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Item Investigation of KIF6 Trp719Arg in a Case-Control Study of Myocardial Infarction: A Costa Rican Population(Public Library of Science, 2010-9-29) Bare, Lance A.; Ruiz-Narvaéz, Edward A.; Tong, Carmen H.; Arellano, Andre R.; Rowland, Charles M.; Catanese, Joseph J.; Sacks, Frank M.; Devlin, James J.; Campos, HanniaBACKGROUND AND METHODOLOGY. The 719Arg allele of KIF6 (rs20455) was associated with coronary events in Caucasian participants of five prospective studies. We investigated whether this KIF6 variant was associated with non-fatal myocardial infarction (MI) in a case-control study of an admixed population from the Central Valley of Costa Rica. Genotypes of the KIF6 variant were determined for 4,134 men and women. Cases (1,987) had survived a first MI; controls (2,147) had no history of MI and were matched to cases by age, sex, and area of residence. We tested the association between the KIF6 719Arg allele and non-fatal MI by conditional logistic regression and adjusted for admixture of founder populations. PRINCIPAL FINDINGS. Compared with the reference Trp/Trp homozygotes, KIF6 719Arg carriers were not at significantly higher risk for non-fatal MI in this study after adjustment for traditional risk factors or admixture (OR=1.12; 95%CI, 0.98-1.28). Heterozygotes of the KIF6 Trp719Arg variant were at increased risk of non-fatal MI: the adjusted odds ratio was 1.16 (95% confidence interval, 1.01-1.34), but this association would not be significant after a multiple testing correction. CONCLUSIONS/SIGNIFICANCE. We found that carriers of the KIF6 719Arg allele were not at increased risk of non-fatal MI in a case-control study of Costa Ricans living in the Central Valley of Costa Rica.Item Lung Cancer Occurrence in Never-Smokers: An Analysis of 13 Cohorts and 22 Cancer Registry Studies(Public Library of Science, 2008-9-9) Thun, Michael J.; Hannan, Lindsay M.; Adams-Campbell, Lucile L.; Boffetta, Paolo; Buring, Julie E.; Feskanich, Diane; Flanders, W. Dana; Jee, Sun Ha; Katanoda, Kota; Kolonel, Laurence N.; Lee, I-Min; Marugame, Tomomi; Palmer, Julie R.; Riboli, Elio; Sobue, Tomotaka; Avila-Tang, Erika; Wilkens, Lynne R.; Samet, Jon M.BACKGROUND. Better information on lung cancer occurrence in lifelong nonsmokers is needed to understand gender and racial disparities and to examine how factors other than active smoking influence risk in different time periods and geographic regions. METHODS AND FINDINGS. We pooled information on lung cancer incidence and/or death rates among self-reported never-smokers from 13 large cohort studies, representing over 630,000 and 1.8 million persons for incidence and mortality, respectively. We also abstracted population-based data for women from 22 cancer registries and ten countries in time periods and geographic regions where few women smoked. Our main findings were: (1) Men had higher death rates from lung cancer than women in all age and racial groups studied; (2) male and female incidence rates were similar when standardized across all ages 40+ y, albeit with some variation by age; (3) African Americans and Asians living in Korea and Japan (but not in the US) had higher death rates from lung cancer than individuals of European descent; (4) no temporal trends were seen when comparing incidence and death rates among US women age 40–69 y during the 1930s to contemporary populations where few women smoke, or in temporal comparisons of never-smokers in two large American Cancer Society cohorts from 1959 to 2004; and (5) lung cancer incidence rates were higher and more variable among women in East Asia than in other geographic areas with low female smoking. CONCLUSIONS. These comprehensive analyses support claims that the death rate from lung cancer among never-smokers is higher in men than in women, and in African Americans and Asians residing in Asia than in individuals of European descent, but contradict assertions that risk is increasing or that women have a higher incidence rate than men. Further research is needed on the high and variable lung cancer rates among women in Pacific Rim countries. Michael Thun and colleagues pooled and analyzed comprehensive data on lung cancer incidence and death rates among never-smokers to examine what factors other than active smoking affect lung cancer risk.Item HIV and Pre-Neoplastic and Neoplastic Lesions of the Cervix in South Africa: A Case-Control Study(BioMed Central, 2006-5-23) Moodley, Jennifer R.; Hoffman, Margaret; Carrara, Henri; Allan, Bruce R.; Cooper, Diane; Rosenberg, Lynn; Denny, Lynette ; Shapiro, Samuel; Williamson, Anna-LiseBACKGROUND. Cervical cancer and infection with human immunodeficiency virus (HIV) are both major public health problems in South Africa. The aim of this study was to determine the risk of cervical pre-cancer and cancer among HIV positive women in South Africa. METHODS. Data were derived from a case-control study that examined the association between hormonal contraceptives and invasive cervical cancer. The study was conducted in the Western Cape (South Africa), from January 1998 to December 2001. There were 486 women with invasive cervical cancer, 103 control women with atypical squamous cells of undetermined significance (ASCUS), 53 with low-grade squamous intraepithelial lesions (LSIL), 50 with high-grade squamous intraepithelial lesions (HSIL) and 1159 with normal cytology. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multiple logistic regression. RESULTS. The adjusted odds ratios associated with HIV infection were: 4.4 [95% CI (2.3 – 8.4) for ASCUS, 7.4 (3.5 – 15.7) for LSIL, 5.8 (2.4 – 13.6) for HSIL and 1.17 (0.75 – 1.85) for invasive cervical cancer. HIV positive women were nearly 5 times more likely to have high-risk human papillomavirus infection (HR-HPV) present compared to HIV negative women [OR 4.6 (95 % CI 2.8 – 7.5)]. Women infected with both HIV and high-risk HPV had a more than 40 fold higher risk of SIL than women infected with neither of these viruses. CONCLUSION. HIV positive women were at an increased risk of cervical pre-cancer, but did not demonstrate an excess risk of invasive cervical cancer. An interaction between HIV and HR-HPV infection was demonstrated. Our findings underscore the importance of developing locally relevant screening and management guidelines for HIV positive women in South Africa.Item Determinants of Sexual Activity and Its Relation to Cervical Cancer Risk among South African Women(BioMed Central, 2007-11-27) Cooper, Diane; Hoffman, Margaret; Carrara, Henri; Rosenberg, Lynn; Kelly, Judy; Stander, Ilse; Denny, Lynette; Williamson, Anna-Lise; Shapiro, SamuelBACKGROUND. Invasive cervical cancer is the commonest cause of cancer morbidity and mortality in South African women. This study provides information on adult women's sexual activity and cervical cancer risk in South Africa. METHODS. The data were derived from a case-control study of hormonal contraceptives and cervical cancer risk. Information on age of sexual debut and number of lifetime sexual partners was collected from 524 incident cases and 1541 hospital controls. Prevalence ratios and adjusted prevalence ratios were utilised to estimate risk in exposures considered common. Crude and adjusted relative risks were estimated where the outcome was uncommon, using multiple logistic regression analysis. RESULTS. The median age of sexual debut and number of sexual partners was 17 years and 2 respectively. Early sexual debut was associated with lower education, increased number of life time partners and alcohol use. Having a greater number of sexual partners was associated with younger sexual debut, being black, single, higher educational levels and alcohol use. The adjusted odds ratio for sexual debut < 16 years and ≥ 4 life-time sexual partners and cervical cancer risk were 1.6 (95% CI 1.2 – 2.2) and 1.7 (95% CI 1.2 – 2.2), respectively. CONCLUSION. Lower socio-economic status, alcohol intake, and being single or black, appear to be determinants of increased sexual activity in South African women. Education had an ambiguous effect. As expected, cervical cancer risk is associated with increased sexual activity. Initiatives to encourage later commencement of sex, and limiting the number of sexual partners would have a favourable impact on risk of cancer of the cervix and other sexually transmitted infections.Item Quantitative Ultrasound in Relation to Risk Factors for Low Bone Mineral Density in South African Pre-Menopausal Women(Springer-Verlag, 2009-9-24) Constant, Deborah; Rosenberg, Lynn; Zhang, Yuqing; Cooper, Diane; Kalla, Asgar A.; Micklesfield, Lisa; Hoffman, MargaretSUMMARY. The study describes the association between risk factors and quantitative ultrasound bone measures in black and mixed-race pre-menopausal South African women. Despite some differences between the two study groups, the findings generally lend support to the use of ultrasound for epidemiological studies of bone mass in resource-limited settings. INTRODUCTION. Quantitative ultrasound at the calcaneus is a convenient and inexpensive method of estimating bone strength well suited to community-based research in countries with limited resources. This study determines, in a large sample of pre-menopausal South African women, whether characteristics associated with quantitative ultrasound measures are similar to those shown to be associated with bone mineral density as measured by dual X-ray absorptiometry. METHODS. This cross-sectional study included 3,493 women (1,598 black and 1,895 mixed race), aged 18–44 living in Cape Town. Study nurses administered structured interviews on reproductive history, lifestyle factors, and measured height and weight. Calcaneus quantitative ultrasound measurements were obtained using the Sahara device. Adjusted means of ultrasound measures according to categories of risk factors were obtained using multivariable regression analysis. RESULTS. Associations between quantitative ultrasound measures and age, body mass index, age at menarche, parity, and primary school physical activity were similar to those known for bone mineral density as measured by dual X-ray absorptiometry. There were no clear associations between quantitative ultrasound measures and educational level, alcohol use, cigarette smoking, and current calcium intake. CONCLUSION. The data give qualified support to the use of quantitative ultrasound as an epidemiological tool in large studies of bone strength in pre-menopausal women.Item Medications as a Potential Source of Exposure to Phthalates in the U.S. Population(National Institute of Environmental Health Sciences, 2009-02) Hernández-Díaz, Sonia; Mitchell, Allen A.; Kelley, Katherine E.; Calafat, Antonia M.; Hauser, RussBACKGROUND. Widespread human exposure to phthalates, some of which are developmental and reproductive toxicants in experimental animals, raises concerns about potential human health risks. Underappreciated sources of exposure include phthalates in the polymers coating some oral medications. OBJECTIVE. The objective of this study was to evaluate whether users of phthalate-containing medications have higher urinary concentrations of phthalate metabolites than do nonusers. METHODS. We used publically available files from the National Health and Nutrition Examination Survey for the years 1999-2004. For certain survey periods, participants were asked to recall use of prescription medication during the past 30 days, and for a subsample of individuals, the urinary concentrations of phthalate metabolites were measured. We a priori identified medications potentially containing phthalates as inactive ingredients and then compared the mean urinary concentration of phthalate metabolites between users and nonusers of those medications. RESULTS: Of the 7,999 persons with information on urinary phthalate concentrations, 6 reported using mesalamine formulations, some of which may include dibutyl phthalate (DBP); the mean urinary concentration of monobutyl phthalate, the main DBP metabolite, among these mesalamine users was 50 times higher than the mean for nonusers (2,257 μg/L vs. 46 μg/L; p < 0.0001). Users of didanosine, omeprazole, and theophylline products, some of which may contain diethyl phthalate (DEP), had mean urinary concentrations of monoethyl phthalate, the main DEP metabolite, significantly higher than the mean for nonusers. CONCLUSION. Select medications might be a source of high exposure to some phthalates, one of which, DBP, shows adverse developmental and reproductive effects in laboratory animals. These results raise concern about potential human health risks, specifically among vulnerable segments of the general population and particularly pregnant women and children.Item Association of Exposure to Phthalates with Endometriosis and Uterine Leiomyomata: Findings from NHANES, 1999-2004(National Institute of Environmental Health Sciences, 2010-06) Weuve, Jennifer; Hauser, Russ; Calafat, Antonia M.; Missmer, Stacey A.; Wise, Lauren A.BACKGROUND. Phthalates are ubiquitous chemicals used in consumer products. Some phthalates are reproductive toxicants in experimental animals, but human data are limited. OBJECTIVE. We conducted a cross-sectional study of urinary phthalate metabolite concentrations in relation to self-reported history of endometriosis and uterine leiomyomata among 1,227 women 20-54 years of age from three cycles of the National Health and Nutrition Examination Survey (NHANES), 1999-2004. METHODS. We examined four phthalate metabolites: mono(2-ethylhexyl) phthalate (MEHP), monobutyl phthalate (MBP), monoethyl phthalate (MEP), and monobenzyl phthalate (MBzP). From the last two NHANES cycles, we also examined mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP). We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for potential confounders. RESULTS. Eighty-seven (7%) and 151 (12%) women reported diagnoses of endometriosis and leiomyomata, respectively. The ORs comparing the highest versus lowest three quartiles of urinary MBP were 1.36 (95% CI, 0.77-2.41) for endometriosis, 1.56 (95% CI, 0.93-2.61) for leiomyomata, and 1.71 (95% CI, 1.07-2.75) for both conditions combined. The corresponding ORs for MEHP were 0.44 (95% CI, 0.19-1.02) for endometriosis, 0.63 (95% CI, 0.35-1.12) for leiomyomata, and 0.59 (95% CI, 0.37-0.95) for both conditions combined. Findings for MEHHP and MEOHP agreed with findings for MEHP with respect to endometriosis only. We observed null associations for MEP and MBzP. Associations were similar when we excluded women diagnosed > 7 years before their NHANES evaluation. CONCLUSION. The positive associations for MBP and inverse associations for MEHP in relation to endometriosis and leiomyomata warrant investigation in prospective studies.Item Secondary Sex Ratio among Women Exposed to Diethylstilbestrol in Utero(National Institute of Environmental Health Sciences, 2007-09) Wise, Lauren A.; Palmer, Julie R.; Hatch, Elizabeth E.; Troisi, Rebecca; Titus-Ernstoff, Linda; Herbst, Arthur L.; Kaufman, Raymond; Noller, Kenneth L.; Hoover, Robert N.BACKGROUND. Diethylstilbestrol (DES), a synthetic estrogen widely prescribed to pregnant women during the mid-1900s, is a potent endocrine disruptor. Previous studies have suggested an association between endocrine-disrupting compounds and secondary sex ratio. METHODS. Data were provided by women participating in the National Cancer Institute (NCI) DES Combined Cohort Study. We used generalized estimating equations to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the relation of in utero DES exposure to sex ratio (proportion of male births). Models were adjusted for maternal age, child's birth year, parity, and cohort, and accounted for clustering among women with multiple pregnancies. RESULTS. The OR for having a male birth comparing DES-exposed to unexposed women was 1.05 (95% CI, 0.95-1.17). For exposed women with complete data on cumulative DES dose and timing (33%), those first exposed to DES earlier in gestation and to higher doses had the highest odds of having a male birth. The ORs were 0.91 (95% C, 0.65-1.27) for first exposure at ≥ 13 weeks gestation to < 5 g DES; 0.95 (95% CI, 0.71-1.27) for first exposure at ≥ 13 weeks to ≥ 5 g; 1.16 (95% CI, 0.96-1.41) for first exposure at < 13 weeks to < 5 g; and 1.24 (95% CI, 1.04-1.48) for first exposure at < 13 weeks to ≥ 5 g compared with no exposure. Results did not vary appreciably by maternal age, parity, cohort, or infertility history. CONCLUSIONS. Overall, no association was observed between in utero DES exposure and secondary sex ratio, but a significant increase in the proportion of male births was found among women first exposed to DES earlier in gestation and to a higher cumulative dose.Item Urogenital Abnormalities in Men Exposed to Diethylstilbestrol in Utero: A Cohort Study(BioMed Central, 2009-8-18) Palmer, Julie R.; Herbst, Arthur L.; Noller, Kenneth L.; Boggs, Deborah A.; Troisi, Rebecca; Titus-Ernstoff, Linda; Hatch, Elizabeth E.; Wise, Lauren A.; Strohsnitter, William C.; Hoover, Robert N.BACKGROUND: Diethylstilbestrol (DES), a synthetic estrogen widely prescribed to pregnant women during the 1940s-70s, has been shown to cause reproductive problems in the daughters. Studies of prenatally-exposed males have yielded conflicting results. METHODS: In data from a collaborative follow-up of three U.S. cohorts of DES-exposed sons, we examined the relation of prenatal DES exposure to occurrence of male urogenital abnormalities. Exposure status was determined through review of prenatal records. Mailed questionnaires (1994, 1997, 2001) asked about specified abnormalities of the urogenital tract. Risk ratios (RR) were estimated by Cox regression with constant time at risk and control for year of birth. RESULTS: Prenatal DES exposure was not associated with varicocele, structural abnormalities of the penis, urethral stenosis, benign prostatic hypertrophy, or inflammation/infection of the prostate, urethra, or epididymus. However, RRs were 1.9 (95% confidence interval 1.1-3.4) for cryptorchidism, 2.5 (1.5-4.3) for epididymal cyst, and 2.4 (1.5-4.4) for testicular inflammation/infection. Stronger associations were observed for DES exposure that began before the 11th week of pregnancy: RRs were 2.9 (1.6-5.2) for cryptorchidism, 3.5 (2.0-6.0) for epididymal cyst, and 3.0 (1.7-5.4) for inflammation/infection of testes. CONCLUSION: These results indicate that prenatal exposure to DES increases risk of male urogenital abnormalities and that the association is strongest for exposure that occurs early in gestation. The findings support the hypothesis that endocrine disrupting chemicals may be a cause of the increased prevalence of cryptorchidism that has been seen in recent years.