Eye patches: Protein assembly of index-gradient squid lenses.

A parabolic relationship between lens radius and refractive index allows spherical lenses to avoid spherical aberration. We show that in squid, patchy colloidal physics resulted from an evolutionary radiation of globular S-crystallin proteins. Small-angle x-ray scattering experiments on lens tissue show colloidal gels of S-crystallins at all radial positions. Sparse lens materials form via low-valence linkages between disordered loops protruding from the protein surface. The loops are polydisperse and bind via a set of hydrogen bonds between disordered side chains. Peripheral lens regions with low particle valence form stable, volume-spanning gels at low density, whereas central regions with higher average valence gel at higher densities. The proteins demonstrate an evolved set of linkers for self-assembly of nanoparticles into volumetric materials.

Preconception stress increases the risk of infertility: results from a couple-based prospective cohort study--the LIFE study.

STUDY QUESTION: Are women's stress levels prospectively associated with fecundity and infertility? SUMMARY ANSWER: Higher levels of stress as measured by salivary alpha-amylase are associated with a longer time-to-pregnancy (TTP) and an increased risk of infertility. WHAT IS KNOWN ALREADY: Data suggest that stress and reproduction are interrelated; however, the directionality of that association is unclear. STUDY DESIGN, SIZE, DURATION: In 2005-2009, we enrolled 501 couples in a prospective cohort study with preconception enrollment at two research sites (Michigan and Texas, USA). Couples were followed for up to 12 months as they tried to conceive and through pregnancy if it occurred. A total of 401 (80%) couples completed the study protocol and 373 (93%) had complete data available for this analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Enrolled women collected saliva the morning following enrollment and then the morning following their first observed study menses for the measurement of cortisol and alpha-amylase, which are biomarkers of stress. TTP was measured in cycles. Covariate data were captured on both a baseline questionnaire and daily journals. MAIN RESULTS AND THE ROLE OF CHANCE: Among the 401 (80%) women who completed the protocol, 347 (87%) became pregnant and 54 (13%) did not. After adjustment for female age, race, income, and use of alcohol, caffeine and cigarettes while trying to conceive, women in the highest tertile of alpha-amylase exhibited a 29% reduction in fecundity (longer TTP) compared with women in the lowest tertile [fecundability odds ratios (FORs) = 0.71; 95% confidence interval (CI) = (0.51, 1.00); P < 0.05]. This reduction in fecundity translated into a >2-fold increased risk of infertility among these women [relative risk (RR) = 2.07; 95% CI = (1.04, 4.11)]. In contrast, we found no association between salivary cortisol and fecundability. LIMITATIONS, REASONS FOR CAUTION: Due to fiscal and logistical concerns, we were unable to collect repeated saliva samples and perceived stress questionnaire data throughout the duration of follow-up. Therefore, we were unable to examine whether stress levels increased as women continued to fail to get pregnant. Our ability to control for potential confounders using time-varying data from the daily journals, however, minimizes residual confounding. WIDER IMPLICATIONS OF THE FINDINGS: This is the first US study to demonstrate a prospective association between salivary stress biomarkers and TTP, and the first in the world to observe an association with infertility. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts #N01-HD-3-3355, N01-HD-3-3356, N01-HD-3358). There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: Not applicable.

Baldness, acne and testicular germ cell tumours.

Androgen levels during critical periods of testicular development may be involved in the aetiology of testicular germ cell tumours (TGCT). We evaluated the roles of adolescent and early adult life correlates of androgen exposure and TGCT in a hospital-based case-control study. TGCT cases (n=187) and controls (n=148), matched on age, race and state of residence, participated in the study. Unconditional logistic regression was used to estimate associations between TGCT and male pattern baldness, severe acne, markers of puberty onset and body size. Cases were significantly less likely to report hair loss than controls [odds ratio (OR): 0.6; 95% confidence interval (CI): 0.4, 1.0]. Amount of hair loss, increasing age at onset and increasing rate of loss were all inversely associated with TGCT (rate of hair loss: p-trend=0.03; age at onset: p-trend=0.03; amount of hair loss: p-trend=0.01). History of severe acne was inversely associated with TGCT (OR: 0.5; 95% CI: 0.3, 0.9) and height was positively associated with TGCT (p-trend=0.02). Increased endogenous androgen levels during puberty and early adulthood may be associated with a decreased risk of TGCT. Additional studies of endogenous hormone levels during puberty and early adult life are warranted, especially studies evaluating the role of androgen synthesis, metabolism and uptake.

Impairments of memory and learning in older adults exposed to polychlorinated biphenyls via consumption of Great Lakes fish.

An association between in utero polychlorinated biphenyl (PCB) exposure and impaired childhood intellectual functioning has been reported, but the potential impact of PCB exposure during adulthood on intellectual functioning has received little attention. We assessed the impact of PCBs and other fish-borne contaminants on intellectual functioning in older adults. The subjects were 49- to 86-year-old Michigan residents recruited from an existing cohort. Fish eaters ate > 24 lb of sport-caught Lake Michigan fish per year and non-fish eaters ate < 6 lb of Lake Michigan fish per year. A battery of cognitive tests including tests of memory and learning, executive function, and visual-spatial function was administered to 180 subjects (101 fish eaters and 79 non-fish eaters). Blood samples were analyzed for PCBs and 10 other contaminants. We evaluated cognitive outcomes using multiple regression. PCBs and dichlorodiphenyl dichloroethene (DDE) were markedly elevated in fish eaters. After controlling for potential confounders PCB, but not DDE, exposure was associated with lower scores on several measures of memory and learning. These included the Weschler Memory Scale verbal delayed recall (p = 0.001), the semantic cluster ratio (p = 0.006), and list A, trial 1 (p = 0.037), from the California Verbal Learning Test. In contrast, executive and visual-spatial function were not impaired by exposure to either PCBs or DDE. In conclusion, PCB exposure during adulthood was associated with impairments in memory and learning, whereas executive and visual-spatial function were unaffected. These results are consistent with previous research showing an association between in utero PCB exposure and impairments of memory during infancy and childhood.

Changes in serum PBB and PCB levels over time among women of varying ages at exposure.

The identification of host factors that are predictors of changes in serum polyhalogenated biphenyl contaminants over time has been a difficult challenge in epidemiologic studies of exposed individuals. Of particular concern are age at exposure, reproductive and lactational histories, and changes in body mass index. Using both cross-sectional and longitudinal approaches, this study examined factors related to high initial serum PBB and PCB levels and changes in these levels over time among women of varying ages at exposure (n=1772; age range<1 to 45 years). In 1973, PBB exposure occurred through consumption of farm products contaminated with PBB added to cattle feed. Exposures to PCBs began in 1941 through PCB-contaminated silo sealant deteriorating into animal feed. The Michigan Department of Public Health began enrolling participants in 1977 and has continued to follow them through annual updates. At enrollment, questionnaires were administered to obtain demographic, lifestyle, and anthropometric measurements, medical/reproductive and occupational histories, and contaminated food consumption patterns. Blood samples were collected for PBB and PCB analysis at enrollment for all participants; additional serum tests were done on a subset of the population during follow-up. Median serum levels at enrollment were 2.0 ppb PBB and 5.0 ppb PCB. A decline in serum PBB level over an interval that ranged from 1 to 146 months (median=31) was observed for 44.6% of the women (median=1.0 ppb), while 12.2% showed an increase (median=1.0 ppb). PCB levels declined in 50.3% of the women (median=3.0 ppb) while 12.2% increased (median=2.0 ppb). Relative to women whose contaminant levels were stable, higher initial serum level was a predictor of decline for both PBB and PCB (OR=1.66, 95% CI 1.52-1.82; OR=3.26, 95% CI 2.58-4.12, respectively); a yearly increase in interval between tests was related to declining PCBs (OR=1.65, 95% CI 1.46-1.87). In addition, age< or =10 years at exposure (OR=1.72, 95% CI 1.03-2.86) and residence on a quarantined farm (OR=1.40, 95- CI 1.03-1.90) were predictors of a decrease in PBBs. Factors related to an increase in PBB levels were age< or =10 years at exposure (OR=0.30, 95% CI 0.10-0.96) and initial PBB level (OR=1.24, 95% CI 1.15-1.33); and for PCBs, high initial level (OR=1.34, 95% CI 1.17-1.53) and body mass index (OR=1.07, 95% CI 1.01-1.13). One or more live births during the interval between tests were not related to changing levels of either contaminant; breastfeeding data were not available for examination. Early age at exposure appears to be an important predictor of changes in serum PBB levels over time.

Neural tube defects among Mexican Americans living on the US-Mexico border: effects of folic acid and dietary folate.

Populations of Mexican descent have high occurrences of neural tube defects (NTDs). A recent study suggested that folic acid supplements may not protect these populations from NTDs. In a case-control study, the authors investigated the role of folic acid and dietary folate intake in NTD risk among Mexican Americans living along the Texas-Mexico border. From January 1995 to February 1999, 148 Mexican-American women with NTD-affected pregnancies and 158 women with normal live births were interviewed in person about use of vitamin supplements and dietary intakes during a 6-month periconceptional period (from 3 months before conception to 3 months after conception). Daily preconceptional consumption of vitamin supplements containing folic acid was 2.5% in control women and 2.0% in case women (odds ratio = 0.77; 95% confidence interval (CI): 0.19, 3.22). With adjustment for maternal age, education, obesity, and previous stillbirth or miscarriage, the risk estimate was essentially null (odds ratio = 1.12; 95% CI: 0.22, 5.78). Combined folic acid intake from diet and supplements showed only a modest risk reduction for intakes of > or = 1.0 mg per day (adjusted odds ratio = 0.73; 95% CI: 0.31, 1.72). The fact that the primary folic acid exposure was in the form of dietary polyglutamates rather than the more easily absorbed supplemental monoglutamates may explain an apparent decreased effect in this population.

PCB congener profile in the serum of humans consuming Great Lakes fish.

The State of Michigan has a long history of research into human exposure to environmental contaminants through consumption of recreationally caught fish. A large cohort of Lake Michigan residents who eat fish (fish-eaters) and those who do not eat fish (nonfish-eaters) established in 1980 served as the basis for the congener-specific polychlorinated biphenyl (PCB) exposure evaluation reported here. In this paper we present the serum PCB congener profile for a subset of this cohort who were over 50 years of age. Serum samples were collected in 1993-1995 and were evaluated by a dual column capillary column gas chromatography procedure capable of detecting over 90 PCB congeners. This evaluation demonstrated significant PCB exposure in the fish-eaters (mean serum PCB of 14.26 ppb; n = 101). This elevated exposure allowed the establishment of a detailed profile of the PCB congeners found in humans exposed by this route. Twenty-two congeners of varying concentrations were the most prevalent and constituted over 95% of the total PCB present in most subjects. Four congeners, 138/163 (2,2',3,4,4',5-PCB/2,3,3',4', 5,6-PCB), 180 (2,2',3,4,4',5,5'-PCB), and 153 (2,2',4,4',5,5'-PCB), accounted for 55-64% of the total PCB load. Other congeners, some of toxicologic significance, were also detected by this analytical protocol. Nonfish-eaters had lower total serum PCB levels (mean = 4. 56; n = 78), but the same general pattern of PCB congeners was present. It was demonstrated that careful selection of a subset of prevalent PCB congeners could provide a cost-effective assessment of exposure without losing critical scientific information.

A case-control study of diet and testicular carcinoma.

No risk factor other than cryptorchidism has been consistently associated with testicular cancer, and the influence of diet on testicular cancer risk has not been extensively explored. A few studies have found increased testicular cancer risk in men whose diets are high in fat, red meats, and milk or low in fruits and vegetables. We evaluated the relationship of dietary factors and risk of testicular cancer and also examined whether this risk varied by type of testicular cancer. We conducted a hospital-based case-control study at The University of Texas M. D. Anderson Cancer Center (Houston, TX) of 160 testicular cancer cases diagnosed between 1990 and 1996 and 136 friend-matched controls. The results of multivariable logistic regression analysis showed that after adjustment for age, education, income, ethnicity, cryptorchidism, and total daily calories, increasing total fat, saturated fat, and cholesterol consumption were associated with increasing risk of nonseminoma testicular cancer, with odds ratios (ORs) for the highest vs. the lowest quartiles of 6.3, 5.3, and 4.6, respectively. The risk for seminoma testicular cancer marginally increased with increasing intake of total fat and saturated fat, with ORs for the highest vs. lowest quartiles of 1.9 and 2.1, respectively. Higher total fat consumption was nearly significantly related to increased mixed germ cell tumor risk, with an OR for highest vs. lowest quartile of 4.2. This study supports the hypothesis that diet (particularly high fat consumption) increases testicular cancer risk in young men. However, the small sample size and the possibility that these observations may be due to bias indicate that the relationship of diet and testicular cancer risk needs to be further examined within a prospective or incident case-control study.

Motor function in aging Great Lakes fisheaters.

Exposure to contaminants in Great Lakes fish has been linked to impaired neuropsychological functioning in children, but neurological function of exposed adults has not been evaluated. This report describes a cross-sectional analysis of the effects of PCB/DDE exposure from contaminated fish on fine motor function in older adults. The subjects were 50-90-year-old Michigan residents who were members of a previously established study cohort. Fisheaters ate 24 lbs or more of sport-caught Lake Michigan fish/year at the time they were originally recruited in 1980-1982. Age- and sex-matched non-fisheaters ate 6 or fewer lbs/year. Outcome measures were scores on the Static Motor Steadiness Test (SMST) and Grooved Pegboard Test (GPT). PCB/DDE exposure was determined through serum analyses performed at the time of recruitment into the present study in 1993-1995. Because of the high correlation between serum PCB and DDE levels in this sample (Spearman r=0.64, P<0.0001), the effects of the two contaminants were assessed jointly using a single derived exposure variable=Low=both PCB and DDE at or below the medians of their respective distributions, intermediate=PCB and/or DDE in the third quartile, and high=PCB and/or DDE in the upper quartile. In unadjusted analyses, high exposure to PCBs/DDE was associated with significantly poorer performance on the GPT (P=0.03). However, in the multiple regression model, age and gender emerged as the most significant factors affecting GPT scores, and exposure to PCB/DDE was not significant. Performance on the SMST was not related to PCB/DDE exposure in initial unadjusted analyses, but performance with the dominant hand was marginally (P=0.052) associated with exposure in the final model. Scores on the SMST improved slightly as PCB/DDE exposure increased. A similar trend was not observed for the nondominant hand (P=0.46). These findings suggest that PCB/DDE exposure from Great Lakes fish has not significantly impaired hand steadiness or visual-motor coordination in this sample of older adults.

Cancer among a Michigan cohort exposed to polybrominated biphenyls in 1973.

The long-term health effects of human exposure to polybrominated biphenyls are not known. In this nested case-control study, we evaluated the association between site-specific cancer risk and serum polybrominated biphenyl levels among a Michigan cohort accidentally exposed to polybrominated biphenyls in 1973. The Michigan Department of Public Health has followed 3,899 people through 1993, among whom 195 primary cancers were identified in 187 persons. Controls were 696 randomly selected cancer-free individuals who were frequency matched to cases by sex and age (in 5-year strata). Baseline serum polybrominated biphenyl levels were measured using standard methods. We found an increasing dose-response relation for digestive system cancer risk with higher serum polybrominated biphenyl category [4-20 parts per billion (ppb), 21-50 ppb, and > 50 ppb] after adjustment for age, family cancer history, cigarette smoking, alcohol drinking, and baseline serum polychlorinated biphenyl level. Adjusted odds ratios (ORs) for each category were 8.23 [95% confidence interval (CI) = 1.27-53.3], 12.3 (95% CI = 0.80-191), and 22.9 (95% CI = 1.34-392), respectively. Univariate analysis for polybrominated biphenyl level and lymphoma risk also showed a dose-response relation, with corresponding ORs of 3.24 (95% CI = 0.24-95.9), 20.5 (95% CI = 1.51-608), and 32.6 (95% CI = 3.33-861).

Fish consumption and other characteristics of reproductive-aged Michigan anglers--a potential population for studying the effects of consumption of Great Lakes fish on reproductive health.

There has been considerable interest in the benefits and risks of eating Great Lakes fish, particularly with regard to reproductive health. We report the results of a survey conducted from 1993-1995 among Michigan anglers. The survey was designed to identify a reproductive-aged cohort of persons who consume high or low levels of Great Lakes fish in order to study the impact of polyhalogenated biphenyl (PHB) compounds and other toxins on human reproduction outcomes. Using fishing license data obtained from the Michigan Department of Natural Resources, we identified anglers of early reproductive age (18-34 years) in ten Michigan counties. The screening survey ascertained demographic, behavioral, fish consumption, and reproductive history information on anglers and their partners. Over 4,000 angler households were contacted. One thousand nine hundred fifty questionnaires were returned from 1,168 households. The median age of respondents was 30 years; 58% were male and 64% reported being married. Slightly more than one-half the respondents had attended or graduated from college, and less than 10% had not completed high school. In the past year, most respondents (46%) reported having eaten sport-caught fish 1-12 times, while 20% reported having eaten no sport-caught fish; 20% had consumed 13-24 meals. More sport-caught fish was consumed in the spring and summer than in the fall and winter, and males reported eating more fish than females. About 43% of our respondents reported that they intend to have one or more children in the next five years. Of these respondents, 287 couples had no identified impairments to reproduction and therefore would be eligible to participate in the future reproductive study.

Neuropsychological assessment of an aging population of Great Lakes fisheaters.

Because of the decline in central nervous system function that occurs with age, older people may be at greater risk of neurological dysfunction following exposure to neurotoxic contaminants in the environment. This study was designed to assess the neuropsychological functioning of a group of 50-90-year-old fisheaters exposed to polychlorinated biphenyls (PCBs) through Great Lakes fish consumption, and a group of age- and sex-matched nonfisheaters selected from the Michigan Department of Public Health's established cohort of fisheaters and nonfisheaters. A neuropsychological assessment battery, demographic interview, and fish consumption questionnaire were developed and piloted on similarly aged men and women in the Lansing and Detroit, Michigan, areas. The assessment battery included tests of motor function, memory and learning, executive functions, and visual-spatial functions, and took approximately two hours to administer. Most of the tests included in the battery have been shown to be sensitive to subtle, age-related declines in cognitive and motor function. The demographic questionnaire included questions on a number of important control variables that could influence the neuropsychological end points that were assessed in the study. These included demographic background, alcohol consumption, tobacco use, prescription and nonprescription drug use, medical history (including psychiatric illnesses), employment history, and activity level. The fish consumption questionnaire asked about historical and current consumption of specific fish species from each of the Great Lakes and its tributaries and was based on the fish consumption advisories published in the 1992 Michigan Fishing Guide. The questionnaire also asked about consumption of wild game, fish preparation and cooking methods, serving size, and changes in fish consumption patterns over time. After each subject completed the neuropsychological assessment, demographic interview, and fish consumption questionnaire, a blood sample was collected for analysis of PCBs, dichloro diphenyl dichloroethene (DDE), and ten other contaminants frequently detected in Great Lakes fish. Subject recruitment for the study began in July 1993 and was completed in November 1995. The data will be analyzed in two steps: first, to assess differences in confounding variables between fisheaters and nonfisheaters; and secondly, to determine the independent effects of Great Lakes fish consumption, as well as serum PCB and DDE levels, on cognitive and motor function after controlling for all identified covariates. Three indices of PCB exposure-total PCBs, total ortho-substituted PCBs and total coplanar PCBs-will be assessed. These studies should shed light on three questions: 1) Does consumption of contaminated fish from the Great Lakes exacerbate or accelerate the normal age-related decline in cognitive and motor function? 2) Do serum PCB or DDE concentrations predict the degree of behavioral dysfunction? and 3) If PCB exposure is related to behavioral outcomes, which class of PCB congeners, ortho-substituted or coplanar, are responsible for the cognitive and motor deficits?

Advances in early fetal loss research: importance for risk assessment.

The assessment of early fetal losses (EFLs) in relationship to environmental agents offers unique advantages compared to other end points for hazard assessment. There is a high incidence (greater than 20% of all pregnancies end in an EFL), and the interval between exposure and end point is the short duration between conception and event, i.e., approximately 12 weeks. In contrast, cancer, which is the primary end point evaluated in risk assessment models, occurs with much lower frequency, and the latency period is measured in years or decades. EFLs have not been used effectively for risk assessment because most of the events are not detected. Prospective studies provide the only approach whereby it is possible to link exposure to EFLs. Recent methodologic advancements have demonstrated that it is now possible to conduct population-based studies of EFLs. It is likely that EFLs could serve as sentinels to monitor adverse health effects of many potential environmental hazards. The methodology will be demonstrated using lead exposure in utero as an example.

Evaluation of recruitment strategies for prospective studies of spontaneous abortion.

The examination of spontaneous abortions may offer a sensitive index to potential adverse health effects due to environmental exposures. However, difficulties in ascertaining spontaneous abortions on a population basis, as well as problems in recruiting unselected women into studies of this nature, have severely limited the use of this end point in environmental epidemiology studies. The current research assesses the feasibility of recruiting a representative sample of women into a prospective pregnancy study. Four protocols varying in intensity of data collection were offered to the participants. Fifty-two percent of the eligible women agreed to participate. Seventy-four percent chose the most intensive protocol level. Overall compliance for urine collection and questionnaire completion were 80% and 81%, respectively. Four pregnancies were observed, which was the expected number for the study area during this time frame, suggesting that the majority of pregnancies occurring within a population could be ascertained with this approach.

Evaluation of methods for the prospective identification of early fetal losses in environmental epidemiology studies.

A major problem in the epidemiologic investigation of early fetal losses has been incomplete or biased ascertainment. In order to assess early fetal losses more accurately, one must first develop a simple method to identify early pregnancy. This study, conducted at the University of Pittsburgh from October 1985 through October 1986, has developed such a method through the use of monoclonal antibody urine pregnancy testing kits. A total of 88 volunteers collected urine samples beginning on the seventh postovulatory day and continued until either menses occurred or a serum radioimmunoassay pregnancy test was performed on day 16. If pregnancy was diagnosed, all of the participants' urine specimens from that menstrual cycle were analyzed by five monoclonal antibody tests. A total of 34 pregnancies were diagnosed, six (18%) of which resulted in early fetal losses. Pregnancy was first detectable between eight and 18 days postovulation. The mean time to the first positive test was 14 days for all five kits. The results indicate that it is possible to diagnose early pregnancy with urine testing and that this method is likely to prove acceptable for use in large-scale prospective studies.

PIP: In order to determine the role of toxic agents in the work place or elsewhere in the environment in early fetal loss, it is necessary to be able to diagnose pregnancy within 2 weeks after ovulation. Normally, pregnancy tests are done when a woman misses her 2nd menstrual period. Early fetal loss is estimated to be about 40%, but women rarely seek medical attention for it, so there is no medical record, and it is not reported in retrospective studies due to recall bias; therefore, 3/4 of all early fetal loss is never recognized. The purpose of this study is to evaluate whether monoclonal antibody urine pregnancy testing kits are sensitive enough to detect human chorionic gonadotropin within 10 days of ovulation. 88 women, aged 20 to 38, who were trying to become pregnant, were taught cervical mucus-basal body temperature monitoring, so they could tell when ovulation occurred. 7 days later they began collecting daily urine samples. If they did not menstruate by the 16th postovulatory day, serum radioimmunoassay for the detection of the beta subunit of human chorionic gonadotropin was done. 32 women became pregnant, and their daily urine samples were analyzed using 5 monoclonal antibody urine pregnancy testing kits. 90% of the pregnancies were detected by all 5 kits by the 16th day. 6 of the pregnancies ended in early fetal loss within 90 days, 2/3 of them within 60 days. The urine testing kits all measured a sharp rise in human chorionic gonadotropin levels after the 14th postovulatory day for the women who maintained their pregnancy, but not for those who suffered the early fetal losses. Weekly, rather than daily, urine sampling would have revealed 66% of them. Thus, it is established that the monoclonal antibody urine pregnancy detection kits can diagnose pregnancy within 14 days after ovulation. Urine tests also have the advantage that they may also reveal traces of the environmental toxins. Moreover, they are economically feasible, since they cost on average $2.13 per test as opposed to $22.50 for each serum assay.