributions of feasible muscle activations, providing important contextual information into learning, optimization and adaptation of motor patterns in future research.

The Early Determinants of Adult Health Study.

This issue of the Journal features collaborative follow-up studies of two unique pregnancy cohorts recruited during 1959-1966 in the United States. Here we introduce the Early Determinants of Adult Health (EDAH) study. EDAH was designed to compare health outcomes in midlife (age 40s) for same-sex siblings discordant on birthweight for gestational age. A sufficient sample of discordant siblings could only be obtained by combining these two cohorts in a single follow-up study. All of the subsequent six papers are either based upon the EDAH sample or are related to it in various ways. For example, three papers report results from studies that significantly extended the 'core' EDAH sample to address specific questions. We first present the overall design of and rationale for the EDAH study. Then we offer a synopsis of past work with the two cohorts to provide a context for both EDAH and the related studies. Next, we describe the recruitment and assessment procedures for the core EDAH sample. This includes the process of sampling and recruitment of potential participants; a comparison of those who were assessed and not assessed based on archived data; the methods used in the adult follow-up assessment; and the characteristics at follow-up of those who were assessed. We provide online supplementary tables with much further detail. Finally, we note further work in progress on EDAH and related studies, and draw attention to the broader implications of this endeavor.

Effect of maternal coffee, smoking and drinking behavior on adult son's semen quality: prospective evidence from the Child Health and Development Studies.

Fetal exposure to caffeine is associated with adverse pregnancy outcomes. Animal and human studies suggest that caffeine may have effects on the developing reproductive system. Here we report on mothers' smoking, coffee and alcohol use, recorded during pregnancy, and semen quality in sons in the age group of 38-47 years. Subjects were a subset of the Child Health and Development Studies, a pregnancy cohort enrolled between 1959 and 1967 in the Kaiser Foundation Health Plan near Oakland, California. In 2005, adult sons participated in a follow-up study (n = 338) and semen samples were donated by 196 participants. Samples were analyzed for sperm concentration, motility and morphology according to the National Cooperative Reproductive Medicine Network (Fertile Male Study) Protocol. Mean sperm concentration was reduced by approximately 16 million sperms for sons with high prenatal exposure (5 cups of maternal coffee use per day) compared with unexposed sons (P-value for decreasing trend = 0.09), which translates to a proportionate reduction of 25%. Mean percent motile sperm decreased by approximately 7 points (P-value = 0.04), a proportionate decline of 13%, and mean percent sperm with normal morphology decreased by approximately 2 points (P-value = 0.01), a proportionate decline of 25%. Maternal cigarette and alcohol use were not associated with son's semen quality. Adjusting for son's contemporary coffee, alcohol and cigarette use did not explain the maternal associations. Findings for son's coffee intake and father's prenatal coffee, cigarette and alcohol use were non-significant and inconclusive. These results contribute to the evidence that maternal coffee use during pregnancy may impair the reproductive development of the male fetus.

Hydroxylated PCB metabolites (OH-PCBs) in archived serum from 1950-60s California mothers: a pilot study.

We are studying participants selected from the Child Health and Development Studies (CHDS), a longitudinal birth cohort of over 20,000 California pregnancies between 1959 and 1967, for associations between maternal body burden of organochlorine contaminants and thyroid function. We designed a pilot study using 30 samples selected among samples with high and low PCB concentrations to evaluate the feasibility of measuring OH-PCBs in the larger study population. GC-ECD and GC-NCI/MS were used to determine PCBs and OH-PCBs as methyl derivatives, respectively. Maternal serum levels of Sigma11PCBs and Sigma8OH-PCB metabolites varied from 0.74 to 7.99 ng/mL wet wt. with a median of 3.05 ng/mL, and from 0.12 to 0.98 ng/mL wet wt. with a median of 0.39 ng/mL, respectively. Average concentrations of Sigma8OH-PCB metabolites in the high PCB group were significantly higher than those in the low PCB group (p < 0.05). The levels of OH-PCB metabolites were dependent on PCB levels (r = 0.58, p < 0.05) but approximately an order of magnitude lower (p < 0.05). The average ratio of Sigma8OH-PCBs to Sigma11PCBs was 0.14 +/- 0.08. The primary metabolite was 4-OH-CB187 followed by 4-OH-CB107. Both of these metabolites interfere with the thyroid system in in vitro, animal, and human studies. OH-PCBs were detectable in all archived sera analyzed, supporting the feasibility to measure OH-PCB metabolites in the entire cohort.

Placental characteristics and reduced risk of maternal breast cancer.

BACKGROUND: Women who have preeclampsia during pregnancy are at reduced risk of subsequent breast cancer. We examined whether other markers of reduced placental size or function, including increased blood pressure during pregnancy, predict a reduction in maternal breast cancer. METHODS: The Child Health and Development Studies is a 40-year follow-up of pregnant women enrolled in the Kaiser Permanente health plan between 1959 and 1967. We identified 3804 white women for whom data were available on placental examinations and other study variables. As of 1997, 146 women had developed invasive breast cancer. Proportional hazards models were used to estimate associations of breast cancer with markers of placental function. All statistical tests were two-sided. RESULTS: A blood pressure increase between the second and third trimesters exhibited a linear relationship with breast cancer rate, with the highest quartile showing a 51% reduction (95% confidence interval [CI] = 20% to 70%) that was not explained by preeclampsia. Smaller placental diameter was independently associated with a reduced breast cancer rate; the association increased with age at first pregnancy (P =.008). Maternal floor infarction of the placenta was associated with a 60% reduction in breast cancer rate (95% CI = 12% to 82%). In combination, placental risk factors were associated with a reduction in the breast cancer rate of as high as 94% (95% CI = 80% to 98%). CONCLUSIONS: Smaller placentas, maternal floor infarction of the placenta, and increasing blood pressure during pregnancy were associated with reduced maternal breast cancer. In the case of smaller placental diameter, the larger reduction observed with older age at first pregnancy suggests a process in which promotion of an existing lesion is blocked. Elucidating the mechanisms for these associations could provide clues to breast cancer prevention and treatment.

Gender differences in hospitalizations for IDDM among adolescents in California, 1991. Implications for prevention.

OBJECTIVE: Describe gender differences in hospitalizations for IDDM to investigate the need for gender-specific interventions to reduce diabetes-related morbidity. RESEARCH DESIGN AND METHODS: Analyses were based on hospital discharges with any mention of IDDM (n = 2,889) and the subset of these for IDDM as a principal diagnosis (n = 2,270) in California children, ages 0-18 years during 1991. Pregnancy-related hospitalizations were excluded. RESULTS: Females had more diabetes hospitalizations among discharges with any mention of diabetes, among discharges with diabetes as a principal diagnosis, and among discharges with diabetic ketoacidosis as a principal diagnosis. For diabetes as a principal diagnosis, females had 40% more hospitalizations, 44% more repeated hospitalizations, 23% more individuals hospitalized, and significantly higher rates of hospitalizations for ages 10-14 years (50 vs. 38 per 100,000) and for ages 15-18 years (68 vs. 29 per 100,000). Gender differences occurred primarily in adolescents, were independent of complicating conditions at the time of hospitalization, and were observed for diabetic ketoacidosis alone. CONCLUSIONS: Adolescent females had more diabetes hospitalizations than did males. The underlying cause may be biological or behavioral. Management protocols tailored for young women may be required to reduce hospitalizations for IDDM among females.

DES awareness and exposure: the 1994 California Behavioral Risk Factor Survey.

INTRODUCTION: Diethylstilbestrol (DES), a drug used in millions of pregnancies between 1938 and 1971, is the first known human transplacental carcinogen. DES is also associated with other serious health problems for those exposed to it either in utero or while pregnant; however, many men and women are unaware of their exposure or how to protect their health. This first population-based study of DES awareness is part of the National Cancer Instututes's National DES Education Program. METHODS: In 1994, 2,077 women and 1,625 men 23 years of age and over responded to the California Behavioral Risk Factor Survey (BRFS). These subjects were either born during the years DES was in use (men and women 23-53 years old in 1994) or could have been pregnant during those years (women 39 years or older). RESULTS: Analyses weighted to the 1994 California age and ethnicity distribution indicate that only 43% of women and 22% of men had over heard of DES (P < .001). Although 44% of Caucasians had heard of DES, only 10% of Hispanics, 27% of African Americans, and 24% of other races had heard of DES. Within each group, women had heard of DES significantly more often than men. Only 17% of women and 5% of men had ever tried to confirm whether they were exposed to DES in utero, and 8% of women whether they were exposed while pregnant. CONCLUSIONS: Given the serious health consequences of DES exposure and available prevention strategies, this lack of awareness warrants an immediate educational effort.

In search of human skin pheromones.

The term pheromone was first designated by Karlson and Lüscher in 1959 as a substance secreted by an animal to the outside of that individual, which was then received by another individual, classically of the same species, and which then elicited some behavioral or developmental response in the latter. They composed the term from the Greek words pherein, which means to bring or to transfer, and hormon, which means to excite. In the usual context, this response in the second individual is of a sexual or of a reproductive physiologic nature, although sometimes the definition might even be extended to include other social responses such as when a dog uses pheromones in urine to mark territory. Classically, pheromones are thought of as being olfactory, but these chemicals may also be received by contact. Pheromones may be present in many different sites in animals, such as in the skin, including some of its glands, saliva, urine, vaginal discharge, and feces.

Dyslipidemia and ischemic heart disease mortality among men and women with diabetes.

BACKGROUND: We investigated whether the greater increased risk of ischemic heart disease mortality associated with diabetes among women compared with men could be explained by their more pronounced lipoprotein abnormalities. METHODS AND RESULTS: Seventy-six men and 45 women with diabetes and 327 men and 496 women without diabetes were followed for an average of 16 years in a population-based study. Cox proportional hazards models were used to determine the relative hazard of ischemic heart disease mortality for changes in lipoprotein subfractions after adjustment for age, hypertension, obesity, smoking, exercise, alcohol consumption, and estrogen use (among women). The relative hazard of ischemic heart disease mortality among diabetic women was 1.76 (P = .10) for a 10-mg/dL decrement in high-density lipoprotein cholesterol (HDL-C) and 3.13 (P = .01) for a 1-U increment in log very-low-density lipoprotein cholesterol (VLDL-C). The risk of ischemic heart disease mortality among diabetic women relative to nondiabetic women for an HDL-C level of 50 mg/dL and a log(e) VLDL-C of 3 (about 20 mg/dL) were 4.1 and 3.4, respectively (P < .05). These lipoprotein changes were not associated with ischemic heart disease mortality among men or among nondiabetic women. CONCLUSIONS: Excess ischemic heart disease mortality among diabetic women is partially explained by deleterious levels of HDL-C and VLDL-C. HDL-C levels of < or = 50 mg/dL and VLDL-C levels of > or = 20 mg/dL appear to predict ischemic heart disease mortality among these women and may help identify women who would benefit most from intervention.