Abortions are the most important reason for unintentional childlessness. During pregnancy, maternal immune cells are in close contact to cells of the semi-allogeneic foetus. Dysregulation of the maternal immune system leading to defective adaptation to pregnancy often plays a role in pathogenesis of abortions. Myeloid-derived suppressor cells (MDSC) are myeloid cells that suppress functions of other immune cells, especially T-cells, thereby negatively affecting diseases such as cancer, sepsis or trauma. They seem, however, also necessary for maintenance of maternal-foetal tolerance. Mechanisms regulating MDSC expansion and function during pregnancy are only incompletely understood. In tumour environment, hypoxia is crucial for MDSC accumulation and activation. Hypoxia is also important for early placenta and embryo development. Effects of hypoxia are mediated through hypoxia-inducible factor 1a (HIF-1a). In the present study we aimed to examine the role of HIF-1a in myeloid cells for MDSC accumulation and MDSC function during pregnancy and for pregnancy outcome. We therefore used a mouse model with targeted deletion of HIF-1a in myeloid cells (myeloid HIF-KO) and analysed blood, spleens and uteri of pregnant mice at gestational day E 10.5 in comparison to non-pregnant animals and wildtype (WT) animals. Further we analysed pregnancy success by determining rates of failed implantation and abortion in WT and myeloid HIF-KO animals. We found that myeloid HIF-KO in mice led to an abrogated MDSC accumulation in the pregnant uterus and to impaired suppressive activity of MDSC. While expression of chemokine receptors and integrins on MDSC was not affected by HIF-1a, myeloid HIF-KO led to increased apoptosis rates of MDSC in the uterus. Myeloid-HIF-KO resulted in increased proportions of non-pregnant animals after positive vaginal plug and increased abortion rates, suggesting that activation of HIF-1a dependent pathways in MDSC are important for maintenance of pregnancy.
Establishing and maintaining maternal-fetal tolerance is essential for a successful pregnancy; failure of immunological adaptation to pregnancy leads to severe complications such as abortion or preterm delivery. Myeloid-derived suppressor cells (MDSCs) are innate immune cells that suppress T-cell responses, expand during pregnancy and thus may play a role in tolerance induction. Human leucocyte antigen G (HLA-G) is a major histocompatibility complex (MHC) I molecule with immune-modulatory properties, which is expressed during pregnancy. Here, we investigated the impact of HLA-G on MDSCs accumulation and activation in pregnant women. We demonstrate that granulocytic MDSCs (GR-MDSCs) express receptors for HLA-G, namely immunoglobulin-like transcript (ILT) 2 and 4, and that ILT4-expression by GR-MDSCs is regulated during pregnancy. Stimulation with soluble HLA-G (sHLA-G) increased suppressive activity of GR-MDSCs, induced MDSCs from peripheral blood mononuclear cells (PBMCs) and led to phosphorylation of the signal transducer and activator of transcription 3 (STAT3) and induction of indoleamine-2,3-dioxygenase (IDO) in myeloid cells. Effects of sHLA-G on MDSC accumulation were mediated through ILT4. These results suggest an interaction between MDSCs and HLA-G in humans as a potential mechanism for maintaining maternal-fetal tolerance. Modulating MDSC function during pregnancy via HLA-G might provide new opportunities for a therapeutic manipulation of immunological pregnancy complications.
Hintergrund: Etwa 80 % aller kindlichen distalen Humerusfrakturen sind suprakondyläre Frakturen. Patienten und Methoden: Operativ behandelte Kinder mit suprakondylären Humerusfrakturen aus den Jahren 2000–2008 wurden retrospektiv analysiert und auf Funktion, Zufriedenheit, Schmerzausmaß und mit dem MAYO Elbow Performance Score (MEPS) nachuntersucht. Ergebnisse: 46 Patienten wurden eingeschlossen. Offene Frakturen (2 %) oder Gefäß- (0 %) und Nervenschäden (4 %) waren selten, begleitende Unterarmfrakturen (15 %) häufig. Die Versorgung erfolgte mit geschlossener/offener Reposition und gekreuzter Kirschner-Draht-Spickung. Hauptkomplikationen waren Bewegungseinschränkung und Kirschner-Draht-Migration. Alle Frakturen heilten. 72 % der Patienten wurden Ø 51 Monate postoperativ nachuntersucht: Die durchschnittliche Differenz zwischen nicht betroffenem und betroffenem Arm betrug in Flexion 8°, in Extension 1°, in Pronation 1° und in Supination 0°. Im MEPS erreichten 88 % der Patienten exzellente oder gute Ergebnisse. Schlussfolgerung: Aufgrund der Frakturheilung in allen Fällen, gut zu beherrschenden Komplikationen, guten bis exzellenten Werten im MEPS und guter Funktion ist die gekreuzte Kirschner-Draht-Spickung nach geschlossener/offener Reposition ein sicheres Standardverfahren für die Versorgung dieser Frakturen.
We consider generalized Nash equilibrium problems (GNEPs) with non-convex strategy spaces and non-convex cost functions. This general class of games includes the important case of games with mixed-integer variables for which only a few results are known in the literature. We present a new approach to characterize equilibria via a convexification technique using the Nikaido-Isoda function. To any given instance of the GNEP, we construct a set of convexified instances and show that a feasible strategy profile is an equilibrium for the original instance if and only if it is an equilibrium for any convexified instance and the convexified cost functions coincide with the initial ones. We further develop this approach along three dimensions. We first show that for quasi-linear models, where a convexified instance exists in which for fixed strategies of the opponent players, the cost function of every player is linear and the respective strategy space is polyhedral, the convexification reduces the GNEP to a standard (non-linear) optimization problem. Secondly, we derive two complete characterizations of those GNEPs for which the convexification leads to a jointly constrained or a jointly convex GNEP, respectively. These characterizations require new concepts related to the interplay of the convex hull operator applied to restricted subsets of feasible strategies and may be interesting on their own. Finally, we demonstrate the applicability of our results by presenting a numerical study regarding the computation of equilibria for a class of integral network flow GNEPs.
Newborns and especially preterm infants are much more susceptible to infections than adults. The pathogens causing infections in newborns are often detectable in the intestinal flora of affected children even before disease onset. Therefore, it seems reasonable to prevent dysbiosis in newborns and preterm infants. An approach followed in many neonatal intensive care units (NICUs) is to prevent infections in preterm infants with probiotics however their mechanisms of action of probiotics are incompletely understood. Here, we investigated the effect of perinatal probiotic exposure on immune cells in newborn mice.
Newborns and especially preterm infants are much more susceptible to infections than adults. Due to immature adaptive immunity, especially innate immune cells play an important role in a newborn's infection defense. Neonatal neutrophils exhibit profound differences in their functionality compared to neutrophils of adults. In particular, neonates possess a relevant population of suppressive neutrophils, which not only inhibit but also specifically modulate the function of T-cells. In this study, we investigated whether neonatal neutrophils are already involved in T-cell development in the thymus. For this purpose, we used a newly developed model of antibody-mediated immune cell depletion in which we administered a depleting antibody to pregnant and then lactating dams. Using this method, we were able to sufficiently deplete Ly6G-positive neutrophils in offspring. We demonstrated that the depletion of neutrophils in newborn mice resulted in altered peripheral T-cell homeostasis with a decreased CD4+/CD8+ T-cell ratio and decreased expression of CD62L. Neutrophil depletion even affected T-cell development in the thymus, with increased double positive thymocytes and a decreased CD4+/CD8+ single positive thymocyte ratio. Altogether, we demonstrated a previously unknown mechanism mediating neutrophils' immunomodulatory effects in newborns.
The famous edge flow decomposition theorem of Gallai (1958) states that any static edge $s$,$d$-flow in a directed graph can be decomposed into a linear combination of incidence vectors of paths and cycles. In this paper, we study the decomposition problem for the setting of dynamic edge $s$,$d$-flows assuming a quite general dynamic flow propagation model. We prove the following decomposition theorem: For any dynamic edge $s$,$d$-flow with finite support, there exists a decomposition into a linear combination of $s$,$d$-walk inflows and circulations, i.e. edge flows that circulate along cycles with zero transit time. We show that a variant of the classical algorithmic approach of iteratively subtracting walk inflows from the current dynamic edge flow converges to a dynamic circulation. The algorithm terminates in finite time, if there is a lower bound on the minimum edge travel times. We further characterize those dynamic edge flows which can be decomposed purely into linear combinations of $s$,$d$-walk inflows. The proofs rely on the new concept of parameterized network loadings which describe how particles of a different walk flow would hypothetically propagate throughout the network under the fixed travel times induced by the given edge flow. We show several technical properties of this type of network loading and as a byproduct we also derive some general results on dynamic flows which could be of interest outside the context of this paper as well.
