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1.  Influence of Body Weight, Ethnicity, Oral Contraceptives, and Pregnancy on the Pharmacokinetics of Azithromycin in Women of Childbearing Age 
Women of childbearing age commonly receive azithromycin for the treatment of community-acquired infections, including during pregnancy. This study determined azithromycin pharmacokinetics in pregnant and nonpregnant women and identified covariates contributing to pharmacokinetic variability. Plasma samples were collected by using a sparse-sampling strategy from pregnant women at a gestational age of 12 to 40 weeks and from nonpregnant women of childbearing age receiving oral azithromycin for the treatment of an infection. Pharmacokinetic data from extensive sampling conducted on 12 healthy women were also included. Plasma samples were assayed for azithromycin by high-performance liquid chromatography. Population data were analyzed by nonlinear mixed-effects modeling. The population analysis included 53 pregnant and 25 nonpregnant women. A three-compartment model with first-order absorption and a lag time provided the best fit of the data. Lean body weight, pregnancy, ethnicity, and the coadministration of oral contraceptives were covariates identified as significantly influencing the oral clearance of azithromycin and, except for oral contraceptive use, intercompartmental clearance between the central and second peripheral compartments. No other covariate relationships were identified. Compared to nonpregnant women not receiving oral contraceptives, a 21% to 42% higher dose-adjusted azithromycin area under the plasma concentration-time curve (AUC) occurred in non-African American women who were pregnant or receiving oral contraceptives. Conversely, azithromycin AUCs were similar between pregnant African American women and nonpregnant women not receiving oral contraceptives. Although higher levels of maternal and fetal azithromycin exposure suggest that lower doses be administered to non-African American women during pregnancy, the consideration of azithromycin pharmacodynamics during pregnancy should guide any dose adjustments.
PMCID: PMC3264225  PMID: 22106226
2.  Influence of Gestational Age and Body Weight on the Pharmacokinetics of Labetalol in Pregnancy 
Clinical pharmacokinetics  2014;53(4):373-383.
Background and Objectives
Labetalol is frequently prescribed for treatment of hypertension during pregnancy. However, the influence of pregnancy on labetalol pharmacokinetics is uncertain, with inconsistent findings reported by previous studies. This study examined the population pharmacokinetics of oral labetalol during and after pregnancy in women receiving labetalol for hypertension.
Data were collected from 57 women receiving the drug for hypertension from the 12th week of pregnancy through 12 weeks postpartum using a prospective, longitudinal design. A sparse sampling strategy guided collection of plasma samples. Samples were assayed for labetalol by high performance liquid chromatography. Estimation of population pharmacokinetic parameters and covariate effects was performed by nonlinear mixed effects modeling using NONMEM. Final population model was validated by bootstrap analysis and visual predictive check. Simulations were performed with the final model to evaluate the appropriate body weight to guide labetalol dosing.
Lean body weight (LBW) and gestational age, i.e., weeks of pregnancy, were identified as significantly influencing oral clearance (CL/F) of labetalol, with CL/F ranging from 1.4-fold greater than postpartum values at 12 weeks gestational age to 1.6-fold greater at 40 weeks. Doses adjusted for LBW provide more consistent drug exposure than doses adjusted for total body weight. The apparent volumes of distribution for the central compartment and at steady-state were 1.9-fold higher during pregnancy.
Gestational age and LBW impact the pharmacokinetics of labetalol during pregnancy and have clinical implications for adjusting labetalol doses in these women.
PMCID: PMC4310214  PMID: 24297680
3.  Women's Health: Racial and Ethnic Health Inequities 
Starting in the late 1980s and throughout the 1990s, reports appeared in the literature describing the poor health status and poor health outcomes experienced by minority populations, especially blacks, in the United States. Additionally, attention was brought to the limited access to health services for minority populations. These reports prompted Congress to request the Institute of Medicine (IOM) to conduct a study to assess differences in the kinds and quality of healthcare received by US racial and ethnic minorities and nonminorities. The study culminated in the report Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care.1 Among the recommendations included in the report published in 2003 is a need for (1) change in legal, regulatory, and policy interventions and (2) health systems interventions. The committee extended the recommendations to include (3) implementation of programs to enhance individual education and empowerment, (4) a need for research into identifying racial and ethnic disparities and the development of and assessment of intervention strategies, and (5) a need to integrate cross-cultural education into the training of all health professionals.1 Subsequent to this report, there has been an increase in efforts to increase diversity among healthcare providers and research investigators.2 The American Association of Medical Colleges (AAMC) continues to encourage recruitment of minorities to careers in medicine, to stress the importance of a diverse medical school faculty and administration, and to graduate culturally competent healthcare providers who will decrease health disparities and improve health equity. Additionally, as noted by Ginther et al in 2011, there continues to be a need to increase diversity at the National Institutes of Health (NIH) not only among the workforce but also among the recipients of awards.3 To this end, the NIH has established the Working Group on Diversity in the Biomedical Research Workforce to monitor the efforts of the NIH to increase diversity and to suggest remedies.4
PMCID: PMC3833574  PMID: 24416694
Women's health; racial; ethnic; inequities
5.  Nutrition and Physical Activity Cancer Prevention Guidelines, Cancer Risk, and Mortality in the Women's Health Initiative 
Healthy lifestyle behaviors are recommended to reduce cancer risk and overall mortality. Adherence to cancer-preventive health behaviors and subsequent cancer risk has not been evaluated in a diverse sample of postmenopausal women. We examined the association between the American Cancer Society (ACS) Nutrition and Physical Activity Cancer Prevention Guidelines score and risk of incident cancer, cancer-specific mortality, and all-cause mortality in 65,838 postmenopausal women enrolled in the Women’s Health Initiative Observational Study. ACS guidelines scores (0–8 points) were determined from a combined measure of diet, physical activity, body mass index (current and at age 18 years), and alcohol consumption. After a mean follow-up of 12.6 years, 8,632 incident cancers and 2,356 cancer deaths were identified. The highest ACS guidelines scores compared with the lowest were associated with a 17% lower risk of any cancer [HR, 0.83; 95% confidence interval (CI), 0.75–0.92], 22% lower risk of breast cancer (HR, 0.78; 95% CI, 0.67–0.92), 52% lower risk of colorectal cancer (HR, 0.48; 95% CI, 0.32–0.73), 27% lower risk of all-cause mortality, and 20% lower risk of cancer-specific mortality (HR, 0.80; 95% CI, 0.71–0.90). Associations with lower cancer incidence and mortality were generally strongest among Asian, black, and Hispanic women and weakest among non-Hispanic whites. Behaviors concordant with Nutrition and Physical Activity Cancer Prevention Guidelines were associated with lower risk of total, breast, and colorectal cancers and lower cancer-specific mortality in postmenopausal women.
PMCID: PMC4090781  PMID: 24403289
6.  The rationale, design, and baseline characteristics of the Women’s Health Initiative Memory Study of Younger Women (WHIMS-Y) 
Brain research  2013;1514:3-11.
The Women’s Health Initiative Memory Study-Younger (WHIMS-Y) was designed to assess the effect of prior random assignment to hormone therapy (HT) (conjugated equine estrogen (CEE) alone or CEE plus medroxyprogesterone acetate (MPA)) on global cognitive function in younger middle-aged women relative to placebo. WHIMS-Y was an ancillary study to the Women’s Health Initiative (WHI) HT trial and enrolled 1361 women who were aged 50-54 years and postmenopausal at WHI enrollment. WHIMS-Y will examine whether an average of 5.4 years of HT during early menopause has longer term protective effects on global cognitive function and if these effects vary by regimen, time between menopause and study initiation, and prior use of HT. We present the study rationale and design. We describe enrollment, adherence to assigned WHI therapy, and compare risk factor characteristics of the WHIMS-Y cohort at the time of WHI enrollment to similar aged women in the WHI HT who did not enroll in WHIMS-Y. Challenges of WHIMS-Y include lower than expected and differential enrollment. Strengths of WHIMS-Y include balance in baseline risk factors between treatment groups, standardized and masked data collection, and high rates of retention and on-trial adherence and exposure. In addition, the telephone-administered cognitive battery showed adequate construct validity. WHIMS-Y provided an unprecedented chance to examine the hypothesis that HT may have protective effects on cognition in younger postmenopausal women aged 50-54 years. Integrated into the WHI, WHIMS-Y optimized the experience of WHI investigators to ensure high retention and excellent quality assurance across sites.
PMCID: PMC3684042  PMID: 23578696
Postmenopausal hormone therapy; Cognitive function; Aging
7.  Breast Cancer after Use of Estrogen plus Progestin in Postmenopausal Women 
The New England journal of medicine  2009;360(6):573-587.
Following the release of the 2002 report of the Women’s Health Initiative (WHI) trial of estrogen plus progestin, the use of menopausal hormone therapy in the United States decreased substantially. Subsequently, the incidence of breast cancer also dropped, suggesting a cause-and-effect relation between hormone treatment and breast cancer. However, the cause of this decrease remains controversial.
We analyzed the results of the WHI randomized clinical trial — in which one study group received 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxy-progesterone acetate daily and another group received placebo — and examined temporal trends in breast-cancer diagnoses in the WHI observational-study cohort. Risk factors for breast cancer, frequency of mammography, and time-specific incidence of breast cancer were assessed in relation to combined hormone use.
In the clinical trial, there were fewer breast-cancer diagnoses in the group receiving estrogen plus progestin than in the placebo group in the initial 2 years of the study, but the number of diagnoses increased over the course of the 5.6-year intervention period. The elevated risk decreased rapidly after both groups stopped taking the study pills, despite a similar frequency of mammography. In the observational study, the incidence of breast cancer was initially about two times as high in the group receiving menopausal hormones as in the placebo group, but this difference in incidence decreased rapidly in about 2 years, coinciding with year-to-year reductions in combined hormone use. During this period, differences in the frequency of mammography between the two groups were unchanged.
The increased risk of breast cancer associated with the use of estrogen plus progestin declined markedly soon after discontinuation of combined hormone therapy and was unrelated to changes in frequency of mammography.
PMCID: PMC3963492  PMID: 19196674
8.  Determinants of Racial/Ethnic Disparities in Incidence of Diabetes in Postmenopausal Women in the U.S. 
Diabetes Care  2012;35(11):2226-2234.
To examine determinants of racial/ethnic differences in diabetes incidence among postmenopausal women participating in the Women’s Health Initiative.
Data on race/ethnicity, baseline diabetes prevalence, and incident diabetes were obtained from 158,833 women recruited from 1993–1998 and followed through August 2009. The relationship between race/ethnicity, other potential risk factors, and the risk of incident diabetes was estimated using Cox proportional hazards models from which hazard ratios (HRs) and 95% CIs were computed.
Participants were aged 63 years on average at baseline. The racial/ethnic distribution was 84.1% non-Hispanic white, 9.2% non-Hispanic black, 4.1% Hispanic, and 2.6% Asian. After an average of 10.4 years of follow-up, compared with whites and adjusting for potential confounders, the HRs for incident diabetes were 1.55 for blacks (95% CI 1.47–1.63), 1.67 for Hispanics (1.54–1.81), and 1.86 for Asians (1.68–2.06). Whites, blacks, and Hispanics with all factors (i.e., weight, physical activity, dietary quality, and smoking) in the low-risk category had 60, 69, and 63% lower risk for incident diabetes. Although contributions of different risk factors varied slightly by race/ethnicity, most findings were similar across groups, and women who had both a healthy weight and were in the highest tertile of physical activity had less than one-third the risk of diabetes compared with obese and inactive women.
Despite large racial/ethnic differences in diabetes incidence, most variability could be attributed to lifestyle factors. Our findings show that the majority of diabetes cases are preventable, and risk reduction strategies can be effectively applied to all racial/ethnic groups.
PMCID: PMC3476929  PMID: 22833490
9.  Genetic Determinants of Macular Pigments in Women of the Carotenoids in Age-Related Eye Disease Study 
To investigate genetic determinants of macular pigment optical density in women from the Carotenoids in Age-Related Eye Disease Study (CAREDS), an ancillary study of the Women's Health Initiative Observational Study.
1585 of 2005 CAREDS participants had macular pigment optical density (MPOD) measured noninvasively using customized heterochromatic flicker photometry and blood samples genotyped for 440 single nucleotide polymorphisms (SNPs) in 26 candidate genes related to absorption, transport, binding, and cleavage of carotenoids directly, or via lipid transport. SNPs were individually tested for associations with MPOD using least-squares linear regression.
Twenty-one SNPs from 11 genes were associated with MPOD (P ≤ 0.05) after adjusting for dietary intake of lutein and zeaxanthin. This includes variants in or near genes related to zeaxanthin binding in the macula (GSTP1), carotenoid cleavage (BCMO1), cholesterol transport or uptake (SCARB1, ABCA1, ABCG5, and LIPC), long-chain omega-3 fatty acid status (ELOVL2, FADS1, and FADS2), and various maculopathies (ALDH3A2 and RPE65). The strongest association was for rs11645428 near BCMO1 (βA = 0.029, P = 2.2 × 10−4). Conditional modeling within genes and further adjustment for other predictors of MPOD, including waist circumference, diabetes, and dietary intake of fiber, resulted in 13 SNPs from 10 genes maintaining independent association with MPOD. Variation in these single gene polymorphisms accounted for 5% of the variability in MPOD (P = 3.5 × 10−11).
Our results support that MPOD is a multi-factorial phenotype associated with variation in genes related to carotenoid transport, uptake, and metabolism, independent of known dietary and health influences on MPOD.
In 1585 postmenopausal women of the Carotenoids in Age-Related Eye Disease Study sample, common genetic variants in or near genes involved in carotenoid transport, uptake, and metabolism were associated with density of lutein and zeaxanthin in the macula, independent of other known predictors, including dietary intake of carotenoids.
PMCID: PMC3626525  PMID: 23404124
10.  The Effect of Calcium plus Vitamin D on Risk for Invasive Cancer: Results of the Women’s Health Initiative (WHI) Calcium Plus Vitamin D Randomized Clinical Trial 
Nutrition and Cancer  2011;63(6):827-841.
In the Women’s Health Initiative (WHI) trial of calcium plus vitamin D (CaD), we examined the treatment effect on incidence and mortality for all invasive cancers. Postmenopausal women (N = 36,282) were randomized to 1,000 mg of elemental calcium with 400 IU vitamin D3 or placebo. Cox models estimated risk of cancer incidence and mortality. After 7.0 yr, 1,306 invasive cancers were diagnosed in the supplement and 1,333 in the placebo group [hazard ratio (HR) = 0.98; CI = 0.90, 1.05, unweighted P = 0.54]. Mortality did not differ between supplement (315, annualized% = .26) and placebo [(347, 0.28%; P = 0.17; HR = 0.90 (0.77, 1.05)]. Significant treatment interactions on incident cancer were found for family history of cancer, personal total intake of vitamin D, smoking, and WHI dietary trial randomized group. Calcium/vitamin D supplementation did not reduce invasive cancer incidence or mortality. Supplementation lowered cancer risk in the WHI healthy diet trial arm and in women without a first-degree relative with cancer. The interactions are only suggestive given multiple testing considerations. The low vitamin D dose provided, limited adherence, and lack of serum 25(OH)D values should be considered when interpreting these findings.
PMCID: PMC3403703  PMID: 21774589
11.  Duration of Physical Activity and Serum 25-hydroxyvitamin D Status of Postmenopausal Women 
Annals of epidemiology  2011;21(6):440-449.
To investigate whether the association between physical activity and serum 25-hydroxyvitamin D (25(OH)D) concentrations is independent of sun exposure, body size, and other potential explanatory variables.
Using data from a sample of 1,343 postmenopausal women, from the Women’s Health Initiative, linear regression was used to examine the associations of duration (minutes/week) of recreational activity and of yard work with 25(OH)D concentrations (nmol/L).
In age-adjusted analyses, positive associations were observed between 25(OH)D concentrations and both duration of recreational physical activity (β=0.71, SE(0.09), P<0.001) and yard work (β=0.36, SE(0.10), P=0.004). After further adjustment for vitamin D intake, self-reported sunlight exposure, waist circumference, and season of blood draw, 25(OH)D was significantly associated with recreational activity (β=0.21, SE(0.09), P=0.014) but not with yard work (β=0.18, SE(0.09), P=0.061). Interactions were observed between season and both recreational activity (Pinteraction=0.082) and yard work (Pinteraction=0.038) such that these activity-25(OH)D associations were greater during summer/fall compared to winter/spring. Self-reported sunlight exposure and measures of body size did not modify the associations.
The observed age-adjusted activity-25(OH)D associations were attenuated after adjusting for explanatory variables and were modified by season of blood draw. Adopting a lifestyle that incorporates outdoor physical activity during summer/fall, consuming recommended amounts of vitamin D, and maintaining a healthy weight may improve or maintain vitamin D status in postmenopausal women.
PMCID: PMC3090482  PMID: 21414803
25-hydroxyvitamin D; vitamin D; serum; sunlight exposure; physical activity; epidemiology; women
12.  Vasomotor symptoms and cardiovascular events in postmenopausal women 
Menopause (New York, N.Y.)  2011;18(6):603-610.
Emerging evidence suggests that women with menopausal vasomotor symptoms (VMS) have increased cardiovascular disease (CVD) risk as measured by surrogate markers. We investigated the relationships between VMS and clinical CVD events and all-cause mortality in the Women's Health Initiative Observational Study (WHI-OS).
We compared the risk of incident CVD events and all-cause mortality between four groups of women (total N=60,027): (1) No VMS at menopause onset and no VMS at WHI-OS enrollment (no VMS [referent group]); (2) VMS at menopause onset, but not at WHI-OS enrollment (early VMS); (3) VMS at both menopause onset and WHI-OS enrollment (persistent VMS [early and late]); and (4) VMS at WHI-OS enrollment, but not at menopause onset (late VMS).
For women with early VMS (N=24,753), compared to no VMS (N=18,799), hazard ratios (HRs) and 95% confidence intervals (CIs) in fully-adjusted models were: major CHD, 0.94 (0.84, 1.06); stroke, 0.83 (0.72, 0.96); total CVD, 0.89 (0.81, 0.97); and all-cause mortality, 0.92 (0.85, 0.99). For women with persistent VMS (N=15,084), there was no significant association with clinical events. For women with late VMS (N=1,391) compared to no VMS, HRs and 95% CIs were: major CHD, 1.32 (1.01, 1.71); stroke, 1.14 (0.82, 1.59); total CVD, 1.23 (1.00, 1.52); and all-cause mortality, 1.29 (1.08, 1.54).
Early VMS were not associated with increased CVD risk. Rather, early VMS were associated with decreased risk of stroke, total CVD events, and all-cause mortality. Late VMS were associated with increased CHD risk and all-cause mortality. The predictive value of VMS for clinical CVD events may vary with onset of VMS at different stages of menopause. Further research examining the mechanisms underlying these associations is needed. Future studies will also be necessary to investigate whether VMS that develop for the first time in the later postmenopausal years represent a pathophysiologic process distinct from classical perimenopausal VMS.
PMCID: PMC3123435  PMID: 21358352
Vasomotor symptoms; Hot flashes; Cardiovascular disease; Women's health
13.  Characterization of 9p24 risk locus and colorectal adenoma and cancer: gene-environment interaction and meta-analysis 
A potential susceptibility locus for colorectal cancer on chromosome 9p24 (rs719725) was initially identified through a genome-wide association study, though replication attempts have been inconclusive.
We genotyped this locus and explored interactions with known risk factors as potential sources of heterogeneity, which may explain the previously inconsistent replication. We included Caucasians with colorectal adenoma or colorectal cancer and controls from four studies (total 3891 cases, 4490 controls): the Women’s Health Initiative (WHI); the Diet, Activity and Lifestyle Study (DALS); a Minnesota population-based case-control study (MinnCCS); and the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO). We used logistic regression to evaluate the association and test for gene-environment interactions.
SNP rs719725 was statistically significantly associated with risk of colorectal cancer in WHI (OR per A allele 1.19; 95% CI 1.01–1.40; p-trend 0.04), marginally associated with adenoma risk in PLCO (OR per A allele 1.11; 95% CI 0.99–1.25; p-trend 0.07), and not associated in DALS and MinnCCS. Evaluating for gene-environment interactions yielded no consistent results across the studies. A meta-analysis of seventeen studies (including these four) gave an OR per A allele of 1.07 (95% CI 1.03–1.12; p-trend 0.001).
Our results suggest the A allele for SNP rs719725 at locus 9p24 is positively associated with a small increase in risk for colorectal tumors. Environmental risk factors for colorectal cancer do not appear to explain heterogeneity across studies.
If this finding is supported by further replication and functional studies, it may highlight new pathways underlying colorectal neoplasia.
PMCID: PMC3005543  PMID: 20978172
colorectal; adenoma; cancer; 9p24; rs719725
14.  Excess Weight and Physical Health-Related Quality of Life in Postmenopausal Women of Diverse Racial/Ethnic Backgrounds 
Journal of Women's Health  2010;19(8):1449-1458.
Studies of weight and health-related quality of life (HRQOL) generally focus on white populations. This analysis examines the association between clinical weight categories and physical HRQOL in five racial/ethnic groups of older women and determines the extent to which emotional/psychological (social support, caregiver burden) and physical health (diabetes, osteoarthritis) factors modify this relationship.
The cross-sectional analysis, completed in 2007, used baseline data from postmenopausal women enrolled in the Women's Health Initiative (WHI) during the 5-year recruitment period (1993–1998).
Of 161,393 women, 83% were non-Hispanic white, 9% were African American, 4% were Hispanic/Latina, 3% were Asian/Pacific Islander, and <1% were American Indian/Alaska Native. Obesity (body mass index [BMI] ≥30 kg/m2) was most common in non-Asian minority groups. Regression modeling showed higher odds of poor physical HRQOL with increasing weight category in all groups. In the total sample, these odds were at least 6 times as high in women with class 3 obesity as in women of normal weight and were only mildly attenuated after the analysis adjusted for emotional/psychological factors. Further adjustment for physical health factors made odds ratio (OR) estimates drop from 2.36 to 1.59 for class 1 obesity and from 6.96 to 3.71 for class 3 obesity. This pattern generally persisted within each racial/ethnic group.
Heavier weight negatively affects physical HRQOL in postmenopausal women across diverse racial/ethnic backgrounds. Weight-relevant physical health factors have a greater impact on this weight-HRQOL association than do emotional/psychological factors.
PMCID: PMC2941408  PMID: 20629574
15.  Vitamin D Status and Early Age-Related Macular Degeneration in Postmenopausal Women 
Archives of ophthalmology  2011;129(4):481-489.
The relationship between serum 25-hydroxyvitamin D (25(OH)D) concentrations (nmol/L) and the prevalence of early age-related macular degeneration (AMD) was investigated among participants of the Carotenoids in Age-Related Eye Disease Study.
Stereoscopic fundus photographs, taken from 2001–2004, assessed AMD status. Baseline (1994–1998) serum samples were available for 25(OH)D assays in 1,313 women with complete ocular and risk factor data. Odds ratios (ORs) and 95% confidence intervals (CIs) for early AMD (n=241), among 1,287 without advanced disease, were estimated with logistic regression and adjusted for age, smoking, iris pigmentation, family history of AMD, cardiovascular disease, diabetes, and hormone therapy use.
In multivariate models, no significant relationship was observed between early AMD and 25(OH)D (OR for quintile 5 vs. 1=0.79, 95% CI=0.50–1.24; p for trend=0.47). A significant age interaction (p=0.0025) suggested selective mortality bias in women ≥75 years: serum 25(OH)D was associated with decreased odds of early AMD in women <75 years (n=968) and increased odds in women ≥75 years (n=319) (OR for quintile 5 vs. 1=0.52, 95% CI=0.29–0.91; p for trend=0.02 and 1.76, 95% CI=0.77–4.13; p for trend=0.05, respectively). Further adjustment for body mass index and recreational physical activity, predictors of 25(OH)D, attenuated the observed association in women <75 years. Additionally, among women <75 years, intake of vitamin D from foods and supplements was related to decreased odds of early AMD in multivariate models; no relationship was observed with self-reported time spent in direct sunlight.
High serum 25(OH)D concentrations may protect against early AMD in women <75 years.
PMCID: PMC3075411  PMID: 21482873
vitamin D; 25-hydroxyvitamin D; sunlight; diet; macular degeneration; cohort studies; epidemiology
16.  Characterization of the association between 8q24 and colon cancer: gene-environment exploration and meta-analysis 
BMC Cancer  2010;10:670.
Genome-wide association studies and subsequent replication studies have shown that single nucleotide polymorphisms (SNPs) in the chromosomal region 8q24 are associated with colorectal cancer susceptibility.
We examined 11 SNP markers in the 8q24 region between 128.47 and 128.54 Mb, using a total of 1,987 colon cases and 2,339 controls who self-reported as white from two independent, well-characterized study populations. Analysis was performed separately within each study, and combined using random effects meta-analysis. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) and to test for effect modification by known colon cancer risk factors. We also performed a meta-analysis combining our results with previous studies.
We observed evidence of association for four SNPs in low to high linkage disequilibrium (r2 ranging from 0.18 to 0.93) localized in a 16.2 kb region defined by rs10505477 and rs1056368. The combined results for our two studies of colon cancer showed an OR of 1.10 (95% CI: 1.01-1.20, Ptrend = 0.023), and a meta-analysis of our results with previously reported studies of colon and colorectal cancer strongly support the association for this SNP (combined OR for rs6983267 = 1.21, 95% CI: 1.18-1.24, p = 5.5 × 10-44). We did not observe any notable evidence of effect modification by known colon cancer risk factors, and risk did not differ significantly by tumor site or stage.
Our study confirms the association between polymorphisms on chromosome 8q24 and colon cancer risk and suggests that the susceptibility locus in region 8q24 is not strongly modified by various lifestyle, environmental, and demographic risk factors for colon cancer.
PMCID: PMC3017062  PMID: 21129217
17.  Psychiatric Disorders and Cognitive Dysfunction Among Older, Postmenopausal Women: Results From the Women’s Health Initiative Memory Study 
To estimate the frequency of depressive symptoms and selected psychiatric disorders in the Women’s Health Initiative Memory Study (WHIMS) cohort and related them to cognitive syndromes.
WHIMS was a randomized, double-blinded, placebo-controlled prevention clinical trial examining whether opposed and unopposed hormone therapy reduced the risk of dementia in healthy postmenopausal women. Participants scoring below a designated cutpoint on a cognitive screener received a comprehensive neuropsychiatric workup and adjudicated outcome of no cognitive impairment, mild cognitive impairment, or probable dementia.
Seven thousand four hundred seventy-nine WHIMS participants between age 65 and 79 years and free of dementia at the time of enrollment in WHIMS. Five hundred twenty-one unique participants contributed complete data required for these analyses.
Depressive symptoms were measured with the 15-item Geriatric Depression Scale and the presence of selected psychiatric disorders (major depression, generalized anxiety, and panic and alcohol abuse) was made using the PRIME-MD.
The 18% of women had at least one psychiatric disorder with depression being the most common (16%) followed by general anxiety or panic (6%) and alcohol abuse (1%). Depression and the presence of a psychiatric disorder were associated with impaired cognitive status. Participants having a psychiatric disorder were more than twice as likely to be diagnosed with cognitive impairment as those with no psychiatric disorder (odds ratio = 2.06, 95% confidence interval = 1.17–3.60). Older age, white race, and diabetes were also associated with cognitive impairment.
The frequency of a psychiatric disorder is associated with poorer cognitive functioning among older women enrolled in WHIMS. That approximately one in five women had a probable psychiatric disorder, most typically depression, highlights the need for greater detection and treatment efforts in this population.
PMCID: PMC2939041  PMID: 20104074
Psychiatric disorders; cognition; MCI; risk of dementia; comorbidity
18.  Resting heart rate as a low tech predictor of coronary events in women: prospective cohort study 
Objective To evaluate resting heart rate as an independent predictor of cardiovascular risk in women.
Design Prospective cohort study.
Setting The Women’s Health Initiative was undertaken at 40 research clinics in the United States.
Participants 129 135 postmenopausal women.
Main outcome measure Clinical cardiovascular events.
Results During a mean of 7.8 (SD 1.6) years of follow up, 2281 women were identified with myocardial infarction or coronary death and 1877 with stroke. We evaluated associations between resting heart rate and cardiovascular events in Cox regression models adjusted for multiple covariates. Higher resting heart rate was independently associated with coronary events (hazard ratio 1.26, 95% confidence interval 1.11 to 1.42 for highest [>76 beats per minute] v lowest quintile [≤62 beats per minute]; P=0.001), but not with stroke. The relation between heart rate and coronary events did not differ between white women and women from other ethnic groups (P for interaction=0.45) or between women with and without diabetes (P for interaction=0.31), but it was stronger in women aged 50-64 at baseline than in those aged 65-79 (P for interaction=0.009).
Conclusion Resting heart rate, a low tech and inexpensive measure of autonomic tone, independently predicts myocardial infarction or coronary death, but not stroke, in women.
Trial registration NCT00000611.
PMCID: PMC2640113  PMID: 19193613
19.  The XY Gonadal Agenesis Syndrome 
Journal of Medical Genetics  1973;10(3):288-293.
A patient with a 46,XY chromosome constitution showed the following main characteristics: eunuchoidal body habitus, lack of secondary sexual development, normal female external genitalia with absence of vagina, no gonadal structures, and complete lack of internal genitalia except for rudimentary ductal structures defined by histological examination. Her condition is clearly different from that of feminizing testis syndrome and Swyer syndrome individuals. We would like to include her and six similar patients from the literature in a newly defined `XY gonadal agenesis' syndrome.
PMCID: PMC1013035  PMID: 4774539

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