We conclude that corneas contain mRNA for VDR and 1α-hydroxylase as well as significant vitamin D concentrations. 25(OH)D(3) and its active metabolite 1,25(OH)(2)D(3), both enhance corneal epithelial barrier function.

Polychlorinated biphenyls (PCBs) pose significant risk to the developing human brain; however, mechanisms of PCB developmental neurotoxicity (DNT) remain controversial. Two widely posited mechanisms are tested here using PCBs identified in pregnant women in the MARBLES cohort who are at increased risk for having a child with a neurodevelopmental disorder (NDD). As determined by gas chromatography-triple quadruple mass spectrometry, the mean PCB level in maternal serum was 2.22 ng/mL. The 12 most abundant PCBs were tested singly and as a mixture mimicking the congener profile in maternal serum for activity at the thyroid hormone receptor (THR) and ryanodine receptor (RyR). Neither the mixture nor the individual congeners (2 fM to 2 μM) exhibited agonistic or antagonistic activity in a THR reporter cell line. However, as determined by equilibrium binding of [ 3 H]ryanodine to RyR1enriched microsomes, the mixture and the individual congeners (50 nM to 50 μM) increased RyR activity by 2.4−19.2-fold. 4-Hydroxy (OH) and 4-sulfate metabolites of PCBs 11 and 52 had no TH activity; but 4-OH PCB 52 had higher potency than the parent congener toward RyR. These data support evidence implicating RyRs as targets in environmentally triggered NDDs and suggest that PCB effects on the THR are not a predominant mechanism driving PCB DNT. These findings provide scientific rationale regarding a point of departure for quantitative risk assessment of PCB DNT, and identify in vitro assays for screening other environmental pollutants for DNT potential.

The effect of CYP2D6 genotype on the dose-exposure relationship for atomoxetine has not been well characterized in children. Children 6–17 years of age diagnosed with ADHD were stratified by CYP2D6 genotype into groups with 0 (PM, n=4), 0.5 (IM, n=3), one (EM1, n=8) or two (EM2, n=8) functional alleles) and administered a single 0.5 mg/kg oral dose of atomoxetine. Plasma and urine samples were collected for 24 (IM, EM1 and EM2) or 72 hours (PMs). Dose-corrected atomoxetine systemic exposure (AUC0-∞) varied 29.6-fold across the study cohort, ranging from 4.4±2.7 μM*h in EM2s to 5.8±1.7 μM*h, 16.3±2.9 μM*h and 50.2±7.3 μM*h in EM1s, IMs and PMs, respectively (p<0.0001). Simulated steady state profiles at the maximum FDA-recommended dose suggest that most patients are unlikely to attain adequate ATX exposures. These data support the need for individualized dosing strategies for more effective use of the medication.

3,3'-Dichlorobiphenyl (PCB 11), a byproduct of pigment production, is increasingly detected in environmental samples. While more highly chlorinated PCB congeners are known developmental neurotoxicants, nothing is known about the potential developmental neurotoxicity of PCB 11. To address this critical data gap, we measured PCB 11 levels in human maternal plasma and quantified the effects of PCB 11 and its major metabolites on morphometric parameters of neuronal connectivity in cultured primary neurons. Mass spectrometry analyses of plasma from 241 pregnant women enrolled in the MARBLES study (University of California, Davis) detected PCB 11 in all samples at concentrations ranging from 0.005 to 1.717 ng/ml. Morphometric analyses of primary neuron-glia co-cultures dissociated from the neocortices or hippocampi of neonatal Sprague Dawley rats exposed to vehicle or concentrations ranging from 1 attamolar (aM) to 1 micromolar (µM) of PCB 11, OH-PCB 11, or PCB 11 sulfate indicated that PCB 11 and both metabolites significantly increased axonal and dendritic growth in cortical and hippocampal pyramidal neurons. PCB 11 significantly altered neuronal morphogenesis at concentrations as low as 1 femtomolar (fM), which is ∼0.22 ng/ml. These data suggest the potential for the developing human brain to be exposed to PCB 11, and demonstrate that environmentally relevant levels of PCB 11 alter axonal and dendritic growth in neuronal cell types critically involved in cognitive and higher-order behaviors. These findings identify PCB 11 as a potential environmental risk factor for adverse neurodevelopmental outcomes in humans.

Control of airway inflammation is critical in asthma treatment. Soluble epoxide hydrolase (sEH) has recently been demonstrated as a novel therapeutic target for treating inflammation, including lung inflammation. We hypothesized that pharmacological inhibition of sEH can modulate the inflammatory response in a murine ovalbumin (OVA) model of asthma. BALB/c mice were sensitized and exposed to OVA over 6 weeks. A sEH inhibitor (sEHI) was administered for 2 weeks. Respiratory system compliance, resistance, and forced exhaled nitric oxide were measured. Lung lavage cell counts were performed, and selected cytokines and chemokines in the lung lavage fluid were measured. A LC/MS/MS method was used to measure 87 regulatory lipids mediators in plasma, lung tissue homogenates, and lung lavage fluid. The pharmacological inhibition of sEH increased concentrations of the antiinflammatory epoxy eicosatrienoic acids and simultaneously decreased the concentrations of the proinflammatory dihydroxyeicosatrienoic acids and dihydroxyoctadecenoic acids. All monitored inflammatory markers, including FeNO levels, and total cell and eosinophil numbers in the lung lavage of OVA-exposed mice were reduced by sEHI. The type 2 T helper cell (Th2) cytokines (IL-4, IL-5) and chemokines (Eotaxin and RANTES) were dramatically reduced after sEHI administration. Resistance and dynamic lung compliance were also improved by sEHI. We demonstrated that sEHI administration attenuates allergic airway inflammation and airway responsiveness in a murine model. sEHI may have potential as a novel therapeutic strategy for allergic asthma.Keywords: soluble epoxide hydrolase; asthma; inflammation; lipid mediators; type 2 T helper cell cytokines Clinical RelevanceWe demonstrated that inhibition of soluble epoxide hydrolase attenuates allergic airway inflammation and airway responsiveness in a murine model. Therefore, sEH inhibitors may have potential as a novel therapeutic strategy for allergic asthma.Three hundred million people worldwide suffer from episodic or persistent asthma (1). The cornerstones of treatment for persistent asthma are inhaled corticosteroids and b-agonist bronchodilators; however, a significant minority of patients with asthma does not respond well to these therapies (2). Thus, there are ongoing efforts to develop novel treatment strategies (3), such as specific antagonists of type 2 T helper cell (Th2) cytokines and mediators.

ObjectivesDuhuo Jisheng decoction (DJD) is considered beneficial for controlling knee osteoarthritis (KOA)-related symptoms in some Asian countries. This review compiles the evidence from randomised clinical trials and quantifies the effects of DJD on KOA.Designs7 online databases were investigated up to 12 October 2015. Randomised clinical trials investigating treatment of KOA for which DJD was used either as a monotherapy or in combination with conventional therapy compared to no intervention, placebo or conventional therapy, were included. The outcomes included the evaluation of functional activities, pain and adverse effect. The risk of bias was evaluated using the Cochrane Collaboration tool. The estimated mean difference (MD) and SMD was within a 95% CI with respect to interstudy heterogeneity.Results12 studies with 982 participants were identified. The quality presented a high risk of bias. Meta-analysis found that DJD combined with glucosamine (MD 4.20 (1.72 to 6.69); p<0.001) or DJD plus meloxicam and glucosamine (MD 3.48 (1.59 to 5.37); p<0.001) had a more significant effect in improving Western Ontario and McMaster Universities Arthritis Index (total WOMAC scores). Also, meta-analysis presented more remarkable pain improvement when DJD plus sodium hyaluronate injection (MD 0.89 (0.26 to 1.53); p=0.006) was used. These studies demonstrated that active treatment of DJD in combination should be practiced for at least 4 weeks. Information on the safety of DJD or comprehensive therapies was insufficient in few studies.ConclusionsDJD combined with Western medicine or sodium hyaluronate injection appears to have benefits for KOA. However, the effectiveness and safety of DJD is uncertain because of the limited number of trials and low methodological quality. Therefore, practitioners should be cautious when applying DJD in daily practice. Future clinical trials should be well designed; more research is needed.

Purpose This study was designed to measure vitamin D metabolites in the aqueous and vitreous humor and in tear fluid, and to determine if dietary vitamin D3 supplementation affects these levels. We also determined if the corneal epithelium can synthesize vitamin D following UV-B exposure. Methods Rabbits were fed a control or vitamin D3 supplemented diet. Pilocarpine-stimulated tear fluid was collected and aqueous and vitreous humor were drawn from enucleated eyes. Plasma vitamin D was also measured. To test for epithelial vitamin D synthesis, a human corneal limbal epithelial cell line was irradiated with two doses of UV-B (10 and 20 mJ/cm2/day for three days) and vitamin D was measured in control or 7-dehydrocholesterol treated culture medium. Measurements were made using mass spectroscopy. Results 25(OH)-vitamin D3 and 24,25(OH)2-vitamin D3 increased significantly following D3 supplementation in all samples except vitreous humor. Tear fluid and aqueous humor had small but detectable 1,25(OH)2-vitamin D3 levels. Vitamin D2 metabolites were observed in all samples. Vitamin D3 levels were below the detection limit for all samples. Minimal vitamin D3 metabolites were observed in control and UV-B-irradiated epithelial culture medium except following 7-dehydrocholesterol treatment, which resulted in a UV-B-dose dependent increase in vitamin D3, 25(OH)-vitamin D3 and 24,25(OH)2-vitamin D3. Conclusions There are measurable concentrations of vitamin D metabolites in tear fluid and aqueous and vitreous humor, and oral vitamin D supplementation affects vitamin D metabolite concentrations in the anterior segment of the eye. In addition, the UV exposure results lead us to conclude that corneal epithelial cells are likely capable of synthesizing vitamin D3 metabolites in the presence of 7-dehydrocholesterol following UV-B exposure.

We determined 12 polybrominated diphenyl ethers (PBDEs) and 19 polychlorinated biphenyls (PCBs) congeners in eight different brands of commercial whole milk (WM) and fat free milk (FFM) produced and distributed in California. Congeners were extracted using a modified quick, easy, cheap, effective, rugged and safe (QuEChERS) method, purified by gel permeation chromatography, and quantified using gas chromatography-triple quadruple mass spectrometry. PBDEs and PCBs were detected in all FFM and WM samples. The most prevalent PBDE congeners in WM were BDE-47 (geometric mean: 18.0 pg/mL, 0.51 ng/g lipid), BDE-99 (geometric mean: 9.9 pg/mL, 0.28 ng/g lipid), and BDE-49 (geometric mean: 6.0 pg/mL, 0.17 ng/g lipid). The dominant PCB congeners in WM were PCB-101(geometric mean: 23.6 pg/mL, 0.67 ng/g lipid), PCB-118 (geometric mean: 25.2 pg/mL, 0.72 ng/g lipid), and PCB-138 (geometric mean: 25.3 pg/mL, 0.72 ng/g lipid). The sum of all 19 PCB congeners in FFM and WM were several orders of magnitude below the U.S. FDA tolerance. The sum of PBDEs in milk samples suggest close proximity to industrial emissions, and confirm previous findings of elevated PBDE levels in California compared to other regions in the United States.