An A2A adenosine receptor agonist, ATL313, reduces inflammation and improves survival in murine sepsis models

<p>Abstract</p> <p>Background</p> <p>The pathophysiology of sepsis is due in part to early systemic inflammation. Here we describe molecular and cellular responses, as well as survival, in A_2Aadenosine receptor (AR) agonist treated and untreated animals during experimental sepsis.</p> <p>Methods</p> <p>Sepsis was induced in mice by intraperitoneal inoculation of live bacteria (<it>Escherichia coli </it>or <it>Staphylococcus aureus</it>) or lipopolysaccharide (LPS). Mice inoculated with live bacteria were treated with an A_2AAR agonist (ATL313) or phosphate buffered saline (PBS), with or without the addition of a dose of ceftriaxone. LPS inoculated mice were treated with ATL313 or PBS. Serum cytokines and chemokines were measured sequentially at 1, 2, 4, 8, and 24 hours after LPS was administered. In survival studies, mice were followed until death or for 7 days.</p> <p>Results</p> <p>There was a significant survival benefit in mice infected with live <it>E. coli </it>(100% vs. 20%, <it>p </it>= 0.013) or <it>S. aureus </it>(60% vs. 20%, <it>p </it>= 0.02) when treated with ATL313 in conjunction with an antibiotic versus antibiotic alone. ATL313 also improved survival from endotoxic shock when compared to PBS treatment (90% vs. 40%, <it>p </it>= 0.005). The serum concentrations of TNF-α, MIP-1α, MCP-1, IFN-γ, and IL-17 were decreased by ATL313 after LPS injection (<it>p </it>< 0.05). Additionally, ATL313 increased the concentration of IL-10 under the same conditions (<it>p </it>< 0.05). Circulating white blood cell concentrations were higher in ATL313 treated animals (<it>p </it>< 0.01).</p> <p>Conclusion</p> <p>Further studies are warranted to determine the clinical utility of ATL313 as a novel treatment for sepsis.</p

Effect of Ibandronate on Bending Strength and Toughness on Rodent Cortical bone; possible implications for fracture prevention

OBJECTIVES: There remains conflicting evidence regarding cortical bone strength following bisphosphonate therapy. As part of a study to assess the effects of bisphosphonate treatment on the healing of rat tibial fractures, the mechanical properties and radiological density of the uninjured contralateral tibia was assessed. METHODS: Skeletally mature aged rats were used. A total of 14 rats received 1µg/kg ibandronate (iban) daily and 17 rats received 1 ml 0.9% sodium chloride (control) daily. Stress at failure and toughness of the tibial diaphysis were calculated following four-point bending tests. RESULTS: Uninjured cortical bone in the iban group had a significantly greater mean (standard deviation (sd)), p < 0.001, stress at failure of 219.2 MPa (sd 45.99) compared with the control group (169.46 MPa (sd 43.32)) following only nine weeks of therapy. Despite this, the cortical bone toughness and work to failure was similar. There was no significant difference in radiological density or physical dimensions of the cortical bone. CONCLUSIONS: Iban therapy increases the stress at failure of uninjured cortical bone. This has relevance when normalising the strength of repair in a limb when comparing it with the unfractured limb. However, the 20% increase in stress at failure with iban therapy needs to be interpreted with caution as there was no corresponding increase in toughness or work to failure. Further research is required in this area, especially with the increasing clinical burden of low-energy diaphyseal femoral fractures following prolonged use of bisphosphonates. Cite this article: Bone Joint Res 2015;4:99–10

Production Test Rig for the ATLAS Level-1 Calorimeter Trigger Digital Processors

The Level-1 Calorimeter Trigger is a digital pipelined system, reducing the 40 MHz bunch-crossing rate down to 75 kHz. It consists of a Preprocessor, a Cluster Processor (CP), and a Jet/Energy-sum Processor (JEP). The CP and JEP receive digitised trigger-tower data from the Preprocessor and produce electron/photon, tau, and jet trigger multiplicities, total and missing transverse energies, and Region-of-Interest (RoI) information. Data are read out to the data acquisition (DAQ) system to monitor the trigger by using readout driver modules (ROD). A dedicated backplane has been designed to cope with the demanding requirements of the CP and JEP sub-systems. A number of pre-production boards were manufactured in order to fully populate a crate and test the robustness of the design on a large scale. Dedicated test modules to emulate digitised calorimeter signals have been used. All modules, cables and backplanes on test are final versions for use at the LHC. This test rig represents up to one third of the Level-1 digital processor system. Real-time data between modules were processed and time-slice readout data was transferred to the ROD at a trigger rate up to 100 kHz. Intensive testing consisted of checking the readout data by comparing to hardware simulations of the trigger. Domains of validity of the boards were also measured and dedicated stressful data patterns were used to check the reliability of the system. Tests results have been successful and the Level-1 calorimeter trigger system is proceeding to full production

The ATLAS Level-1 muon topological trigger information for run 2 of the LHC

For run 2 of the LHC, the ATLAS Level-1 trigger system will include topological information on trigger objects in order to cope with the increased trigger rates. The existing Muon-to-Central-Trigger- Processor interface (MUCTPI) has been modified in order to provide coarse-grained topological information on muon candidates. A MUCTPI- to-Level-1-Topological-Processor interface (MuCTPiToTopo) has been developed to receive the electrical information and to send it optically to the Level-1 Topological Processor (L1TOPO). This poster will describe the different modules mentioned above and present results of functionality and connection tests performed

First Measurements with the ATLAS Level-1 Calorimeter Trigger PreProcessor System

The ATLAS level-1 calorimeter trigger is a hardware-based system with the goal of identifying high-pT objects within an overall latency of 2.5 μs. It is composed of a PreProcessor system which digitises 7200 analogue channels, determines the bunchcrossing of the interaction and provides a fine timing and energy calibration; and two subsequent digital processors. The PreProcessor plays a central role during integration of the system as it provides digitisation and readout of calorimeter signals and serves as a digital signal source for the subsequent processors. In this presentation the system architecture, the board production testing, and cable installation are described. Results on commissioning efforts and signal integrity tests are presented

First data with the ATLAS Level-1 Calorimeter Trigger

The ATLAS Level-1 Calorimeter Trigger is one of the main elements of the first stage of event selection for the ATLAS experiment at the LHC. The input stage consists of a mixed analogue/digital component taking trigger sums from the ATLAS calorimeters. The trigger logic is performed in a digital, pipelined system with several stages of processing, largely based on FPGAs, which perform programmable algorithms in parallel with a fixed latency to process about 300 Gbyte/s of input data. The real-time output consists of counts of different types of physics objects, and energy sums. The final system consists of over 300 custom-built VME modules, of several different types. The installation at ATLAS of these modules, and the necessary infrastructure, was completed at the end of 2007. The system has since undergone intensive testing, both in standalone mode, and in conjunction with the whole of the ATLAS detector in combined running. The final steps of commissioning, and experience with running the full-scale system are presented. Results of integration tests performed with the upstream calorimeters, and downstream trigger and data-flow systems, are shown, along with an analysis of the performance of the calorimeter trigger in full ATLAS data-taking. This includes trigger operation during the cosmic muon runs from before LHC start-up, and a first look at LHC proton beam data