Long-Term Velaglucerase Alfa Treatment in Children with Gaucher Disease Type 1 Naïve to Enzyme Replacement Therapy or Previously Treated with Imiglucerase

Background Gaucher Disease type 1 (GD1) often manifests in childhood. Early treatment with enzyme replacement therapy (ERT) may prevent disease complications. We report the assessment of velaglucerase alfa ERT in pediatric GD1 patients who participated in a long-term extension study (HGT-GCB-044, ClinicalTrials.gov Identifier NCT00635427). Methods Safety and efficacy were evaluated in pediatric patients receiving velaglucerase alfa 30–60 U/kg by intravenous infusion every other week. In addition to key hematological and visceral efficacy assessments, exploratory assessments conducted specifically in pediatric patients included evaluation of height, bone age, bone marrow burden, and Tanner stage of puberty. Results The study included 24 pediatric patients. Fifteen patients were naïve to ERT on entry into the preceding trials TKT032 (12-month trial) or HGT-GCB-039 (9-month trial): in the preceding trials, ten of these 15 patients received velaglucerase alfa and five patients received imiglucerase ERT. Nine patients in the study were previously treated with imiglucerase for \u3e 30 months and were switched to velaglucerase alfa in the preceding trial TKT034 (12-month trial). Cumulative ERT exposure in the clinical studies ranged from 2.0 to 5.8 years. Three serious adverse events, including a fatal convulsion, were reported; none were deemed related to velaglucerase alfa. One patient tested positive for anti-velaglucerase alfa antibodies. An efficacy assessment at 24 months showed that velaglucerase alfa had positive effects on primary hematological and visceral parameters in treatment-naïve patients, which were maintained with longer-term treatment. Disease parameters were stable in patients switched from long-term imiglucerase ERT. Exploratory results may suggest benefits of early treatment to enable normal growth in pediatric patients. Conclusion The safety profile and clinical response seen in pediatric patients are consistent with results reported in adults

Adjunctive Azithromycin Prophylaxis for Cesarean Delivery

The addition of azithromycin to standard regimens for antibiotic prophylaxis before cesarean delivery may further reduce the rate of postoperative infection. We evaluated the benefits and safety of azithromycin-based extended-spectrum prophylaxis in women undergoing nonelective cesarean section

Widespread occurrence of distinct alkenones from Group I haptophytes in freshwater lakes: Implications for paleotemperature and paleoenvironmental reconstructions

Alkenones are C35-C42 polyunsaturated ketone lipids that are commonly employed to reconstruct changes in sea surface temperature. However, their use in coastal seas and saline lakes can be hindered by species-mixing effects. We recently hypothesized that freshwater lakes are immune to species-mixing effects because they appear to exclusively host Group I haptophyte algae, which produce a distinct distribution of alkenones with a relatively consistent response of alkenone unsaturation to temperature. To evaluate this hypothesis and explore the geographic extent of Group I haptophytes, we analyzed alkenones in sediment and suspended particulate matter samples from lakes distributed throughout the mid- and high latitudes of the Northern Hemisphere (n = 30). Our results indicate that Group I-type alkenone distributions are widespread in freshwater lakes from a range of different climates (mean annual air temperature range: -17.3-10.9 degrees C; mean annual precipitation range: 125-1657 mm yr(-1); latitude range: 40-81 degrees N), and are commonly found in neutral to basic lakes (pH > 7.0), including volcanic lakes and lakes with mafic bedrock. We show that these freshwater lakes do not feature alkenone distributions characteristic of Group II lacustrine haptophytes, providing support for the hypothesis that freshwater lakes are immune to species-mixing effects. In lakes that underwent temporal shifts in salinity, we observed mixed Group I/II alkenone distributions and the alkenone contributions from each group could be quantified with the RIK37 index. Additionally, we observed significant correlations of alkenone unsaturation (U-37(K)) with seasonal and mean annual air temperature with this expanded freshwater lakes dataset, with the strongest correlation occurring during the spring transitional season (U-37(K) = 0.029 * T - 0.49; r(2) = 0.60; p < 0.0001). We present new sediment trap data from two lakes in northern Alaska (Toolik Lake, 68.632 degrees N, 149.602 degrees W; lake E5, 68.643 degrees N, 149.458 degrees W) that demonstrate the highest sedimentary fluxes of alkenones in the spring transitional season, concurrent with the period of lake ice melt and isothermal mixing. Together, these data provide a framework for evaluating lacustrine alkenone distributions and utilizing alkenone unsaturation as a lake temperature proxy. (C) 2018 Elsevier B.V. All rights reserved

Risk Factors for Postcesarean Maternal Infection in a Trial of Extended-Spectrum Antibiotic Prophylaxis

To identify maternal clinical risk factors for postcesarean maternal infection in a randomized clinical trial of preincision extended-spectrum antibiotic prophylaxis

Out-of-Sequence Signal 3 Paralyzes Primary CD4+ T-Cell-Dependent Immunity

SummaryPrimary T cell activation involves the integration of three distinct signals delivered in sequence: (1) antigen recognition, (2) costimulation, and (3) cytokine-mediated differentiation and expansion. Strong immunostimulatory events such as immunotherapy or infection induce profound cytokine release causing “bystander” T cell activation, thereby increasing the potential for autoreactivity and need for control. We show that during strong stimulation, a profound suppression of primary CD4+ T-cell-mediated immune responses ensued and was observed across preclinical models and patients undergoing high-dose interleukin-2 (IL-2) therapy. This suppression targeted naive CD4+ but not CD8+ T cells and was mediated through transient suppressor of cytokine signaling-3 (SOCS3) inhibition of the STAT5b transcription factor signaling pathway. These events resulted in complete paralysis of primary CD4+ T cell activation, affecting memory generation and induction of autoimmunity as well as impaired viral clearance. These data highlight the critical regulation of naive CD4+ T cells during inflammatory conditions

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Turf Management Club by John Traynor (page 1) Who Is Superintendent Here by H.E. Frenette (1) Good Turf Can Result from good Sodding (3) Golf Course Superintendent by Edwart Wiacek (4) Picture - Outstanding Senior Prof. Troll Picture - recognition for Blazers St. Andrew\u27s, Scotland by William Hynd (5) Analogy of a Turf Manager by James B. Cole (6) Fish Trouble by Peter A. Langelier and Dennis P. Leger (8) Square Rings by Robert P. McGuire (9) A Different Type of Course by Robert Hall (10) Literature by Pierre Coste (11) Weeds in Golf Course Turf and Their Control by John F. Cornman (A-1) The USe of Liquid Fertilizer by Anthony B. Longo (A-3) Fertilizing a Golf Course Through an Irrigation System by Herbert E. Berg (A-6) The Extent of Winter Injury on Golf Courses by James L. Holmes (A-11) The Problem of Winter Injury by James B. Beard (A-13) Establishing, Maintaining, and Selling Sod for Turf Areas in New England by George F. Stewart (A-20) Problems of Maintaining Turf Around Industrial Grounds by George Moore (A-22) Landscaping Industrial sites by A.W. Boicourt (A-25) Introduction to the panel Discussion on Grasses for Tees and Their Management by Alexander M. Radko (A-28) Building a Golf Tee by Phil Cassidy (A-29) Grasses for Tees and Their Management by Wm. Dest (A-31) Golf Course Tee maintenance by Jim Fulwider (A-32) Tees by F. Thompson (A-33) How to Draw up a Contract by Lawrence D. Rhoades (A-34) My Contract by Lucien E. Duval (A-37) The Golf Car Problem by Geoffrey S. Cornish (A-41) Golf Cars and Turfgrass by Lee Record (A-42) Course Design and Golf Cars by William F. Mitchell (A-42) Golf Cars and the Established Course by Sherwood Moore (A-45) Course Design and Golf Cars by Phil Wogan (a-52) Introduction of Cars to the New Course by M. Ovian (A-56

The Sediment Green-Blue Color Ratio as a Proxy for Biogenic Silica Productivity Along the Chilean Margin

Sediment cores recently collected from the Chilean Margin during D/V JOIDES Resolution Expedition 379T (JR100) document variability in shipboard-generated records of the green/blue (G/B) ratio. These changes show a strong coherence with benthic foraminiferal δ18O, Antarctic ice core records, and sediment lithology (e.g., higher diatom abundances in greener sediment intervals), suggesting a climate-related control on the G/B. Here, we test the utility of G/B as a proxy for diatom productivity at Sites J1002 and J1007 by calibrating G/B to measured biogenic opal. Strong exponential correlations between measured opal% and the G/B were found at both sites. We use the empirical regressions to generate high-resolution records of opal contents (opal%) on the Chilean Margin. Higher productivity tends to result in more reducing sedimentary conditions. Redox-sensitive sedimentary U/Th generally co-varies with the reconstructed opal% at both sites, supporting the association between sediment color, sedimentary U/Th, and productivity. Lastly, we calculated opal mass accumulation rate (MAR) at Site J1007 over the last ∼150,000 years. The G/B-derived opal MAR record from Site J1007 largely tracks existing records derived from traditional wet-alkaline digestion from the south and eastern equatorial Pacific (EEP) Ocean, with a common opal flux peak at ∼50 ka suggesting that increased diatom productivity in the EEP was likely driven by enhanced nutrient supply from the Southern Ocean rather than dust inputs as previously suggested. Collectively, our results identify the G/B ratio as a useful tool with the potential to generate reliable, high-resolution paleoceanographic records that circumvent the traditionally laborious methodology.publishedVersio

Microbial production of long-chain n-alkanes: Implication for interpreting sedimentary leaf wax signals

Relative distributions as well as compound-specific carbon and hydrogen isotope ratios of long-chain C-25 to C-33 n-alkanes in sediments provide important paleoclimate and paleoenvironmental information. These compounds in aquatic sediments are generally attributed to leaf waxes produced by higher plants. However, whether microbes, such as fungi and bacteria, can make a significant contribution to sedimentary long-chain n-alkanes is uncertain, with only scattered reports in the early 1960s to 1970s that microbes can produce long-chain n-alkanes. Given the rapidly expanding importance of leaf waxes in paleoclimate and paleoenvironmental studies, the impact of microbial contribution to long-chain n-alkanes in sediments must be fully addressed. In this study, we performed laboratory incubation of peat-land soils under both anaerobic and aerobic conditions in the absence of light with deuterium-enriched water over 1.5 years and analyzed compound-specific hydrogen isotopic ratios of n-alkanes. Under aerobic conditions, we find n-alkanes of different chain length display variable degrees of hydrogen isotopic enrichments, with short-chain (C-18-C-21) n-alkanes showing the greatest enrichment, followed by long-chain "leaf wax" (C-27-C-31) n-alkanes, and minimal or no enrichment for mid-chain (C-22-C-25) n-alkanes. In contrast, only the shorter chain (C-18 and C-19) n-alkanes display appreciable isotopic enrichment under anaerobic conditions. The degrees of isotopic enrichment for individual n-alkanes allow for a quantitative assessment of microbial contributions to n-alkanes. Overall our results show the microbial contribution to long-chain n-alkanes can reach up to 0.1% per year in aerobic conditions. For shorter chain n-alkanes, up to 2.5% per year could be produced by microbes in aerobic and anaerobic conditions respectively. Our results indicate that prolonged exposure to aerobic conditions can lead to substantial accumulation of microbially derived long-chain n-alkanes in sediments while original n-alkanes of leaf wax origin are degraded; hence caution must be exercised when interpreting sedimentary records of long-chain n-alkanes, including chain length distributions and isotopic ratios. (c) 2017 Elsevier Ltd. All rights reserved

Fermi Large Area Telescope Constraints on the Gamma-ray Opacity of the Universe

The Extragalactic Background Light (EBL) includes photons with wavelengths from ultraviolet to infrared, which are effective at attenuating gamma rays with energy above ~10 GeV during propagation from sources at cosmological distances. This results in a redshift- and energy-dependent attenuation of the gamma-ray flux of extragalactic sources such as blazars and Gamma-Ray Bursts (GRBs). The Large Area Telescope onboard Fermi detects a sample of gamma-ray blazars with redshift up to z~3, and GRBs with redshift up to z~4.3. Using photons above 10 GeV collected by Fermi over more than one year of observations for these sources, we investigate the effect of gamma-ray flux attenuation by the EBL. We place upper limits on the gamma-ray opacity of the Universe at various energies and redshifts, and compare this with predictions from well-known EBL models. We find that an EBL intensity in the optical-ultraviolet wavelengths as great as predicted by the "baseline" model of Stecker et al. (2006) can be ruled out with high confidence.Comment: 42 pages, 12 figures, accepted version (24 Aug.2010) for publication in ApJ; Contact authors: A. Bouvier, A. Chen, S. Raino, S. Razzaque, A. Reimer, L.C. Reye

Protein-tyrosine Phosphatase (PTP) Wedge Domain Peptides: A NOVEL APPROACH FOR INHIBITION OF PTP FUNCTION AND AUGMENTATION OF PROTEIN-TYROSINE KINASE FUNCTION

Inhibition of protein-tyrosine phosphatases (PTPs) counterbalancing protein-tyrosine kinases (PTKs) offers a strategy for augmenting PTK actions. Conservation of PTP catalytic sites limits development of specific PTP inhibitors. A number of receptor PTPs, including the leukocyte common antigen-related (LAR) receptor and PTPmu, contain a wedge-shaped helix-loop-helix located near the first catalytic domain. Helix-loop-helix domains in other proteins demonstrate homophilic binding and inhibit function; therefore, we tested the hypothesis that LAR wedge domain peptides would exhibit homophilic binding, bind to LAR, and inhibit LAR function. Fluorescent beads coated with LAR or PTPmu wedge peptides demonstrated PTP-specific homophilic binding, and LAR wedge peptide-coated beads precipitated LAR protein. Administration of LAR wedge Tat peptide to PC12 cells resulted in increased proliferation, decreased cell death, increased neurite outgrowth, and augmented Trk PTK-mediated responses to nerve growth factor (NGF), a phenotype matching that found in PC12 cells with reduced LAR levels. PTPmu wedge Tat peptide had no effect on PC12 cells but blocked the PTPmu-dependent phenotype of neurite outgrowth of retinal ganglion neurons on a PTPmu substrate, whereas LAR wedge peptide had no effect. The survival- and neurite-promoting effect of the LAR wedge peptide was blocked by the Trk inhibitor K252a, and reciprocal co-immunoprecipitation demonstrated LAR/TrkA association. The addition of LAR wedge peptide inhibited LAR co-immunoprecipitation with TrkA, augmented NGF-induced activation of TrkA, ERK, and AKT, and in the absence of exogenous NGF, induced activation of TrkA, ERK, and AKT. PTP wedge domain peptides provide a unique PTP inhibition strategy and offer a novel approach for augmenting PTK function