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1.  Trace Elements and Endometriosis: The ENDO Study 
Reproductive toxicology (Elmsford, N.Y.)  2013;0:10.1016/j.reprotox.2013.05.009.
There has been limited study of trace elements and endometriosis. Using a matched cohort design, 473 women aged 18–44 years were recruited into an operative cohort, along with 131 similarly-aged women recruited into a population cohort. Endometriosis was defined as surgically visualized disease in the operative cohort, and magnetic resonance imaging diagnosed disease in the population cohort. Twenty trace elements in urine and three in blood were quantified using inductively coupled plasma mass spectrometry. Logistic regression estimated the adjusted odds (aOR) of endometriosis diagnosis for each element by cohort. No association was observed between any element and endometriosis in the population cohort. In the operative cohort, blood cadmium was associated with a reduced odds of diagnosis (aOR=0.55; 95% CI: 0.31, 0.98), while urinary chromium and copper reflected an increased odds (aOR=1.97; 95% CI: 1.21, 3.19; aOR=2.66; 95% CI: 1.26, 5.64, respectively). The varied associations underscore the need for continued research.
doi:10.1016/j.reprotox.2013.05.009
PMCID: PMC3836840  PMID: 23892002
arsenic; cadmium; chromium; endometriosis; lead; metals; mercury; trace elements
2.  Perfluorochemicals and Endometriosis The ENDO Study 
Epidemiology (Cambridge, Mass.)  2012;23(6):799-805.
Background:
Environmental chemicals may be associated with endometriosis. No published research has focused on the possible role of perfluorochemicals (PFCs) despite their widespread presence in human tissues.
Methods:
We formulated two samples. The first was an operative sample comprising 495 women aged 18–44 years scheduled for laparoscopy/laparotomy at one of 14 participating clinical sites in the Salt Lake City or San Francisco area, 2007–2009. The second was a population-based sample comprising 131 women matched to the operative sample on age and residence within a 50-mile radius of participating clinics. Interviews and anthropometric assessments were conducted at enrollment, along with blood collection for the analysis of nine PFCs, which were quantified using liquid chromatography-tandem mass spectrometry. Endometriosis was defined based on surgical visualization (in the operative sample) or magnetic resonance imaging (in the population sample). Using logistic regression, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) for each PFC (log-transformed), adjusting for age and body mass index, and then parity.
Results:
Serum perfluorooctanoic acid (PFOA; OR = 1.89 [95% CI = 1.17–3.06]) and perfluorononanoic acid (2.20 [1.02–4.75]) were associated with endometriosis in the operative sample; findings were moderately attenuated with parity adjustment (1.62 [0.99–2.66] and 1.99 [0.91–4.33], respectively). Perfluorooctane sulfonic acid (1.86 [1.05–3.30]) and PFOA (2.58 [1.18–5.64]) increased the odds for moderate/severe endometriosis, although the odds were similarly attenuated with parity adjustment (OR = 1.50 and 1.86, respectively).
Conclusions:
Select PFCs were associated with an endometriosis diagnosis. These associations await corroboration.
doi:10.1097/EDE.0b013e31826cc0cf
PMCID: PMC4122261  PMID: 22992575
3.  Risk factors associated with endometriosis: importance of study population for characterizing disease in the ENDO Study 
OBJECTIVE
We sought to identify risk factors for endometriosis and their consistency across study populations in the Endometriosis: Natural History, Diagnosis, and Outcomes (ENDO) Study.
STUDY DESIGN
In this prospective matched, exposure cohort design, 495 women aged 18–44 years undergoing pelvic surgery (exposed to surgery, operative cohort) were compared to an age- and residence-matched population cohort of 131 women (unexposed to surgery, populationcohort). Endometriosis was diagnosed visually at laparoscopy/laparotomy or by pelvic magnetic resonance imaging in the operative and population cohorts, respectively. Logistic regression estimated the adjusted odds ratios (AORs) and 95% confidence intervals (CIs) for each cohort.
RESULTS
The incidence of visualized endometriosis was 40% in the operative cohort (11.8% stage 3–4 by revised criteria from the American Society for Reproductive Medicine), and 11% stage 3–4 in the population cohort by magnetic resonance imaging. An infertility history increased the odds of an endometriosis diagnosis in both the operative (AOR, 2.43; 95% CI, 1.57–3.76) and population (AOR, 7.91; 95% CI, 1.69–37.2) cohorts. In the operative cohort only, dysmenorrhea (AOR, 2.46; 95% CI, 1.28–4.72) and pelvic pain (AOR, 3.67; 95% CI, 2.44–5.50) increased the odds of diagnosis, while gravidity (AOR, 0.49; 95% CI, 0.32–0.75), parity (AOR, 0.42; 95% CI, 0.28–0.64), and body mass index (AOR, 0.95; 95% CI, 0.93–0.98) decreased the odds of diagnosis. In all sensitivity analyses for different diagnostic subgroups, infertility history remained a strong risk factor.
CONCLUSION
An infertility history was a consistent risk factor for endometriosis in both the operative and population cohorts of the ENDO Study. Additionally, identified risk factors for endometriosis vary based upon cohort selection and diagnostic accuracy. Finally, endometriosis in the population may be more common than recognized.
doi:10.1016/j.ajog.2013.02.040
PMCID: PMC4114145  PMID: 23454253
Body mass index; dysmenorrhea; endometriosis; epidemiology; infertility; laparoscopy; magnetic resonance imaging; risk factors
4.  Bisphenol A and Phthalates and Endometriosis, The ENDO Study 
Fertility and sterility  2013;100(1):162-169.e2.
Objective
To explore the relation between bisphenol A and 14 phthalate metabolites and endometriosis.
Design
Matched cohort design.
Setting
14 clinical centers in Salt Lake City, Utah or San Francisco, California, 2007–2009.
Patients
The operative cohort comprised 495 women undergoing laparoscopy/laparotomy, while the population cohort comprised 131 women matched on age and residence.
Interventions
None
Main Outcome Measure(s)
Surgically visualized or pelvic magnetic resonance imaging (MRI) diagnosed endometriosis in the two cohorts, respectively.
Results
Odds ratios (OR) and 95% confidence intervals (CIs) were estimated using logistic regression adjusting for age, body mass index and creatinine. In the population cohort, six phthalate metabolites (mBP, mCMHP, mECPP, mEHP, mEHHP, and mEOHP) were significantly associated with approximately a twofold increase in the odds of an endometriosis diagnosis. Two phthalates were associated with endometriosis in the operative cohort when restricting to visualized and histologic endometriosis (mOP; OR=1.38; 95% CI 1.10, 1.72), or when restricting comparison women to those with a postoperative diagnosis of a normal pelvis (mEHP; OR=1.35; 95% CI 1.03, 1.78).
Conclusions
Select phthalates were associated with higher odds of an endometriosis diagnosis for women with MRI diagnosed endometriosis. The lack of consistency of findings across cohorts underscores the impact of methodology on findings.
doi:10.1016/j.fertnstert.2013.03.026
PMCID: PMC3700684  PMID: 23579005
Bisphenol A; endometriosis; endocrine disrupting chemicals; epidemiology; phthalates
5.  COMPARATIVE PHARMACOKINETICS OF PAMAM-OH DENDRIMERS AND HPMA COPOLYMERS IN OVARIAN-TUMOR-BEARING MICE 
The purpose of this study was to model data from a head to head comparison of the in vivo fate of hyper-branched PAMAM dendrimers with linear HPMA copolymers in order to understand the influence of molecular weight (MW), hydrodynamic size (Rh) and polymer architecture on biodistribution in tumor-bearing mice using compartmental pharmacokinetic analysis. Plasma concentration data was modeled by two-compartment analysis using Winnonlin® to obtain elimination clearance (E.CL) and plasma exposure (AUCplasma). Renal clearance (CLR) was calculated from urine data collected over 1 week. A plasma-tumor link model was fitted to experimental plasma and tumor data by varying the tumor extravasation (K4, K6) and elimination (K5) rate constants using multivariable constrained optimization solver in Matlab®. Tumor exposures (AUCtumor) were computed from area under the tumor concentration time profile curve by the linear trapezoidal method. Along with MW and Rh, polymer architecture was critical in affecting the blood and tumor pharmacokinetics of the PAMAM-OH dendrimers and HPMA copolymers. Elimination clearance decreased more rapidly with increase in hydrodynamic size for PAMAM-OH dendrimers as compared to HPMA copolymers. HPMA copolymers were eliminated renally to a higher extent than PAMAM-OH dendrimers. These results are suggestive of a difference in extravasation of polymers of varying architecture through the glomerular basement membrane. While the linear HPMA copolymers can potentially reptate through a pore smaller in size than their hydrodynamic radii in a random coil conformation, PAMAM dendrimers have to deform in order to permeate across the pores. With increase in molecular weight or generation, the deforming capacity of PAMAM-OH dendrimers is known to decrease, making it harder for higher generation PAMAM-OH dendrimers to sieve through the glomerulus as compared to HPMA copolymers of comparable molecular weights. PAMAM-OH dendrimer had greater tumor extravsation rate constants and higher tumor to plasma exposure ratios than HPMA copolymers of comparable molecular weights which indicated that in the size range studied, when in circulation, PAMAM-OH dendrimers had a higher affinity to accumulate in the tumor than the HPMA copolymers.
doi:10.1007/s13346-012-0119-6
PMCID: PMC3685189  PMID: 23795337
poly(amido amine) (PAMAM) dendrimer; N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer; polymer architecture; compartmental pharmacokinetics
6.  IN UTERO EXPOSURES AND ENDOMETRIOSIS, THE ENDO STUDY 
Fertility and sterility  2012;99(3):790-795.
Objective
To assess in utero exposures and the odds of an endometriosis diagnosis.
Design
Matched cohort design.
Setting
Fourteen participating clinical centers in geographically defined areas in Utah and California.
Study cohorts
The operative cohort comprised 473 women undergoing laparoscopy/laparotomy, and was matched on age and residence to a population cohort comprising 127 women undergoing pelvic magnetic resonance imaging (MRI), 2007–2009.
Interventions
None
Main outcome measures
Women completed standardized interviews prior to surgery or MRI regarding in utero exposures: mothers’ lifestyle during the index pregnancy, and the index woman’s gestation and birth size. Endometriosis was defined as visually confirmed disease in the operative cohort, and MRI visualized disease in the population cohort. The odds of an endometriosis diagnosis and corresponding 95% confidence intervals (AOR; 95% CI) were estimated for each exposure by cohort using logistic regression and adjusting for current smoking, age at menarche, body mass index, and study site.
Results
Endometriosis was diagnosed in 41% and 11% of women in the operative and population cohorts, respectively. In the primary analysis, AORs were elevated for maternal vitamin usage (1.27; 95% CI =0.85–1.91), maternal cigarette smoking (1.16; 95% CI=0.61–2.24), and low birth weight (1.1; 95% CI=0.92–1.32). Reduced odds were observed for maternal usage of caffeine (0.99; 95% CI=0.64–1.54), alcohol (0.82; 95% CI=0.35–1.94), paternal cigarette smoking (0.72; 95% CI=0.43–1.19) and preterm delivery (0.98; 95% CI=0.47–2.03). Sensitivity analyses mostly upheld the primary results except for a decreased AOR for preterm birth (0.41; 95% CI=0.18–0.94) when restricting to visualized and histologically-confirmed endometriosis in the operative cohort.
Conclusions
In utero exposures were not significantly associated with the odds of an endometriosis diagnosis in either cohort.
doi:10.1016/j.fertnstert.2012.11.013
PMCID: PMC3604121  PMID: 23211710
endometriosis; epidemiology; in utero; ovarian dysgenesis hypothesis
7.  Comparing Apples and Pears: Women's Perceptions of Their Body Size and Shape 
Journal of Women's Health  2012;21(10):1074-1081.
Abstract
Background
Obesity is a growing public health problem among reproductive-aged women, with consequences for chronic disease risk and reproductive and obstetric morbidities. Evidence also suggests that body shape (i.e., regional fat distribution) may be independently associated with risk, yet it is not known if women adequately perceive their shape. This study aimed to assess the validity of self-reported body size and shape figure drawings when compared to anthropometric measures among reproductive-aged women.
Methods
Self-reported body size was ascertained using the Stunkard nine-level figures and self-reported body shape using stylized pear, hourglass, rectangle, and apple figures. Anthropometry was performed by trained researchers. Body size and body mass index (BMI) were compared using Spearman's correlation coefficient. Fat distribution indicators were compared across body shapes for nonobese and obese women using analysis of variance (ANOVA) and Fisher's exact test. Percent agreement and kappa statistics were computed for apple and pear body shapes.
Results
The 131 women studied were primarily Caucasian (81%), aged 32 years, with a mean BMI of 27.1 kg/m2 (range 16.6–52.8 kg/m2). The correlation between body size and BMI was 0.85 (p<0.001). Among nonobese women, waist-to-hip ratios (WHR) were 0.75, 0.75, 0.80, and 0.82 for pear, hourglass, rectangle, and apple, respectively (p<0.001). Comparing apples and pears, the percent agreement (kappa) for WHR≥0.80 was 83% (0.55).
Conclusions
Self-reported size and shape were consistent with anthropometric measures commonly used to assess obesity and fat distribution, respectively. Self-reported body shape may be a useful proxy measure in addition to body size in large-scale surveys.
doi:10.1089/jwh.2012.3634
PMCID: PMC3466911  PMID: 22873752
8.  The Effect of Nicotinamide on Gene Expression in a Traumatic Brain Injury Model 
Microarray-based transcriptional profiling was used to determine the effect of nicotinamide on gene expression in an experimental traumatic brain injury (TBI) model. Ingenuity Pathway Analysis (IPA) was used to evaluate the effect on relevant functional categories and canonical pathways. At 24 h, 72 h, and 7 days, respectively, 70, 58, and 76%, of the differentially expressed genes were up-regulated in the vehicle treated compared to the sham animals. At 24 h post-TBI, there were 150 differentially expressed genes in the nicotinamide treated animals compared to vehicle; the majority (82%) down-regulated. IPA analysis identified a significant effect of nicotinamide on the functional categories of cellular movement, cell-to-cell-signaling, antigen presentation and cellular compromise, function, and maintenance and cell death. The canonical pathways identified were signaling pathways primarily involved with the inflammatory process. At 72 h post-cortical contusion injury, there were 119 differentially expressed genes in the nicotinamide treated animals compared to vehicle; the majority (90%) was up-regulated. IPA analysis identified a significant effect of nicotinamide on cell signaling pathways involving neurotransmitters, neuropeptides, growth factors, and ion channels with little to no effect on inflammatory pathways. At 7 days post-TBI, there were only five differentially expressed genes with nicotinamide treatment compared to vehicle. Overall, the effect of nicotinamide on counteracting the effect of TBI resulted in significantly decreased number of genes differentially expressed by TBI. In conclusion, the mechanism of the effect of nicotinamide on secondary injury pathways involves effects on inflammatory response, signaling pathways, and cell death.
doi:10.3389/fnins.2013.00021
PMCID: PMC3581799  PMID: 23550224
nicotinamide; gene expression; cortical contusion model; traumatic brain injury
9.  Association of 25-hydroxy-vitamin D levels with semen and hormonal parameters 
Asian Journal of Andrology  2012;14(6):855-859.
Vitamin D levels have been linked to various health outcomes including reproductive disorders. The purpose of this study was to explore the association between serum vitamin D level (25-hydroxy-vitamin D, or 25OHD) and semen and hormonal parameters. This is a cross-sectional study that included 170 healthy men recruited for the study of spermatogenesis from the general population. Men completed general and reproductive health questionnaires, and donated blood and semen samples. The main measures were hormonal (total and free testosterone, sex hormone-binding globulin, estradiol, follicle-stimulating hormone and luteinizing hormone) and semen parameters, adjusted (n=147) for age, body mass index (BMI), season, alcohol intake and smoking, in relation to categories of vitamin D levels, determined a priori. The mean age of the study population was 29.0±8.5 years and mean BMI was 24.3±3.2 kg m−2. The mean 25OHD was 34.1±15.06 ng ml−1. BMI showed a negative association with 25OHD. Sperm concentration, sperm progressive motility, sperm morphology, and total progressively motile sperm count were lower in men with ‘25OHD≥50 ng ml−1' when compared to men with ‘20 ng ml−1≤25OHD<50 ng ml−1'. Total sperm count and total progressive motile sperm count were lower in men with ‘25OHD<20 ng ml−1' when compared to men with ‘20 ng ml−1≤25OHD<50 ng ml−1'. The adjusted means of various hormonal parameters did not show statistical difference in the different categories of 25OHD. In conclusion, serum vitamin D levels at high and low levels can be negatively associated with semen parameters.
doi:10.1038/aja.2012.77
PMCID: PMC3720097  PMID: 23042450
low semen count; obesity; semen parameters; vitamin D
10.  COMPARATIVE BIODISTRIBUTION OF PAMAM DENDRIMERS AND HPMA COPOLYMERS IN OVARIAN TUMOR-BEARING MICE 
Biomacromolecules  2010;12(1):88-96.
The biodistribution profile of a series of linear N-(2-hydroxylpropyl)methacrylamide (HPMA) copolymers were compared with that of branched poly (amido amine) dendrimers containing surface hydroxyl groups (PAMAM-OH) in orthotopic ovarian tumor-bearing mice. Below an average molecular weight (MW) of 29 kDa, the HPMA copolymers were smaller than the PAMAM-OH dendrimers of comparable molecular weight. In addition to molecular weight, hydrodynamic size and polymer architecture affected the biodistribution of these constructs. Biodistribution studies were performed by dosing mice with 125Iodine-labeled polymers and collecting all major organ systems, carcass and excreta at defined time points. Radiolabeled polymers were detected in organ systems by measuring gamma emission of the 125Iodine radiolabel. The hyperbranched PAMAM dendrimer, hydroxyl terminated, generation 5 (G5.0-OH) was retained in the kidney over one week while the linear HPMA copolymer of comparable molecular weight was excreted into the urine and did not show persistent renal accumulation. PAMAM dendrimer, hydroxyl terminated, generation 6.0 (G6.0-OH) was taken up by the liver to a higher extent while the HPMA copolymer of comparable molecular weight was observed to have a plasma exposure three times that of this dendrimer. Tumor accumulation and plasma exposure were correlated with the hydrodynamic sizes of the polymers. PAMAM dendrimer, hydroxyl terminated, generation 7.0 (G7.0-OH) showed extended plasma circulation, enhanced tumor accumulation and prolonged retention with the highest tumor/blood ratio for the polymers under study. Head-to-head comparative study of HPMA copolymers and PAMAM dendrimers can guide the rational design and development of carriers based on these systems for delivery of bioactive and imaging agents.
doi:10.1021/bm101046d
PMCID: PMC3476841  PMID: 21128624
PAMAM dendrimers; N-(2-hydroxypropyl)methacrylamide copolymers; enhanced permeability and retention effect; drug delivery; polymer architecture; ovarian tumor
11.  VcR-CVAD induction chemotherapy followed by maintenance rituximab in mantle cell lymphoma: a Wisconsin Oncology Network study 
British journal of haematology  2011;155(2):190-197.
Intensive chemotherapy regimens are not feasible in many adults with mantle cell lymphoma (MCL). We sought to build upon our previous experience with a non-intensive regimen, modified R-hyperCVAD chemotherapy (rituximab, cyclophosphamide, vincristine, doxorubicin, dexamethasone) with maintenance rituximab (MR), by the incorporation of bortezomib (VcR-CVAD) and the extension of MR beyond 2 years. Patients with previously untreated MCL received VcR-CVAD chemotherapy every 21 days for 6 cycles. Patients achieving at least a partial response to induction chemotherapy received rituximab consolidation (375 mg/m2 × 4 weekly doses) and MR (375 mg/m2 every 12 weeks × 20 doses). The primary end points were overall and complete response (CR), and secondary endpoints were progression-free (PFS) and overall survival (OS). Thirty patients were enrolled, with a median age of 61 years. All patients had advanced stage disease, and 60% had medium/high MCL International Prognostic Index risk factors. A CR or unconfirmed CR was achieved in 77% of patients. After a median follow-up of 42 months, the 3-year PFS and OS were 63% and 86%, respectively. The observed 3-year PFS and OS with VcR-CVAD in MCL were comparable to reported outcomes with more intensive regimens. A cooperative group trial (E1405) is attempting to replicate these promising results.
doi:10.1111/j.1365-2141.2011.08820.x
PMCID: PMC3188692  PMID: 21848883
bortezomib; chemotherapy; mantle cell lymphoma; non-Hodgkin lymphoma; rituximab
12.  Incidence of endometriosis by study population and diagnostic method: the ENDO Study 
Fertility and sterility  2011;96(2):360-365.
Study Objective
To estimate the incidence of endometriosis in an operative cohort of women seeking clinical care and in a matched population cohort to delineate more fully the scope and magnitude of endometriosis in the context of and beyond clinical care.
Design
Matched exposure cohort design.
Setting
Surgical centers in the Salt Lake City, Utah and San Francisco, California areas.
Patients
The operative cohort comprised 495 women undergoing laparoscopy/laparotomy between 2007–2009, while the population cohort comprised 131 women from the surgical centers’ catchment areas.
Interventions
None
Main Outcome Measure(s)
Incidence of endometriosis by diagnostic method in the operative cohort and by pelvic magnetic resonance imaged (MRI) disease in the population cohort.
Results
Endometriosis incidence in the operative cohort ranged by two orders of magnitude by diagnostic method: 0.7% for only histology, 7% for only MRI and 41% for visualized disease. Endometriosis staging was skewed toward minimal (58%) and mild disease (15%). The incidence of MRI-diagnosed endometriosis was 11% in the population cohort.
Conclusions
Endometriosis incidence is dependent upon the diagnostic method and choice of sampling framework. Conservatively, 11% of women have undiagnosed endometriosis at the population level with implications for the design and interpretation of etiologic research.
doi:10.1016/j.fertnstert.2011.05.087
PMCID: PMC3143230  PMID: 21719000
Endometriosis; epidemiology; histology; incidence; laparoscopy; magnetic resonance imaging
13.  Geometry and Surface Characteristics of Gold Nanoparticles Influence their Biodistribution and Uptake by Macrophages 
Spherical and rod-shaped gold nanoparticles with surface poly (ethylene glycol) (PEG) chains were characterized for size, shape, charge, poly dispersity and surface plasmon resonance. The nanoparticles were injected intravenously to 6–8 weeks old female nu/nu mice bearing orthotopic ovarian tumors and their biodistribution in vital organs was compared. Gold nanorods were taken up to a lesser extent by the liver, had longer circulation time in the blood, and higher accumulation in the tumors, compared with their spherical counterparts. The cellular uptake of PEGylated gold nanoparticles by a murine macrophage-like cell line as a function of geometry was examined. Compared to nanospheres, PEGylated gold nanorods were taken up to a lesser extent by macrophages. These studies point to the importance of gold nanoparticle geometry and surface properties on transport across biological barriers.
doi:10.1016/j.ejpb.2010.11.010
PMCID: PMC3379889  PMID: 21093587
gold nanoparticles; nanorods; nanomedicine; biodistribution; ovarian tumor; macrophages; phagocytosis
14.  Relationships between Muscle Contributions to Walking Subtasks and Functional Walking Status in Persons with Post-Stroke Hemiparesis 
Background
Persons with post-stroke hemiparesis usually walk slowly and asymmetrically. Stroke severity and functional walking status are commonly predicted by post-stroke walking speed. The mechanisms that limit walking speed, and by extension functional walking status, need to be understood to improve post-stroke rehabilitation methods.
Methods
Three-dimensional forward dynamics walking simulations of hemiparetic subjects (and speed-matched controls) with different levels of functional walking status were developed to investigate the relationships between muscle contributions to walking subtasks and functional walking status. Muscle contributions to forward propulsion, swing initiation and power generation were analyzed during the pre-swing phase of the gait cycle and compared between groups.
Findings
Contributions from the paretic leg muscles (i.e., soleus, gastrocnemius and gluteus medius) to forward propulsion increased with improved functional walking status, with the non-paretic leg muscles (i.e., rectus femoris and vastii) compensating for reduced paretic leg propulsion in the limited community walker. Contributions to swing initiation from both paretic (i.e., gastrocnemius, iliacus and psoas) and non-paretic leg muscles (i.e., hamstrings) also increased as functional walking status improved. Power generation was also an important indicator of functional walking status, with reduced paretic leg power generation limiting the paretic leg contribution to forward propulsion and leg swing initiation.
Interpretation
These results suggest that deficits in muscle contributions to the walking subtasks of forward propulsion, swing initiation and power generation are directly related to functional walking status and that improving output in these muscle groups may be an effective rehabilitation strategy for improving post-stroke hemiparetic walking.
doi:10.1016/j.clinbiomech.2010.12.010
PMCID: PMC3086953  PMID: 21251738
forward dynamics simulation; modeling; biomechanics; gait; muscle function
15.  Persistent Lipophilic Environmental Chemicals and Endometriosis: The ENDO Study 
Environmental Health Perspectives  2012;120(6):811-816.
Background: An equivocal literature exists regarding the relation between persistent organochlorine pollutants (POPs) and endometriosis in women, with differences attributed to methodologies.
Objectives: We assessed the association between POPs and the odds of an endometriosis diagnosis and the consistency of findings by biological medium and study cohort.
Methods: Using a matched cohort design, we assembled an operative cohort of women 18–44 years of age undergoing laparoscopy or laparotomy at 14 participating clinical centers from 2007 to 2009 and a population-based cohort matched on age and residence within a 50-mile catchment area of the clinical centers. Endometriosis was defined as visualized disease in the operative cohort and as diagnosed by magnetic resonance imaging in the population cohort. Logistic regression analysis was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for each POP in relation to an endometriosis diagnosis, with separate models run for each medium (omental fat in the operative cohort, serum in both cohorts) and cohort. Adjusted models included age, body mass index, breast-feeding conditional on parity, cotinine, and lipids.
Results: Concentrations were higher in omental fat than in serum for all POPs. In the operative cohort, γ-hexachlorocyclohexane (γ-HCH) was the only POP with a significant positive association with endometriosis [per 1-SD increase in log-transformed γ-HCH: adjusted OR (AOR) = 1.27; 95% CI: 1.01, 1.59]; β-HCH was the only significant predictor in the population cohort (per 1-SD increase in log-transformed β-HCH: AOR = 1.72; 95% CI: 1.09, 2.72).
Conclusions: Using a matched cohort design, we found that cohort-specific and biological-medium–specific POPs were associated with endometriosis, underscoring the importance of methodological considerations when interpreting findings.
doi:10.1289/ehp.1104432
PMCID: PMC3385438  PMID: 22417635
endocrine-disrupting chemicals; organochlorine pesticides; persistent organochlorine pollutants; polybrominated diphenyl ethers; polychlorinated biphenyls
16.  Updates on the relation of weight excess and reproductive function in men: sleep apnea as a new area of interest 
Asian Journal of Andrology  2011;14(1):77-81.
Obesity has a negative effect on male reproductive function. It is associated with low testosterone levels and alteration in gonadotropin secretion. Male obesity has been linked to reduced male fertility. Data regarding the relation of obesity to sperm parameters are conflicting in terms of the nature and magnitude of the effect. New areas of interest are emerging that can help explain the variation in study results, such as genetic polymorphism and sleep apnea. Sleep disorders have been linked to altered testosterone production and hypogonadism in men. It was also correlated to erectile dysfunction. The relation of sleep disorders to male fertility and sperm parameters remains to be investigated. Men with hypogonadism and infertility should be screened for sleep apnea. Treatment of obesity and sleep apnea improves testosterone levels and erectile function.
doi:10.1038/aja.2011.64
PMCID: PMC3735143  PMID: 22138900
infertility; male infertility; reproductive function; sleep apnea; weight excess
17.  Long-term Adjustment After Surviving Open Heart Surgery: The Effect of Using Prayer for Coping Replicated in a Prospective Design 
The Gerontologist  2010;50(6):798-809.
Purpose: Despite the growing evidence for effects of religious factors on cardiac health in general populations, findings are not always consistent in sicker and older populations. We previously demonstrated that short-term negative outcomes (depression and anxiety) among older adults following open heart surgery are partially alleviated when patients employ prayer as part of their coping strategy. The present study examines multifaceted effects of religious factors on long-term postoperative adjustment, extending our previous findings concerning prayer and coping with cardiac disease. Design and Methods: Analyses capitalized on a preoperative survey and medical variables from the Society of Thoracic Surgeons’ National Database of patients undergoing open heart surgery. The current participants completed a mailed survey 30 months after surgery. Two hierarchical regressions were performed to evaluate the extent to which religious factors predicted depression and anxiety, after controlling for key demographics, medical indices, and mental health. Results: Predicting lower levels of depression at the follow-up were preoperative use of prayer for coping, optimism, and hope. Predicting lower levels of anxiety at the follow-up were subjective religiousness, marital status, and hope. Predicting poorer adjustment were reverence in religious contexts, preoperative mental health symptoms, and medical comorbidity. Including optimism and hope in the model did not eliminate effects of religious factors. Several other religious factors had no long-term influences. Implications: The influence of religious factors on the long-term postoperative adjustment is independent and complex, with mediating factors yet to be determined. Future research should investigate mechanisms underlying religion–health relations.
doi:10.1093/geront/gnq046
PMCID: PMC2982210  PMID: 20634280
Depression; Anxiety; Cardiovascular diseases and surgery; Religion, faith, and spirituality; Intended use of private prayer for coping; Reverence; Optimism and hope
18.  Pharmacokinetic Modeling of Absorption Behavior of 9-Aminocamptothecin (9-AC) Released from Colon-specific HPMA Copolymer–9-AC Conjugate in Rats 
Pharmaceutical research  2007;25(1):218-226.
Purpose
To quantitate and predict colon-specific 9-aminocamptothecin (9-AC) release from the N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer–9-AC conjugate and its absorption behavior after oral administration in rats.
Methods
Drug distribution in the gastrointestinal (GI) tract and the plasma concentration-time profile of 9-AC released from the HPMA copolymer conjugate were predicted using the degradation, transit, and absorption rate constants in cecum. The fate of 9-AC in cecum and liver was measured by in-situ cecum absorption and liver perfusion.
Results
Following oral administration of the conjugate, 9-AC was released rapidly in cecum. Based on the pharmacokinetic model, up to 60% of the dose was in the cecum at ∼6 h, and 7% of the dose still remained there at 24 h. The predicted plasma concentration curve for released 9-AC after an oral dose of 3 mg/kg of 9-AC equivalent increased gradually and reached a peak of 98 nM at 7 h, then started decreasing slowly to 16 nM at 24 h. The bioavailability value was estimated as 0.31 after the first-pass elimination.
Conclusions
A pharmacokinetic model delineated the impact of GI transit, drug absorption rate, and first-pass metabolism on drug disposition following oral administration of HPMA copolymer–9-AC conjugate in rats.
doi:10.1007/s11095-007-9465-3
PMCID: PMC3136142  PMID: 17929146
absorption prediction; colon-specific drug delivery; HPMA copolymer–9-aminocamptothecin conjugate; oral dosing; pharmacokinetic modeling
19.  Differences in Self-Selected and Fastest Comfortable Walking in Post-stroke Hemiparetic Persons 
Gait & posture  2009;31(3):311-316.
Post-stroke hemiparetic walking is typically asymmetric. Assessment of symmetry is often performed at either self-selected or fastest-comfortable walking speeds to gain insight into coordination deficits and compensatory mechanisms. However, how walking speed influences the level of asymmetry is unclear. This study analyzed relative changes in paretic and non-paretic leg symmetry to assess whether one speed is more effective at highlighting asymmetries in hemiparetic walking and whether there is a systematic effect of speed on asymmetry. Forty-six subjects with chronic hemiparesis walked at their self-selected and fastest-comfortable speeds on an instrumented split-belt treadmill. Relative proportions (paretic leg value/(paretic + non-paretic leg value)) were computed at each speed for step length (PSR), propulsion (PP), and joint moment impulses at the ankle and hip. Thirty-six subjects did not change their step length symmetry with speed, while three subjects changed their step length values toward increased asymmetry and seven changed toward increased symmetry. Propulsion symmetry did not change uniformly with speed for the group, with fifteen subjects changing their propulsion values toward increased asymmetry while increasing speed from their self-selected to fastest-comfortable and eleven decreasing the asymmetry. Both step length and propulsion symmetry were correlated with ankle impulse proportion at self-selected and fastest-comfortable speed (c.f., hip impulse proportion), but ratios (self-selected value / fastest-comfortable value) of the proportion measures (PSR and PP) showed that neither step length nor propulsion symmetry correlated with the ankle impulse proportions. Thus, the individual kinetic mechanisms used to increase speed could not be predicted from PSR or PP.
doi:10.1016/j.gaitpost.2009.11.011
PMCID: PMC2826561  PMID: 20006505
gait; walking speed; biomechanics; stroke
20.  Differences in the prevalence of growth, endocrine and vitamin D abnormalities among the various thalassemia syndromes in North America 
British journal of haematology  2009;146(5):546-556.
Objective
To determine differences in the rates of growth, endocrine and calcium related abnormalities in the various thalassemia syndromes in North America with current therapy.
Methods
Medical history, physical examinations and blood and urine collections were obtained from patients with all thalassemia syndromes age 6 years and older in the Thalassemia Clinical Research Network.
Results
361 subjects, 49% male, mean age 23.2 years (range 6.1 to 75 years) were studied. Approximately 25% of children and adults, regardless of the thalassemia syndrome, had short stature. Overall growth in children was mildly affected. Final height was close to midparental height (z = -0.73 ± 1.24). Patients with beta thalassemia major (TM) had higher rates of hypogonadism, multiple endocrinopathies, worse hyperglycemia, subclinical hypoparathyroidism and hypercalciuria. Hypogonadism remained the most frequent endocrinopathy and was frequently under-treated. 12.8% of the subjects had 25 vitamin D concentrations less than 27nmol/L and 82% less than 75nmol/L, regardless of the thalassemia syndrome. Adolescents had lower 25 vitamin D levels than children and adults.
Conclusions
Compared to patients with other thalassemia syndromes, those with beta TM suffer from higher rates of multiple endocrinopathies, abnormal calcium metabolism and hypercalciuria. Vitamin D abnormalities are high among adolescents.
doi:10.1111/j.1365-2141.2009.07793.x
PMCID: PMC2798591  PMID: 19604241
21.  Pharmacogenetics during standardised initiation of thiopurine treatment in inflammatory bowel disease 
Gut  2006;55(10):1423-1431.
Background
Firm recommendations about the way thiopurine drugs are introduced and the use of thiopurine methyltransferase (TPMT) and metabolite measurements during treatment in inflammatory bowel disease (IBD) are lacking.
Aim
To evaluate pharmacokinetics and tolerance after initiation of thiopurine treatment with a fixed dosing schedule in patients with IBD.
Patients
60 consecutive patients with Crohn's disease (n = 33) or ulcerative colitis (n = 27) were included in a 20 week open, prospective study.
Methods
Thiopurine treatment was introduced using a predefined dose escalation schedule, reaching a daily target dose at week 3 of 2.5 mg azathioprine or 1.25 mg 6‐mercaptopurine per kg body weight. TPMT and ITPA genotypes, TPMT activity, TPMT gene expression, and thiopurine metabolites were determined. Clinical outcome and occurrence of adverse events were monitored.
Results
27 patients completed the study per protocol, while 33 were withdrawn (early protocol violation (n = 5), TPMT deficiency (n = 1), thiopurine related adverse events (n = 27)); 67% of patients with adverse events tolerated long term treatment on a lower dose (median 1.32 mg azathioprine/kg body weight). TPMT activity did not change during the 20 week course of the study but a significant decrease in TPMT gene expression was found (TPMT/huCYC ratio; p = 0.02). Patients with meTIMP concentrations >11 450 pmol/8×108 red blood cells during steady state at week 5 had an increased risk of developing myelotoxicity (odds ratio = 45.0; p = 0.015).
Conclusions
After initiation of thiopurine treatment using a fixed dosing schedule, no general induction of TPMT enzyme activity occurred, though TPMT gene expression decreased. The development of different types of toxicity was unpredictable, but we found that measurement of meTIMP early in the steady state phase helped to identify patients at risk of developing myelotoxicity.
doi:10.1136/gut.2005.074930
PMCID: PMC1856436  PMID: 16543290
inflammatory bowel disease; thiopurine methyltransferase; thioguanine nucleotides; methylated metabolites
22.  Examining a Psychosocial Interactive Model of Binge Eating and Vomiting in Women with Bulimia Nervosa and Subthreshold Bulimia Nervosa 
Behaviour research and therapy  2008;46(7):887-894.
The current study tested a psychosocial interactive model of perfectionism, self-efficacy, and weight/shape concern within a sample of women with clinically significant bulimic symptoms, examining how different dimensions of perfectionism operated in the model. Individuals with bulimia nervosa (full diagnostic criteria or subthreshold) completed measures of bulimic symptoms, multidimensional perfectionism, self-efficacy, and weight/shape concern. Among those who were actively binge eating (n = 180), weight/shape concern was associated with binge eating frequency in the context of high perfectionism (either maladaptive or adaptive) and low self-efficacy. Among those who were actively vomiting (n = 169), weight/shape concern was associated with vomiting frequency only in the context of high adaptive perfectionism and low self-efficacy. These findings provide support for the value of this psychosocial interactive model among actively binge eating and purging samples and for the importance of considering different dimensions of perfectionism in research and treatment related to bulimia nervosa.
doi:10.1016/j.brat.2008.04.003
PMCID: PMC2515388  PMID: 18501334
Perfectionism; Self-efficacy; Body dissatisfaction; Binge eating; Vomiting
23.  Circadian function in patients with advanced non-small-cell lung cancer 
British Journal of Cancer  2005;93(11):1202-1208.
This study aimed to evaluate whether patients with advanced non-small-cell lung cancer experience disrupted rest–activity daily rhythms, poor sleep quality, weakness, and maintain attributes that are linked to circadian function such as fatigue. This report describes the rest–activity patterns of 33 non-small-cell lung cancer patients who participated in a randomised clinical trial evaluating the benefits of melatonin. Data are reported on circadian function, health-related quality of life (QoL), subjective sleep quality, and anxiety/depression levels prior to randomisation and treatment. Actigraphy data, an objective measure of circadian function, demonstrated that patients' rest–activity circadian function differs significantly from control subjects. Our patients reported poor sleep quality and high levels of fatigue. Ferrans and Powers QoL Index instrument found a high level of dissatisfaction with health-related QoL. Data from the European Organization for Research and Treatment for Cancer reported poor capacity to fulfil the activities of daily living. Patients studied in the hospital during or near chemotherapy had significantly more abnormal circadian function than those studied in the ambulatory setting. Our data indicate that measurement of circadian sleep/activity dynamics should be accomplished in the outpatient/home setting for a minimum of 4–7 circadian cycles to assure that they are most representative of the patients' true condition. We conclude that the daily sleep/activity patterns of patients with advanced lung cancer are disturbed. These are accompanied by marked disruption of QoL and function. These data argue for investigating how much of this poor functioning and QoL are actually caused by this circadian disruption, and, whether behavioural, light-based, and or pharmacologic strategies to correct the circadian/sleep activity patterns can improve function and QoL.
doi:10.1038/sj.bjc.6602859
PMCID: PMC2361523  PMID: 16265345
circadian function; non-small-cell lung cancer; rest/activity function; sleep quality; quality of life; actigraphy
24.  Comparative analysis of follicle morphology and oocyte diameter in four mammalian species (mouse, hamster, pig, and human) 
Background
Laboratory animals are commonly used for evaluating the physiological properties of the mammalian ovarian follicle and the enclosed oocyte. The use of different species to determine the morphological relationship between the follicle and oocyte has led to a recognizable pattern of follicular stages, but differences in follicle size, oocyte diameter and granulosa cell proliferation are not consistent across the different species. In an effort to better understand how these differences are expressed across multiple species, this investigation evaluates oocyte and follicle diameters and granulosa cell proliferation in the mouse, hamster, pig, and human.
Methods
Histological sections of ovaries from the mouse, hamster, pig, and human were used to calculate the diameter of the oocyte and follicle and the number of granulosa cells present at pre-determined stages of follicular development. A statistical analysis of these data was performed to determine the relationship of follicular growth and development within and between the species tested.
Results
These data have revealed that the relationships of the features listed are tightly regulated within each species, but they vary between the species studied.
Conclusion
This information may be useful for comparative studies conducted in different animal models and the human.
doi:10.1186/1743-1050-3-2
PMCID: PMC1413548  PMID: 16509981
25.  Cell specific markers for eosinophils and neutrophils in sputum and bronchoalveolar lavage fluid of patients with respiratory conditions and healthy subjects 
Thorax  2002;57(5):449-451.
Methods: Induced sputum and bronchoalveolar lavage fluid samples from 14 patients with respiratory conditions and four healthy individuals were studied. Antigens were detected at their intracellular sites in cells with well preserved structures using optimal techniques for fixation, permeabilisation, and immunolabelling.
Results: Anti-EPO antibodies reacted only with eosinophils, and anti-HNL antibodies only with neutrophils. Anti-ECP antibodies reacted with both eosinophils and neutrophils and anti-MPO antibodies with neutrophils and monocytes. Cells not stained by monoclonal anti-EPO and anti-HNL antibodies included lymphocytes, monocytes, macrophages, squamous epithelial cells, and ciliated epithelial cells.
Conclusions: EPO, a unique component of eosinophils, and HNL, a unique component of neutrophils, are useful markers for the identification of eosinophils and neutrophils, respectively, in sputum and bronchoalveolar lavage fluid.
doi:10.1136/thorax.57.5.449
PMCID: PMC1746329  PMID: 11978925

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