Coexistence of autoantibodies and alloantibodies to red blood cells due to blood transfusions

Bisher wurde angenommen, dass Patienten mit einer AIHA vermehrt Alloantikörper bilden. Es war nicht allgemein bekannt, dass Bluttransfusionen zu einer Autoimmunisierung führen können. Aufgetretene Autoantikörper wurden oft als „Begleitantikörper“ angesehen und das klinische Bild häufig mit der AIHA vom Wärmetyp verwechselt. Um Transfusionszwischenfälle zu verhindern, wurden mit diesem Hintergrund Transfusionen bei Patienten mit einer AIHA vermieden. Dies bedeutete eine inadäquate Versorgung der Patienten und konnte bis zum Tod der Patienten führen. In der vorliegenden Arbeit konnte gezeigt werden, dass Bluttransfusionen nicht nur zu einer Alloimmunisierung, sondern auch zu einer Autoimmunisierung führen können. Die Ergebnisse dieser Arbeit wurden inzwischen durch weitere neue Studien von anderen Gruppen bestätigt. Autoantikörper bei Patienten mit Alloantikörpern sind zumeist auf einen Alloimmunisierungsprozeß zurückzuführen und sollten typischerweise nicht als Alloimmunisierung von autoimmunisierten Patienten mißinterpretiert werden. Bei den analysierten 717 Patienten mit Autoantikörpern und positiver Transfusionsanamnese war bei 63 Patienten eine Autoimmunhämolytische Anämie aufgetreten. Bei diesen 63 Patienten wurden bei 6 Patienten nach einer Bluttransfusion Alloantikörper gefunden, von denen nur bei 3 Patienten klinisch relevante Alloantikörper wie Anti-S und Anti-E nachgewiesen wurden. In dieser Studie konnte gezeigt werden, dass Patienten mit einer AIHA ein geringes Risiko haben, Alloantikörper zu entwickeln. Bei Patienten mit Autoimmunhämolytischen Anämien vom Wärmetyp sind Besonderheiten zu beachten. Die oft auffällige positive Kreuzprobe infolge freier antierythrozytärer Autoantikörper im Serum der Patienten darf nicht eine lebensnotwendige Transfusion verzögern oder verhindern. Bei lebensbedrohlichen hämolytischen Krisen ist die Gabe von Erythrozytenkonzentraten unter entsprechender Immunsuppression die schnellst wirksame Therapie. Begleitende Alloantikörper, deren Diagnostik häufig zeitaufwendig ist, kommen eher selten vor. Die mögliche Gefahr einer immunologischen Reaktion, ausgelöst durch Alloantikörper ist jedoch nicht zu unterschätzen.Blood transfusion may induce autoimmune hemolytic anemia (AIHA) that may in some instances be severe.1-6 In addition, 32 percent (weighted mean) of patients with autoantibodies (AUTO) to red blood cells (RBCs) are associated with alloantibodies (ALLO).6-16 These findings have led to the assumption that patients with AIHA are easily alloimmunized after RBC transfusion. This belief, however, is largely based on serologic findings without any information pertaining to the clinical background of the patient. To date, there has been no study that has investigated the incidence of alloimmunization in patients with significant AIHA. Nevertheless, the fear that ALLO might be masked by AUTO or might be developed in patients with AIHA remains an area of confusion and causes delays in cases where blood transfusion is required. From a serologic perspective, roughly 30 to 40 percent of these patients not only have a positive direct antiglobulin test (DAT), but also both a positive indirect antiglobulin test (IAT) and a crossmatch due to serum AUTO. Thus, the recommendation to exclude ALLO before blood transfusion in patients with a positive cross-match due to AUTO17 cannot be invariably realized, particularly in patients with severe AIHA and high- titer serum AUTO due to a shortage of time and materials. This study will demonstrate that the majority of cases of AUTO associated with ALLO were simultaneously developed after blood transfusion. This study demonstrates that blood transfusion appears to play a role in the majority of cases of AUTO associated with ALLO. In contrast, alloimmunization in patients with AIHA seems to be less frequent as the coincidence of AUTO and ALLO might suggest

Host-pathogen systems biology: logical modelling of hepatocyte growth factor and Helicobacter pylori induced c-Met signal transduction

<p>Abstract</p> <p>Background</p> <p>The hepatocyte growth factor (HGF) stimulates mitogenesis, motogenesis, and morphogenesis in a wide range of tissues, including epithelial cells, on binding to the receptor tyrosine kinase c-Met. Abnormal c-Met signalling contributes to tumour genesis, in particular to the development of invasive and metastatic phenotypes. The human microbial pathogen <it>Helicobacter pylori </it>can induce chronic gastritis, peptic ulceration and more rarely, gastric adenocarcinoma. The <it>H. pylori </it>effector protein cytotoxin associated gene A (CagA), which is translocated via a type IV secretion system (T4SS) into epithelial cells, intracellularly modulates the c-Met receptor and promotes cellular processes leading to cell scattering, which could contribute to the invasiveness of tumour cells. Using a logical modelling framework, the presented work aims at analysing the c-Met signal transduction network and how it is interfered by <it>H. pylori </it>infection, which might be of importance for tumour development.</p> <p>Results</p> <p>A logical model of HGF and <it>H. pylori </it>induced c-Met signal transduction is presented in this work. The formalism of logical interaction hypergraphs (LIH) was used to construct the network model. The molecular interactions included in the model were all assembled manually based on a careful meta-analysis of published experimental results. Our model reveals the differences and commonalities of the response of the network upon HGF and <it>H. pylori </it>induced c-Met signalling. As another important result, using the formalism of minimal intervention sets, phospholipase Cγ1 (PLCγ1) was identified as knockout target for repressing the activation of the extracellular signal regulated kinase 1/2 (ERK1/2), a signalling molecule directly linked to cell scattering in <it>H. pylori </it>infected cells. The model predicted only an effect on ERK1/2 for the <it>H. pylori </it>stimulus, but not for HGF treatment. This result could be confirmed experimentally in MDCK cells using a specific pharmacological inhibitor against PLCγ1. The <it>in silico </it>predictions for the knockout of two other network components were also verified experimentally.</p> <p>Conclusion</p> <p>This work represents one of the first approaches in the direction of host-pathogen systems biology aiming at deciphering signalling changes brought about by pathogenic bacteria. The suitability of our network model is demonstrated by an <it>in silico </it>prediction of a relevant target against pathogen infection.</p

Surface antibody changes protein corona both in human and mouse serum but not final opsonization and elimination of targeted polymeric nanoparticles

Background: Nanoparticles represent one of the most important innovations in the medical field. Among nanocarriers, polymeric nanoparticles (PNPs) attracted much attention due to their biodegradability, biocompatibility, and capacity to increase efficacy and safety of encapsulated drugs. Another important improvement in the use of nanoparticles as delivery systems is the conjugation of a targeting agent that enables the nanoparticles to accumulate in a specific tissue. Despite these advantages, the clinical translation of therapeutic approaches based on nanoparticles is prevented by their interactions with blood proteins. In fact, the so-formed protein corona (PC) drastically alters the biological identity of the particles. Adsorbed activated proteins of the complement cascade play a pivotal role in the clearance of nanoparticles, making them more easily recognized by macrophages, leading to their rapid elimination from the bloodstream and limiting their efficacy. Since the mouse is the most used preclinical model for human disease, this work compared human and mouse PC formed on untargeted PNPs (uPNPs) and targeted PNPs (tPNPs), paying particular attention to complement activation. Results: Mouse and human serum proteins adsorbed differently to PNPs. The differences in the binding of mouse complement proteins are minimal, whereas human complement components strongly distinguish the two particles. This is probably due to the human origin of the Fc portion of the antibody used as targeting agent on tPNPs. tPNPs and uPNPs mainly activate complement via the classical and alternative pathways, respectively, but this pattern did not affect their binding and internalization in macrophages and only a limited consumption of the activity of the human complement system was documented. Conclusions: The results clearly indicate the presence of complement proteins on PNPs surface but partially derived from an unspecific deposition rather than an effective complement activation. The presence of a targeting antibody favors the activation of the classical pathway, but its absence allows an increased activation of the alternative pathway. This results in similar opsonization of both PNPs and similar phagocytosis by macrophages, without an impairment of the activity of circulating complement system and, consequently, not enhancing the susceptibility to infection. Graphical abstract: [Figure not available: see fulltext.

Education at the Refugee Camp

The northern Iraqi part of Kurdistan has been an area of protection for many people who have fled since the genocide by the so-called Islamic State in 2014. The refugee camps there, originally intended as a short-term solution, have become a permanent reality of life for many children and teenagers, some of whom are severely traumatized. The school of Our Bridge is located directly next to the refugee camp of Khanke in Kurdistan and has developed a specific pedagogical concept for children of the refugee camp. They are offered a carefully balanced, multi-faceted everyday experience, and access to a variety of educational opportunities. ‘School development at refugee camps (SchoolDeC)' is a research project of the University of Tübingen in cooperation with the school of Our Bridge. The objective is to assess and systematise the status of its school development and to derivedevelop recommendations from the perspectives given by different local key actors. The results, recommendations, and possible perspectives for development are presented in this volume

Inhibitors of Dipeptidyl Peptidase IV and Aminopeptidase N Target Major Pathogenetic Steps in Acne Initiation

Acne is a chronic disease hallmarked by sebaceous hyperplasia, follicular hyperkeratosis, and inflammation. Parallel targeting of these factors is required to treat acne effectively. Inhibitors of dipeptidyl peptidase IV (DP IV) and aminopeptidase N (APN) show strong anti-inflammatory effects on immune cells and therapeutic efficacy in autoimmune disorders. Our investigation focused on the expression and functional relevance of these ectopeptidases in three cell types which exhibit an altered phenotype in early acne lesions. We showed for the first time expression of DP IV and APN on human sebocytes. In the SZ95 sebocyte cell line, the DP IV inhibitors Lys[Z(NO2)]-thiazolidide and Lys[Z(NO2)]-pyrrolidide and the APN inhibitors actinonin and bestatin suppressed proliferation, enhanced terminal differentiation, and slightly decreased total neutral lipid production. The anti-inflammatory and differentiation-restoring cytokine IL-1 receptor antagonist was significantly upregulated in SZ95 sebocytes and the HaCaT keratinocyte cell line in the presence of inhibitors. Furthermore, the inhibitors suppressed proliferation and IL-2 production of Propionibacterium acnes-stimulated T cells ex vivo and enhanced the expression of the immunosuppressive cytokine transforming growth factor-β1. Our data provide first evidence for a functional role of DP IV and APN in the sebaceous gland apparatus and for their inhibitors, used alone or in combination, as completely new substances possibly affecting acne pathogenesis in a therapeutic manner

Tamo gdje završava drama mentaliteta započinje drama političkog trenutka. Ivan Vidić, Octopussy, HNK, Zagreb & Veliki bijeli zec, ZeKaeM

<p><b>Copyright information:</b></p><p>Taken from "Host-pathogen systems biology: logical modelling of hepatocyte growth factor and induced c-Met signal transduction"</p><p>http://www.biomedcentral.com/1752-0509/2/4</p><p>BMC Systems Biology 2008;2():4-4.</p><p>Published online 14 Jan 2008</p><p>PMCID:PMC2254585.</p><p></p

Stage I Retinal Waves

Data and Cod

The Outcome of Digital Movie Offers in Relation to Marketing and Corporal Home Video Markets in Germany

Die vorliegende Arbeit vergleicht die Blu-ray als physisches Home-Video-Medium mit den Video-on-Demand-Angeboten im Internet. Weiterhin stellt sich die Frage, ob die Standard Blu-ray-Qualität für den Endverbraucher ausreicht, oder ob eine zusätzliche Qualitätssteigerung benötigt wird, um gegen die steigenden Video-on-Demand-Angebote bestehen zu können. Es werden vorerst die nötigen thematischen Grundlagen ausgearbeitet und anschließend die durchgeführte Online-Erhebung ausgewertet, um die These in Kapitel eins der Arbeit zu bekräftigen oder zu widerlegen