Stimulation of endothelial adenosine Al receptors enhances adhesion of neutrophils in the intact guinea pig coronary system

Objective: The primary aim was to determine the action of pathophysiologically relevant adenosine concentrations (0.1-1 μM) on adhesion of neutrophils to coronary endothelium. Further aims were to evaluate the nature and localisation of the adenosine receptor involved. and to assess the effect of endogenous adenosine. Methods: Adhesion was studied in isolated perfused guinea pig hearts by determining the number of cells emerging in the coronary effluent after intracoronary bolus injections of 600 000 neutrophils prepared from guinea pig or human blood. The system was characterised by the use of the proadhesive stimulus thrombin. Results: A 5 rnin infusion of adenosine (0.1-0.3 μM) or the A1 receptor agonist N6-cyclopentyladenosine (CPA, 0.01 μM) significantly increased adhesion from about 20% (control) to 30%. This effect was prevented by the A1 receptor antagonist dipropyl-8-cyclopentylxanthine (DPCPX. 0.1 μM). It was not diminished by cessation of adenosine infusion 90 s prior to neutrophil injection. At a higher concentration of adenosine (1 μM), adhesion did not seem to be enhanced. However, coinfusion of the A2 receptor antagonist 3,7-dimethyl-1-propargylxanthine (DMPX. 0.1 μM) with 1 μM adenosine unmasked the A1 action, adhesion rising to 39%. Adenosine had a quantitatively identical effect on adhesion of human neutrophils. Total ischaemia of 15 min duration raised adhesion of subsequently applied neutrophils to 35%. This effect was completely blocked by DPCPX, as well as by ischaemic preconditioning (3 X 3 min). Preconditioning raised initial postischaemic coronary effluent adenosine from about 0.8 μM to 1.5 μM. Conclusions: The findings suggest a bimodal participation of adenosine in the development of postischaemic dysfunction by an endothelium dependent modulation of neutrophil adhesion. Stimulation occurs via endothelial A1 receptors at submicromolar adenosine levels, whereas cardioprotection by adenosine may in part relate to the use of pharmacologically high concentrations of adenosine or enhanced endogenous production after preconditioning

Application of Peptides Containing the Cleavage Sequence of Pro-TNFα in Assessing TACE Activity of Whole Cells

Tumor necrosis factor-α (TNFα) is presumably shed from cell membranes by TNFα-cleaving enzyme (TACE). The peptides SPLAQAVRSSSR and Dabcyl-LAQAVRSSSR-Edans, each encompassing the cleavage sequence of pro-TNFα recognized by TACE, were applied to intact umbilical vein endothelium (HUVEC), peripheral blood leukocytes (PBL) and the mast cell line HMC-1, which express TACE, to homogenates of rat heart tissue and to membrane and cytoplasmic extracts of PBL. Formation of SPLAQA (specific cleavage) was determined by HPLC, while cleavage (specific plus non-specific) of Dabcyl-TNFα-Edans was followed over time by measuring fluorescence. Participation of TACE was assessed from inhibition due to the drug TAPI-2. Incubation with recombinant human TACE gave specific cleavage, fully inhibitable by TAPI-2 (IC50<0.1 μM). HUVEC rapidly degraded TNFα-peptide, but in a non-specific manner (no SPLAQA detectable) and 50 μM TAPI-2 was without effect. Fluorescence was evoked when Dabcyl- LAQAVRSSSR-Edans was incubated with HMC-1 or PBL and also with cytoplasmic and membrane fractions of lysed PBL, but in no case was there significant inhibition by TAPI-2. However, marginal (10%) inhibition of fluorescence by 50 μM TAPI-2 was observed with homogenized heart tissue. This contained TACE, about 75% of which was without the inhibitory cysteine switch (Western blot). In conclusion, simple peptide analogs of pro-TNFα cannot be employed as substrates for measuring membrane TACE activity, largely due to extensive non-specific proteolytic cleavage by whole cells and cell extracts

Search for rare leptonic B decays at the Tevatron

Results of a search for the Flavor-Changing Neutral Current decay $B^0_{s,d} \to \mu^+ \mu^-$ using $p\bar{p}$ collision data at $\sqrt{s}=1.96$ TeV collected at Fermilab Tevatron collider by the CDF and D{\O}detectors are presented. CDF reports upper limits on ${\cal B} (B^0_{s} \to \mu^+ \mu^-) \leq 7.5 \cdot10^{-7}$ and ${\cal B}(B^0_{d} \to \mu^+ \mu^-) \leq 1.9 \cdot10^{-7}$ at the 95% C.L. using 171 pb$^{-1}$. The D{\O}Collaboration used 240 pb$^{-1}$ to set an even more stringent limit on the branching ratio for $B^0_{s} \to \mu^+ \mu^-$ of $5.0\cdot 10^{-7}$ at the 95% C.L.Comment: 5 pages, 2 figures, submitted to DPF 2004 conference proceedings, UC Riverside, C

Analyzing Bangladesh’s Debt Sustainability Using SimSIP Debt

The ability to pay for a government-led investment strategy to achieve the millennium development goals (MDGs) is determined by the resources available to the government through economic growth, taxation, loans, and grants. Unsustainable public debts increase poverty directly through negative impacts on economic growth as well as indirectly through cuts in spending. Hence, the issue of fiscal debt sustainability is critical for achieving the MDGs. In this paper, we use the debt projection module of SimSIP Debt to project the evolution of Bangladesh’s public debt over a 15-year horizon (from fiscal year 2006 to fiscal year 2021) under three different macroeconomic scenarios and two different financing scenarios of an ambitious government-led investment strategy.Bangladesh, debt sustainability, aid