Sphingosine-1-phosphate receptor 3 promotes leukocyte rolling by mobilizing endothelial P-selectin

Sphingosine-1-phosphate (S1P) participates in inflammation;however, its role in leukocyte rolling is still unclear. Here we use intravital microscopy in inflamed mouse cremaster muscle venules and human endothelial cells to show that S1P contributes to P-selectin-dependent leukocyte rolling through endothelial S1P receptor 3 (S1P(3)) and G alpha(q), PLC beta and Ca2+. Intraarterial S1P administration increases leukocyte rolling, while S1P(3) deficiency or inhibition dramatically reduces it. Mast cells involved in triggering rolling also release S1P that mobilizes P-selectin through S1P(3). Histamine and epinephrine require S1P(3) for full-scale effect accomplishing it by stimulating sphingosine kinase 1 (Sphk1). In a counter-regulatory manner, S1P1 inhibits cAMP-stimulated Sphk1 and blocks rolling as observed in endothelial-specific S1P(1)(-/-) mice. In agreement with a dominant pro-rolling effect of S1P(3),FTY720 inhibits rolling in control and S1P(1)(-/-) but not in S1P(3)(-/-) mice. Our findings identify S1P as a direct and indirect contributor to leukocyte rolling and characterize the receptors mediating its action

Extracellular MRP8/14 is a regulator of β2 integrin-dependent neutrophil slow rolling and adhesion

Myeloid-related proteins (MRPs) 8 and 14 are cytosolic proteins secreted from myeloid cells as proinflammatory mediators. Currently, the functional role of circulating extracellular MRP8/14 is unclear. Our present study identifies extracellular MRP8/14 as an autocrine player in the leukocyte adhesion cascade. We show that E-selectin-PSGL-1 interaction during neutrophil rolling triggers Mrp8/14 secretion. Released MRP8/14 in turn activates a TLR4-mediated, Rap1-GTPase-dependent pathway of rapid beta 2 integrin activation in neutrophils. This extracellular activation loop reduces leukocyte rolling velocity and stimulates adhesion. Thus, we identify Mrp8/14 and TLR4 as important modulators of the leukocyte recruitment cascade during inflammation in vivo

Extracellular MRP8/14 is a regulator of β2 integrin-dependent neutrophil slow rolling and adhesion

Myeloid-related proteins (MRPs) 8 and 14 are cytosolic proteins secreted from myeloid cells as proinflammatory mediators. Currently, the functional role of circulating extracellular MRP8/14 is unclear. Our present study identifies extracellular MRP8/14 as an autocrine player in the leukocyte adhesion cascade. We show that E-selectin-PSGL-1 interaction during neutrophil rolling triggers Mrp8/14 secretion. Released MRP8/14 in turn activates a TLR4-mediated, Rap1-GTPase-dependent pathway of rapid beta 2 integrin activation in neutrophils. This extracellular activation loop reduces leukocyte rolling velocity and stimulates adhesion. Thus, we identify Mrp8/14 and TLR4 as important modulators of the leukocyte recruitment cascade during inflammation in vivo

The Tumorigenicity of Mouse Embryonic Stem Cells and In Vitro Differentiated Neuronal Cells Is Controlled by the Recipients' Immune Response

Embryonic stem (ES) cells have the potential to differentiate into all cell types and are considered as a valuable source of cells for transplantation therapies. A critical issue, however, is the risk of teratoma formation after transplantation. The effect of the immune response on the tumorigenicity of transplanted cells is poorly understood. We have systematically compared the tumorigenicity of mouse ES cells and in vitro differentiated neuronal cells in various recipients. Subcutaneous injection of 1×106 ES or differentiated cells into syngeneic or allogeneic immunodeficient mice resulted in teratomas in about 95% of the recipients. Both cell types did not give rise to tumors in immunocompetent allogeneic mice or xenogeneic rats. However, in 61% of cyclosporine A-treated rats teratomas developed after injection of differentiated cells. Undifferentiated ES cells did not give rise to tumors in these rats. ES cells turned out to be highly susceptible to killing by rat natural killer (NK) cells due to the expression of ligands of the activating NK receptor NKG2D on ES cells. These ligands were down-regulated on differentiated cells. The activity of NK cells which is not suppressed by cyclosporine A might contribute to the prevention of teratomas after injection of ES cells but not after inoculation of differentiated cells. These findings clearly point to the importance of the immune response in this process. Interestingly, the differentiated cells must contain a tumorigenic cell population that is not present among ES cells and which might be resistant to NK cell-mediated killing

CMS physics technical design report : Addendum on high density QCD with heavy ions

Peer reviewe

Noninvasive Ventilation in Preterm Infants: Factors Influencing Weaning Decisions and the Role of the Silverman-Andersen Score

The factors influencing weaning of preterm infants from noninvasive ventilation (NIV) are poorly defined and the weaning decisions are often driven by subjective judgement rather than objective measures. To standardize quantification of respiratory effort, the Silverman-Andersen Score (SAS) was included in our nursing routine. We investigated the factors that steer the weaning process and whether the inclusion of the SAS would lead to more stringent weaning. Following SAS implementation, we prospectively evaluated 33 neonates born ≤ 32 + 0 weeks gestational age. Age-, weight- and sex-matched infants born before routine SAS evaluation served as historic control. In 173 of 575 patient days, NIV was not weaned despite little respiratory distress (SAS ≤ 2), mainly due to bradycardias (60% of days without weaning), occurring alone (40%) or in combination with other factors such as apnea/desaturations. In addition, “soft factors” that are harder to grasp impact on weaning decisions, whereas the SAS overall played a minor role. Consequently, ventilation times did not differ between the groups. In conclusion, NIV weaning is influenced by various factors that override the absence of respiratory distress limiting the predictive value of the SAS. An awareness of the factors that influence weaning decisions is important as prolonged use of NIV has been associated with adverse outcome. Guidelines are necessary to standardize NIV weaning practice