Synthesis of 13C-labeled parabens from isotopically enriched phenols using the Houben–Hoesch reaction

Parabens are antimicrobial additives found in a wide array of consumer products. However, the halogenated compounds formed from parabens during wastewater disinfection are a potential environmental concern. In order to identify these transformation products and investigate their mechanism of formation, a synthetic route to ethyl parabens labeled with the stable isotope carbon-13 at specific positions within the benzene ring was developed. This efficient two-step procedure starts from commercially available ¹³C-labeled phenols and involves (1) initial acylation of the phenol via a Houben–Hoesch reaction with trichloroacetonitrile followed by (2) a modified haloform reaction of the resulting trichloromethyl ketone to afford the corresponding ¹³C-labeled ethyl parabens in 65%–80% overall yield. The scope of the modified haloform reaction was also investigated, allowing for the synthesis of other parabens derived from primary or secondary alcohols, including ¹³C- and deuterium-labeled esters. In addition, 4-hydroxybenzoic acid can be formed directly from the common trichloromethyl ketone intermediate upon treatment with lithium hydroxide. This protocol complements existing methods for preparing ¹³C-labeled paraben derivatives and offers the specific advantages of exhibiting complete regioselectivity in the Houben–Hoesch reaction (to form the para-disubstituted product) and avoiding the need for protecting groups in the modified haloform reaction that forms the paraben esters.     

A benchmark dose study of prenatal exposure to di(2-ethylhexyl) phthalate and behavioral problems in children

IntroductionPrenatal exposure to di(2-ethylhexyl) phthalate (DEHP) has been reported to be associated with adverse effects on neurodevelopment that yield behavior syndromes in young children with an estimated median exposure lower than the currently recommended tolerable daily intake (TDI) and reference dose (RfD).ObjectivesOur aim was to derive the benchmark dose for prenatal exposure to DEHP for the neurodevelopmental health in children.MethodsA total of 122 mother-child pairs from the Taiwan Maternal and Infant Cohort Study were analyzed for the dose-response relationship between maternal exposure to DEHP and children's behavioral syndromes evaluated at 8 years (n = 122, 2009), 11 years (n = 96, 2012), and 14 years (n = 78, 2015) of age. We employed a multivariate regression model to assess the statistical associations between the estimated maternal average daily intake of DEHP and child's individual CBCL scores for boys and girls at each separate age, followed by a mixed model for all the children across three ages accounting for individual variations. We then employed structural equation models by combining the children's specific behavioral problem scores at different ages and obtained a simulated overall latent score in relation to maternal exposure. Based on the established dose-response relationship, we derived the benchmark dose (BMD) and the lower limit (BMDL).ResultsAssociations of maternal DEHP exposure (median 4.54$\mu g/kg\_bw/day$) with the Child Behavior Checklist (CBCL) scores were all significant, except for somatic complaints, adjusting for child's age, gender, IQ, and family income. The BMDL, given a benchmark response of 0.10 (0.05) and a background response of 0.05, was 6.01 (2.16) $\mu g/kg\_bw/day$for an integrated CBCL score.ConclusionsThe current TDI (RfD) of 50 (20) $\mu g/kg\_bw/day$ for DEHP might not protect pregnant women for their children from behavioral problems. There remains the lack of comparable toxicological data. Further investigations are needed.     

活血利水法在骨伤科疾病中的应用

基于骨伤疾病瘀血内阻的重要病机和现代医家"治血重治水"的学术观点,探索概括了活血利水法在骨伤疾病中的应用现状,结合现代医学的认识,全方位分析了活血利水法的优势和缺点。活血利水法可应用于骨折、筋伤等骨伤科大部分疾病及骨伤科疾病的围手术期,能改善肢体肿胀,促进伤口愈合,便于患者早期功能康复,但目前的临床应用尚缺乏统一的规范和标准,且处方不良反应尚未完全阐明。     

Iron intake,oxidative stress-related genes and breast cancer risk

Iron has been suggested to contribute to breast cancer development through oxidative stress generation. Our study investigated associations between iron intake and breast cancer risk, overall and by menopausal and estrogen receptor/progesterone receptor (ER/PR) status, and modification by oxidative stress-related genetic polymorphisms (MnSOD, GSTM1 and GSTT1). A population-based case–control study (3,030 cases and 3,402 controls) was conducted in Ontario, Canada. Iron intake (total, dietary, supplemental, heme, nonheme) was assessed using a validated food frequency questionnaire. Odds ratios (OR) and 95% confidence intervals (CI) were estimated from multivariable logistic regression models. Interactions between iron intake and genotypes were assessed among 1,696 cases and 1,761 controls providing DNA. Overall, no associations were observed between iron intake and breast cancer risk. Among premenopausal women, total, dietary and dietary nonheme iron were positively associated with ER–/PR– breast cancer risk (all p_trend < 0.05). Among postmenopausal women, supplemental iron was associated with reduced breast cancer risk (OR_{>18 vs. 0 mg/day} = 0.68, 95% CI: 0.51–0.91), and dietary heme iron was associated with an increased risk, particularly the ER–/PR– subtype (OR_{highest vs. lowest quintile} = 1.69, 95% CI: 1.16–2.47; p_trend = 0.02). Furthermore, GSTT1 and combined GSTM1/GSTT1 polymorphisms modified some of the associations. For example, higher dietary iron was most strongly associated with increased breast cancer risk among women with GSTT1 deletion or GSTM1/GSTT1 double deletions (p_interaction < 0.05). Findings suggest that iron intake may have different effects on breast cancer risk according to menopausal and hormone receptor status, as well as genotypes affecting antioxidant capacity.     

Dietary fat intake and metabolic syndrome in adults: A systematic review

Background and aimsThe metabolic syndrome (MetS) is a cluster of coexisting cardiovascular risk factors. The role of specific dietary fats was reemphasized by dietary recommendations. This systematic review aims to assess evidence for the effect of dietary fat intake on MetS occurrence and reversion in adults.Methods and ResultsThe MEDLINE database was used to search the existing literature. We included observational studies that analyzed dietary fat intake in adults with MetS and clinical trials that compared the effects of different dietary fat diets on MetS and/or its components. Thirty articles were selected (14 observational and 16 clinical trials), and we included information of dietary fat and fatty acids as well as MetS, body mass index, cholesterol, hypertension, and diabetes in adults. SFA intake was found to be positively associated with MetS components. Most of the observational reviewed studies found beneficial associations between MUFA and PUFA (including n-3 and n-6 subtypes) intake and MetS components. Clinical trials also supported the benefits of MUFA- or PUFA-enriched diets (including low-fat diets) in reducing MetS.ConclusionsThe effects of dietary SFAs on MetS will be influenced by other specific nutrients. Replacement of SFA by MUFA and PUFA has been associated with a decrease in MetS. Dietary recommendations should emphasize on different qualities of fat intake, not only to reduce total fat intake, to obtain health benefits in adults.     

Impact of Food Intake on Liver Stiffness Determined by 2-D Shear Wave Elastography: Prospective Interventional Study in 100 Healthy Patients

The aim was to evaluate the influence of food intake on liver stiffness measurement (LSM), performed with 2-D shear wave elastography (Logiq E9, GE Medical Systems, Wauwatosa, WI, USA). One hundred healthy volunteers were prospectively enrolled. Mean age was 25.8 (19–55) y, and mean body mass index was 22.43 (17.3–30.8) kg/m². Patients fasted for at least 3 h and subsequently ingested a liquid meal of 800 kcal. Liver stiffness and portal vein velocity were measured before and after food intake. Food intake resulted in significantly higher LSM values compared with baseline LSM (5.74 ± 0.94 kPa vs. 4.80 ± 0.94 kPa, p < 0.001). On multiple linear regression analysis, body mass index was significantly positively correlated with the LSM increase after food intake (p?=?0.01). No correlation between the increase in LSM and the increase in post-prandial portal vein velocity was observed (r?=?0.09). In summary, food intake has a significant influence on LSM. There is an 11% risk of misclassifying non-fasting, healthy patients as having significant fibrosis.     

Breakfast in Latin America: Evaluation of Nutrient and Food Group Intake Toward a Nutrient-Based Recommendation

BackgroundLittle is known about breakfast habits of the Latin American (LA) population to support nutritional recommendations for a balanced breakfast in this region.ObjectiveTo evaluate the nutritional composition of breakfast in the LA population and to propose recommendations for a balanced breakfast.DesignThis multicenter cross-sectional study evaluated food and nutrient intake of nationally representative samples of urban populations of 8 LA countries (Argentina, Brazil, Chile, Colombia, Costa Rica, Ecuador, Peru, and Venezuela) in 2014-2015.Participants/settingThe sample comprised 8714 participants from the Latin American Study of Nutrition and Health, aged 15 to 65 years, randomly recruited according to geographical location, sex, age, and socioeconomic level.Main outcome measuresTwo 24-hour recalls were used to examine dietary intake. Breakfast consumers were stratified by tertiles of Nutrient-Rich Foods Index 9.3 (NRF9.3) to assess the overall diet quality of individuals. Nutrient intake at breakfast of those in the upper tertile of NRF9.3 pooled for the 8 countries was used as a reference for the development of recommendations for LA adolescents and adults.Statistical analysesComparison of food and nutrient intake of breakfast across NRF9.3 tertiles were analyzed using the Kruskal-Wallis rank sum test.ResultsOverall breakfast was an important contributor to protein, carbohydrate, and B vitamin intakes but also to added sugar and total and saturated fat intakes relative to daily intakes. Individuals in the upper NRF9.3 tertile had higher intake of key micronutrients such as calcium and potassium at breakfast compared with other tertiles. White breads/rolls/tortillas were the most consumed food group (60%), followed by butter/margarine (40%) and coffee/tea without milk (34%-50%).ConclusionsBreakfast contributed to the daily intake of B vitamins, protein, and carbohydrates but also added sugar and total and saturated fat intakes for all countries. The proposed recommendations support the nutrient density of existing highest-quality breakfast in the LA population while addressing concerns about nutrients to be encouraged or reduced.