B cell development in fetal liver and adult bone marrow

In the present work different aspects of B cell development were investigated. The first part focused on differential activation of variable regions of the immunoglobulin light chain loci for the rearrangement process. Activation was monitored in a synchronously differentiating pro-B cell line by detection of germline transcripts. Differential expression of Vkappa germline transcripts from Vkappa families proximal or distal to the JCkappa cluster was observed. Nevertheless, both clusters opened roughly at the same time as the JCkappa cluster. Similarly, Vlambda and JClambda opened almost synchronously. However compared to the kappa locus, activation was found at a later developmental stage. The second part concerned differences in B cell ontogeny between fetal liver and adult bone marrow. B cell precursors from either hematopoietic sites obviously give rise to distinct mature B cell subpopulations. Therefore, the gene expression patterns of early B cell precursors from fetal liver and adult bone marrow were compared using microarrays. This analysis confirmed previous findings and revealed further significant differences between both populations. In the last part, a new mouse model with inducible lymphopoiesis was established, that should provide further insights into the different ontogeny between fetal liver and bone marrow derived B cell precursors.In der vorliegenden Arbeit wurden verschiedene Aspekte der B- Zellentwicklung untersucht. Der erste Teil befasste sich mit der differentiellen Aktivierung von variablen Regionen der Immunglobulin leichte Kette-Loci für den Rekombinationsprozess. Die Aktivierung wurde in einer synchron differenzierenden Pro-B- Zelllinie durch Detektion von Keimbahntranskripten verfolgt. Differentielle Expression von Vkappa-Keimbahntranskripten von Vkappa-Familien proximal oder distal vom JCkappa-Cluster wurde beobachtet. Beide Cluster wurden jedoch etwa zur gleichen Zeit wie das JCkappa-Cluster zugänglich. In ähnlicher Weise wurden auch Vlambda und JClambda nahezu synchron aktiviert. Im Vergleich zum Kappa-Locus fand diese Aktivierung allerdings zu einem späteren Entwicklungsstadium statt. Der zweite Teil der Arbeit beschäftigte sich mit den Unterschieden in der B- Zellentwicklung zwischen fötaler Leber und dem adulten Knochenmark. B-Zellvorläufer der beiden hämatopoetischen Organe entwickeln sich offensichtlich zu unterschiedlichen reifen B- Zellsubpopulationen. Daher wurden die Genexpressionsprofile von frühen B-Zellvorläufern aus fötaler Leber und adultem Knochenmark mit Hilfe von Microarrays verglichen. Diese Analyse konnte bisherige Befunde bestätigen und weitere signifikante Unterschiede zwischen den beiden Populationen aufdecken. Im letzten Teil wurde ein neues Mausmodell mit induzierbarer Lymphozytenentwicklung etabliert. Dieses Modell soll weitere Einblicke in die unterschiedliche Ontogenese von B- Zellvorläufern aus fötaler Leber und adultem Knochenmark liefern

Zeitschrift für Praktische Philosophie / Überzeugen, Stupsen, Zwingen Die Konzeption von Nudge und Libertärem Paternalismus und ihr Verhältnis zu anderen Formen der Verhaltenssteuerung

Trotz der überwältigenden öffentlichen wie wissenschaftlichen Resonanz, auf die der Nudge-Ansatz von Thaler und Sunstein gestoßen ist, bleiben die genauen Konturen dieses Theorie und Policyvorschlages unscharf. So ist an vielen Stellen unklar, worin die spezifische Differenz gegenüber klassischen Formen der Verhaltenssteuerung liegen soll. Für eine Bewertung des Ansatzes in seinen Vorzügen und Nachteilen gegenüber klassischen Steuerungsformen ist eine solche klärende Einordnung jedoch notwendige Vorbedingung. Der Aufsatz arbeitet daher die bestehenden Definitions- und Abgrenzungsprobleme von „Nudge“ und „Libertärem Paternalismus“ heraus und plädiert sodann für einen Kernbegriff von „Nudge“, der dessen Extension einschränkt, um ihn als originären und eigenständigen Vorschlag einzugrenzen. Ein so präzisiertes Verständnis von Nudge wird dann hinsichtlich seiner Eigenschaften sowie der Gemeinsamkeiten und Unterschiede zu klassischen Formen der Verhaltenssteuerung ins Verhältnis gesetzt.Despite the overwhelming public and scientific feedback to the nudging approach by Thaler and Sunstein, the more concrete shapes of their theory and policy suggestion remain unclear. In many places it is unclear wherein the specific difference to classical forms of behavioural control should lie. However, such a clarifying classification is a necessary precondition for an evaluation of the approach and its advantages and disadvantages in comparison to classical behavioural control forms. Therefore, this article works out the existing definition and differentiation problems of “nudge“ and “Libertarian Paternalism“ and argues for the core term “nudge” which limits its extension, to narrow it down as distinct and independent suggestion. This specified understanding of nudging is then put into perspective with classical behavioural control forms in regard to their similarities and differences

Novel Biodegradable Composite of Calcium Phosphate Cement and the Collagen I Mimetic P-15 for Pedicle Screw Augmentation in Osteoporotic Bone

Osteoporotic vertebral fractures often necessitate fusion surgery, with high rates of implant failure. We present a novel bioactive composite of calcium phosphate cement (CPC) and the collagen I mimetic P-15 for pedicle screw augmentation in osteoporotic bone. Methods involved expression analysis of osteogenesis-related genes during osteoblastic differentiation by RT-PCR and immunostaining of osteopontin and Ca2+ deposits. Untreated and decalcified sheep vertebrae were utilized for linear pullout testing of pedicle screws. Bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry (DEXA). Expression of ALPI II (p p p p p p p p p = 0.04) with PMMA, and 1252 ± 131 N (p < 0.0078) with CPC-P-15. CPC-P-15 induces osteoblastic differentiation of human MES and improves pullout resistance of pedicle screws in osteoporotic and non-osteoporotic bone

Severe Developmental B Lymphopoietic Defects in Foxp3-Deficient Mice are Refractory to Adoptive Regulatory T Cell Therapy

The role of Foxp3-expressing regulatory T (Treg) cells in tolerance and autoimmunity is well-established. However, although of considerable clinical interest, the role of Treg cells in the regulation of hematopoietic homeostasis remains poorly understood. Thus, we analysed B and T lymphopoiesis in the scurfy (Sf) mouse model of Treg cell deficiency. In these experiments, the near-complete block of B lymphopoiesis in the BM of adolescent Sf mice was attributed to autoimmune T cells. We could exclude a constitutive lympho-hematopoietic defect or a B cell-intrinsic function of Foxp3. Efficient B cell development in the BM early in ontogeny and pronounced extramedullary B lymphopoietic activity resulted in a peripheral pool of mature B cells in adolescent Sf mice. However, marginal zone B and B-1a cells were absent throughout ontogeny. Developmental B lymphopoietic defects largely correlated with defective thymopoiesis. Importantly, neonatal adoptive Treg cell therapy suppressed exacerbated production of inflammatory cytokines and restored thymopoiesis but was ineffective in recovering defective B lymphopoiesis, probably due to a failure to compensate production of stroma cell-derived IL-7 and CXCL12. Our observations on autoimmune-mediated incapacitation of the BM environment in Foxp3-deficient mice will have direct implications for the rational design of BM transplantation protocols for patients with severe genetic deficiencies in functional Foxp3+ Treg cells

Quantification of intramuscular fat in patients with late-onset Pompe disease by conventional magnetic resonance imaging for the long-term follow-up of enzyme replacement therapy

OBJECTIVE: The objective of this study was to evaluate a quantitative method based on conventional T1-weighted magnetic resonance (MR) imaging to assess fatty muscular degeneration in patients with late-onset Pompe disease and to compare it with semi-quantitative visual evaluation (the Mercuri score). In addition, a long-term retrospective data analysis was performed to evaluate treatment response to enzyme replacement therapy with alglucosidase alfa. METHODS: MR images of the lumbar spine were acquired in 41 patients diagnosed with late-onset Pompe disease from 2006 through 2015. Two independent readers retrospectively evaluated fatty degeneration of the psoas and paraspinal muscles by applying the Mercuri score. Quantitative semi-automated muscle and fat tissue separation was performed, and inter-observer agreement and correlations with clinical parameters were assessed. Follow-up examinations were performed in 13 patients treated with alglucosidase alfa after a median of 39 months; in 7/13 patients, an additional follow-up examination was completed after a median of 63 months. RESULTS: Inter-observer agreement was high. Measurements derived from the quantitative method correlated well with Medical Research Council scores of muscle strength, with moderate correlations found for the 6-minute walk test, the 4-step stair climb test, and spirometry in the supine position. A significant increase in the MR-derived fat fraction of the psoas muscle was found between baseline and follow-up 1 (P = 0.016), as was a significant decrease in the performance on the 6-minute walk test (P = 0.006) and 4-step stair climb test (P = 0.034), as well as plasma creatine kinase (P = 0.016). No statistically significant difference in clinical or MR-derived parameters was found between follow-up 1 and follow-up 2. CONCLUSIONS: Quantification of fatty muscle degeneration using the semi-automated method can provide a more detailed overview of disease progression than semi-quantitative Mercuri scoring. MR-derived data correlated with clinical symptoms and patient exercise capacity. After an initial worsening, the fat fraction of the psoas muscle and performance on the 6-minute walk test stayed constant during long-term follow-up under enzyme replacement therapy

Validation of the SNACOR clinical scoring system after transarterial chemoembolisation in patients with hepatocellular carcinoma

Background Transarterial chemoembolisation is the standard of care for intermediate stage (BCLC B) hepatocellular carcinoma, but it is challenging to decide when to repeat or stop treatment. Here we performed the first external validation of the SNACOR (tumour Size and Number, baseline Alpha-fetoprotein, Child-Pugh and Objective radiological Response) risk prediction model. Methods A total of 1030 patients with hepatocellular carcinoma underwent transarterial chemoembolisation at our tertiary referral centre from January 2000 to December 2016. We determined the following variables that were needed to calculate the SNACOR at baseline: tumour size and number, alpha-fetoprotein level, Child-Pugh class, and objective radiological response after the first transarterial chemoembolisation. Overall survival, time-dependent area under receiver-operating characteristic curves, Harrell’s C-index, and the integrated Brier score were calculated to assess predictive ability. Finally, multivariate analysis was performed to identify independent predictors of survival. Results The study included 268 patients. Low, intermediate, and high SNACOR scores predicted a median survival of 31.5, 19.9, and 9.2 months, respectively. The areas under the receiver-operating characteristic curve for overall survival were 0.641, 0.633, and 0.609 at 1, 3, and 6 years, respectively. Harrell’s C-index was 0.59, and the integrated Brier Score was 0.175. Independent predictors of survival included tumour size (P < 0.001), baseline alpha-fetoprotein level (P < 0.001) and Child-Pugh class (P < 0.004). Objective radiological response (P = 0.821) and tumour number (P = 0.127) were not additional independent predictors of survival. Conclusions The SNACOR risk prediction model can be used to identify patients with a dismal prognosis after the first transarterial chemoembolisation who are unlikely to benefit from further transarterial chemoembolisation. However, Harrell’s C-index showed only moderate performance. Accordingly, this risk prediction model can only serve as one of several components used to make the decision about whether to repeat treatment

Planning and Development of Social Services for Persons with Disabilities

Soziale Dienste zur Unterstützung von Menschen mit Behinderungen haben sich in den letzten Jahren dynamisch entwickelt und unterliegen auch aktuell einem erheblichen Veränderungsdruck. Die Forschungsarbeiten, die in diesem Band versammelt sind, haben die Entwicklung hin zu einer inklusionsorientierten Unterstützung in zahlreichen Projekten auf unterschiedlichen Ebenen aktiv begleitet.Social services to support persons with disabilities have developed dynamically in recent years and are currently subject to considerable pressure to change. The research work collected in this volume has actively accompanied the development towards inclusion-oriented support in numerous projects at different levels

Digitale Teilhabe

Das Themenheft Digitale Teilhabe beschäftigt sich zentral mit den Potentialen der Nutzung der neuen Informations- und Kommunikationstechnologien durch benachteiligte Menschen. Im Leitartikel wird der Versuch unternommen, mögliche theoretische Anknüpfungspunkte und Forschungsfragen für weitere Studien- und Forschungsarbeiten in dem noch jungen Themenfeld der Digitalen Teilhabe zu identifizieren. Hierzu wird zunächst das zugrunde liegende Verständnis von Behinderung/Benachteiligung diskutiert und inklusive (Medien-)Bildung als Teil der Persönlichkeitsbildung skizziert. In verschiedenen Diskursen bzw. Disziplinen werden dann theoretische Anknüpfungspunkte für weitere Forschungsarbeiten benannt. Die Idee für das Themenheft ist im Rahmen des Projekts "Begleitforschung im PIKSL-Labor" des Zentrums für Planung und Evaluation Sozialer Dienste der Uni Siegen (ZPE) entstanden. Das PIKSL-Projekt zielt darauf ab, Menschen mit Behinderungen moderne Kommunikationstechnologien zugänglich zu machen, um ihnen Teilhabemöglichkeiten zu erleichtern und zugleich die personale Abhängigkeit von professioneller Unterstützung zu reduzieren. Der inter- und transdisziplinäre Ansatz von PIKSL wird durch die Vielfalt der Artikel in dem Heft deutlich: Digitale Teilhabe wird nicht alleine aus (medien-)pädagogischer bzw. sozialwissenschaftlicher Perspektive betrachtet. Die Besonderheit liegt in der Kooperation unterschiedlicher Disziplinen wie Soziale Arbeit, Kunst und Webdesign

The effects of grain size, dendritic structure and crystallographic orientation on fatigue crack propagation in IN713C nickel-based superalloy

The polycrystalline IN713C produced via investment casting is one of the widely-used nickel-based superalloy in automotive and aerospace industries. This alloy, however, has an apparent inhomogeneous microstructure generated during casting and contains dendritic structure that gives rise to strain localisation during loading. Yet, the effect of dendritic structure, grain size and shape as well as crystallographic orientation, which directly influence fatigue property and deformation micromechanism in the components, is rarely studied. In the present study, IN713C cast bars are tailored with three different grain structures, i.e., transition, equiaxed and columnar, with substantial grain size variations. The produced bars were tested under strain controlled LCF (Low Cycle Fatigue) and stress controlled HCF (High Cycle Fatigue) conditions at 650 °C. The results showed that most of fatigue cracks initiated from casting pores and fatigue life extended in the microstructure with a small grain size during both HCF and LCF loadings. It is also demonstrated that fatigue striations were mainly observed within dendritic areas during crack propagation, whereas the higher GND (Geometrically Necessary Dislocation) density were predominantly observed in the interdendritic areas. Here, we propose a concept of ‘Crack Propagation Unit (CPU)’ for better description of deformation mechanism at local scale during fatigue loading by combining fracture surface characteristic methodology and dislocation distribution analyses within the dendritic structural unit. Furthermore, this model to understand the deformation micromechanism can provide a new perspective on the interpretation of Hall-Petch relationship in casting materials that contain dendritic structure. This is further demonstrated via direct correlation of the high crack propagation resistance with the crack path divergence instead of the dislocation pile-up at the grain boundary or in-between the γ/γ′ channels. Moreover, by utilising serial sectioning method followed by layered EBSD scanning, quasi-3-D grain orientation mappings were obtained, and crystallographic texture information were directly correlated with the fracture surface observations. This allowed an investigation of the influence of orientation of individual grains and micro/macro texture on crack propagation rate. The critical stage of crack propagation in fatigue life and its correlations with microstructural features is established, offering potential practical applications by controlling the investment casting process parameters