Tuning immune tolerance with vasoactive intestinal peptide: a new therapeutic approach for immune disorders

The induction of immune tolerance is essential for the maintenance of immune homeostasis and to limit the occurrence of exacerbated inflammatory and autoimmune conditions. Multiple mechanisms act together to ensure self-tolerance, including central clonal deletion, cytokine deviation and induction of regulatory T cells. Identifying the factors that regulate these processes is crucial for the development of new therapies of autoimmune diseases and transplantation. The vasoactive intestinal peptide (VIP) is a well-characterized endogenous anti-inflammatory neuropeptide with therapeutic potential for a variety of immune disorders. Here, we examine the latest research findings, which indicate that VIP participates in maintaining immune tolerance in two distinct ways: by regulating the balance between pro-inflammatory and anti-inflammatory factors, and by inducing the emergence of regulatory T cells with suppressive activity against autoreactive T-cell effectors.     

Eco-efficiency

Goal, Scope and Background The eco-efficiency analysis and portfolio is a powerful decision support tool for various strategic and marketing issues. Since its original academic development, the approach has been refined during the last decade and applied to a multitude of projects. BASF, as possibly the most prominent company using and developing this tool, has applied the eco-efficiency approach to more than 300 projects in the last 7 years. One of the greatest difficulties is to cover both dimensions of eco-efficiency (costs or value added and environmental impact) in a comparable manner. This is particularly a challenge for the eco-efficiency analyses of products. Methods In this publication, an important approach and field of application dealing with product decisions based on the combination of Life Cycle Cost (LCC) and Life Cycle Assessment (LCA) is described in detail. Special emphasis is put on the quantitative assessment of the relation of costs and environmental impacts. In conventional LCA an assessment of environmental impact categories is often made by normalization with inhabitant equivalents. This is necessary to be able to compare the different environmental impact categories, because of each different unit. For the proposed eco-efficiency analysis, the costs of products or processes are also normalized with adapted gross domestic product figures. Results and Discussion The ratio between normalized environmental impact categories and normalized costs (R_E,C) is used for the graphical presentation of the results in an eco-efficiency portfolio. For the interpretation of the results of an eco-efficiency analysis, it is important to distinguish ratios R_E,C which are higher than one from ratios lower than one. In the first case, the environmental impact is higher than the cost impact, while the inverse is true in the second case. This is very important for defining which kind of improvement is needed and defining strategic management decisions. The paper shows a statistical evaluation of the R_E,C factor based on the results of different eco-efficiency analyses made by BASF. For industries based on large material flows (e.g. chemicals, steel, metals, agriculture), the R_E,C factor is typically higher than one. Conclusions and Recommendations This contribution shows that LCC and LCA may be combined in a way that they mirror the concept of eco-efficiency. LCAs that do not consider LCC may be of very limited use for company management. For that very reason, corporations should install a data management system that ensures equal information on both sides of the eco-efficiency coin.     

Fracture prevention in COPD patients; a clinical 5-step approach

Although osteoporosis and its related fractures are common in patients with COPD, patients at high risk of fracture are poorly identified, and consequently, undertreated. Since there are no fracture prevention guidelines available that focus on COPD patients, we developed a clinical approach to improve the identification and treatment of COPD patients at high risk of fracture. We organised a round-table discussion with 8 clinical experts in the field of COPD and fracture prevention in the Netherlands in December 2013. The clinical experts presented a review of the literature on COPD, osteoporosis and fracture prevention. Based on the Dutch fracture prevention guideline, they developed a 5-step clinical approach for fracture prevention in COPD. Thereby, they took into account both classical risk factors for fracture (low body mass index, older age, personal and family history of fracture, immobility, smoking, alcohol intake, use of glucocorticoids and increased fall risk) and COPD-specific risk factors for fracture (severe airflow obstruction, pulmonary exacerbations and oxygen therapy). Severe COPD (defined as postbronchodilator FEV₁ < 50% predicted) was added as COPD-specific risk factor to the list of classical risk factors for fracture. The 5-step clinical approach starts with case finding using clinical risk factors, followed by risk evaluation (dual energy X-ray absorptiometry and imaging of the spine), differential diagnosis, treatment and follow-up. This systematic clinical approach, which is evidence-based and easy-to-use in daily practice by pulmonologists, should contribute to optimise fracture prevention in COPD patients at high risk of fracture.     

Evidence for cadherin-11 cleavage in the synovium and partial characterization of its mechanism

IntroductionEngagement of the homotypic cell-to-cell adhesion molecule cadherin-11 on rheumatoid arthritis (RA) synovial fibroblasts with a chimeric molecule containing the cadherin-11 extracellular binding domain stimulated cytokine, chemokine, and matrix metalloproteinases (MMP) release, implicating cadherin-11 signaling in RA pathogenesis. The objective of this study was to determine if cadherin-11 extracellular domain fragments are found inside the joint and if a physiologic synovial fibroblast cleavage pathway releases those fragments.MethodsCadherin-11 cleavage fragments were detected by western blot in cell media or lysates. Cleavage was interrupted using chemical inhibitors or short-interfering RNA (siRNA) gene silencing. The amount of cadherin-11 fragments in synovial fluid was measured by western blot and ELISA.ResultsSoluble cadherin-11 extracellular fragments were detected in human synovial fluid at significantly higher levels in RA samples compared to osteoarthritis (OA) samples. A cadherin-11 N-terminal extracellular binding domain fragment was shed from synovial fibroblasts after ionomycin stimulation, followed by presenilin 1 (PSN1)-dependent regulated intramembrane proteolysis of the retained membrane-bound C-terminal fragments. In addition to ionomycin-induced calcium flux, tumor necrosis factor (TNF)-α also stimulated cleavage in both two- and three-dimensional fibroblast cultures. Although cadherin-11 extracellular domains were shed by a disintegrin and metalloproteinase (ADAM) 10 in several cell types, a novel ADAM- and metalloproteinase-independent activity mediated shedding in primary human fibroblasts.ConclusionsCadherin-11 undergoes ectodomain shedding followed by regulated intramembrane proteolysis in synovial fibroblasts, triggered by a novel sheddase that generates extracelluar cadherin-11 fragments. Cadherin-11 fragments were enriched in RA synovial fluid, suggesting they may be a marker of synovial burden and may function to modify cadherin-11 interactions between synovial fibroblasts.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0647-9) contains supplementary material, which is available to authorized users.     

Denitrifying activity of Xanthobacter autotrophicus strains isolated from a submerged fixed-film reactor

Xanthobacter autotrophicus strains with the ability to reduce nitrate and nitrite to either nitrous oxide or molecular nitrogen were isolated from submerged fixed-film reactors. Isolated strains were Gram-negative rods able to grow on methanol, ethanol and sucrose. The yellow cellular pigmentation, pleomorphic appearance, and the presence of poly-β-hydroxybutyrate granules suggest that the organisms might belong to the genus Xanthobacter. Comparison of 16S rDNA gene sequences demonstrated the affiliation of the strains to X. autotrophicus species. The results show that X. autotrophicus may play a role in inorganic nitrogen removal from a denitrifying submerged filter used for the treatment of contaminated groundwater. To our knowledge, no data on denitrifying activity in X. autotrophicus strains have been reported previously.     

Characterization of intracellular Ca(2+) stores in gallbladder smooth muscle

The existence of functionally distinct intracellular Ca(2+) stores has been proposed in some types of smooth muscle. In this study, we sought to examine Ca(2+) stores in the gallbladder by measuring intracellular Ca(2+) concentration ([Ca(2+)](i)) in fura 2-loaded isolated myocytes, membrane potential in intact smooth muscle, and isometric contractions in whole mount preparations. Exposure of isolated myocytes to 10 nM CCK caused a transient elevation in [Ca(2+)](i) that persisted in Ca(2+)-free medium and was inhibited by 2-aminoethoxydiphenylborane (2-APB). Application of caffeine induced a rapid spike-like elevation in [Ca(2+)](i) that was insensitive to 2-APB but was abolished by pretreatment with 10 muM ryanodine. These data support the idea that both inositol trisphosphate (IP(3)) receptors (IP(3)R) and ryanodine receptors (RyR) are present in this tissue. When caffeine was applied in Ca(2+)-free solution, the [Ca(2+)](i) transients decreased as the interval between Ca(2+) removal and caffeine application was increased, indicating a possible leakage of Ca(2+) in these stores. The refilling of caffeine-sensitive stores involved sarcoendoplasmic reticulum Ca(2+)-ATPase activation, similar to IP(3)-sensitive stores. The moderate Ca(2+) elevation caused by CCK was associated with a gallbladder contraction, but caffeine or ryanodine failed to induce gallbladder contraction. Nevertheless, caffeine caused a concentration-dependent relaxation in gallbladder strips either under resting tone conditions or precontracted with 1 muM CCK. Taken together, these results suggest that, in gallbladder smooth muscle, multiple pharmacologically distinct Ca(2+) pools do not exist, but IP(3)R and RyR must be spatially separated because Ca(2+) release via these pathways leads to opposite responses.