PRICE DISCRIMINATIONS AND THEIR JUSTIFICATIONS UNDER THE ROBINSON-PATMAN ACT OF 1936

The Robinson-Patman Act was approved by the President on June 19, 1936. The purpose of the act was to amend section 2 of the Clayton Act, which prohibited price discriminations in interstate commerce. Congress, by amending section 2 of the Clayton Act, broadened the scope of the section by extending its purposes and prohibitions to price discriminations not formerly covered and by prohibiting other forms of discrimination which give favored purchasers undue cost advantages over their non-favored competitors. It also reduced the extent of requisite competitive injury

Flavones induce neutrophil apoptosis by down-regulation of Mcl-1 via a proteasomal-dependent pathway

Neutrophil apoptosis and subsequent nonphlogistic clearance by surrounding phagocytes are key to the successful resolution of neutrophilic inflammation, with dysregulated apoptosis reported in multiple human inflammatory diseases. Enhancing neutrophil apoptosis has proresolution and anti-inflammatory effects in preclinical models of inflammation. Here we investigate the ability of the flavones apigenin, luteolin, and wogonin to induce neutrophil apoptosis in vitro and resolve neutrophilic inflammation in vivo. Human neutrophil apoptosis was assessed morphologically and by flow cytometry following incubation with apigenin, luteolin, and wogonin. All three flavones induced time- and concentration-dependent neutrophil apoptosis (apigenin, EC(50)=12.2 μM; luteolin, EC(50)=14.6 μM; and wogonin, EC(50)=28.9 μM). Induction of apoptosis was caspase dependent, as it was blocked by the broad-spectrum caspase inhibitor Q-VD-OPh and was associated with both caspase-3 and caspase-9 activation. Flavone-induced apoptosis was preceded by down-regulation of the prosurvival protein Mcl-1, with proteasomal inhibition preventing flavone-induced Mcl-1 down-regulation and apoptosis. The flavones abrogated the survival effects of mediators that prolong neutrophil life span, including lipoteichoic acid, peptidoglycan, dexamethasone, and granulocyte-macrophage colony stimulating factor, by driving apoptosis. Furthermore, wogonin enhanced resolution of established neutrophilic inflammation in a zebrafish model of sterile tissue injury. Wogonin-induced resolution was dependent on apoptosis in vivo as it was blocked by caspase inhibition. Our data show that the flavones induce neutrophil apoptosis and have potential as neutrophil apoptosis-inducing anti-inflammatory, proresolution agents.—Lucas, C. D., Allen, K. C., Dorward, D. A., Hoodless, L. J., Melrose, L. A., Marwick, J. A., Tucker, C. S., Haslett, C., Duffin, R., Rossi, A. G. Flavones induce neutrophil apoptosis by down-regulation of Mcl-1 via a proteasomal-dependent pathway

Downregulation of Mcl-1 has anti-inflammatory pro-resolution effects and enhances bacterial clearance from the lung

Phagocytes not only coordinate acute inflammation and host defense at mucosal sites, but also contribute to tissue damage. Respiratory infection causes a globally significant disease burden and frequently progresses to acute respiratory distress syndrome, a devastating inflammatory condition characterized by neutrophil recruitment and accumulation of protein-rich edema fluid causing impaired lung function. We hypothesized that targeting the intracellular protein myeloid cell leukemia 1 (Mcl-1) by a cyclin-dependent kinase inhibitor (AT7519) or a flavone (wogonin) would accelerate neutrophil apoptosis and resolution of established inflammation, but without detriment to bacterial clearance. Mcl-1 loss induced human neutrophil apoptosis, but did not induce macrophage apoptosis nor impair phagocytosis of apoptotic neutrophils. Neutrophil-dominant inflammation was modelled in mice by either endotoxin or bacteria (Escherichia coli). Downregulating inflammatory cell Mcl-1 had anti-inflammatory, pro-resolution effects, shortening the resolution interval (R(i)) from 19 to 7 h and improved organ dysfunction with enhanced alveolar–capillary barrier integrity. Conversely, attenuating drug-induced Mcl-1 downregulation inhibited neutrophil apoptosis and delayed resolution of endotoxin-mediated lung inflammation. Importantly, manipulating lung inflammatory cell Mcl-1 also accelerated resolution of bacterial infection (R(i); 50 to 16 h) concurrent with enhanced bacterial clearance. Therefore, manipulating inflammatory cell Mcl-1 accelerates inflammation resolution without detriment to host defense against bacteria, and represents a target for treating infection-associated inflammation

Characterization of the effects of cross-linking of macrophage CD44 associated with increased phagocytosis of apoptotic PMN

Control of macrophage capacity for apoptotic cell clearance by soluble mediators such as cytokines, prostaglandins and lipoxins, serum proteins, and glucocorticoids may critically determine the rate at which inflammation resolves. Previous studies suggested that macrophage capacity for clearance of apoptotic neutrophils was profoundly altered following binding of CD44 antibodies. We have used a number of different approaches to further define the mechanism by which CD44 rapidly and specifically augment phagocytosis of apoptotic neutrophils. Use of Fab ’ fragments unequivocally demonstrated a requirement for cross-linking of macrophage surface CD44. The molecular mechanism of CD44-augmented phagocytosis was shown to be opsonin-independent and to be distinct from the Mer/protein S pathway induced by glucocorticoids and was not functional for clearance of apoptotic eosinophils. CD44-cross-linking also altered macrophage migration and induced cytoskeletal re-organisation together with phosphorylation of paxillin and activation of Rac2. Investigation of signal transduction pathways that might be critical for CD44 augmentation of phagocytosis revealed that Ca 2+ signalling, PI-3 kinase pathways and altered cAMP signalling were not involved, but did implicate a key role for tyrosine phosphorylation events. Finally, although CD44 antibodies were able to augment phagocytosis of apoptotic neutrophils by murine peritoneal and bone marrow-derived macrophages, we did not observe a difference in the clearance of neutrophils following induction of peritonitis with thioglycollate in CD44-deficient animals. Together, these data demonstrate that CD4

Bioavailability in soils

The consumption of locally-produced vegetables by humans may be an important exposure pathway for soil contaminants in many urban settings and for agricultural land use. Hence, prediction of metal and metalloid uptake by vegetables from contaminated soils is an important part of the Human Health Risk Assessment procedure. The behaviour of metals (cadmium, chromium, cobalt, copper, mercury, molybdenum, nickel, lead and zinc) and metalloids (arsenic, boron and selenium) in contaminated soils depends to a large extent on the intrinsic charge, valence and speciation of the contaminant ion, and soil properties such as pH, redox status and contents of clay and/or organic matter. However, chemistry and behaviour of the contaminant in soil alone cannot predict soil-to-plant transfer. Root uptake, root selectivity, ion interactions, rhizosphere processes, leaf uptake from the atmosphere, and plant partitioning are important processes that ultimately govern the accumulation ofmetals and metalloids in edible vegetable tissues. Mechanistic models to accurately describe all these processes have not yet been developed, let alone validated under field conditions. Hence, to estimate risks by vegetable consumption, empirical models have been used to correlate concentrations of metals and metalloids in contaminated soils, soil physico-chemical characteristics, and concentrations of elements in vegetable tissues. These models should only be used within the bounds of their calibration, and often need to be re-calibrated or validated using local soil and environmental conditions on a regional or site-specific basis.Mike J. McLaughlin, Erik Smolders, Fien Degryse, and Rene Rietr

A randomised control trial of atorvastatin in bronchiectasis patients infected with <i>Pseudomonas aeruginosa</i>- a proof of concept study

Introduction: There are no randomised control trials of statin therapy in patients with severe bronchiectasis, chronically infected with Pseudomonas aeruginosa.Methods: 32 patients chronically infected with P. aeruginosa were recruited in this double blind cross over RCT. 16 patients were recruited in each arm, given atorvastatin 80mg or placebo for 3months, followed by a washout period for 6weeks, crossed over and administered the alternative therapy for 3months.Results: 27 patients completed the study. Atorvastatin did not significantly improve the primary endpoint of cough as measured by Leicester Cough Questionnaire [mean difference=1.92, 95% CI for difference (-0.57, 4.41), p=0.12]. However, atorvastatin treatment resulted in improved St Georges Respiratory Questionnaire (-5.62points, p=0.016), reduced serum CXCL8 (p=0.04), TNF (p=0.01) and ICAM1 (p=0.04). There was a trend towards improvement in serum CRP and serum neutrophil counts (p=0.07 and p=0.06 respectively). In vitro, we demonstrated that atorvastatin 10μM reduced fMLF induced upregulation of CD11b expression and changes in calcium flux reflecting an ability to decrease neutrophil activation.Conclusion: We demonstrated that atorvastatin reduced systemic inflammation and improved quality of life in bronchiectasis patients infected with P. aeruginosa. These effects may be due to an ability of atorvastatin to modulate neutrophil activation.</p

The Aminopeptidase CD13 Induces Homotypic Aggregation in Neutrophils and Impairs Collagen Invasion.

Aminopeptidase N (CD13) is a widely expressed cell surface metallopeptidase involved in the migration of cancer and endothelial cells. Apart from our demonstration that CD13 modulates the efficacy of tumor necrosis factor-α-induced apoptosis in neutrophils, no other function for CD13 has been ascribed in this cell. We hypothesized that CD13 may be involved in neutrophil migration and/or homotypic aggregation. Using purified human blood neutrophils we confirmed the expression of CD13 on neutrophils and its up-regulation by pro-inflammatory agonists. However, using the anti-CD13 monoclonal antibody WM-15 and the aminopeptidase enzymatic inhibitor bestatin we were unable to demonstrate any direct involvement of CD13 in neutrophil polarisation or chemotaxis. In contrast, IL-8-mediated neutrophil migration in type I collagen gels was significantly impaired by the anti-CD13 monoclonal antibodies WM-15 and MY7. Notably, these antibodies also induced significant homotypic aggregation of neutrophils, which was dependent on CD13 cross-linking and was attenuated by phosphoinositide 3-kinase and extracellular signal-related kinase 1/2 inhibition. Live imaging demonstrated that in WM-15-treated neutrophils, where homotypic aggregation was evident, the number of cells entering IL-8 impregnated collagen I gels was significantly reduced. These data reveal a novel role for CD13 in inducing homotypic aggregation in neutrophils, which results in a transmigration deficiency; this mechanism may be relevant to neutrophil micro-aggregation in vivo.This work was funded by a Medical Research Council Research Training Fellowship to CAF (G0900329), Addenbrooke’s Charitable Trust (ACT), CUHNHSFT, Papworth Hospital NHS Foundation Trust and the NIHR Cambridge Biomedical Research Centre. CAF received a Raymond and Beverly Sackler Studentship.This is the final version of the article. It first appeared from the Public Library of Science via http://dx.doi.org/10.1371/journal.pone.016010

Demystifying Beer... Do You Want Fries With That?

This paper concerns the strongly theory based organisational intervention - Stafford Beers' Viable Systems Diagnosis (VSD). The assumption that organisations have difficulty in transforming good theories into effective workplace practices is examined using VSD. We propose levels of knowledge or recursions of the Beer system that are appropriate and effective in terms of organisational interventions. We contend that the lexis emanating from Brain of the Firm, and The Heart of the Enterprise exacerbates the complexity of VSD causing readers to focus on Diagnosing the System. We suggest this outcome contributes to the non-popularity of VSD, but that Beer himself cannot be exonerated. The lack of fundamental VSD principles, identified as a deficiency in Diagnosing the System is expanded from the antecedents, Brain and Heart. The paper concludes by considering a systematic categorisation of Beer's work that will guide organizational change agents wishing to use this intellectually complex and powerful system