These studies uncover mechanisms for food allergy sensitization and anaphylaxis in neonatal mice that are consistent with features of human early-life exposures and genetics in patients with clinical food allergy and demonstrate that changes in barrier function drive development of anaphylaxis to food allergen.
In animals and humans, offspring of allergic mothers have increased responsiveness to allergen and the allergen-specificity of the offspring can be different than that of the mother. In our preclinical models, the mother's allergic responses influence development of the fetus and offspring by elevating numbers of cells in dendritic cell subsets. A major question is the identity of maternal factors of allergic mothers that alter offspring development of responsiveness to allergen. Lipids are altered during allergic responses and lipids are transported to the fetus for growth and formation of fetal membranes. We hypothesized that pro-inflammatory lipids, that are elevated in allergic mothers, are transported to the fetus and regulate fetal immune development. We demonstrate in this report that there was a significant 2-fold increase in β-glucosylceramides (βGlcCer) in allergic mothers, the fetal liver and her offspring. The βGlcCer were transported from mother's plasma, across the placenta, to the fetus and in breastmilk to the offspring. Administration of βGlcCer to non-allergic mothers was sufficient for offspring responses to allergen. Importantly, maternal administration of a clinically relevant pharmacological inhibitor of βGlcCer synthase returned βGlcCer to normal levels in the allergic mothers and her offspring and blocked the offspring increase in dendritic cell subsets and offspring allergen responsiveness. In summary, allergic mothers had increased βGlcCer that was transported to offspring and mediated increases in offspring DCs and responsiveness to allergen. These data have a significant impact on our understanding of mechanisms for development of allergies in offspring of allergic mothers and have the potential to lead to novel interventions that significantly impact risk for allergic disease early in life.
Severe asthma (SA) significantly reduces patients' healthrelated quality of life (HRQoL) and productivity. However, there are no contemporary estimates of HRQoL and productivity from a national, realworld sample of U.S. adults with SA. METHODS: CHRONICLE (NCT03373045) is an ongoing observational study of SA patients treated by U.S. allergists/immunologists or pulmonologists. Eligible patients are adults receiving biologic therapy, those uncontrolled on high-dosage inhaled corticosteroids with additional controllers (HD ICS+) and/or those receiving maintenance systemic corticosteroids (mSCS). At enrollment, patients complete the St. George's Respiratory Questionnaire (SGRQ; referencing prior 3 months, range 0-100, 1005maximum impairment) and Work Productivity and Activity Impairment-Asthma survey (WPAI; referencing prior 7 days, percentage impairment). Responses were summarized by treatment category for patients enrolled February 2018 to February 2019. RESULTS: Of 796 patients enrolled across 89 sites, 481 (60%) completed both surveys. Patient demographics and other characteristics were generally similar for those completing/not completing surveys. For biologic (N5370), HD ICS+ (N591), and mSCS (N564) patients, mean total SGRQ scores were 39, 45, and 58, respectively; 54%, 55%, and 19% reported good or very good health. For WPAI, mean activity impairment was 31%, 38%, and 55%. Among those employed (55%, 53%, and 38%, respectively), mean overall work impairment was 19%, 26%, and 38%. CONCLUSIONS: U.S. SA patients had reduced HRQoL and productivity, with greater impairment among those receiving mSCS and less among those receiving biologics. Rates of patient-reported good health were similar among biologic and HD ICS+ patients despite HRQoL and productivity differences, suggesting patient-reported health may mask meaningful impairment.
Fluorescence quenching was used to investigate the interaction of six fluoroquinolones with humic acid. Static quenching was observed for the binding of ciprofloxacin, enoxacin, fleroxacin, levofloxacin, norfloxacin, and ofloxacin to humic acid. The equilibrium binding constants were found from Stern-Volmer plots of the data. The quenching experiments were repeated over a temperature range of 25-45 ℃ and van't Hoff plots were generated. From these linear plots, thermodynamic values were calculated for Δ H, Δ G, and Δ S for each of the fluoroquinolones. The equilibrium binding constants were found to be <1 for all the antibiotics studied. The calculated ΔH values were all negative and ranged from -9.5 to -27.6 kJ/mol. The high water solubility of the antibiotics and low ΔH of binding suggests that the antibiotics will be transported easily through the environment. Finally, whether the fluoroquinolones are in a protonated, deprotonated, or partially protonated state is found to correlate to the strength of binding to humic acid.
Background: Tocopherol isoforms may regulate child lung growth and spirometric measures. Objective: Our aim was to determine the extent to which plasma a-tocopherol (a-T) or g-tocopherol (g-T) isoform levels in early childhood or in utero are associated with childhood lung function. Methods: We included 622 participants in the Project Viva cohort who had lung function at a mid-childhood visit (age 6-10 years). Maternal and child tocopherol isoform levels were measured by HPLC at the second trimester and 3 years of age, respectively. Multivariable linear regression models (adjusted for mid-childhood body mass index z scores, maternal education, smoking in pregnancy, and prenatal particulate matter with diameter of <2.5 micrometers (PM 2.5) particulate exposure) stratified by tertiles of child g-T level were used to assess the association of aT levels with FEV 1 and forced vital capacity (FVC) percent predicted. Similarly, models stratified by child aT tertile evaluated associations of g-T levels with lung function. We performed similar analyses with maternal second trimester tocopherol isoform levels. Results: The median maternal second trimester aT level was 63 mM (interquartile range 5 47-82). The median early-childhood level was 25 mM (interquartile range 5 20-33 mM). In the lowest tertile of early-childhood g-T, children with a higher aT level (per 10 mM) had a higher mid-childhood FEV 1 percent predicted (b 5 3.09; 95% CI 5 0.58-5.59 and a higher FVC percent predicted (b 5 2.77; 95% CI 5 0.47-5.06). This protective association of aT was lost at higher g-T levels. We did not see any consistent associations of second trimester levels of either aT or g-T with mid-childhood FEV 1 or FVC. Conclusion: When g-T levels were in the lowest tertile, a higher early-childhood aT level was associated with better lung function at mid-childhood. Second trimester maternal plasma aT concentration was 3-fold higher than in the adult nonpregnant female population.
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