Megaoesofagus bij hond en kat

Megaoesofagus wordt gekarakteriseerd door een gedilateerde slokdarm met een verminderde peristaltiek. Het is de meest voorkomende oorzaak van regurgitatie bij de hond. De ziekte komt zelden voor bij de kat. De aandoening kan congenitaal zijn of verworven worden. Bij de aangeboren vorm komen de symptomen meestal pas tot uiting rond de speenleeftijd. Een erfelijke basis werd aangetoond bij bepaalde rassen. De verworven vorm ontstaat meestal op volwassen leeftijd, met een erg ruime leeftijdsmarge. Regurgitatie en ademhalingsproblemen zijn de meest voorkomende symptomen. De diagnose wordt gesteld door middel van radiografie of fluoroscopie. Bijkomende onderzoeken zijn doorgaans aangewezen om een onderliggende oorzaak op te sporen. In ongeveer de helft van de gevallen wordt geen onderliggende oorzaak gevonden en wordt de megaoesofagus beschouwd als zijnde idiopathisch. Patiënten met megaoesofagus worden meestal conservatief en symptomatisch behandeld. De onderliggende ziekte, slechte voeding en verslikkingspneumonie vereisen een directe en grondige aanpak. De prognose is vaak gereserveerd bij de hond. Bij congenitale megaoesofagus beschrijft men iets gunstigere vooruitzichten. Katten lijken beter te reageren op de ingestelde behandeling

The mucosal adjuvant cholera toxin B instructs non-mucosal dendritic cells to promote IgA production via retinoic acid and TGF-β

It is currently unknown how mucosal adjuvants cause induction of secretory immunoglobulin A (IgA), and how T cell-dependent (TD) or -independent (TI) pathways might be involved. Mucosal dendritic cells (DCs) are the primary antigen presenting cells driving TI IgA synthesis, by producing a proliferation-inducing ligand (APRIL), B cell activating factor (BAFF), Retinoic Acid (RA), TGF-beta or nitric oxide (NO). We hypothesized that the mucosal adjuvant Cholera Toxin subunit B (CTB) could imprint non-mucosal DCs to induce IgA synthesis, and studied the mechanism of its induction. In vitro, CTB-treated bone marrow derived DCs primed for IgA production by B cells without the help of T cells, yet required co-signaling by different Toll-like receptor (TLR) ligands acting via the MyD88 pathway. CTB-DC induced IgA production was blocked in vitro or in vivo when RA receptor antagonist, TGF-beta signaling inhibitor or neutralizing anti-TGF-beta was added, demonstrating the involvement of RA and TGF-beta in promoting IgA responses. There was no major involvement for BAFF, APRIL or NO. This study highlights that synergism between CTB and MyD88-dependent TLR signals selectively imprints a TI IgA-inducing capacity in non-mucosal DCs, explaining how CTB acts as an IgA promoting adjuvant

Large-scale Scanning Transmission Electron Microscopy (Nanotomy) of Healthy and Injured Zebrafish Brain

textabstractLarge-scale 2D electron microscopy (EM), or nanotomy, is the tissue-wide application of nanoscale resolution electron microscopy. Others and we previously applied large scale EM to human skin pancreatic islets, tissue culture and whole zebrafish larvae1-7. Here we describe a universally applicable method for tissue-scale scanning EM for unbiased detection of sub-cellular and molecular features. Nanotomy was applied to investigate the healthy and a neurodegenerative zebrafish brain. Our method is based on standardized EM sample preparation protocols: Fixation with glutaraldehyde and osmium, followed by epoxy-resin embedding, ultrathin sectioning and mounting of ultrathin-sections on onehole grids, followed by post staining with uranyl and lead. Large-scale 2D EM mosaic images are acquired using a scanning EM connected to an external large area scan generator using scanning transmission EM (STEM). Large scale EM images are typically ~ 5 - 50 G pixels in size, and best viewed using zoomable HTML files, which can be opened in any web browser, similar to online geographical HTML maps. This method can be applied to (human) tissue, cross sections of whole animals as well as tissue culture1-5. Here, zebrafish brains were analyzed in a noninvasive neuronal ablation model. We visualize within a single dataset tissue, cellular and subcellular changes which can be quantified in various cell types including neurons and microglia, the brain's macrophages. In addition, nanotomy facilitates the correlation of EM with light microscopy (CLEM)8 on the same tissue, as large surface areas previously imaged using fluorescent microscopy, can subsequently be subjected to large area EM, resulting in the nano-anatomy (nanotomy) of tissues. In all, nanotomy allows unbiased detection of features at EM level in a tissue-wide quantifiable manner

Canine non-structural megaesophagus as a clinical sign of potential neurological disease: 99 cases

Knowledge regarding the etiology and prognosis for canine megaesophagus (ME) is currently limited to small case series that may now be out-of-date in light of recent advances in the understanding of neurological syndromes and the availability of advanced diagnostic testing. Ninety-nine dogs diagnosed with non-structural ME were included. Congenital idiopathic ME was present in 10 cases, with complete resolution of clinical signs in only a single case. Eighty-nine cases were considered acquired with most cases being either idiopathic (42.7%) or associated with myasthenia gravis (38.2%). Idiopathic cases represented a smaller percentage of acquired ME than previously reported. Death or euthanasia directly related to ME occurred in almost 50% of acquired cases, whilst clinical signs persisted in around 20% of cases and resolved in 30% of cases. A diagnosis of an underlying etiology, in particular myasthenia gravis, was associated with a better outcome in acquired ME. Megaesophagus continues to be a challenging condition to manage, with a guarded to poor prognosis, particularly when an underlying etiology is not identified. Thorough diagnostic testing for an underlying neurological disorder is important in cases with ME as this may allow institution of appropriate treatment and the potential for a better prognosis

Unraveling university-community engagement:a literature review

University-community engagement has been implemented by an increasing number of universities across the world, in a period characterized by growing international competition. The growing interest in university-community engagement has resulted in a variety of definitions and a high level of complexity as to what the concept means and what it entails. Using a literature review, this paper offers a critical assessment of the academic literature on university-community engagement. The paper aims to provide insight into trends, commonalities and variation in the literature, to enable the identification of an agenda for future research. Four main gaps in the literature are distinguished. The paper calls for a more critical conceptual discussion that should be supported by empirical research. The paper suggests to broaden the theoretical lens, and the use of particular research approaches such as theories of change, in order to obtain a more comprehensive understanding of the concept of university-community engagement

Unraveling university-community engagement : a literature review

University-community engagement has been implemented by an increasing number of universities across the world, in a period characterized by growing international competition. The growing interest in university-community engagement has resulted in a variety of definitions and a high level of complexity as to what the concept means and what it entails. Using a literature review, this paper offers a critical assessment of the academic literature on university-community engagement. The paper aims to provide insight into trends, commonalities and variation in the literature, to enable the identification of an agenda for future research. Four main gaps in the literature are distinguished. The paper calls for a more critical conceptual discussion that should be supported by empirical research. The paper suggests to broaden the theoretical lens, and the use of particular research approaches such as theories of change, in order to obtain a more comprehensive understanding of the concept of university-community engagement.PostprintPeer reviewe

Canine nonstructural megaesophagus as a clinical sign of potential neurological disease : 99 cases

Knowledge regarding the etiology and prognosis for canine megaesophagus (ME) is currently limited to small case series that may now be out of date in light of recent advances in the understanding of neurological syndromes and the availability of advanced diagnostic testing. Ninety-nine dogs diagnosed with nonstructural ME were included. Congenital idiopathic ME was present in 10 cases, with complete resolution of clinical signs in a single case. Eighty-nine cases were considered acquired, with most cases being either idiopathic (42.7%) or associated with myasthenia gravis (38.2%). Idiopathic cases represented a smaller percentage of acquired ME than previously reported. Death or euthanasia directly related to ME occurred in almost 50% of acquired cases, whereas clinical signs persisted in w20% of cases and resolved in 30% of cases. A diagnosis of an underlying etiology, in particular myasthenia gravis, was associated with a better outcome in acquired ME. ME continues to be a challenging condition to manage, with a guarded-to-poor prognosis, particularly when an underlying etiology is not identified. Thorough diagnostic testing for an underlying neurological disorder is important in cases with ME as this may allow institution of appropriate treatment and the potential for a better prognosis

Differential effects of anaphylatoxin C5a on antigen presenting cells, roles for C5aR1 and C5aR2

The anaphylatoxin C5a is well-known for its role as chemoattractant and contributes to immune cell recruitment into inflamed tissue and local inflammation. C5a has recently been implicated in modulation of antigen presenting cell function, such as macrophages and dendritic cells, which are pivotal for T cell activation and final T cell effector function. The published data on the effect of C5a on APC function and subsequent adaptive immune responses are in part conflicting, as both pro and anti-inflammatory effects have been described. In this review the opposing effects of C5a on APC function in mice and human are summarized and discussed in relation to origin of the involved APC subset, being either of the monocyte-derived lineage or dendritic cell lineage. In addition, the current knowledge on the expression of C5aR1 and C5aR2 on the different APC subsets is summarized. Based on the combined data, we propose that the differential effects of C5a on APC function may be attributed to absence or presence of co-expression of C5aR2 and C5aR1 on the specific APC

Crosstalk between Toll like receptors and C5a receptor in human monocyte derived DCs suppress inflammatory cytokine production

The complement anaphylatoxin, C5a has been implicated in regulation of adaptive immune responses through modulation of APC function as shown mainly in studies in mice. C5a was shown to enhance cytokine production in immature DCs, but the effect of C5a on DC function during DC activation has not been elucidated in human. In this study we investigated the effect of C5a on human monocyte derived DCs when simultaneously stimulated with TLR ligands. While C5a indeed enhanced cytokine production of immature DCs, the addition of C5a inhibited production of IL-12, IL-23 and TNFα induced by various TLR ligands such as LPS, R848 and Pam(3)CSK(4). The inhibitory effect of C5a on LPS induced IL-6 production was less pronounced and LPS induced IL-10 was not affected at all. This indicates that C5aR signaling has a differential effect on human DC differentiation depending on the crosstalk with other receptors. Furthermore we found that C5a affects the LPS induced cytokines in a small time frame, and requires almost concurrent signaling of C5a receptor and TLR4. These data emphasize the complexity of DC regulation by anaphylatoxins. While complement activation may provide proinflammatory signals to immature DCs in the absence of pathogens, the same products may serve to downmodulate or deviate immune responses upon combat against infections. These context depending effects of anaphylatoxins on immune responses may have important implications for the emerging use of complement inhibitors in clinical practic

TLR4 and C5aR crosstalk in dendritic cells induces a core regulatory network of RSK2, PI3K, SGK1, and FOXO transcription factors

Crosstalk between complement component 5a receptors (C5aRs) and TLRs in dendritic cells (DCs) occurs upon pathogen invasion; however, studies on C5aR and TLR crosstalk mainly focused on the modulating effect of C5a on TLR-induced cytokine production. To elucidate the breadth of C5aR and TLR4 crosstalk, the effect of simultaneous treatment with C5a and LPS was investigated in human monocyte-derived DCs (moDCs) 2 h after stimulation using whole transcriptome sequencing analysis. Although the effect of C5a on hallmark genes defining TLR4-induced DC maturation was limited at this time point, RNA sequencing analysis revealed a great variety of novel C5a targets, of which many interfere with TLR4-mediated immune activation. Analysis of functional relationships among these genes uncovered induction of a central immune regulatory network upon C5aR and TLR4 crosstalk, involving the transcription factors forkhead box (FOX)O1 and FOXO3 and the signaling molecules serum- and glucocorticoid-inducible kinase (SGK1), ribosomal S6 kinase 2 (RSK2), and PI3K. C5aR and TLR crosstalk, furthermore, yielded down-regulation of mainly proinflammatory network branches, including IL-12B, IL-2R (IL-2RA), and jagged 1 (JAG1) and cooperative induction of predominantly anti-inflammatory network branches, including sphingosine kinase 1 (SPHK1), 2 adrenergic receptor (ADRB2), gastric inhibitory polypeptide receptor (GIPR), and four-and-a-half Lin11, Isl-1, and Mec-3 domains protein 2 (FHL2). Together, these data point toward induction of generalized immune regulation of DC function. Motif enrichment analysis indicate a prominent role for basic leucine zipper (bZIP) and IFN regulatory factor 4 (IRF4) transcription factors upon C5aR and TLR4 crosstalk. Additionally, differences were observed in the modulating capacity of C5a on DCs in the absence or presence of a pathogen (TLR stimulus). Our findings shed new light on the depth and complexity of C5aR and TLR4 crosstalk and provide new foci of research for future studie