Good practice for dialogue and communication as strategic principle for policing political manifestations in Europe (GODIAC):field study handbook

This handbook describes the peer review methodology that was applied at the GODIAC project fi eld studies1. The peer review evaluation method as initiated by Otto Adang in the Netherlands and further developed in a European football context (Adang & Brown, 2008) involves experienced police offi cers cooperating with researchers to perform observational fi eld studies to identify good practices and learning points for public order management. The handbook builds on the GODIAC seminars and workshops, for the fi eld study members, which took place in September 2010, January 2012 and January 2013. The handbook has been discussed in the project group and in the steering committee. It is primarily written for the GODIAC fi eld study members as background material for understanding the fi eld study process and for clarifying the different responsibilities that enable active participation in the fi eld study. The handbook has been developed during the project period and incorporates learning points and developments of the peer review method. The handbook aims at promoting the use of fi eld studies for evaluation of policing major events.

Good practice for dialogue and communication as strategic principle for policing political manifestations in Europe (GODIAC):the anthology

The volume is divided into two parts; the fi rst deals with issues related to the police, and the second addresses issues related to demonstrators and protesters. We hope that this volume will provide further insight into issues associated with policing at major events and shed light on the complexity of the organisations, motives, and strategies in play whenever protester groups are involved.

Good practice for dialogue and communication as strategic principle for policing political manifestations in Europe (GODIAC):recommendations for policing political manifestations in Europe

This report summarises the fi eld study results of the project ’Good practice for dialogue and communication as strategic principles for policing political manifestations in Europe’ (GODIAC).1 The overall idea was to integrate operative police work, research and training within the fi eld and to build international and institutional networks, ensuring and recognising the responsibilities of the organisers. The purpose of the GODIAC project was to contribute to the development of a European approach to policing political manifestations.

Frequency and chronology of extraintestinal manifestations in the Swiss Inflammatory Bowel Disease Cohort

Background: Data on the frequency of extraintestinal manifestations (EIM) in inflammatory bowel disease (IBD) is scarce, especially the one evaluating the time of occurrence of the EIM relative to IBD diagnosis. Aim: To assess the type and frequency of EIM in IBD patients and to evaluate when EIMs occur relative to IBD diagnosis. Methods: Analysis of data from the Swiss Inflammatory Bowel Disease Cohort (SIBDCS) which collects data on a large sample of IBD patients from hospitals and private practices across Switzerland starting in 2005. While parametric data are shown as mean ± SD, non-parametric data are presented as median and interquartile range (IQR). Results: A total of 1143 patients were analyzed (572 (50%) female, mean age 42.1 ± 14.4 years): 629 (55%) with Crohn's disease (CD), 501 (44%) with ulcerative colitis (UC), and 13 (1%) with indeterminate colitis (IC). Of 1143 patients, 374 (32.7%) presented with EIM (65% with CD, 33% with UC, 2% with IC). Of those patients suffering from EIMs, 37.4% presented with one, 41.7% with two, 12.4% with three, 5.3% with four, and 3.2% with five EIM during their lifetime. The IBD patients initially presented with the following EIMs: peripheral arthritis (PA) 63.4%, ankylosing spondylitis (AS) 8.1%, primary sclerosing cholangitis (PSC) 6.0%, uveitis 5.7%, oral aphthosis 5.7%, erythema nodosum (EN) 5.0%, pyoderma gangrenosum 1.8%, psoriasis 0.7%. While 92.9% of EIM occurred once IBD diagnosis was established (median 72 months, IQR 9-147 months, p < 0.001), 7.1% of EIMs preceded IBD diagnosis (median time 28 months before IBD diagnosis, IQR 7-60 months). Over a course of a lifetime, IBD patients presented with the following EIM (total exceeds 100 due to potential presence of multiple EIM): peripheral arthritis 69.3%, oral aphthosis 23%, ankylosing spondylitis 19.4%, uveitis 15.5%, erythema nodosum 14.5%, PSC 7.8%, pyoderma gangrenosum 6%, psoriasis 2.8%. Conclusion: EIMs frequently occur in a lifetime of IBD patients. The vast majority of patients present with EIMs once IBD diagnosis has been established. IBD patients most often present with peripheral arthritis, ankylosing spondylitis and PSC as their first EIM. However, peripheral arthritis, oral aphthosis, and ankylosing spondylitis are the most common EIMs in a lifetime of IBD patients.

Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations.

The cause of many autoimmune and inflammatory diseases is unresolved, although dysregulated production of tumor necrosis factor (TNF) family members appears to be important in many cases. BAFF, a new member of the TNF family, binds to B cells and costimulates their growth in vitro. Mice transgenic for BAFF have vastly increased numbers of mature B and effector T cells, and develop autoimmune-like manifestations such as the presence of high levels of rheumatoid factors, circulating immune complexes, anti-DNA autoantibodies, and immunoglobulin deposition in the kidneys. This phenotype is reminiscent of certain human autoimmune disorders and suggests that dysregulation of BAFF expression may be a critical element in the chain of events leading to autoimmunity.

Complications et atteintes systémiques de la polyarthrite rhumatoïde [Complications and systemic manifestations of rheumatoid arthritis].

Rheumatoid arthritis (RA), in addition to the traditional joint damage can affect all organs as a systemic disease. Extra-articular manifestations of RA are highly variable ranging from rheumatoid nodules (most common) to rheumatoid vasculitis presenting a significant morbidity and mortality (49% at 5 years). With the new algorithms of treatment (earlier) and the use of biologics, the incidence of severe extra-articular manifestations decreases. Regarding the treatment of rheumatoid vasculitis, rituximab looks promising. RA also increases cardiovascular risk and the risk of osteoporosis. It is therefore important to identify these risks and, if appropriate, treat them. Collaboration with the general practitioner is essential in this situation.

Metastatic leishmaniasis. A chronic inflammatory response to Leishmania's viral endosymbiont.

Leishmania parasites have been plaguing humankind for centuries as a range of skin diseases named the cutaneous leishmaniases (CL). Carried in a hematophagous sand fly, Leishmania usually infests the skin surrounding the bite site, causing a destructive immune response that may persist for months or even years. The various symptomatic outcomes of CL range from a benevolent self- healing reddened bump to extensive open ulcerations, resistant to treatment and resulting in life- changing disfiguration. Many of these more aggressive outcomes are geographically isolated within the habitats of certain Neotropical Leishmania species; where about 15% of cases experience metastatic complications. However, despite this correlation, genetic analysis has revealed no major differences between species causing the various disease forms. We have recently identified a cytoplasmic dsRNA virus within metastatic L. guyanensis parasites that acts as a potent innate immunogen capable of worsening lesionai inflammation and prolonging parasite survival. The dsRNA genome of Leishmania RNA virus (LRV) binds and stimulates Toll-Like-Receptor-3 (TLR3), inducing this destructive inflammation, which we speculate as a factor contributing to the development of metastatic disease. This thesis establishes the first experimental model of LRV-mediated leishmanial metastasis and investigates the role of non-TLR3 viral recognition pathways in LRV-mediated pathology. Viral dsRNA can be detected by various non-TLR3 pattern recognition receptors (PRR); two such PRR groups are the RLRs (Retinoic acid-inducible gene 1 like receptors) and the NLRs (nucleotide- binding domain, leucine-rich repeat containing receptors). The RLRs are designed to detect viral dsRNA in the cytoplasm, while the NLRs react to molecular "danger" signals of cell damage, often oligomerizing into molecular scaffolds called "inflammasomes" that activate a potent inflammatory cascade. Interestingly, we found that neither RLR signalling nor the inflammasome pathway had an effect on LRV-mediated pathology. In contrast, we found a dramatic inflammasome independent effect for the NLR family member, NLRP10, where a knockout mouse model showed little evidence of disease. This phenotype was mimicked in an NLR knockout with which NLRP10 is known to interact: NLRC2. As this pathway induces the chronic inflammatory cell lineage TH17, we investigated the role of its key chronic inflammatory cytokine, IL-17A, in human patients infected by L. guyanensis. Indeed, patients infected with LRV+ parasites had a significantly increased level of IL-17A in lesionai biopsies. Interestingly, LRV presence was also associated with a significant decrease in the correlate of protection, IFN-y. This association was repeated in our murine model, where after we were able to establish the first experimental model of LRV-dependent leishmanial metastasis, which was mediated by IL-17A in the absence of IFN-y. Finally, we tested a new inhibitor of IL-17A secretion, SR1001, and reveal its potential as a Prophylactic immunomodulator and potent parasitotoxic drug. Taken together, these findings provide a basis for anti-IL-17A as a feasible therapeutic intervention to prevent and treat the metastatic complications of cutaneous leishmaniasis. -- Les parasites Leishmania infectent l'homme depuis des siècles causant des affections cutanées, appelées leishmanioses cutanées (LC). Le parasite est transmis par la mouche des sables et réside dans le derme à l'endroit de la piqûre. Au niveau de la peau, le parasite provoque une réponse immunitaire destructrice qui peut persister pendant des mois voire des années. Les symptômes de LC vont d'une simple enflure qui guérit spontanément jusqu' à de vastes ulcérations ouvertes, résistantes aux traitements. Des manifestations plus agressives sont déterminées par les habitats géographiques de certaines espèces de Leishmania. Dans ces cas, environ 15% des patients développent des lésions métastatiques. Aucun «facteur métastatique» n'a encore été trouvé à ce jour dans ces espèces. Récemment, nous avons pu identifier un virus résidant dans certains parasites métastatiques présents en Guyane française (appelé Leishmania-virus, ou LV) et qui confère un avantage de survie à son hôte parasitaire. Ce virus active fortement la réponse inflammatoire, aggravant l'inflammation et prolongeant l'infection parasitaire. Afin de diagnostiquer, prévenir et traiter ces lésions, nous nous sommes intéressés à identifier les composants de la voie de signalisation anti-virale, responsables de la persistance de cette inflammation. Cette étude décrit le premier modèle expérimental de métastases de la leishmaniose induites par LV, et identifie plusieurs composants de la voie inflammatoire anti-virale qui facilite la pathologie métastatique. Contrairement à l'homme, les souris de laboratoire infectées par des Leishmania métastatiques (contenant LV, LV+) ne développent pas de lésions métastatiques et guérissent après quelques semaines d'infection. Après avoir analysé un groupe de patients atteints de leishmaniose en Guyane française, nous avons constaté que les personnes infectées avec les parasites métastatiques LV+ avaient des niveaux significativement plus faibles d'un composant immunitaire protecteur important, appelé l'interféron (IFN)-y. En utilisant des souris génétiquement modifiées, incapables de produire de l'IFN-y, nous avons observé de telles métastases. Après inoculation dans le coussinet plantaire de souris IFN-y7" avec des parasites LV+ ou LV-, nous avons démontré que seules les souris infectées avec des leishmanies ayant LV développent de multiples lésions secondaires sur la queue. Comme nous l'avons observé chez l'homme, ces souris sécrètent une quantité significativement élevée d'un composant inflammatoire destructeur, l'interleukine (IL)-17. IL-17 a été incriminée pour son rôle dans de nombreuses maladies inflammatoires chroniques. On a ainsi trouvé un rôle destructif similaire pour l'IL-17 dans la leishmaniose métastatique. Nous avons confirmé ce rôle en abrogeant IL-17 dans des souris IFN-y7- ce qui ralentit l'apparition des métastases. Nous pouvons donc conclure que les métastases de la leishmaniose sont induites par l'IL-17 en absence d'IFN-v. En analysant plus en détails les voies de signalisation anti-virale induites par LV, nous avons pu exclure d'autres voies d'activation de la réponse inflammatoire. Nous avons ainsi démontré que la signalisation par LV est indépendante de la signalisation inflammatoire de type « inflammasome ». En revanche, nous avons pu y lier plusieurs autres molécules, telles que NLRP10 et NLRC2, connues pour leur synergie avec les réponses inflammatoires. Cette nouvelle voie pourrait être la cible pour des médicaments inhibant l'inflammation. En effet, un nouveau médicament qui bloque la production d'IL-17 chez la souris s'est montré prometteur dans notre modèle : il a réduit le gonflement des lésions ainsi que la charge parasitaire, indiquant que la voie anti-virale /inflammatoire est une approche thérapeutique possible pour prévenir et traiter cette infection négligée.

Extraintestinal manifestations in inflammatory bowel disease: frequency and associated risk factors in the nationwide Swiss IBD cohort study (SIBDCS)

Background: Data on the frequency of extraintestinal manifestations (EIM) in Crohnʼs disease (CD) and ulcerative colitis (UC) are scarce. Goal: to evaluate prevalences, forms of EIM and risk factors in a large nationwide IBD cohort. Methods: Data from validated physician enrolment questionnaires of the adult Swiss IBD cohort were analyzed. Logistic regression models were used to identify EIM risk factors. Results: 950 patients were included, 580 (61%) with CD (mean age 43yrs) and 370 (39%) with UC (mean age 49yrs), of these, 249 (43%) of CD and 113 (31%) of UC patients had one to 5 EIM. The following EIM were found: arthritis (CD 33%, UC 21%), aphthous stomatitis (CD 10%, UC 4%), uveitis (CD 6%, UC 4%), erythema nodosum (CD 6%, UC 3%), ankylosing spondylitis (CD 6%, UC 2%), psoriasis (CD 2%, UC 1%), pyoderma gangrenosum (CD and UC each 2%), primary sclerosing cholangitis (CD 1%, UC 4%). Logistic regression in CD identified the following items as risk factors for ongoing EIM: active disease (OR 1.95, 95% CI 1.17-3.23, P=0.01), positive IBD family history (OR 1.77, 95% CI 1.07-2.92, P=0.025). No risk factors were identified in UC patients. Conclusions: EIM are a frequent problem in CD and UC patients. Active disease and positive IBD family history are associated with ongoing EIM in CD patients. Identification of EIM prevalence and associated risk factors may result in increased awareness for this problem and thereby facilitate their diagnosis and management.

UVB-Induced Skin Inflammation and Cutaneous Tissue Injury Is Dependent on the MHC Class I-Like Protein, CD1d.

CD1d is a major histocompatibility complex class 1-like molecule that regulates the function and development of natural killer T (NKT) cells. Previously, we identified a critical role for the CD1d-NKT cell arm of innate immunity in promoting the development of UVB-induced p53 mutations, immune suppression, and skin tumors. Sunburn, an acute inflammatory response to UVB-induced cutaneous tissue injury, represents a clinical marker for non-melanoma skin cancer (NMSC) risk. However, the innate immune mechanisms controlling sunburn development are not considered relevant in NMSC etiology, and remain poorly investigated. Here we found that CD1d knockout (CD1d(-/-)) mice resist UVB-induced cutaneous tissue injury and inflammation compared with wild-type (WT) mice. This resistance was coupled with a faster epithelial tissue healing response. In contrast, the skins of UVB-irradiated invariant NKT cell-knockout (Jα18(-/-)) and NKT cell-deficient (TCRα(-/-)) mice, which express CD1d but are deficient in CD1d-dependent NKT cells, exhibited as much cutaneous tissue injury and inflammation as WT mice. In the absence of NKT cells, CD1d-deficient keratinocytes, dendritic cells, and macrophages exhibited diminished basal and stress-induced levels of pro-inflammatory mediators. Thus, our findings identify an essential role for CD1d in promoting UVB-induced cutaneous tissue injury and inflammation. They also suggest sunburn and NMSC etiologies are immunologically linked.

Lepromatous leprosy: a review and case report

Leprosy is a contagious and chronic systemic granulomatous disease caused by Mycobacterium leprae (Hansen"s bacillus). It is transmitted from person to person and has a long incubation period (between two and six years). The disease presents polar clinical forms (the"multibacillary" lepromatous leprosy and the"paucibacillary" tuberculoid leprosy), as well as other intermediate forms with hybrid characteristics. Oral manifestations usually appear in lepromatous leprosy and occur in 20-60% of cases. They may take the form of multiple nodules (lepromas) that progress to necrosis and ulceration. The ulcers are slow to heal, and produce atrophic scarring or even tissue destruction. The lesions are usually located on the hard and soft palate, in the uvula, on the underside of the tongue, and on the lips and gums. There may also be destruction of the anterior maxilla and loss of teeth. The diagnosis, based on clinical suspicion, is confirmed through bacteriological and histopathological analyses, as well as by means of the lepromin test (intradermal reaction that is usually negative in lepromatous leprosy form and positive in the tuberculoid form). The differential diagnosis includes systemic lupus erythematosus, sarcoidosis, cutaneous leishmaniasis and other skin diseases, tertiary syphilis, lymphomas, systemic mycosis, traumatic lesions and malignant neoplasias, among other disorders. Treatment is difficult as it must be continued for long periods, requires several drugs with adverse effects and proves very expensive, particularly for less developed countries. The most commonly used drugs are dapsone, rifampicin and clofazimine. Quinolones, such as ofloxacin and pefloxacin, as well as some macrolides, such as clarithromycin and minocyclin, are also effective. The present case report describes a patient with lepromatous leprosy acquired within a contagious family setting during childhood and adolescence

Cutaneous leukocytoclastic vasculitis associated with letrozole.

Aromatase inhibitors are increasingly used in the treatment of early and metastatic breast cancer. They can produce various skin adverse effects but are only rarely associated with cutaneous vasculitis. We report the first case of cutaneous vasculitis clearly associated with the use of aromatase inhibitor letrozole.

Cytokines in parasitic diseases: the example of cutaneous leishmaniasis.

The essential role of cytokines in parasitic diseases has been emphasised since the in vivo description of the importance of T helper 1 (Th1) and T helper 2 (Th2) CD4+ T cell responses in resistance and susceptibility to infection with L. major in mice. Th1 cells produced IL-2, IFN-gamma and Lymphotoxin T (LT) and Th2 cells produce IL-4, IL-5 and IL-13. In this model of infection the correlation between on the one hand resistance to infection and the development of a Th1 response and on the other hand susceptibility and Th2 cell development allowed the identification of the mechanisms directing the differentiation of CD4+ T cell precursors towards either Th1 type or Th2 type responses. Cytokines are the crucial inducer of functional CD4+ T cell subset differentiation during infection with L. major. IL-12 and IFN-gamma direct the differentiation of Th1 response and IL-4 of a Th2 response. In susceptible mice, careful analysis of IL-4 production during the first days of infection has shown that the IL-4 produced as a result of a very early burst of IL-4 mRNA expression (16 hours) plays a essential role in the maturation of a Th2 CD4+ T cell response by rendering the CD4+ T cell precursors unresponsive to IL-12. Activation of a restricted population of CD4+ T cells expressing the V beta 4 V alpha 8 TCR heterodimer after recognition of a single antigen, the LACK (Leishmania Activated c Kinase) antigen, resulted in this rapid production of IL-4 required for the subsequent CD4+ T cell differentiation. Thus, tolerization of these cells might contribute a strategy for preventing infection with L. major.

Prevention of cutaneous melanoma: an epidemiological evaluation of the Swiss campaign.

A national information program, focusing on the main recognized risk factors (primary prevention) and on the potential benefits of early detection (secondary prevention) of cutaneous malignant melanoma, was launched in Switzerland in May 1988. The first campaign, based on a pilot study conducted in 1986 in the canton of Basel, was followed by a recall campaign in July 1989. This report describes the organization of this program and presents an assessment of its initial impact. The number of newly diagnosed cases increased more than twofold (+ 116%) in the two months following the launch of the first campaign (May to June 1988). This trend was accompanied by a statistically significant shift of case distribution towards younger ages (< 60 years; p = 0.003), and a non-significant shift was observed towards less advanced lesions (thickness < or = 1.5 mm). The incidence decreased quickly, though in the twelve month period between the two campaigns it remained 21% higher than before the inception of the program. No appreciable effects were detected from the recall campaign and no difference was seen among regions or between sexes.