Search

Background: The etiology of inflammatory bowel disease (IBD) is unclear but involves both genetics and environmental factors, including the gut microbiota. Indeed, exacerbated activation of the gastrointestinal immune system toward the gut microbiota occurs in genetically susceptible hosts and under the influence of the environment. For instance, a majority of IBD susceptibility loci lie within genes involved in immune responses, such as caspase recruitment domain member 9 (Card9). However, the relative impacts of genotype versus microbiota on colitis susceptibility in the context of CARD9 deficiency remain unknown. Results: Card9 gene directly contributes to recovery from dextran sodium sulfate (DSS)-induced colitis by inducing the colonic expression of the cytokine IL-22 and the antimicrobial peptides Reg3β and Reg3γ independently of the microbiota. On the other hand, Card9 is required for regulating the microbiota capacity to produce AhR ligands, which leads to the production of IL-22 in the colon, promoting recovery after colitis. In addition, cross-fostering experiments showed that 5 weeks after weaning, the microbiota transmitted from the nursing mother before weaning had a stronger impact on the tryptophan metabolism of the pups than the pups' own genotype. Conclusions: These results show the role of CARD9 and its effector IL-22 in mediating recovery from DSS-induced colitis in both microbiota-independent and microbiota-dependent manners. Card9 genotype modulates the microbiota metabolic capacity to produce AhR ligands, but this effect can be overridden by the implantation of a WT or "healthy" microbiota before weaning. It highlights the importance of the weaning reaction occurring between the immune system and microbiota for host metabolism and immune functions throughout life. A better understanding of the impact of genetics on microbiota metabolism is key to developing efficient therapeutic strategies for patients suffering from complex inflammatory disorders. -8ZHpF322gum1G2x3b5Gvy Video Abstract [ABSTRACT FROM AUTHOR]

This article presents a case study of a 20-year-old woman, who had worked as a hairdresser for four years. She had noticed worsening of pre-existing irritant hand dermatitis after skin contact with a particular permanent-waving solution. Patch testing was performed and components of ester-free waving solution, not yet available as commercial allergens, were tested as recommended. Thiolactic acid is a permanent waving agent mainly used as its ammonium salt. An irritant reaction to thiolactic acid, unlikely tested to all patients were negative.

Objective: FMF is the most common monogenic autoinflammatory disease associated with MEFV mutations. Disease phenotype and response to treatment vary from one patient to another, despite similar genotype, suggesting the role of environmental factors. The objective of this study was to analyse the gut microbiota of a large cohort of FMF patients in relation to disease characteristics., Methods: The gut microbiotas of 119 FMF patients and 61 healthy controls were analysed using 16 s rRNA gene sequencing. Associations between bacterial taxa, clinical characteristics, and genotypes were evaluated using multivariable association with linear models (MaAslin2), adjusting on age, sex, genotype, presence of AA amyloidosis (n = 17), hepatopathy (n = 5), colchicine intake, colchicine resistance (n = 27), use of biotherapy (n = 10), CRP levels, and number of daily faeces. Bacterial network structures were also analysed., Results: The gut microbiotas of FMF patients differ from those of controls in having increased pro-inflammatory bacteria, such as the Enterobacter, Klebsiella and Ruminococcus gnavus group. Disease characteristics and resistance to colchicine correlated with homozygous mutations and were associated with specific microbiota alteration. Colchicine treatment was associated with the expansion of anti-inflammatory taxa such as Faecalibacterium and Roseburia, while FMF severity was associated with expansion of the Ruminococcus gnavus group and Paracoccus. Colchicine-resistant patients exhibited an alteration of the bacterial network structure, with decreased intertaxa connectivity., Conclusion: The gut microbiota of FMF patients correlates with disease characteristics and severity, with an increase in pro-inflammatory taxa in the most severe patients. This suggests a specific role for the gut microbiota in shaping FMF outcomes and response to treatment., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Chronic obstructive pulmonary disease (COPD) is a major health issue primarily caused by cigarette smoke (CS) and characterized by breathlessness and repeated airway inflammation. NLRP6 is a cytosolic innate receptor controlling intestinal inflammation and orchestrating the colonic host-microbial interface. However, its roles in the lungs remain largely unexplored. Using CS exposure models, our data show that airway inflammation is strongly impaired in Nlrp6-deficient mice with drastically fewer recruited neutrophils, a key cell subset in inflammation and COPD. We found that NLRP6 expression in lung epithelial cells is important to control airway and lung tissue inflammation in an inflammasome-dependent manner. Since gut-derived metabolites regulate NLRP6 inflammasome activation in intestinal epithelial cells, we investigated the link between NLRP6, CS-driven lung inflammation, and gut microbiota composition. We report that acute CS exposure alters gut microbiota in both wild-type (WT) and Nlrp6-deficient mice and that antibiotic treatment decreases CS-induced lung inflammation. In addition, gut microbiota transfer from dysbiotic Nlrp6-deficient mice to WT mice decreased airway lung inflammation in WT mice, highlighting an NLRP6-dependent gut-to-lung axis controlling pulmonary inflammation., Competing Interests: Author FT was employed by company ArtImmunne SAS. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Nascimento, Huot-Marchand, Fanny, Straube, Le Bert, Savigny, Apetoh, Van Snick, Trovero, Chamaillard, Quesniaux, Ryffel, Gosset, Gombault, Riteau, Sokol and Couillin.)

Background: Lipin-1 deficiency is a life-threatening disease that causes severe rhabdomyolysis (RM) and chronic symptoms associated with oxidative stress. In the absence of treatment, Hydroxychloroquine sulfate (HCQ) was administered to patients off label use on a compassionate basis in order to improve their physical conditions., Methods: Eleven patients with LPIN1 mutations were treated with HCQ. Clinical and biological efficacy and tolerance were assessed, including pain and quality of life, physical capacities, cardiopulmonary parameters, creatine kinase levels and plasma proinflammatory cytokines. To explore a dose-dependent effect of HCQ, primary myoblasts from 4 patients were incubated with various HCQ concentrations in growth medium (GM) or during starvation (EBSS medium) to investigate autophagy and oxidative stress., Findings: Under HCQ treatment, patient physical capacities improved. Abnormal cardiac function and peripheral muscle adaptation to exercise were normalized. However, two patients who had the highest mean blood HCQ concentrations experienced RM. We hypothesized that HCQ exerts deleterious effects at high concentrations by blocking autophagy, and beneficial effects on oxidative stress at low concentrations. We confirmed in primary myoblasts from 4 patients that high in vitro HCQ concentration (10 µM) but not low concentration (1 µM and 0.1 µM) induced autophagy blockage by modifying endolysosomal pH. Low HCQ concentration (1 µM) prevented reactive oxygen species (ROS) and oxidized DNA accumulation in myoblasts during starvation., Interpretation: HCQ improves the condition of patients with lipin-1 deficiency, but at low concentrations. In vitro, 1 µM HCQ decreases oxidative stress in myoblasts whereas higher concentrations have a deleterious effect by blocking autophagy., Competing Interests: Declaration of Competing Interest PVE and PDL have filed PCT (WO/2017/085115; EP3377095; PCT/EP2016/077843) and US patent applications (US20180325890). PVE and PDL have filed PCT (WO/2019/020732; PCT/EP2018/070256) patent applications. The remaining authors have no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The discovery of bats as reservoir hosts for a number of highly pathogenic zoonotic agents has led to an increasing interest of infectious disease research in experimental studies with bats. Therefore, we established breeding colonies of Rousettus aegyptiacus and Eidolon helvum fruit bats, which both have been identified as reservoir hosts for relevant zoonotic disease agents, such as Marburg virus and Lagos bat virus. Since 2013, individuals of both species have been recruited to the Friedrich-Loeffler-Institut (FLI) from zoological gardens in Europe, to where these species had been introduced from the wild several decades ago. The aviaries have been designed according to national recommendations published by the Federal Ministry of Agriculture. Under these conditions, both species have been reproducing for years. To better understand the physiology of these animals, and to generate baseline knowledge for infection experiments, we monitored the body core temperatures of R. aegyptiacus bats in the aviaries, and found a circadian variation between 34°C and 41.5°C. We also determined the hematological parameters of both species, and detected specific differences between both bat species. For values of clinical chemistry, no correlation to age or sex was observed. However, species-specific differences were detected since ALT, BUN and CREA were found to be significantly higher in R. aegyptiacus and GLU and TP were significantly higher in E. helvum bats. A higher hematocrit, hemoglobin and red blood cell level was observed in subadult R. aegyptiacus , with hemoglobin and red blood cells also being significantly increased compared to E. helvum . Lymphocytes were found to be the dominant white blood cells in both species and are higher in female E. helvum . Neutrophil granulocytes were significantly higher in E. helvum bats. This underlines the necessity to define baseline profiles for each bat species prior to their use in experimental challenge., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Rissmann, Friedrichs, Kley, Straube, Sadeghi and Balkema-Buschmann.)

Abundance of Faecalibacterium prausnitzii, a dominant bacterium of the human microbiota that exhibits antiinflammatory effects, is decreased in patients with inflammatory bowel diseases (IBD). In humans, colonic lamina propria contains IL-10-secreting, Foxp3- Tregs characterized by a double expression of CD4 and CD8α (DP8α) and a specificity for F. prausnitzii. This Treg subset is decreased in IBD. The in vivo effect of DP8α cells has not been evaluated yet to our knowledge. Here, using a humanized model of a NSG immunodeficient mouse strain that expresses the HLA D-related allele HLA-DR*0401 but not murine class II (NSG-Ab° DR4) molecules, we demonstrated a protective effect of a HLA-DR*0401-restricted DP8α Treg clone combined with F. prausnitzii administration in a colitis model. In a cohort of patients with IBD, we showed an independent association between the frequency of circulating DP8α cells and disease activity. Finally, we pointed out a positive correlation between F. prausnitzii-specific DP8α Tregs and the amount of F. prausnitzii in fecal microbiota in healthy individuals and patients with ileal Crohn's disease.

Alterations in brain/gut/microbiota axis are linked to Irritable Bowel Syndrome (IBS) physiopathology. Upon gastrointestinal infection, chronic abdominal pain and anxio-depressive comorbidities may persist despite pathogen clearance leading to Post-Infectious IBS (PI-IBS). This study assesses the influence of tryptophan metabolism, and particularly the microbiota-induced AhR expression, on intestinal homeostasis disturbance following gastroenteritis resolution, and evaluates the efficacy of IL-22 cytokine vectorization on PI-IBS symptoms. The Citrobacter rodentium infection model in C57BL6/J mice was used to mimic Enterobacteria gastroenteritis. Intestinal homeostasis was evaluated as low-grade inflammation, permeability, mucosa-associated microbiota composition, and colonic sensitivity. Cognitive performances and emotional state of animals were assessed using several tests. Tryptophan metabolism was analyzed by targeted metabolomics. AhR activity was evaluated using a luciferase reporter assay method. One Lactococcus lactis strain carrying an eukaryotic expression plasmid for murine IL-22 ( L. lactis IL-22 ) was used to induce IL-22 production in mouse colonic mucosa. C. rodentium -infected mice exhibited persistent colonic hypersensitivity and cognitive impairments and anxiety-like behaviors after pathogen clearance. These post-infectious disorders were associated with low-grade inflammation, increased intestinal permeability, decrease of Lactobacillaceae abundance associated with the colonic layer, and increase of short-chain fatty acids (SCFAs). During post-infection period, the indole pathway and AhR activity were decreased due to a reduction of tryptophol production. Treatment with L. lactis IL-22 restored gut permeability and normalized colonic sensitivity, restored cognitive performances and decreased anxiety-like behaviors. Data from the video-tracking system suggested an upgrade of welfare for mice receiving the L.lactis IL-22 strain. Our findings revealed that AhR/IL-22 signaling pathway is altered in a preclinical PI-IBS model. IL-22 delivering alleviate PI-IBS symptoms as colonic hypersensitivity, cognitive impairments, and anxiety-like behaviors by acting on intestinal mucosa integrity. Thus, therapeutic strategies targeting this pathway could be developed to treat IBS patients suffering from chronic abdominal pain and associated well-being disorders.

Objective: Chronic alcohol consumption is an important cause of liver-related deaths. Specific intestinal microbiota profiles are associated with susceptibility or resistance to alcoholic liver disease in both mice and humans. We aimed to identify the mechanisms by which targeting intestinal microbiota can improve alcohol-induced liver lesions., Design: We used human associated mice, a mouse model of alcoholic liver disease transplanted with the intestinal microbiota of alcoholic patients and used the prebiotic, pectin, to modulate the intestinal microbiota. Based on metabolomic analyses, we focused on microbiota tryptophan metabolites, which are ligands of the aryl hydrocarbon receptor (AhR). Involvement of the AhR pathway was assessed using both a pharmacological approach and AhR-deficient mice., Results: Pectin treatment modified the microbiome and metabolome in human microbiota-associated alcohol-fed mice, leading to a specific faecal signature. High production of bacterial tryptophan metabolites was associated with an improvement of liver injury. The AhR agonist Ficz (6-formylindolo (3,2-b) carbazole) reduced liver lesions, similarly to prebiotic treatment. Conversely, inactivation of the ahr gene in alcohol-fed AhR knock-out mice abrogated the beneficial effects of the prebiotic. Importantly, patients with severe alcoholic hepatitis have low levels of bacterial tryptophan derivatives that are AhR agonists., Conclusions: Improvement of alcoholic liver disease by targeting the intestinal microbiota involves the AhR pathway, which should be considered as a new therapeutic target., Competing Interests: Competing interests: Disclosures: DC received travel funds from Biocodex and Gilead, lecture fees from Gilead, and royalties from John Libbey Eurotext. GK is a cofounder of everImmune. HS received unrestricted study grants from Danone, Biocodex, and Enterome and board membership, consultancy or lecture fees from Carenity, Abbvie, Astellas, Danone, Ferring, Mayoly Spindler, MSD, Novartis, Roche, Tillots, Enterome, Maat, BiomX, Biose, Novartis, and Takeda and is a cofounder of Exeliom Biosciences. GP received travel funds from Janssen and Gilead, consulting fees from Bayer, Biocodex, Roche, Gilead, Pierre Fabre, and Servier, and royalties from Elsevier-Masson, Solar, Flammation/Versilio, and John Libbey Eurotext. A-MC received travel funds and consulting fees from Biocodex and royalties from Elsevier-Masson, Solar, Flammation/Versilio and John Libbey Eurotext. All other authors declare no conflicts of interest., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Acidithiobacillus ferrooxidans is an acidophilic bacterium able to grow in environments with high concentrations of metals. It is a chemolithoautotroph able to form biofilms on the surface of solid minerals to obtain its energy. The response of both planktonic and sessile cells of A. ferrooxidans ATCC 23270 grown in elemental sulfur and adapted to high copper concentration was analyzed by quantitative proteomics. It was found that 137 proteins varied their abundance when comparing both lifestyles. Copper effllux proteins, some subunits of the ATP synthase complex, porins, and proteins involved in cell wall modification increased their abundance in copper-adapted sessile lifestyle cells. On the other hand, planktonic copper-adapted cells showed increased levels of proteins such as: cupreredoxins involved in copper cell sequestration, some proteins related to sulfur metabolism, those involved in biosynthesis and transport of lipopolysaccharides, and in assembly of type IV pili. During copper adaptation a decreased formation of biofilms was measured as determined by epifluorescence microscopy. This was apparently due not only to a diminished number of sessile cells but also to their exopolysaccharides production. This is the first study showing that copper, a prevalent metal in biomining environments causes dispersion of A. ferrooxidans biofilms. SIGNIFICANCE: Copper is a metal frequently found in high concentrations at mining environments inhabitated by acidophilic microorganisms. Copper resistance determinants of A. ferrooxidans have been previously studied in planktonic cells. Although biofilms are recurrent in these types of environments, the effect of copper on their formation has not been studied so far. The results obtained indicate that high concentrations of copper reduce the capacity of A. ferrooxidans ATCC 23270 to form biofilms on sulfur. These findings may be relevant to consider for a bacterium widely used in copper bioleaching processes., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Airborne ozone exposure causes severe lung injury and inflammation. The aryl hydrocarbon Receptor (AhR) (1), activated in pollutant-induced inflammation, is critical for cytokine production, especially IL-22 and IL-17A. The role of AhR in ozone-induced lung inflammation is unknown. We report here that chronic ozone exposure activates AhR with increased tryptophan and lipoxin A4 production in mice. AhR -/- mice show increased lung inflammation, airway hyperresponsiveness, and tissue remodeling with an increased recruitment of IL-17A and IL-22-expressing cells in comparison to control mice. IL-17A- and IL-22-neutralizing antibodies attenuate lung inflammation in AhR -/- and control mice. Enhanced lung inflammation and recruitment of ILC3, ILC2, and T cells were observed after T cell-specific AhR depletion using the AhR CD4cre -deficient mice. Together, the data demonstrate that ozone exposure activates AhR, which controls lung inflammation, airway hyperresponsiveness, and tissue remodeling via the reduction of IL-22 expression., (Copyright © 2020 Michaudel, Bataille, Maillet, Fauconnier, Colas, Sokol, Straube, Couturier-Maillard, Dumoutier, van Snick, Quesniaux, Togbe and Ryffel.)

Individuals with impaired immune responses, such as ventilated and cystic fibrosis patients are often infected with Pseudomonas aeruginosa ( P.a ) bacteria, and a co-infection with the Influenza virus (IAV) is often present. It has been known for many years that infection with IAV predisposes the host to secondary bacterial infections (such as Streptococcus pneumoniae or Staphylococcus aureus ), and there is an abundance of mechanistic studies, including those studying the role of desensitization of TLR signaling, type I IFN- mediated impairment of neutrophil chemokines and antimicrobial production, attenuation of IL1β production etc., showing this. However, little is known about the mechanistic events underlying the potential deleterious synergy between Influenza and P.a co-infections. We demonstrate here in vitro in epithelial cells and in vivo in three independent models (two involving mice given IAV +/- P.a , and one involving mice given IAV +/- IL-1β) that IAV promotes secondary P.a -mediated lung disease or augmented IL-1β-mediated inflammation. We show that IAV- P.a -mediated deleterious responses includes increased matrix metalloprotease (MMP) activity, and MMP-9 in particular, and that the use of the MMP inhibitor improves lung resilience. Furthermore, we show that IAV post-transcriptionally inhibits the antimicrobial/anti-protease molecule elafin/trappin-2, which we have shown previously to be anti-inflammatory and to protect the host against maladaptive neutrophilic inflammation in P.a infections. Our work highlights the capacity of IAV to promote further P.a -mediated lung damage, not necessarily through its interference with host resistance to the bacterium, but by down-regulating tissue resilience to lung inflammation instead. Our study therefore suggests that restoring tissue resilience in clinical settings where IAV/ P.a co-exists could prove a fruitful strategy., (Copyright © 2020 Villeret, Solhonne, Straube, Lemaire, Cazes, Garcia-Verdugo and Sallenave.)

Objective: Patients with primary sclerosing cholangitis (PSC) were previously shown to display a bacterial gut dysbiosis but fungal microbiota has never been examined in these patients. The aim of this study was to assess the fungal gut microbiota in patients with PSC., Design: We analysed the faecal microbiota of patients with PSC and concomitant IBD (n=27), patients with PSC and no IBD (n=22), patients with IBD and no PSC (n=33) and healthy subjects (n=30). Bacterial and fungal composition of the faecal microbiota was determined using 16S and ITS2 sequencing, respectively., Results: We found that patients with PSC harboured bacterial dysbiosis characterised by a decreased biodiversity, an altered composition and a decreased correlation network density. These alterations of the microbiota were associated with PSC, independently of IBD status. For the first time, we showed that patients with PSC displayed a fungal gut dysbiosis, characterised by a relative increase in biodiversity and an altered composition. Notably, we observed an increased proportion of Exophiala and a decreased proportion of Saccharomyces cerevisiae . Compared with patients with IBD and healthy subjects, the gut microbiota of patients with PSC exhibited a strong disruption in bacteria-fungi correlation network, suggesting an alteration in the interkingdom crosstalk., Conclusion: This study demonstrates that bacteria and fungi contribute to gut dysbiosis in PSC., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Familial Mediterranean fever (FMF) can be complicated by AA amyloidosis (AAA), though it remains unclear why only some patients develop amyloidosis. We examined the gut microbiota composition and inflammatory markers in patients with FMF complicated or not by AAA., Methods: We analysed the gut microbiota of 34 patients with FMF without AAA, 7 patients with FMF with AAA, 19 patients with AAA of another origin, and 26 controls using 16S ribosomal RNA gene sequencing with the Illumina MiSeq platform. Associations between bacterial taxa and clinical phenotypes were evaluated using multivariate association with linear models statistical method. Blood levels of interleukin (IL)-1β, IL-6, tumour necrosis factor-α and adipokines were assessed by ELISA; indoleamine 2,3-dioxygenase (IDO) activity was determined by high-performance liquid chromatography., Results: Compared with healthy subjects, specific changes in faecal microbiota were observed in FMF and AAA groups. Several operational taxonomic units (OTUs) were associated with FMF. Moreover, two OTUs were over-represented in FMF-related AAA compared with FMF without AAA. Additionally, higher adiponectin levels and IDO activity were observed in FMF-related AAA compared with FMF without AAA (p<0.05)., Conclusion: The presence of specific changes in faecal microbiota in FMF and in FMF-related AAA suggests that intestinal microorganisms may play a role in the pathogenesis of these diseases. These findings may offer an opportunity to use techniques for gut microbiota manipulation., Competing Interests: Competing interests: None., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Each year, large numbers of bats move across Europe between their summer and winter areas, yet even though many of them are endangered and legally protected, we are unaware about many aspects of their migratory behaviour. Here, taking Nyctalus noctula as a model species, we used stable hydrogen isotopic values in fur ( δ 2 H f ) as an endogenous marker to shed light on the migratory behaviour of more than 1000 bats from hibernacula across Central Europe. Specifically, we asked the following questions: how flexible is migration in temperate zone bats? Which general migration pattern do noctule bats follow? How repeatable and thus predictable is the migratory behaviour of individuals? Do morphological correlates of migration occur in bats? Our study confirmed that noctule bats engage in partial and female-biased migration across Europe, suggesting the strongest migration pressures for northern populations. Further, we revealed a combination of partial and differential migration patterns with highly variable migration distances which lead to a pronounced mixing of different source populations in hibernacula where mating occurs. Most individuals were consistent in their migration strategy over time, i.e. 86% could be repeatedly assigned to either long-distance or regional origin across years. This is consistent with our finding that the between-individual component explained 84% of the variation in δ 2 H f values, suggesting specialized individual migratory behaviours and a strong natal philopatry. We discovered a positive correlation between forearm length and migration distance and support for sex-specific effects of migration on body condition. Our study elucidated migration patterns over large geographical scales, demonstrating that considerable numbers of migratory bats originating from distant populations depend on hibernacula across Central Europe, calling for international conservation management.

The extent to which microbiota alterations define or influence the outcome of metabolic diseases is still unclear, but the byproducts of microbiota metabolism are known to have an important role in mediating the host-microbiota interaction. Here, we identify that in both pre-clinical and clinical settings, metabolic syndrome is associated with the reduced capacity of the microbiota to metabolize tryptophan into derivatives that are able to activate the aryl hydrocarbon receptor. This alteration is not merely an effect of the disease as supplementation with AhR agonist or a Lactobacillus strain, with a high AhR ligand-production capacity, leads to improvement of both dietary- and genetic-induced metabolic impairments, particularly glucose dysmetabolism and liver steatosis, through improvement of intestinal barrier function and secretion of the incretin hormone GLP-1. These results highlight the role of gut microbiota-derived metabolites as a biomarker and as a basis for novel preventative or therapeutic interventions for metabolic disorders., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The gut microbiota is essential for the normal function of the gut immune system, and microbiota alterations are associated with autoimmune disorders. However, how the gut microbiota prevents autoimmunity in distant organs remains poorly defined. Here we reveal that gut microbiota conditioned innate lymphoid cells (ILCs) induce the expression of mouse β-defensin 14 (mBD14) by pancreatic endocrine cells, preventing autoimmune diabetes in the non-obese diabetic (NOD) mice. MBD14 stimulates, via Toll-like receptor 2, interleukin-4 (IL-4)-secreting B cells that induce regulatory macrophages, which in turn induce protective regulatory T cells. The gut microbiota-derived molecules, aryl hydrocarbon receptor (AHR) ligands and butyrate, promote IL-22 secretion by pancreatic ILCs, which induce expression of mBD14 by endocrine cells. Dysbiotic microbiota and low-affinity AHR allele explain the defective pancreatic expression of mBD14 observed in NOD mice. Our study reveals a yet unidentified crosstalk between ILCs and endocrine cells in the pancreas that is essential for the prevention of autoimmune diabetes development., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Host-microbe balance maintains intestinal homeostasis and strongly influences inflammatory conditions such as inflammatory bowel diseases (IBD). Here we focused on bacteria-fungi interactions and their implications on intestinal inflammation, a poorly understood area., Methods: Dextran sodium sulfate (DSS)-induced colitis was assessed in mice treated with vancomycin (targeting gram-positive bacteria) or colistin (targeting Enterobacteriaceae) and supplemented with either Saccharomyces boulardii CNCM I-745 or Candida albicans. Inflammation severity as well as bacterial and fungal microbiota compositions was monitored., Results: While S. boulardii improved DSS-induced colitis and C. albicans worsened it in untreated settings, antibiotic treatment strongly modified DSS susceptibility and effects of fungi on colitis. Vancomycin-treated mice were fully protected from colitis, while colistin-treated mice retained colitis phenotype but were not affected anymore by administration of fungi. Antibacterial treatments not only influenced bacterial populations but also had indirect effects on fungal microbiota. Correlations between bacterial and fungal relative abundance were dramatically decreased in colistin-treated mice compared to vancomycin-treated and control mice, suggesting that colistin-sensitive bacteria are involved in interactions with fungi. Restoration of the Enterobacteriaceae population by administrating colistin-resistant Escherichia coli reestablished both beneficial effects of S. boulardii and pathogenic effects of C. albicans on colitis severity. This effect was at least partly mediated by an improved gut colonization by fungi., Conclusions: Fungal colonization of the gut is affected by the Enterobacteriaceae population, indirectly modifying effects of mycobiome on the host. This finding provides new insights into the role of inter-kingdom functional interactions in intestinal physiopathology and potentially in IBD.

Silver nanoparticles (AgNPs) are microbicidal agents which could be potentially used as an alternative to antivirals to treat human infectious diseases, especially influenza virus infections where antivirals have generally proven unsuccessful. However, concerns about the use of AgNPs on humans arise from their potential toxicity, although mechanisms are not well-understood. We show here, in the context of an influenza virus infection of lung epithelial cells, that AgNPs down-regulated influenza induced CCL-5 and -IFN-β release (two cytokines important in antiviral immunity) through RIG-I inhibition, while enhancing IL-8 production, a cytokine important for mobilizing host antibacterial responses. AgNPs activity was independent of coating and was not observed with gold nanoparticles. Down-stream analysis indicated that AgNPs disorganized the mitochondrial network and prevented the antiviral IRF-7 transcription factor influx into the nucleus. Importantly, we showed that the modulation of RIG-I-IRF-7 pathway was concomitant with inhibition of either classical or alternative autophagy (ATG-5- and Rab-9 dependent, respectively), depending on the epithelial cell type used. Altogether, this demonstration of a AgNPs-mediated functional dichotomy (down-regulation of IFN-dependent antiviral responses and up-regulation of IL-8-dependent antibacterial responses) may have practical implications for their use in the clinic.

Mature teratoma is a benign germ cell tumor rarely located in the temporal bone. We are reporting a case of a mature teratoma of the temporal bone in a healthy borne 3.5-month-old baby girl with a 2-day suggestive history of otitis media and polypoidal mass expulsing from the external auditory canal of the left ear. A definitive diagnosis is made after complete excision and histological examination of the tissue. Total surgical excision of the tumor is the treatment of choice.

The European Commission has recently issued a marketing authorisation valid throughout the European Union for 5-aminolaevulinic acid (Ameluz). The decision was based on the favorable opinion of the CHMP recommending a marketing authorization for 5-aminolaevulinic acid for treatment of actinic keratosis of mild to moderate intensity on the face and scalp. The active substance is a sensitizer used in photodynamic/radiation therapy (ATC code L01XD04). The gel should cover the lesions and approximately 5 mm of the surrounding area with a film of about 1 mm thickness. The entire treatment area should be illuminated with a red light source, either with a narrow spectrum around 630 nm and a light dose of approximately 37 J/cm(2) or a broader and continuous spectrum in the range between 570 and 670 nm with a light dose between 75 and 200 J/cm(2). One session of photodynamic therapy should be administered for single or multiple lesions. Non- or partially responding lesions should be retreated in a second session 3 months after the first treatment. 5-aminolaevulinic acid is metabolized to protoporphyrin IX, a photoactive compound which accumulates intracellularly in the treated actinic keratosis lesions. Protoporphyrin IX is activated by illumination with red light of a suitable wavelength and energy. In the presence of oxygen, reactive oxygen species are formed which causes damage of cellular components and eventually destroys the target cells. The benefit with 5-aminolaevulinic acid is its ability to improve the complete response rate of actinic keratosis lesions. The most common side effects are reactions at the site of application. The objective of this article is to summarize the scientific review of the application. The detailed scientific assessment report and product information, including the summary of product characteristics (SmPC), are available on the EMA website (www.ema.europa.eu).

Background: Often described as an extremely rare zoonosis, cowpox virus (CPXV) infections are on the increase in Germany. CPXV is rodent-borne with a broad host range and contains the largest and most complete genome of all poxviruses, including parts with high homology to variola virus (smallpox). So far, most CPXV cases have occurred individually in unvaccinated animals and humans and were caused by genetically distinguishable virus strains., Methodology/principal Findings: Generalized CPXV infections in banded mongooses (Mungos mungo) and jaguarundis (Herpailurus yagouaroundi) at a Zoological Garden were observed with a prevalence of the affected animal group of 100% and a mortality of 30%. A subsequent serological investigation of other exotic animal species provided evidence of subclinical cases before the onset of the outbreak. Moreover, a time-delayed human cowpox virus infection caused by the identical virus strain occurred in a different geographical area indicating that handling/feeding food rats might be the common source of infection., Conclusions/significance: Reports on the increased zoonotic transmission of orthopoxviruses have renewed interest in understanding interactions between these viruses and their hosts. The list of animals known to be susceptible to CPXV is still growing. Thus, the likely existence of unknown CPXV hosts and their distribution may present a risk for other exotic animals but also for the general public, as was shown in this outbreak. Animal breeders and suppliers of food rats represent potential multipliers and distributors of CPXV, in the context of increasingly pan-European trading. Taking the cessation of vaccination against smallpox into account, this situation contributes to the increased incidence of CPXV infections in man, particularly in younger age groups, with more complicated courses of clinical infections.

The various noxious agents to which these occupational groups can be exposed are described in detail. We have constructed a supplementary questionnaire to aid the occupational dermatologist in evaluating such individuals. We describe measures for skin protection, and methods for reduce exposure of harmful agents.

This paper presents a vision of the future in which standards exist at all levels necessary to accomplish true interoperability. The infrastructure has been established to support connectivity among all healthcare-related institutions as well as the population at large. Provider and patient care integrated in the process of an individual's care.

The use of computer-based patient record systems (CPRS) in the primary care setting will increase significantly over the next few years. Real-time, point-of-care use of such systems must provide adequate payback to justify the intrusion into the provider/patient relationship. The authors describe, through the transition of a legacy system into a state-of-the art system, how such a system might be integrated into the primary care setting. Information flow is organized around an event, such as a patient encounter, or around the patient. The Medical Record (TMR) optimizes the provider/computer interaction through the use of protocols and clinical guidelines. Documentation is enhanced through the use of computer-generated progress notes.

Study Objective: To analyze the extent of pericardial constraint on right ventricular function in humans., Patients and Methods: Twenty patients, 59 +/- 2 (mean +/- SEM) years old, undergoing coronary bypass surgery. Right ventricular volumes and pressures were evaluated using a rapid response Swan-Ganz thermodilution catheter., Interventions: Parameters were determined before and after pericardiotomy, both before and during increased right ventricular systolic pressure by partial compression of the pulmonary artery (before pulmonary compression: 25 +/- 1 mm Hg; during: 39 +/- 1 mm Hg)., Results: Pericardiotomy alone did not significantly affect right ventricular end-diastolic volume (before: 79 +/- 4 mL m-2; after: 78 +/- 3 mL m-2), right ventricular ejection fraction (before: 48 +/- 1%; after: 48 +/- 2%), and right atrial pressure (before: 4.3 +/- 0.8 mm Hg; after: 4.3 +/- 0.7 mm Hg). Before pericardiotomy, the increase in right ventricular afterload significantly increased right atrial pressure (to 5.5 +/- 0.7 mm Hg, p < 0.05) and reduced right ventricular ejection fraction (to 43 +/- 2%, p < 0.01). Right ventricular end-diastolic volume remained unchanged. After pericardiotomy, the increase in right ventricular afterload significantly increased right ventricular end-diastolic volume (to 85 +/- 3 mL m-2, p < 0.01) and also reduced right ventricular ejection fraction (to 42 +/- 2%, p < 0.01), while right atrial pressure was not significantly changed. During increased right ventricular afterload, the right ventricular diastolic pressure-volume relation was shifted rightward., Conclusions: At normal levels of right ventricular diastolic filling, the pericardium does not exert constraining effects on right ventricular function. However, with increasing levels of right ventricular preload, pericardial constraint significantly influences right ventricular function in humans.