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1.  Familial aggregation of circulating c-reactive protein in polycystic ovary syndrome 
STUDY QUESTION
What is the heritability of C-reactive protein (CRP) levels in women with polycystic ovary syndrome (PCOS) and their first-degree relatives?
SUMMARY ANSWER
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.
WHAT IS KNOWN ALREADY
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.
STUDY DESIGN, SIZE AND DURATION
A familial based phenotyping study consisting of 81 families comprised of PCOS patients and their first-degree relatives for 305 subjects.
PARTICIPANTS/MATERIALS, SETTING AND METHODS
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.
MAIN RESULTS AND THE ROLE OF CHANCE
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.
LIMITATIONS, REASONS FOR CAUTION
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.
WIDER IMPLICATION OF THE FINDINGS
These findings support the concept that there is an increased cardiovascular disease risk profile in families of women with PCOS.
STUDY FUNDING/COMPETING INTEREST
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.
doi:10.1093/humrep/des416
PMCID: PMC3571499  PMID: 23257395
C-reactive protein; cardiovascular risk; hyperandrogenism; heritability; first-degree relatives
2.  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.
Background
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).
Conclusions
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.
doi:10.1161/CIRCHEARTFAILURE.112.000135
PMCID: PMC3738175  PMID: 23395933
autonomic; regional blood flow; vasodilation; heart failure
3.  Determination of vitamin D in relation to body mass index and race in a defined population of black and white women 
Objective
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.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1016/j.ijgo.2012.05.024
PMCID: PMC3438362  PMID: 22818533
25-hydroxyvitamin D; Obesity; Parathyroid hormone; Race; Vitamin D
4.  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.)
doi:10.1016/j.fertnstert.2011.05.048
PMCID: PMC3783023  PMID: 21704212
Ovarian function; insulin action; nutrition; exercise; androgen
5.  Epinephrine is associated with both erectile dysfunction and lower urinary tract symptoms 
Fertility and sterility  2008;93(3):837-842.
Objective
To determine whether patients with erectile dysfunction (ED) have a higher incidence of insulin resistance (IR) when compared with controls.
Design
Prospective case–control study.
Setting
Academic medical center.
Patient(s)
Twenty-nine nondiabetic men aged 18–66 years were enrolled. Of these, 28 completed the study: 17 had ED, and 11 did not.
Intervention(s)
Validated ED questionnaires, examination, serum hormones evaluation, and oral glucose tolerance testing.
Main Outcome Measure(s)
Association of IR with ED.
Result(s)
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.
Conclusion(s)
Epinephrine may be the common link between ED and LUTS.
doi:10.1016/j.fertnstert.2008.10.034
PMCID: PMC3742327  PMID: 19062003
Erectile dysfunction; lower urinary tract symptoms; epinephrine; insulin resistance; metabolic syndrome
6.  Continuous Compared With Cyclic Oral Contraceptives for the Treatment of Primary Dysmenorrhea: A Randomized Controlled Trial 
Obstetrics and gynecology  2012;119(6):1143-1150.
Objective
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.
Results
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.
Conclusions
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.
doi:10.1097/AOG.0b013e318257217a
PMCID: PMC3631421  PMID: 22617578
7.  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.
doi:10.1055/s-0031-1295643
PMCID: PMC3649547  PMID: 22147639
ambulatory blood pressure monitor; preeclampsia; gestational hypertension and heart rate
8.  THE PREGNANCY IN POLYCYSTIC OVARY SYNDROME II (PPCOS II) TRIAL: RATIONALE AND DESIGN OF A DOUBLE-BLIND RANDOMIZED TRIAL OF CLOMIPHENE CITRATE AND LETROZOLE FOR THE TREATMENT OF INFERTILITY IN WOMEN WITH POLYCYSTIC OVARY SYNDROME 
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.
doi:10.1016/j.cct.2011.12.005
PMCID: PMC3312939  PMID: 22265923
Polycystic Ovary Syndrome; Infertility; Ovulation Induction; Hyperandrogenism; Clomiphene Citrate; Letrozole
9.  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.
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
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.
doi:10.1093/humrep/der101
PMCID: PMC3137384  PMID: 21505042
insulin resistance; androgens; dyslipidemia; hypertension; stroke
10.  Racial Influence on the Polycystic Ovary Syndrome Phenotype: A Black White Case-Control Study 
Fertility and sterility  2011;96(1):224-229.e2.
Objective
To estimate racial disparities in PCOS phenotype between White and Black women with PCOS.
Design
Case/control study
Setting
Two academic medical centers
Patients
242 women off of confounding medications in otherwise good health
Interventions
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.
Results
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)).
Conclusion
Racial disparities in PCOS phenotype are minor and mixed. Future studies should explore if race impacts on treatment effects.
doi:10.1016/j.fertnstert.2011.05.002
PMCID: PMC3132396  PMID: 21723443
11.  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.
doi:10.1016/j.fertnstert.2011.02.040
PMCID: PMC3124604  PMID: 21435640
miscarriage; multiple pregnancy; morbidity; mortality; fetal anomaly; intrauterine fetal demise; adverse event
12.  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.
doi:10.1289/ehp.1104175
PMCID: PMC3385426  PMID: 22334053
bisphenol A; BPA; child; cotinine; prenatal; tobacco; wheeze
13.  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.
doi:10.1016/j.fertnstert.2010.11.040
PMCID: PMC3062732  PMID: 21144505
statin; PCOS; hyperandrogenemia; vascular function; hyperinsulinemia
14.  Brachial Artery Conductance During Reactive Hyperemia is Increased in Women with Polycystic Ovary Syndrome 
Objective
To examine changes in brachial artery conductance (BAC) during reactive hyperemia in women with polycystic ovary syndrome (PCOS) compared to controls.
Study Design
This is a pilot case-control study performed at a single academic medical center. Changes in BAC during reactive hyperemia were evaluated in 31 women with PCOS and 11 healthy control women. Fasting glucose, insulin, lipids and androgen levels were also determined. A mixed-effects model was used to compare the PCOS curve to the control curve for change in BAC from baseline during reactive hyperemia.
Results
Body mass index (BMI) and testosterone levels were significantly increased in the PCOS group compared to controls (P < 0.05). In addition, the PCOS group had higher total and LDL cholesterol levels (P = 0.05 and 0.09, respectively). Change in BAC from baseline during reactive hyperemia was significantly increased in the PCOS group compared to controls even after adjusting for age, BMI and LDL cholesterol levels (P < 0.0001). There were no significant differences between the two groups in age, blood pressure, or fasting glucose or insulin levels.
Conclusions
Brachial artery conductance during reactive hyperemia is significantly increased in women with PCOS compared to controls and may be a novel early indicator of increased cardiovascular risk in women with PCOS.
doi:10.1016/j.ejogrb.2010.10.027
PMCID: PMC3046318  PMID: 21112136
polycystic ovary syndrome; androgen excess; brachial artery; conductance; cardiovascular risk
15.  The Effects of Metformin with Lifestyle Therapy in Polycystic Ovary Syndrome: A Randomized Double Blind Study 
Fertility and sterility  2010;95(3):1059-66.e1-7.
Objective
To determine if the combination of lifestyle(caloric restriction and exercise) and metformin(MET) would be superior to placebo and lifestyle(PBO) in improving PCOS phenotype.
Design
Double-blind randomized 6 month trial of MET vs PBO
Setting
Two academic medical centers
Patients
114 subjects
Interventions
Subjects collected urines daily for ovulation monitoring, had monthly monitoring of hormones/weight, and determination of body composition by DXA, glucose tolerance, and quality of life at baseline and completion.
Main outcome measures
Ovulation rates and testosterone levels
Results
Dropout rates were high. There was no significant difference in ovulation rates. Testosterone levels were significantly lower compared to baseline in the MET group at 3 mos but not at 6 mos. There were no differences in weight loss between groups, but MET showed a significant decline at 6 mos compared to baseline(−3.4 kg, 95% CI:(−5.3, −1.5)). We noted divergent effects of MET vs PBO on OGTT indices of insulin sensitivity (increased) and secretion (worsened). Total bone mineral density (BMD) increased significantly in MET. There were no differences in QOL measures between groups. MET had increased diarrhea and headache, but fewer bladder infections and musculoskeletal complaints.
Conclusions
The addition of metformin to lifestyle produced little reproductive or glycemic benefit in women with PCOS, though our study had limited power due to high dropout. It is not possible at baseline to identify women likely to drop out.
doi:10.1016/j.fertnstert.2010.12.002
PMCID: PMC3073705  PMID: 21193187
ovarian function; insulin action; nutrition; exercise; androgen
16.  A Variant in the Fibrillin-3 Gene is Associated with TGF-β and Inhibin B Levels in Women with Polycystic Ovary Syndrome 
Fertility and sterility  2010;94(7):2916-2919.
In an attempt to evaluate the association between Allele 8 (A8) of D19S884 in the fibrillin-3 gene and circulating TGF-β and inhibin levels in women with polycystic ovary syndrome (PCOS), we studied 120 similarly aged women from families with PCOS and compared 40 women with PCOS who did not have A8 (A8− PCOS) to 40 women with PCOS who had A8 (A8+ PCOS) and 40 normally menstruating women who did not have either PCOS or A8 (A8− Non-PCOS). A8−PCOS is associated with higher levels of TGF-β1 compared to A8+ PCOS or A8− Non-PCOS, similar levels of TGF-β2 compared to A8+ PCOS but lower levels of TGF-β2 compared to A8− Non-PCOS, and lower levels of Inhibin B and aldosterone compared to A8+ PCOS.
doi:10.1016/j.fertnstert.2010.05.047
PMCID: PMC2989416  PMID: 20630504
polycystic ovary syndrome; TGF-β; inhibin; fibrillin; genetic association study; hyperandrogenism; insulin resistance
17.  A Water Extract of Mucuna pruriens Provides Long-Term Amelioration of Parkinsonism with Reduced Risk for Dyskinesias 
Parkinsonism & related disorders  2010;16(7):458-465.
Dopaminergic anti-parkinsonian medications, such as levodopa (LD) cause drug-induced dyskinesias (DID) in majority of patients with Parkinson's disease (PD). Mucuna pruriens, a legume extensively used in Ayurveda to treat PD, is reputed to provide anti-parkinsonian benefits without inducing DID. We compared the behavioral effects of chronic parenteral administration of a water extract of Mucuna pruriens seed powder (MPE) alone without any additives, MPE combined with the peripheral dopa-decarboxylase inhibitor (DDCI) benserazide (MPE+BZ), LD+BZ and LD alone without BZ in the hemiparkinsonian rat model of PD. A battery of behavioral tests assessed by blinded investigators served as outcome measures in these randomized trials. In experiment 1, animals that received LD+BZ or MPE+BZ at high (6mg/Kg) and medium (4mg/Kg) equivalent doses demonstrated significant alleviation of parkinsonism, but, developed severe dose-dependent DID. LD+BZ at low doses (2mg/Kg) did not provide significant alleviation of parkinsonism. In contrast, MPE+BZ at an equivalent low dose significantly ameliorated parkinsonism. In experiment 2, MPE without any additives (12mg/Kg and 20mg/Kg LD equivalent dose) alleviated parkinsonism with significantly less DID compared to LD+BZ or MPE+BZ. In experiment 3, MPE without additives administered chronically provided long-term anti-parkinsonian benefits without causing DID. In experiment 4, MPE alone provided significantly more behavioral benefit when compared to the equivalent dose of synthetic LD alone without BZ. In experiment 5, MPE alone reduced the severity of DID in animals initially primed with LD+BZ. These findings suggest that Mucuna pruriens contains water soluble ingredients that either have an intrinsic DDCI-like activity or mitigate the need for an add-on DDCI to ameliorate parkinsonism. These unique long-term antiparkinsonian effects of a parenterally administered water extract of Mucuna pruriens seed powder may provide a platform for future drug discoveries and novel treatment strategies in PD.
doi:10.1016/j.parkreldis.2010.04.015
PMCID: PMC2909380  PMID: 20570206
basal ganglia; 6-hydroxydopamine (6-OHDA); nigrostriatal degeneration; movement disorders; complementary and alternative medicine
19.  Comparison of hormonal and metabolic markers after a high-fat, Western meal versus a low-fat, high-fiber meal in women with polycystic ovary syndrome 
Fertility and sterility  2008;91(4):1175-1182.
Objective
To determine the effect of meal composition on postprandial testosterone levels in women with polycystic ovary syndrome (PCOS).
Design
Randomized, crossover design.
Setting
Academic research center.
Patients
Fifteen women with PCOS.
Intervention
We evaluated changes in testosterone, sex hormone binding globulin (SHBG), DHEA-S, cortisol, glucose, and insulin for six hours after a high-fat, Western meal (HIFAT) (62% fat, 24% carbohydrate, 1g fiber) and an isocaloric low-fat, high-fiber meal (HIFIB) (6% fat, 81% carbohydrate, 27g fiber).
Main outcome measure
Change in testosterone.
Results
Testosterone decreased 27% within two hours after both meals (P<0.001). However, testosterone remained below premeal values for four hours after the HIFIB meal (P<0.004) and six hours after the HIFAT meal (P<0.004). Insulin was two fold higher for two hours after the HIFIB meal compared with the HIFAT meal (P<0.03). Glucose was higher for one hour after the HIFIB meal compared with the HIFAT meal (P<0.003). DHEA-S decreased 8−10% within 2−3 hours after both meals, then increased over the remainder of the study period (P<0.001). Cortisol decreased over the 6-hour period after both meals (P<0.001).
Conclusions
Diet plays a role in the regulation of testosterone levels in women with PCOS. Further studies are needed to determine the role of diet composition in the treatment of PCOS. (ClinicalTrials.gov Identifier: NCT0455338).
doi:10.1016/j.fertnstert.2008.01.035
PMCID: PMC2677685  PMID: 18331737
insulin resistance; hyperandrogenism; postprandial; testosterone; fiber
20.  Diminished Paternity and Gonadal Function with Increasing Obesity in Males 
Fertility and sterility  2008;90(2):346-351.
Objective
To examine the relationship of male obesity and reproductive function.
Design
Observational study
Setting
Academic medical center
Patients
87 adult males, body mass index (BMI) range from 16.1 to 47.0 kg/m2 (mean = 29.3 kg/m2 ,SD=6.5 kg/m2).
Interventions
None
Main Outcome Measures
Reproductive history, physical examination, inhibin B, FSH, LH, testosterone, unbound testosterone (uT) levels and semen-analysis.
Results
BMI was negatively correlated with testosterone (R = −0.38, P <0.001), FSH (R = −0.22, P = 0.042) and inhibin B levels (R = −0.21, P = 0.048), and was positively correlated with estradiol levels (R = 0.34, P = 0.001). Testosterone also negatively correlated with skin fold thickness (SFT) (R = −0.30, P = 0.005). There was no correlation of BMI or SFT with semen-analysis parameters (sperm density, volume, motility or morphology). Inhibin B level correlated significantly with sperm motility (R = 0.23, P = 0.045). Males with paternity had lower BMIs (28.0 kg/m2 vs. 31.6 kg/m2; P = 0.037) and lower SFT (24.7 mm vs. 34.1 mm; P = 0.016) than males without.
Conclusions
Obesity is an infertility factor in otherwise normal males. Obese males demonstrate a relative hypogonadotropic hypogonadism. Reduced inhibin B levels and diminished paternity suggest compromised reproductive capacity in this population.
doi:10.1016/j.fertnstert.2007.06.046
PMCID: PMC2597471  PMID: 18291378
Male infertility; inhibin B; semen; body fat distribution
21.  Urine Markers Do Not Predict Biopsy Findings or Presence of Bladder Ulcers in Interstitial Cystitis/Painful Bladder Syndrome 
The Journal of urology  2008;179(5):1850-1856.
Purpose
To test for associations between urine markers, bladder biopsy features and bladder ulcers in interstitial cystitis/painful bladder syndrome (IC/PBS).
Materials and Methods
Subjects were 72 patients with IC/PBS undergoing bladder distention and biopsy. Urine was collected before the procedure. Urine marker levels were correlated with biopsy and cystoscopic findings. Patients with no previous IC/PBS treatments (n=47) were analyzed separately from previously treated patients (n=25).
Results
For untreated patients, urine IL-6 and cGMP were associated with urothelial EGF receptor staining (for IL-6 r=0.29, 95% CI (0.07, 0.51), p=0.01; for cGMP r=0.34, 95% CI (0.13, 0.55), p=0.002). Urine IL-8 was negatively associated with urothelial HB-EGF staining (r=-0.34, 95% CI (-0.55, -0.12), p=0.002) and positively associated with lamina propria mast cell count (r=0.29, 95% CI (0.06, 0.52), p=0.01). The latter association also was seen in treated patients (r=0.46, 95% CI (0.20, 0.73), p<0.001). None of the urine markers was significantly different for ulcer vs. nonulcer patients. All of the ulcer patients had extensive inflammation on bladder biopsy: severe mononuclear cell infiltration, moderate or strong IL-6 staining in the urothelium and lamina propria, and LCA staining in >10% of the lamina propria. However, these features also were seen in 24-76% of the nonulcer patients.
Conclusions
Overall, urine markers did not associate robustly with biopsy findings. The strongest association was a positive association between urine IL-8 levels and bladder mast cell count. Ulcer patients consistently had bladder inflammation, but the cystoscopic finding of ulcers was not a sensitive indicator of inflammation on bladder biopsy.
doi:10.1016/j.juro.2008.01.047
PMCID: PMC2705752  PMID: 18353383
interstitial cystitis, urine; interstitial cystitis, pathology; interstitial cystitis, physiopathology
22.  Analysis of neonatal clinical trials with twin births 
Background
In neonatal trials of pre-term or low-birth-weight infants, twins may represent 10–20% of the study sample. Mixed-effects models and generalized estimating equations are common approaches for handling correlated continuous or binary data. However, the operating characteristics of these methods for mixes of correlated and independent data are not well established.
Methods
Simulation studies were conducted to compare mixed-effects models and generalized estimating equations to linear regression for continuous outcomes. Similarly, mixed-effects models and generalized estimating equations were compared to ordinary logistic regression for binary outcomes. The parameter of interest is the treatment effect in two-armed clinical trials. Data from the National Institute of Child Health & Human Development Neonatal Research Network are used for illustration.
Results
For continuous outcomes, while the coverage never fell below 0.93, and the type I error rate never exceeded 0.07 for any method, overall linear mixed-effects models performed well with respect to median bias, mean squared error, coverage, and median width. For binary outcomes, the coverage never fell below 0.90, and the type I error rate never exceeded 0.07 for any method. In these analyses, when randomization of twins was to the same treatment group or done independently, ordinary logistic regression performed best. When randomization of twins was to opposite treatment arms, a rare method of randomization in this setting, ordinary logistic regression still performed adequately. Overall, generalized linear mixed models showed the poorest coverage values.
Conclusion
For continuous outcomes, using linear mixed-effects models for analysis is preferred. For binary outcomes, in this setting where the amount of related data is small, but non-negligible, ordinary logistic regression is recommended.
doi:10.1186/1471-2288-9-12
PMCID: PMC2676314  PMID: 19245713
23.  CHANGES IN URINE MARKERS AND SYMPTOMS AFTER BLADDER DISTENTION FOR INTERSTITIAL CYSTITIS 
The Journal of urology  2007;177(2):556-560.
Purpose
To evaluate changes in urine markers and symptom scores after bladder distention in interstitial cystitis (IC) patients.
Materials and Methods
Subjects were 33 new patients with no prior IC treatments. Urine specimens were taken before and one month after bladder distention. University of Wisconsin (UW) symptom scores were done the same day as the urine specimen collection. Urine marker levels and symptom scores before and after distention were compared. Changes in markers were tested for associations with changes in symptom scores and other markers. Pre-distention markers and specific pre-distention symptoms were tested for their association with post-distention symptom improvement.
Results
After distention, the median total UW score decreased significantly (28.5 before, 10 after, p<0.001). Twelve patients (36%) had at least 30% improvement in UW score, and eight patients (24%) had at least 50% improvement. No pre-distention markers or symptoms predicted which patients would have a good response. Two of the urine markers improved significantly after distention: anti-proliferative factor (APF) activity (median −96% before, −17% after, p< 0.001) and heparin binding-epidermal growth factor-like growth factor (HB-EGF) levels (median 0.34 ng/mg creatinine before, 4.1 after, p<0.001). None of the changes in urine markers associated with changes in symptom scores.
Conclusions
The median symptom score for newly diagnosed IC patients decreased after distention, but only a minority of patients had at least 30% symptom improvement. Bladder distention altered urine APF activity and HB-EGF levels towards normal, but the mechanism of symptom relief after distention is still unknown.
doi:10.1016/j.juro.2006.09.029
PMCID: PMC2373609  PMID: 17222633
interstitial cystitis, urine; interstitial cystitis, surgery; interstitial cystitis, therapy; interstitial cystitis, physiopathology
24.  Patients' request for and emergency physicians' prescription of antimicrobial prophylaxis for anthrax during the 2001 bioterrorism-related outbreak 
BMC Public Health  2005;5:2.
Background
Inappropriate use of antibiotics by individuals worried about biological agent exposures during bioterrorism events is an important public health concern. However, little is documented about the extent to which individuals with self-identified risk of anthrax exposure approached physicians for antimicrobial prophylaxis during the 2001 bioterrorism attacks in the United States.
Methods
We conducted a telephone survey of randomly selected members of the Pennsylvania Chapter of the American College of Emergency Physicians to assess patients' request for and emergency physicians' prescription of antimicrobial agents during the 2001 anthrax attacks.
Results
Ninety-seven physicians completed the survey. Sixty-four (66%) respondents had received requests from patients for anthrax prophylaxis; 16 (25%) of these physicians prescribed antibiotics to a total of 23 patients. Ten physicians prescribed ciprofloxacin while 8 physicians prescribed doxycycline.
Conclusion
During the 2001 bioterrorist attacks, the majority of the emergency physicians we surveyed encountered patients who requested anthrax prophylaxis. Public fears may lead to a high demand for antibiotic prophylaxis during bioterrorism events. Elucidation of the relationship between public health response to outbreaks and outcomes would yield insights to ease burden on frontline clinicians and guide strategies to control inappropriate antibiotic allocation during bioterrorist events.
doi:10.1186/1471-2458-5-2
PMCID: PMC546188  PMID: 15634353

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