The Role of TLR4 in the Paclitaxel Effects on Neuronal Growth In Vitro

Paclitaxel (Pac) is an antitumor agent that is widely used for treatment of solid cancers. While being effective as a chemotherapeutic agent, Pac in high doses is neurotoxic, specifically targeting sensory innervations. In view of these toxic effects associated with conventional chemotherapy, decreasing the dose of Pac has been recently suggested as an alternative approach, which might limit neurotoxicity and immunosuppression. However, it remains unclear if low doses of Pac retain its neurotoxic properties or might exhibit unusual effects on neuronal cells. The goal of this study was to analyze the concentration-dependent effect of Pac on isolated and cultured DRG neuronal cells from wild-type and TLR4 knockout mice. Three different morphological parameters were analyzed: the number of neurons which developed neurites, the number of neurites per cell and the total length of neurites per cell. Our data demonstrate that low concentrations of Pac (0.1 nM and 0.5 nM) do not influence the neuronal growth in cultures in both wild type and TLR4 knockout mice. Higher concentrations of Pac (1-100 nM) had a significant effect on DRG neurons from wild type mice, affecting the number of neurons which developed neurites, number of neurites per cell, and the length of neurites. In DRG from TLR4 knockout mice high concentrations of Pac showed a similar effect on the number of neurons which developed neurites and the length of neurites. At the same time, the number of neurites per cell, indicating the process of growth cone initiation, was not affected by high concentrations of Pac. Thus, our data showed that Pac in high concentrations has a significant damaging effect on axonal growth and that this effect is partially mediated through TLR4 pathways. Low doses of Pac are devoid of neuronal toxicity and thus can be safely used in a chemomodulation mode. © 2013 Ustinova et al

Policy Monitor

The management of air quality in the United States has evolved into a sophisticated array of rules, strategies, and initiatives since the landmark Clean Air Act (CAA) legislation of 1970 and the subsequent creation of the U.S. Environmental Protection Agency (EPA). In particular, the CAA Amendments of 1990 introduced several new programs that have substantially reshaped the nation's approach to air pollution control. This article describes the 1990 CAA Amendments, regulations issued by EPA following their passage, progress made in air quality management in the nearly twenty years since their enactment, and the likely future direction of U.S. air quality management programs at the federal level. Copyright 2010, Oxford University Press.

Collection and Storage of Human Plasma for Measurement of Oxylipins

Oxylipins derived from omega-3 and -6 fatty acids are actively involved in inflammatory and immune processes and play important roles in human disease. However, as the interest in oxylipins increases, questions remain regarding which molecules are detectable in plasma, the best methods of collecting samples, and if molecules are stable during collection and storage. We thereby built upon existing studies by examining the stability of an expanded panel of 90 oxylipins, including specialized pro-resolving lipid mediators (SPMs), in human plasma (n = 5 subjects) during sample collection, processing, and storage at −80 °C. Oxylipins were quantified using liquid chromatography-tandem mass spectrometry (LC/MS/MS). Blood samples collected in ethylenediaminetetraacetic acid (EDTA) or heparin followed by up to 2 h at room temperature prior to processing showed no significant differences in oxylipin concentrations compared to immediately processed samples, including the SPMs lipoxin A4 and resolvin D1. The majority of molecules, including SPMs, remained stable following storage for up to 1 year. However, in support of previous findings, changes were seen in a small subset of oxylipins including 12-HETE, TXB2, 14-HDHA, and 18-HEPE. Overall, this study showed that accurate measurements of most oxylipins can be obtained from stored EDTA or heparin plasma samples using LC/MS/MS

Birth weight and carotid artery intima-media thickness

To determine the association between birth weight and carotid artery intima-media thickness (CIMT), a measure of atherogenesis, in a population of 11-year-old children.; CIMT measured by high-resolution ultrasound, and birth registry data were available for 670 children of the Southern California Children's Health Study. Multivariate regression analyses were performed to investigate the association between birth weight and CIMT, with adjustment for child's health status and lifestyle, pregnancy information, and parental health.; Mean CIMT was 0.57 mm (SD 0.04). We found a nonlinear association between birth weight and CIMT, with an increase in CIMT of 0.014 mm in the fifth (P value .01) compared with the third birth weight quintile. These associations were robust in subsample analyses in children considered normal-weight by gestational age or in term-born children. No significant association with CIMT was found for the lowest quintile.; Greater birth weight was significantly associated with increased CIMT at age 11 years. No evidence for an impact of lower birth weight was found. The predictive value of childhood CIMT on future cardiovascular outcomes is largely unknown, but strong associations between childhood cardiovascular disease risk factors and adult vascular disease suggest that increased CIMT in childhood may be clinically important