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1.  Peri-implant stress correlates with bone and cement morphology: micro-FE modeling of implanted cadaveric glenoids 
Aseptic loosening of cemented joint replacements is a complex biological and mechanical process, and remains a clinical concern especially in patients with poor bone quality. Utilizing high resolution finite element analysis of a series of implanted cadaver glenoids, the objective of this study was to quantify relationships between construct morphology and resulting mechanical stresses in cement and trabeculae.
Eight glenoid cadavers were implanted with a cemented central peg implant. Specimens were imaged by micro-CT, and subject-specific finite element models were developed. Bone volume fraction, glenoid width, implant-cortex distance, cement volume, cement-cortex contact, and cement-bone interface area were measured. Axial loading was applied to the implant of each model and stress distributions were characterized. Correlation analysis was completed across all specimens for pairs of morphological and mechanical variables.
The amount of trabecular bone with high stress was strongly negatively correlated with both cement volume and contact between the cement and cortex (r = −0.85 and −0.84, p < 0.05). Bone with high stress was also correlated with both glenoid width and implant-cortex distance.
Contact between the cement and underlying cortex may dramatically reduce trabecular bone stresses surrounding the cement, and this contact depends on bone shape, cement amount, and implant positioning.
PMCID: PMC4591115  PMID: 25929691
Finite element; Implant fixation; Cement morphology; Glenoid implant
2.  In-Vitro Evaluation of Two Types of Neonatal Oxygenators in Handling Gaseous Microemboli and Maintaining Optimal Hemodynamic Stability During Cardiopulmonary Bypass 
Usually only FDA-approved oxygenators are subject of studies by the international scientific community. The objective of this study is to evaluate two types of neonatal membrane oxygenators in terms of transmembrane pressure gradient, hemodynamic energy transmission and gaseous microemboli capture in simulated cardiopulmonary bypass systems.
We investigated the Braile Infant 1500 (Braile Biomédica, São José do Rio Preto, Brazil), an oxygenator commonly used in Brazilian operating rooms, and compared it to the Dideco Kids D100 (Sorin Group, Arvada, CO, USA), that is an FDA-approved and widely used model in the USA. Cardiopulmonary bypass circuits were primed with lactated Ringer's solution and packed red blood cells (Hematocrit 40%). Trials were conducted at flow rates of 500 ml/min and 700 ml/min at 35ºC and 25ºC. Real-time pressure and flow data were recorded using a custom-based data acquisition system. For gaseous microemboli testing, 5cc of air were manually injected into the venous line. Gaseous microemboli were recorded using the Emboli Detection and Classification Quantifier.
Braile Infant 1500 had a lower pressure drop (P<0.01) and a higher total hemodynamic energy delivered to the pseudopatient (P<0.01). However, there was a higher raw number of gaseous microemboli seen prior to oxygenator at lower temperatures with the Braile oxygenator compared to the Kids D100 (P<0.01).
Braile Infant 1500 oxygenator had a better hemodynamic performance compared to the Dideco Kids D100 oxygenator. Braile had more gaseous microemboli detected at the pre-oxygenator site under hypothermia, but delivered a smaller percentage of air emboli to the pseudopatient than the Dideco oxygenator.
PMCID: PMC5144558  PMID: 27982342
Cardiopulmonary Bypass. Pediatrics; Oxygenators, Membrane
3.  Bisphenol A Exposure and the Development of Wheeze and Lung Function in Children through Age Five Years 
JAMA pediatrics  2014;168(12):1131-1137.
Bisphenol A (BPA), a prevalent endocrine disrupting chemical, has been associated with wheezing in children, but few studies have examined its impact on lung function or wheeze in older children.
The objectives of this study were to test whether BPA exposure was associated with lung function, with wheeze, and with pattern of wheeze in children over the first five years.
A birth cohort study, enrolled during early pregnancy.
Greater Cincinnati, Ohio area.
398 mother-infant dyads,.
We collected maternal urine during pregnancy (16 and 28 weeks) and child urine annually to assess gestational and child BPA exposure.
Main Outcome Measures
We assessed parent-reported wheeze every 6 months for 5 years and measured child forced expiratory volume in one second (FEV1) at age 4 and 5 years. We evaluated associations of BPA with respiratory outcomes: FEV1, child wheeze, and wheeze phenotype.
Urinary BPA concentrations and FEV1 data were available for 208 children, and urinary BPA and parent-reported wheeze data were available for 360 children. Mean maternal urinary BPA ranged from 0.5 to 316 μg/g of creatinine. In multivariable analysis, every 10-fold increase in mean maternal urinary BPA was associated with 14.2% decrease in %FEV1 at 4 years (95% CI −24.5, −3.9) but no association was found at 5 years. In multivariable analysis, every 10-fold increase in mean maternal urinary BPA concentration was marginally associated with a 55% increase in the odds of wheezing (OR 1.55, 95% CI 0.91, 2.63). While mean maternal urinary BPA concentration was not associated with wheeze phenotypes, a 10-fold increase in 16 week maternal BPA was associated with a 4.3 fold increase in odds of persistent wheeze (OR 4.3, 95% CI 1.4, 13.3). Child BPA concentrations were not associated with FEV1 or wheeze.
Conclusions and Relevance
These results provide evidence that suggest that prenatal, but not postnatal, exposure to BPA is associated with diminished lung function and the development of persistent wheeze in children.
PMCID: PMC4535321  PMID: 25286153
4.  Identifying factors predicting iron deficiency in United States adolescent females using the ferritin and the body iron models 
Clinical nutrition ESPEN  2015;10(3):e118-e123.
Background & Aims
Iron deficiency is the most prevalent nutritional deficiency in the United States affecting 9–16% of female adolescents. With the primary purpose of detecting iron deficiency, primary care screening consists of a hemoglobin or hematocrit laboratory test. This method is simple and inexpensive, but tests for anemia, and is neither sensitive nor specific for iron deficiency. Alternate methods for diagnosing iron deficiency using the ferritin and body iron models are not widely utilized. The study objective was to compare iron deficiency risk factors among adolescent females defined by the ferritin and body iron models to better characterize those who may benefit from iron deficiency testing as opposed to the current anemia-based screen.
This cross-sectional study of female adolescents aged 12–21 years utilized National Health and Nutrition Examination Survey 2003–2006 data. Anemia was defined by standard hemoglobin cutoffs. The ferritin model defines iron deficiency through transferrin saturation, ferritin and erythrocyte protoporphyrin laboratory testing. Body iron calculates iron status with a formula involving transferrin receptor and ferritin. Bivariate and multivariable analyses examined associations between questionnaire responses and iron deficiency defined by each model.
Among 1765 participants, 2.7% were anemic. Iron deficiency prevalence was 13.1% and 9.1% by the ferritin and body iron models, respectively. Based on the model, anemia-based screening had a sensitivity of 15.6–18.8% for iron deficiency. Multivariable associations for ferritin model iron deficiency included age, race/ethnicity, activity level and medroxyprogresterone acetate injection. Age and food insecurity were significant using the body iron model.
Universal anemia-based screening misses the majority of iron-deficient adolescent females. The common risk factor identified here, adolescent age, may both inform preventive care guidelines on age-based screenings and prospective studies of adolescent iron deficiency risk factors.
PMCID: PMC4465114  PMID: 26086044
iron deficiency; anemia; adolescent females; screening; adolescent health; primary care
5.  Adolescent Anemia Screening During Ambulatory Pediatric Visits in the United States 
Journal of community health  2015;40(2):331-338.
The Centers for Disease Control and Prevention recommends anemia screening for reproductive age women every 5–10 years and annually for those with risk factors. Due to the lower risk of anemia among males, screening for men is recommended only if risk factors exist. The study objective was to examine health care professionals’ current anemia screening patterns for male and female adolescents. Data are from the 2001 –2004 National Ambulatory Medical Care Survey, a nationally representative sample of ambulatory visits to primary care practices. The frequency of anemia screening during preventive care visits by 12-21-year-olds was estimated by sex using a reported hemoglobin/hematocrit or complete blood count as an indicator of screening. Multivariable logistic regression identified patient, provider and practice-level factors associated with screening. During the study period, 1,263 preventive care visits occurred for 12-21 year-olds. In bivariate analysis, higher odds of anemia screening were observed for both younger females (OR 1.85; 95% CI [1.09-3.14]) and older males (1.83 [1.02-3.26]) compared to older females (> 16 years). In the multivariable model, odds of screening increased with non-white race 3.29 (1.84-5.88), tobacco use 3.57 (1.94-6.58), longer visit length 1.03 (1.01-1.06), and practice site acceptance of managed care plans 2.08 (1.04-4.14). Patient sex and age were not statistically significant predictors of screening. Although anemia is more prevalent among older adolescent females, they were not more likely to be screened. This suggests providers are not targeting groups at highest risk of anemia for screening.
PMCID: PMC4348148  PMID: 25194577
anemia; iron-deficiency; screening; adolescents
6.  Mindfulness-Based Stress Reduction for Overweight/Obese Women With and Without Polycystic Ovary Syndrome: Design and Methods of a Pilot Randomized Controlled Trial 
Contemporary clinical trials  2015;41:287-297.
Mindfulness-based stress reduction (MBSR) may be beneficial for overweight/obese women, including women with polycystic ovary syndrome (PCOS), as it has been shown to reduce psychological distress and improve quality of life in other patient populations. Preliminary studies suggest that MBSR may also have salutary effects on blood pressure and blood glucose. This paper describes the design and methods of an ongoing pilot randomized controlled trial evaluating the feasibility and effects of MBSR in PCOS and non-PCOS women who are overweight or obese. Eighty six (86) women with body mass index ≥25 kg/m2, including 31 women with PCOS, have been randomized to 8 weeks of MBSR or health education control, and followed for 16 weeks. The primary outcome is mindfulness assessed with the Toronto Mindfulness Scale. Secondary outcomes include measures of blood pressure, blood glucose, quality of life, anxiety and depression. Our overall hypothesis is that MBSR will increase mindfulness and ultimately lead to favorable changes in blood pressure, blood glucose, psychological distress and quality of life in PCOS and non-PCOS women. This would support the integration of MBSR with conventional medical treatments to reduce psychological distress, cardiovascular disease and diabetes in PCOS and non-PCOS women who are overweight or obese.
PMCID: PMC4380576  PMID: 25662105
Glucose; Obesity; Stress
7.  Time Related Increase in Urinary Testosterone Levels and Stable Semen Analysis Parameters after Bariatric Surgery in Men 
Reproductive biomedicine online  2014;30(2):150-156.
We sought to determine the time-course in androgen and semen parameters in men after weight loss associated with bariatric surgery with a prospective cohort study of 6 male subjects, age 18-40 years, meeting NIH bariatric surgery guidelines, conducted in 2005-2008, with study visits at baseline, then 1, 3, 6 and 12 months after surgery. All men had a Roux-en-y-Gastric-Bypass (RYGB) performed at Penn State Milton S. Hershey Medical Center. We collected at each visit biometric, questionnaire, serum, and urinary specimens as well as a semen analysis. Urinary integrated total testosterone levels increased significantly by 3 months after surgery, and remained elevated throughout the study. Circulating testosterone levels were also higher at 1 and 6 months after surgery, compared to baseline. Serum SHBG levels were significantly elevated at all time points post-operatively. After RYGB surgery, there were no significant changes in urinary estrogen metabolites (estrone 3-glucuronide) or serum estradiol levels, serial semen parameters, or male sexual function by questionnaire. This study supports the idea that a threshold of weight loss is necessary to improve male reproductive function by reversing male hypogonadism, manifested as increased testosterone levels. Further serial semen analysis results showed normal ranges for most parameters despite massive weight loss.
PMCID: PMC4566141  PMID: 25498592
hypogonadism; sexual dysfunction; obesity; androgens; semen; weight loss
8.  Chinese Obstetrics & Gynecology journal club: a randomised controlled trial 
BMJ Open  2016;6(1):e010178.
To assess whether a journal club model could improve comprehension and written and spoken medical English in a population of Chinese medical professionals.
Setting and participants
The study population consisted of 52 medical professionals who were residents or postgraduate master or PhD students in the Department of Obstetrics and Gynecology, Heilongjiang University of Chinese Medicine, China.
After a three-part baseline examination to assess medical English comprehension, participants were randomised to either (1) an intensive journal club treatment arm or (2) a self-study group. At the conclusion of the 8-week intervention participants (n=52) were re-tested with new questions.
Outcome measures
The primary outcome was the change in score on a multiple choice examination. Secondary outcomes included change in scores on written and oral examinations which were modelled on the Test of English as a Foreign Language (TOEFL).
Both groups had improved scores on the multiple choice examination without a statistically significant difference between them (90% power). However, there was a statistically significant difference between the groups in mean improvement in scores for both written (95% CI 1.1 to 5.0; p=0.003) and spoken English (95% CI 0.06 to 3.7; p=0.04) favouring the journal club intervention.
Interacting with colleagues and an English-speaking facilitator in a journal club improved both written and spoken medical English in Chinese medical professionals. Journal clubs may be suitable for use as a self-sustainable teaching model to improve fluency in medical English in foreign medical professionals.
Trial registration number
PMCID: PMC4735128  PMID: 26823180
9.  Smoking in infertile women with polycystic ovary syndrome: baseline validation of self-report and effects on phenotype 
Human Reproduction (Oxford, England)  2014;29(12):2680-2686.
Do women with polycystic ovary syndrome (PCOS) seeking fertility treatment report smoking accurately and does participation in infertility treatment alter smoking?
Self-report of smoking in infertile women with PCOS is accurate (based on serum cotinine levels) and smoking is unlikely to change over time with infertility treatment.
Women with PCOS have high rates of smoking and it is associated with worse insulin resistance and metabolic dysfunction.
Secondary study of smoking history from a large randomized controlled trial of infertility treatments in women with PCOS (N = 626) including a nested case–control study (N = 148) of serum cotinine levels within this cohort to validate self-report of smoking.
Women with PCOS, age 18–40, seeking fertility who participated in a multi-center clinical trial testing first-line ovulation induction agents conducted at academic health centers in the USA.
Overall, self-report of smoking in the nested case–control study agreed well with smoking status as determined by measure of serum cotinine levels, at 90% or better for each of the groups at baseline (98% of never smokers had cotinine levels <15 ng/ml compared with 90% of past smokers and 6% of current smokers). There were minor changes in smoking status as determined by serum cotinine levels over time, with the greatest change found in the smoking groups (past or current smokers). In the larger cohort, hirsutism scores at baseline were lower in the never smokers compared with past smokers. Total testosterone levels at baseline were also lower in the never smokers compared with current smokers. At end of study follow-up insulin levels and homeostatic index of insulin resistance increased in the current smokers (P < 0.01 for both) compared with baseline and with non-smokers. The chance for ovulation was not associated with smoking status, but live birth rates were increased (non-significantly) in never or past smokers.
The limitations include the selection bias involved in our nested case–control study, the possibility of misclassifying exposure to second hand smoke as smoking and our failure to capture self-reported changes in smoking status after enrollment in the trial.
Because self-report of smoking is accurate, further testing of smoking status is not necessary in women with PCOS. Because smoking status is unlikely to change during infertility treatment, extra attention should be focused on smoking cessation in current or recent smokers who seek or who are receiving infertility treatment.
Sponsored by the Eugene Kennedy Shriver National Institute of Child Health and Human Development of the U.S. National Institutes of Health.
PMCID: PMC4227579  PMID: 25324541
cigarette smoking; anovulation; hyperandrogenism; infertility; obesity
10.  High-dose Vitamin D Supplementation and Measures of Insulin Sensitivity in Polycystic Ovary Syndrome: a Randomized Controlled Pilot Trial 
Fertility and sterility  2014;101(6):1740-1746.
To determine the effects of high-dose vitamin D on insulin sensitivity in Polycystic Ovary Syndrome (PCOS).
Randomized placebo-controlled trial.
Academic medical center.
28 PCOS women.
Vitamin D3 12,000 International Units or placebo daily for 12 weeks.
Main Outcome Measures
The primary outcome was quantitative insulin sensitivity check index (QUICKI). Secondary outcomes included glucose and insulin levels during a 75-gram oral glucose tolerance test and blood pressure.
Twenty-two women completed the study. Compared to placebo, vitamin D significantly increased 25-hydroxyvitamin D (mean (95% confidence interval) in vitamin D group 20.1 (15.7 to 24.5) ng/ml at baseline and 65.7 (52.3 to 79.2) ng/ml at 12 weeks; placebo 22.5 (18.1 to 26.8) ng/ml at baseline and 23.8 (10.4 to 37.2) ng/ml at 12 weeks). There were no significant differences in QUICKI and other measures of insulin sensitivity, however we observed trends towards lower 2-hour insulin and lower 2-hour glucose. We also observed a protective effect of vitamin D on blood pressure.
In women with PCOS, insulin sensitivity was unchanged with high-dose vitamin D but there was a trend towards decreased 2-hour insulin and a protective effect on blood pressure.
Clinical Trial registration number Identifier: NCT00907153
PMCID: PMC4537163  PMID: 24636395
Polycystic Ovary Syndrome; vitamin D; insulin resistance; blood pressure
11.  Seasonal variation in muscle sympathetic nerve activity 
Physiological Reports  2015;3(8):e12492.
Epidemiologic data suggest there are seasonal variations in the incidence of severe cardiac events with peak levels being evident in the winter. Whether autonomic indices including muscle sympathetic nerve activity (MSNA) vary with season remains unclear. In this report, we tested the hypothesis that resting MSNA varies with the seasons of the year with peak levels evident in the winter. We analyzed the supine resting MSNA in 60 healthy subjects. Each subject was studied during two, three, or four seasons (total 237 visits). MSNA burst rate in the winter (21.0 ± 6.8 burst/min, mean ± SD) was significantly greater than in the summer (13.5 ± 5.8 burst/min, P < 0.001), the spring (17.1 ± 9.0 burst/min, P = 0.03), and the fall (17.9 ± 7.7 burst/min, P = 0.002). There was no significant difference in MSNA for other seasonal comparisons. The results suggest that resting sympathetic nerve activity varies along the seasons, with peak levels evident in the winter. We speculate that the seasonal changes in sympathetic activity may be a contribution to the previously observed seasonal variations in cardiovascular morbidity and mortality.
PMCID: PMC4562578  PMID: 26265752
Cardiovascular diseases; hemodynamic; nervous system; risk factors; sympathetic
12.  Elevated Dehydroepiandrosterone Sulfate Levels as the Reproductive Phenotype in the Brothers of Women with Polycystic Ovary Syndrome 
There is an inherited susceptibility to polycystic ovary syndrome (PCOS). Some investigators have suggested that premature male-pattern balding is a male phenotype in PCOS families, but this remains controversial. We recently reported evidence for an autosomal monogenic abnormality in ovarian and adrenal steroidogenesis in the sisters of women with PCOS. We performed this study to determine whether we could identify a clinical or biochemical phenotype in the brothers of women with PCOS. One hundred nineteen brothers of 87 unrelated women with PCOS and 68 weight- and ethnicity-comparable unrelated control men were examined and had fasting blood samples obtained. The odds of balding (Hamilton score ≥ V) did not differ in the brothers of PCOS women compared with control men. Brothers of women with PCOS had significantly elevated dehydroepiandrosterone sulfate (DHEAS) levels [brothers 3035 ± 1132 ng/ml (mean ± SD) vs. control men 2494 ± 1172 ng/ml; P < 0.05]. There was a significant positive linear relationship between DHEAS levels in PCOS probands and their brothers (r = 0.35; P = 0.001). There was no significant bimodal distribution in DHEAS levels, and there were no significant differences in other parameters in brothers of PCOS women with high DHEAS levels compared with those with low DHEAS levels. There is familial clustering of elevated DHEAS levels in the brothers of women with PCOS, suggesting that this is a genetic trait. This might reflect the same underlying defect in steroidogenesis that we found in the sisters of women with PCOS. Balding was not increased in the brothers of women with PCOS. We conclude that there is a biochemical reproductive endocrine phenotype in men in PCOS families.
PMCID: PMC4428582  PMID: 11994353
13.  Familial aggregation of circulating c-reactive protein in polycystic ovary syndrome 
What is the heritability of C-reactive protein (CRP) levels in women with polycystic ovary syndrome (PCOS) and their first-degree relatives?
Women with PCOS and their siblings are more likely to have elevated CRP levels when both of their parents have elevated CRP. This PCOS family-based study indicates that CRP levels are likely a heritable trait.
Previous studies have established that an elevated blood level of CRP is variably present in women with PCOS, and may be present independent of metabolic status.
A familial based phenotyping study consisting of 81 families comprised of PCOS patients and their first-degree relatives for 305 subjects.
Study conducted at an academic health center. An elevated CRP level was defined as >28.6 nmol/l. To account for familial clustering, generalized estimating equations with a logit link were used to model the association between elevated CRP levels in patients with PCOS and their siblings with their parental group (A = neither parent with elevated CRP; B = one parent with elevated CRP; C= both parents with elevated CRP), adjusting for gender, age and BMI of the offspring. We did additional heritability analyses by using a variance component estimation method for CRP levels, adjusting for sex, age and BMI.
We observed elevated CRP levels in 94% of the offspring in group C, 45% in group B and 10% in group A after adjusting for age, gender and BMI of the offspring. The median BMI of the offspring in group A, B and C were 30.0, 28.7 and 31.2 kg/m2, respectively. Heritability estimates of CRP levels ranged from 0.75 to 0.83 and remained significant after excluding for type 2 diabetes mellitus. Our small sample size increases the possibility of a type 1 error.
This is a single report in an adequately powered but limited sample size study identifying the strong heritability of CRP levels. Replication in other large family cohorts is necessary.
These findings support the concept that there is an increased cardiovascular disease risk profile in families of women with PCOS.
This research was supported by National Institutes of Health grants U54HD-034449 and P50 HD044405 (A.D.). Priyathama Vellanki is supported in part by NIH/NIDDK Training Grant T32 DK007169.
PMCID: PMC3571499  PMID: 23257395
C-reactive protein; cardiovascular risk; hyperandrogenism; heritability; first-degree relatives
14.  Chronic Heart Failure Does Not Attenuate the Total Activity of Sympathetic Outflow to Skin During Whole Body Heating 
Circulation. Heart failure  2013;6(2):271-278.
Previous studies show that the rise in skin blood flow and cutaneous vascular conductance (CVC) during heat stress is substantially attenuated in chronic heart failure (CHF) patients. The mechanism(s) responsible for this finding is not clear. In particular, little is known regarding the responses of skin sympathetic nerve activity (SSNA) that control the skin blood flow during heat stress in CHF patients. We examined the effects of a modest heat stress to test the hypothesis that SSNA responses could be attenuated in CHF.
Methods and Results
We assessed SSNA (microneurography) from the peroneal nerve and skin blood flow (forearm laser Doppler) in 9 patients with stable class II-III CHF and in matched healthy subjects during passive whole body heating with a water perfused suit. Whole body heating induced similar increases in internal temperature (~0.6 °C) in both groups. Whole body heat stress evoked similar SSNA activation in CHF patients (Δ891±110 units/min) and the control subjects (Δ787±84 units/min, P=0.66), while the elevation in forearm CVC in patients with CHF was significantly lower than that in healthy control subjects (Δ131±29 vs. Δ623±131%, P=0.001).
The present data show that SSNA activation during a modest whole body heat stress is not attenuated in CHF. Thus, the attenuated skin vasodilator response in CHF patients is not due to a reduction in total activity of sympathetic outflow to skin.
PMCID: PMC3738175  PMID: 23395933
autonomic; regional blood flow; vasodilation; heart failure
15.  Determination of vitamin D in relation to body mass index and race in a defined population of black and white women 
To examine the contributions of obesity and race to levels of 25-hydroxyvitamin D [25(OH)D] and parathyroid hormone (PTH) in a defined cohort of black and white women.
An interventional study was conducted from October 2004 to March 2008, among 219 healthy female volunteers. Serum 25(OH)D and PTH levels were determined in 117 African American women and 102 white women and the results were compared with body mass index (BMI), percentage body fat, serum lipids, and PTH levels.
Black women had lower median levels of 25(OH)D compared with white women (27.3 nmol/L vs 52.4 nmol/L; P<0.001). Serum levels of 25(OH)D below 50 nmol/L were found in 98% of black women and 45% of white women (P<0.001). The differences between the racial groups in the levels of 25(OH)D persisted despite adjustments for body weight, percentage body fat, and BMI. Black women had higher median serum levels of PTH than white women (31.9 pg/mL vs 22.3 pg/mL; P<0.01).
African American women are at significant risk for low vitamin D levels. Studies are needed to determine if low vitamin D status in young African American women is associated with a greater risk for vitamin D-related chronic diseases that can be reduced with vitamin D supplementation.
PMCID: PMC3438362  PMID: 22818533
25-hydroxyvitamin D; Obesity; Parathyroid hormone; Race; Vitamin D
16.  Effects of metformin in adolescents with polycystic ovary syndrome undertaking lifestyle therapy: a pilot randomized double-blind study 
Fertility and sterility  2011;95(8):2595-8.e1-6.
Our small study does not support the addition of metformin to the lifestyle of adolescents. Although there are favorable trends toward hyperandrogenism with metformin, these must be balanced against the increased rate of gastrointestinal side effects. However, other treatments were associated with an improved quality of life. (Fertil Steril® 2011;95:2595–8.©2011 by American Society for Reproductive Medicine.)
PMCID: PMC3783023  PMID: 21704212
Ovarian function; insulin action; nutrition; exercise; androgen
17.  Epinephrine is associated with both erectile dysfunction and lower urinary tract symptoms 
Fertility and sterility  2008;93(3):837-842.
To determine whether patients with erectile dysfunction (ED) have a higher incidence of insulin resistance (IR) when compared with controls.
Prospective case–control study.
Academic medical center.
Twenty-nine nondiabetic men aged 18–66 years were enrolled. Of these, 28 completed the study: 17 had ED, and 11 did not.
Validated ED questionnaires, examination, serum hormones evaluation, and oral glucose tolerance testing.
Main Outcome Measure(s)
Association of IR with ED.
The association between worsening degrees of both lower urinary tract symptoms (LUTS) and ED was reaffirmed, as was a potential correlation between the two—epinephrine. There was a negative association between serum levels of epinephrine and scores on the 5-item version of the International Index of Erectile Dysfunction for ED (Spearman correlation coefficient = −0.38). On the other hand, men with ED were not more likely to have IR compared with controls.
Epinephrine may be the common link between ED and LUTS.
PMCID: PMC3742327  PMID: 19062003
Erectile dysfunction; lower urinary tract symptoms; epinephrine; insulin resistance; metabolic syndrome
18.  Continuous Compared With Cyclic Oral Contraceptives for the Treatment of Primary Dysmenorrhea: A Randomized Controlled Trial 
Obstetrics and gynecology  2012;119(6):1143-1150.
To estimate whether continuous OCP (oral contraceptive pills) will result in more pain relief in primary dysmenorrhea patients than cyclic OCP, which induces withdrawal bleeding with associated pain and symptoms.
Material and Methods
We conducted a double-blind, randomized controlled trial comparing continuous to a cyclic 21/7 OCP regimen (gestodene 0.075 mg and ethinyl estradiol 20 mcg) for 6 months in 38 primary dysmenorrhea patients. The primary outcome was the difference in subjective perception of pain as measured by the Visual Analog Scale (VAS) over the period of 6 months.
Twenty-nine patients completed the study. In both groups, pain reduction measured by VAS declined over time and was significant at 6 months compared to baseline with no difference between groups. Continuous regimen was superior to cyclic regimen after one month (mean difference: -27.3; 95% CI: (-40.5,-14.2); p<0.001) and 3 months (mean difference: -17.8; 95% CI: (-33.4,-2.1); p=0.03) of treatment. Secondary outcomes noted no difference between groups in terms of menstrual distress as measured by the Moos Menstrual Distress Questionnaire. After 6 months, there was an increase in weight and decrease in systolic blood pressure in continuous compared with the cyclic group.
Both regimens of OCP are effective in the treatment of primary dysmenorrhea. Continuous OCP outperforms cyclic OCP in the short term, but this difference is lost after 6 months.
PMCID: PMC3631421  PMID: 22617578
19.  Twenty-four-Hour Ambulatory Blood Pressure Monitor Heart Rate: A Potential Marker for Gestational Hypertension in at-Risk Women 
American journal of perinatology  2011;29(5):339-346.
We prospectively correlated the 24-hour ambulatory blood pressure measurements (ABPM) to conventional sphygmomanometer blood pressure measurements (CSM) in women at risk for gestational hypertensive disorders (GHTNDs) and identified predictive factors from ABPM for GHTND. We analyzed 73 women with ≥1 risk factor for developing a GHTND. Using both the CSM and ABPM, the systolic blood pressure, diastolic blood pressure, mean arterial pressure (MAP), and heart rate (HR) were measured for 24 hours during three periods (14 to 24 weeks; 24 to 32 weeks; and 33 weeks to delivery). Correlation between the CSM and ABPM lessened as pregnancy progressed. Seventeen (25%) of women developed a GHTND. MAP variability increased in the GHTND group versus those without a GHTND. The odds of developing a GHTND increased 1.5 times for every 1 beat per minute increase in the ABPM 24-hour HR at visit 1 and reversed by visit 3. In women at risk for a GHTND, CSM and ABPM correlate less well as pregnancy advances. HR changes in at-risk women may be a marker for the development of a GHTND and may reflect increased sympathetic activity and/or decreased baroreceptor sensitivity.
PMCID: PMC3649547  PMID: 22147639
ambulatory blood pressure monitor; preeclampsia; gestational hypertension and heart rate
Contemporary Clinical Trials  2012;33(3):470-481.
Polycystic Ovary Syndrome (PCOS) is a common cause of female infertility and first line treatment is currently oral clomiphene citrate, a selective estrogen receptor modulator, which results in both a high nonresponse rate and multiple pregnancy rate. Aromatase inhibitors such as letrozole may have more favorable ovarian and endometrial effects. The goal of the Pregnancy in Polycystic Ovary Syndrome II (PPCOSII) study is to determine the safety and efficacy of clomiphene citrate (CC) compared to letrozole, in achieving live birth in infertile women with PCOS. The population will consist of 750 infertile women with PCOS. Additionally, the couple will have no other major infertility factor. This will be a multi-center, prospective, double-blind clinical trial of CC vs. letrozole for 5 treatment cycles (or approximately up to 25 weeks). The randomization scheme will be coordinated through the central data coordinating center (DCC) and the randomization is stratified by each participating site. After progestin withdrawal as needed, 750 women will be equally randomized to two different treatment arms: A) CC 50 mg every day for 5 days (day 3–7 of cycle), or B) letrozole 2.5 mg every day for 5 days (day 3–7 of cycle), for a total of 5 cycles or 25 weeks. The dose will be increased in subsequent cycles in both treatment groups for non-response or poor ovulatory response up to a maximum of 150 mg of CC a day (× 5 days) or 7.5 mg of letrozole a day (× 5 days). The primary analysis will use an intent-to-treat approach to examine differences in the live birth rate in the two treatment arms.
PMCID: PMC3312939  PMID: 22265923
Polycystic Ovary Syndrome; Infertility; Ovulation Induction; Hyperandrogenism; Clomiphene Citrate; Letrozole
21.  Evidence for increased cardiovascular events in the fathers but not mothers of women with polycystic ovary syndrome 
Human Reproduction (Oxford, England)  2011;26(8):2226-2231.
Polycystic ovary syndrome (PCOS) is a familial syndrome, associated with multiple cardiovascular disease (CVD) risk factors. Thus, parents of affected women may have a higher prevalence of CVD events than the general population.
PCOS probands (n = 410) and their participating parents (n = 180 fathers and 211 mothers) were queried for CVD events in themselves and non-participating family members. In order to include the family CVD history of all parents, agreement between the proband and parental reports of CVD events was assessed. Estimated 10-year coronary heart disease (CHD) risk was calculated using the Framingham risk calculator. The National Health and Nutrition Examination Survey (NHANES) 2001–2002 database was used to generate gender, age and body mass index-relevant population parameters of CVD prevalence in the USA population.
Ninety-eight percent of the parents' self-reporting of CVD events agreed with the proband's report of parental heart attack history [Kappa = 0.82; 95% CI: (0.69, 0.94)] and 99% with parental stroke history [Kappa = 0.79; 95% CI: (0.62, 0.97)]. Fathers of women with PCOS had a higher prevalence of heart attack and stroke compared with the reference NHANES population (heart attack: 11.1 versus 5.3%, P < 0.0001; stroke: 3.0 versus 1.0%, P = 0.002). Fathers of women with PCOS had an elevated 10-year risk for CHD (11.5 versus 9.9% in NHANES, P = 0.03). No statistically significant increased prevalence of CVD events or 10-year risk was noted in probands or mothers.
Fathers, and not mothers, may be disproportionately burdened with CVD in PCOS families. The strengths of this study include the size of our cohort, the consistent phenotyping and the validation of proband's reporting of parental CVD events.
PMCID: PMC3137384  PMID: 21505042
insulin resistance; androgens; dyslipidemia; hypertension; stroke
22.  Racial Influence on the Polycystic Ovary Syndrome Phenotype: A Black White Case-Control Study 
Fertility and sterility  2011;96(1):224-229.e2.
To estimate racial disparities in PCOS phenotype between White and Black women with PCOS.
Case/control study
Two academic medical centers
242 women off of confounding medications in otherwise good health
Phenotyping during the follicular phase or anovulation after overnight fast in women.
Main outcome measures
Biometric, serum hormones, glycemic and metabolic parameters, and body composition by DEXA.
We studied 77 White and 43 Black women with PCOS and 35 White and 87 Black controls. Black women with PCOS were very similar reproductively to White women with PCOS. Black women with PCOS had lower serum transaminases, higher HDL-C levels[mean difference (MD): 18.2; 95% CI: (14.3, 22.1) mg/dL], lower triglycerides(MD: -43.2 mg/dL; 95% CI: (-64.5, -21.9)), and enhanced insulinogenic index on the oral glucose tolerance test compared to White women with PCOS. Blacks with PCOS had higher bone mineral density(MD: 0.1 g/cm2; 95% CI: (0.1, 0.2)) and lower percent body fat on DXA (MD: -2.8%; 95% CI:(-5.1, - 0.5)), and overall a higher quality of life. While most of these findings disappeared when the differences with racially matched controls were compared, Black women with PCOS compared to Black controls had lower estradiol levels than White PCOS women compared to White controls(MD: -12.9 pg/mL; 95% CI: (-24.9, -0.8)), higher systolic blood pressure(MD: 9.1 mm Hg; 95% CI: (0.8, 17.4)), and lower fasting glucose levels(MD: -12.0 mg/dL; 95% CI: (-22.3, - 1.7)).
Racial disparities in PCOS phenotype are minor and mixed. Future studies should explore if race impacts on treatment effects.
PMCID: PMC3132396  PMID: 21723443
23.  Incomplete and Inconsistent Reporting of Maternal and Fetal Outcomes in Infertility Treatment Trials 
Fertility and sterility  2011;95(8):2527-2530.
Pregnancy outcomes and adverse outcomes in infertility trials are reported to varying extents, e.g. 35% of clinical trials reported no information on pregnancy loss, only 43% reported adverse events during the preconception treatment period and only 7% reported any serious adverse events. Incomplete reporting limits the value of these studies in counseling patients on the risk/benefit ratio of treatment to themselves and their babies.
PMCID: PMC3124604  PMID: 21435640
miscarriage; multiple pregnancy; morbidity; mortality; fetal anomaly; intrauterine fetal demise; adverse event
24.  Prenatal Exposure to Bisphenol A and Child Wheeze from Birth to 3 Years of Age 
Environmental Health Perspectives  2012;120(6):916-920.
Background: Bisphenol A (BPA), an endocrine-disrupting chemical that is routinely detected in > 90% of Americans, promotes experimental asthma in mice. The association of prenatal BPA exposure and wheeze has not been evaluated in humans.
Objective: We examined the relationship between prenatal BPA exposure and wheeze in early childhood.
Methods: We measured BPA concentrations in serial maternal urine samples from a prospective birth cohort of 398 mother–infant pairs and assessed parent-reported child wheeze every 6 months for 3 years. We used generalized estimating equations with a logit link to evaluate the association of prenatal urinary BPA concentration with the dichotomous outcome wheeze (wheeze over the previous 6 months).
Results: Data were available for 365 children; BPA was detected in 99% of maternal urine samples during pregnancy. In multivariable analysis, a one-unit increase in log-transformed creatinine-standardized mean prenatal urinary BPA concentration was not significantly associated with child wheeze from birth to 3 years of age, but there was an interaction of BPA concentration with time (p = 0.003). Mean prenatal BPA above versus below the median was positively associated with wheeze at 6 months of age [adjusted odds ratio (AOR) = 2.3; 95% confidence interval (CI): 1.3, 4.1] but not at 3 years (AOR = 0.6; 95% CI: 0.3, 1.1). In secondary analyses evaluating associations of each prenatal BPA concentration separately, urinary BPA concentrations measured at 16 weeks gestation were associated with wheeze (AOR = 1.2; 95% CI: 1.0, 1.5), but BPA concentrations at 26 weeks of gestation or at birth were not.
Conclusions: Mean prenatal BPA was associated with increased odds of wheeze in early life, and the effect diminished over time. Evaluating exposure at each prenatal time point demonstrated an association between wheeze from 6 months to 3 years and log-transformed BPA concentration at 16 weeks gestation only.
PMCID: PMC3385426  PMID: 22334053
bisphenol A; BPA; child; cotinine; prenatal; tobacco; wheeze
25.  Effects of atorvastatin on vascular function, inflammation, and androgens in women with polycystic ovary syndrome: a double-blind, randomized placebo-controlled trial 
Fertility and sterility  2010;95(5):1849-1852.
In order to determine the effects of statins on vascular function, inflammation and androgen levels in women with polycystic ovary syndrome (PCOS), we randomized 20 women with PCOS who had LDL-cholesterol levels >100 mg/dl to atorvastatin (40 mg/day) or placebo for six weeks and found that atorvastatin reduced androgen levels, biomarkers of inflammation, and blood pressure, increased insulin levels and brachial artery conductance during reactive hyperemia, and failed to improve brachial artery flow-mediated dilation. We conclude that until additional studies demonstrate a clear risk-to-benefit ratio favoring statin therapy in PCOS, statins should only be used in PCOS women who meet current indications for statin treatment.
PMCID: PMC3062732  PMID: 21144505
statin; PCOS; hyperandrogenemia; vascular function; hyperinsulinemia

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