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BackgroundDespite their large numbers and widespread use, very little is known about the extent to which per- and polyfluoroalkyl substances (PFAS) can cross the placenta and expose the developing fetus.ObjectiveThe aim of our study is to develop a computational approach that can be used to evaluate the of extend to which small molecules, and in particular PFAS, can cross to cross the placenta and partition to cord blood.MethodsWe collected experimental values of the concentration ratio between cord and maternal blood (RCM) for 260 chemical compounds and calculated their physicochemical descriptors using the cheminformatics package Mordred. We used the compiled database to, train and test an artificial neural network (ANN). And then applied the best performing model to predict RCM for a large dataset of PFAS chemicals (n = 7982). We, finally, examined the calculated physicochemical descriptors of the chemicals to identify which properties correlated significantly with RCM.ResultsWe determined that 7855 compounds were within the applicability domain and 127 compounds are outside the applicability domain of our model. Our predictions of RCM for PFAS suggested that 3623 compounds had a log RCM > 0 indicating preferable partitioning to cord blood. Some examples of these compounds were bisphenol AF, 2,2-bis(4-aminophenyl)hexafluoropropane, and nonafluoro-tert-butyl 3-methylbutyrate.SignificanceThese observations have important public health implications as many PFAS have been shown to interfere with fetal development. In addition, as these compounds are highly persistent and many of them can readily cross the placenta, they are expected to remain in the population for a long time as they are being passed from parent to offspring.ImpactUnderstanding the behavior of chemicals in the human body during pregnancy is critical in preventing harmful exposures during critical periods of development. Many chemicals can cross the placenta and expose the fetus, however, the mechanism by which this transport occurs is not well understood. In our study, we developed a machine learning model that describes the transplacental transfer of chemicals as a function of their physicochemical properties. The model was then used to make predictions for a set of 7982 per- and polyfluorinated alkyl substances that are listed on EPA's CompTox Chemicals Dashboard. The model can be applied to make predictions for other chemical categories of interest, such as plasticizers and pesticides. Accurate predictions of RCM can help scientists and regulators to prioritize chemicals that have the potential to cause harm by exposing the fetus.

The aryl hydrocarbon receptor (AhR) is involved in the regulation of immune responses, T-cell differentiation, and immunity. Here, we show that inflammatory stimuli such as LPS induce the expression of AhR in human dendritic cells (DC) associated with an AhR-dependent increase of CYP1A1 (cytochrome P4501A1). In vivo data confirmed the elevated expression of AhR by LPS and the LPS-enhanced 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-mediated induction of CYP1A1 in thymus of B6 mice. Inhibition of nuclear factor-κB (NF-κB) repressed both normal and LPS-enhanced, TCDD-inducible, AhR-dependent gene expression and canonical pathway control of RelA-regulated AhR-responsive gene expression. LPS-mediated induction of AhR was NF-κB-dependent, as shown in mouse embryonic fibroblasts (MEFs) derived from Rel null mice. AhR expression and TCDD-mediated induction of CYP1A1 was significantly reduced in RelA-deficient MEF compared with wild type MEF cells and ectopic expression of RelA restored the expression of AhR and induction of CYP1A1 in MEF RelA null cells. Promoter analysis of the human AhR gene identified three putative NF-κB-binding elements upstream of the transcription start site. Mutation analysis of the AhR promoter identified one NF-κB site as responsible for mediating the induction of AhR expression by LPS and electrophoretic shift assays demonstrated that this NF-κB motif is recognized by the RelA/p50 heterodimer. Our results show for the first time that NF-κB RelA is a critical component regulating the expression of AhR and the induction of AhR-dependent gene expression in immune cells illustrating the interaction of AhR and NF-κB signaling.

Cigarette smoke (CS) induces a rapid, sustained upregulation of ceramide production in human bronchial epithelial cells, leading to increased apoptosis. Using loss-of-function and overexpression analyses, we show that neutral sphingo-myelinase 2 (nSMase2) is required for CS-mediated ceramide generation and apoptosis. Glutathione (GSH), a crucial antioxidant in lung defense, blocks nSMase2 activity and thus inhibits apoptosis triggered by CS. We found that the exposure to CS, as with exposure to [H.sub.2][O.sub.2], results in increased nSMase2 activation leading to ceramide generation and therefore increased apoptosis. Interestingly, exposure of cells to GSH abolishes nSMase2 activation caused by CS and leads to a decrease in CS-induced apoptosis. This suggests that the effects of CS oxidants on nSMase2 are counteracted by GSH. Our data support a model where CS induces nSMase2 activation thereby increasing membrane-sphingomyelin hydrolysis to ceramide. In turn, elevated ceramide enhances airway epithelial cell death, which causes bronchial and alveolar destruction and lung injury in pulmonary diseases. oxidative stress; airway epithelial cells; lung injury

I read with interest the interview with Colin Ovington, director of nursing and midwifery at Mid Staffordshire NHS Foundation Trust (features June 20). Mr Ovington arrived at Mid Staffs in [...]

Exposure to hydrogen peroxide (H2O2), one of the reactive oxidants in the gas phase of cigarette smoke (CS), induces aberrant phosphorylation of the epidermal growth factor receptor (EGFR), resulting in the lack of ubiquitination by c-Cbl, and impaired degradation. EGFR activation without the feedback regulation of normal degradation leads to uncontrolled cell growth and tumor promotion. Using immunoprecipitation, immunoblotting, and confocal microscopy, we now demonstrate that the pattern of EGFR activation by CS is similar to H2O2. We found that exposure of human airway epithelial cells to CS, as with exposure to H2O2, not only results in an increase in EGFR activation over time, but the EGFR activated by H202 or CS is neither ubiquitinated nor subsequently degraded due to its inability to bind the E3 ubiquitin ligase, c-Cbl, either directly or indirectly via the Grb2 adapter protein. Moreover, the stabilized H2O2- and CS-activated EGFR remains plasma membrane-bound, while a population of the receptor is trafficked to a perinuclear region. Concomitantly, CS exposure results in the activation of downstream Akt and ERK1/2 survival and proliferation pathways. Therefore, exposure to CS, like exposure to H2O2, results in prolonged signaling by the EGFR and may contribute to uncontrolled lung cell growth. [ABSTRACT FROM AUTHOR]

Objectives: To determine the level of depression in Rheumatoid Arthritis and its relationship with severity of Rheumatoid Arthritis., Methods: This cross sectional analytical study was conducted from March 2014 to May 2014. Total 102 cases of Rheumatoid Arthritis (RA) diagnosed as per ACR (American College of Rheumatology) 1987 criteria were enrolled from Rheumatology Department, Fatima Memorial Hospital. Severity of Rheumatoid Arthritis was assessed by Health Assessment Questionnaire (HAQ) and disease activity score (DAS - 28) while severity of depression was measured by Beck Depression Inventory (BDI) scale II questionnaire. The relationship between depression and disease activity (severity) of Rheumatoid Arthritis was assessed by calculating correlation coefficient between depression, disease activity score (DAS 28) of Rheumatoid Arthritis and health assessment questionnaire (HAQ)., Results: Out of 102 patients, 77(75.5%) were females and 25(24.5%) males. The mean age of patients was 43.5± 11.9 years and the mean duration of disease was 7.8 ± 5.5 years.71.5% of Rheumatoid Arthritis patients were found to have some degree of depression and this was directly related to the severity of disease. Moderate and severe depression were present in 23 (22.5%) and 19(18.6%) patients respectively., Conclusion: In this study, almost three-fourths of Rheumatoid Arthritis patients were found to have depression. There was a strong association between Rheumatoid Arthritis disease activity and the level of depression. So it is imperative for clinicians treating Rheumatoid Arthritis patients to screen them for co morbid depression and manage it accordingly.