Cooperation of international organisations in peacekeeping operations and issues of international responsibility

The thesis deals with the question as to whether international organisations could be jointly responsible for violations of international law committed by peacekeepers deployed in a peacekeeping operation. The study starts by exploring the development of the concept of peacekeeping operations and the relations between the UN and four specific regional organisations (NATO, EU, AU and ECOWAS) on the basis of the applicable dispositions of the UN Charter. This examination as well as the following analysis of relations among these organisations, illustrate the evolution of a division of labour and an increase of cooperation between the UN and these organisations. It justifies the formulation of a presumption that international organisations could be jointly responsible as well as the formulation of a new criterion of attribution (normative control). The case-studies of specific peacekeeping operations confirm that in certain circumstances the UN and regional organisations have to be considered jointly responsible.Exploring the Frontiers of International La

Uptake of Leishmania major by dendritic cells is mediated by Fcγ receptors and facilitates acquisition of protective immunity

Uptake of Leishmania major by dendritic cells (DCs) results in activation and interleukin (IL)-12 release. Infected DCs efficiently stimulate CD4− and CD8− T cells and vaccinate against leishmaniasis. In contrast, complement receptor 3–dependent phagocytosis of L. major by macrophages (MΦ) leads exclusively to MHC class II–restricted antigen presentation to primed, but not naive, T cells, and no IL-12 production. Herein, we demonstrate that uptake of L. major by DCs required parasite-reactive immunoglobulin (Ig)G and involved FcγRI and FcγRIII. In vivo, DC infiltration of L. major–infected skin lesions coincided with the appearance of antibodies in sera. Skin of infected B cell–deficient mice and Fcγ−/− mice contained fewer parasite-infected DCs in vivo. Infected B cell–deficient mice as well as Fcγ−/− mice (all on the C57BL/6 background) showed similarly increased disease susceptibility as assessed by lesion volumes and parasite burdens. The B cell–deficient mice displayed impaired T cell priming and dramatically reduced IFN-γ production, and these deficits were normalized by infection with IgG-opsonized parasites. These data demonstrate that DC and MΦ use different receptors to recognize and ingest L. major with different outcomes, and indicate that B cell–derived, parasite-reactive IgG and DC FcγRI and FcγRIII are essential for optimal development of protective immunity

Sleep Enforces the Temporal Order in Memory

BACKGROUND: Temporal sequence represents the main principle underlying episodic memory. The storage of temporal sequence information is thought to involve hippocampus-dependent memory systems, preserving temporal structure possibly via chaining of sequence elements in heteroassociative networks. Converging evidence indicates that sleep enhances the consolidation of recently acquired representations in the hippocampus-dependent declarative memory system. Yet, it is unknown if this consolidation process comprises strengthening of the temporal sequence structure of the representation as well, or is restricted to sequence elements independent of their temporal order. To address this issue we tested the influence of sleep on the strength of forward and backward associations in word-triplets. METHODOLOGY/PRINCIPAL FINDINGS: Subjects learned a list of 32 triplets of unrelated words, presented successively (A-B-C) in the center of a screen, and either slept normally or stayed awake in the subsequent night. After two days, retrieval was assessed for the triplets sequentially either in a forward direction (cueing with A and B and asking for B and C, respectively) or in a backward direction (cueing with C and B and asking for B and A, respectively). Memory was better for forward than backward associations (p<0.01). Sleep did not affect backward associations, but enhanced forward associations, specifically for the first (AB) transitions (p<0.01), which were generally more difficult to retrieve than the second transitions. CONCLUSIONS/SIGNIFICANCE: Our data demonstrate that consolidation during sleep strengthens the original temporal sequence structure in memory, presumably as a result of a replay of new representations during sleep in forward direction. Our finding suggests that the temporally directed replay of memory during sleep, apart from strengthening those traces, could be the key mechanism that explains how temporal order is integrated and maintained in the trace of an episodic memory

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p&lt;0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (&lt;1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (&lt;1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Integration of the B Cell Receptor Antigen Neurabin-I into an IgG1 Antibody Format for the Treatment of Primary Diffuse Large B Cell Lymphoma of the CNS

Diese Arbeit stellt ein IgG1-Therapieformat vor, das die malignen B-Lymphozyten des primären diffus großzelligen B-Zell-Lymphoms des zentralen Nervensystems über den Neurabin-I-reaktiven B-Zell-Rezeptor angreift. Die Ergebnisse der zugrundeliegenden Versuche zeigen, dass durch dieses Therapieformat in vitro maligne Zellen gezielt zerstört werden können. Maligne B-Lymphozyten des primären diffus großzelligen B-Zell-Lymphoms des zentralen Nervensystems weisen einen intakten B-Zell-Rezeptor auf und haben somatisch rekombinierte und hypermutierte Immunglobulin-Gene. Dies indiziert, dass die Zellen im Rahmen einer Keimzentrumsreaktion Kontakt mit einem Antigen hatten und fortlaufend durch das Antigen stimuliert werden. Für B-Zell-Rezeptoren des primären diffus großzelligen B-Zell-Lymphoms des zentralen Nervensystems wurde das im Nervengewebe exprimierte Protein Neurabin-I als dominierendes Antigen identifiziert, auf dessen Reiz hin die Zellen proliferieren. Die Neurabin I-reaktiven B-Zell-Rezeptoren stellen eine tumorspezifische Oberflächenstruktur der malignen Klone dar. Über diese können durch Verwendung des B Zell-Rezeptor-Antigens Neurabin-I die Tumorzellen im Rahmen des BAR-Konzepts (B cell receptor antigens for reverse targeting) angegriffen werden. In dem durch diese Arbeit beschriebenen Versuch wurde ein Abschnitt des Neurabin-I-Epitops anstelle der variablen Domänen der leichten und schweren Kette eines Immunglobulins in ein IgG1-Format kloniert. Das Konstrukt wird IgG1-Neurabin-I-BAR-Body genannt. Nach Klonierung, Expression in humanen Zellen und Aufreinigung wurde der BAR-Body in vitro getestet. Es konnte nachgewiesen werden, dass der BAR-Body spezifisch an Zielzellen bindet, die einen Neurabin-I-reaktiven B-Zell-Rezeptor auf der Oberfläche exprimieren, wodurch die Zielzellen für Effektorzellen markiert werden. So konnte eine durch Effektorzellen vermittelte Lyse der mit dem BAR-Body beladenen Tumorzellen erreicht werden. Der Einsatz des BAR-Bodys in vivo ist dadurch limitiert, dass dieser vermutlich die Blut-Hirn-Schranke nicht gut überwinden kann. Es bedarf eines auf den BAR-Body angewandten Konzepts zur Überwindung der Blut-Hirn-Schranke, das gleichzeitig eine Interaktion des BAR-Bodys mit dem B-Zell-Rezeptor gewährleistet. Wenn ein solches Konzept gefunden wird, könnten Patienten mit dem untersuchten Therapieformat von einer höchst spezifisch auf die Tumorzellen gerichteten Behandlung profitieren, die voraussichtlich mit geringeren Nebenwirkungen einhergeht als eine Polychemotherapie.This study presents an IgG1 therapy format that attacks the malignant B lymphocytes of the primary diffuse large B cell lymphoma of the central nervous system via the neurabin-I reactive B cell receptor. The in vitro results of the underlying experiments show that malignant cells can be destroyed specifically by means of this therapy format. Malignant B lymphocytes of the primary diffuse large B cell lymphoma of the central nervous system have an intact B cell receptor and have rearranged immunoglobulin genes with somatic hypermutation. This indicates that the cells were in contact with an antigen during a germinal center reaction and are continuously stimulated by this antigen. For B cell receptors of primary diffuse large B cell lymphomas of the central nervous system the protein neurabin-I, which is expressed in the neural tissue, was identified as the dominant antigen, upon which the cells proliferate. Neurabin-I reactive B cell receptors represent a tumor-specific surface structure of the malignant clones. The tumor cells can be attacked via these receptors by using the B cell receptor antigen neurabin-I in an approach termed BAR (B cell receptor antigens for reverse targeting). In the experiment described in this paper, a section of the neurabin-I epitope was cloned into an IgG1 format replacing the variable domains of the light and heavy chain of an immunoglobulin. This construct is designated IgG1-neurabin-I-BAR-body. After cloning, expression in human cells and purification, the BAR-body was tested in vitro. It was shown that the BAR-body specifically binds to target cells expressing a neurabin-I reactive B cell receptor on the surface, thereby labeling the target cells for effector cells. In this way, effector cell mediated lysis of the tumor cells which were loaded with the BAR-body could be achieved. The use of the BAR-body in vivo is limited by the fact that the BAR-body is probably not able to cross the blood-brain barrier well. A concept applied to the BAR-body is required to overcome the blood-brain barrier, whereas such a concept at the same time must ensure interaction of the BAR-body with the B cell receptor. If such a concept could be found, patients are likely to benefit from a treatment that targets tumor cells very specifically and thus is likely to be associated with fewer side effects than polychemotherapy

Cooperation of international organisations in peacekeeping operations and issues of international responsibility

The thesis deals with the question as to whether international organisations could be jointly responsible for violations of international law committed by peacekeepers deployed in a peacekeeping operation. The study starts by exploring the development of the concept of peacekeeping operations and the relations between the UN and four specific regional organisations (NATO, EU, AU and ECOWAS) on the basis of the applicable dispositions of the UN Charter. This examination as well as the following analysis of relations among these organisations, illustrate the evolution of a division of labour and an increase of cooperation between the UN and these organisations. It justifies the formulation of a presumption that international organisations could be jointly responsible as well as the formulation of a new criterion of attribution (normative control). The case-studies of specific peacekeeping operations confirm that in certain circumstances the UN and regional organisations have to be considered jointly responsible