Efficacy of tofacitinib monotherapy in methotrexate-naive patients with early or established rheumatoid arthritis.

IntroductionTofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Tofacitinib monotherapy was previously shown to inhibit structural damage, reduce clinical signs and symptoms of RA, and improve physical functioning over 24 months in methotrexate (MTX)-naive adult patients with RA. In this post hoc analysis, we compared efficacy and safety of tofacitinib in patients with early (disease duration <1 year) versus established (≥1 year) RA.MethodsMTX-naive patients ≥18 years with active RA received tofacitinib monotherapy (5 or 10 mg two times a day, or MTX monotherapy, in a 24-month Phase 3 trial.ResultsOf 956 patients (tofacitinib 5 mg two times a day, n=373; tofacitinib 10 mg two times a day, n=397; MTX, n=186), 54% had early RA. Baseline disease activity and functional disability were similar in both groups; radiographic damage was greater in patients with established RA. At month 24, clinical response rates were significantly greater in patients with early versus established RA in the tofacitinib 5 mg two times a day group. Both tofacitinib doses had greater effects on clinical, functional and radiographic improvements at 1 and 2 years compared with MTX, independent of disease duration. No new safety signals were observed.ConclusionsTreatment response was generally similar in early and established RA; significantly greater improvements were observed at month 24 with tofacitinib 5 mg two times a day in early versus established RA. Tofacitinib 5 and 10 mg two times a day demonstrated greater efficacy versus MTX irrespective of disease duration. No difference in safety profiles was observed between patients with early or established RA.Trial registration numberNCT01039688; Results

Exposure of Bifidobacterium longum subsp. infantis to Milk Oligosaccharides Increases Adhesion to Epithelial Cells and Induces a Substantial Transcriptional Response

Devon Kavanaugh is in receipt of a Teagasc Walsh Fellowship. The authors would also like to acknowledge the support of Science Foundation Ireland under Grant No. 08/SRC/B1393 and the Alimentary Glycoscience Research Cluster (AGRC).peer-reviewedIn this study, we tested the hypothesis that milk oligosaccharides may contribute not only to selective growth of bifidobacteria, but also to their specific adhesive ability. Human milk oligosaccharides (3′sialyllactose and 6′sialyllactose) and a commercial prebiotic (Beneo Orafti P95; oligofructose) were assayed for their ability to promote adhesion of Bifidobacterium longum subsp. infantis ATCC 15697 to HT-29 and Caco-2 human intestinal cells. Treatment with the commercial prebiotic or 3′sialyllactose did not enhance adhesion. However, treatment with 6′sialyllactose resulted in increased adhesion (4.7 fold), while treatment with a mixture of 3′- and 6′-sialyllactose substantially increased adhesion (9.8 fold) to HT-29 intestinal cells. Microarray analyses were subsequently employed to investigate the transcriptional response of B. longum subsp. infantis to the different oligosaccharide treatments. This data correlated strongly with the observed changes in adhesion to HT-29 cells. The combination of 3′- and 6′-sialyllactose resulted in the greatest response at the genetic level (both in diversity and magnitude) followed by 6′sialyllactose, and 3′sialyllactose alone. The microarray data was further validated by means of real-time PCR. The current findings suggest that the increased adherence phenotype of Bifidobacterium longum subsp. infantis resulting from exposure to milk oligosaccharides is multi-faceted, involving transcription factors, chaperone proteins, adhesion-related proteins, and a glycoside hydrolase. This study gives additional insight into the role of milk oligosaccharides within the human intestine and the molecular mechanisms underpinning host-microbe interactions.Science Foundation IrelandTeagasc Walsh Fellowship Programm

Virginia Rose Bud

I had a flow\u27r within my garden growing,A plant I cherish\u27d with a father\u27s care;While other Darkies round dis spot were roving,To catch de sweets dat fill\u27d de de desert air, I watch\u27d dis plant both day and night, awaitingAnd like her mother she was blithe and gayOne night I left her in her bed a dreaming,And in de mornin she was stole was stole a Chorus:Dey stole, dey stole, dey stole his child away!dey stole, dey stole, dey stole his child away!Oh! hear my story, Oh hear me I pray; my heart, my heart is breaking for my child,my child dey stole away! 2nd verseOh! daddy\u27s heart was widow\u27d and dejectedI wander\u27d forth into de fields in vain,And every plant on me a shade reflected,My tears dey fell unto de ground like rain.De sun above look\u27d down upon my sorrow,My heart had almost burst its bonds in vain.My child was stole, was lost to me forever,I never saw dat angel angel form

The Glutamate and Chloride Permeation Pathways Are Colocalized in Individual Neuronal Glutamate Transporter Subunits

Glutamate transporters have a homotrimeric subunit structure with a large central water-filled cavity that extends partially into the plane of the lipid bilayer (Yernool et al., 2004). In addition to uptake of glutamate, the transporters also mediate a chloride conductance that is increased in the presence of substrate. Whether the chloride channel is located in the central pore of the trimer or within the individual subunits has been controversial. We find that coexpression of wild-type neuronal glutamate transporter EAAT3 subunits with subunits mutated at R447, a residue governing substrate selectivity (Bendahan et al., 2000), results in transport activity consistent with two distinct noninteracting populations of transporters, in agreement with previous work suggesting that each subunit operates independently to transport substrate (Awes et al., 2004; Grewer et al., 2005; Koch and Larsson, 2005). In wild-type homotrimeric transporters, the glutamate concentration dependence of the anion conductance and the kinetics of glutamate flux were isolated and measured, and the anion channel activation was fitted to analytical expressions corresponding to (1) a central pore gated by binding to one or more subunits and (2) a channel pore in each subunit. The data indicate that glutamate-binding sites, transport pathways, and chloride channels reside in individual subunits in a trimer and function independently

Shuttle-launch triangular space station

A triangular space station deployable in orbit is described. The framework is comprized of three trusses, formed of a pair of generally planar faces consistine of foldable struts. The struts expand and lock into rigid structural engagement forming a repetition of equilater triangles and nonfolding diagonal struts interconnecting the two faces. The struts are joined together by node fittings. The framework can be packaged into a size and configuration transportable by a space shuttle. When deployed, the framework provides a large work/construction area and ample planar surface area for solar panels and thermal radiators. A plurity of modules are secured to the framework and then joined by tunnels to make an interconnected modular display. Thruster units for the space station orientation and altitude maintenance are provided

Efficiency of Nitrogen Use with Corn on a Tiled and Untiled Soil

Excessive water is one of the largest contributors to the inefficient use of nitrogen in Kentucky. Because of this, nitrogen is often lost by both leaching and,denitrification. The amount, of these losses can be great depending on soil type and weather. Well-drained soils in Kentucky have been shown to lose less nitrogen than poorly drained soils. The nitrogen lost from well drained soils is usually due, to leaching. The nitrogen in the soil, even soon after applying non-nitrate forms of fertilizer N, is mostly in the water soluble nitrate form. When more water falls onto a well-drained soil than the soil can hold, then both water and nitrogen move through the soil below the root zone and are lost for plant use. On poorly-drained soils, the mostly likely method of nitrogen loss is due to denitrification. Nitrogen loss by this mechanism is due to the soil becoming saturated with water (waterlogged) and forcing the air out of the soil. In an effort to survive, some of the microorganisms in the soil take oxygen from nitrate. This process (denitrification) turns the nitrogen into a gas that will diffuse out of the saturated soil and be lost ,into the air. It usually occurs when the soil temperature is above 50°F and the soil is saturated for more than a two day period. If nitrogen fertilizer has been added to the soil prior to the existence of the above conditions, then fairly large amounts of nitrogen can be lost. These conditions are most prevalent in Kentucky on poorly drained soil in April and May. In the past, most farmers have tried to manage this problem by adding excess fertilizer nitrogen to still obtain maximum yields after the loss has been sustained. This management practice may not be economically feasible in the future if nitrogen prices continue to escalate. An alternative management practice used by many farmers is to reduce the amount of nitrogen lost by simply delaying the application of nitrogen until the conditions for denitrification have little chance of occurring. This usually means that the nitrogen is applied in late May or June after the corn has been planted and the risk of waterlogged soil conditions is greatly reduced. To determine the magnitude of such factors, we began an experiment on a poorly drained bottom soil in 1970 to determine 1) the proper rates of preplant nitrogen 2) effectiveness of sidedressing nitrogen and 3) effect of soil tiling on the above two factors

Using pressure pulse seismology to examine basal criticality and the influence of sticky spots on glacial flow

Here we report results of water pressure pulse studies conducted at Storglaciären (Sweden) and West Washmawapta Glacier (British Columbia, Canada). Comparison of pressure pulse records with meteorological conditions at Storglaciären indicates that several periods of increased basal slip activity observed during a 10 day interval of summer 2008 were due to precipitation loading of the glacier surface, rather than to infiltration of surface water to the glacier bed; this indicates that the glacier bed was close to the failure strength for much of this interval. Pressure pulse magnitudes for the two glaciers were well-fit by power law distributions similar to those earlier observed at Trapridge Glacier (and similar in form to the Gutenberg-Richter relationship commonly used in seismology), suggesting that the mechanical processes that give rise to these distributions are robust features of soft-bedded glaciers. In contrast, interevent time distributions for both glaciers diverge from those observed at Trapridge Glacier for short recurrence intervals, suggesting that the factors that govern the rate at which these processes occur differ between glaciers. An examination of pressure pulse characteristics at West Washmawapta Glacier indicates that the establishment of a basal drainage system in summer 2008 resulted in increased stability and reduced sensitivity to meltwater input, suggesting that common assumptions about the relationship between meltwater production and ice flow are oversimplified. These results demonstrate that water pressure pulse observations can provide valuable insight into the dynamics of soft-bedded glaciers

Structure and function of human hemoglobin covalently labeled with periodate-oxidized adenosine triphosphate

Periodate-oxidized adenosine triphosphate (o-ATP), a ribose ring-opened dialdehyde derivative of ATP, reacts specifically with human deoxyhemoglobin to give a single major covalently modified product after reduction with sodium borohydride. This product, designated di-ATP Hb, was isolated using ion-exchange chromatography and shown to have incorporated two molecules of o-ATP/tetramer. Peptide mapping and x-ray crystallography at 2.8-A resolution indicate that a covalent adduct is formed between the ligand and residues Lys-82 EF6 of each beta chain in the organic phosphate-binding site of the molecule. di-ATP Hb exhibits a significantly decreased oxygen affinity (P50 = 20.8 mm Hg versus 5.8 mm Hg control; 50 mM 2-[bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)-propane-1,3-diol, pH 7.4, 0.1 M C, 20 degrees C). The subunit cooper-activity of di-ATP Hb is also reduced (nmax = 1.9 versus 2.7 control)