Log Unit Increase Research Articles

Circulating RIPK3 levels are associated with mortality and organ failure during critical illness.

Necroptosis is a form of programmed necrotic cell death that is rapidly emerging as an important pathophysiological pathway in numerous disease states. Necroptosis is dependent on receptor-interacting protein kinase 3 (RIPK3), a protein shown to play an important role in experimental models of critical illness. However, there is limited clinical evidence regarding the role of extracellular RIPK3 in human critical illness. Plasma RIPK3 levels were measured in 953 patients prospectively enrolled in 5 ongoing intensive care unit (ICU) cohorts in both the USA and Korea. RIPK3 concentrations among groups were compared using prospectively collected phenotypic and outcomes data. In all 5 cohorts, extracellular RIPK3 levels in the plasma were higher in patients who died in the hospital compared with those who survived to discharge. In a combined analysis, increasing RIPK3 levels were associated with elevated odds of in-hospital mortality (odds ratio [OR] 1.7 for each log10-unit increase in RIPK3 level, P < 0.0001). When adjusted for baseline severity of illness, the OR for in-hospital mortality remained statistically significant (OR 1.33, P = 0.007). Higher RIPK3 levels were also associated with more severe organ failure. Our findings suggest that elevated levels of RIPK3 in the plasma of patients admitted to the ICU are associated with in-hospital mortality and organ failure. Supported by NIH grants P01 HL108801, R01 HL079904, R01 HL055330, R01 HL060234, K99 HL125899, and KL2TR000458-10. Supported by Samsung Medical Center grant SMX1161431.

Long-chain omega-3 fatty acids and headache in the U.S. population

The objective of this study was to assess whether dietary intake of long-chain omega-3 polyunsaturated fatty acids (PUFAs) is associated with lower prevalence of headache in the U.S. population. This cross-sectional study used data for a nationally representative sample of 12,317 men and women aged ≥ 20 years participating in the National Health and Nutrition Examination Surveys of 1999–2004. Interviewers recorded self-report of severe headache or migraine in the past three months. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were quantified from 24-hour dietary recall using the U.S. Department of Agriculture National Nutrient Database. Serum concentration of C-reactive protein, a marker of inflammation and potential mediator of PUFA's analgesic properties, was quantified by latex-enhanced nephelometry. Multivariable generalized linear models estimated prevalence ratios (PR) with 95% confidence limits (CL) for severe headache or migraine adjusting for NHANES cycle, sociodemographic characteristics, body mass index and total energy intake. The unadjusted prevalence of severe headache or migraine was 22.0% (females 28.2%, males 15.5%). In multivariable analysis, greater intake of omega-3 PUFAs was associated with lower prevalence of severe headache or migraine: PR 0.94 (95% CL: 0.88, 0.99, p = 0.035) per log unit increase in EPA, and PR 0.94 (95% CL: 0.90, 0.99, p = 0.023) per log unit increase in DHA. The strength of association was greater for non-Mexican Hispanics than for other racial/ethnic groups but was not attenuated after adjustment for C-reactive protein. In conclusion, higher dietary intakes of EPA and DHA were associated with lower prevalence of headache supporting the hypothesis that omega-3 PUFAs may prevent or reduce headache.

Serum Adipocyte Fatty Acid-Binding Protein Levels Are Linked to Rapid Renal Function Decline in Patients with Type 2 Diabetes and Normal Renal Function

Background: Rapid renal function decline has been recognized as an important predictor for diabetic nephropathy (DN). Adipocyte fatty acid-binding protein (A-FABP) is a major cytoplasmic protein in adipocytes and is closely associated with metabolic syndrome and type 2 diabetes. We aim to investigate the role of adipokines including A-FABP and inflammatory cytokines in the development of rapid renal function decline in type 2 diabetes and normal renal function. Methods: A total of 456 subjects with type 2 diabetes with normal renal function were recruited from an outpatient clinic at the Diabetes Center of Inha University Hospital and were followed up for 6 years with serial glomerular filtration rate (GFR) measurements. The serum levels of tumor necrosis factor (TNF)-a, and interleukin (IL)-6, high molecular weight (HMW) adiponectin, endogenous secretory receptor for advanced glycation end products (esRAGE), A-FABP and pentraxin-related protein (PTX3) were measured at baseline. Rapid renal function decline was defined as an eGFR decline &amp;gt;3.3% per year. Results: During follow-up, 120 participants (26.3%) developed rapid renal function decline and mean annual eGFR decline was -5.4 ± 2.7% and -0.6 ± 2.4% in decliners and non-decliners, respectively. Median A-FABP levels were significantly higher in patients with rapid decliners than in non-decliners (19.1 vs. 16.8 ng/ml, p=0.011). No significant difference of three cytokines levels were observed between groups. Each log unit increase of A-FABP was independently associated with greater risk of rapid renal function decline (odds ratio [OR] = 3.60; 95% confidence interval [CI] 1.95-6.66; p &amp;lt; 0.001) after adjustments for sex, BMI, A1C, GFR, hypertension, presence of carotid artery plaque and urine albumin creatinine ratio. Conclusions: High plasma A-FABP was an independent risk factor for rapid renal function decline in type 2 diabetes and normal renal function. Disclosure D. Seo: None. S. Kim: None. S. Ahn: None. S. Hong: None. M. Nam: None.

Iron Deficiency is Prevalent among HIV-Infected Kenyan Adults and is Better Measured by Soluble Transferrin Receptor than Ferritin.

Iron deficiency (ID) and human immunodeficiency virus (HIV) infection frequently coexist. Little data exist on ID in HIV-infected individuals, partly because the iron marker ferritin is altered by inflammation common in HIV infection. We measured iron biomarkers (ferritin, soluble transferrin receptor [sTfR], hepcidin) and red cell indices (hemoglobin, mean corpuscular volume [MCV]) in newly diagnosed, antiretroviral therapy-naive, HIV-infected (N = 138) and uninfected (N = 52) Kenyan adults enrolled in a study of the immune response to malaria. We compared markers between infected and uninfected groups with t test and Wilcoxon Rank-Sum, used Spearman correlation to determine the association between iron and inflammatory markers, and applied logistic regression to determine which markers best predicted anemia. HIV-infected individuals had lower hemoglobin (P < 0.001), lower MCV (P < 0.001), higher sTfR (P = 0.003), and a greater prevalence of ID (sTfR > 8.3 mg/L) than uninfected individuals. Ferritin was elevated in HIV-infected individuals and was more strongly correlated with C-reactive protein (ρ = 0.43, P < 0.001) and hepcidin (ρ = 0.69, P < 0.001) than with hemoglobin. The best predictor of anemia in HIV-infected participants was sTfR, with a one log-unit increase in sTfR associated with a 6-fold increase in the odds of anemia (odds ratio = 6.3, 95% confidence interval: 1.8-21.8). These data suggest a significant burden of ID among treatment-naive HIV-infected Kenyan adults. Soluble transferrin receptor may be a reliable marker of ID in HIV-mediated inflammation.

Preparation of photodynamic P(MMA-co-MAA) composite nanofibers doped with MMT: A facile method for increasing antimicrobial efficiency

We report the preparation of photodynamic materials from electrospun nanofibers of P(MMA-co-MAA) co-polymer that were doped with montmorillonite (MMT), and further functionalized with the cationic photosensitizer methylene blue (MB). The resultant composite nanofibers were characterized by spectroscopic (infrared, UV − vis, fluorescence) and physical (SEM/TEM, gravimetric) methods. Addition of MMT (0–6 wt%) in the electrospinning process increased the adsorption of the methylene blue photosensitizer from 21.5 mg (67.1 μmol)/g P(MMA-co-MAA) parent copolymer to 30.0 mg (93.8 μmol)/g P(MMA-co-MAA)/MMT-6 composite nanofibers. The MB-decorated P(MMA-co-MAA)/MMT-6 composite nanofibers showed a 99.997% (4.8 log units) and 97% (1.8 log units) reduction in CFU/mL against Staphylococcus aureus (ATCC-6538) and Escherichia coli strain 8099, respectively, after visible light illumination (LED lamp, 30 min, 35 ± 5 mW/cm2), demonstrating that the increased photosensitizer loading attributable to MMT doping led to a 1–2 log unit increase in photodynamic inactivation efficacy over the non-doped MB-decorated P(MMA-co-MAA) parent copolymer (99.9% and 84% reduction for S. aureus and E. coli, respectively). The results demonstrate that MMT and similar additives may be a universal method for increasing the adsorption capacity of cationic photosensitizers in electrospun nanofibers, thereby generating materials with improved photodynamic inactivation efficacy without significantly changing the fiber morphology, cost, or ease of production.

Association of Monocyte Chemoattractant Protein-1 with Death and Atherosclerotic Events in Chronic Kidney Disease

Background: Monocyte chemoattractant protein-1 ­(MCP-1), a marker of inflammation and monocyte recruitment to atherosclerotic plaques, is associated with cardiovascular (CV) outcomes in patients with acute coronary syndrome. Although plasma levels are elevated in chronic kidney disease (CKD), associations with reduced kidney function or outcomes in CKD have not been explored. Methods: In this population-based, probability-sampled, longitudinal cohort of 3,257 participants, including 286 (8.8%) patients with CKD, we studied the association of plasma MCP-1 with estimated glomerular filtration rate (eGFR), albuminuria, death, and intermediate and hard CV outcomes in CKD and non-CKD individuals. Cox proportional hazards regression assessed associations of baseline MCP-1 with all-cause death and atherosclerotic events. Results: MCP-1 was higher in CKD than non-CKD participants (p < 0.001), and negatively associated with eGFR (r = –0.23, p < 0.0001) but not albuminuria in CKD. MCP-1 was associated with pulse wave velocity and coronary artery calcification in non-CKD but not CKD individuals. At 13.5 years, there were 230 (7.7%) deaths and 168 (6.4%) atherosclerotic events in the non-CKD vs. 97 (34.0%) deaths and 62 (27.9%) events in the CKD group (p < 0.001 for each). MCP-1 was associated with death (hazards ratio [HR] 2.0 [1.4–2.9] per log-unit increase) and atherosclerotic events (1.7 [1.0–2.9]) in CKD individuals. The HR for death in CKD remained significant (1.6 [1.1–2.3]) after adjusting for CV risk factors. Conclusions: Although plasma MCP-1 increased with decreased eGFR, it remained an independent risk factor for death in CKD. MCP-1 did not correlate with intermediate CV outcomes, implicating pathways other than atherosclerosis in the association of MCP-1 with death in CKD.

Antimüllerian hormone as a risk factor for miscarriage in naturally conceived pregnancies

To determine the association between antimüllerian hormone (AMH), a measure of ovarian reserve, and miscarriage among naturally conceived pregnancies. Prospective cohort study. Not applicable. Women (n = 533), between 30 and 44years of age with no known history of infertility, polycystic ovarian syndrome, or endometriosis who conceived naturally. None. Miscarriage, defined as an intrauterine pregnancy loss before 20weeks' gestation. After adjusting for maternal age, race, history of recurrent miscarriage, and obesity, risk of miscarriage decreased as AMH increased (risk ratio per unit increase in natural log of AMH = 0.83; 95% confidence interval [CI], 0.73, 0.94). Women with severely diminished ovarian reserve (AMH ≤ 0.4ng/mL) miscarried at over twice the rate of women with an AMH ≥ 1ng/mL (hazard ratio, 2.3; 95% CI, 1.3, 4.3). AMH levels are inversely associated with the risk of miscarriage. Women with severely diminished ovarian reserve are at an increased risk of miscarriage.

Shorter Time to Pregnancy With Increasing Preconception Carotene Concentrations Among Women With 1-2 Previous Pregnancy Losses.

Although maternal nutrition may affect fecundity, associations between preconception micronutrient levels and time to pregnancy (TTP) have not been examined. We assessed the relationship between preconception fat-soluble micronutrient concentrations and TTP among women with 1-2 prior pregnancy losses. This was a prospective cohort study of 1,228 women set within the Effects of Aspirin in Gestation and Reproduction (EAGeR) Trial (United States, 2007-2011), which assessed the association of preconception-initiated daily low-dose aspirin with reproductive outcomes. We measured preconception levels of zeaxanthin, cryptoxanthin, lycopene, α- and β-carotene, and α- and γ-tocopherol in serum. We used discrete Cox regression models, accounting for left-truncation and right-censoring, to calculate fecundability odds ratios and 95% confidence intervals. The models adjusted for age, body mass index, race, smoking, alcohol, physical activity, income, vitamin use, cholesterol, treatment arm, and study site. Serum α-carotene levels (per log unit (μg/dL) increase, fecundability odds ratio (FOR) = 1.17, 95% confidence interval (CI): 1.00, 1.36) and serum α-carotene concentrations at or above the US average (2.92 μg/dL) versus below the average (FOR = 1.21, 95% CI: 1.02, 1.44) were associated with shorter TTP. Compared with levels below the US average (187 μg/dL), γ-tocopherol concentrations at or above the average were associated with longer TTP (FOR = 0.83, 95% CI: 0.69, 1.00). The potential for these nutrients to influence fecundability deserves further exploration.

Polybrominated diphenyl ethers in cord blood and perinatal outcomes from Laizhou Wan Birth Cohort, China.

We explored whether polybrominated diphenyl ethers (PBDEs) exposed in cord blood could have any potential relationship with perinatal outcomes. Participants were pregnant females (n = 222) who were recruited from a prospective birth cohort (Laizhou Wan Birth Cohort, LWBC) between September 2010 and February 2012. We measured eight PBDE congeners (BDE-28, BDE-47, BDE-85, BDE-99, BDE-100, BDE-153, BDE-154, and BDE-183) in cord serum and examined their relationship with perinatal outcomes. The median levels of BDE-28, BDE-47, BDE-85, BDE-99, BDE-100, BDE-153, BDE-154, and BDE-183 were 2.92, 3.93, 2.29, 7.03, 3.03, 3.14, 1.46, and 2.55ng/g lipids, respectively. For each log unit increase in BDE-47, BDE-100, and ∑4PBDEs, gestational age increased by 0.70weeks (95% confidence interval [CI] 0.25, 1.15), 0.48weeks (95% CI 0.03, 0.94), and 0.73weeks (95% CI 0.12, 1.34), respectively. We also found that BDE-47 was positively associated with head circumference (β = 0.42, 95% CI 0.00, 0.84). Given that our study area is one of the major brominated flame retardant production areas in China, and the cord PBDEs levels were relatively higher than those reported in most other Asian areas, more studies on the effects of in utero PBDE exposure on fetal growth and child development are warranted.

Prenatal Phthalates, Maternal Thyroid Function, and Risk of Attention-Deficit Hyperactivity Disorder in the Norwegian Mother and Child Cohort.

Background:There is growing concern that phthalate exposures may have an impact on child neurodevelopment. Prenatal exposure to phthalates has been linked with externalizing behaviors and executive functioning defects suggestive of an attention-deficit hyperactivity disorder (ADHD) phenotype.Objectives:We undertook an investigation into whether prenatal exposure to phthalates was associated with clinically confirmed ADHD in a population-based nested case–control study of the Norwegian Mother and Child Cohort (MoBa) between the years 2003 and 2008.Methods:Phthalate metabolites were measured in maternal urine collected at midpregnancy. Cases of ADHD () were obtained through linkage between MoBa and the Norwegian National Patient Registry. A random sample of controls () from the MoBa population was obtained.Results:In multivariable adjusted coexposure models, the sum of di-2-ethylhexyl phthalate metabolites () was associated with a monotonically increasing risk of ADHD. Children of mothers in the highest quintile of had almost three times the odds of an ADHD diagnosis as those in the lowest [ (95% CI: 1.47, 5.49)]. When was modeled as a log-linear (natural log) term, for each log-unit increase in exposure, the odds of ADHD increased by 47% [ (95% CI: 1.09, 1.94)]. We detected no significant modification by sex or mediation by prenatal maternal thyroid function or by preterm delivery.Conclusions:In this population-based case–control study of clinical ADHD, maternal urinary concentrations of DEHP were monotonically associated with increased risk of ADHD. Additional research is needed to evaluate potential mechanisms linking phthalates to ADHD. https://doi.org/10.1289/EHP2358

Fibroblast growth factor 23 and renal function among young and healthy individuals.

Fibroblast growth factor 23 (FGF-23), an osteocyte hormone involved in the regulation of phosphate metabolism, is associated with incident and progressive chronic kidney disease. We aimed to assess the association of FGF-23 with renal parameters, vascular function and phosphate metabolism in a large cohort of young and healthy individuals. Healthy individuals aged 25-41 years were included in a prospective population-based study. Fasting venous blood and morning urinary samples were used to measure plasma creatinine, cystatin C, endothelin-1, phosphate and plasma FGF-23 as well as urinary creatinine and phosphate. Multivariable regression models were constructed to assess the relationship of FGF-23 with parameters of renal function, endothelin-1 and fractional phosphate excretion. The median age of 2077 participants was 37 years, 46% were males. The mean estimated glomerular filtration rate (eGFR - CKD-EPI creatinine-cystatin C equation) and fractional phosphate excretion were 110 mL/min/1.73 m2 and 8.7%, respectively. After multivariable adjustment, there was a significant inverse relationship of FGF-23 with eGFR (β per 1 log-unit increase -3.81; 95% CI [-5.42; -2.20]; p<0.0001). Furthermore, we found a linear association between FGF-23 and endothelin-1 (β per 1 log-unit increase 0.06; [0.01, 0.11]; p=0.01). In addition, we established a significant relationship of FGF-23 with fractional phosphate excretion (β per 1 log-unit increase 0.62; [0.08, 1.16]; p=0.03). Increasing plasma FGF-23 levels are strongly associated with decreasing eGFR and increasing urinary phosphate excretion, suggesting an important role of FGF-23 in the regulation of kidney function in young and healthy adults.

Maternal levels of endocrine disrupting chemicals in the first trimester of pregnancy are associated with infant cord blood DNA methylation

ABSTRACTEndocrine disrupting chemicals (EDCs) pose a public health risk through disruption of normal biological processes. Identifying toxicoepigenetic mechanisms of developmental exposure-induced effects for EDCs, such as phthalates or bisphenol A (BPA), is essential. Here, we investigate whether maternal exposure to EDCs is predictive of infant DNA methylation at candidate gene regions. In the Michigan Mother-Infant Pairs (MMIP) cohort, DNA was extracted from cord blood leukocytes for methylation analysis by pyrosequencing (n = 116) and methylation changes related to first trimester levels of 9 phthalate metabolites and BPA. Growth and metabolism-related genes selected for methylation analysis included imprinted (IGF2, H19) and non-imprinted (PPARA, ESR1) genes along with LINE-1 repetitive elements. Findings revealed decreases in methylation of LINE-1, IGF2, and PPARA with increasing phthalate concentrations. For example, a log unit increase in ΣDEHP corresponded to a 1.03 [95% confidence interval (CI): −1.83, −0.22] percentage point decrease in PPARA methylation. Changes in DNA methylation were also inversely correlated with PPARA gene expression determined by RT-qPCR (r = −0.34, P = 0.02), thereby providing evidence in support of functional relevance. A sex-stratified analysis of EDCs and DNA methylation showed that some relationships were female-specific. For example, urinary BPA exposure was associated with a 1.35 (95%CI: −2.69, −0.01) percentage point decrease in IGF2 methylation and a 1.22 (95%CI: −2.27, −0.16) percentage point decrease in PPARA methylation in females only. These findings add to a body of evidence suggesting epigenetically labile regions may provide a conduit linking early exposures with disease risk later in life and that toxicoepigenetic susceptibility may be sex specific.

A model for predicting effect of treatment on progression-free survival using MRD as a surrogate end point in CLL

AbstractOur objective was to evaluate minimal residual disease (MRD) at the end of induction treatment with chemoimmunotherapy as a surrogate end point for progression-free survival (PFS) in chronic lymphocytic leukemia (CLL) based on 3 randomized, phase 3 clinical trials (ClinicalTrials.gov identifiers NCT00281918, NCT00769522, and NCT02053610). MRD was measured in peripheral blood (PB) from treatment-naïve patients in the CLL8, CLL10, and CLL11 clinical trials, and quantified by 4-color flow cytometry or allele-specific oligonucleotide real-time quantitative polymerase chain reaction. A meta-regression model was developed to predict treatment effect on PFS using treatment effect on PB-MRD. PB-MRD levels were measured in 393, 337, and 474 patients from CLL8, CLL10, and CLL11, respectively. The model demonstrated a statistically significant relationship between treatment effect on PB-MRD and treatment effect on PFS. As the difference between treatment arms in PB-MRD response rates increased, a reduction in the risk of progression or death was observed; for each unit increase in the (log) ratio of MRD− rates between arms, the log of the PFS hazard ratio decreased by −0.188 (95% confidence interval, −0.321 to −0.055; P = .008). External model validation on the REACH trial and sensitivity analyses confirm the robustness and applicability of the surrogacy model. Our surrogacy model supports use of PB-MRD as a primary end point in randomized clinical trials of chemoimmunotherapy in CLL. Additional CLL trial data are required to establish a more precise quantitative relationship between MRD and PFS, and to support general applicability of MRD surrogacy for PFS across diverse patient characteristics, treatment regimens, and different treatment mechanisms of action.

Preconception and prenatal urinary concentrations of phenols and birth size of singleton infants born to mothers and fathers from the Environment and Reproductive Health (EARTH) study

BackgroundAlthough pregnancy concentrations of some phenols have been associated with infant size at birth, there is limited data on the effect of preconception exposure. ObjectiveWe aimed to examine paternal and maternal preconception and maternal prenatal urinary phenol concentrations in relation to birth weight and head circumference. MethodsWe evaluated 346 singletons born to 346 mothers and 184 fathers (184 couples) from a prospective preconception cohort of subfertile couples from the Environment and Reproductive Health (EARTH) Study in Boston, USA. We used multiple urine samples collected before the index pregnancy in both men and women to estimate mean preconception urinary benzophenone-3, triclosan, butylparaben, propylparaben, methylparaben, or ethylparaben concentrations. We also estimated mean maternal prenatal urinary phenol concentrations by averaging trimester-specific urine samples. Birth weight and head circumference were abstracted from delivery records. We estimated the association of natural log-phenol concentrations with birth outcomes using multivariable linear regression models, adjusting for known confounders. ResultsIn adjusted models, each log-unit increase in paternal preconception benzophenone-3 concentration was associated with a 137 g increase in birth weight (95% CI: 60, 214). Additional adjustment for prenatal benzophenone-3 concentration strengthened this association. None of the maternal preconception phenol concentrations were associated with birth weight. However, maternal prenatal triclosan concentrations were associated with a 38 g decrease in birth weight (95% CI: −76, 0). Few associations were observed between phenols and head circumference except for a decrease of 0.27 cm (95% CI: −54, 0) in relation to maternal preconception methylparaben concentration. ConclusionsAlthough our findings should be interpreted in light of inherent study limitations, these results suggest potential evidence of associations between some paternal or maternal phenol concentrations and birth size.

Prenatal exposure to perfluoroalkyl and polyfluoroalkyl substances and childhood atopic dermatitis: a prospective birth cohort study

BackgroundPerfluoroalkyl and polyfluoroalkyl substances (PFASs) have been reported to suppress immune function. However, previous studies on prenatal exposure to PFASs and allergic disorders in offspring provided inconsistent results. We aimed to examine the association between prenatal exposure to PFASs and childhood atopic dermatitis (AD) in offspring up to 24 months of age.MethodsA prospective birth cohort study involving 1056 pregnant women was conducted in two hospitals in Shanghai from 2012 to 2015. Prenatal information was collected by an interview with the women and from medical records. Fetal umbilical cord blood was collected at birth. Cord blood plasma PFASs were measured. Children were followed at 6, 12 and 24 months and information on the development of AD was recorded. AD was diagnosed by 2 dermatologists independently based on the questionnaires. Multiple logistic regression was used to compute odds ratio (OR) and corresponding 95% confidence interval (CI) for the association between AD and each PFASs, adjusting for potential confounders.ResultsA total of 687 children completed a 2-year follow-up visit and had PFASs measurement. AD was diagnosed in 173 (25.2%) children during the first 24 months. In female children, a log-unit increase in perfluorooctanoic acid (PFOA) was associated with a 2.1-fold increase in AD risk (AOR 2.07, 95% CI 1.13–3.80) after adjusting for potential confounders. The corresponding risk was 2.22 (1.07–4.58) for perfluorononanoic acid (PFNA). The highest PFOA quartile was significantly associated with AD (2.52, 1.12–5.68) compared with the lowest quartile. The highest quartile of PFNA, perfluorodecanoic acid (PFDA) and perfluorohexane sulfonic acid (PFHxS) were associated with AD with AOR (95% CI) being 2.14 (0.97–4.74), 2.14 (1.00–4.57), and 2.30 (1.03–5.15), respectively. Additionally, the second quartile of perfluorododecanoic acid (PFDoA) was associated with a 3.2-fold increase in AD risk (3.24, 1.44–7.27). However, no significant associations were found in male children.ConclusionsPrenatal exposure to PFOA, PFDA, PFDoA and PFHxS significantly increased the risk of childhood AD in female children during the first 24 months of life. In addition, the associations between AD with prenatal exposure to PFNA were close to statistical significance.

Vitamin A and E Nutritional Status in Relation to Leptin, Adiponectin, IGF-I and IGF-II in Early Life - a Birth Cohort Study

The metabolic health effects of vitamin A and E nutritional status in early life are largely unknown. We assessed whether vitamin A and vitamin E nutritional status may affect circulating leptin, adiponectin, insulin-like growth factor (IGF)-I and IGF-II levels in early life in humans. In a singleton birth cohort (n = 248), vitamin A and E nutritional status in fetuses/newborns were assessed by cord plasma concentrations of retinol, β-carotene, α- and γ-tocopherols. The primary outcomes were cord plasma leptin, adiponectin, IGF-I and IGF-II concentrations. Cord plasma retinol was significantly positively correlated to IGF-I in girls (r = 0.42, P < 0.0001) but not in boys (r = 0.14, P = 0.11). Adjusting for maternal and newborn’s characteristics, one log unit increase in cord plasma retinol was associated with a 28.0% (95% CI: 11.1–47.5%) increase in IGF-I in girls (P < 0.001) but not in boys (P = 0.75). One log unit increment in cord plasma α-tocopherol was associated with a 6.6% (0.4–12.3%) decrease in adiponectin (P = 0.04), while one log unit increment in cord plasma γ-tocopherol was associated with a 21.2% (4.7–34.8%) decrease in leptin (P = 0.01). There may be a sex-specific association between retinol and IGF-I, a negative association between α-tocopherol and adiponectin, and a negative association between γ-tocopherol and leptin in early life in humans.

Interactions Between Bisphenol A Exposure and GSTP1 Polymorphisms in Childhood Asthma.

PurposeBisphenol A (BPA) exposure may increase the risk of asthma. Genetic polymorphisms of oxidative stress-related genes, glutathione S-transferases (GSTM1, GSTP1), manganese superoxide dismutase, catalase, myeloperoxidase, and microsomal epoxide hydrolase may be related to BPA exposure. The aim is to evaluate whether oxidative stress genes modulates associations of BPA exposure with asthma.MethodsWe conducted a case-control study comprised of 126 asthmatic children and 327 controls. Urine Bisphenol A glucuronide (BPAG) levels were measured by ultra-performance liquid chromatography/tandem mass spectrometry, and genetic variants were analyzed by a TaqMan assay. Information on asthma and environmental exposure was collected. Analyses of variance and logistic regressions were performed to determine the association of genotypes and urine BPAG levels with asthma.ResultsBPAG levels were significantly associated with asthma (adjusted odds ratio [aOR], 1.29 per log unit increase in concentration; 95% confidence interval [CI], 1.081.55). Compared to the GG genotype, children with a GSTP1 AA genotype had higher urine BPAG concentrations (geometric mean [standard error], 12.72 [4.16] vs 11.42 [2.82]; P=0.036). In children with high BPAG, the GSTP1 AA genotype was related to a higher odds of asthma than the GG genotype (aOR, 4.84; 95% CI, 1.0223.06).ConclusionsGSTP1 variants are associated with urine BPA metabolite levels. Oxidative stress genes may modulate the effect of BPA exposure on asthma.

Exposure to perfluoroalkyl substances during pregnancy and child behaviour at 5 to 9 years of age

We examined associations between prenatal exposure to perfluorohexane sulfonic acid (PFHxS), perfluoroheptanoic acid (PFHpA), perfluorononanoic acid (PFNA), and perfluorodecanic acid (PFDA) - and child behaviour (SDQ-total) and hyperactivity (sub-scale) at 5–9years of age in birth cohorts from Greenland and Ukraine.Pregnancy serum samples (N=1023) were analysed for perfluoroalkyl substances (PFASs) and categorised into tertiles and also used as continuous exposure variables. Problem behaviour and hyperactivity were assessed, using the Strength and Difficulties Questionnaire (SDQ) and categorised as normal/borderline and abnormal. Associations were analysed using multiple logistic and linear regression.High compared to low prenatal PFHxS exposure was associated with 1.16 (95% confidence interval (CI): 0.08; 2.25) point higher SDQ-total (more problem behaviour) in Greenland and 0.80 (CI: 0.06; 1.54) point higher SDQ-total in the combined analyses, whereas no association was present in Ukraine alone. One natural log-unit increase in prenatal PFNA exposure was associated with 0.90 (CI: 0.10; 1.71) points higher SDQ-total in Greenland and 0.72 (CI: 0.13; 1.31) points higher in the combined analysis and no association in Ukraine. Prenatal PFAS exposure was unrelated to problem behaviour (abnormal SDQ-total). In the combined analysis, odds ratio (OR) (CI) for hyperactivity was 1.8 (1.0; 3.2) for one natural log-unit increase in prenatal PFNA and 1.7 (1.0; 3.1) for one natural log-unit increase in prenatal PFDA exposure.Findings are compatible with weak effects on child behaviour of prenatal exposure to some PFASs although spurious results are not entirely unlikely. The associations were strongest in Greenland.

Childhood exposure to phthalates and pulmonary function

Phthalate exposure is related to the development of allergic diseases; however, studies regarding its effect on lung function are limited. Our study aims to identify an association between phthalate exposure at different ages and lung function in children at age 9 by conducting a cohort study. The Taiwan Birth Panel Study (TBPS) was established from April 2004 to January 2005. Urine samples were collected from children in the TBPS cohort at ages 2, 5, and 9years. Urinary phthalate metabolite concentrations were measured via ultrahigh-performance liquid chromatography coupled with tandem mass spectrometry. Questionnaires, lung function tests and serum IgE levels were obtained from children at the age of 9. Multiple linear regressions adjusted for confounding factors were applied to investigate the associations between phthalate exposure at different ages and lung function at age 9. Our results demonstrate that in children with allergic diseases, a per log unit increase in the urinary phthalate metabolite mono-ethyl phthalate (MEP) concentration at age 9 was associated with a decreasing forced expiratory volume in 1 sec (FEV1) (β=−25.22; 95% CI: −47.53 to −2.91 per log ml/ln-μg/g cr) and forced vital capacity (FVC) (β=−32.3; 95% CI: -63.51 to −1.09 per log ml/ln-μg/g cr). For children with high serum IgE levels (>100kU/L) at age 9, the urinary MEP concentrations at the same age were negatively associated with the FEV1 (β=−30.4; 95% CI: −56.8 to −4.0 per log ml/ln-μg/g cr), FVC (β=−47.6; 95% CI: −84.2 to −11.0 per log ml/ln-μg/g cr) and peak expiratory flow (PEF) (β=−102.4; 95% CI: 180.2 to −24.7 per log ml/ln-μg/g cr). Phthalate exposure at ages 2 and 5 had little effect on lung function at age 9. Our study suggests that concurrent exposure to phthalates, such as MEP, is negatively associated with lung function in children. Further investigation is required to elaborate on this correlation.

Tumor and serum DNA methylation in women receiving preoperative chemotherapy with or without vorinostat in TBCRC008

Methylated gene markers have shown promise in predicting breast cancer outcomes and treatment response. We evaluated whether baseline and changes in tissue and serum methylation levels would predict pathological complete response (pCR) in patients with HER2-negative early breast cancer undergoing preoperative chemotherapy. The TBCRC008 trial investigated pCR following 12weeks of preoperative carboplatin and albumin-bound paclitaxel+vorinostat/placebo (n=62). We measured methylation of a 10-gene panel by quantitative multiplex methylation-specific polymerase chain reaction and expressed results as cumulative methylation index (CMI). We evaluated association between CMI level [baseline, day 15 (D15), and change] and pCR using univariate and multivariable logistic regression models controlling for treatment and hormone receptor (HR) status, and performed exploratory subgroup analyses. In univariate analysis, one log unit increase in tissue CMI levels at D15 was associated with 40% lower chance of obtaining pCR (odds ratio, OR0.60, 95% CI 0.37-0.97; p=0.037). Subgroup analyses suggested a significant association between tissue D15 CMI levels and pCR in vorinostat-treated [OR 0.44 (0.20, 0.93), p=0.03], but not placebo-treated patients. In this study investigating the predictive roles of tissue and serum CMI levels in patients with early breast cancer for the first time, we demonstrate that high D15 tissue CMI levels may predict poor response. Larger studies and improved analytical procedures to detect methylated gene markers in early stage breast cancer are needed. TBCRC008 is registered on ClinicalTrials.gov (NCT00616967).