An essential role for transmembrane TNF in the resolution of the inflammatory lesion induced by Leishmania major infection.

TNF is an essential player in infections with Leishmania major, contributing to the control of the inflammatory lesion and, to a lesser degree, to parasite killing. However, the relative contribution of the soluble and transmembrane forms of TNF in these processes is unknown. To investigate the role of transmembrane TNF (mTNF) in the control of L. major infections, mTNF-knock-in (mTNF(Delta/Delta)) mice, which express functional mTNF but do not release soluble TNF, were infected with L. major, and the development of the inflammatory lesion and the immune response was compared to that occurring in L. major-infected TNF(-/-) and wild-type mice. mTNF(Delta/Delta) mice controlled the infection and resolved their inflammatory lesion as well as wild-type mice, a process associated with the early clearance of neutrophils at the site of parasite infection. In contrast, L. major-infected TNF(-/-) mice developed non-healing lesions, characterized by an elevated presence of neutrophils at the site of infection and partial control of parasite number within the lesions. Altogether, the results presented here demonstrate that mTNF, in absence of soluble TNF, is sufficient to control infection due to L. major, enabling the regulation of inflammation, and the optimal killing of Leishmania parasites at the site of infection.

Les rachialgies inflammatoires [Inflammatory back pain]

Inflammatory back pain is more than just inflammatory pain, but a set of symptoms which presence must evoke a diagnosis of ankylosing spondylitis. However, it is insufficient by itself for a diagnosis which can only be reach as part of a diagnostic strategy searching for other clinical, biological or radiological abnormalities in order to obtain adequate diagnostic probability, while acknowledging the limitations of all these examinations.

Online teaching of inflammatory skin pathology by a French-speaking International University Network.

INTRODUCTION: Developments in technology, web-based teaching and whole slide imaging have broadened the teaching horizon in anatomic pathology. Creating online learning material including many types of media such as radiologic images, whole slides, videos, clinical and macroscopic photographs, is now accessible to most universities. Unfortunately, a major limiting factor to maintain and update the learning material is the amount of resources needed. In this perspective, a French-national university network was initiated in 2011 to build joint online teaching modules consisting of clinical cases and tests. The network has since expanded internationally to Québec, Switzerland and Ivory Coast. METHOD: One of the first steps of the project was to build a learning module on inflammatory skin pathology for interns and residents in pathology and dermatology. A pathology resident from Québec spent 6 weeks in France and Switzerland to develop the contents and build the module on an e-learning Moodle platform under the supervision of two dermatopathologists. The learning module contains text, interactive clinical cases, tests with feedback, virtual slides, images and clinical photographs. For that module, the virtual slides are decentralized in 2 universities (Bordeaux and Paris 7). Each university is responsible of its own slide scanning, image storage and online display with virtual slide viewers. RESULTS: The module on inflammatory skin pathology includes more than 50 web pages with French original content, tests and clinical cases, links to over 45 virtual images and more than 50 microscopic and clinical photographs. The whole learning module is being revised by four dermatopathologists and two senior pathologists. It will be accessible to interns and residents in the spring of 2014. The experience and knowledge gained from that work will be transferred to the next international resident whose work will be aimed at creating lung and breast pathology learning modules. CONCLUSION: The challenges of sustaining a project of this scope are numerous. The technical aspect of whole-slide imaging and storage needs to be developed by each university or group. The content needs to be regularly updated and its accuracy reviewed by experts in each individual domain. The learning modules also need to be promoted within the academic community to ensure maximal benefit for trainees. A collateral benefit of the project was the establishment of international partnerships between French-speaking universities and pathologists with the common goal of promoting pathology education through the use of multi-media technology including whole slide imaging.

Inhibition of tumor angiogenesis by non-steroidal anti-inflammatory drugs: emerging mechanisms and therapeutic perspectives.

Chronic intake of non steroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced risk of developing gastrointestinal tumors, in particular colon cancer. Increasing evidence indicates that NSAID exert tumor-suppressive activity on pre-malignant lesions (polyps) in humans and on established experimental tumors in mice. Some of the tumor-suppressive effects of NSAIDs depend on the inhibition of cyclooxygenase-2 (COX-2), a key enzyme in the synthesis of prostaglandins and thromboxane, which is highly expressed in inflammation and cancer. Recent findings indicate that NSAIDs exert their anti-tumor effects by suppressing tumor angiogenesis. The availability of COX-2-specific NSAIDs opens the possibility of using this drug class as anti-angiogenic agents in combination with chemotheapy or radiotherapy for the treatment of human cancer. Here we will briefly review recent advances in the understanding of the mechanism by which NSAIDs suppress tumor angiogenesis and discuss their potential clinical application as anti-cancer agents.

Delta-9-tetrahydrocannabinol (THC) protects partly against demyelination by modulating the inflammatory response: an in vitro study in aggregating brain cell cultures

Delta 9-tetrahydrocannabinol (THC) has been proposed as therapeutic agent in the treatment of multiple sclerosis. In the present study, we examined whether a modulation of brain inflammatory by THC may protect against demyelination. Myelinating aggregating brain cell cultures were subjected to demyelination by a repeated treatment (3x) with the two inflammatory agents interferon-y (IFN-y) and lipopolysaccharide (LPS). The effects of THC on an acute inflammatory reponse were also examined by treating the aggregates with a single application of the two inflammatory agents. THC effects on the demyelinating process and on several mediators of the inflammatory reponse were analyzed. THC treatment partially prevented the decreased immunoreactivity for MBP, and the decrease in MBP content measured by immunoblotting. It prevented IFN-y + LPS -induced microglial reactivity; and decreased the IFN-y + LPS-induced i8ncreased phosphorylation of p44/42 MAP kinase. The other inflammatory markers, I-NOS and TNF-a mRNA expression, and p38 MAP kinase phosphorylation of p44/42 MAP kinase. The other inflammatory markers, I-NOS and TNF-a mRNA expression, and p38 MAP kinase phosphorylation were downregulated by THC treatment following a single application of the inflammatory agents, but not after repeated applications. THC protected partially against the IFN-y + LPS-induced demyelination. The protective effect of THC on IFN-y + LPS-induced demyelination may be due to a decrease of the inflammatory reponse. However, the anti-inflammatory effect of THC on some inflammatory markers is lost when the inflammatory response is more proeminent and of longer duration, suggesting either that the anti-inflammatory effect of a molecule may depend on the properties of the inflammatory response, or that the anti-inflammatory potential of THC decreases in case of repeated exposure.

Association of socioeconomic status with inflammatory markers: a two cohort comparison.

OBJECTIVE: To assess the association between socioeconomic status (SES) and inflammatory markers using two different European population samples. METHODS: We used data from the CoLaus (N=6412, Lausanne, Switzerland) and EPIPorto (N=1205, Porto, Portugal) studies. Education and occupational position were used as indicators of socioeconomic status (SES). High-sensitivity C-reactive protein (hs-CRP) was available for both cohorts. Interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) were available in CoLaus; leukocyte count and fibrinogen in EPIPorto. RESULTS: We showed that low SES was significantly associated with high inflammation in both studies. We also showed that behavioural factors contributed the most to SES differences in inflammation. In both studies the larger difference between the lowest and the highest SES was observed for hs-CRP. In the Swiss sample, a linear association between education and hs-CRP persisted after adjustment for all mediating factors and confounders considered (p for linear trend <0.001). CONCLUSION: Large social differences exist in inflammatory activity, in part independently from demographic and behavioural factors, chronic conditions and medication use. SES differences in inflammation are also similar in countries with different underlying socioeconomic conditions.

Atmung, Aufmerksamkeit und Ablenkung als Funktion emotionaler Stimuli: Ablenkung, Atmung, Aufmerksamkeit, Emotion, Erregung, Valenz

Mittels Bilder, Musikstücken und Geräuschen induzierten wir Emotionen und gingen einerseits der Frage nach, wie emotionale Bewertung und physiologische Vorgänge, insbesondere die Atmung, miteinander verknüpft sind. Andererseits untersuchten wir mit Geruchsexpositionen während einer Mehrfachverrichtung, welche Rolle die Geruchs-Valenz bei der Arbeitsablenkung spielt. Unsere Versuche zeigten, dass die Atmungsantworten auf induzierte Emotionen in einem gewissen Rahmen dem Dimensionsmodell von Valenz und Arousal folgten, insbesondere bildeten sie die induzierte Erregung konsistent ab. Auch das Aufmerksamkeits-Engagement hing von der emotionalen Bedeutung des Stimulus ab, da nur die negativ attribuierten Gerüche eine Leistungsminderung in der Mehrfachverrichtung auslösten. [Autoren]

Associations between mood, anxiety or substance use disorders and inflammatory markers after adjustment for multiple covariates in a population-based study.

Inflammation is one possible mechanism underlying the associations between mental disorders and cardiovascular diseases (CVD). However, studies on mental disorders and inflammation have yielded inconsistent results and the majority did not adjust for potential confounding factors. We examined the associations of several pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) and high sensitive C-reactive protein (hsCRP) with lifetime and current mood, anxiety and substance use disorders (SUD), while adjusting for multiple covariates. The sample included 3719 subjects, randomly selected from the general population, who underwent thorough somatic and psychiatric evaluations. Psychiatric diagnoses were made with a semi-structured interview. Major depressive disorder was subtyped into "atypical", "melancholic", "combined atypical-melancholic" and "unspecified". Associations between inflammatory markers and psychiatric diagnoses were assessed using multiple linear and logistic regression models. Lifetime bipolar disorders and atypical depression were associated with increased levels of hsCRP, but not after multivariate adjustment. After multivariate adjustment, SUD remained associated with increased hsCRP levels in men (β = 0.13 (95% CI: 0.03,0.23)) but not in women. After multivariate adjustment, lifetime combined and unspecified depression were associated with decreased levels of IL-6 (β = -0.27 (-0.51,-0.02); β = -0.19 (-0.34,-0.05), respectively) and TNF-α (β = -0.16 (-0.30,-0.01); β = -0.10 (-0.19,-0.02), respectively), whereas current combined and unspecified depression were associated with decreased levels of hsCRP (β = -0.20 (-0.39,-0.02); β = -0.12 (-0.24,-0.01), respectively). Our data suggest that the significant associations between increased hsCRP levels and mood disorders are mainly attributable to the effects of comorbid disorders, medication as well as behavioral and physical CVRFs.

Tissue-specific opposing functions of the inflammasome adaptor ASC in the regulation of epithelial skin carcinogenesis.

A chronic inflammatory microenvironment favors tumor progression through molecular mechanisms that are still incompletely defined. In inflammation-induced skin cancers, IL-1 receptor- or caspase-1-deficient mice, or mice specifically deficient for the inflammasome adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD) in myeloid cells, had reduced tumor incidence, pointing to a role for IL-1 signaling and inflammasome activation in tumor development. However, mice fully deficient for ASC were not protected, and mice specifically deficient for ASC in keratinocytes developed more tumors than controls, suggesting that, in contrast to its proinflammatory role in myeloid cells, ASC acts as a tumor-suppressor in keratinocytes. Accordingly, ASC protein expression was lost in human cutaneous squamous cell carcinoma, but not in psoriatic skin lesions. Stimulation of primary mouse keratinocytes or the human keratinocyte cell line HaCaT with UVB induced an ASC-dependent phosphorylation of p53 and expression of p53 target genes. In HaCaT cells, ASC interacted with p53 at the endogenous level upon UVB irradiation. Thus, ASC in different tissues may influence tumor growth in opposite directions: it has a proinflammatory role in infiltrating cells that favors tumor development, but it also limits keratinocyte proliferation in response to noxious stimuli, possibly through p53 activation, which helps suppressing tumors.

The stereochemistry of the amino acid side chain influences the inflammatory potential of muramyl dipeptide in experimental meningitis.

Intrathecal injections of 50 to 100 micro g of (N-acetylmuramyl-L-alanyl-D-isoglutamine) muramyl dipeptide (MDP)/rabbit dose-dependently triggered tumor necrosis factor alpha (TNF-alpha) secretion (12 to 40,000 pg/ml) preceding the influx of leukocytes in the subarachnoid space of rabbits. Intrathecal instillation of heat-killed unencapsulated R6 pneumococci produced a comparable leukocyte influx but only a minimal level of preceding TNF-alpha secretion. The stereochemistry of the first amino acid (L-alanine) of the MDP played a crucial role with regard to its inflammatory potential. Isomers harboring D-alanine in first position did not induce TNF-alpha secretion and influx of leukocytes. This stereospecificity of MDPs was also confirmed by measuring TNF-alpha release from human peripheral mononuclear blood cells stimulated in vitro. These data show that the inflammatory potential of MDPs depends on the stereochemistry of the first amino acid of the peptide side chain and suggest that intact pneumococci and MDPs induce inflammation by different pathways.

Pro-inflammatory cytokines induce the transcription factors C/EBPbeta and C/EBPdelta in astrocytes.

The transcription factors CCAAT/enhancer binding protein (C/EBP)-beta and -delta are key regulators for the expression of the acute phase genes in the liver, such as complement component C3 and antichymotrypsin. In the brain, these acute phase proteins are produced in response to pro-inflammatory cytokines by the reactive astrocytes, in particular those surrounding the amyloid plaques of Alzheimer's disease brains. Here we show that lipopolysaccharides (LPS), IL-1beta, and TNFalpha induce the expression of the c/ebpbeta and -delta genes in mouse primary astrocytes. This induction precedes the expression of the acute phase genes coding for the complement component C3 and the mouse homologue of antichymotrypsin. The induction of these two acute phase genes by LPS is blocked by cycloheximide, whereas this protein synthesis inhibitor does not affect the expression of the c/ebp genes. Altogether, our data support a role as immediate-early genes for c/ebpbeta and -delta, whose expression is induced by pro-inflammatory cytokines in mouse cortical astrocytes. In the liver, these transcription factors are known to play an important role in inflammation and energy metabolism regulation. Therefore, C/EBPbeta and -delta could be pivotal transcription factors involved in brain inflammation, in addition to their previously demonstrated role in brain glycogen metabolism regulation (Cardinaux and Magistretti. J Neurosci 16:919-929, 1996).

Vitamin C and endogenous cortisol in foreign-body inflammatory response in pacus

The objective of this work was to evaluate the effect of food supplementation with vitamin C on macrophage and multinucleated giant cell (MGC) activities of pacus at two stocking densities. The experiment was carried out in a 2x2x3 split-plot factorial arrangement with: 0 and 500 mg kg-1 vitamin C; 5 and 20 kg m-3 stocking densities; and evaluation times at 3, 6, and 12 days after the subcutaneous implantation of glass coverslips (DPI). The number of macrophages and MGC, as well as cortisol and glucose plasma levels were determined. The number of macrophages and MGC with two to five nuclei was significantly greater in fish supplemented with vitamin C at 5 kg m-3 stocking density at 3 DPI in comparison to nonsupplemented ones. The macrophage and MGC counts were lower in fish with high-plasma cortisol concentration. Supplementation with 500 mg vitamin C benefits macrophage activity on foreign-body inflammation, and high-cortisol concentration has suppressive effects on this response.

Predictors for hospitalization and outpatient visits in patients with inflammatory bowel disease: results from the Swiss Inflammatory Bowel Disease Cohort Study.

OBJECTIVES: Patients with inflammatory bowel disease (IBD) have a high resource consumption, with considerable costs for the healthcare system. In a system with sparse resources, treatment is influenced not only by clinical judgement but also by resource consumption. We aimed to determine the resource consumption of IBD patients and to identify its significant predictors. MATERIALS AND METHODS: Data from the prospective Swiss Inflammatory Bowel Disease Cohort Study were analysed for the resource consumption endpoints hospitalization and outpatient consultations at enrolment [1187 patients; 41.1% ulcerative colitis (UC), 58.9% Crohn's disease (CD)] and at 1-year follow-up (794 patients). Predictors of interest were chosen through an expert panel and a review of the relevant literature. Logistic regressions were used for binary endpoints, and negative binomial regressions and zero-inflated Poisson regressions were used for count data. RESULTS: For CD, fistula, use of biologics and disease activity were significant predictors for hospitalization days (all P-values <0.001); age, sex, steroid therapy and biologics were significant predictors for the number of outpatient visits (P=0.0368, 0.023, 0.0002, 0.0003, respectively). For UC, biologics, C-reactive protein, smoke quitters, age and sex were significantly predictive for hospitalization days (P=0.0167, 0.0003, 0.0003, 0.0076 and 0.0175 respectively); disease activity and immunosuppressive therapy predicted the number of outpatient visits (P=0.0009 and 0.0017, respectively). The results of multivariate regressions are shown in detail. CONCLUSION: Several highly significant clinical predictors for resource consumption in IBD were identified that might be considered in medical decision-making. In terms of resource consumption and its predictors, CD and UC show a different behaviour.