The pharmacokinetics and toxicity of morning vs. evening tobramycin dosing for pulmonary exacerbations of cystic fibrosis:A randomised comparison

AbstractBackgroundCircadian variation in renal toxicity of aminoglycosides has been demonstrated in animal and human studies. People with CF are frequently prescribed aminoglycosides. Altered pharmacokinetics of aminoglycosides are predictive of toxicity.AimTo investigate whether the time of day of aminoglycoside administration modulates renal excretion of tobramycin and toxicity in children with CF. To determine whether circadian rhythms are disrupted in children with CF during hospital admission.MethodsChildren (age 5–18years) with CF scheduled for tobramycin therapy were randomly allocated to receive tobramycin at 0800 or 2000h. Serum tobramycin levels were drawn at 1h and between 3.5 and 5h post-infusion between days 5 and 9 of therapy. Melatonin levels were measured serially at intervals from 1800h in the evening until 1200h on the next day. Circadian rhythm was categorised as normal when dim light melatonin onset was demonstrated between 1800 and 2200h and/or peak melatonin levels were observed during the night. Weight and spirometry were measured at the start and end of the therapy. Urinary biomarkers of kidney toxicity (KIM1, NAG, NGAL, IL-18 and CysC) were assayed at the start and end of the course of tobramycin.ResultsEighteen children were recruited to the study. There were no differences in renal clearance between the morning and evening groups. The increase in urinary KIM-1 was greater in the evening dosage group compared to the morning group (mean difference, 0.73ng/mg; 95% CI, 0.14 to 1.32; p=0.018). There were no differences in the other urinary biomarkers. There was normal circadian rhythm in 7/11 participants (64%).ConclusionsRenal elimination of tobramycin was not affected by the time of day of administration. Urinary KIM-1 raises the possibility of greater nephrotoxicity with evening administration. Four children showed disturbed circadian rhythm and high melatonin levels (ClinicalTrials.gov NCT01207245)

A selected ion flow tube study of the reactions of gas-phase cations with PSCl3

A selected ion flow tube was used to investigate the positive ion chemistry of thiophosphoryl chloride, PSCl$_3$. Rate coefficients and ion product branching ratios have been determined at room temperature for reactions with nineteen cations ; H$_3$O$^+$, CF$_3^+$, CF$^+$, NO$^+$, NO$_2^+$, SF$_2^+$, SF$^+$, CF$_2^+$, O$_2^+$, H$_2$O$^+$, N$_2$O$^+$, O$^+$, CO$_2^+$, CO$^+$, N$^+$, N$_2^+$, Ar$^+$, F$^+$ and Ne$^+$ (in order of increasing recombination energy). Complementary data described in the previous paper have been obtained for this molecule via the observation of threshold photoelectron photoion coincidences. For ions whose recombination energies are in the range 10-22 eV, comparisons are made between the product ion branching rations of PSCl$_3$ from photoionisation and from ion-molecule reactions. In most instances, the data from the two experiments are well correlated, suggesting that long-range charge transfer is the dominant mechanism for these ion-molecule reactions ; the agreement is particularly good for the atomic ions Ar$^+$, F$^+$ and Ne$^+$. Some reactions (e.g. O$_2^+$ + PSCl$_3$), however, exhibit significant differences; short-range charge transfer must then be occurring following the formation of an ion-molecule complex. For ions whose recombination energies are less than 10 eV (i.e. H$_3$O$^+$, CF$_3^+$, CF$^+$ and NO$^+$), reactions can only occur via a chemical process in which bonds are broken and formed, because the recombination energy of the cation is less than the ionisation energy of PSCl$_3$

Salt Marsh Denitrification Provides a Significant Nitrogen Sink in Barnegat Bay, New Jersey

Velinsky, D.J.; Paudel, B.; Quirk, T.; Piehler, M., and Smyth, A., 2017. Salt marsh denitrification provides a significant nitrogen sink in Barnegat Bay, New Jersey. In: Buchanan, G.A.; Belton, T.J., and Paudel, B. (eds.), A Comprehensive Assessment of Barnegat Bay-Little Egg Harbor, New Jersey. Denitrification in salt marshes can be an important removal mechanism for inorganic nitrogen, particularly in coastal estuaries subject to high nutrient loading and eutrophication. Barnegat Bay, New Jersey has had high nutrient loading in the northern part of the Bay and has exhibited symptoms of eutrophication. The first goal of this study was to examine seasonal denitrification, other N fluxes, and sediment oxygen demand in salt marshes of Barnegat Bay where inputs and concentrations of nutrients vary spatially within the Bay. Second, differences in N process rates among emergent vegetated marsh and permanently flooded isolated ponds were investigated. Finally, the percentage of the N load to the Bay removed by denitrification in the salt marshes of Barnegat Bay was calculated. It was hypothesized that denitrification rates would be the highest in summer and depend on water-column nutrient concentration. In addition, denitrification rate would be higher in vegetated marsh than in inundated ponds because of the aerobic/anaerobic interfaces present in marshes required by coupled nitrification-denitrification. Denitrification rate was three times greater in July than in October (p < 0.05). There were significant differences among marshes in N fluxes related to local availability of nutrients in the water column. Denitrification rates in vegetated marsh on thin sediment layers were more variable than in ponds. Overall, denitrification removed an average of 27.9% ± 6.9% of the total N load transported to the Bay, highlighting the important ecosystem service that the marshes provide to the Bay

Temperature dependence and mechanisms for vortex pinning by periodic arrays of Ni dots in Nb films

Pinning interactions between superconducting vortices in Nb and magnetic Ni dots were studied as a function of current and temperature to clarify the nature of pinning mechanisms. A strong current dependence is found for a square array of dots, with a temperature dependent optimum current for the observation of periodic pinning, that decreases with temperature as (1-T/Tc)3/2. This same temperature dependence is found for the critical current at the first matching field with a rectangular array of dots. The analysis of these results allows to narrow the possible pinning mechanisms to a combination of two: the interaction between the vortex and the magnetic moment of the dot and the proximity effect. Moreover, for the rectangular dot array, the temperature dependence of the crossover between the low field regime with a rectangular vortex lattice to the high field regime with a square configuration has been studied. It is found that the crossover field increases with decreasing temperature. This dependence indicates a change in the balance between elastic and pinning energies, associated with dynamical effects of the vortex lattice in the high field range.Comment: 12 text pages (revtex), 6 figures (1st jpeg, 2nd-6th postscript) accepted in Physical Review

Oral delivery of a functional algal-expressed TGF-β mimic halts colitis in a murine DSS model

Inflammatory bowel disease (IBD) is a set of immunological disorders which can generate chronic pain and fatigue associated with the inflammatory symptoms. The treatment of IBD remains a significant hurdle with current therapies being only partially effective or having significant side effects, suggesting that new therapies that elicit different modes of action and delivery strategies are required. TGM1 is a TGF-β mimic that was discovered from the intestinal helminth parasite Heligmosomoides polygyrus and is thought to be produced by the parasite to suppress the intestinal inflammation response to help evade host immunity, making it an ideal candidate to be developed as a novel anti-inflammatory bio-therapeutic. Here we utilized the expression system of the edible green algae Chlamydomonas reinhardtii in order to recombinantly produce active TGM1 in a form that could be ingested. C. reinhardtii robustly expressed TGM1, and the resultant recombinant protein is biologically active as measured by regulatory T cell induction. When delivered orally to mice, the algal expressed TGM1 is able to ameliorate weight loss, lymphadenopathy, and disease symptoms in a mouse model of DSS-induced colitis, demonstrating the potential of this biologic as a novel treatment of IBD

Nitrogen atom detection in low-pressure flames by two-photon laser-excited fluorescence

Bittner J, Lawitzki A, Meier U, Kohse-Höinghaus K. Nitrogen atom detection in low-pressure flames by two-photon laser-excited fluorescence. Applied Physics, B. 1991;52(2):108-116.Nitrogen atoms have been detected in stoichiometric flat premixed H2/O2/N2 flames at 33 and 96 mbar doped with small amounts of NH3, HCN, and (CN)2 using two-photon laser excitation at 211 nm and fluorescence detection around 870 nm. The shape of the fluorescence intensity profiles versus height above the burner surface is markedly different for the different additives. Using measured quenching rate coefficients and calibrating with the aid of known N-atom concentrations in a discharge flow reactor, peak N-atom concentrations in these flames are estimated to be on the order of 10 12–5×10 13 cm –3; the detection limit is about 1×10 11 cm –3

Growth and mortality of coccolithophores during spring in a temperate Shelf Sea (Celtic Sea, April 2015)

Coccolithophores are key components of phytoplankton communities, exerting a critical impact on the global carbon cycle and the Earth’s climate through the production of coccoliths made of calcium carbonate (calcite) and bioactive gases. Microzooplankton grazing is an important mortality factor in coccolithophore blooms, however little is currently known regarding the mortality (or growth) rates within non-bloom populations. Measurements of coccolithophore calcite production (CP) and dilution experiments to determine microzooplankton (≤63 µm) grazing rates were made during a spring cruise (April 2015) at the Central Celtic Sea (CCS), shelf edge (CS2), and within an adjacent April bloom of the coccolithophore Emiliania huxleyi at station J2. CP at CCS ranged from 10.4 to 40.4 µmol C m−3 d−1 and peaked at the height of the spring phytoplankton bloom (peak chlorophyll-a concentrations ∼6 mg m−3). Cell normalised calcification rates declined from ∼1.7 to ∼0.2 pmol C cell−1 d−1, accompanied by a shift from a mixed coccolithophore species community to one dominated by the more lightly calcified species E. huxleyi and Calciopappus caudatus. At the CCS, coccolithophore abundance increased from 6 to 94 cells mL−1, with net growth rates ranging from 0.06 to 0.21 d−1 from the 4th to the 28th April. Estimates of intrinsic growth and grazing rates from dilution experiments, at the CCS ranged from 0.01 to 0.86 d−1 and from 0.01 to 1.32 d−1, respectively, which resulted in variable net growth rates during April. Microzooplankton grazers consumed 59 to >100% of daily calcite production at the CCS. Within the E. huxleyi bloom a maximum density of 1986 cells mL−1 was recorded, along with CP rates of 6000 µmol C m−3 d−1 and an intrinsic growth rate of 0.29 d−1, with ∼80% of daily calcite production being consumed. Our results show that microzooplankton can exert strong top-down control on both bloom and non-bloom coccolithophore populations, grazing over 60% of daily growth (and calcite production). The fate of consumed calcite is unclear, but may be lost either through dissolution in acidic food vacuoles, and subsequent release as CO2, or export to the seabed after incorporation into small faecal pellets. With such high microzooplankton-mediated mortality losses, the fate of grazed calcite is clearly a high priority research direction

Seasonality and spatial heterogeneity of the surface ocean carbonate system in the northwest European continental shelf

In 2014–5 the UK NERC sponsored an 18 month long Shelf Sea Biogeochemistry research programme which collected over 1500 nutrient and carbonate system samples across the NW European Continental shelf, one of the largest continental shelves on the planet. This involved the cooperation of 10 different Institutes and Universities, using 6 different vessels. Additional carbon dioxide (CO2) data were obtained from the underway systems on three of the research vessels. Here, we present and discuss these data across 9 ecohydrodynamic regions, adapted from those used by the EU Marine Strategy Framework Directive (MSFD). We observed strong seasonal and regional variability in carbonate chemistry around the shelf in relation to nutrient biogeochemistry. Whilst salinity increased (and alkalinity decreased) out from the near-shore coastal waters offshore throughout the year nutrient concentrations varied with season. Spatial and seasonal variations in the ratio of DIC to nitrate concentration were seen that could impact carbon cycling. A decrease in nutrient concentrations and a pronounced under-saturation of surface pCO2 was evident in the spring in most regions, especially in the Celtic Sea. This decrease was less pronounced in Liverpool Bay and to the North of Scotland, where nutrient concentrations remained measurable throughout the year. The near-shore and relatively shallow ecosystems such as the eastern English Channel and southern North Sea were associated with a thermally driven increase in pCO2 to above atmospheric levels in summer and an associated decrease in pH. Non-thermal processes (such as mixing and the remineralisation of organic material) dominated in winter in most regions but especially in the northwest of Scotland and in Liverpool Bay. The large database collected will improve understanding of carbonate chemistry over the North-Western European Shelf in relation to nutrient biogeochemistry, particularly in the context of climate change and ocean acidification

Track D Social Science, Human Rights and Political Science

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138414/1/jia218442.pd

A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk

Combined analyses of gene networks and DNA sequence variation can provide new insights into the aetiology of common diseases that may not be apparent from genome-wide association studies alone. Recent advances in rat genomics are facilitating systems-genetics approaches. Here we report the use of integrated genome-wide approaches across seven rat tissues to identify gene networks and the loci underlying their regulation. We defined an interferon regulatory factor 7 (IRF7)-driven inflammatory network (IDIN) enriched for viral response genes, which represents a molecular biomarker for macrophages and which was regulated in multiple tissues by a locus on rat chromosome 15q25. We show that Epstein-Barr virus induced gene 2 (Ebi2, also known as Gpr183), which lies at this locus and controls B lymphocyte migration, is expressed in macrophages and regulates the IDIN. The human orthologous locus on chromosome 13q32 controlled the human equivalent of the IDIN, which was conserved in monocytes. IDIN genes were more likely to associate with susceptibility to type 1 diabetes (T1D)-a macrophage-associated autoimmune disease-than randomly selected immune response genes (P = 8.85 x 10(-6)). The human locus controlling the IDIN was associated with the risk of T1D at single nucleotide polymorphism rs9585056 (P = 7.0 x 10(-10); odds ratio, 1.15), which was one of five single nucleotide polymorphisms in this region associated with EBI2 (GPR183) expression. These data implicate IRF7 network genes and their regulatory locus in the pathogenesis of T1D