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Background: To investigate whether obesity with or without metabolic syndrome is prospectively associated with coronary artery calcium (CAC) progression and incident cardiovascular disease events. Methods: A total of 1730 participants from the CARDIA study (Coronary Artery Risk Development in Young Adults) were included (age, 40.1±3.6 years; 38.3% men), who completed computed tomography of CAC at baseline (year 15: 2000–2001) and follow-up (year 20 or 25). Metabolically healthy obesity (MHO) was defined as body mass index≥30 kg/m 2 without any metabolic syndrome components in our main analysis. Sensitivity analyses were conducted for several conditions characterizing 4 metabolic phenotypes. Results: During a mean follow-up of 9.1 years, 439 participants had CAC progression. MHO subjects had a significantly higher risk of CAC progression than their metabolically healthy normal weight counterparts (adjusted hazard ratios [95% CIs] from 1.761 [1.369–2.264] to 2.047 [1.380–3.036]) depending on the definition of MHO adopted. Obesity with unhealthy metabolic profile remained the highest significant risk of CAC progression and cardiovascular disease events whatever the definitions adopted for metabolically unhealthy status. Up to 60% of participants with MHO converted to metabolically unhealthy obesity from year 15 to year 20 or year 25. Further sensitivity analysis showed that MHO throughout carried a similar risk of incident cardiovascular disease events compared with metabolically healthy normal weight throughout. Conclusions: Different metabolic phenotypes of obesity beginning at a young age exhibit distinct risks of CAC progression and subsequent cardiovascular disease events in later midlife. MHO represents an intermediate phenotype between metabolically low- to high-risk obese individuals. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00005130.

ObjectiveThe study aimed to assess the associations of physical activity (PA) trajectories across a 25-year span with coronary artery calcium (CAC) progression, and subsequent risk of cardiovascular disease (CVD) events.MethodsWe included 2497 participants from the Coronary Artery Disease Risk Development in Young Adults study who had computed tomography-assessment of CAC at baseline (year 15: 2000–2001) and follow-up (year 20 or 25) and at least three measures of PA from year 0 to year 25. Long-term PA trajectories were determined by latent class modelling using a validated questionnaire.ResultsAmong the included participants, 1120 (44.9%) were men, 1418 (56.8%) were white, and the mean (SD) age was 40.4 (3.6) years. We identified three distinct PA trajectories based on PA average levels and change patterns: low (below PA guidelines, n=1332; 53.3%); moderate (meeting and slightly over PA guidelines, n=919; 36.8%) and high (about three times PA guidelines or more, n=246; 9.9%). During a mean (SD) follow-up of 8.9 (2.1) years, 640 (25.6%) participants had CAC progression. Participants in the high PA trajectory group had a higher risk of CAC progression than those in the low PA trajectory group after adjustment for traditional cardiovascular risk factors (HR 1.51; 95% CI 1.18 to 1.94). However, high PA trajectory was not associated with an increased risk of incident CVD events (HR 1.01; 95% CI 0.44 to 2.31) and the incidence of CVD events in participants with CAC progression was similar across all three PA trajectory groups (p=0.736).ConclusionLong-term PA about three times the guidelines or more is independently associated with CAC progression; however, no additional risk of incident CVD events could be detected.

Resume Les echinococcoses sont des zoonoses touchant les humains de maniere accidentelle et leur prise en charge implique l’intervention de specialistes issus de nombreuses disciplines. Un consensus a recemment ete obtenu par l’Association mondiale de l’echinococcose sur la standardisation de la terminologie internationale, en anglais. Un groupe de travail francophone multidisciplinaire a ete constitue pour proposer une adaptation specifique a la langue francaise, en prenant en compte les principales regions du monde francophone endemiques pour les echinococcoses. Les principaux changements adoptes sont : 1) la denomination des differentes maladies associees au developpement du metacestode des differentes especes d’echinocoques, « echinococcose kystique », « echinococcose alveolaire » et « echinococcose neotropicale » ; 2) la restriction de l’usage de l’adjectif « hydatique » au stade larvaire du cluster d’especes Echinococcus granulosus sensu lato ; 3) l’harmonisation des expressions qui decrivent la structure des kystes ; 4) la mise en coherence avec la terminologie internationale de la denomination des ex-« vesicules filles », qui sont desormais appelees « kystes filles ». Concernant le traitement chirurgical de l’echinococcose kystique, le systeme de description et l’acronyme « AORC », identique en francais et en anglais pour Abord/Approach, Ouverture/Opening, Resection/Resection, Completude/Completeness, ont ete retenus. L’adoption de cette nouvelle terminologie est essentielle pour la coherence des publications et des ouvrages pedagogiques, et surtout pour une meilleure comprehension de la transmission de ces maladies et une meilleure prise en charge des patients.

Background and aims The cestode Echinococcus multilocularis infection, a serious health problem worldwide, causes alveolar echinococcosis (AE), a tumor-like disease predominantly located in the liver and able to spread to any organs. Until now, there have been few studies that explore how T-cell exhaustion contributes to the parasite's escape from immune attack and how it might be reversed. Approach and results In this study, we found that liver T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) expression was significantly enhanced and positively correlated with lesion activity in AE patients. High TIGIT expression in both liver-infiltrating and blood T cells was associated with their functional exhaustion, and its ligand CD155 was highly expressed by hepatocytes surrounding the infiltrating lymphocytes. In co-culture experiments using human blood T cells and hepatic cell line HL-7702, CD155 induced functional impairment of TIGIT+ T cells, and in vitro blockade with TIGIT antibody restored the function of AE patients' T cells. Similar TIGIT-related functional exhaustion of hepatic T cells and an abundant CD155 expression on hepatocytes were observed in E. multilocularis-infected mice. Importantly, in vivo blocking TIGIT prevented T-cell exhaustion and inhibited disease progression in E. multilocularis-infected mice. Mechanistically, CD4+ T cells were totally and CD8+ T cells partially required for anti-TIGIT-induced regression of parasite growth in mice. Conclusions This study demonstrates that E. multilocularis can induce T-cell exhaustion through inhibitory receptor TIGIT, and that blocking this checkpoint may reverse the functional impairment of T cells and represent a possible approach to immunotherapy against AE.

L’étude de cohorte PASTURE qui combine depuis 18 ans dans 5 pays européens des études environnementales, microbiologiques, génétiques, et immunologiques chez des enfants vivant ou non dans des fermes d’élevage laitier montre que la biodiversité des milieux de vie traditionnels ruraux est un rempart à l’augmentation sans précédent de la prévalence des maladies allergiques dans la deuxième moitié du XXème siècle.

L’échinocoque multiloculaire est un parasite provoquant une maladie mortelle pour les humains, l’échinococcose alvéolaire. La combinaison des recherches menées sur les plateaux du Jura, puis en Chine de l’ouest et au Kirgizhistan, permet d’établir, par une approche écoépidémiologique, un tableau des facteurs écologiques et socio-économiques qui favorisent l’émergence de « paysages à risque » et l’enclenchement de processus qui mènent le parasite jusqu’aux personnes.

Resume L’augmentation de la susceptibilite des animaux experimentaux immunodeprimes vis-a-vis de l’echinococcose alveolaire (EA) est connue depuis plus de 30 ans, ainsi que la progression rapide des lesions residuelles chez les patients transplantes pour EA. Cependant, ce n’est que depuis le debut des annees 2000 que des publications isolees ont fait etat de cas d’EA chez des patients atteints d’immunosuppression acquise. Une etude systematique des cas d’EA chez les transplantes d’organe et les patients atteints de sida ou d’affections malignes et/ou inflammatoires chroniques traites pas immunosuppresseurs a beneficie de l’existence d’un Registre Francais des cas d’EA (FrancEchino). Elle a confirme l’augmentation significative du nombre et du pourcentage de cas d’EA associes a une immunosuppression de 1992 a 2012, placant desormais l’EA au sein des infections « opportunistes ». Dans cette situation l’EA est generalement une decouverte fortuite lors du bilan de la pathologie sous-jacente. Le diagnostic est souvent retarde et son traitement parfois errone du fait de la confusion avec cette pathologie, en particulier en cas de cancer. Si l’EA est symptomatique, le caractere aigu des symptomes, simulant un abces hepatique, est aussi source d’errance diagnostique, d’autant que la serologie est plus souvent negative et l’imagerie plus souvent atypique que chez les patients sans immunosuppression. La strategie therapeutique de l’EA s’applique cependant : resection hepatique complete des lesions si elle est possible et si la maladie sous-jacente le permet, et traitement a vie par albendazole chez les patients inoperables ; dans ce dernier cas, l’amelioration peut etre spectaculaire, mais les effets secondaires semblent plus frequents. Des etudes complementaires permettront de dire si l’EA est due a une reactivation d’une infection ancienne ou a une contamination recente.

Background and aims Alveolar echinococcosis (AE) is a lethal helminthic liver disease caused by persistent infection with Echinococcus multilocularis. Although more attention has been paid to the immunotolerance of T cells caused by E. multilocularis infection, the role of natural killer (NK) cell, a critical player in liver immunity, is seldom studied. Approach and results Here, we observed that NK cells from the blood and closed liver tissue (CLT) of AE patients expressed a higher level of inhibitory receptor TIGIT and were functionally exhausted with a lower expression of granzyme B, perforin, interferon-gamma (IFN-γ), and TNF-α. Addition of anti-TIGIT (T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain) monoclonal antibody into AE patients' peripheral blood mononuclear cell culture significantly enhanced the synthesis of IFN-γ and TNF-α by NK cells, indicating the reversion of exhausted NK cells by TIGIT blockade. In the mouse model of E. multilocularis infection, liver and splenic TIGIT+ NK cells progressively increased dependent of infection dosage and timing and were less activated and less degranulated with lower cytokine secretion. Furthermore, TIGIT deficiency or blockade in vivo inhibited liver metacestode growth, reduced liver injury, and increased the level of IFN-γ produced by liver NK cells. Interestingly, NK cells from mice with persistent chronic infection expressed a higher level of TIGIT compared to self-healing mice. To look further into the mechanisms, more regulatory CD56bright and murine CD49a+ NK cells with higher TIGIT expression existed in livers of AE patients and mice infected with E. multilocularis, respectively. They coexpressed higher surface programmed death ligand 1 and secreted more IL-10, two strong inducers to mediate the functional exhaustion of NK cells. Conclusions Our results indicate that inhibitory receptor TIGIT is involved in NK cell exhaustion and immune escape from E. multilocularis infection.

Background It remains unclear whether triglyceride-glucose (TyG) index, a surrogate marker of insulin resistance, is prospectively associated with incident peripheral arterial disease (PAD). Methods We included 12,320 Atherosclerosis Risk in Communities Study participants (aged 54.3 ± 5.7 years) free of a history of PAD at baseline (visit 1: 1987–1989). The TyG index was determined using ln (fasting triglycerides [mg/dL] × fasting glucose [mg/dL]/2), and measured at 5 visits between 1987 and 2013. Incident PAD was defined as the first hospitalization with PAD diagnosis or a new onset of measured ABI Results Over a median follow-up of 23 years, 1300 participants developed PAD. After adjustment for traditional PAD risk factors, each 1-SD (0.58) increase in TyG index was associated with an 11.9% higher risk of incident PAD [hazard ratio, 1.119 (95% CI, 1.049–1.195)]. Results were similar when individuals were categorized by TyG index quartiles [hazard ratio, 1.239 (95% CI, 1.028–1.492); comparing extreme quartiles]. Four distinct trajectories of stable TyG indexes at various levels along the follow-up duration were identified [low (22.2%), moderate (43.2%), high (27.5%), and very high (7.1%) trajectory groups]. Compared with those with a TyG index trajectory at a low level, those participants with TyG index trajectories at high and very high levels had an even greater risk of future incident PAD [odds ratio (95%CI): 1.404 (1.132–1.740) and 1.742 (1.294–2.344), respectively] after multivariate adjustments for traditional PAD risk factors. Conclusions Higher TyG index is independently associated with an increased risk of incident PAD. Long-term trajectories of TyG index help identify individuals at a higher risk of PAD who deserve specific preventive and therapeutic approaches. Trial registration: Clinical trial registration number: The ARIC trial was registered at clinicaltrials.gov as NCT00005131.

Cystic echinococcosis (CE) is a zoonotic parasitic disease caused by infection with the larvae ofEchinococcus granulosus sensu lato(s.l.) cluster. It is urgent to identify novel drug targets and develop new drug candidates against CE. Glucose transporter 1 (GLUT1) is mainly responsible for the transmembrane transport of glucose to maintain its constant cellular availability and is a recent research hotspot as a drug target in various diseases. However, presence and role of GLUT1 inE. granulosus s.l.(EgGLTU1) was unknown. In this study, we cloned a conserved GLUT1 homology gene (named EgGLUT1-ss) fromE. granulosus sensu stricto(s.s.) and found EgGLUT1-ss was crucial for glucose uptake of the protoscoleces ofE. granulosus s.s..WZB117, a GLUT1 inhibitor, inhibited glucose uptake ofE. granulosus s.s.and the viability of the metacestodein vitro.In addition, WZB117 showed potent therapeutic activity inE. granulosus s.s.-infected mice: a 10 mg/kg dose of WZB117 significantly reduced the number and weight of parasite cysts as well as the reference drug, albendazole. Our data have defined EgGLUT1 as a keyE. granulosus s.l.vulnerability target, involved in its glucose uptake from the host; this opens a new avenue to identify drugs with an ideal activity profile for the treatment of CE.

Alveolar echinococcosi. Alveolar echinococcosis is a parasitic anthropo-zoonosis which looks like a slow-growing liver cancer. The lesions progressively obstruct hepatic vessels and bile ducts and invade neighboring organs, and it may metastasize to the lung and the brain and possibly all distant organs. Since the 1990s earlier diagnosis by imaging, advances in surgical and less invasive interventions, and prolonged anti-parasitic treatment using albendazole, have totally transformed the prognosis of the disease. However, in Europe, the endemic area has considerably increased, the number of alveolar echinococcosis cases has more than doubled in the previously identified endemic regions, and the disease may now be considered to be an 'opportunistic infection', especially diagnosed in those patients treated with immunosuppressive drugs and biologic agents. Alveolar echinococcosis is currently more and more often diagnosed incidentally, at an early stage of development, and not in the usual 'at risk' regions and populations. This makes differential diagnosis and care management more challenging.Échinococcose alvéolaire. L’échinococcose alvéolaire est une anthropozoonose parasitaire qui se comporte comme un cancer du foie d’évolution lente. Les lésions envahissent de proche en proche les axes vasculaires et biliaires et les organes de voisinage et sont capables de métastaser, le plus souvent vers le poumon et le cerveau mais potentiellement aussi vers tous les organes. Depuis les années 1990, les progrès en imagerie, l’utilisation judicieuse de la chirurgie et des interventions non chirurgicales et le traitement antiparasitaire par albendazole au long cours ont transformé le pronostic de l’infection. Cependant, en Europe, la zone d’endémie s’est considérablement étendue, le nombre de cas a plus que doublé dans les zones d’endémie « traditionnelles », et la maladie peut maintenant être comptée parmi les infections « opportunistes », touchant tout particulièrement les patients traités par des médicaments ou des agents biologiques immunosuppresseurs. La découverte accidentelle de lésions à la phase précoce d’évolution, et de plus en plus fréquemment hors des zones et des populations habituellement considérées à risque, pose actuellement des problèmes difficiles de diagnostic différentiel et de nouveaux défis pour la prise en charge thérapeutique.

International audience

Background: Cystic echinococcosis (CE) is a zoonotic parasitic disease caused by infection with the larvae of Echinococcus granulosus sensu lato (s.l.) cluster. It is urgent to identify novel drug targets and develop new drug candidates against CE. Glucose transporter 1 (GLUT1) is mainly responsible for the transmembrane transport of glucose and is a valuable drug target. However, the role of GLUT1 in E. granulosus s.l. (EgGLUT1) was unknown. Methods: The EgGLUT1-ss gene was cloned from E. granulosus sensu stricto (s.s.). The function of EgGLUT1-ss was identified by interfereing with EgGLUT1-specific siRNA or GLUT1 inhibitor WZB117 in vitro. The therapeutic effect of WZB117 and its effect on the glucose metabolism of larvae of E. granulosus s.s. in vivo were further validated in murine models. Findings: Knockdown of EgGLUT1 and WZB117 inhibited the glucose uptake and the viability of the larvae of E. granulosus s.s. in vitro (P < 0.01). In addition, WZB117 showed significant therapeutic activity in E. granulosus s.s.-infected mice: a 10 mg/kg dose of WZB117 significantly reduced the number and weight of parasite cysts (P < 0.05) as efficiently as the reference drug, albendazole. Interpretation: Our results demonstrate that EgGLUT1-ss is crucial for glucose uptake by the protoscoleces of E. granulosus s.s., and its inhibitor WZB117 has a therapeutic effect on CE. Funding Information: The National Natural Science Foundation of China (82060373, 81760369 and 81360251); State Key Laboratory of Pathogenesis, Prevention and Treatment of Central Asian High Incidence Diseases Fund (SKL-HIDCA-2020-BC3); "Tianshan Cedar" Science and Technology Innovation Talents Support Plan of Xinjiang Uygur Autonomous Region (No. 2019XS13). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: All procedures carried out with animals were approved by the Ethical Committee of the First Affiliated Hospital of Xinjiang Medical University (IACUC-20130425012).

7 páginas, Cystic (CE) and alveolar (AE) echinococcosis are chronic, neglected parasitic diseases burdened by high morbidity and, for AE, by high mortality, if left untreated. CE and AE have a widespread distribution, including Europe. Albendazole (ABZ), a broad-spectrum benzimidazole drug widely used to treat parasitic infections, is the drug of choice for the management of CE and AE, and is parasitostatic on echinococcal metacestodes. In Europe, ABZ is licensed for interrupted “cyclic” treatment, for a maximum of 3 cycles. However, better efficacy with no increased side effects has been shown when the drug is administered continuously and for longer periods. Current international recommendations, on the basis of clinical, pharmacological, and biological studies, recommend continuous administration of ABZ for months to years for the treatment of CE and AE, and this schedule has been widely in use for the past 20 years. However, in Europe this internationally recommended schedule, with the exception of France, is technically “off-label”, and, as such, requires an informed consent by the patient and, in some countries, even precludes the reimbursement of the drug cost. Adding to the very high cost of the drug, frequent “out-of-stock” situation, and packaging format impractical for long therapies, these conditions put patients with CE and AE regularly at risk of treatment discontinuation and disease progression. European regulations envisage variations to marketing authorization, but postauthorization studies should be carried out by the holder of the license of the drug, in the form of randomized controlled trials. While such studies do not seem feasible and would probably not be ethically justified for CE and AE, European regulations envisage other possibilities in particular situations, which apply to CE and AE, but there is limited interest to invest in this perspective. We urge a coordination between stakeholders to find effective and feasible ways to take action to revise the benzimidazole dosage regimens for CE and AE and to ensure a fair, regular, and easy access to the appropriate treatment to those suffering from these serious diseases., This work was partly supported by the Italian Ministry of Health “Fondi Ricerca Corrente –Progetto L3P1” – IRCCS Sacro Cuore Don Calabria Hospital.

International audience; Background The effect of exposure to micro-organisms on allergic diseases has been well studied. The protective effect of early food diversity against allergic diseases was previously shown in the PASTURE cohort study. The consumption of cheese, a food potentially rich in microbial diversity, deserves further examination. We aimed to evaluate whether cheese consumption is associated with allergic diseases. Methods In the PASTURE study (birth cohort in 5 European countries), data on feeding practices, environmental factors and allergic diseases were collected by questionnaires from birth to 6 years (N=931). Cheese consumption at 18 months of age was quantified in terms of frequency and diversity (i.e., number of consumed types among 6 types: hard pressed, semi-pressed, soft, blue, fresh cheese, from the farm). Multiple logistic regressions were performed to evaluate the effect of cheese consumption on atopic dermatitis (AD), food allergy (FA), allergic rhinitis, asthma and atopic sensitization at 6 years after adjustment for confounders of atopy. Results Cheese consumption (vs. non-consumption) had a significant protective effect on AD (OR=0.51 [0.29-0.90], p=0.02) and FA (OR=0.32, [0.15-0.71], p=0.004), but no effect on atopic sensitization, allergic rhinitis and asthma at 6 years. This effect on AD and FA may be related to the diversity of consumed cheeses (OR=0.64 [0.48-0.85] per cheese type, p=0.002; OR=0.55 [0.33-0.92], p=0.02, respectively). Conclusions Although reverse causality cannot totally be ruled out, cheese diversity at 18 months had a protective effect against AD and FA at 6 years in addition to the protective effect of diversity of other foods.

Summary The tumor-like growth of larval Echinococcus multilocularis tissue (causing alveolar echinococcosis, AE) is directly linked to the nature/orientation of the periparasitic host immune-mediated processes. Parasite-mediated immune suppression is a hallmark triggering infection outcome in both chronic human and murine AE. So far, little is known about secondary systemic immune effects of this pathogen on other concomitant diseases, e.g. endogenous gut inflammation. We examined the influence of E. multilocularis infection on murine Dextran sodium sulfate (DSS)-induced colitis. At 3 months post-E. multilocularis infection (chronic stage), the mice were challenged with 3% DSS in the drinking water for 5 days plus subsequently with tap water (alone) for another 4 days. After necropsy, fixed tissues/organs were sectioned and stained with Hematoxylin and Eosin (H&E) for assessing inflammatory reaction. Cytokine levels were measured by flow cytometry and quantitative RT-PCR. Colitis severity was assessed (by board-certified veterinary pathologists) regarding (i) colon length, (ii) weight loss and (iii) a semiquantitative score of morphologic changes. The histopathological analysis of the colon showed a significant reduction of DSS-induced gut inflammation by concomitant E. multilocularis infection, which correlated with down-regulation of Th1/Th17 T cell responses in the colon tissue. E. multilocularis infection markedly reduced the severity of DSS-induced gut inflammation upon down-regulation of Th1/Th17 cytokine expression, and attenuation of CD11b+ Dendritic Cell maturation cell activation. In conclusion, E. multilocularis infection remarkably reduces DSS-induced colitis in mice by attenuating Th1/Th17 mediated immune reactions. This article is protected by copyright. All rights reserved.

Introduction The growth potential of the tumor-like Echinococcus multilocularis metacestode (causing alveolar echinococcosis, AE) is directly linked to the nature/function of the periparasitic host immune-mediated processes. Previous studies had shown that regulatory T cells (Tregs) become gradually up-regulated in the course of both chronic human and murine AE. Thus we now tackled the role of FoxP3+ Tregs and FoxP3+-Treg-regulated immune response in contributing to the control of this helminthic infection. Methods The infection outcome in E. multilocularis-infected DEREG mice was measured upon determining parasite load (wet weight of parasitic metacestode tissue). Flow cytometry and qRT-PCR were used to assess Treg, Th17-, Th1-, Th2-type immune responses and antigen presenting cell activation. Results We showed that E. multilocularis-infected DEREG-mice treated with DT (as compared to infected control DEREG-mice without DT application) exhibited a significantly lower parasite load, associated with a persisting capacity of co-stimulation, and an increased Th1/Th17-polarization. Conclusions FoxP3+ Tregs appear as one of the key players in immune regulatory processes favoring (i) metacestode survival by inhibiting the maturation potential of co-stimulatory activity and (ii) T cell exhaustion (suppressing Th1/Th17-type immune responses). We showed as well that prospectively, targeting FoxP3+ Tregs could be an option to develop an immunotherapy against AE.

The local immune mechanisms responsible for the establishment and development of Echinococcus granulosus sensu stricto infection in the liver, have been little explored. We developed a suitable experimental model that mimics naturally infected livers using portal injection of protoscoleces. Opposite to Echinococcus multilocularis infection which is dose-dependent, fully mature hydatid cysts can be established in the liver whatever the injection dose; although most of the infection sites were seen at the establishment phase as inflammatory granulomas associated with fibrosis, they never matured into cysts. At the establishment phase, a strong immune response was composed of T and B cells, with T1-type, T2-type cells and cytokines and IL-10-secreting CD8+ T cells in the liver. At the established phase, results suggested a local production of antibodies by B cells, and an involvement of NK and NKT cells. Infection outcome and local immune response in the liver, were different in the mouse models of Echinococcus granulosus sensu stricto and Echinococcus multilocularis respectively; however, only early specificities at the microenvironment level might explain the major differences found between the lesions induced by the two species. Our quantitative experimental model appears fully appropriate to further study this microenvironment and its relationship with each cestode species.

To correlate the presence of calcifications in alveolar echinococcosis (AE) hepatic lesions to the metabolic activity in 18 fluorodeoxyglucose positron emission tomography combined with computed tomography (FDG-PET/CT). Our institutional review board approved this study. 61 patients (29 women, 32 men, aged from 15 to 86 years) were included in the study. Images of FDG-PET/CT were interpreted by two independent nuclear medicine physicians. AE hepatic lesions were classified as AE lesions with or without hypermetabolic activity. The presence of calcifications was assessed on unenhanced CT scans by two independent radiologists blinded with regard to the metabolic activity of the AE hepatic lesions. Every single calcification the size of which was

International audience

Echinococcosis is a zoonosis caused by cestodes of the genus Echinococcus (family Taeniidae). This serious and near-cosmopolitan disease continues to be a significant public health issue, with western China being the area of highest endemicity for both the cystic (CE) and alveolar (AE) forms of echinococcosis. Considerable advances have been made in the 21st century on the genetics, genomics, and molecular epidemiology of the causative parasites, on diagnostic tools, and on treatment techniques and control strategies, including the development and deployment of vaccines. In terms of surgery, new procedures have superseded traditional techniques, and total cystectomy in CE, ex vivo resection with autotransplantation in AE, and percutaneous and perendoscopic procedures in both diseases have improved treatment efficacy and the quality of life of patients. In this review, we summarize recent progress on the biology, epidemiology, diagnosis, management, control, and prevention of CE and AE. Currently there is no alternative drug to albendazole to treat echinococcosis, and new compounds are required urgently. Recently acquired genomic and proteomic information can provide a platform for improving diagnosis and for finding new drug and vaccine targets, with direct impact in the future on the control of echinococcosis, which continues to be a global challenge.

Cystic echinococcosis is a zoonosis caused by the larval stage of Echinococcus granulosussensu lato. There is an urgent need to develop new drugs for the treatment of this disease. In this study, we identified two new members of mitogen-activated protein kinase (MAPK) cascades, MKK3/6 and MEK1/2 homologs (termed EgMKK1 and EgMKK2, respectively), from E. granulosussensu stricto. Both EgMKK1 and EgMKK2 were expressed at the larval stages. As shown by yeast two-hybrid and coimmunoprecipitation analyses, EgMKK1 interacted with the previously identified Egp38 protein but not with EgERK. EgMKK2, on the other hand, interacted with EgERK. In addition, EgMKK1 and EgMKK2 displayed kinase activity toward the substrate myelin basic protein. When sorafenib tosylate, PD184352, or U0126-ethanol (EtOH) was added to the medium for in vitro culture of E. granulosus protoscoleces (PSCs) or cysts, an inhibitory and cytolytic effect was observed via suppressed phosphorylation of EgMKKs and EgERK. Nonviability of PSCs treated with sorafenib tosylate or U0126-EtOH, and not with PD184352, was confirmed through bioassays, i.e., inoculation of treated and untreated protoscoleces into mice. In vivo treatment of E. granulosussensu stricto-infected mice with sorafenib tosylate or U0126-EtOH for 4 weeks demonstrated a reduction in parasite weight, but the results did not show a significant difference. In conclusion, the MAPK cascades were identified as new targets for drug development, and E. granulosus was efficiently inhibited by their inhibitors in vitro. The translation of these findings into in vivo efficacy requires further adjustment of treatment regimens using sorafenib tosylate or, possibly, other kinase inhibitors.

Biliary complications represent a turning point in the course of Alveolar Echinococcosis (AE). We conducted a European survey to collect data on the current usage and results of perendoscopic interventions (PEIs) for their treatment.Patient's characteristics and follow-up until January 31st, 2015 were recorded using an online questionnaire.From 18 centers 129 PEIs were analyzed in 38 patients; 139 plastic stents were inserted during 85 PEIs; median time between stent placements was significantly longer when 3 stents or more were placed. Initial symptoms disappeared in 95% and long-term bile duct patency was obtained in 73% of cases. Cholangitis was a more frequent complication of the PEIs (10%) than in other indications; intensive lavage of the bile ducts may prevent this complication.European centers use perendoscopic biliary drainage as an efficient and safe alternative to surgery to treat AE biliary complications. Insertion of multiple plastic stents delays stent occlusion and leads to effective and prolonged bile duct patency.

International audience; Alveolar echinococcosis (AE) is a lethal disease caused by infection with the metacestode stage of the helminth Echinococcus multilocularis, which develops into a tumorlike mass in susceptible intermediate hosts. The growth potential of this parasite stage is directly linked to the nature of the surrounding periparasitic immune-mediated processes. In a first step (experiment 1), mice were orally infected with E. multilocularis eggs, to be used for assessing the hepatic expression profiles of 15 selected cytokine and chemokine genes related to acquired immunity from 21 to 120 days postinfection. The early stage of infection in immunocompetent animals was marked by a mixed Th1/Th2 immune response, as characterized by the concomitant presence of gamma interferon (IFN-γ) and interleukin-4 (IL-4) and their related chemokines. At the late stage of AE, the profile extended to a combined tolerogenic mode including Foxp3, IL-10, and transforming growth factor beta (TGF-β) as key components. In a second step (experiment 2), the effect of T regulatory cell (Treg) deficiency on metacestode growth was assessed in E. multilocularis-infected DEREG (depletion of regulatory T cells) mice upon induction of Treg deficiency with diphtheria toxin (DT). The parasite lesions were significantly smaller in the livers of treated mice than in corresponding control groups. Foxp3+ Tregs appear to be one of the key players in immune-regulatory processes favoring metacestode survival by affecting antigen presentation and suppressing Th1-type immune responses. For these reasons, we suggest that affecting Foxp3+ Tregs could offer an attractive target in the development of an immunotherapy against AE.

Alveolar echinococcosis (AE) is a lethal disease caused by infection with the metacestode stage of the helminth Echinococcus multilocularis, which develops into a tumorlike mass in susceptible intermediate hosts. The growth potential of this parasite stage is directly linked to the nature of the surrounding periparasitic immune-mediated processes., Alveolar echinococcosis (AE) is a lethal disease caused by infection with the metacestode stage of the helminth Echinococcus multilocularis, which develops into a tumorlike mass in susceptible intermediate hosts. The growth potential of this parasite stage is directly linked to the nature of the surrounding periparasitic immune-mediated processes. In a first step (experiment 1), mice were orally infected with E. multilocularis eggs, to be used for assessing the hepatic expression profiles of 15 selected cytokine and chemokine genes related to acquired immunity from 21 to 120 days postinfection. The early stage of infection in immunocompetent animals was marked by a mixed Th1/Th2 immune response, as characterized by the concomitant presence of gamma interferon (IFN-γ) and interleukin-4 (IL-4) and their related chemokines. At the late stage of AE, the profile extended to a combined tolerogenic mode including Foxp3, IL-10, and transforming growth factor beta (TGF-β) as key components. In a second step (experiment 2), the effect of T regulatory cell (Treg) deficiency on metacestode growth was assessed in E. multilocularis-infected DEREG (depletion of regulatory T cells) mice upon induction of Treg deficiency with diphtheria toxin (DT). The parasite lesions were significantly smaller in the livers of treated mice than in corresponding control groups. Foxp3+ Tregs appear to be one of the key players in immune-regulatory processes favoring metacestode survival by affecting antigen presentation and suppressing Th1-type immune responses. For these reasons, we suggest that affecting Foxp3+ Tregs could offer an attractive target in the development of an immunotherapy against AE.

This review gives a critical update of the situation regarding alveolar echinococcosis (AE) in Europe in humans, based on existing publications and on findings of national and European surveillance systems. All sources point to an increase in human cases of AE in the “historic endemic areas” of Europe, namely Germany, Switzerland, Austria and France and to the emergence of human cases in countries where the disease had never been recognised until the end of the 20th century, especially in central-eastern and Baltic countries. Both increase and emergence could be only due to methodological biases; this point is discussed in the review. One explanation may be given by changes in the animal reservoir of the parasite, Echinococcus multilocularis (increase in the global population of foxes in Europe and its urbanisation, as well as a possible increased involvement of pet animals as definitive infectious hosts). The review also focuses onto 2 more original approaches: (1) how changes in therapeutic attitudes toward malignant and chronic inflammatory diseases may affect the epidemiology of AE in the future in Europe, since a recent survey of such cases in France showed the emergence of AE in patients with immune suppression since the beginning of the 21st century; (2) how setting a network of referral centres in Europe based on common studies on the care management of patients might contribute to a better knowledge of AE epidemiology in the future.

International audience; Alveolar echinococcosis (AE) is a neglected 'malignant' parasitic disease. The European endemic area of Echinococcus multilocularis in foxes is larger than previously anticipated, and there is new evidence that both fox populations and the prevalence of E. multilocularis have increased in many areas, indicating increased pressure for infection with E. multilocularis eggs in intermediate and accidental hosts, including humans. This may result in more human AE cases within the next decades. Current numbers of both immunocompetent and immunocompromised AE patients, and the anticipated future increase, call for scaling-up research to rapidly improve the development and implementation of prevention measures, early diagnosis, and curative treatment of human AE.

Human cystic echinococcosis (CE) is known to be endemic in the Tibet Autonomous Region (TAR), China; however, there is relatively little data from hospital records or community prevalence studies, and the situation regarding occurrence of human alveolar echinococcosis (AE) is unclear. Here we review the available reports about human echinococcosis in the seven prefectures of TAR. In addition, two pilot studies by mass screening using ultrasound (with serology) were undertaken (2006/7) in Dangxiong County of Lhasa Prefecture (north central TAR) and Dingqing County of Changdu Prefecture (eastern TAR). In Dangxiong County a prevalence of 9.9% (55/557) for human CE was obtained but no human AE cases were detected. By contrast, in Dingqing County (N= 232 persons screened), 11 CE cases (4.7%) and 12 AE cases (5.2%) (including one mixed CE and AE case) were diagnosed by ultrasound. Hospital records and published reports indicated that CE cases were recorded in all of seven prefectures in Tibet Autonomous Region, and AE cases in four prefectures. Incidence rates of human CE were estimated to range from 1.9 to 155 per 100,000 across the seven prefectures of TAR, with a regional incidence of 45.1 per 100,000. Incidence of AE was estimated to be between 0.6 and 2.8 cases per 100,000. Overall for TAR, human AE prevalence appeared relatively low; however, the pilot mass screening in Dingqing in eastern TAR indicated that human AE disease is a potential public health problem, possibly similar to that already well described in Tibetan communities bordering TAR in north-west Sichuan and south-west Qinghai provinces.

Any ambiguity in texts used in the communication about vaccines can not only interfere with comprehension, but also generate safety and liability issues. Within a survey on the quality of written protocols for at-risk interventional procedures and sanitary crises, we analyzed documents relating to vaccination, and among them, the "package-leaflet" of an anti-H1N1 influenza vaccine, widely disseminated to the public in 2009-2010. Among the most common mistakes, we observed that 1) language was not always adjusted to the non-specialist's level of knowledge; 2) chronology, logic, consistency, and homogeneity were often missing; 3) crucial pieces of information were disseminated all over the text, 4) use of the passive voice did not distinguish between instructions and information; 5) use of synonyms could be misleading and impair translation. We propose the use of "Controlled language" (CL) to improve the situation. By constraining lexicon, grammar and syntax, CL is a way to write documents that are clear, accurate and devoid of ambiguity. However, the set of rules necessary to write in CL is difficult to memorize. We thus developed authoring software (Rédacticiel Prolipsia) to make the creation of a CL by linguists and its use by health professionals easy and adapted to any domain. It may considerably improve the writing of vaccine package inserts/leaflets. It could be used to write information documents about vaccines and their safety, and operating procedures for professionals to prepare, store, and administer vaccines, decide upon proper indication of vaccines, and follow patients after vaccine injection.