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El ballet ecuestre La contesa dell’Aria e dell’Acqua fue una de las fiestas mas espectaculares de la corte imperial de Viena durante todo el siglo XVII. Se celebro el 24 de enero de 1667 con motivo de la boda del emperador Leopoldo I con su sobrina, la infanta Margarita, hija del monarca espanol Felipe IV con la hermana de Leopoldo, Mariana de Austria. El espectaculo esta muy bien documentado por la relacion oficial de la fiesta y por varios informes impresos. La descripcion de Francesco Sbarra, editada en italiano y en aleman, incluye gran cantidad de estampas y contiene la partitura impresa de la musica de Johann Heinrich Schmelzer. La perspectiva digital aporta una nueva dimension de esta fiesta a partir de la animacion de las estampas contenidas en la relacion de Francesco Sbarra. La intencion ha sido introducir, con ayuda de la narrativa grafica, una realidad virtual en movimiento, reconstruyendo la compleja coreografia puesta en escena tanto a caballo como a pie, ademas mostrar el recorrido de las grandiosas maquinas escenograficas en el patio del palacio imperial.

Immune checkpoint inhibition with ipilimumab has revolutionized cancer immunotherapy and significantly improved outcomes of patients with advanced malignant melanoma. Local peripheral treatments (LPT), such as radiotherapy or electrochemotherapy, have been shown to modulate systemic immune responses, and preliminary data have raised the hypothesis that the combination of LPT with systemic immune checkpoint blockade might be beneficial. Clinical data from 127 consecutively treated melanoma patients at four cancer centers in Germany and Switzerland were analyzed. Patients received either ipilimumab (n = 82) or ipilimumab and additional LPT (n = 45) if indicated for local tumor control. The addition of LPT to ipilimumab significantly prolonged overall survival (OS; median OS 93 vs. 42 weeks, unadjusted HR, 0.46; P = 0.0028). Adverse immune-related events were not increased by the combination treatment, and LPT-induced local toxicities were in most cases mild. In a multivariable Cox regression analysis, we show that the effect of added LPT on OS remained statistically significant after adjusting for BRAF status, tumor stage, tumor burden, and central nervous system metastases (adjusted HR, 0.56; 95% confidence interval, 0.31–1.01, P = 0.05). Our data suggest that the addition of LPT to ipilimumab is safe and effective in patients with metastatic melanoma irrespective of clinical disease characteristics and known risk factors. Induction of antitumor immune responses is most likely the underlying mechanism and warrants prospective validation. Cancer Immunol Res; 4(9); 744–54. ©2016 AACR.

Within the last decade, vitamin D has emerged as a central regulator of host defense against infections. In this regard, vitamin D triggers effective antimicrobial pathways against bacterial, fungal and viral pathogens in cells of the human innate immune system. However, vitamin D also mediates potent tolerogenic effects: it is generally believed that vitamin D attenuates inflammation and acquired immunity, and thus potentially limits collateral tissue damage. Nevertheless, several studies indicate that vitamin D promotes aspects of acquired host defense. Clinically, vitamin D deficiency has been associated with an increased risk for various infectious diseases in epidemiological studies; yet, robust data from controlled trials investigating the use of vitamin D as a preventive or therapeutic agent are missing. In this review, we summarize the current knowledge regarding the effect of vitamin D on innate and acquired host defense, and speculate on the difficulties to translate the available molecular medicine data into practical therapeutic or preventive recommendations.

The ability of T cells to activate antimicrobial pathways in infected macrophages is essential to host defence against many intracellular pathogens. Here, we compared the ability of two T-cell-mediated mechanisms to trigger antimicrobial responses against Mycobacterium tuberculosis in humans, CD40 activation and the release of interferon-γ (IFN-γ). Given that IFN-γ activates a vitamin D-dependent antimicrobial response, we focused on induction of the key components of this pathway. We show that activation of human monocytes via CD40 ligand (CD40L) and IFN-γ, alone, and in combination, induces the CYP27b1-hydroxylase, responsible for the conversion of 25-hydroxyvitamin D (25D) to the bioactive 1,25-dihydroxyvitamin D (1,25D), and the vitamin D receptor (VDR). The activation of the vitamin D pathway by CD40L and IFN-γ results in up-regulated expression of the antimicrobial peptides, cathelicidin and DEFB4, as well as induction of autophagy. Finally, activation of monocytes via CD40L and IFN-γ results in an antimicrobial activity against intracellular M. tuberculosis. Our data suggest that at least two parallel T-cell-mediated mechanisms, CD40L and IFN-γ, activate the vitamin D-dependent antimicrobial pathway and trigger antimicrobial activity against intracellular M. tuberculosis, thereby contributing to human host defence against intracellular infection.

Glucocorticoids are extensively used to treat inflammatory diseases; however, their chronic intake increases the risk for mycobacterial infections. Meanwhile, the effects of glucocorticoids on innate host responses are incompletely understood. In this study, we investigated the direct effects of glucocorticoids on antimycobacterial host defense in primary human macrophages. We found that glucocorticoids triggered the expression of cathelicidin, an antimicrobial critical for antimycobacterial responses, independent of the intracellular vitamin D metabolism. Despite upregulating cathelicidin, glucocorticoids failed to promote macrophage antimycobacterial activity. Gene expression profiles of human macrophages treated with glucocorticoids and/or IFN-γ, which promotes induction of cathelicidin, as well as antimycobacterial activity, were investigated. Using weighted gene coexpression network analysis, we identified a module of highly connected genes that was strongly inversely correlated with glucocorticoid treatment and associated with IFN-γ stimulation. This module was linked to the biological functions autophagy, phagosome maturation, and lytic vacuole/lysosome, and contained the vacuolar H+-ATPase subunit a3, alias TCIRG1, a known antimycobacterial host defense gene, as a top hub gene. We next found that glucocorticoids, in contrast with IFN-γ, failed to trigger expression and phagolysosome recruitment of TCIRG1, as well as to promote lysosome acidification. Finally, we demonstrated that the tyrosine kinase inhibitor imatinib induces lysosome acidification and antimicrobial activity in glucocorticoid-treated macrophages without reversing the anti-inflammatory effects of glucocorticoids. Taken together, we provide evidence that the induction of cathelicidin by glucocorticoids is not sufficient for macrophage antimicrobial activity, and identify the vacuolar H+-ATPase as a potential target for host-directed therapy in the context of glucocorticoid therapy.

Biosimilars sind Nachfolgeprodukte biotechnologischer Arzneimittel (Biopharmazeutika), deren Patentschutz abgelaufen ist. In der EU-Gesetzgebung wurde der Begriff “einem biologischen Referenzarzneimittel ahnliches biologisches Arzneimittel” (Biosimilar) gepragt, da ein biopharmazeutisches Nachahmerpraparat nur ahnlich (similar), aber nicht identisch mit dem Originalpraparat sein kann.

The rumen, the foregut of herbivorous ruminant animals such as cattle, functions as a bioreactor to process complex plant material. Among the numerous and diverse microbes involved in ruminal digestion are the ruminal protozoans, which are single-celled, ciliated eukaryotic organisms. An activity-based screen was executed to identify genes encoding fibrolytic enzymes present in the metatranscriptome of a bovine ruminal protozoan-enriched cDNA expression library. Of the four novel genes identified, two were characterized in biochemical assays. Our results provide evidence for the effective use of functional metagenomics to retrieve novel enzymes from microbial populations that cannot be maintained in axenic cultures.

Metabotropic GABA(B) receptors are abundantly expressed at glutamatergic synapses where they control excitability of the synapse. Here, we tested the hypothesis that glutamatergic neurotransmission may regulate GABA(B) receptors. We found that application of glutamate to cultured cortical neurons led to rapid down-regulation of GABA(B) receptors via lysosomal degradation. This effect was mimicked by selective activation of AMPA receptors and further accelerated by coactivation of group I metabotropic glutamate receptors. Inhibition of NMDA receptors, blockade of L-type Ca(2+) channels, and removal of extracellular Ca(2+) prevented glutamate-induced down-regulation of GABA(B) receptors, indicating that Ca(2+) influx plays a critical role. We further established that glutamate-induced down-regulation depends on the internalization of GABA(B) receptors. Glutamate did not affect the rate of GABA(B) receptor endocytosis but led to reduced recycling of the receptors back to the plasma membrane. Blockade of lysosomal activity rescued receptor recycling, indicating that glutamate redirects GABA(B) receptors from the recycling to the degradation pathway. In conclusion, the data indicate that sustained activation of AMPA receptors down-regulates GABA(B) receptors by sorting endocytosed GABA(B) receptors preferentially to lysosomes for degradation on the expense of recycling. This mechanism may relieve glutamatergic synapses from GABA(B) receptor-mediated inhibition resulting in increased synaptic excitability.

Inszenierung bestimmt unser Leben: Soziales Handeln bedarf Rollen und Spielregeln. Mediale Selbstinszenierungen erheischen Aufmerksamkeit, um ins Spiel zu kommen. Und die Politik bedient sich der Inszenierung, um Authentizität vorzuspielen. Aber auch die Erinnerung führt Regie, konstruiert das Chaos von Begebenheiten zu identitätsstiftenden Erzählungen - Gedächtnis ist inszenierte Vergangenheit. Die Kunst thematisiert Spiele und Regeln, vermag vergessene zu aktualisieren und neue zu erfinden. Dieser Band fragt nach dem Wechselspiel von Inszenierung und Gedächtnis, Bedeutetes zu verwirklichen und Verwirklichtes zu bedeuten, in Politik, Wissen, Kunst und Gesellschaft.

Background: We sought to determine the histologic effects of metal stent placement on tumor tissue and on normal tissue proximal and distal to the tumor in patients with expandable metal stents implanted in vivo. Methods: Twelve patients with 10 to 16 mm uncovered Wallstents were studied, 5 with esophageal stents, 4 with biliary stents and 3 with antral-duodenal stents. Stent duration ranged from 18 days to 15 months. Eleven autopsy specimens and one surgical specimen were examined. The organs with the stent in place were removed, and histologic specimens were obtained using a special saw-microtome that cuts through the tissue and the material of the stent. Results: In all organs examined, the stent was incorporated into the material of the tumor to a varying degree. In the normal areas above and below the stenosis, the stent was incorporated into the wall of the organ and was covered by a collagenous reactive layer on the luminal aspect. The collagenous reaction was limited and did not cause exuberant growth or obstruction in any of the cases. Conclusions: The struts of uncovered Wallstents of 10 to 16 mm in diameter migrate into the submucus space above and below the tumor, probably by pressure necrosis, and become incorporated into the wall of the organ. (Gastrointest Endosc 1996;43:596-602.)

Melorheostosis of the hand is rare. We report a 7-year-old girl who presented with a contracture of the left hand. Diagnosis was made by conventional radiography and bone scintigraphy. MRI proved to be a very useful tool to visualize the soft-tissue changes. This is especially important when surgical repair is considered.