Altered prostanoid production by fibroblasts cultured from the lungs of human subjects with idiopathic pulmonary fibrosis

BACKGROUND: Prostanoids are known to participate in the process of fibrogenesis. Because lung fibroblasts produce prostanoids and are believed to play a central role in the pathogenesis of idiopathic pulmonary fibrosis (IPF), we hypothesized that fibroblasts (HF) cultured from the lungs of patients with IPF (HF-IPF) have an altered balance between profibrotic (thromboxane [TX]A(2)) and antifibrotic (prostacyclin [PGI(2)]) prostaglandins (PGs) when compared with normal human lung fibroblasts (HF-NL). METHODS: We measured inducible cyclooxygenase (COX)-2 gene and protein expression, and a profile of prostanoids at baseline and after IL-1β stimulation. RESULTS: In both HF-IPF and HF-NL COX-2 expression was undetectable at baseline, but was significantly upregulated by IL-1β. PGE(2) was the predominant COX product in IL-1β-stimulated cells with no significant difference between HF-IPF and HF-NL (28.35 [9.09–89.09] vs. 17.12 [8.58–29.33] ng/10(6) cells/30 min, respectively; P = 0.25). TXB(2) (the stable metabolite of TXA(2)) production was significantly higher in IL-1β-stimulated HF-IPF compared to HF-NL (1.92 [1.27–2.57] vs. 0.61 [0.21–1.64] ng/10(6) cells/30 min, respectively; P = 0.007) and the ratio of PGI(2) (as measured by its stable metabolite 6-keto-PGF(1α)) to TXB(2) was significantly lower at baseline in HF-IPF (0.08 [0.04–0.52] vs. 0.12 [0.11–0.89] in HF-NL; P = 0.028) and with IL-1β stimulation (0.24 [0.05–1.53] vs. 1.08 [0.51–3.79] in HF-NL; P = 0.09). CONCLUSION: An alteration in the balance of profibrotic and antifibrotic PGs in HF-IPF may play a role in the pathogeneses of IPF

Bi-cultural dynamics for risk and protective factors for cardiometabolic health in an Alaska Native (Yup\u27ik) population

Alaska Native people experience disparities in mortality from heart disease and stroke. This work attempts to better understand the relationships between socioeconomic, behavioral, and cardiometabolic risk factors among Yup\u27ik people of southwestern Alaska, with a focus on the role of the socioeconomic, and cultural components. Using a cross-sectional sample of 486 Yup\u27ik adults, we fitted a Partial Least Squares Path Model (PLS-PM) to assess the associations between components, including demographic factors [age and gender], socioeconomic factors [education, economic status, Yup\u27ik culture, and Western culture], behavioral factors [diet, cigarette smoking and smokeless tobacco use, and physical activity], and cardiometabolic risk factors [adiposity, triglyceride-HDL and LDL lipids, glycemia, and blood pressure]. We found relatively mild associations of education and economic status with cardiometabolic risk factors, in contrast with studies in other populations. The socioeconomic factor and participation in Yup\u27ik culture had potentially protective associations with adiposity, triglyceride-HDL lipids, and blood pressure, whereas participation in Western culture had a protective association with blood pressure. We also found a moderating effect of participation in Western culture on the relationships between Yup\u27ik culture participation and both blood pressure and LDL lipids, indicating a potentially beneficial additional effect of biculturalism. Our results suggest that reinforcing protective effects of both Yup\u27ik and Western cultures could be useful for interventions aimed at reducing cardiometabolic health disparities

Evidence that histidine protonation of receptor-bound anthrax protective antigen is a trigger for pore formation

The protective antigen (PA) component of the anthrax toxin forms pores within the low pH environment of host endosomes, through mechanisms that are poorly understood. It has been proposed that pore formation is dependent on histidine protonation. In previous work, we biosynthetically incorporated 2-fluorohistidine (2-FHis), an isosteric analog of histidine with a significantly reduced pKa (~1), into PA, and showed that the pH-dependent conversion from the soluble prepore to a pore was unchanged. However, we also observed that 2-FHisPA was non-functional in the ability to mediate cytotoxicity of CHO-K1 cells by LFN-DTA, and was defective in translocation through planar lipid bilayers. Here, we show that the defect in cytotoxicity is due to both a defect in translocation and, when bound to the host cellular receptor, an inability to undergo low pH-induced pore formation. Combining X-ray crystallography with hydrogen-deuterium (H-D) exchange mass spectrometry, our studies lead to a model in which hydrogen bonds to the histidine ring are strengthened by receptor binding. The combination of both fluorination and receptor binding is sufficient to block low pH-induced pore formation

Early outcomes in human lung transplantation with Thymoglobulin or Campath-1H for recipient pretreatment followed by posttransplant tacrolimus near-monotherapy

Objectives: Acute and chronic rejection remain unresolved problems after lung transplantation, despite heavy multidrug immunosuppression. In turn, the strong immunosuppression has been responsible for mortality and pervasive morbidity. It also has been postulated to interdict potential mechanisms of alloengraftment. Methods: In 48 lung recipients we applied 2 therapeutic principles: (1) recipient pretreatment with antilymphoid antibody preparations (Thymoglobulin [SangStat, Fremont, Calif] or Campath [alemtuzumab; manufactured by ILEX Pharmaceuticals, LP, San Antonio, Tex; distributed by Berlex Laboratories, Richmond, Calif]) and (2) minimal posttransplant immunosuppression with tacrolimus monotherapy or near-monotherapy. Our principal analysis was of the events during the critical first 6 posttransplant months of highest immunologic and infectious disease risk. Results were compared with those of 28 historical lung recipients treated with daclizumab induction and triple immunosuppression (tacrolimus-prednisone-azathioprine). Results: Recipient pretreatment with both antilymphoid preparations allowed the use of postoperative tacrolimus monotherapy with prevention or control of acute rejection. Freedom from rejection was significantly greater with Campath than with Thymoglobulin (P = .03) or daclizumab (P = .05). After lymphoid depletion with Thymoglobulin or Campath, patient and graft survival at 6 months was 90% or greater. Patient and graft survival after 9 to 24 months is 84.2% in the Thymoglobulin cohort, and after 10 to 12 months, it is 90% in the Campath cohort. There has been a subjective improvement in quality of life relative to our historical experience. Conclusion: Our results suggest that improvements in lung transplantation can be accomplished by altering the timing, dosage, and approach to immunosuppression in ways that might allow natural mechanisms of alloengraftment and diminish the magnitude of required maintenance immunosuppression. Copyright © 2005 by The American Association for Thoracic Surgery

TNF-Receptor Inhibitor Therapy for the Treatment of Children with Idiopathic Pneumonia Syndrome. A Joint Pediatric Blood and Marrow Transplant Consortium and Children's Oncology Group Study (ASCT0521)

AbstractIdiopathic pneumonia syndrome (IPS) is an acute, noninfectious lung disorder associated with high morbidity and mortality after hematopoietic cell transplantation. Previous studies have suggested a role for TNFα in the pathogenesis of IPS. We report a multicenter phase II trial investigating a soluble TNF-binding protein, etanercept (Enbrel, Amgen, Thousand Oaks, CA), for the treatment of pediatric patients with IPS. Eligible patients were < 18 years old, within 120 days after transplantation, and with radiographic evidence of a diffuse pneumonitis. All patients underwent a pretherapy broncho-alveolor lavage (BAL) to establish the diagnosis of IPS. Systemic corticosteroids (2.0 mg/kg/day) plus etanercept (.4 mg/kg twice weekly × 8 doses) were administered. Response was defined as survival and discontinuation of supplemental oxygen support by day 28 of study. Thirty-nine patients (median age, 11 years; range, 1 to 17) were enrolled, with 11 of 39 patients nonevaluable because of identification of pathogens from their pretherapy BAL. In the remaining 28 patients, the median fraction of inspired oxygen at study entry was 45%, with 17 of 28 requiring mechanical ventilation. Complete responses were seen in 20 (71%) patients, with a median time to response of 10 days (range, 1 to 24). Response rates were higher for patients not requiring mechanical ventilation at study entry (100% versus 53%, P = .01). Overall survival at 28 days and 1 year after therapy were 89% (95% confidence interval [CI], 70% to 96%) and 63% (95% CI, 42% to 79%), respectively. Plasma levels of proinflammatory cytokines were significantly increased at onset of therapy, subsequently decreasing in responding patients. The addition of etanercept to high-dose corticosteroids was associated with high response rates and survival in children with IPS

Iron Addition to Soil Specifically Stabilized Lignin

The importance of lignin as a recalcitrant constituent of soil organic matter (SOM) remains contested. Associations with iron (Fe) oxides have been proposed to specifically protect lignin from decomposition, but impacts of Fe-lignin interactions on mineralization rates remain unclear. Oxygen (O2) fluctuations characteristic of humid tropical soils drive reductive Fe dissolution and precipitation, facilitating multiple types of Fe-lignin interactions that could variably decompose or protect lignin. We tested impacts of Fe addition on 13C methoxyl-labeled lignin mineralization in soils that were exposed to static or fluctuating O2. Iron addition suppressed lignin mineralization to 21% of controls, regardless of O2 availability. However, Fe addition had no effect on soil CO2 production, implying that Fe oxides specifically protected lignin methoxyls but not bulk SOM. Iron oxide-lignin interactions represent a specific mechanism for lignin stabilization, linking SOM biochemical composition to turnover via geochemistry

Performance of a Limiting-Antigen Avidity Enzyme Immunoassay for Cross-Sectional Estimation of HIV Incidence in the United States

Background: A limiting antigen avidity enzyme immunoassay (HIV-1 LAg-Avidity assay) was recently developed for cross-sectional HIV incidence estimation. We evaluated the performance of the LAg-Avidity assay alone and in multi-assay algorithms (MAAs) that included other biomarkers. Methods and Findings: Performance of testing algorithms was evaluated using 2,282 samples from individuals in the United States collected 1 month to >8 years after HIV seroconversion. The capacity of selected testing algorithms to accurately estimate incidence was evaluated in three longitudinal cohorts. When used in a single-assay format, the LAg-Avidity assay classified some individuals infected >5 years as assay positive and failed to provide reliable incidence estimates in cohorts that included individuals with long-term infections. We evaluated >500,000 testing algorithms, that included the LAg-Avidity assay alone and MAAs with other biomarkers (BED capture immunoassay [BED-CEIA], BioRad-Avidity assay, HIV viral load, CD4 cell count), varying the assays and assay cutoffs. We identified an optimized 2-assay MAA that included the LAg-Avidity and BioRad-Avidity assays, and an optimized 4-assay MAA that included those assays, as well as HIV viral load and CD4 cell count. The two optimized MAAs classified all 845 samples from individuals infected >5 years as MAA negative and estimated incidence within a year of sample collection. These two MAAs produced incidence estimates that were consistent with those from longitudinal follow-up of cohorts. A comparison of the laboratory assay costs of the MAAs was also performed, and we found that the costs associated with the optimal two assay MAA were substantially less than with the four assay MAA. Conclusions: The LAg-Avidity assay did not perform well in a single-assay format, regardless of the assay cutoff. MAAs that include the LAg-Avidity and BioRad-Avidity assays, with or without viral load and CD4 cell count, provide accurate incidence estimates

A Comparison of Two Measures of HIV Diversity in Multi-Assay Algorithms for HIV Incidence Estimation

Background: Multi-assay algorithms (MAAs) can be used to estimate HIV incidence in cross-sectional surveys. We compared the performance of two MAAs that use HIV diversity as one of four biomarkers for analysis of HIV incidence. Methods: Both MAAs included two serologic assays (LAg-Avidity assay and BioRad-Avidity assay), HIV viral load, and an HIV diversity assay. HIV diversity was quantified using either a high resolution melting (HRM) diversity assay that does not require HIV sequencing (HRM score for a 239 base pair env region) or sequence ambiguity (the percentage of ambiguous bases in a 1,302 base pair pol region). Samples were classified as MAA positive (likely from individuals with recent HIV infection) if they met the criteria for all of the assays in the MAA. The following performance characteristics were assessed: (1) the proportion of samples classified as MAA positive as a function of duration of infection, (2) the mean window period, (3) the shadow (the time period before sample collection that is being assessed by the MAA), and (4) the accuracy of cross-sectional incidence estimates for three cohort studies. Results: The proportion of samples classified as MAA positive as a function of duration of infection was nearly identical for the two MAAs. The mean window period was 141 days for the HRM-based MAA and 131 days for the sequence ambiguity-based MAA. The shadows for both MAAs were <1 year. Both MAAs provided cross-sectional HIV incidence estimates that were very similar to longitudinal incidence estimates based on HIV seroconversion. Conclusions: MAAs that include the LAg-Avidity assay, the BioRad-Avidity assay, HIV viral load, and HIV diversity can provide accurate HIV incidence estimates. Sequence ambiguity measures obtained using a commercially-available HIV genotyping system can be used as an alternative to HRM scores in MAAs for cross-sectional HIV incidence estimation

LSST: from Science Drivers to Reference Design and Anticipated Data Products

(Abridged) We describe here the most ambitious survey currently planned in the optical, the Large Synoptic Survey Telescope (LSST). A vast array of science will be enabled by a single wide-deep-fast sky survey, and LSST will have unique survey capability in the faint time domain. The LSST design is driven by four main science themes: probing dark energy and dark matter, taking an inventory of the Solar System, exploring the transient optical sky, and mapping the Milky Way. LSST will be a wide-field ground-based system sited at Cerro Pach\'{o}n in northern Chile. The telescope will have an 8.4 m (6.5 m effective) primary mirror, a 9.6 deg$^2$ field of view, and a 3.2 Gigapixel camera. The standard observing sequence will consist of pairs of 15-second exposures in a given field, with two such visits in each pointing in a given night. With these repeats, the LSST system is capable of imaging about 10,000 square degrees of sky in a single filter in three nights. The typical 5$\sigma$ point-source depth in a single visit in $r$ will be $\sim 24.5$ (AB). The project is in the construction phase and will begin regular survey operations by 2022. The survey area will be contained within 30,000 deg$^2$ with $\delta<+34.5^\circ$, and will be imaged multiple times in six bands, $ugrizy$, covering the wavelength range 320--1050 nm. About 90\% of the observing time will be devoted to a deep-wide-fast survey mode which will uniformly observe a 18,000 deg$^2$ region about 800 times (summed over all six bands) during the anticipated 10 years of operations, and yield a coadded map to $r\sim27.5$. The remaining 10\% of the observing time will be allocated to projects such as a Very Deep and Fast time domain survey. The goal is to make LSST data products, including a relational database of about 32 trillion observations of 40 billion objects, available to the public and scientists around the world.Comment: 57 pages, 32 color figures, version with high-resolution figures available from https://www.lsst.org/overvie