Measurement of Compton Scattering at MAMI for the Extraction of the Electric and Magnetic Polarizabilities of the Proton.

A precise measurement of the differential cross sections dσ/dΩ and the linearly polarized photon beam asymmetry Σ_{3} for Compton scattering on the proton below pion threshold has been performed with a tagged photon beam and almost 4π detector at the Mainz Microtron. The incident photons were produced by the recently upgraded Glasgow-Mainz photon tagging facility and impinged on a cryogenic liquid hydrogen target, with the scattered photons detected in the Crystal Ball/TAPS setup. Using the highest statistics Compton scattering data ever measured on the proton along with two effective field theories (both covariant baryon and heavy-baryon) and one fixed-t dispersion relation model, constraining the fits with the Baldin sum rule, we have obtained the proton electric and magnetic polarizabilities with unprecedented precision: α_{E1}=10.99±0.16±0.47±0.17±0.34, ß_{M1}=3.14±0.21±0.24±0.20±0.35; in units of 10^{-4} fm^{3} where the errors are statistical, systematic, spin polarizability dependent, and model dependent.

Signatures of the d

We report a measurement of the spin polarization of the recoiling neutron in deuterium photodisintegration, utilizing a new large acceptance polarimeter within the Crystal Ball at MAMI. The measured photon energy range of 300-700 MeV provides the first measurement of recoil neutron polarization at photon energies where the quark substructure of the deuteron plays a role, thereby providing important new constraints on photodisintegration mechanisms. A very high neutron polarization in a narrow structure centered around E_{γ}∼570 MeV is observed, which is inconsistent with current theoretical predictions employing nucleon resonance degrees of freedom. A Legendre polynomial decomposition suggests this behavior could be related to the excitation of the d^{*}(2380) hexaquark.

Helicity-Dependent Cross Sections for the Photoproduction of π

The double-polarization observable E and helicity-dependent cross sections σ_{1/2}, σ_{3/2} have been measured for the photoproduction of π^{0} pairs off quasifree protons and neutrons at the Mainz MAMI accelerator with the Crystal Ball/TAPS setup. A circularly polarized photon beam was produced by bremsstrahlung from longitudinally polarized electrons and impinged on a longitudinally polarized deuterated butanol target. The reaction products were detected with an almost 4π covering calorimeter. The results reveal for the first time the helicity- and isospin-dependent structure of the γN→Nπ^{0}π^{0} reaction. They are compared to predictions from reaction models in view of nucleon resonance contributions and also to a refit of one model that predicted results for the proton and for the neutron target. The comparison of the prediction and the refit demonstrates the large impact of the new data.

Study of η and η' Photoproduction at MAMI.

The reactions γp→ηp and γp→η^{'}p are measured from their thresholds up to the center-of-mass energy W=1.96 GeV with the tagged-photon facilities at the Mainz Microtron, MAMI. Differential cross sections are obtained with unprecedented statistical accuracy, providing fine energy binning and full production-angle coverage. A strong cusp is observed in the total cross section for η photoproduction at the energies in the vicinity of the η^{'} threshold, W=1896 MeV (E_{γ}=1447 MeV). Within the framework of a revised ηMAID isobar model, the cusp, in connection with a steep rise of the η^{'} total cross section from its threshold, can only be explained by a strong coupling of the poorly known N(1895)1/2^{-} state to both ηp and η^{'}p. Including the new high-accuracy results in the ηMAID fit to available η and η^{'} photoproduction data allows the determination of the N(1895)1/2^{-} properties.

Insight into the Narrow Structure in η Photoproduction on the Neutron from Helicity-Dependent Cross Sections.

The double polarization observable E and the helicity dependent cross sections σ_{1/2} and σ_{3/2} were measured for η photoproduction from quasifree protons and neutrons. The circularly polarized tagged photon beam of the A2 experiment at the Mainz MAMI accelerator was used in combination with a longitudinally polarized deuterated butanol target. The almost 4π detector setup of the Crystal Ball and TAPS is ideally suited to detect the recoil nucleons and the decay photons from η→2γ and η→3π^{0}. The results show that the narrow structure previously observed in η photoproduction from the neutron is only apparent in σ_{1/2} and hence, most likely related to a spin-1/2 amplitude. Nucleon resonances that contribute to this partial wave in η production are only N 1/2^{-} (S_{11}) and N 1/2^{+} (P_{11}). Furthermore, the extracted Legendre coefficients of the angular distributions for σ_{1/2} are in good agreement with recent reaction model predictions assuming a narrow resonance in the P_{11} wave as the origin of this structure.

Photoproduction of π0 mesons off neutrons in the nucleon resonance region.

Precise angular distributions have been measured for the first time for the photoproduction of π0 mesons off neutrons bound in the deuteron. The effects from nuclear Fermi motion have been eliminated by a complete kinematic reconstruction of the final state. The influence of final-state-interaction effects has been estimated by a comparison of the reaction cross section for quasifree protons bound in the deuteron to the results for free protons and then applied as a correction to the quasifree neutron data. The experiment was performed at the tagged photon facility of the Mainz Microtron MAMI with the Crystal Ball and TAPS detector setup for incident photon energies between 0.45 and 1.4 GeV. The results are compared to the predictions from reaction models and partial-wave analyses based on data from other isospin channels. The model predictions show large discrepancies among each other and the present data will provide much tighter constraints. This is demonstrated by the results of a new analysis in the framework of the Bonn-Gatchina coupled-channel analysis which included the present data.

N(1520) 3/2(-) helicity amplitudes from an energy-independent multipole analysis based on new polarization data on photoproduction of neutral pions.

New data on the polarization observables T, P, and H for the reaction γp→pπ(0) are reported. The results are extracted from azimuthal asymmetries when a transversely polarized butanol target and a linearly polarized photon beam are used. The data were taken at the Bonn electron stretcher accelerator ELSA using the CBELSA/TAPS detector. These and earlier data are used to perform a truncated energy-independent partial wave analysis in sliced-energy bins. This energy-independent analysis is compared to the results from energy-dependent partial wave analyses.

Narrow structure in the excitation function of η photoproduction off the neutron.

The photoproduction of η mesons off nucleons bound in 2H and 3He has been measured in coincidence with recoil protons and recoil neutrons for incident photon energies from threshold up to 1.4 GeV. The experiments were performed at the Mainz MAMI accelerator, using the Glasgow tagged photon facility. Decay photons from the η→2γ and η→3π0 decays and the recoil nucleons were detected with an almost 4π electromagnetic calorimeter combining the Crystal Ball and TAPS detectors. The data from both targets are of excellent statistical quality and show a narrow structure in the excitation function of γn→nη. The results from the two measurements are consistent, taking into account the expected effects from nuclear Fermi motion. The best estimates for position and intrinsic width of the structure are W=(1670±5) MeV and Γ=(30±15) MeV. For the first time precise results for the angular dependence of this structure have been extracted.

[Diagnosis and treatment of iron deficiency and anaemia in inflammatory bowel diseases. Consensus of the Austrian IBD Working Party]. / Diagnose und Behandlung von Eisenmangel und Anämie bei chronisch entzündlichen Darmerkrankungen. Konsensus der österreichischen Arbeitsgruppe für CED.

Iron deficiency with and without anaemia is a common burden of patients with inflammatory bowel diseases (IBD) and has considerable impact on their quality of life and the ability to perform. The IBD working group of the Austrian Society of Gastroenterology and Hepatology developed five consensus statements on the following topics: (i) diagnosis of iron deficiency and (ii) anaemia, (iii) screening of iron deficiency, (iv) treatment of iron deficiency and (v) therapeutic goals. The clinical importance of intravenous iron replacement therapy in IBD with regard to effectiveness and compliance was discussed.

[Infliximab therapy for Crohn's disease - a practical guideline: actualised consensus of the working group for chronic inflammatory bowel diseases of the Austrian Society for Gastroenterology and Hepatology]. / Infliximab in der Therapie des Morbus Crohn - ein praktischer Leitfaden: aktualisierter ÖGGH-Konsensus der Arbeitsgruppe Chronisch-entzündliche Darmerkrankungen der ÖGGH.

Infliximab is a monoclonal antibody against tumor necrosis factor alpha (TNF-α), which is approved for the treatment of chronic inflammatory bowel disease (IBD) such as Crohn's disease (CD), fistulating Crohn's disease (FCD), ulcerative colitis (UC), and paediatric ulcerative colitis (PUC) from 6 years onwards. Besides its therapeutic efficacy, this antibody therapy is characterised by its side effects profile, which has been addressed in a seperate consensus statement by the Working Group for chronic inflammatory bowel diseases within the Austrian Society for Gastroenterology and Hepatology. Infliximab is an effective treatment option for the above-mentioned indications; however, use of this agent requires special knowledge to assess the benefit-risk profile for each patient individually.

Gut, inflammation and osteoporosis: basic and clinical concepts.

Chronic inflammatory disorders such as inflammatory bowel diseases (IBD) affect bone metabolism and are frequently associated with the presence of osteoporosis. Bone loss is regulated by various mediators of the immune system such as the pro-inflammatory cytokines tumour necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), IL-6, or interferon-gamma. TNF-alpha, a master cytokine in human IBD, causes bone erosions in experimental models and these effects are exerted by osteoclasts. Other TNF-related cytokines such as receptor activator of nuclear factor kappa B (RANK), its ligand, RANKL, and osteoprotegerin are important mediators in inflammatory processes in the gut and are critically involved in the pathophysiology of bone loss. The awareness and early diagnosis of osteoporosis in states of chronic inflammation, together with applied therapies such as bisphosphonates, may be beneficial in inflammation-associated osteoporosis. Although several mechanisms may contribute to osteoporosis in patients with IBD and coeliac disease, inflammation as an important factor has so far been neglected. As key inflammatory mediators in IBD such as TNF-alpha are involved in the disease process both in gut and bone, we hypothesise that neutralisation of TNF-alpha could prove an efficient strategy in the treatment of inflammation-related osteoporosis in the future.

CD1 expression on antigen-presenting cells.

CD1 proteins present self and microbial glycolipids to CD 1-restricted T cells, or in the case of CD1d, to NKT cells. The CD1 family in humans consists of group I proteins CDla, CDlb, CDlc, and CDle and the group II protein CDld. Rodents express only CDld, but as CD1d is broadly expressed and traffics to all endosomal compartments, this single CD1 family member is thereby able to acquire antigens in many subcellular compartments. A complete understanding of the CD 1 family requires an appreciation of which cells express CD1 and how CD1 contributes to the unique function of each cell type. While group I CD 1 expression is limited to thymocytes and professional APCs, CD1d has a wider tissue distribution and can be found on many nonhematopoietic cells. The expression and regulation of CD1 are presented here with particular emphasis on the function of CD1 in thymocytes, B cells, monocytes and macrophages, dendritic cells (DCs), and intestinal epithelial cells (IECs). Altered expression of CD 1 in cancer, autoimmunity, and infectious disease is well documented, and the implication of CD 1 expression in these diseases is discussed.

Interleukin-16 supports the migration of Langerhans cells, partly in a CD4-independent way.

Migration of cutaneous dendritic cells is essential for the induction of primary immune responses. Chemotaxis plays an important part in guiding migrating cells through the skin. Therefore, we investigated the influence of interleukin-16, a potent chemoattractant, on the migratory properties of cutaneous dendritic cells. Interleukin-16 added to murine and human skin explant cultures, enhanced emigration of Langerhans cells as well as dermal dendritic cells out of the skin. In contrast to tumor necrosis factor-alpha, intradermally injected interleukin-16 did not reduce the density of Langerhans cells suggesting a chemotactic rather than a mechanistic migration-inducing effect of interleukin-16. In support of these findings, the known migration-promoting effect of tumor necrosis factor-alpha in skin explant cultures could be neutralized by anti-interleukin-16 antibody and vice versa, indicating different but cooperative ways of action for both cytokines. In whole skin explant cultures blocking of the interleukin-16 effect was also achieved with a monoclonal antibody against CD4, the receptor for interleukin-16. In contrast, in cultures of murine epidermis alone no blocking by anti-CD4 became obvious and in CD4-deficient mice Langerhans cell migration in response to interleukin-16 was maintained. This suggests that another receptor for interleukin-16 might be operative for Langerhans cells in the mouse epidermis. Finally, we detected interleukin-16-positive cells in the dermis of skin explants, tumor necrosis factor-alpha-treated and contact allergen-treated skin. Taken together, it seems likely that locally secreted interleukin-16 might serve to enhance the migration of cutaneous dendritic cells and optimize the response to foreign antigen encountering the skin.

Interferons and their role In inflammation.

Cytokines are pleiotropic molecules showing a wide variety of biologic functions on various cells and tissues, and several different cytokines exert similar and overlapping functions on certain cells. Interferons (IFNs), among the first cytokines identified, play a crucial role in human disease. The IFN cytokine family consists of type I IFNs (IFN-a and IFN-b) and type II IFN (IFN-g). In the first decades of IFN research, type I IFNs were considered primarily as viral inhibitors, whereas type II IFN, also termed "immune IFN", was generally considered to be uniquely involved in immune reactions. This view has changed considerably in the last years. The importance of type I IFNs in inflammation, immunoregulation and T-cell responses has been identified and has changed dramatically our interpretation of the biological relevance of type I and II IFNs. Recent data suggest that IFN-a is a multifunctional immunomodulatory cytokine with profound effects on the cytokine cascade including several anti-inflammatory properties, whereas IFN-g remains a classical proinflammatory cytokine. These different effects on critical mediators of inflammation may also explain why type I and II IFNs are clinically successful in different diseases. These newly identified immunoregulatory and anti-inflammatory functions of type I IFNs may be of importance in the treatment of diseases such as chronic viral hepatitis or multiple sclerosis and help to explain some of the mechanisms of IFNs.

Dendritic cell migration in different micropore filter assays.

Dendritic cells (DC) are highly motile and have been shown to migrate in vitro or in vivo towards various chemoattractants. Micropore filter methods with polycarbonate filters are generally used in these in vitro experiments. Among others, the main drawback of these filters is their thickness, which does not allow any assessment of effects of absolute concentration compared to gradients. The aim of this study was to establish a chemotaxis assay for dendritic cells using nitrocellulose filters, which can be adapted for checkerboard studies to distinguish between chemokinesis and chemotaxis. Immature DC were generated by culture of peripheral blood mononuclear cells using granulocyte-macrophage colony-stimulating factor and interleukin-4. We tested cell migration into nitrocellulose in a Boyden microchemotaxis chamber (leading front assay) and compared this method to the commonly used polycarbonate filter technique. Dendritic cells migrated well into nitrocellulose towards gradients of formyl peptide, complement fragment 5a, and monocyte chemotactic protein-3. The nitrocellulose method appeared to be more sensitive as compared to experiments testing migration across polycarbonate filters. Subsequent checkerboard analyses confirmed chemotactic activities of formyl peptide and complement fragment 5a. However, depending on the assay system, chemotaxis in polycarbonate filters but chemokinesis in nitrocellulose filters were observed for monocyte chemotactic protein-3. Measurement of DC migration in a cellulose nitrate micropore filter assay is more sensitive than the commonly used polycarbonate method and can be adapted for checkerboard analyses.

Activation of caspase-3 by interferon alpha causes interleukin-16 secretion but fails to modulate activation induced cell death.

Interferon alpha (IFN-alpha) is the mainstay in the treatment of chronic hepatitis C virus (HCV) infection. Interleukin-16 (IL-16) attracts CD4+ cells to sites of inflammation and plays a role in the interaction of dendritic cells, T cells and B cells. In this study, we show that IFN-alpha itself induces IL-16 secretion by peripheral blood lymphocytes (PBL) and enhances IL-16 secretion by anti-CD3 stimulated PBL. Pro-IL-16 is cleaved into its active form by caspase-3. IFN-alpha increases caspase-3 mRNA levels in activated T cells (ATC), as shown by Northern blot analysis, whereas IL-16 mRNA levels are not affected by IFN-alpha. IL-16 secretion into culture supernatants correlates tightly with intracellular caspase-3 activity in ATC. In our experiments addition of specific caspase inhibitors did not reduce the proportion of ATC undergoing Fas-mediated cell death, but completely blocked IFN-alpha-induced IL-16 secretion into culture supernatants. In conclusion, our results suggest that IFN-alpha activates caspase-3, thereby increasing secretion of IL-16, whereas IFN-alpha-enhanced Fas-mediated cell death in ATC is not caspase-dependent.

Elevated circulating levels of soluble interleukin-1 receptor type II during interleukin-2 immunotherapy.

Interleukin-1 (IL-1) is a critical mediator of inflammation. Two naturally occurring IL-1 antagonists have been described, namely the IL-1 receptor antagonist (IL-1Ra) and the IL-1 receptor type II (IL-1RII). IL-1RII does not transmit a signal upon binding of IL-1, but competes with the signaling of IL-1RI for binding of IL-1. Shedding of IL-1RII yields the soluble IL-1 receptor type II (IL-1sRII) which retains the ability of membrane-bound IL-1RII to bind IL-1beta avidly, but binds IL-1Ra and IL-1alpha with low affinity. In contrast, IL-1sRI retains the ability of membrane-bound IL-1RI to bind IL-1Ra and IL-1alpha with high affinity, but binds IL-1beta poorly. We have previously shown that immunotherapy with IL-2 or IL-6 in cancer patients is associated with a dramatic increase in IL-1Ra plasma levels. In the present study, plasma levels of soluble IL-1 receptors were monitored in healthy individuals and cancer patients. In healthy controls, the mean IL-1sRII level was 4.76 0.16 ng/ml. IL-1sRII levels in cancer patients were comparable to those measured in healthy controls. IL-1sRII levels did not vary during the first 52 hours after initiation of IL-2 therapy, but increased significantly thereafter to reach 9.56 1.16 ng/ml on day 5. In contrast, IL-6 immunotherapy with a 5-day continuous infusion did not trigger an increase in IL-1sRII levels. IL-1sRI levels did not increase during immunotherapy with IL-2 or IL-6. Our results indicate that IL-1sRII, unlike IL-1Ra, remains a modest, natural, anti-inflammatory mechanism triggered by immunotherapy with IL-2, but not with IL-6.

CD40 ligand-dependent maturation of human monocyte-derived dendritic cells by activated platelets.

Atherosclerosis is defined as an inflammatory immunological disease that is triggered by platelet activation, endothelial injury and consequent innate and adaptive immune processes. Dendritic cells are critical for the cell-mediated arm of the immune response as they activate naïve T cells after maturation. Platelets play a crucial role in thrombus formation in the injured vessel walls. We investigated the role of resting and thrombin-activated platelets in dendritic cell maturation in vitro using platelets and monocyte-derived dendritic cells from healthy donors. Resting platelet supernatants did not affect maturation, whereas supernatants from thrombin-activated platelets induced dendritic cell maturation as demonstrated by FACS analysis of HLA-DR expression. This effect was inhibited by anti CD40 ligand antibody, but not by aspirin pretreatment of platelets. Supernatants of platelet-dendritic cell co-cultures induced augmented monocyte migration when platelets were activated by thrombin, again reversible by blocking CD40 ligand. These data show that activated platelets trigger dendritic cell maturation independent of cyclooxygenase-derived arachidonic acid metabolites by mechanisms involving CD40 ligand, which is also involved in monocyte chemotactic mediator release from platelets and dendritic cells. The results of this study suggest a role of CD40 ligand from activated platelets in connecting innate and adaptive immunity.

IL-6 and arthritis: a detrimental or beneficial mediator?

Acute inflammation is accompanied by changes in the concentrations of several plasma proteins. Cytokines play a crucial role in the regulation of inflammatory events. Inflammatory disorders such as rheumatoid arthritis are characterized by an overproduction of several cytokines including interleukin-6 (IL-6). Recent data suggest that IL-6 and other members of the IL-6-cytokine family have anti-inflammatory and immunosuppressive properties, and therefore may negatively regulate inflammatory processes.

Infliximab in severe steroid-refractory ulcerative colitis: a pilot study.

Tumor necrosis factor-alpha (TNF alpha)-neutralization by infliximab has previously proven efficacious in chronic active Crohn's disease (CD). We performed an open-label pilot study of a single infusion of 5 mg/kg infliximab in six patients with severe active, steroid-refractory ulcerative colitis (UC). Clinical activity was evaluated according to Lichtiger on days -1, day 7, and day 28. Colonoscopy with biopsy was performed on day -1 and day 7. All patients showed marked clinical improvement by day 7 (Lichtiger score 16.3 +/- 0.4 [day -1] vs 4.8 +/- 0.7 [day 7], p < 0.0001). Four of six patients had long-term remission (Lichtiger score 7.7 +/- 2.2 [day 28], P < 0.01 compared to day -1), with a median follow-up of 5.5 months. Colonoscopy confirmed significant healing of endoscopic lesions. The inflammatory infiltrate disappeared on H&E stains, with a marked reduction in infiltrating neutrophils. Semiquantitative evaluation of T and B lymphocytes and macrophages by immunohistochemistry did not reveal major differences compared to pre-treatment. Apoptotic cells in the mucosa were reduced on day 7. Our data point toward a novel efficacious treatment option in severe steroid-refractory UC and raise the need for controlled trials.