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Aims. The aim of this work was to study the nature of the diabetes affecting six sibs of one generation of a family. Methods. Full clinical histories of all six members of the family were ascertained plus an assessment of beta cell reserve and insulin gene sequencing. Only one member of the family had children and these, and his grandchildren, were investigated for diabetes by glucose tolerance testing and for insulin C-peptide and proinsulin release to detect possible abnormalities. Results. Except in one instance, the onset of the disease was gradual and treatment was initiated with diet or oral hypoglycaemic agents. The BMI at onset of diabetes was low. Insulin treatment was required between the ages of 69 and 74. Insulin dosage was generally small and tests on some members of the family revealed residual beta cell function. No abnormalities in carbohydrate metabolism were shown in the children of one member of the family or in his grandchildren. The insulin gene investigated in two members of the family was normal. Antibodies to glutamic acid decarboxylase or tyrosine phosphatase were not detected in the propositus and her niece. Conclusions. This case report describes familial diabetes progressing to insulin dependency in later life that affected six members of one generation of a family. It is tempting to assume that the diabetes in this family is a consequence of a shared environmental factor. However, it is equally possible that an as yet unidentified gene variant predisposing to diabetes will account for the clinical picture. Copyright © 2001 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Importance: Previous meta-analyses suggest that fluoride exposure is adversely associated with children's IQ scores. An individual's total fluoride exposure comes primarily from fluoride in drinking water, food, and beverages., Objective: To perform a systematic review and meta-analysis of epidemiological studies investigating children's IQ scores and prenatal or postnatal fluoride exposure., Data Sources: BIOSIS, Embase, PsycInfo, PubMed, Scopus, Web of Science, CNKI, and Wanfang, searched through October 2023., Study Selection: Studies reporting children's IQ scores, fluoride exposure, and effect sizes., Data Extraction and Synthesis: Data were extracted into the Health Assessment Workplace Collaborative system. Study quality was evaluated using the OHAT risk-of-bias tool. Pooled standardized mean differences (SMDs) and regression coefficients were estimated with random-effects models., Main Outcomes and Measures: Children's IQ scores., Results: Of 74 studies included (64 cross-sectional and 10 cohort studies), most were conducted in China (n = 45); other locations included Canada (n = 3), Denmark (n = 1), India (n = 12), Iran (n = 4), Mexico (n = 4), New Zealand (n = 1), Pakistan (n = 2), Spain (n = 1), and Taiwan (n = 1). Fifty-two studies were rated high risk of bias and 22 were rated low risk of bias. Sixty-four studies reported inverse associations between fluoride exposure measures and children's IQ. Analysis of 59 studies with group-level measures of fluoride in drinking water, dental fluorosis, or other measures of fluoride exposure (47 high risk of bias, 12 low risk of bias; n = 20 932 children) showed an inverse association between fluoride exposure and IQ (pooled SMD, -0.45; 95% CI, -0.57 to -0.33; P < .001). In 31 studies reporting fluoride measured in drinking water, a dose-response association was found between exposed and reference groups (SMD, -0.15; 95% CI, -0.20 to -0.11; P < .001), and associations remained inverse when exposed groups were restricted to less than 4 mg/L and less than 2 mg/L; however, the association was null at less than 1.5 mg/L. In analyses restricted to low risk-of-bias studies, the association remained inverse when exposure was restricted to less than 4 mg/L, less than 2 mg/L, and less than 1.5 mg/L fluoride in drinking water. In 20 studies reporting fluoride measured in urine, there was an inverse dose-response association (SMD, -0.15; 95% CI, -0.23 to -0.07; P < .001). Associations remained inverse when exposed groups were restricted to less than 4 mg/L, less than 2 mg/L, and less than 1.5 mg/L fluoride in urine; the associations held in analyses restricted to the low risk-of-bias studies. Analysis of 13 studies with individual-level measures found an IQ score decrease of 1.63 points (95% CI, -2.33 to -0.93; P < .001) per 1-mg/L increase in urinary fluoride. Among low risk-of-bias studies, there was an IQ score decrease of 1.14 points (95% CI, -1.68 to -0.61; P < .001). Associations remained inverse when stratified by risk of bias, sex, age, outcome assessment type, country, exposure timing, and exposure matrix., Conclusions and Relevance: This systematic review and meta-analysis found inverse associations and a dose-response association between fluoride measurements in urine and drinking water and children's IQ across the large multicountry epidemiological literature. There were limited data and uncertainty in the dose-response association between fluoride exposure and children's IQ when fluoride exposure was estimated by drinking water alone at concentrations less than 1.5 mg/L. These findings may inform future comprehensive public health risk-benefit assessments of fluoride exposures.

Background: Studies have shown an association between hair product use and adverse health outcomes. Scientists have hypothesized that exposure to endocrine-disrupting chemicals (EDCs) drives these associations, but few studies have directly evaluated associations between hair product use and biomarkers of EDCs. Even more limited are studies of Black women, who frequently use EDC-containing products (e.g., hair relaxers)., Objective: We estimated associations between hair product use and EDC biomarker concentrations., Methods: We leveraged cross-sectional data from the Study of Environment, Lifestyle, and Fibroids, a cohort of females aged 23-34 years who self-identified as Black/African American from the Detroit-metropolitan area (USA; n = 425). On structured questionnaires, participants reported their past 24-h and past 12-month use of hair products, including relaxers/straighteners/perms, styling products, moisturizers, oils, and hair food. We quantified urinary concentrations of 19 phthalate/phthalate alternative metabolites, 7 phenols, and 4 parabens using high performance liquid chromatography isotope dilution tandem mass spectrometry. EDC biomarker concentrations were creatinine-adjusted and natural log-transformed. We used multivariable linear regression to estimate mean percent differences in EDC biomarker concentrations and 95% confidence intervals (CIs) associated with hair product use, adjusting for sociodemographic confounders., Results: Hair product use was associated with greater concentrations of multiple EDC biomarkers. Notably, use of hair products in the previous 24 h (compared with non-use) was associated with 16.2% (95% CI = 0.7%, 35.9%), 35.0% (95% CI = 2.6%, 77.6%), and 32.3% (95% CI = 8.8%, 92.0%) higher concentrations of mono-isobutyl phthalate, methyl paraben, and ethyl paraben, respectively. Use of hair relaxers/straighteners/perms, styling products, moisturizers, oils, and hair food in the past 12 months was also associated with higher concentrations of multiple phthalate, phenol, and paraben biomarkers., Conclusion: Hair product use was associated with higher biomarker concentrations of multiple phthalates, phenols, and parabens. These findings suggest that hair products are potentially important exposure sources for hormonally-active chemicals among Black women., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Compared to White women, Black women in the United States are more likely to use personal care products (PCPs) with higher concentrations of endocrine-disrupting chemicals (EDCs) and harsher chemical formulations. This may contribute to differential health outcomes in Black women such as increased risk of breast cancer, cardiometabolic outcomes, adverse birth outcomes, and uterine fibroids., Objective: Classify distinct PCP use patterns across multiple types of products and examine how patterns vary by socio-demographic characteristics., Methods: The Study of Environment, Lifestyle and Fibroids is a cohort study of reproductive-aged Black individuals living around Detroit, Michigan. Using self-reported data on frequency of PCP collected between 2013-2018, we employed latent class analysis to identify distinct groups of participants with similar PCP use. Socio-demographic characteristics were compared across latent classes., Results: Among 1562 participants, we identified 6 latent classes: Lower Overall; Higher Nailcare; Higher Skincare; Moderate Overall; Higher Makeup/Haircare/Skincare; Higher Overall. Makeup and nailcare usage were the most predictive for classifying participants into groups. Participants in classes with less frequent use of all PCPs and those with only high use of nailcare products, were more likely to report lower socio-economic status (SES), be current smokers, have a body mass index of ≥35 kg/m 2 , and have ≥3 births. In comparison, participants in classes with average and more frequent use of PCPs were more likely to report higher SES, be non-smokers, be nulliparous, and have ever used oral contraceptives., Impact Statement: This study is one of the first detailed assessments of PCP usage among a large cohort of young adult Black women that considers multiple product categories including makeup, hair, skin, nail, and vaginal products. Latent class analysis was used to capture complex patterns of PCP use and identify distinct groups of individuals with similar product use. Although the latent classes are specific to this study population, the identified socio-demographic characteristics or behaviors associated with latent classes may inform targeted and impactful exposure reduction strategies in similar populations., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Observational epidemiologic studies provide critical data for the evaluation of the potential effects of environmental, occupational and behavioural exposures on human health. Systematic reviews of these studies play a key role in informing policy and practice. Systematic reviews should incorporate assessments of the risk of bias in results of the included studies., Objective: To develop a new tool, Risk Of Bias In Non-randomized Studies - of Exposures (ROBINS-E) to assess risk of bias in estimates from cohort studies of the causal effect of an exposure on an outcome., Methods and Results: ROBINS-E was developed by a large group of researchers from diverse research and public health disciplines through a series of working groups, in-person meetings and pilot testing phases. The tool aims to assess the risk of bias in a specific result (exposure effect estimate) from an individual observational study that examines the effect of an exposure on an outcome. A series of preliminary considerations informs the core ROBINS-E assessment, including details of the result being assessed and the causal effect being estimated. The assessment addresses bias within seven domains, through a series of 'signalling questions'. Domain-level judgements about risk of bias are derived from the answers to these questions, then combined to produce an overall risk of bias judgement for the result, together with judgements about the direction of bias., Conclusion: ROBINS-E provides a standardized framework for examining potential biases in results from cohort studies. Future work will produce variants of the tool for other epidemiologic study designs (e.g. case-control studies). We believe that ROBINS-E represents an important development in the integration of exposure assessment, evidence synthesis and causal inference., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Judy LaKind reports receipt of support for research on systematic reviews and assessments of review processes from NCASI, the American Petroleum Institute and the National Institute of Environmental Health Sciences and served on the GRADE panel for assessing the certainty of modeled evidence. Annette O’Connor reports funding from the US National Pork Board and the United Soybean Board that includes: consulting or advisory. Jelena Savović reports a relationship with JEMMDx Limited that includes: consulting or advisory. Jelena Savović reports a relationship with Core Models Limited that includes: teaching. Kate Tilling reports a relationship with CHDI Foundation that includes: consulting or advisory. Kate Tilling reports a relationship with UK MHRA that includes: paid expert testimony. Jos Verbeek reports a relationship with World Health Organization that includes: consulting or advisory. The remaining authors report no financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Some personal care products (PCPs) contain endocrine-disrupting chemicals that may affect breast cancer (BC) risk. Patterns of use vary by race and ethnicity. Use often starts in adolescence, when rapidly developing breast tissue may be more susceptible to environmental carcinogens. Few studies have examined associations of BC with PCP use during this susceptible window., Objectives: We characterized race and ethnicity-specific patterns of PCP use at 10-13 years of age and estimated associations of use with incident BC., Methods: At enrollment (2003-2009), Sister Study participants ( n = 4,049 Black, 2,104 Latina, and 39,312 White women) 35-74 years of age reported use of 37 "everyday" PCPs during the ages of 10-13 y (did not use, sometimes, or frequently used). We conducted race and ethnicity-specific latent class analyses to separately identify groups of women with similar patterns of beauty, hair, and skincare/hygiene product use. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for associations of identified PCP classes and single products with incident BC using Cox proportional hazards regression., Results: During a mean follow-up time of 10.8 y, 280 Black, 128 Latina, and 3,137 White women were diagnosed with BC. Classes of adolescent PCP use were not clearly associated with BC diagnosis among Black, Latina, or White women. HRs were elevated but imprecise for frequent nail product and perfume use in Black women ( HR = 1.34; 95% CI: 0.85, 2.12) and greater hair product use in Black ( HR = 1.28; 95% CI: 0.91, 1.80) and Latina ( HR = 1.42; 95% CI: 0.81, 2.48) women compared with lighter use. In single-product models, we observed higher BC incidence associated with frequent use of lipstick, nail products, pomade, perfume, makeup remover, and acne/blemish products in at least one group., Discussion: This work provides some support for the hypothesis that PCP use during puberty is associated with BC risk. More research is needed to confirm these novel findings. https://doi.org/10.1289/EHP13882.

Background: Personal care products (PCPs), a source of endocrine-disrupting chemical exposure, may be associated with the risk of hormone-sensitive cancers. Few studies have investigated associations for PCP use with the incidence of hormone-sensitive cancers or considered the joint effect of multiple correlated PCPs. We examined associations between frequently used, or "everyday", PCPs and incident cancers of the breast, ovary, and uterus with a fucus on the joint effect of multiple product exposure., Methods: Sister Study participants (n=49 899) self-reported frequency of use in the year before enrollment (2003-2009) for 41 PCPs. Using five-level frequency categories based on questionnaire options, hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for the associations between multiple PCP use and incident breast, ovarian, and uterine cancer using quantile-based g-computation with Cox proportional hazards regression as the underlying model. Multiple PCP use was examined using groupings (beauty, hygiene, and skincare products) determined by both a priori knowledge and Spearman correlation coefficients for co-occurring product use. Associations between individual PCPs and the three cancers were also examined using Cox proportional hazards models coupling with Benjamini-Hochberg procedure for multiple comparisons., Results: Over an average of 11.6 years, 4 226 breast, 277 ovarian, and 403 uterine cancer cases were identified. Positive associations were observed between the hygiene mixture and ovarian cancer (HR=1.35, 95%CI=1.00, 1.83) and the beauty mixture with postmenopausal breast cancer (HR=1.08, 95%CI=1.01, 1.16). Additionally, we observed an inverse association between the skincare mixture and breast cancer (HR=0.91, 95%CI=0.83, 0.99). No significant associations were observed for individual products after corrected for multiple comparison., Conclusions: Findings from this multi-product, joint-effect approach contribute to the growing body of evidence for associations between PCPs and breast cancer and provides novel information on ovarian and uterine cancer., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Personal care products (PCPs) contain many different compounds and are a source of exposure to endocrine disrupting chemicals (EDCs), including phthalates and phenols. Early-life exposure to EDCs commonly found in PCPs has been linked to earlier onset of puberty., Objective: To characterize the human and animal evidence on the association between puberty-related outcomes and exposure to PCPs and their chemical constituents and, if there is sufficient evidence, identify groups of chemicals and outcomes to support a systematic review for a class-based hazard or risk assessment., Methods: We followed the OHAT systematic review framework to characterize the human and animal evidence on the association between puberty-related health outcomes and exposure to PCPs and their chemical constituents., Results: Ninety-eight human and 299 animal studies that evaluated a total of 96 different chemicals were identified and mapped by key concepts including chemical class, data stream, and puberty-related health outcome. Among these studies, phthalates and phenols were the most well-studied chemical classes. Most of the phthalate and phenol studies examined secondary sex characteristics and changes in estradiol and testosterone levels. Studies evaluating PCP use and other chemical classes (e.g., parabens) had less data., Conclusions: This systematic evidence map identified and mapped the published research evaluating the association between exposure to PCPs and their chemical constituents and puberty-related health outcomes. The resulting interactive visualization allows researchers to make evidence-based decisions on the available research by enabling them to search, sort, and filter the literature base of puberty-related studies by key concepts. This map can be used by researchers and regulators to prioritize and target future research and funding to reduce uncertainties and address data gaps. It also provides information to inform a class-based hazard or risk assessment on the association between phthalate and phenol exposures and puberty-related health outcomes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Some studies indicate that Black women have higher exposure to multiple non-persistent endocrine disrupting chemicals (EDCs) than white women, but little is known about correlates of exposure to EDC mixtures. Using baseline data from a prospective cohort study of reproductive-aged Black women (N = 751), we characterized profiles of EDC mixtures and identified correlates of exposure. At baseline, we quantified biomarkers of 16 phthalates, 7 phenols, 4 parabens, and triclocarban in urine and collected covariate data through self-administered questionnaires and interviews. We used principal component (PC) analysis and k-means clustering to describe EDC mixture profiles. Associations between correlates and PCs were estimated as the mean difference (β) in PC scores, while associations between correlates and cluster membership were estimated as the odds ratio (OR) of cluster membership. Personal care product use was consistently associated with profiles of higher biomarker concentrations of non-persistent EDCs. Use of nail polish, menstrual and vaginal products (e.g., vaginal powder, vaginal deodorant), and sunscreen was associated with a mixture of phthalate and some phenol biomarkers using both methods. Current vaginal ring use, a form of hormonal contraception placed inside the vagina, was strongly associated with higher concentrations of high molecular weight phthalate biomarkers (k-means clustering: OR = 2.42, 95% CI = 1.28, 4.59; PCA: β = -0.32, 95% CI = -0.71, 0.07). Several dietary, reproductive, and demographic correlates were also associated with mixtures of EDC biomarkers. These findings suggest that personal care product use, diet, and contraceptive use may be sources of exposure to multiple non-persistent EDCs among reproductive-aged Black women. Targeted interventions to reduce exposure to multiple EDCs among Black women are warranted., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Small relative effect sizes are common in observational studies of exposure in environmental and public health. However, such effects can still have considerable policy importance when the baseline rate of the health outcome is high, and many persons are exposed. Assessing the certainty of the evidence based on these effect sizes is challenging because they can be prone to residual confounding due to the non-randomized nature of the evidence. When applying GRADE, a precise relative risk >2.0 increases the certainty in an existing effect because residual confounding is unlikely to explain the association. GRADE also suggests rating up when opposing plausible residual confounding exists for other effect sizes. In this concept paper, we propose using the E-value, defined as the smallest effect size of a confounder that still can reduce an observed RR to the null value, and a reference confounder to assess the likelihood of residual confounding. We propose a 4-step approach. 1. Assess the association of interest for relevant exposure levels. 2. Calculate the E-value for this observed association. 3. Choose a reference confounder with sufficient strength and information and assess its effect on the observed association using the E-value. 4. Assess how likely it is that residual confounding will still bias the observed RR. We present three case studies and discuss the feasibility of the approach., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Personal exposure to volatile organic compounds (VOCs) from indoor sources including consumer products is an understudied public health concern. To develop and evaluate methods for monitoring personal VOC exposures, we performed a pilot study and examined time-resolved sensor-based measurements of geocoded total VOC (TVOC) exposures across individuals and microenvironments (MEs). We integrated continuous (1 min) data from a personal TVOC sensor and a global positioning system (GPS) logger, with a GPS-based ME classification model, to determine TVOC exposures in four MEs, including indoors at home (Home-In), indoors at other buildings (Other-In), inside vehicles (In-Vehicle), and outdoors (Out), across 45 participant-days for five participants. To help identify places with large emission sources, we identified high-exposure events (HEEs; TVOC > 500 ppb) using geocoded TVOC time-course data overlaid on Google Earth maps. Across the 45 participant-days, the MEs ranked from highest to lowest median TVOC were: Home-In (165 ppb), Other-In (86 ppb), In-Vehicle (52 ppb), and Out (46 ppb). For the two participants living in single-family houses with attached garages, the median exposures for Home-In were substantially higher (209, 416 ppb) than the three participant homes without attached garages: one living in a single-family house (129 ppb), and two living in apartments (38, 60 ppb). The daily average Home-In exposures exceeded the estimated Leadership in Energy and Environmental Design (LEED) building guideline of 108 ppb for 60% of the participant-days. We identified 94 HEEs across all participant-days, and 67% of the corresponding peak levels exceeded 1000 ppb. The MEs ranked from the highest to the lowest number of HEEs were: Home-In (60), Other-In (13), In-Vehicle (12), and Out (9). For Other-In and Out, most HEEs occurred indoors at fast food restaurants and retail stores, and outdoors in parking lots, respectively. For Home-In HEEs, the median TVOC emission and removal rates were 5.4 g h -1 and 1.1 h -1 , respectively. Our study demonstrates the ability to determine individual sensor-based time-resolved TVOC exposures in different MEs, in support of identifying potential sources and exposure factors that can inform exposure mitigation strategies.

Hair products can contain hormonally active and carcinogenic compounds. Adolescence may be a period of enhanced susceptibility of the breast tissue to exposure to chemicals. We therefore evaluated associations between adolescent hair product use and breast cancer risk. Sister Study participants (ages 35-74 years) who had completed enrollment questionnaires (2003-2009) on use of hair dyes, straighteners/relaxers and perms at ages 10 to 13 years (N = 47 522) were included. Cox proportional hazards regression was used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) for associations between hair products and incident breast cancer (invasive cancer or ductal carcinoma in situ), with consideration of heterogeneity by menopausal status and race/ethnicity. Over an average of 10 years of follow-up, 3380 cases were diagnosed. Frequent use of straighteners and perms was associated with a higher risk of premenopausal (HR = 2.11, 95% CI: 1.26-3.55 and HR = 1.55, 95% CI: 0.96-2.53, respectively) but not postmenopausal breast cancer (HR = 0.99, 95% CI: 0.76-1.30 and HR = 1.09, 95% CI: 0.89-1.35, respectively). Permanent hair dye use during adolescence was uncommon (<3%) and not associated with breast cancer overall (HR = 0.97, 95% CI: 0.78-1.20), though any permanent dye use was associated with a higher risk among black women (HR = 1.77, 95% CI: 1.01-3.11). Although frequency of use of perms (37% non-Hispanic white vs 9% black) and straighteners (3% non-Hispanic white vs 75% black) varied by race/ethnicity, associations with breast cancer did not. Use of hair products, specifically perms and straighteners, during adolescence may be associated with a higher risk of premenopausal breast cancer., (© 2020 UICC.)

Background: Phthalates are endocrine-disrupting chemicals that are widely present in consumer products. In the United States, Black women are more highly exposed to phthalates than other racial/ethnic groups, yet information on predictors of phthalate exposure among Black women is limited., Objective: We evaluated the association of demographics, lifestyle, reproductive history, and personal care product use with urinary concentrations of phthalate and phthalate alternative metabolites, using cross-sectional data from a study of 754 Black women from Detroit, Michigan (2010-2012)., Methods: Women completed questionnaires and provided urine specimens which were analyzed for 16 phthalate and phthalate alternative metabolites. We used linear regression models to estimate mean percentage differences and 95% confidence intervals (CIs) in concentrations across levels of correlates., Results: Monoethyl phthalate (MEP) and MBP concentrations were positively associated with personal care product use, particularly nail products. Educational attainment was positively associated with high molecular weight phthalate concentrations but inversely associated with monobenzyl phthalate (MBzP) concentrations. Parity was positively associated with MBzP concentrations and inversely associated with concentrations of MEP and high molecular weight phthalates., Significance: We found that sociodemographics, reproductive characteristics, and use of certain personal care products were associated with urinary phthalate concentrations among Black women. Our results emphasize the importance of examining exposure determinants among multiply marginalized populations.

Systematic reviews are powerful tools for drawing causal inference for evidence-based decision-making. Published systematic reviews and meta-analyses of environmental and occupational epidemiology studies have increased dramatically in recent years; however, the quality and utility of published reviews are variable. Most methodologies were adapted from clinical epidemiology and have not been adequately modified to evaluate and integrate evidence from observational epidemiology studies assessing environmental and occupational hazards, especially in evaluating the quality of exposure assessments. Although many reviews conduct a systematic and transparent assessment for the potential for bias, they are often deficient in subsequently integrating across a body of evidence. A cohesive review considers the impact of the direction and magnitude of potential biases on the results, systematically evaluates important scientific issues such as study sensitivity and effect modifiers, identifies how different studies complement each other, and assesses other potential sources of heterogeneity. Given these challenges of conducting informative systematic reviews of observational studies, we provide a series of specific recommendations based on practical examples for cohesive evidence integration to reach an overall conclusion on a body of evidence to better support policy making in public health.

Many hair products contain endocrine-disrupting compounds and carcinogens potentially relevant to breast cancer. Products used predominately by black women may contain more hormonally-active compounds. In a national prospective cohort study, we examined the association between hair dye and chemical relaxer/straightener use and breast cancer risk by ethnicity. Sister Study participants (n = 46,709), women ages 35-74, were enrolled between 2003 and 2009, and had a sister with breast cancer but were breast cancer-free themselves. Enrollment questionnaires included past 12-month hair product use. Cox proportional hazards models estimated adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the association between hair products and breast cancer; effect measure modification by ethnicity was evaluated. During follow-up (mean = 8.3 years), 2,794 breast cancers were identified. Fifty-five percent of participants reported using permanent dye at enrollment. Permanent dye use was associated with 45% higher breast cancer risk in black women (HR = 1.45, 95% CI: 1.10-1.90), and 7% higher risk in white women (HR = 1.07, 95% CI: 0.99-1.16; heterogeneity p = 0.04). Among all participants, personal straightener use was associated with breast cancer risk (HR = 1.18, 95% CI 0.99-1.41); with higher risk associated with increased frequency (p for trend = 0.02). Nonprofessional application of semipermanent dye (HR = 1.28, 95% CI 1.05-1.56) and straighteners (HR = 1.27, 95% CI 0.99-1.62) to others was associated with breast cancer risk. We observed a higher breast cancer risk associated with any straightener use and personal use of permanent dye, especially among black women. These results suggest that chemicals in hair products may play a role in breast carcinogenesis., (© 2019 UICC.)

Sarin is a highly toxic nerve agent that was developed for chemical warfare during World War II and is used in present conflicts. Immediate effects of acute sarin exposure are established; however, whether effects persist after initial signs have subsided is debated. The National Toxicology Program (NTP) conducted a systematic review to evaluate the evidence for long-term neurological effects following acute (<24 hour) exposure to sarin. The literature search and screening process identified 32 data sets within the 34 human studies and 47 data sets within the 51 animal studies (from 6837 potentially relevant references) that met the objective and the inclusion criteria. Four main health effect categories of neurological response were identified as having sufficient data to reach hazard conclusions: (1) cholinesterase levels; (2) visual and ocular effects; (3) effects on learning, memory, and intelligence; and (4) morphology and histopathology in nervous system tissues. NTP concluded that acute sarin exposure is known to be a neurological hazard to humans in the period following exposure up to 7 days and suspected to be a hazard week to years after exposure, given a lower level of evidence in later time periods. Effects included reduced cholinesterase, visual and ocular effects, impaired learning and memory, and altered nervous system morphology. Further mechanistic, targeted animal studies, translational research, and rapid research responses after human exposures may reduce uncertainties on long-term consequences of sarin.

Tomato Atypical Receptor Kinase 1 (TARK1) is a pseudokinase required for postinvasion immunity. TARK1 was originally identified as a target of the Xanthomonas euvesicatoria effector protein Xanthomonas outer protein N (XopN), a suppressor of early defense signaling. How TARK1 participates in immune signal transduction is not well understood. To gain insight into TARK1's role in tomato ( Solanum lycopersicum ) immunity, we used a proteomics approach to isolate and identify TARK1-associated immune complexes formed during infection. We found that TARK1 interacts with proteins predicted to be associated with stomatal movement. TARK1 CRISPR mutants and overexpression (OE) lines did not display differences in light-induced stomatal opening or abscisic acid-induced stomatal closure; however, they did show altered stomatal movement responses to bacteria and biotic elicitors. Notably, we found that TARK1 CRISPR plants were resistant to Pseudomonas syringae pathovar tomato strain DC3000-induced stomatal reopening, and TARK1 OE plants were insensitive to P syringae pathovar tomato strain DC3118 (coronatine deficit)-induced stomatal closure. We also found that TARK1 OE in leaves resulted in increased susceptibility to bacterial invasion. Collectively, our results indicate that TARK1 functions in stomatal movement only in response to biotic elicitors and support a model in which TARK1 regulates stomatal opening postelicitation., (© 2020 American Society of Plant Biologists. All Rights Reserved.)

Background: Cardiovascular disease (CVD) is the leading cause of death among individuals with diabetes, but little is known about the role of exposures to environmental chemicals such as pesticides in the early development of CVD risk in this population., Objectives: To describe changes over time in concentrations of pesticide biomarkers among youth with diabetes in the United States and to estimate the longitudinal association between these concentrations and established risk factors for CVD., Methods: Pesticide biomarkers were quantified in urine and serum samples from 87 youth with diabetes participating in the multi-center SEARCH cohort study. Samples were obtained around the time of diagnosis (baseline visit, between 2006 and 2010) and, on average, 5.4 years later (follow-up visit, between 2012 and 2015). We calculated geometric mean (95% CI) pesticide biomarker concentrations. Eight CVD risk factors were measured at these two time points: body mass index (BMI) z-score, HbA1c, insulin sensitivity, fasting C-peptide (FCP), LDL cholesterol, HDL cholesterol, total cholesterol, and triglycerides. Linear regression models were used to estimate the associations between each pesticide biomarker at baseline and each CVD risk factor at follow-up, adjusting for baseline health outcome, elapsed time between baseline and follow up, sex, age, race/ethnicity, and diabetes type., Results: Participants were, on average, 14.2 years old at their baseline visit, and most were diagnosed with type 1 diabetes (57.5%). 4-nitrophenol, 3-phenoxybenzoic acid, 2,4-dichlorophenoxyacetic acid (2,4-D), 3,5,6-trichloro-2-pyridinol, 2,2-bis(4-chlorophenyl)-1,1-dichloroethene, and hexachlorobenzene were detected in a majority of participants at both time points. Participants in the highest quartile of 2,4-D and 4-nitrophenol at baseline had HbA1c levels at follow-up that were 1.05 percentage points (95% CI: -0.40, 2.51) and 1.27 percentage points (0.22, 2.75) higher, respectively, than participants in the lowest quartile of these pesticide biomarkers at baseline. These participants also had lower log FCP levels (indicating reduced beta-cell function) compared to participants in the lowest quartile at baseline: beta (95% CI) for log FCP of -0.64 (-1.17, -0.11) for 2,4-D and -0.39 (-0.96, 0.18) for 4-nitrophenol. In other words, participants in the highest quartile of 2,4-D had a 47.3% lower FCP level compared to participants in the lowest quartile, and those in the highest quartile of 4-nitrophenol had a 32.3% lower FCP level than those in the lowest quartile. Participants with trans-nonachlor concentrations in the highest quartile at baseline had HbA1c levels that were 1.45 percentage points (-0.11, 3.01) higher and log FCP levels that were -0.28 (-0.84, 0.28) lower than participants in the lowest quartile at baseline, that is to say, participants in the highest quartile of trans-nonachlor had a 24.4% lower FCP level than those in the lowest quartile. While not all of these results were statistically significant, potentially due to the small same size, clinically, there appears to be quantitative differences. No associations were observed between any pesticide biomarker at baseline with BMI z-score or insulin sensitivity at follow-up., Conclusions: Exposure to select pesticides may be associated with impaired beta-cell function and poorer glycemic control among youth with diabetes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Few studies have characterized life course hair product usage beyond ever/never. We investigated hair product use from childhood to adulthood, usage patterns in adulthood, and socioeconomic status (SES) correlates among African-American (AA) women. Using self-reported data from 1555 AA women enrolled in the Study of Environment, Lifestyle, and Fibroids (2010-2018), we estimated the usage frequency of chemical relaxer/straightener (≥twice/year, once/year, and rarely/never) and leave-in/leave-on conditioner (≥once/week, 1-3 times/month, and rarely/never) during childhood, adolescence, and adulthood. Latent class analysis was used to identify patterns of adulthood usage of multiple hair products. SES was compared across latent classes. With a mean age of 33 ± 3.4 years, most women reported ever using chemical relaxers/straighteners (89%), and use ≥twice/year increased from childhood (9%) to adolescence (73%) but decreased in adulthood (29%). Leave-in/leave-on conditioner use followed the same pattern. Each of three identified latent classes reported frequent styling product use and infrequent relaxer/straightener use. Class One was unlikely to use any other products, Class Two moderately used shampoo and conditioner, and Class Three frequently used multiple product types (e.g., moisturizers and conditioners). Participants in the latter two classes reported higher SES. Ever/never characterization may miss important and distinctive patterns of hair product use, which may vary by SES.

Purpose: Cannabis use is increasing due to recent legislative changes. In addition, cannabis is often used in conjunction with alcohol. The airway epithelium is the first line of defense against infectious microbes. Toll-like receptors (TLR) recognize airborne microbes and initiate the inflammatory cytokine response. The mechanism by which cannabis use in conjunction with alcohol affects pulmonary innate immunity mediated by TLRs is unknown., Methods: Samples and data from an existing cohort of individuals with alcohol use disorders (AUDs), along with samples from additional participants with cannabis use alone and with AUD were utilized. Subjects were categorized into the following groups: no alcohol use disorder (AUD) or cannabis use (control) (n = 46), AUD only (n = 29), cannabis use-only (n = 39), and AUD and cannabis use (n = 29). The participants underwent bronchoscopy with bronchoalveolar lavage (BAL) and airway epithelial brushings. We measured IL-6, IL-8, TNF⍺, and IL-10 levels in BAL fluid, and performed real-time PCR for TLR1-9 on the airway epithelial brushings., Results: We found significant increases in TLR2 with AUD alone, cannabis use alone, and cannabis use with AUD, compared to control. TLR5 was increased in cannabis users compared to control, TLR6 was increased in cannabis users and cannabis users with AUD compared to control, TLR7 was increased in cannabis users compared to control, and TLR9 was increased in cannabis users compared to control. In terms of cytokine production, IL-6 was increased in cannabis users compared to control. IL-8 and IL-10 were increased in AUD only., Conclusions: AUD and cannabis use have complex effects on pulmonary innate immunity that promote airway inflammation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Prasugrel hydrochloride is the active ingredient in Effient™, a thienopyridine platelet inhibitor. An extensive study of the degradation chemistry of prasugrel hydrochloride (LY640315 hydrochloride) has been carried out on the drug substance (part I) and on the drug product (part II, future article) using a multidimensional approach including hydrolytic, oxidative, and photolytic stressing, computational chemistry, HPLC analysis, and structure elucidation by various spectroscopic techniques. The major degradation products formed from the drug substance under the various stress conditions have been isolated and structures unambiguously determined, and the pathways leading to these products have been proposed. Fourteen new (not previously disclosed) products were discovered and characterized, in addition to 4 degradation products that had been previously identified in the literature. The pathways indicate that prasugrel is susceptible to hydrolysis, autoxidation (both radical-initiated and single-electron mediated), and peroxide-mediated oxidation; in solution, prasugrel is susceptible to photodegradation., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

In a recent study, repeated cold application induced beiging in subcutaneous white adipose tissue (SC WAT) of humans independent of body mass index. To identify factors that promote or inhibit beiging, we performed multiplex analysis of gene expression with the Nanostring nCounter system (the probe set contained genes for specific immune cell markers, cytokines, and chemokines) on the SC WAT from lean subjects. Multiple correlations analysis identified mast cell tryptase and CCL26, a chemokine for mast cells, as genes whose change correlated positively with the change in UCP1 in SC WAT, leading to the hypothesis that mast cells promote SC WAT beiging in response to cold. We quantified mast cell recruitment into SC WAT and degranulation. Mast cells increased in number in SC WAT in lean subjects, and there was an increase in the number of degranulated mast cells in both lean subjects and subjects with obesity. We determined that norepinephrine stimulated mast cell degranulation and histamine release in vitro. In conclusion, cold stimulated adipose tissue mast cell recruitment in lean subjects and mast cell degranulation in SC WAT of all research participants independent of baseline body mass index, suggesting that mast cells promote adipose beiging through the release of histamine or other products.

Background: Many personal care products include chemicals that might act as endocrine disruptors and thus increase the risk of breast cancer., Objective: We examined the association between usage patterns of beauty, hair, and skin-related personal care products and breast cancer incidence in the Sister Study, a national prospective cohort study (enrollment 2003-2009)., Methods: Non-Hispanic black (4,452) and white women (n=42,453) were examined separately using latent class analysis (LCA) to identify groups of individuals with similar patterns of self-reported product use in three categories (beauty, skin, hair). Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between product use and breast cancer incidence., Results: A total of 2,326 women developed breast cancer during follow-up (average follow-up=5.4y). Among black women, none of the latent class hazard ratios was elevated, but there were <100 cases in any category, limiting power. Among white women, those classified as "moderate" and "frequent" users of beauty products had increased risk of breast cancer relative to "infrequent" users [HR=1.13 (95% CI: 1.00, 1.27) and HR=1.15 (95% CI: 1.02, 1.30), respectively]. Frequent users of skincare products also had increased risk of breast cancer relative to infrequent users [HR=1.13 (95% CI: 1.00, 1.29)]. None of the hair product classes was associated with increased breast cancer risk. The associations with beauty and skin products were stronger in postmenopausal women than in premenopausal women, but not significantly so., Conclusions: This work generates novel hypotheses about personal care product use and breast cancer risk. Whether these results are due to specific chemicals or to other correlated behaviors needs to be evaluated. https://doi.org/10.1289/EHP1480.

It is hypothesized that certain chemicals in personal care products may alter the risk of adverse health outcomes. The primary aim of this study was to use a data-centered approach to classify complex patterns of exposure to personal care products and to understand how these patterns vary according to use of exogenous hormone exposures, oral contraceptives (OCs) and post-menopausal hormone therapy (HT). The NIEHS Sister Study is a prospective cohort study of 50,884 US women. Limiting the sample to non-Hispanic blacks and whites (N=47,019), latent class analysis (LCA) was used to identify groups of individuals with similar patterns of personal care product use based on responses to 48 survey questions. Personal care products were categorized into three product types (beauty, hair, and skincare products) and separate latent classes were constructed for each type. Adjusted prevalence differences (PD) were calculated to estimate the association between exogenous hormone use, as measured by ever/never OC or HT use, and patterns of personal care product use. LCA reduced data dimensionality by grouping of individuals with similar patterns of personal care product use into mutually exclusive latent classes (three latent classes for beauty product use, three for hair, and four for skin care. There were strong differences in personal care usage by race, particularly for haircare products. For both blacks and whites, exogenous hormone exposures were associated with higher levels of product use, especially beauty and skincare products. Relative to individual product use questions, latent class variables capture complex patterns of personal care product usage. These patterns differed by race and were associated with ever OC and HT use. Future studies should consider personal care product exposures with other exogenous exposures when modeling health risks.

Objectives: Evaluate the impact of wrist MRI in children on clinical diagnosis and management., Materials and Methods: Four year retrospective analysis including demographics, MRI diagnoses, and effect on diagnoses and management were determined., Results: 101 patients were included. Wrist MRI altered management in 86% (95% CI: 77-92%) and diagnosis in 46% (36-56%) of patients. MRI changed both diagnosis and management in 41% (31-51%), changed management only in 46% (35-56%), changed diagnosis only in 5% (2-12%), and had no change in diagnosis or management in 9% (95% CI: 4-17%)., Conclusion: Wrist MRI in children changes clinical diagnosis and management in a substantial proportion of cases., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Current exposure assessment research does not sufficiently address multi-pollutant exposure and their correlations in human media. Understanding the extent of chemical exposure in reproductive-aged women is of particular concern due to the potential for in utero exposure and fetal susceptibility., Objectives: The objectives of this study were to characterize concentrations of chemical biomarkers during preconception and examine correlations between and within chemical classes., Methods: We examined concentrations of 135 biomarkers from 16 chemical classes in blood and urine from 73 women aged 18-40 enrolled in Snart Foraeldre/Milieu, a prospective cohort study of pregnancy planners in Denmark (2011-2014). We compared biomarker concentrations with United States similarly-aged, non-pregnant women who participated in the National Health and Nutrition Environmental Survey (NHANES) and with other international biomonitoring studies. We performed principal component analysis to examine biomarker correlations., Results: The mean number of biomarkers detected in the population was 92 (range: 60-108). The most commonly detected chemical classes were phthalates, metals, phytoestrogens and polycyclic aromatic hydrocarbons. Except blood mercury, urinary barium and enterolactone, geometric means were higher in women from NHANES. Chemical classes measured in urine generally did not load on a single component, suggesting high between-class correlation among urinary biomarkers, while there is high within-class correlation for biomarkers measured in serum and blood., Conclusions: We identified ubiquitous exposure to multiple chemical classes in reproductive-aged Danish women, supporting the need for more research on chemical mixtures during preconception and early pregnancy. Inter- and intra-class correlation between measured biomarkers may reflect common exposure sources, specific lifestyle factors or shared metabolism pathways., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Competing Interests: J.M.B. was financially compensated for conducting a re-analysis of a study of child lead exposure for the plaintiffs in a public nuisance case related to childhood lead poisoning. None of these activities were directly related to the present study. The other authors declare they have no actual or potential competing financial interests.

The presence of a di-unsaturated highly branched isoprenoid (HBI) lipid biomarker (diene II) in Southern Ocean sediments has previously been proposed as a proxy measure of palaeo Antarctic sea ice. Here we show that a source of diene II is the sympagic diatom Berkeleya adeliensis Medlin. Furthermore, the propensity for B. adeliensis to flourish in platelet ice is reflected by an offshore downward gradient in diene II concentration in >100 surface sediments from Antarctic coastal and near-coastal environments. Since platelet ice formation is strongly associated with super-cooled freshwater inflow, we further hypothesize that sedimentary diene II provides a potentially sensitive proxy indicator of landfast sea ice influenced by meltwater discharge from nearby glaciers and ice shelves, and re-examination of some previous diene II downcore records supports this hypothesis. The term IPSO25-Ice Proxy for the Southern Ocean with 25 carbon atoms-is proposed as a proxy name for diene II.

Rationale: Stable isotope analysis is a powerful tool in understanding the generation, history and correlation of hydrocarbons. Compound-specific δ(13) C measurements of oils allow detailed comparison of individual compound groupings; however, most studies of these sample materials separate and isolate individual fractions based on the chemistries of particular compound groups, potentially losing considerable valuable isotopic data. Even if all fractions are analyzed, this represents a large increase in the data-processing burden, effectively multiplying data evaluation time and effort by the number of fractions produced. Gas chromatography/isotope ratio mass spectrometry (GC/IRMS) of untreated, whole crude oils allows the immediate collection of a larger suite of valuable isotopic data for these studies., Methods: Untreated ('neat', undiluted), whole crude oils were directly injected and measured on a GC/IRMS system, using split (40:1) injections and a 50 m HP-PONA column. The GC method, 97 min in duration, was designed to maximize baseline separation of target analyte peaks, while an additional oxygen flow was admitted into the combustion reactor to maximize the lifetime of the combustion chemicals., Results: The method and setup utilized allow the measurement of a much greater range of the n-alkanes (n-C4 to n-C25+ ) than traditional methods, while also retaining important cycloalkane, aromatic and isoprenoid peaks within the same analysis. Carbon isotope (δ(13) C) evaluation of these additional compound classes reveals trends in maturity and origins which are not identifiable when exclusively assessing the traditional n-alkane package (>n-C12 )., Conclusions: The described setup and method open up new possibilities for assessing the origins and histories of crude oil samples. The data generated for the whole oil n-alkanes by this method is equivalent to that reported for isolated n-alkane studies, while also providing valuable additional data on many other important compounds. The end result of this method is a more complete assessment of the carbon isotopic composition of crude oils. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Background: Bisphenol A (BPA) is a high-production-volume chemical associated with a wide range of health outcomes in animal and human studies. BPA is used as a developer in thermal paper products, including cash register receipt paper; however, little is known about exposure of cashiers to BPA and alternative compounds in receipt paper., Objective: We determined whether handling receipt paper results in measurable absorption of BPA or the BPA alternatives bisphenol S (BPS) and 4-hydroxyphenyl 4-isoprooxyphenylsulfone (BPSIP)., Methods: Cashiers (n = 77) and non-cashiers (n = 25) were recruited from the Raleigh-Durham-Chapel Hill region of North Carolina during 2011-2013. Receipts were analyzed for the presence of BPA or alternatives considered for use in thermal paper. In cashiers, total urine and serum BPA, BPS, and BPSIP levels in post-shift samples (collected ≤ 2 hr after completing a shift) were compared with pre-shift samples. Levels of these compounds in urine from cashiers were compared to levels in urine from non-cashiers., Results: Each receipt contained 1-2% by weight of the paper of BPA, BPS, or BPSIP. The post-shift geometric mean total urinary BPS concentration was significantly higher than the pre-shift mean in 33 cashiers who handled receipts containing BPS. The mean urine BPA concentrations in 31 cashiers who handled BPA receipts were as likely to decrease as to increase after a shift, but the mean post-shift concentrations were significantly higher than those in non-cashiers. BPSIP was detected more frequently in the urine of cashiers handling BPSIP receipts than in the urine of non-cashiers. Only a few cashiers had detectable levels of total BPA or BPS in serum, whereas BPSIP tended to be detected more frequently., Conclusions: Thermal receipt paper is a potential source of occupational exposure to BPA, BPS, and BPSIP., Citation: Thayer KA, Taylor KW, Garantziotis S, Schurman SH, Kissling GE, Hunt D, Herbert B, Church R, Jankowich R, Churchwell MI, Scheri RC, Birnbaum LS, Bucher JR. 2016. Bisphenol A, bisphenol S, and 4-hydro​xyphenyl 4-isopro​oxyphenyl​sulfone (BPSIP) in urine and blood of cashiers. Environ Health Perspect 124:437-444; http://dx.doi.org/10.1289/ehp.1409427.

Background: Polyfluoroalkyl chemicals (PFCs) such as perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) have been associated with early menopause. However, previous cross-sectional studies have lacked adequate data to investigate possible reverse causality (i.e., higher serum concentrations due to decreased excretion after menopause)., Objectives: We investigated the association between PFOS, PFOA, perfluorononanoate (PFNA), and perfluorohexane sulfonate (PFHxS) and age at natural menopause among women 20-65 years of age in NHANES (National Health and Nutrition Examination Survey)., Methods: We used proportional hazard models to estimate hazard ratios (HRs) for the onset of natural menopause as a function of age and serum PFC levels, and to investigate reverse causation by estimating associations between PFC levels and the rate of hysterectomy. We also used multivariable linear regression to determine whether time since menopause predicted serum PFC levels., Results: After adjusting for age at survey, race/ethnicity, education, ever smoking, and parity, women with higher levels of PFCs had earlier menopause than did women with the lowest PFC levels. We observed a monotonic association with PFHxS: The HR was 1.42 (95% CI: 1.08, 1.87) for serum concentrations in tertile 2 versus tertile 1, and 1.70 (95% CI: 1.36, 2.12) for tertile 3 versus tertile 1. We also found evidence of reverse causation: PFCs were positively associated with rate of hysterectomy, and time since natural menopause was positively associated with serum PFCs., Conclusions: Our findings suggest a positive association between PFCs and menopause; however, at least part of the association may be due to reverse causation. Regardless of underlying cause, women appear to have higher PFC concentrations after menopause.

Background: Diabetes is a major threat to public health in the United States and worldwide. Understanding the role of environmental chemicals in the development or progression of diabetes is an emerging issue in environmental health., Objective: We assessed the epidemiologic literature for evidence of associations between persistent organic pollutants (POPs) and type 2 diabetes., Methods: Using a PubMed search and reference lists from relevant studies or review articles, we identified 72 epidemiological studies that investigated associations of persistent organic pollutants (POPs) with diabetes. We evaluated these studies for consistency, strengths and weaknesses of study design (including power and statistical methods), clinical diagnosis, exposure assessment, study population characteristics, and identification of data gaps and areas for future research., Conclusions: Heterogeneity of the studies precluded conducting a meta-analysis, but the overall evidence is sufficient for a positive association of some organochlorine POPs with type 2 diabetes. Collectively, these data are not sufficient to establish causality. Initial data mining revealed that the strongest positive correlation of diabetes with POPs occurred with organochlorine compounds, such as trans-nonachlor, dichlorodiphenyldichloroethylene (DDE), polychlorinated biphenyls (PCBs), and dioxins and dioxin-like chemicals. There is less indication of an association between other nonorganochlorine POPs, such as perfluoroalkyl acids and brominated compounds, and type 2 diabetes. Experimental data are needed to confirm the causality of these POPs, which will shed new light on the pathogenesis of diabetes. This new information should be considered by governmental bodies involved in the regulation of environmental contaminants.

XopN is a type III effector protein from Xanthomonas campestris pathovar vesicatoria that suppresses PAMP-triggered immunity (PTI) in tomato. Previous work reported that XopN interacts with the tomato 14-3-3 isoform TFT1; however, TFT1's role in PTI and/or XopN virulence was not determined. Here we show that TFT1 functions in PTI and is a XopN virulence target. Virus-induced gene silencing of TFT1 mRNA in tomato leaves resulted in increased growth of Xcv ΔxopN and Xcv ΔhrpF demonstrating that TFT1 is required to inhibit Xcv multiplication. TFT1 expression was required for Xcv-induced accumulation of PTI5, GRAS4, WRKY28, and LRR22 mRNAs, four PTI marker genes in tomato. Deletion analysis revealed that the XopN C-terminal domain (amino acids 344-733) is sufficient to bind TFT1. Removal of amino acids 605-733 disrupts XopN binding to TFT1 in plant extracts and inhibits XopN-dependent virulence in tomato, demonstrating that these residues are necessary for the XopN/TFT1 interaction. Phos-tag gel analysis and mass spectrometry showed that XopN is phosphorylated in plant extracts at serine 688 in a putative 14-3-3 recognition motif. Mutation of S688 reduced XopN's phosphorylation state but was not sufficient to inhibit binding to TFT1 or reduce XopN virulence. Mutation of S688 and two leucines (L64,L65) in XopN, however, eliminated XopN binding to TFT1 in plant extracts and XopN virulence. L64 and L65 are required for XopN to bind TARK1, a tomato atypical receptor kinase required for PTI. This suggested that TFT1 binding to XopN's C-terminal domain might be stabilized via TARK1/XopN interaction. Pull-down and BiFC analyses show that XopN promotes TARK1/TFT1 complex formation in vitro and in planta by functioning as a molecular scaffold. This is the first report showing that a type III effector targets a host 14-3-3 involved in PTI to promote bacterial pathogenesis.

XopD is a type III effector protein that is required for Xanthomonas campestris pathovar vesicatoria (Xcv) growth in tomato. It is a modular protein consisting of an N-terminal DNA-binding domain, two ethylene-responsive element binding factor-associated amphiphilic repression (EAR) transcriptional repressor motifs and a C-terminal small ubiquitin-related modifier (SUMO) protease. In tomato, XopD functions as a transcriptional repressor, resulting in the suppression of defence responses at late stages of infection. A survey of available genome sequences for phytopathogenic bacteria revealed that XopD homologues are limited to species within three genera of Proteobacteria--Xanthomonas, Acidovorax and Pseudomonas. Although the EAR motif(s) and SUMO protease domain are conserved in all XopD-like proteins, variation exists in the length and sequence identity of the N-terminal domains. Comparative analysis of the DNA sequences surrounding xopD and xopD-like genes led to revised annotation of the xopD gene. Edman degradation sequence analysis and functional complementation studies confirmed that the xopD gene from Xcv encodes a 760-amino-acid protein with a longer N-terminal domain than previously predicted. None of the XopD-like proteins studied complemented Xcv ΔxopD mutant phenotypes in tomato leaves, suggesting that the N-terminus of XopD defines functional specificity. Xcv ΔxopD strains expressing chimeric fusion proteins containing the N-terminus of XopD fused to the EAR motif(s) and SUMO protease domain of the XopD-like protein from X. campestris pathovar campestris strain B100 were fully virulent in tomato, demonstrating that the N-terminus of XopD controls specificity in tomato., (© 2011 THE AUTHORS. MOLECULAR PLANT PATHOLOGY © 2011 BSPP AND BLACKWELL PUBLISHING LTD.)

An important hypothesis is that the degree of infilling of secondary osteons (Haversian systems) is controlled by the inhibitory effect of osteocytes on osteoblasts, which might be mediated by sclerostin (a glycoprotein produced by osteocytes). Consequently, this inhibition could be proportional to cell number: relatively greater repression is exerted by progressively greater osteocyte density (increased osteocytes correlate with thinner osteon walls). This hypothesis has been examined, but only weakly supported, in sheep ulnae. We looked for this inverse relationship between osteon wall thickness (On.W.Th) and osteocyte lacuna density (Ot.Lc.N/B.Ar) in small and large osteons in human ribs, calcanei of sheep, deer, elk, and horses, and radii and third metacarpals of horses. Analyses involved: (1) all osteons, (2) smaller osteons, either ≤150 μm diameter or less than or equal to the mean diameter, and (3) larger osteons (>mean diameter). Significant, but weak, correlations between Ot.Lc.N/B.Ar and On.W.Th/On.Dm (On.Dm = osteon diameter) were found when considering all osteons in limb bones (r values -0.16 to -0.40, P < 0.01; resembling previous results in sheep ulnae: r = -0.39, P < 0.0001). In larger osteons, these relationships were either not significant (five/seven bone types) or very weak (two/seven bone types). In ribs, a negative relationship was only found in smaller osteons (r = -0.228, P < 0.01); this inverse relationship in smaller osteons did not occur in elk calcanei. These results do not provide clear or consistent support for the hypothesized inverse relationship. However, correlation analyses may fail to detect osteocyte-based repression of infilling if the signal is spatially nonuniform (e.g., increased near the central canal)., (Copyright © 2011 Wiley-Liss, Inc.)

XopN is a virulence factor from Xanthomonas campestris pathovar vesicatoria (Xcv) that is translocated into tomato (Solanum lycopersicum) leaf cells by the pathogen's type III secretion system. Xcv DeltaxopN mutants are impaired in growth and have reduced ability to elicit disease symptoms in susceptible tomato leaves. We show that XopN action in planta reduced pathogen-associated molecular pattern (PAMP)-induced gene expression and callose deposition in host tissue, indicating that XopN suppresses PAMP-triggered immune responses during Xcv infection. XopN is predicted to have irregular, alpha-helical repeats, suggesting multiple protein-protein interactions in planta. Consistent with this prediction, XopN interacted with the cytosolic domain of a Tomato Atypical Receptor-Like Kinase1 (TARK1) and four Tomato Fourteen-Three-Three isoforms (TFT1, TFT3, TFT5, and TFT6) in yeast. XopN/TARK1 and XopN/TFT1 interactions were confirmed in planta by bimolecular fluorescence complementation and pull-down analysis. Xcv DeltaxopN virulence defects were partially suppressed in transgenic tomato leaves with reduced TARK1 mRNA levels, indicating that TARK1 plays an important role in the outcome of Xcv-tomato interactions. These data provide the basis for a model in which XopN binds to TARK1 to interfere with TARK1-dependent signaling events triggered in response to Xcv infection.

We demonstrate that XopD, a type III effector from Xanthomonas campestris pathovar vesicatoria (Xcv), suppresses symptom production during the late stages of infection in susceptible tomato (Solanum lycopersicum) leaves. XopD-dependent delay of tissue degeneration correlates with reduced chlorophyll loss, reduced salicylic acid levels, and changes in the mRNA abundance of senescence- and defense-associated genes despite high pathogen titers. Subsequent structure-function analyses led to the discovery that XopD is a DNA binding protein that alters host transcription. XopD contains a putative helix-loop-helix domain required for DNA binding and two conserved ERF-associated amphiphilic motifs required to repress salicylic acid- and jasmonic acid-induced gene transcription in planta. Taken together, these data reveal that XopD is a unique virulence factor in Xcv that alters host transcription, promotes pathogen multiplication, and delays the onset of leaf chlorosis and necrosis.

Transformation technology as a research or breeding tool to improve maize is routinely used in most industrial and some specialized public laboratories. However, transformation of many inbred lines remains a challenging task, especially when using Agrobacterium tumefaciens as the delivery method. Here we report success in generating transgenic plants and progeny from three maize inbred lines using an Agrobacterium-mediated standard binary vector system to target maize immature embryos. Eleven maize inbred lines were pre-screened for transformation frequency using N6 salts. A subset of three maize inbred lines was then systematically evaluated for frequency of post-infection embryogenic callus induction and transformation on four media regimes: N6 or MS salts in each of two distinct media backgrounds. Transgenic plants recovered from inbred lines B104, B114, and Ky21 were analyzed for transgene integration, expression, and transmission. Average transformation frequencies of 6.4% (for B104), 2.8% (for B114), and 8% (for Ky21) were achieved using MS salts. Availability of Agrobacterium-mediated maize inbred line transformation will improve future opportunities for maize genetic and functional genomic studies.