Serum omega-3 fatty acids and treatment outcomes among women undergoing assisted reproduction.

STUDY QUESTION: Are serum polyunsaturated fatty acids (PUFA) concentrations, including omega-3 (ω3-PUFA) and omega-6 (ω6-PUFA), related to ART outcomes? SUMMARY ANSWER: Serum levels of long-chain ω3-PUFA were positively associated with probability of live birth among women undergoing ART. WHAT IS KNOWN ALREADY: Intake of ω3-PUFA improves oocyte and embryo quality in animal and human studies. However, a recent cohort study found no relation between circulating ω3-PUFA levels and pregnancy rates after ART. STUDY DESIGN SIZE, AND DURATION: This analysis included a random sample of 100 women from a prospective cohort study (EARTH) at the Massachusetts General Hospital Fertility Center who underwent 136 ART cycles within one year of blood collection. PARTICIPANTS/MATERIALS, SETTING, METHODS: Serum fatty acids (expressed as percentage of total fatty acids) were measured by gas chromatography in samples taken between Days 3 and 9 of a stimulated cycle. Primary outcomes included the probability of implantation, clinical pregnancy and live birth per initiated cycle. Cluster-weighted generalized estimating equation (GEE) models were used to analyze the association of total and specific PUFAs with ART outcomes adjusting for age, body mass index, smoking status, physical activity, use of multivitamins and history of live birth. MAIN RESULTS AND ROLE OF CHANCE: The median [25th, 75th percentile] serum level of ω3-PUFA was 4.7% [3.8%, 5.8%] of total fatty acids. Higher levels of serum long-chain ω3-PUFA were associated with higher probability of clinical pregnancy and live birth. Specifically, after multivariable adjustment, the probability of clinical pregnancy and live birth increased by 8% (4%, 11%) and 8% (95% CI: 1%, 16%), respectively, for every 1% increase in serum long-chain ω3-PUFA levels. Intake of long-chain ω3-PUFA was also associated with a higher probability of life birth in these women, with RR of 2.37 (95% CI: 1.02, 5.51) when replacing 1% energy of long-chain ω3-PUFA for 1% energy of saturated fatty acids. Serum ω6-PUFA, ratios of ω6 and ω3-PUFA, and total PUFA were not associated with ART outcomes. LIMITATIONS REASONS FOR CAUTION: The generalizability of the findings to populations not undergoing infertility treatment may be limited. The use of a single measurement of serum fatty acids to characterize exposure may lead to potential misclassification during follow up. WIDER IMPLICATIONS OF THE FINDINGS: Serum ω3-PUFA are considered biomarkers of dietary intake. The association of higher serum long chain ω3-PUFA levels with improved ART outcomes suggests that increased intake of these fats be may be beneficial for women undergoing infertility treatment with ART. STUDY FUNDING/COMPETING INTERESTS: NIH grants R01-ES009718 from the National Institute of Environmental Health Sciences, P30-DK046200 and T32-DK007703-16 from the National Institute of Diabetes and Digestive and Kidney Diseases, and L50-HD085359 from the National Institute of Child Health and Human Development, and the Early Life Nutrition Fund from Danone Nutricia US. Dr Rueda is involved in a patent 9,295,662, methods for enhancing, improving, or increasing fertility or reproductive function (http://patents.com/us-9295662.html). This patent, however, does not lead to financial gain for Dr Rueda, or for Massachusetts General Hospital. Dr Rueda does not own any part of the company nor does he have any equity in any fertility related company. As Dr Rueda is not a physician, he does not evaluate patients or prescribe medications. All other coauthors have no conflicts of interest to declare.

The association between pre-treatment maternal alcohol and caffeine intake and outcomes of assisted reproduction in a prospectively followed cohort.

STUDY QUESTION: Is pre-treatment alcohol and caffeine intake associated with infertility treatment outcomes among women undergoing ART? SUMMARY ANSWER: Low to moderate alcohol and caffeine intakes in the year prior to infertility treatment were not related to ART outcomes. WHAT IS KNOWN ALREADY: Alcohol and caffeine intake have been found to be associated with infertility in some studies. Nevertheless, data on their relation with outcomes of infertility treatments are scarce and inconsistent. STUDY DESIGN, SIZE, DURATION: We included 300 women (493 ART cycles) from the Environment and Reproductive Health Study, an ongoing cohort study (2006-2016). PARTICIPANTS/MATERIALS, SETTING, METHODS: Pre-treatment intakes of alcohol and caffeine were assessed retrospectively using a validated food frequency questionnaire. Intermediate and clinical endpoints of ART were abstracted from electronic medical records. Generalized linear mixed models with random intercepts to account for multiple ART cycles per woman were used to evaluate the association with ART outcomes adjusting for age, BMI, smoking status, infertility diagnosis, protocol type, race, dietary patterns, and calories, vitamin B12 and folate intake. MAIN RESULTS AND THE ROLE OF CHANCE: Median (range) pre-treatment alcohol and caffeine intakes were 5.6 (0.0-85.8) g/day and 124.9 (0.3-642.2) mg/day, respectively. The adjusted percentage of initiated cycles resulting in live birth (95% CI) for women in increasing categories of pre-treatment alcohol intake was 34% (20, 52%) for non-consumers, 46% (36, 57%) for 0.1-6 g/day, 41% (29, 53%) for 6.1-12 g/day, 42% (31, 55%) for 12.1-24 g/day, and 41% (22, 63%) for >24 g/day (P, trend = 0.87). The adjusted percentage of cycles resulting in live birth (95% CI) for women in increasing categories of caffeine intake was 46% (36-57%) for <50 mg/day, 44% (29, 60%) for 50.1-100 mg/day, 42% (31, 53%) for 100.1-200 mg/day, 40% (28, 53%) for 200.1-300 mg/day and 40% (21, 63%) for >300 mg/day (P, trend = 0.34). When specific types of alcoholic and caffeinated beverages were evaluated, no relations with ART treatment outcomes were observed. LIMITATIONS, REASONS FOR CAUTION: Residual confounding by other diet and lifestyle factors cannot be ruled out owing to the observational nature of this study. It is also unclear how generalizable these results are to women who are conceiving without the assistance of ART. WIDER IMPLICATIONS OF THE FINDINGS: Our results provide reassurance that low to moderate intakes of alcohol (e.g. ≤12 g/day) and caffeine (e.g. <200 mg/day) in the year prior to infertility treatment initiation do not have an adverse effect on intermediate or clinical outcomes of ART. STUDY FUNDING/COMPETING INTEREST(S): The authors are supported by National Institutes of Health (NIH) grants ES022955, R01ES009718, R01ES000002, P30DK46200 and L50-HD085359. No conflicts of interest to declare. TRIAL REGISTRATION NUMBER: NCT00011713.

The association of protein intake (amount and type) with ovarian antral follicle counts among infertile women: results from the EARTH prospective study cohort.

OBJECTIVE: To evaluate the association between protein intake (amount and type) and antral follicle count (AFC). DESIGN: Prospective cohort. SETTING: Academic fertility centre. POPULATION: Two hundred and sixty-five women undergoing fertility treatments at an academic fertility centre and participating in an ongoing study on environment and reproductive health. METHODS: We measured AFC in ultrasonographic evaluation among women undergoing infertility treatments. Women completed a previously validated semi-quantitative food frequency questionnaire. We used Poisson regression to evaluate the relation between protein intake and AFC while adjusting for age, body mass index, race, smoking status, and total energy intake. MAIN OUTCOME MEASURES: Antral follicle count. RESULTS: Among 265 women (mean age: 35.0 ± 3.9 years, 85% Caucasian), total protein intake (% energy) was unrelated to AFC. When protein from different food sources was considered separately, we found a negative association between dairy protein intake and AFC. The mean AFC was 14.4% (3.9-23.7%) lower for women in the highest quintile of dairy protein intake than for women in the bottom quintile after adjusting for potential confounders (P-trend = 0.04). This association was stronger among women who had never smoked (P-trend = 0.002) but was not observed among previous smokers (P-trend = 0.36). There were no associations between protein intake from either non-dairy animal or vegetable sources and AFC. CONCLUSION: Higher dairy protein intake (≥5.24% of energy) was associated with lower antral follicle counts among women presenting for infertility treatment. These findings should be further investigated in prospective studies also designed to clarify the biology underlying the observed associations. TWEETABLE ABSTRACT: Higher dairy protein intake was associated with lower antral follicle counts in an infertile population.

Dairy intake in relation to in vitro fertilization outcomes among women from a fertility clinic.

STUDY QUESTION: Is dairy food consumption associated with live birth among women undergoing infertility treatment? SUMMARY ANSWER: There was a positive association between total dairy food consumption and live birth among women ≥35 years of age. WHAT IS KNOWN ALREADY: Dairy food intake has been previously related to infertility risk and measures of fertility potential but its relation to infertility treatment outcomes are unknown. STUDY DESIGN, SIZE, DURATION: Our study population comprised a total of 232 women undergoing 353 in vitro fertilization (IVF) treatment cycles between February 2007 and May 2013, from the Environment and Reproductive Health study, an ongoing prospective cohort. PARTICIPANTS/MATERIALS, SETTING, METHODS: Diet was assessed before assisted reproductive technology (ART) treatment using a validated food frequency questionnaire. Study outcomes included ovarian stimulation outcomes (endometrial thickness, estradiol levels and oocyte yield), fertilization rates, embryo quality measures and clinical outcomes (implantation, clinical pregnancy and live birth rates). We used generalized linear mixed models with random intercepts to account for multiple ART cycles per woman while simultaneously adjusting for age, caloric intake, BMI, race, smoking status, infertility diagnosis, protocol type, alcohol intake and dietary patterns. MAIN RESULTS AND THE ROLE OF CHANCE: The age- and calorie-adjusted difference in live birth between women in the highest (>3.0 servings/day) and lowest (<1.34 servings/day) quartile of dairy intake was 21% (P = 0.02). However, after adjusting for additional covariates, this association was observed only among women ≥35 years (P, interaction = 0.04). The multivariable-adjusted live birth (95% CI) in increasing quartiles of total dairy intake was 23% (11, 42%), 39% (24, 56%), 29% (17, 47%) and 55% (39, 69%) (P, trend = 0.02) among women ≥35 years old, and ranged from 46 to 54% among women <35 years old (P, trend = 0.69). There was no association between dairy intake and any of the intermediate outcomes. LIMITATIONS, REASONS FOR CAUTION: The lack of a known biological mechanism linking dairy intake to infertility treatment outcomes calls for caution when interpreting these results and for additional work to corroborate or refute them. WIDER IMPLICATIONS OF THE FINDINGS: Dairy intake does not appear to harm IVF outcomes and, if anything, is associated with higher chances of live birth. STUDY FUNDING/COMPETING INTERESTS: This work was supported by NIH grants R01-ES009718 and R01ES000002 from NIEHS, P30 DK046200 from NIDDK and T32HD060454 from NICHD. M.C.A. was supported by a Ruth L. Kirschstein National Research Service Award T32 DK 007703-16 from NIDDK. She is currently employed at the Nestlé Research Center, Switzerland and completed this work while at the Harvard School of Public Health. The other authors declare no conflicts of interest.

Newborn Hearing Screenings in Human Immunodeficiency Virus-Exposed Uninfected Infants.

Perinatal HIV infection and congenital cytomegalovirus (CMV) infection may increase the risk for hearing loss. We examined 1,435 infants enrolled in the Surveillance Monitoring of ART Toxicities (SMARTT) study of the Pediatric HIV/AIDS Cohort Study (PHACS) network, a prospective study of the safety of in utero antiretroviral (ARV) exposures. We determined the proportion of perinatally HIV-exposed uninfected (HEU) newborns who were referred for additional hearing testing, and evaluated the association between in utero ARV exposures and newborn hearing screening results. Using a nested case-control design, we also examined congenital CMV infection in infants with and without screening referral. Congenital CMV infection was determined based on CMV DNA detection using a nested PCR assay in peripheral blood mononuclear cells obtained within 14 days of birth. Among the 1,435 infants (70% black, 31% Hispanic, 51% male), 45 (3.1%) did not pass the hearing screen and were referred for further hearing testing. Based on exact logistic regression models controlling for maternal use of tobacco and ototoxic medications, first trimester exposure to Tenofovir was associated with lower odds of a newborn hearing screening referral [adjusted odds ratio (aOR) = 0.41, 95% confidence interval (CI): 0.14-1.00]. Exposure to Atazanavir was linked to higher odds of newborn screening referral, although not attaining significance [aOR = 1.84, 95% CI: 0.92-3.56]. Maternal ARV use may have varying effects on newborn hearing screenings. These results highlight the importance for audiologists to be knowledgeable of in utero ARV exposures in HEU children because of the possibility of higher referrals in these children.

Human sperm sex chromosome disomy and sperm DNA damage assessed by the neutral comet assay.

STUDY QUESTION: Is there an association between human sperm sex chromosome disomy and sperm DNA damage? SUMMARY ANSWER: An increase in human sperm XY disomy was associated with higher comet extent; however, there was no other consistent association of sex chromosome disomies with DNA damage. WHAT IS KNOWN ALREADY: There is limited published research on the association between sex chromosome disomy and sperm DNA damage and the findings are not consistent across studies. STUDY DESIGN, SIZE, AND DURATION: We conducted a cross-sectional study of 190 men (25% ever smoker, 75% never smoker) from subfertile couples presenting at the Massachusetts General Hospital Fertility Clinic from January 2000 to May 2003. PARTICIPANTS/MATERIALS, SETTING, METHODS: Multiprobe fluorescence in situ hybridization for chromosomes X, Y and 18 was used to determine XX, YY, XY and total sex chromosome disomy in sperm nuclei using an automated scoring method. The neutral comet assay was used to measure sperm DNA damage, as reflected by comet extent, percentage DNA in the comet tail, and tail distributed moment. Univariate and multiple linear regression models were constructed with sex chromosome disomy (separate models for each of the four disomic conditions) as the independent variable, and DNA damage parameters (separate models for each measure of DNA damage) as the dependent variable. MAIN RESULTS AND THE ROLE OF CHANCE: Men with current or past smoking history had significantly greater comet extent (µm: regression coefficients with 95% CI) [XX18: 15.17 (1.98, 28.36); YY18: 14.68 (1.50, 27.86); XY18: 15.41 (2.37, 28.45); Total Sex Chromosome Disomy: 15.23 (2.09, 28.38)], and tail distributed moment [XX18: 3.01 (0.30, 5.72); YY18: 2.95 (0.24, 5.67); XY18: 3.04 (0.36, 5.72); Total Sex Chromosome Disomy: 3.10 (0.31, 5.71)] than men who had never smoked. In regression models adjusted for age and smoking, there was a positive association between XY disomy and comet extent. For an increase in XY disomy from 0.56 to 1.47% (representing the 25th to 75th percentile), there was a mean increase of 5.08 µm in comet extent. No other statistically significant findings were observed. LIMITATIONS, REASONS FOR CAUTION: A potential limitation of this study is that it is cross-sectional. Cross-sectional analyses by nature do not lend themselves to inference about directionality for any observed associations; therefore we cannot determine which variable is the cause and which one is the effect. A small sample size may be a further limitation. Comparison of these findings to other studies is limited due to methodological differences. WIDER IMPLICATIONS OF THE FINDINGS: Although consistent associations across sex chromosome disomies or DNA damage measures were not observed, this study highlights the need to explore etiologies of sperm DNA damage and sex chromosome disomy to better understand the potential mechanistic overlaps between the two. STUDY FUNDING/COMPETING INTERESTS: This work was supported by NIOSH Grant T42 OH008416, and NIH/NIEHS Grants ES 009718, ES 000002, and R01 ES017457. During the study M.E.M. was affiliated with the Department of Environmental Health at the Harvard School of Public Health. TRIAL REGISTRATION NUMBER: N/A.

Dairy food intake in relation to semen quality and reproductive hormone levels among physically active young men.

STUDY QUESTION: Is increased consumption of dairy foods associated with lower semen quality? SUMMARY ANSWER: We found that intake of full-fat dairy was inversely related to sperm motility and morphology. These associations were driven primarily by intake of cheese and were independent of overall dietary patterns. WHAT IS KNOWN ALREADY: It has been suggested that environmental estrogens could be responsible for the putative secular decline in sperm counts. Dairy foods contain large amounts of estrogens. While some studies have suggested dairy as a possible contributing factor for decreased semen quality, this finding has not been consistent across studies. STUDY DESIGN, SIZE, DURATION: The Rochester Young Men's Study (n = 189) was a cross-sectional study conducted between 2009 and 2010 at the University of Rochester. PARTICIPANTS/MATERIALS, SETTING, METHODS: Men aged 18-22 years were included in this analysis. Diet was assessed via food frequency questionnaire. Linear regression was used to analyze the relation between dairy intake and conventional semen quality parameters (total sperm count, sperm concentration, progressive motility, morphology and ejaculate volume) adjusting for age, abstinence time, race, smoking status, body mass index, recruitment period, moderate-to-intense exercise, TV watching and total calorie intake. MAIN RESULTS AND THE ROLE OF CHANCE: Total dairy food intake was inversely related to sperm morphology (P-trend = 0.004). This association was mostly driven by intake of full-fat dairy foods. The adjusted difference (95% confidence interval) in normal sperm morphology percent was -3.2% (-4.5 to -1.8) between men in the upper half and those in the lower half of full-fat dairy intake (P < 0.0001), while the equivalent contrast for low-fat dairy intake was less pronounced [-1.3% (-2.7 to -0.07; P= 0.06)]. Full-fat dairy intake was also associated with significantly lower percent progressively motile sperm (P= 0.05). LIMITATIONS, REASONS FOR CAUTION: As it was a cross-sectional study, causal inference is limited. WIDER IMPLICATIONS OF THE FINDINGS: Further research is needed to prove a causal link between a high consumption of full-fat dairy foods and detrimental effects on semen quality. If verified our findings would mean that intake of full-fat dairy foods should be considered in attempts to explain secular trends in semen quality and that men trying to have children should restrict their intake. STUDY FUNDING/COMPETING INTEREST(S): European Union Seventh Framework Program (Environment), 'Developmental Effects of Environment on Reproductive Health' (DEER) grant 212844. Grant P30 DK046200 and Ruth L. Kirschstein National Research Service Award T32 DK007703-16 from the National Institutes of Health. None of the authors has any conflicts of interest to declare.

The association between sperm sex chromosome disomy and semen concentration, motility and morphology.

STUDY QUESTION: Is there an association between sex chromosome disomy and semen concentration, motility and morphology? SUMMARY ANSWER: Higher rates of XY disomy were associated with a significant increase in abnormal semen parameters, particularly low semen concentration. WHAT IS KNOWN ALREADY: Although some prior studies have shown associations between sperm chromosomal abnormalities and reduced semen quality, results of others are inconsistent. Definitive findings have been limited by small sample sizes and lack of adjustment for potential confounders. STUDY DESIGN, SIZE AND DURATION: Cross-sectional study of men from subfertile couples presenting at the Massachusetts General Hospital Fertility Clinic from January 2000 to May 2003. PARTICIPANTS/MATERIALS, SETTING, METHODS: With a sample of 192 men, multiprobe fluorescence in situ hybridization for chromosomes X, Y and 18 was used to determine XX, YY, XY and total sex chromosome disomy in sperm nuclei. Sperm concentration and motility were measured using computer-assisted sperm analysis; morphology was scored using strict criteria. Logistic regression models were used to evaluate the odds of abnormal semen parameters [as defined by World Health Organization (WHO)] as a function of sperm sex chromosome disomy. MAIN RESULTS AND THE ROLE OF CHANCE: The median percentage disomy was 0.3 for XX and YY, 0.9 for XY and 1.6 for total sex chromosome disomy. Men who had abnormalities in all three semen parameters had significantly higher median rates of XX, XY and total sex chromosome disomy than controls with normal semen parameters (0.43 versus 0.25%, 1.36 versus 0.87% and 2.37 versus 1.52%, respectively, all P< 0.05). In logistic regression models, each 0.1% increase in XY disomy was associated with a 7% increase (odds ratio: 1.07, 95% confidence interval: 1.02-1.13) in the odds of having below normal semen concentration (<20 million/ml) after adjustment for age, smoking status and abstinence time. Increases in XX, YY and total sex chromosome disomy were not associated with an increase in the odds of a man having abnormal semen parameters. In addition, autosomal chromosome disomy (1818) was not associated with abnormal semen parameters. LIMITATIONS, REASONS FOR CAUTION: A potential limitation of this study, as well as those currently in the published literature, is that it is cross-sectional. Cross-sectional analyses by nature do not lend themselves to inference about directionality for any observed associations; therefore, we cannot determine which variable is the cause and which one is the effect. Additionally, the use of WHO cutoff criteria for dichotomizing semen parameters may not fully define fertility status; however, in this study, fertility status was not an outcome we were attempting to assess. WIDER IMPLICATIONS OF THE FINDINGS: This is the largest study to date seeking to understand the association between sperm sex chromosome disomy and semen parameters, and the first to use multivariate modeling to understand this relationship. The findings are similar to those in the published literature and highlight the need for mechanistic studies to better characterize the interrelationships between sex chromosome disomy and standard indices of sperm health. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by grants from NIOSH (T42 OH008416) and NIEHS (R01 ES009718, P30 ES000002 and R01 ES017457). The authors declare no competing interests. At the time this work was conducted and the initial manuscript written, MEM was affiliated with the Environmental Health Department at the Harvard School of Public Health. Currently, MEM is employed by Millennium: The Takeda Oncology Company. TRIAL REGISTRATION NUMBER: N/A.

An assessment of bone fluoride and osteosarcoma.

The association between fluoride and risk for osteosarcoma is controversial. The purpose of this study was to determine if bone fluoride levels are higher in individuals with osteosarcoma. Incident cases of osteosarcoma (N = 137) and tumor controls (N = 51) were identified by orthopedic physicians, and segments of tumor-adjacent bone and iliac crest bone were analyzed for fluoride content. Logistic regression adjusted for age and sex and potential confounders of osteosarcoma was used to estimate odds ratios (OR) and 95% confidence intervals (CI). There was no significant difference in bone fluoride levels between cases and controls. The OR adjusted for age, gender, and a history of broken bones was 1.33 (95% CI: 0.56-3.15). No significant association between bone fluoride levels and osteosarcoma risk was detected in our case-control study, based on controls with other tumor diagnoses.

Imaging the pericardium: appearances on ECG-gated 64-detector row cardiac computed tomography.

Multidetector row computed tomography (MDCT) with its high spatial and temporal resolution has now become an established and complementary method for cardiac imaging. It can now be used reliably to exclude significant coronary artery disease and delineate complex coronary artery anomalies, and has become a valuable problem-solving tool. Our experience with MDCT imaging suggests that it is clinically useful for imaging the pericardium. It is important to be aware of the normal anatomy of the pericardium and not mistake normal variations for pathology. The pericardial recesses are visible in up to 44% of non-electrocardiogram (ECG)-gated MDCT images. Abnormalities of the pericardium can now be identified with increasing certainty on 64-detector row CT; they may be the key to diagnosis and therefore must not be overlooked. This educational review of the pericardium will cover different imaging techniques, with a significant emphasis on MDCT. We have a large research and clinical experience of ECG-gated cardiac CT and will demonstrate examples of pericardial recesses, their variations and a wide variety of pericardial abnormalities and systemic conditions affecting the pericardium. We give a brief relevant background of the conditions and reinforce the key imaging features. We aim to provide a pictorial demonstration of the wide variety of abnormalities of the pericardium and the pitfalls in the diagnosis of pericardial disease.

Urinary bisphenol A concentrations and ovarian response among women undergoing IVF.

Bisphenol A (BPA) is a synthetic chemical used in the manufacture of materials present in many common consumer products. In experimental animals, BPA caused oocyte aneuploidy and reduced production of oestradiol. In a prospective cohort study, we investigated the association between urinary BPA concentrations and ovarian response among women undergoing in vitro fertilization (IVF) at the Massachusetts General Hospital (MGH) Fertility Center. The geometric mean of two specific-gravity (SG) adjusted urinary BPA concentrations collected during each IVF cycle was used as the cycle-specific BPA exposure level. BPA concentrations were measured using online solid phase extraction coupled to isotope dilution-high-performance liquid chromatography-tandem mass spectrometry. Peak serum oestradiol was measured using the Elecsys Estradiol II immunoassay kit. Multivariable mixed effect models and Poisson regression models adjusting for correlation between multiple IVF cycles in the same woman were used to evaluate the association between urinary BPA concentrations and ovarian response, adjusting for age, BMI and day 3 follicle stimulating hormone (FSH) levels, a clinical measure of ovarian reserve. Urinary BPA concentrations were measured in 84 women (mean age 35.6 years) undergoing 112 IVF cycles; 23 women (27%) contributed more than one IVF cycle. BPA concentrations ranged from <0.4 to 25.5 microg/L (geometric mean 2.52 +/- SD 3.2); 15% of urine samples had concentrations <0.4 microg/L. Peak serum oestradiol levels correlated with the total number of oocytes retrieved per cycle (r = 0.65, p < 0.001). For each log unit increase in SG-BPA, there was an average decrease of 12% (95% CI: 4, 23%; p = 0.007) in the number of oocytes retrieved and an average decrease of 213 pg/ml (95% CI: -407, -20; p = 0.03) in peak oestradiol. BPA was detected in the urine of the majority of women undergoing IVF, and was inversely associated with number of oocytes retrieved and peak oestradiol levels.

Association of DRB1 shared epitope genotypes with early mortality in rheumatoid arthritis: results of eighteen years of followup from the early rheumatoid arthritis study.

OBJECTIVE: To determine whether the HLA-DRB1 shared epitope (SE) is associated with early mortality and specific causes of death in rheumatoid arthritis (RA). METHODS: HLA-DRB1 genotyping was carried out on blood samples from 767 patients recruited for the Early RA Study (ERAS), a multicenter, inception cohort study with followup over 18 years. Dates and causes of death (n = 186) were obtained from the Office of National Statistics. The association of HLA-DRB1 alleles with risk of mortality was assessed using Cox proportional hazards regression analyses. Multivariate stepwise models were used to assess the predictive value of HLA-DRB1 genotypes compared with other potential baseline risk factors. RESULTS: The SE was not significantly associated with overall mortality. However, the presence of 2 SE alleles was associated with risk of mortality from ischemic heart disease (hazard ratio [HR] 2.02 [95% confidence interval 1.04-3.94], P = 0.04), and malignancy (HR 2.18 [95% confidence interval 1.17-4.08], P = 0.01). Analysis of specific SE genotypes (corrected for age and sex) revealed that the HLA-DRB1*0101/*0401 and 0404/*0404 genotypes were the strongest predictors of mortality from ischemic heart disease (HR 5.11 and HR 7.55, respectively), and DRB1*0101/*0401 showed a possible interaction with smoking. Male sex, erythrocyte sedimentation rate, and Carstairs Deprivation Index were also predictive, but the Health Assessment Questionnaire score, rheumatoid factor, nodules, and swollen joint counts were not. Mortality due to malignancy was particularly associated with DRB1*0101 genotypes. CONCLUSION: The risk of mortality due to ischemic heart disease or cancer in RA is increased in patients carrying HLA-DRB1 genotypes with particular homozygous and compound heterozygous SE combinations.

Temporal expression of inflammatory mediators in brain basilar artery vasculitis and cerebrospinal fluid of rabbits with coccidioidal meningitis.

Strokes due to transmural vasculitis associated with coccidioidal meningitis result in significant morbidity and mortality. The immunological and inflammatory processes responsible are poorly understood. To determine the inflammatory mediators, i.e. cytokines, chemokines, iNOS, matrix metalloproteinase-9 (MMP-9), that possibly contribute to vasculitis, temporal mRNA expression in brain basilar artery samples and MMP-9 protein in the CSF of male NZW rabbits infected intracisternally with 6.5 x 10(4) arthroconidia of Coccidioides immitis were assessed. Five infected and 3 sham-injected rabbits at each time point were euthanized 4, 9, 14 and 20 days post infection. All infected rabbits had neurological abnormalities and severe vasculitis in the basilar arteries on days 9-20. In basilar arteries of infected animals versus controls, mRNAs encoding for IL-6, iNOS, IFN-gamma, IL-2, MCP-1, IL-1beta, IL-10, TNF-alpha, CCR-1, MMP-9, TGF-beta, as well as MMP-9 protein in CSF, were found to be significantly up-regulated. Thus, this study identified inflammatory mediators associated with CNS vasculitis and meningitis due to C. immitis infection. Assessment of the individual contribution of each mediator to vasculitis may offer novel approaches to the treatment of coccidioidal CNS infection. This study also provides unique methodology for immunology studies in a rabbit model.

-308GA and TNFB polymorphisms in acute respiratory distress syndrome.

The -308GA and TNFB1/2 polymorphisms of the tumour necrosis factor genes have been associated with increased susceptibility to, and mortality in sepsis, although, prior studies are not consistent. Their role in acute respiratory distress syndrome (ARDS) has not been evaluated. The current authors hypothesised that the -308A allele and TNFB22 genotype would be associated with increased susceptibility to, and mortality in ARDS. The above hypothesis was investigated in a nested case-control study of 441 Caucasian controls and 212 cases admitted to an intensive care unit with sepsis, trauma, aspiration or hyper-transfusions. The -308A and TNFB1 alleles were in linkage disequilibrium. These polymorphisms were not associated with ARDS susceptibility on crude analysis. On subgroup analyses, they were associated with either increased or decreased odds of developing ARDS depending on whether the clinical risk for ARDS results in direct or indirect pulmonary injury. The -308A allele was associated with increased 60-day mortality in ARDS, with the strongest association found among younger patients. There was no association between the TNFB polymorphism and ARDS mortality. The -308GA, but not the TNFB12, polymorphism was associated with increased mortality in acute respiratory distress syndrome, but their association with acute respiratory distress syndrome susceptibility depended on the site of injury predisposing to acute respiratory distress syndrome.

Reproductive and developmental risks from ethylene oxide: a probabilistic characterization of possible regulatory thresholds.

Ethylene oxide is a gas produced in large quantities in the United States that is used primarily as a chemical intermediate in the production of ethylene glycol, propylene glycol, non-ionic surfactants, ethanolamines, glycol ethers, and other chemicals. It has been well established that ethylene oxide can induce cancer, genetic, reproductive and developmental, and acute health effects in animals. The U.S. Environmental Protection Agency is currently developing both a cancer potency factor and a reference concentration (RfC) for ethylene oxide. This study used the rich database on the reproductive and developmental effects of ethylene oxide to develop a probabilistic characterization of possible regulatory thresholds for ethylene oxide. This analysis was based on the standard regulatory approach for noncancer risk assessment, but involved several innovative elements, such as: (1) the use of advanced statistical methods to account for correlations in developmental outcomes among littermates and allow for simultaneous control of covariates (such as litter size); (2) the application of a probabilistic approach for characterizing the uncertainty in extrapolating the animal results to humans; and (3) the use of a quantitative approach to account for the variation in heterogeneity among the human population. This article presents several classes of results, including: (1) probabilistic characterizations of ED10s for two quantal reproductive outcomes-resorption and fetal death, (2) probabilistic characterizations of one developmental outcome-the dose expected to yield a 5% reduction in fetal (or pup) weight, (3) estimates of the RfCs that would result from using these values in the standard regulatory approach for noncancer risk assessment, and (4) a probabilistic characterization of the level of ethylene oxide exposure that would be expected to yield a 1/1,000 increase in the risk of reproductive or developmental outcomes in exposed human populations.

Vasculitic complications associated with coccidioidal meningitis.

Vasculitis complicating coccidioidal meningitis is becoming increasingly recognized. At this time, predisposing clinical features have not been elucidated. Histologically, 2 types of vascular inflammation have been described. The first is a transmural inflammatory process of the intracranial blood vessels that occurs early in the course of disease. Encroachment of the vessel lumen may result in thrombosis. The second process occurs with chronic disease and is associated with intimal thickening and luminal occlusion with little inflammation. Numerous substances, including metalloproteinases, cytokines such as tumor necrosis factor (TNF)-alpha, and an elastase, have been postulated as putative virulence factors. Recently, a rabbit model has been developed that appears to closely mimic human disease. By using this model, a parallel between coccidioidal vasculitis and temporal arteritis has been developed. Currently, there are no established therapies for coccidioidal vasculitis. The use of corticosteroids is controversial. Of interest are agents that may block the pathologic process, such as omega-3 oils, and pentoxyfylline.

Barium: rationale for a new oral reference dose.

The U.S. Environmental Protection Agency (EPA) has an established oral reference dose (RfD) value for Ba of 0.07 mg Ba/kg/d based on a 1984 investigation that reported hypertension. In this study, the toxicological data for Ba has been reevaluated and a revised oral RfD is proposed. The toxicokinetic, acute, and chronic toxicity, carcinogenicity, and reproductive animal studies as well as epidemiological and occupational health human studies for Ba exposure were reviewed for applicability to an oral RfD. The available human studies have some utility but suffer from either a small population size, a short exposure regimen, or difficulties in identifying definitive Ba exposure in the study population. As a result, the available long-term animal studies were found to be more appropriate for the RfD derivation. A dose-response assessment of no-observed-adverse-effect level (NOAEL) and lowest-observed-adverse-effect level (LOAEL) values determined that kidney effects are the most sensitive endpoint for adverse health effects related to chronic soluble Ba ingestion in mammals. The most complete animal studies were conducted by the National Toxicology Program (NTP, 1994) and the lowest species NOAELs were 75 mg Ba/kg/d in male mice and 60 mg Ba/kg/d for male rats. The male rats were identified to be the most sensitive population tested and their NOAEL value was selected for extrapolation to an oral RfD. Application of overall uncertainty factors to the lowest NOAEL value from a chronic animal study of either 90 (based on an approach proposed by Dourson, 1994) or the generally accepted 100 results in an oral RfD of 0.66 mg Ba/kg/d or 0.6 mg Ba/kg/d, respectively. It is proposed to use the more conservative value of 0.6 mg Ba/kg/d. This reassessment results in nearly an order of magnitude increase in the U.S. EPA oral RfD for Ba.

Association of heart rate variability with occupational and environmental exposure to particulate air pollution.

BACKGROUND: Airborne particulate matter has been linked to excess morbidity and mortality. Recent attention has focused on the effects of particulate exposure on cardiac autonomic control. Inhaled particulates may affect the autonomic nervous system either directly, by eliciting a sympathetic stress response, or indirectly, through inflammatory cytokines produced in the lungs and released into the circulation. METHODS AND RESULTS: This longitudinal study examined the association of particulates

Ambient air quality at the site of a former manufactured gas plant.

Prior to the 1950's, manufactured gas was commercially produced from the pyrolysis of coal, coke, and oil at facilities that are termed manufactured gas plants (MGPs). The constituents of residual coal tar present on many MGP sites are an environmental health concern because of their toxicity and the possibility for their off-site migration via water and air. Atmospheric concentrations of five volatile organic compounds (VOCs, e.g., benzene), sixteen polycyclic aromatic hydrocarbons (PAHs, e.g., naphthalene) and particulate matter less than 10 microns in aerodynamic diameter (PM10) were measured at the site of a former MGP. Air samples were obtained before, during, and after excavation of subterranean coal tar at the site. The results of this investigation indicate that subterranean coal tar was not a primary source of VOCs and PAHs in the local atmosphere before or after remediation of the site. However, excavation, treatment, blending, and transfer of the coal tar during remediation generated concentrations of selected aromatic and semi-volatile organic compounds that were substantially greater than typical ambient levels. In addition, these data suggest that blending and mixing of coal tars could lead to exceedance of the U.S. National Ambient Air Quality Standard for PM10, although additional research is required to fully evaluate this possibility. Nuisance odors associated with the site remediation were likely the result of naphthalene and possibly isomers of xylene. Air pollutant concentrations measured adjacent to the excavation area and at the site perimeter during remediation activities were less than the relevant occupational and environmental exposure limits.

Characterizing dose-response relationships in multiple cancer bioassays.

In the evaluation of chemical compounds for carcinogenic risk, regulatory agencies such as the U.S. Environmental Protection Agency and National Toxicology Program (NTP) have traditionally fit a dose-response model to data from rodent bioassays, and then used the fitted model to estimate a Virtually Safe Dose or the dose corresponding to a very small increase (usually 10(-6)) in risk over background. Much recent interest has been directed at incorporating additional scientific information regarding the properties of the specific chemical under investigation into the risk assessment process, including biological mechanisms of cancer induction, metabolic pathways, and chemical structure and activity. Despite the fact that regulatory agencies are currently poised to allow use of nonlinear dose-response models based on the concept of an underlying threshold for nongenotoxic chemicals, there have been few attempts to investigate the overall relationship between the shape of dose-response curves and mutagenicity. Using data from an historical database of NTP cancer bioassays, the authors conducted a repeated-measures Analysis of the estimated shape from fitting extended Weibull dose-response curves. It was concluded that genotoxic chemicals have dose-response curves that are closer to linear than those for nongenotoxic chemicals, though on average, both types of compounds have dose-response curves that are convex and the effect of genotoxicity is small.