Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease

BACKGROUND Ustekinumab, a monoclonal antibody to the p40 subunit of interleukin-12 and inter-leukin-23, was evaluated as an intravenous induction therapy in two populations with moderately to severely active Crohn’s disease. Ustekinumab was also evaluated as subcutaneous maintenance therapy. METHODS We randomly assigned patients to receive a single intravenous dose of ustekinumab (either 130 mg or approximately 6 mg per kilogram of body weight) or placebo in two induction trials. The UNITI-1 trial included 741 patients who met the criteria for primary or secondary nonresponse to tumor necrosis factor (TNF) antagonists or had unacceptable side effects. The UNITI-2 trial included 628 patients in whom conventional therapy failed or unacceptable side effects occurred. Patients who completed these induction trials then participated in IM-UNITI, in which the 397 patients who had a response to ustekinumab were randomly assigned to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 8 weeks or every 12 weeks) or placebo. The primary end point for the induction trials was a clinical response at week 6 (defined as a decrease from baseline in the Crohn’s Disease Activity Index [CDAI] score of ≥100 points or a CDAI score <150). The primary end point for the maintenance trial was remission at week 44 (CDAI score <150). RESULTS The rates of response at week 6 among patients receiving intravenous ustekinumab at a dose of either 130 mg or approximately 6 mg per kilogram were significantly higher than the rates among patients receiving placebo (in UNITI-1, 34.3%, 33.7%, and 21.5%, respectively, with P≤0.003 for both comparisons with placebo; in UNITI-2, 51.7%, 55.5%, and 28.7%, respectively, with P<0.001 for both doses). In the groups receiving maintenance doses of ustekinumab every 8 weeks or every 12 weeks, 53.1% and 48.8%, respectively, were in remission at week 44, as compared with 35.9% of those receiving placebo (P = 0.005 and P = 0.04, respectively). Within each trial, adverse-event rates were similar among treatment groups. CONCLUSIONS Among patients with moderately to severely active Crohn’s disease, those receiving intravenous ustekinumab had a significantly higher rate of response than did those receiving placebo. Subcutaneous ustekinumab maintained remission in patients who had a clinical response to induction therapy. (Funded by Janssen Research and Development; ClinicalTrials.gov numbers, NCT01369329, NCT01369342, and NCT01369355.

Geokinematics of Central Europe: New insights from the CERGOP-2/Environment Project

The Central European Geodynamics Project CERGOP/2, funded by the European Union from 2003to 2006 under the 5th Framework Programme, benefited from repeated measurements of thecoordinates of epoch and permanent GPS stations of the Central European GPS Reference Network(CEGRN), starting in 1994. Here we report on the results of the systematic processing of availabledata up to 2005. The analysis has yielded velocities for some 60 sites, covering a variety of CentralEuropean tectonic provinces, from the Adria indenter to the Tauern window, the Dinarides, thePannonian Basin, the Vrancea seismic zone and the Carpathian Mountains. The estimated velocitiesdefine kinematical patterns which outline, with varying spatial resolution depending on the stationdensity and history, the present day surface kinematics in Central Europe. Horizontal velocities areanalyzed after removal from the ITRF2000 estimated velocities of a rigid rotation accounting forthe mean motion of Europe: a ~2.3 mm/yr north-south oriented convergence rate between Adria andthe Southern Alps that can be considered to be the present day velocity of the Adria indenterrelative to the European foreland. An eastward extrusion zone initiates at the Tauern Window. Thelateral eastward flow towards the Pannonian Basin exhibits a gentle gradient from 1-1.5 mm/yrimmediately east of the Tauern Window to zero in the Pannonian Basin. This kinematic continuityimplies that the Pannonian plate fragment recently suggested by seismic data does not require aspecific Eulerian pole. On the southeastern boundary of the Adria microplate, we report a velocitydrop from 4-4.5 mm/yr motion near Matera to ~1 mm/yr north of the Dinarides, in the southwesternpart of the Pannonian Basin. A positive velocity gradient as one moves south from West Ukraineacross Rumania and Bulgaria is estimated to be 2 mm/yr on a scale of 600-800 km, as if the crustwere dragged by the counterclockwise rotation along the North Anatolian Fault Zone. This regimeapparently does not interfere with the Vrancea seismic zone: earthquakes there are sufficiently deep(&gt; 100 km) that the brittle deformation at depth can be considered as decoupled from the creep atthe surface. We conclude that models of the Quaternary tectonics of Central and Eastern Europeshould not neglect the long wavelength, nearly aseismic deformation affecting the upper crust in theRomanian and Bulgarian regions

Evolution and dynamics of the Cenozoic tectonics of the South Balkan extensional system

The South Balkan extensional system consists of normal faults and associated sedimentary basins within southern Bulgaria, Macedonia, eastern Albania, northern Greece, and northwestern Turkey. Extensional tectonism began during the final convergence across the Vardar, Intra-Pontide, and Izmir-Ankara suture zones, where oceanic regions closed between continental Europe and continental fragments that make up the Pelagonian, Sakar, and western Anatolian tectonic units. Earliest extension of latest Cretaceous-middle Eocene age appears to have occurred within a regional convergent tectonic setting and may be related to an increase in gravitation potential energy within a thickening continental lithosphere. Following diachron-ous closure across the suture zone, from the middle Eocene to late Oligocene, the transition from a regionally convergent to a regionally extensional tectonic setting occurred and was associated with abundant magmatism and formation of sedimentary basins. Extension was associated with lithospheric thinning probably related to changes in geometry of the subducted slab, dynamics of the mantle wedge, and beginning of slab rollback along the Hellenic subduction zone. A short period of local and diachronous (?) shortening (during latest Oligocene-early Miocene time) occurred in the Thrace basin of northwestern Turkey and in some basins in western Bulgaria and eastern Macedonia. Regional extension began in middle Miocene time and was related to the regional extensional tectonic setting that has dominated the Aegean extensional region to the present. Trench rollback was the dominant dynamic process, but during late Miocene time it was modi-fled by the formation of the western part of the North Anatolian fault zone that partially decoupled the South Balkan extensional system from the Aegean extensional region. During late Cenozoic time, east-west-striking normal faults and associated sedimentary basins in the eastern part of the South Balkan extensional system propagated westward in tandem with westward migration of north-south-striking normal faults and sedimentary basins from western Bulgaria into eastern Albania. This migration was caused by evolution of the Hellenic subduction zone as it increased its curvature during trench rollback and clockwise and counterclockwise rotation of crustal fragments in the west and east, respectively. After formation of the western part of the North Anatolian fault zone, extension within the eastern part of the South Balkan extensional system was related to southward movement of its lithosphere at a slower rate than the extension within the Aegean extensional region. Active extension and basin formation show two provinces of extension that are nearly at right angles to one another and their overlap in the central South Balkan extensional system: east-west extension in central Albania to eastern Macedonia and north-south extension from northwestern Greece and eastern Macedonia to eastern Bulgaria and northwestern Turkey

Nonisothermal Melting and Crystallization of Foamed Crosslinked Polyethylene

Foamed crosslinked specimens of low density polyethylene are produced by hot mould injection moulding. Dicumylperoxide, as crosslinking agent and azodicarbonamide as blowing agent, were used. The three components are blended and granulated in advance in an extruder-granulator at temperatures of 100-125°C. The contents of blowing and crosslinking agents in the composites studied are 5-15 and 0.08-0.6, respectively, in percents by weight. The ability for maximum foaming was studied by determining the overall density of the specimens. The crosslinking degree was calculated from the equilibrium strain value defined at temperature 140°C and pressure stress 0.045 MPa. The same parameter was estimated also by the melt flow index. The LDPE morphological parameters were determined on the basis of DSC-graphics obtained by a Perkin-Elmer DSC-7 differential scanning calorimeter at heating and cooling rates of 10°C/min. The activation energy for transport through phase boundary crystal melt, the surface energy of the crystal, the long period and the degree of the crystallinity were calculated by computer programs using formulae of non-isothermal melting and crystallization kinetics theory. It is found that the overall density of the specimens increases with the increase of the crosslinking agent concentration in the range of 0.08-0.6% by wt. At low concentrations of dicumylperoxide, the increase of the blowing agent concentration results in a decrease of the density, while at high crosslinking agent concentration the opposite trend is observed. The crosslinking degree of the foamed polyethylene increases with the increase of the concentrations of dicumylperoxide and azodicarbonamide, and the flowability of the foamed polyethylene melt decreases correspondingly. The crosslinking of the foamed LDPE affects the non-isothermal phase transitions. With the increase of the crosslinking degree, the phase transition temperatures and the degree of crystallinity decrease. The values obtained for the energies of activation for transport through the phase boundary, the surface energy of the crystal and the long period are comparable with the values obtained by other authors. </jats:p