Analysis of mast cells and mast cell-mediator-related histological features in cholinergic urticaria

Mastzellen wird eine zentrale Rolle in der Pathophysiologie der chronischen Urtikaria einschließlich der cholinergischen Urtikaria (CholU) zugeschrieben. Obwohl die genaue Rolle von Mastzellen bei der CholU nicht gut verstanden ist, wird davon ausgegangen, dass Anstrengung und Schwitzen zu deren Degranulation führt. Mastzell-Mediatoren wie Histamin werden für die typischen Symptome der CholU, wie Quaddeln, Rötungen und oftmals starken Juckreiz verantwortlich gemacht. Obwohl die CholU eine schon lange bekannte Erkrankung ist, die klinisch gut charakterisiert ist, gibt es nur sehr wenige Daten die die Rolle von Mastzellen in der Pathogenese der CholU stützen. In dieser Studie hatten wir daher zum Ziel, die Rolle von Mastzellen bei CholU besser zu chrakterisieren. Von klinisch sehr gut charakterisierten Patienten wurden daher Haut- und Blutproben vor und nach einer Puls-kontrollierten Ergometrie (PCE) gewonnen, die Anzahl der Mastzellen in der Haut bestimmt, Mastzell-aktivierende Faktoren wie gesamt-IgE und spezifisches IgE untersucht, Mastzell-Produkte wie Tryptase quantifiziert, die Expression von Rezeptoren für Mastzell-Produkte ermittelt und nicht-IgE vermittelte Mastzell-Aktivierungswege und -Mechanismen wie Acethylcholine/Achethylcholine-Esterase Dysregulierung untersucht. In dieser Studie wurden insgesamt Proben von 13 CholU Patienten und 13 passenden gesunden Kontrollpersonen untersucht. Die CholU Patienten in unserer Kohorte wiesen einen langen Krankheitsverlauf auf und waren meist moderat von der Erkrankung betroffen. In der PCE wiesen Patienten mit CholU ein zeitlich ähnliches aber geringeres Schwitzverhalten im Vergleich zu den gesunden Kontrollen auf. CholU Patienten hatten mehr atopische Stigmata und erhöhte gesamt-IgE Spiegel auf. Einige Patienten wiesen spezifisches IgE gegen den Hautkeim Malassezia auf, das mit längerer Krankheitsdauer assoziiert war. Die Anzahl der Mastzellen in der Haut von CholU Patienten war signifikant erhöht im Vergleich zu gesunden Kontrollen, jedoch konnte wir keine Degranulation der Mastzellen detektieren. Im Serum der Patienten zeigte sich keine Erhöhung der Tryptase, trotz oft stark ausgeprägten Hautbeschwerden nach Provokationstestung. In der Haut von CholU Patienten zeigte sich eine niedrige Expression von Histamin H1 und H2 Rezeptoren und eine hohe Expression der H4 Rezeptoren. H3 Rezeptorexpression konnte nicht nachgewiesen werden. Zusammengefasst ergab unsere Studie eine signifikante Erhöhung der Anzahl kutaner Mastzellen, was auf eine wichtige Rolle in der Pathophysiologie der Erkrankung hinweist, auch wenn die genaue Rolle weiterhin unklar bleibt. Außerdem sahen wir unterschiedliche Histaminrezeptorexpressionsmuster, jedoch müssen hier noch weitere Untersuchungen folgen, um konkrete Schlussfolgerungen ziehen zu können.Mast cells (MCs) are thought to be key effector cells in chronic urticaria including cholinergic urticaria (CholU). Although the pathophysiology of CholU is not well understood, degranulation of mast cells upon exercise and sweating with subsequent release of histamine and other mediators are held to provoke the elicitation of small wheals, flare and often severe itch. However, as of now, only little data support this theory. Accordingly, this study aimed to better characterize the role of MCs in CholU. To this end, we clinically characterized patients with CholU, collected histological samples of the skin before and after puls-controlled provocation testing (PCE), analyzed them for skin MC numbers, analyzed MC activating factors like total and specific IgE, analyzed MC products such as tryptase, investigated the expression of MC product-related receptors like histamine receptors, and looked for non-IgE mediated mast cell activation pathways and mechanisms including acethylcholine/achethylcholine esterase dysregulation. We characterized 13 CholU patients and 13 matched healthy controls. Clinically, patients with CholU in our cohort had a long duration of disease and rated themselves as mostly moderately affected. PCE testing showed comparable onset of sweating in patients with CholU and healthy persons, but most of the patients with CholU had decreased sweating responses. Atopic predisposition was frequent in patients with CholU, and total IgE serum levels were elevated. Specific IgE against the skin resident fungi Malassezia was only seen in CholU patients and may be a marker for more prolonged courses of disease. Our results showed that MC numbers were increased in the skin of CholU patients compared to healthy controls, but we failed in detecting degranulation of MCs upon exercise challenge. The MC mediator tryptase did not increase in the serum upon provocation in CholU patients, despite often severe skin symptoms. Skin of CholU patients expressed low levels of H1 and H2 receptors, high levels of H4 receptors, but no H3 receptors. In summary, the increase in skin MC numbers in CholU patients points towards a role of MC in the pathology of the disease, albeit the exact role remains unclear, as we failed to prove degranulation. It is worth nothing that differences in cutaneous histamine receptor expression were seen, but for meaningful conclusions, further analyses in a larger number of patients are needed

A Vanishing Theorem for Varieties with Finitely Many Solvable Group Orbits

We reprove and generalize the result that the intersection cohomology groups of a toric variety with coefficient in a nontrivial rank one local system vanish. We prove a similar vanishing result for a certain class of varieties on which a connected linear solvable group acts, including all spherical varieties

Systemic similarity analysis of compatibility drug-induced multiple pathway patterns _in vivo_

A major challenge in post-genomic research is to understand how physiological and pathological phenotypes arise from the networks of expressed genes and to develop powerful tools for translating the information exchanged between gene and the organ system networks. Although different expression modules may contribute independently to different phenotypes, it is difficult to interpret microarray experimental results at the level of single gene associations. The global effects and response pathways of small molecules in cells have been investigated, but the quantitative details of the activation mechanisms of multiple pathways _in vivo_ are not well understood. Similar response networks indicate similar modes of action, and gene networks may appear to be similar despite differences in the behaviour of individual gene groups. Here we establish the method for assessing global effect spectra of the complex signaling forms using Global Similarity Index (GSI) in cosines vector included angle. Our approach provides quantitative multidimensional measures of genes expression profile based on drug-dependent phenotypic alteration _in vivo_. These results make a starting point for identifying relationships between GSI at the molecular level and a step toward phenotypic outcomes at a system level to predict action of unknown compounds and any combination therapy

An evacuation simulation model of pedestrian flow using Bayesian Nash equilibrium and a Multi-Agent System

The shortage of experimental data for individual behaviours has hampered systematic research on pedestrian behaviours and the refined development of evidence informed rules for pedestrian movement in simulation models. This research proposes an evacuation simulation model of pedestrian flow based on Bayesian Nash Equilibrium (BNE) and Multi-Agent System (MAS). In this paper, BNE was used to augment the logics of pedestrian decision-making processes in an evacuation MAS simulation and to improve evacuating agents’ movement and behaviours. A detailed introduction of the construction process and implementation details for the initial model as well as the visualization of experiment results are provided in this paper. Limitations and several potential future research directions are also identified

Direction-of-Arrival Estimation Based on Joint Sparsity

We present a DOA estimation algorithm, called Joint-Sparse DOA to address the problem of Direction-of-Arrival (DOA) estimation using sensor arrays. Firstly, DOA estimation is cast as the joint-sparse recovery problem. Then, norm is approximated by an arctan function to represent joint sparsity and DOA estimation can be obtained by minimizing the approximate norm. Finally, the minimization problem is solved by a quasi-Newton method to estimate DOA. Simulation results show that our algorithm has some advantages over most existing methods: it needs a small number of snapshots to estimate DOA, while the number of sources need not be known a priori. Besides, it improves the resolution, and it can also handle the coherent sources well

Contrastive Image Synthesis and Self-supervised Feature Adaptation for Cross-Modality Biomedical Image Segmentation

This work presents a novel framework CISFA (Contrastive Image synthesis and Self-supervised Feature Adaptation)that builds on image domain translation and unsupervised feature adaptation for cross-modality biomedical image segmentation. Different from existing works, we use a one-sided generative model and add a weighted patch-wise contrastive loss between sampled patches of the input image and the corresponding synthetic image, which serves as shape constraints. Moreover, we notice that the generated images and input images share similar structural information but are in different modalities. As such, we enforce contrastive losses on the generated images and the input images to train the encoder of a segmentation model to minimize the discrepancy between paired images in the learned embedding space. Compared with existing works that rely on adversarial learning for feature adaptation, such a method enables the encoder to learn domain-independent features in a more explicit way. We extensively evaluate our methods on segmentation tasks containing CT and MRI images for abdominal cavities and whole hearts. Experimental results show that the proposed framework not only outputs synthetic images with less distortion of organ shapes, but also outperforms state-of-the-art domain adaptation methods by a large margin

Ramified cover of varieties with nef cotangent bundle

We construct examples to show that having nef cotangent bundle is not preserved under finite ramified covers. Our examples also show that a projective manifold with Stein universal cover may not have nef cotangent bundle, disproving a conjecture of Liu–Maxim–Wang [7]

Ramified cover of varieties with nef cotangent bundle

We construct examples to show that having nef cotangent bundle is not preserved under finite ramified covers. Our examples also show that a projective manifold with Stein universal cover may not have nef cotangent bundle, disproving a conjecture of Liu-Maxim-Wang