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The increased incidence of inflammatory bowel disease (IBD) has become a global phenomenon that could be related to adoption of a Western life-style. Westernization of dietary habits is partly characterized by enrichment with the ω-6 polyunsaturated fatty acid (PUFA) arachidonic acid (AA), which entails risk for developing IBD. Glutathione peroxidase 4 (GPX4) protects against lipid peroxidation (LPO) and cell death termed ferroptosis. We report that small intestinal epithelial cells (IECs) in Crohn’s disease (CD) exhibit impaired GPX4 activity and signs of LPO. PUFAs and specifically AA trigger a cytokine response of IECs which is restricted by GPX4. While GPX4 does not control AA metabolism, cytokine production is governed by similar mechanisms as ferroptosis. A PUFA-enriched Western diet triggers focal granuloma-like neutrophilic enteritis in mice that lack one allele of Gpx4 in IECs. Our study identifies dietary PUFAs as a trigger of GPX4-restricted mucosal inflammation phenocopying aspects of human CD., Dietary lipids are linked to the development of inflammatory bowel diseases through unclear mechanisms. Here, the authors report that dietary polyunsaturated fatty acids trigger intestinal inflammation resembling aspects of Crohn’s disease, which is restricted by glutathione peroxidase 4 in the intestinal epithelium.

Allergo journal international 30(5), 155-168 (2021). doi:10.1007/s40629-021-00178-2, Published by Urban & Vogel, München

Cervical cancer constitutes an issue in public health, becoming the leading cause of death by cancer in women between 20-40 years of age in Latin America. In Argentina 5000 new cases are diagnosed each year, where more than 56% are in advanced stages. The aim of the present current opinion or critical review article is to remark the importance of the prognostic significance of the Central Tumor Size in stages IIB and IIIB cervical cancer, as well as to propose a new FIGO Staging System for Cervical cancer and trying to find out a role for the different therapeutic strategies for those cases.

Background and Aims The microbial ecosystem seems to be an important player for therapeutic intervenption in inflammatory bowel disease [IBD]. We assessed longitudinal microbiome changes in IBD patients undergoing therapy with either azathioprine [AZA] or anti-tumour necrosis factor [anti-TNF] antibodies. We predicted the metabolic microbial community exchange and linked it to clinical outcome. Methods Faecal and blood samples were collected from 65 IBD patients at baseline and after 12 and 30 weeks on therapy. Clinical remission was defined as Crohn’s Disease Activity Index [CDAI] Results Paired Bray-Curtis distance between baseline and follow-up time points was significantly different for UC patients treated with anti-TNF antibodies. Longitudinal changes in taxa composition at phylum level showed a significant decrease of Proteobacteria and an increase of Bacteroidetes in CD patients responding to both therapies. At family level, Lactobacilli were associated with persistent disease and Bacteroides abundance with remission in CD. In-silico simulations of microbial metabolite exchange predicted a 1.7-fold higher butyrate production capacity of patients in remission compared with patients without remission [p = 0.041]. In this model, the difference in butyrate production between patients in remission and patients without remission was most pronounced in the CD group treated with AZA [p = 0.008]. Conclusions In-silico simulation identifies microbial butyrate synthesis predictive of therapeutic efficacy in IBD.

Objective Alcohol-related liver disease (ALD) is a global healthcare problem with limited treatment options. Alpha-1 antitrypsin (AAT, encoded by SERPINA1) shows potent anti-inflammatory activities in many preclinical and clinical trials. In our study, we aimed to explore the role of AAT in ALD. Design An unselected cohort of 512 patients with cirrhosis was clinically characterised. Survival, clinical and biochemical parameters including AAT serum concentration were compared between patients with ALD and other aetiologies of liver disease. The role of AAT was evaluated in experimental ALD models. Results Cirrhotic ALD patients with AAT serum concentrations less than 120 mg/dL had a significantly higher risk for death/liver transplantation as compared with patients with AAT serum concentrations higher than 120 mg/dL. Multivariate Cox regression analysis showed that low AAT serum concentration was a NaMELD-independent predictor of survival/transplantation. Ethanol-fed wild-type (wt) mice displayed a significant decline in hepatic AAT compared with pair-fed mice. Therefore, hAAT-Tg mice were ethanol-fed, and these mice displayed protection from liver injury associated with decreased steatosis, hepatic neutrophil infiltration and abated expression of proinflammatory cytokines. To test the therapeutic capability of AAT, ethanol-fed wt mice were treated with human AAT. Administration of AAT ameliorated hepatic injury, neutrophil infiltration and steatosis. Conclusion Cirrhotic ALD patients with AAT concentrations less than 120 mg/dL displayed an increased risk for death/liver transplantation. Both hAAT-Tg mice and AAT-treated wt animals showed protection from ethanol-induced liver injury. AAT could reflect a treatment option for human ALD, especially for alcoholic hepatitis.

Background and Aims Faecal biomarkers, particularly calprotectin [FCAL], have become important diagnostic and monitoring tools in inflammatory bowel diseases [IBD]. As FCAL is mainly produced by neutrophils, we hypothesised that faecal lipocalin-2 [FLCN2], also expressed by intestinal epithelial cells [IEC], could be beneficial in specific clinical situations. Methods We compared clinical and endoscopic activity-related correlations between FCAL and FLCN2, assayed from the same sample, in a cohort of 132 patients (72 Crohn’s disease [CD]) and 40 controls. A detailed analysis of cellular origins was done by confocal microscopy and flow cytometry. To evaluate the potential to detect low-grade inflammation, we studied faecal and tissue concentrations in a cohort with clinical, endoscopic, and histological remission. Results There was an excellent correlation between FCAL and FLCN2 [rS = 0.87, p Conclusions This study corroborates the diagnostic equivalence of FLCN2 and FCAL in IBD. In remission, persistent mucosal overexpression renders LCN2 an attractive candidate for molecular inflammation warranting further investigation.

Introducao O rearranjo KMT2A envolve o gene 11q23 e engloba as translocacoes t(4:11), t(9:11) e t(11;19). Este rearranjo e identificado em leucemias agudas, mais comumente em casos de leucemia/linfoma linfoblastica aguda de linhagem B (LLA B). A LLA B com rearranjo KMT2A tem expressao imunofenotipica do marcador linfoide B CD19, coexpressao dos marcadores mieloides CD15 e CD65 e ausencia de expressao de CD10 e CD24. Em alguns casos, o rearranjo KMT2A tambem pode ser identificado em leucemias agudas de fenotipo misto. O evento raro de troca de linhagem compreende a mudanca de linhagem linfoide em mieloide, ou vice-versa, e geralmente e descrito no momento da recaida ou apos o inicio da terapia. Blinatumomab e um anticorpo monoclonal que recentemente tem sido uso utilizado no tratamento de alguns casos de LLA B recidivados ou refratarios. Neste relato descrevemos um caso de LLA B recaida que apresentou troca de linhagem apos tratamento com blinatumomab. Relato de caso Paciente feminina, 55 anos, apresentando anemia, plaquetopenia e hiperleucocitose. Foi realizada avaliacao da medula ossea. Na analise microscopica, foi identificada hipercelularidade e infiltracao por blastos (74,0% do total de celulas) com citoplasma escasso. A analise de imunofenotipagem por citometria de fluxo (ICF) identificou 82,2% de blastos que expressavam citCD79a, nuTdT, CD58, CD19, CD34 parcial, CD45 fraco, CD123, CD38, CD81 e CD22, apresentavam coexpressao aberrante de CD65 e CD15; e nao expressavam CD10 ou marcadores de linhagem mielomonocitica. Os exames foram compativeis com LLA B com imunofenotipo sugestivo da presenca de t(v;11q23.3) – rearranjo KMT2A. A avalicao cariotipica evidenciou presenca de t(4;11). Posterior ao primeiro ciclo de quimioterapia foi identificada persistencia da doenca atraves de pesquisa doenca residual minima (DRM) positiva e a paciente apresentou recidiva da doenca, sendo iniciado tratamento com blinatumomab. Alguns dias apos o uso de blinatumomab, a paciente apresentou importantes anemia e plaquetopenia no hemograma. Em nova avaliacao medular, foram identificados 81,0% de blastos expressando CD38, CD15 fraco, CD65 fraco, CD45, HLA-DR, CD4, CD33, CD56, CD11b heterogeneo, CD64 e cMPO, imunofenotipo compativel com leucemia monocitica aguda. Na avaliacao morfologica, os blastos apresentavam citoplasma hipogranular, nucleo por vezes chanfrado e nucleolo evidente. O uso de blinatumomab foi suspenso e a paciente recebeu tratamento para leucemia mieloide aguda (LMA). Em reavaliacao posterior, a paciente apresentou remissao da LMA e aumento de blastos com imunofenotipo identico ao identificado no diagnostico inicial, compativel com clone de LLA B. Conclusao Apesar da troca de linhagem ser considerado um fenomeno raro, ha relatos recentes na literatura de pacientes diagnosticados com LLA B com rearranjo KMT2A e que apresentaram troca de linhagem para LMA posterior ao uso de blinatumomab.

ZusammenfassungBiologika nehmen eine herausragende Rolle in der Therapie chronisch-entzündlicher Darmerkrankungen (CED) ein. Diese aus lebenden Zellen biotechnologisch hergestellten Antikörper (Ak) ermöglichen zunehmend selektive antientzündliche Behandlungsansätze, wobei deren Produktion und Zulassung einem komplexen und kostenintensiven Entwicklungsprozess unterliegen. Mit Patentablauf einzelner Biologika kommen seit einigen Jahren nun zunehmend Biosimilars, ebenso biotechnologisch produzierte Nachfolgepräparate, auf den Markt und führen zu einer zunehmenden Präparatevielfalt bei sinkenden Kosten für das Gesundheitssystems. Das vorliegende Positionspapier der Arbeitsgruppe (AG) CED der Österreichischen Gesellschaft für Gastroenterologie und Hepatologie (ÖGGH) versucht mit dieser Entwicklung aufkommende Fragen betreffend Wirksamkeit, Sicherheit, Präparatewechsel (Switch) und Verschreibungsgebarung zu beantworten, um eine höchstmögliche Patientensicherheit auch zukünftig zu gewährleisten.

This article is the second in a series of two publications relating to the European Crohn's and Colitis Organisation [ECCO] evidence-based consensus on the management of Crohn's disease. The first article covers medical management; the present article addresses surgical management, including preoperative aspects and drug management before surgery. It also provides technical advice for a variety of common clinical situations. Both articles together represent the evidence-based recommendations of the ECCO for Crohn's disease and an update of previous guidelines. ispartof: JOURNAL OF CROHNS & COLITIS vol:14 issue:2 pages:155-168 ispartof: location:England status: published

ZusammenfassungImmunmediierte inflammatorische Erkrankungen (IMID) sind eine klinisch heterogene Gruppe von Erkrankungen, die genetische, ätiologische und auch klinische Überschneidungen aufweisen. Nach dem heutigen Stand der Forschung liegen den sog. primären IMID gemeinsame pathogene Mechanismen und zytokinassoziierte Signaltransduktionswege zugrunde. Zu den primären IMID zählen unter anderem chronisch-entzündliche Darm‑, Haut- und Augenerkrankungen sowie rheumatische Erkrankungen. Patienten, die an einer primären IMID erkrankt sind, weisen ein erhöhtes Risiko für die Entwicklung einer sekundären IMID auf. Die vorliegende Arbeit skizziert die Abgrenzung zwischen primären und sekundären IMID unter Berücksichtigung von Komplikationen und Komorbiditäten. Ausgehend von den Fächern Gastroenterologie, Dermatologie, Rheumatologie und Ophthalmologie wird ein möglicher optimaler interdisziplinärer Umgang mit IMID-Patienten diskutiert. Im speziellen werden Leitsymptome, die auf eine IMID hinweisen, und diagnostische Maßnahmen beschrieben, die vor Überweisung eines Patienten zum entsprechenden Spezialisten durchgeführt werden sollten. Da einzelne Patienten, die unter mehreren IMID leiden, eine therapeutische Herausforderung darstellen, können hierfür interdisziplinäre Sprechstunden bzw. sog. Immunoboards in der klinischen Praxis hilfreich sein.

O artigo tem como temas a interatividade digital e gestão de marca. Seu objetivo é analisar as interações digitais do Hotel Alpestre, localizado em Gramado, RS, com seus clientes, através do TripAdvisor, como parte de um processo de gestão de marca e de construção de reputação. O estudo utiliza pesquisa bibliográfica e documental, bem como entrevistas. Os dados levantados, juntamente com as informações obtidas através das entrevistas. A interatividade digital e a gestão de marca mostram-se conectadas por meio das ações realizadas pelo hotel e os colaboradores sentem-se inseridos e relevantes para os processos da organização, um dos princípios do endobranding, demonstrando consciência de seu papel para a gestão de marca e a construção da equidade de marca.

Purpose The aims of this study is to put on the agenda discussions concerning the approach of sustainable goals and indicators, in terms of how they relate to each other and how to list their importance within a network of contemporary city management. From the millennium objectives experience, UN has launched the continuity of the development program, through the sustainable development goals (SDG), which have the purpose of giving support to local and regional governments for the 2030 agenda in local sphere. In the city context, sustainable development has also been approached in regulations, like ISO 37120: 2017 “Sustainable development of communities: Indicators for city services and quality of life”. These instruments have in common the concern of offering parameters of public services to citizens and promoting in a uniform manner both social and economic growth of the urban environment. Design/methodology/approach The present study aims to compare these two sustainable development tools by means of a documentary analysis and to analyze the feasibility of the proposed indicators and their qualitative evaluation goals to improve citizens’ quality of life. Findings The results suggest that the main urban challenges are related to unplanned urban growth and poor-quality public services, which generate a lack of commitment to enforce laws and to achieve sustainable development goals. Originality/value The study establishes bases for guiding the discussion to support managers and investors decisions to promote paradigm changes in the citizens’ life and in the way cities are planned.

Summary Background In recent months numerous health care professional acquired COVID-19 at the workplace resulting in significant shortages in medical and nursing staff. We investigated how prior COVID-19 affects SARS-CoV-2 vaccination and how such knowledge could facilitate frugal vaccination strategies. Methods In a cohort of 41 healthcare professionals with (n=14) and without (n=27) previous SARS-CoV-2 infection, we assessed the immune status before, during and after vaccination with BNT162b2. The humoral immune response was assessed by receptor binding domain ELISA and different SARS-CoV-2 neutralisation assays using wildtype and pseudo-typed viruses. T cell immunity against SARS-CoV-2 surface and nucleocapsid peptides were studied using interferon-γ release assays and intracellular flow cytometry. Vaccine-related side effects were captured. Findings Prior COVID-19 resulted in improved vaccine responses both in the B and T cell compartment. In vaccine recipients with prior COVID-19, the first vaccine dose induced high antibody concentrations comparable to seronegative vaccine recipients after two injections. This translated into more efficient neutralisation of virus particles, even more pronounced than expected from the RBD ELISA results. Furthermore, T cell responses were stronger in convalescents and particularly strong against the SARS-CoV-2 nucleocapsid protein. Interpretation Herein, we corroborate recent findings suggesting that in convalescents a single vaccine dose is sufficient to boost adequate in vitro neutralisation of SARS-CoV-2 and therefore may be sufficient to induce adequate protection against severe COVID-19. New spike mutated virus variants render the highly conserved nucleocapsid protein – eliciting strong SARS-CoV-2 specific T cell immunity – an interesting additional vaccine target. Funding Christian Doppler Research Association, Johannes Kepler University Linz

Study question Uterine microbiota: are there differences within three major time points of the menstrual cycle in healthy controls, recurrent miscarriage (RM) and recurrent implantation failure (RIF) patients? Summary answer Compared to controls, RM and RIF patients showed an altered uterine microbiota throughout the menstrual cycle, with a lower dominance of lactobacilli. What is known already In contrast to the former notion of a sterile womb, bacterial colonization in the uterus and the placenta has been demonstrated. Studies showed that Lactobacillus-dominated endometrial microbiota correlate with reproductive success. Moreover, the presence of non-Lactobacillus-dominated microbiota, especially with detection of Gardnerella and Streptococcus in the endometrial fluid, seems to be associated with lower implantation-, ongoing pregnancy- and live birth-rates. However, intra-cycle variations in healthy women as well as possible alterations in patients with RM or RIF remain unknown. Study design, size, duration In total, n = 20 RM patients (≥ 3 consecutive miscarriages), n = 20 RIF patients (≥3 fresh or frozen embryo transfers with negative serum hCG, good quality embryos) and n = 10 healthy controls (no pregnancy) were included in this study. All patients had a 28 day menstrual cycle. During follicular, ovulatory and luteal-phase, after a thorough cleaning of the cervix, a flexible catheter was introduced into the uterine cavity and a uterine flushing with 1ml of NaCl was performed. Participants/materials, setting, methods Bacterial DNA was extracted using a QIAamp DNA kit (Qiagen) in combination with a PrecellysR24 homogenizer (Peqlab, Erlangen, Germany) according to the manufacturer’s instructions. The V3-V4 region of the bacterial 16S rRNA gene was amplified. Samples were pooled in equimolar ratios and progressed to pyrosequencing using an Illumina MiSeq se-quencer with MiSeq Kit V2 (250 bp paired-end). Analysis of 16S rRNA data, including alpha- and beta-diversity, were calculated using the phyloseq package in R. Main results and the role of chance For the Shannon index (species richness and evenness) a significant decrease during the ovulation period was shown in the control group, indicating a more uniform microbiota (p Limitations, reasons for caution To minimize the impact of a potential contamination, we performed pre-experiments with paired samples both from the vaginal fornix and the endometrial cavum and could show a significant difference in overall microbiome configuration. However, the route of sample can still be prone to contamination. Wider implications of the findings For the first time, we were able to show cycle-dependent alterations in the endometrial microbiome. These findings underline the role of an altered endometrial microbiome as a cause for RM and RIF and can contribute to the future establishment of therapeutic strategies in cases of a dysbalanced microbiome. Trial registration number Drks00020803

Background: In recent months numerous health care professional acquired COVID-19 at the workplace resulting in significant shortages in medical and nursing staff. We investigated how prior COVID-19 affects SARS-CoV-2 vaccination and how such knowledge could facilitate frugal vaccination strategies. Methods: In a cohort of 41 healthcare professionals with (n=14) and without (n=27) previous SARS-CoV-2 infection, we assessed the immune status before, during and after vaccination with BNT162b2. The humoral immune response was assessed by receptor binding domain ELISA and different SARS-CoV-2 neutralisation assays using wildtype and pseudo-typed viruses. T cell immunity against SARS-CoV-2 surface and nucleocapsid peptides were studied using interferon g release assays and intracellular flow cytometry. Vaccine-related side effects were captured. Findings: Prior COVID-19 resulted in improved vaccine responses both in the B and T cell compartment. In vaccine recipients with prior COVID-19, the first vaccine dose induced high antibody concentrations comparable to seronegative vaccine recipients after two injections. This translated into more efficient neutralisation of virus particles, even more pronounced than expected from the RBD ELISA results. Furthermore, T cell responses were stronger in convalescents and particularly strong against the SARS-CoV-2 nucleocapsid protein. Interpretation: Herein, we corroborate recent findings suggesting that in convalescents a single vaccine dose may be sufficient to boost adequate protection against SARS-CoV-2. New spike mutated virus variants render the highly conserved nucleocapsid protein – eliciting strong SARS-CoV-2 specific T cell immunity – an interesting additional vaccine target. Funding: Christian Doppler Research Association, Johannes Kepler University Linz Declaration of Interests: TRK and MF are employees of Baxter AG, Vienna, Austria, now part of the Takeda group of companies and have Takeda stock interest. All other authors declare no competing interests. Ethics Approval Statement: This study was approved by the ethics committee of the Johannes Kepler University Linz (EC-No. 1322/2020) and informed consent was obtained from all study subjects.

Given the increase of women with excess weight or obesity and its possible effects on birth weight, the present study aimed to investigate the association between pregestational maternal body mass index (BMI) and birth weight in a birth cohort from Ribeirão Preto, SP, Brazil. This was a prospective study conducted on 1362 mother-child pairs involving singleton births. The women were evaluated using standardized questionnaires during the second trimester of pregnancy and at the time of childbirth. Information about the newborns was obtained from their medical records. The dependent variable was birth weight, categorized as low, adequate, or high. The independent variable was pregestational maternal BMI, categorized as malnutrition, adequate weight, overweight, and obesity. A multinomial regression model was used to estimate the crude and adjusted relative risk (RR) of low and high birth weight. A high frequency of pregestational excess weight (39.6%) was detected and found to be independently associated with high birth weight (RR=2.13, 95%CI: 1.19-3.80 for overweight and RR=3.34, 95%CI: 1.80-6.19 for obese pregnant women). There was no association between pregestational malnutrition and low birth weight (RR=1.70; 95%CI: 0.81-3.55). The present data showed a high rate of women with excess pregestational weight, supporting the hypothesis that pregestational BMI may contribute to high birth weight babies and indicating the need for actions aiming to prevent excessive weight in women at reproductive age.

Background: Over the last few years, clinicians focused their attention on the gender-related features in patients with tinnitus, often leading to controversial results. An interesting aspect of tinnitus patients is linked to the complexity of clinical presentation, where besides audiological symptoms, other co-occurrence psychological disorders may complicate the diagnostic evaluation. Methods: Therefore, we studied 107 patients with tinnitus, investigating their psychological comorbidities in the light of gender differences. All patients were evaluated with ENT/audiological and psychological examination to consider presence/absence, type and gender distribution of psychopathological comorbidities. Patients completed questionnaires on tinnitus distress (Tinnitus Handicap Inventory, THI), anxiety (Beck Anxiety Inventory, BAI), depression (Beck Depression Inventory, BDI), metacognition (Metacognition Questionnaire-30, MCQ-30) and worry (Penn State Worry Questionnaire). The influence of gender on the relationship between tinnitus distress and psychological comorbidities was investigated with simple moderation analyses using the SPSS PROCESS macro. Results: The total sample included 65 male and 42 female patients (60.7% vs. 39.3%), matched for age and duration of tinnitus. We found no significant differences for tinnitus distress (THI total score, THI subscales) and MCQ-30 subscales, except for the control over thoughts, where men showed significantly higher scores than women (p=.045). Also, in our sample women showed significantly higher values for depression (BDI total score, p=.019), anxiety (BAI total score, p=.010) and worries (PSQW total score, p=.015). Moderation analyses revealed a significant influence of gender on the relationship of tinnitus distress with depression: higher scores of tinnitus distress were associated with significantly elevated levels of depression amongst men. No further gender influences could be observed in our sample. Discussion: In conclusion, our results indicate general gender differences for psychological comorbidities in tinnitus patients, with women reporting more depression, anxiety and worries. Men, on the other hand, showed a higher need to control their thoughts. Additionally, our results indicate that men might have more coping problems with increasing levels of tinnitus distress, leading to increased depressive symptoms. However, the question about the distinction between female and male patients remains an open area of research for future studies on tinnitus.

The gastrointestinal tract represents a target organ for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), warranting a thorough discussion on the consequences, particularly regarding inflammatory bowel diseases. Here, aspects of gastrointestinal involvement with SARS-CoV-2, the role of viruses as modulators of mucosal immunity and as treatment-related safety hazards, and the current clinical evidence will be discussed.

The scope of this study is the quantification of vertical peak floor acceleration demands at column lines and along the length of beams of elastic moment-resisting steel frames subjected to recorded ground motions. These demands correlate with the maximum strength demands on rigid nonstructural components attached to a frame structure. Since it is commonly assumed that buildings behave flexibly in the horizontal direction and rigidly in the vertical direction, the assessment of vertical acceleration demands is typically not considered in most cases. The results of this study show that vertical peak floor accelerations can be up to five times larger than the vertical peak ground acceleration, in contrast to horizontal peak floor accelerations that are only up to two times larger than the horizontal peak ground acceleration for the numerical models used in this study. The most significant amplifications estimated in the vertical direction are found at the center of the girders. Further investigations of modified steel frames indicate that the story-wise mass distribution has an influence not only on the vertical acceleration demand, but also on the horizontal component of the response, though to a lesser degree. In contrast, the response in the vertical and horizontal direction is only slightly affected by an increase in the flexural stiffness of the beams. The results of this study strongly indicate that in steel frames it can be considered highly questionable to ignore the amplification of the vertical acceleration component along the height of the structure.

The sino-nasal outcomes test-22 (SNOT-22) represents the reference questionnaire to assess patients with chronic rhinosinusitis (CRS). As weak correlations between objective CRS parameters and SNOT-22 total score have been observed, factor analyses have aimed to identify underlying factorial structures. However, ambiguous factor loadings and problematic item-domain assignments have resulted. Moreover, such factor analyses have mainly been performed in non-European CRS patients, while European data remain sparse. This study thus sought to address these issues.Principal component analysis and confirmatory factor analysis were performed from SNOT-22 questionnaires completed by European CRS patients. Goodness of fit, internal consistencies, and factor loadings were calculated. Item-domain assignment was based on statistical grounds and clinical meaningfulness. Additionally, this study investigated correlations between SNOT-22 domains and external reference criteria, including Lund-Mackay score, Lund-Naclerio score and the brief symptom inventory 18 (BSI-18).One hundred and thirty-four European CRS patients were included. Principal component analysis proposed four SNOT-22 domains ("nasal symptoms", "otologic symptoms", "sleep symptoms", "emotional symptoms"), which explained 63.6% of variance. Observed item-domain-assignment differed from previously proposed item-domain assignments. All factor loadings were 0.5, except "cough" (0.42) and "facial pain or pressure" (0.49). For confirmatory factor analysis, satisfactory goodness of fit (RMSEA = 0.66; CFI = 0.92; TLI = 0.90) and internal consistencies (Cronbach-α: total score = 0.93; domains = 0.75-0.91) were observed. Significant positive correlations were found between the "nasal symptoms" domain and both the Lund-Mackay score (r = 0.48; p 0.001) and the Lund-Naclerio score (r = 0.27, p 0.01). Significant positive correlations were also identified between "emotional symptoms" and BSI-18 total score (r = 0.64, p 0.001).Principal component analysis performed for SNOT-22 questionnaires completed by European CRS patients indicated a different item-domain-assignment than previously reported. Confirmatory factor analysis suggested acceptable and clinically plausible psychometric properties for the resulting factorial structure. Significant correlations between the "nasal symptoms" and the "emotional symptoms" domains were observed with objective CRS parameters. The resulting factorial structure with different item-domain assignments may thus be more suitable for European CRS patients.

Introduction Coronavirus disease (COVID-19) has spread from Wuhan, China, and become a worldwide pandemic. Most patients display respiratory symptoms but up to 50% report gastrointestinal symptoms. Neopterin is a surrogate marker for viral inflammation, and its production by macrophages is driven by interferon-γ. Methods We measured fecal neopterin in 37 hospitalized COVID-19 patients not requiring intensive care measures and 22 healthy controls. Results Fecal neopterin was elevated in stool samples from COVID-19 patients compared with that in samples from healthy controls. Especially, patients reporting gastrointestinal symptoms exhibited increased fecal neopterin values. Discussion COVID-19 is associated with an inflammatory immune response in the gastrointestinal tract.

Zusammenfassung In dieser Arbeit wird eine Strategie zur Abschätzung der Antwort von Wiener Gründerzeithäusern unter Erdbebeneinwirkung mithilfe von nicht-linearen Zeitverlaufsberechnungen vorgestellt. Im ersten Teil wird aus einer Datenbank ein Satz von 14 aufgezeichneten Erdbebenschrieben für den Standort Wien südwestlich der Donau extrahiert. Da diese Schriebe im Mittel das Antwortspektrum für diesen Standort in einem weiten Periodenbereich abbilden, können sie für den Erdbebennachweis einer großen Klasse von Tragwerken, deren Grundperioden in diesen Periodenbereich fallen, verwendet werden. Der zweite Teil widmet sich der Modellbildung unter Berücksichtigung des für den betrachteten Bauwerkstypus speziellen konstruktiven Aufbaus sowie der inelastischen Verformungskapazitäten des Tragwerks. Die beschriebene Strategie wird am sogenannten Wiener Gründerzeit-Mustergebäude angewendet, um dessen Antwort unter Erdbebenanregung abzuschätzen.

IL-12 and IL-23 are closely related cytokines with important roles in the regulation of tissue inflammation. Converging evidence from studies in mice, human observational studies and population genetics supports the importance of these cytokines in the regulation of mucosal inflammation in the gut in particular. Ustekinumab, a therapeutic antibody targeting both cytokines is now widely licensed for the treatment of Crohn's disease, including in Europe, the USA, Canada and Japan, whilst agents targeting IL-23 specifically are in late-phase clinical trials. We review the emerging understanding of the biology of IL-12 and IL-23, as well as that of their major downstream cytokines, including IL-17. In particular, we discuss how their biology has influenced the development of clinical trials and therapeutic strategies in IBD, as well as how findings from clinical trials, at times surprising, have in turn refocused our understanding of the underlying biology.

ZusammenfasungAnti-TNF-α-Antikörper haben die Therapie chronisch-entzündlicher Darmerkrankungen und anderer immunmediierter inflammatorischer Erkrankungen revolutioniert. Der zunehmende Einsatz dieser Substanzen war Anlass, den Konsensusbericht zur sicheren Anwendung von Infliximab der Arbeitsgruppe für Chronisch Entzündliche Darmerkrankungen der Österreichischen Gesellschaft für Gastroenterologie und Hepatologie aus dem Jahr 2010 zu aktualisieren und auf alle anti-TNF-α-Antikörper zu erweitern. Der vorliegende Konsensusbericht fasst die aktuelle Datenlage zur sicheren Anwendung von anti-TNF-α-Antikörpern zusammen und berücksichtigt folgende Themen: allgemeines Infektionsrisiko, bakterielle Infekte (inkl. Clostridium difficile, Tuberkulose, Nahrungsmittelhygiene), Pneumozystis jiroveci, virale Infektionen (inkl. Hepatitis B, Hepatitis C, HIV, CMV, VZV), Impfungen und Impfempfehlungen, gastrointestinale Aspekte (perianale Fistel, abdominale Fistel, Stenose), dermatologische Aspekte (Haut-Malignome, Ekzem-ähnliche anti-TNF-α-assoziierte Hautläsionen), Infusionsreaktionen und Immunogenität, demyelinisierende Erkrankungen, Hepatotoxizität, Hämatotoxizität, Herzinsuffizienz, Malignomrisiko und Einsatz nach Malignomen, sowie Schwangerschaft und Stillen. Da der Konsensusbericht als praktischer Leitfaden für die sichere Anwendung dieser Substanzen dienen soll, wurden die relevanten Aspekte in einer Checkliste zusammengefasst, die sich in zwei Teile „vor Therapie“ und „während Therapie“ gliedert.

Head and neck cancer (HNC) and its treatment can lead to various functional impairments. We developed and validated an instrument for rapid physician-rated assessment of basic functional outcomes in HNC patients. HNC-relevant functional domains were identified through a literature review and assigned to verbal ratings based on observable criteria. The instrument draft was subjected to systematic expert review to assess its face and content validity. Finally, the empirical validity, reliability, and responsiveness of the expert-adapted Functional Integrity in Head and Neck Cancer (HNC-FIT) scales were assessed in healthy controls and in HNC patients. A matrix of the 6 functional domains of oral food intake, respiration, speech, pain, mood, and neck and shoulder mobility was created, each with 5 verbal rating levels. Face and content validity levels of the HNC-FIT scales were judged to be adequate by 17 experts. In 37 control subjects, 24 patients with HNC before treatment, and in 60 HNC patients after treatment, the HNC-FIT ratings in the 3 groups behaved as expected and functional domains correlated closely with the outcome of corresponding scales of the EORTC-HN35-QoL questionnaire, indicating good construct and criterion validity. Interrater reliability (rICC) was ≥0.9 for all functional domains and retest reliability (rICC) was ≥0.93 for all domains except mood (rICC = 0.71). The treatment effect size (eta-square) as a measure of responsiveness was ≥0.15 (p &lt, 0.01) for fall domains except for breathing and neck and shoulder mobility. The median HNC-FIT scale completion time was 1 min 17 s. The HNC-FIT scale is a rapid tool for physician-rated assessment of functional outcomes in HNC patients with good validity, reliability, and responsiveness.

The evaluation of the seismic safety and reliability of buildings and building contents within a probabilistic framework often requires response history analyses using site-specific ground motion records. The ground motion selection method proposed in this paper addresses this issue by a stochastic search procedure in which record sets are selected such that first- and second-order statistics (median and dispersion) satisfy predefined ground motion spectrum targets over a wide period range. Once a ground motion record set is selected, it can be used for seismic assessment of a broad class of buildings within the target period range at the given location.

Background & Aims Alcohol‐related liver disease (ALD) comprises different liver disorders which impose a health care issue. ALD and particularly alcoholic steatohepatitis, an acute inflammatory condition, cause a substantial morbidity and mortality as effective treatment options remain elusive. Inflammation in ALD is fuelled by macrophages (Kupffer cells [KCs]) which are activated by intestinal pathogen associated molecular patterns, eg lipopolysaccharide (LPS), disseminated beyond a defective intestinal barrier. We hypothesized that the immunomodulator dimethyl‐fumarate (DMF), which is approved for the treatment of human inflammatory conditions such as multiple sclerosis or psoriasis, ameliorates the course of experimental ALD. Methods Dimethyl‐fumarate or vehicle was orally administered to wild‐type mice receiving a Lieber‐DeCarli diet containing 5% ethanol for 15 days. Liver injury, steatosis and inflammation were evaluated by histology, biochemical‐ and immunoassays. Moreover, we investigated a direct immunosuppressive effect of DMF on KCs and explored a potential impact on ethanol‐induced intestinal barrier disruption. Results Dimethyl‐fumarate protected against ethanol‐induced hepatic injury, steatosis and inflammation in mice. Specifically, we observed reduced hepatic triglyceride and ALT accumulation, reduced hepatic expression of inflammatory cytokines (Tnf‐α, Il‐1β, Cxcl1) and reduced abundance of neutrophils and macrophages in ethanol‐fed and DMF‐treated mice when compared to vehicle. DMF protected against ethanol‐induced barrier disruption and abrogated systemic LPS concentration. In addition, DMF abolished LPS‐induced cytokine responses of KCs. Conclusions Dimethyl‐fumarate counteracts ethanol‐induced barrier dysfunction, suppresses inflammatory responses of KCs and ameliorates hepatic inflammation and steatosis, hallmarks of experimental ALD. Our data indicates that DMF treatment might be beneficial in human ALD and respective clinical trials are eagerly awaited., In a preclinical model of alcohol‐related liver disease (ALD), the oral administration of dimethyl fumarate (DMF), a drug already used and approved for treatment of multiple sclerosis and psoriasis, revealed to be highly effective to prevent hepatic inflammation, steatosis and liver injury. In particular, DMF directly suppresses Kupffer cell activation and counteracts alcohol‐induced gut barrier disruption, preventing lipopolysaccharide (LPS) translocation.

Introduction: Epidemiological studies have shown associations between placental measurements and perinatal and later life outcomes. Objectives: To report placental measurements and evaluate their association with birth weight in a Brazilian birth cohort. Methods: Retrospective cohort study with 958 mothers, placentas, and newborns delivered at the Ribeirão Preto Medical School Hospital, Universidade de São Paulo, Brazil, in 2010 and 2011. The information was collected from interviews, medical records, and pathology reports. The placental measurements were: weight, largest and smallest diameters, eccentricity, thickness, shape, area, and birth weight/placental weight and placental weight/birth weight ratios. We analyzed the associations between birth weight and placental measurements using multiple linear regression. Results: Placental weight alone accounted for 48% of birth weight variability (p < 0.001), whereas placental measurements combined (placental weight, largest and smallest diameters, and thickness) were responsible for 50% (p < 0.001). When adjusted for maternal and neonatal characteristics, placental measurements explained 74% of birth weight variability (p < 0.001). Conclusion: Placental measurements are powerful independent predictors of birth weight. Placental weight is the most predictive of them, followed by the smallest diameter. RESUMO: Introdução: Estudos epidemiológicos demonstraram associações entre medidas placentárias, resultados perinatais e futuros. Objetivos: Descrever medidas placentárias e avaliar suas associações com peso ao nascer numa coorte de nascimentos brasileira. Metodologia: Estudo de coorte retrospectiva de 958 mães, placentas e recém-nascidos no Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo, Brasil, em 2010 e 2011. As informações foram coletadas por entrevistas, prontuários médicos e laudos de patologia. As medidas placentárias foram: peso, diâmetros maior e menor, excentricidade, espessura, forma, área, relações peso ao nascer/ peso da placenta e peso da placenta/ peso ao nascer. As associações entre peso ao nascer e medidas placentárias foram examinadas por meio de regressão linear múltipla. Resultados: O peso da placenta foi responsável por 48% da variabilidade do peso ao nascer (p < 0,001), enquanto o conjunto de medidas placentárias (peso, diâmetros maior e menor e espessura) foi responsável por 50% (p < 0,001). Quando ajustadas pelas características maternas e neonatais, as medidas placentárias explicaram 74% da variabilidade do peso ao nascer (p < 0,001). Conclusão: medidas placentárias são preditores independentes do peso ao nascer. O peso placentário é o mais forte preditor dentre elas, seguido pelo diâmetro menor.

Leaf senescence is a complex mechanism controlled by multiple genetic and environmental variables. Different crops present a delay in leaf senescence with an important impact on grain yield trough the maintenance of the photosynthetic leaf area during the reproductive stage. Additionally, because of the temporal gap between the onset and phenotypic detection of the senescence process, candidate genes are key tools to enable the early detection of this process. In this sense and given the importance of some transcription factors as hub genes in senescence pathways, we present a comprehensive review on senescence-associated transcription factors, in model plant species and in agronomic relevant crops. This review will contribute to the knowledge of leaf senescence process in crops, thus providing a valuable tool to assist molecular crop breeding. Fil: Bengoa Luoni, Sofia Ailin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas "Dr. Raúl Alfonsín" (sede Chascomús). Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas "Dr. Raúl Alfonsín" (sede Chascomús); Argentina Fil: Astigueta, Francisco Horacio. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación en Ciencias Veterinarias y Agronómicas. Instituto de Biotecnología; Argentina Fil: Nicosia, Salvador. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación en Ciencias Veterinarias y Agronómicas. Instituto de Biotecnología; Argentina Fil: Moschen, Sebastián Nicolás. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Tucuman-Santiago del Estero. Estación Experimental Agropecuaria Famaillá; Argentina. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación en Ciencias Veterinarias y Agronómicas. Instituto de Biotecnología; Argentina Fil: Fernández, Paula del Carmen. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación en Ciencias Veterinarias y Agronómicas. Instituto de Biotecnología; Argentina Fil: Heinz, Ruth Amelia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación en Ciencias Veterinarias y Agronómicas. Instituto de Biotecnología; Argentina

Objectives To evaluate the overvall survival (OS)and disease free survival (DFS) rates related to surgical radicality in the ART sparing the uterine arteries and hypogastric plexus in patiens with early stage cervical cancer(CC). Methods Twenty seven pts. FIGO stages Ia2 & Ib1, were included between 10/04 a 10/15. Stages Ib1 >2 cm and An ART sparing the uterine arteries and hypogastric plexus was performed. Surgical radicality was compared with an historical control group of C1 radical hysterectomies. The OS& DFS rates, complications, pregnancies, recurrences, and follow-up,were analyzed. Results The ART was performed in 25/27 patients (95,2%). Age: 27,5 years (25–35). Five patients received NCH. In 2 cases the procedure had to be completed with a C1RH because of positive margins in the surgical specimen. Radicality (surgical specimen): tumor size 2,36 (1,-4,1) cm; Vaginal length 2,62 (0,8–3,1) cm; Right parametrium 3,2 (1,8–3,9) cm; left parametrium 3,04 ( 2,3–3,5) cm; cervix length 2,8 (2,3–3,3) cm; Lymph nodes 13,5 (2–22). No statisticaly differences were observed in surgical radicality between ART vs C1RH. Complications: 1 case of dyspareunia + cervical polyposis. 1 case of dysmenorrhea. Four pregnancies were observed. Three healthy newborns and 1 abortion were registered,all in NCH cases). Recurrences: 2/27 (8,4%). Deaths: 2/27 (7,3%) . DFS & OS: 92,5%. Follow-up: 127 months (85–180). Conclusions The ART sparing the uterine arteries and hypogastric plexus (C1 ART), showed to be feasible and oncologicaly safe. This variant of ART, could be considered as an alternative to C1RH for these initial FIGO stages.

Objectives The aims of the present study were: 1) to define the prognostic significance of the CTS in stages IIB and IIIB cervical cancer and its impact on disease-free survival (DFS) and overall survival (OS) rates; 2) to propose a new FIGO Staging System for CC based on this evidence. Methods Retrospective study including 450 pts. between 1/2007 to 9/2011 FIGO stages IIB (229 pts.) and IIIB (221 pts.) cervical cancer (cc) . MRI was added to mesure the CTS. It was stratified in ≤-3.99 cm, 4–5.99 cm, 6–7.99 cm & >8 cm. The disease-free survival (DFS) and overall survival (OS) related to tumor size.were analyzed . Results The median age were 45 & 49 years old for stages IIB & IIIB groups. Median Follow up: 45 months. The DFS & OS rates were: stage IIb,58.5% & 64%; and 40% and 43% for the IIIb,respectively The DSF and OS rates were 65,1% and 71,5% in CTS between 4- 5.99cm, vs 27,7% and 36.6% for CTS >6 cm (p 6 cm (p Conclusions Patients with CTS >6 cm ihad a worse prognosis. These FIGO Stages could be modified into IIb1 & IIb2; and IIIb1 & IIIb2, with a 6m cut off. It is needed a personalized treatment strategy for those cases.

Objectives To assess the impact of age as a determining prognostic factor in the survival of women with uterine cervical cancer (UCC). Methods A retrospective observational study was carried out in which patients who consulted in Oncological Hospital of Buenos Aires, in the period between January 2007 and December 2011. The variables were studied: age and tumor stage. Three age groups were established: patients 60. For the analysis of disease-free survival (DFS) and overall survival (OS), the Kaplan-Meier method was used and for the comparison between the different groups, the Log Rank test method using the statistical package IBM Statics Version 21. A statistically significant P value of ≤0.05 was considered. Results 748 patients were included, of which 145 (19.4%) 60 years. The median general age was 46 years. The general OS was 59.3% (P=0.04), 48.3%, 63.3% and 57.4% respectively in the groups. The general DFS was 55.5% (P=0.04), in the groups: 45.8%, 59% and 53.6% respectively. The distribution by stages was predominantly locally advanced: IIB 30.6% (229), IIIB 29.5% (221), being statistically significant for OS stages IB2, IIA2, IIB, IIIA and IVA. Conclusions In addition to the widely known prognostic factors, age also seems to be an important factor, although probably underestimated by current treatment guidelines. There is a population of patients with UCC whose diagnosis at an early age implies an alarming prognosis.

Objectives To analyze our data collected at the referral Cancer Hospital of Buenos Aires City in order to describe demographic and clinical patterns. Methods Frequency, survival and demography retrospective assessment (2007–2011) of those patients admitted with a diagnosis of invasive cervical cancer. It was understood by the Metropolitan Area of Buenos Aires, the Buenos Aires City together with the 24 districts that surround it. Age, type and histological grade and clinical stage were considered in the analysis analysis. Survival rates (5-year disease-free and cause-specific) was performed using Kaplan-Meier method and Log-Rank test methods. To investigate the independent effect on the survival, function Cox regression was performed. Results 748 were assessed. 84% resided in the Metropolitan Area of Buenos Aires; 77% were admitted at an advanced stage. Regarding tumor size, 53.6% had tumors >4 cm diameter and 24.2% >6 cm. The lowest rates of disease-free survival and cause-specific survival were observed for tumor sizes >6 cm and the age subgroup Conclusions It is generally accepted that cervical cancer frequency among young women is low, being the most exposed those over 35 years old. Nevertheless, as gynecologic oncologists, we daily accompany young patients to their death. These figures raise a public health alert on young women in the Metropolitan Area of Buenos Aires, which concentrates almost one third of the country population.

ObjectiveLow-grade chronic inflammation emerges as a potent driver of insulin resistance and glucose dysregulation in obesity and associated non-alcoholic fatty liver disease (NAFLD). The liver, subcutaneous fat and the immune system participate in disturbances of metabolism. Type I interferon (IFN) signalling initiated by innate and adaptive immunity modulates inflammatory responses consequent to infection. However, little is known about the role of type I IFN signalling in metabolic diseases and the development of NAFLD.DesignWe determined the impact of type I IFN signalling by tissue-specific deletion of interferon (α and β) receptor 1 (Ifnar1) in hepatocytes (Ifnar1Δhep), adipocytes (Ifnar1Δat), intestinal epithelial cells (Ifnar1ΔIEC) or myelocytes (Ifnar1Δmyel) on glucose metabolism, obesity and hepatic disease in mice exposed to a high-fat or methionine-choline-deficient (MCD) diet. Furthermore, we investigated the expression of type I IFN-regulated genes in patients with obesity undergoing laparoscopic adjustable gastric banding (LAGB).ResultsLong chain fatty acids induce type I IFN responses in murine hepatocytes and macrophages and exposure to a high-fat diet elicited type I IFN-regulated gene expression in the liver of wild-type mice. Hepatocyte-specific, but not adipose tissue-specific deletion of Ifnar1 worsened steatosis and inflammation induced by the MCD diet. In contrast, adipose-specific, but not hepatocyte-specific deletion of Ifnar1 deteriorated metabolic dysregulation induced by a high-fat diet, indicated by increased weight gain, insulin resistance and an impaired glucose tolerance. Abrogated type I IFN signalling in myeloid or intestinal epithelial cells did not modulate susceptibility to metabolic or hepatic disease. Improved metabolic control in patients with obesity after LAGB was associated with increased expression of type I IFN-regulated genes in subcutaneous adipose tissue and liver.ConclusionsOur study implicates a role for adipose and hepatocyte type I IFN signalling in diet-induced metabolic dysregulation and hepatic disease. Further studies on type I IFN signalling in metabolic diseases are warranted.

The association between NAFLD and diabetes mellitus has garnered increasing attention in the past few years. In this Review, Tilg and colleagues explore in detail the molecular mechanisms linking NAFLD and diabetes mellitus, and discuss clinical aspects arising from the interaction of both diseases. The liver constitutes a key organ in systemic metabolism, contributing substantially to the development of insulin resistance and type 2 diabetes mellitus (T2DM). The mechanisms underlying these processes are not entirely understood, but involve hepatic fat accumulation, alterations of energy metabolism and inflammatory signals derived from various cell types including immune cells. Lipotoxins, mitochondrial function, cytokines and adipocytokines have been proposed to play a major part in both NAFLD and T2DM. Patients with NAFLD are commonly insulin resistant. On the other hand, a large number of patients with T2DM develop NAFLD with its inflammatory complication, NASH. The high incidence of NASH in patients with T2DM leads to further complications, such as liver cirrhosis and hepatocellular carcinoma, which are increasingly recognized. Therapeutic concepts such as thiazolidinediones (glitazones) for treating T2DM also show some efficacy in the treatment of NASH. This Review will describe the multifaceted and complex interactions between the liver and T2DM.

This paper addresses the prediction of the median peak floor acceleration (PFA) demand of elastic structures subjected to seismic excitation by means of an adapted response spectrum method. Modal combination is based on a complete quadratic combination (CQC) rule. In contrast to previous studies, in the present contribution closed form solutions for the correlation coefficients and peak factors entering the CQC rule are derived using concepts of normal stationary random vibration theory. A ground motion set, which matches the design response spectrum for a specific site and a target dispersion, is used to define the stochastic base excitation. The response spectrum method is tested for various planar and spatial generic high-rise structures subjected to this particular ground motion set. A comparison of the outcomes with the results of computationally more expensive response history analyses shows the applicability and accuracy of the proposed simplified method.

Background & Aims Alcoholic steatohepatitis (ASH) is characterised by neutrophil infiltration that contributes to hepatic injury and disease. Lipocalin-2 (LCN2) was originally identified as siderophore binding peptide in neutrophils, which exerted tissue protective effects in several disease models. Here we investigate the role of LCN2 in the pathogenesis of alcohol-induced liver injury. Methods We compared hepatic LCN2 expression in ASH patients, alcoholic cirrhosis patients without evidence of ASH and patients with non-alcoholic fatty liver disease (NAFLD; i.e. simple steatosis). To mechanistically dissect LCN2 function in alcohol-induced liver injury, we subjected wild-type (WT) and Lcn2 -deficient ( Lcn2 −/− ) mice to the Lieber-DeCarli diet containing 5% ethanol (EtOH) or isocaloric maltose. Adoptive transfer experiments were performed to track neutrophil migration. Furthermore, we tested the effect of antibody-mediated LCN2 neutralisation in an acute model of ethanol-induced hepatic injury. Results Patients with ASH exhibited increased hepatic LCN2 immunoreactivity compared to patients with alcoholic cirrhosis or simple steatosis, which mainly localised to neutrophils. Similarly, ethanol-fed mice exhibited increased LCN2 expression that mainly localised to leukocytes and especially neutrophils. Lcn2 −/− mice were protected from alcoholic liver disease (ALD) as demonstrated by reduced neutrophil infiltration, liver injury and hepatic steatosis compared to WT controls. Adoptive transfers revealed that neutrophil-derived LCN2 critically determines hepatic neutrophil immigration and persistence during chronic alcohol exposure. Antibody-mediated neutralisation of LCN2 protected from hepatic injury and neutrophilic infiltration after acute alcohol challenge. Conclusions LCN2 drives ethanol-induced neutrophilic inflammation and propagates the development of ALD. Despite a critical role for LCN2 in immunity and infection, pharmacological neutralisation of LCN2 might be of promise in ALD.

Introduction. Obesity and related nonalcoholic fatty liver disease (NAFLD) are an emerging health care issue that imposes substantial morbidity to individuals. Growth and differentiation factor 15 (GDF15) limits food uptake, body weight, and energy balance by modulation of GDNF-family receptor α-like (GFRAL) signalling in the hindbrain. However, the regulation of GDF15 expression in obesity and NAFLD is incompletely understood. We sought to define the impact of weight loss achieved by laparoscopic adjustable gastric banding (LAGB) on hepatic and adipose GDF15 expression in a cohort of severely obese patients. Methods. We analysed GDF15 expression of liver and subcutaneous adipose tissue before and 6 months after LAGB in severely obese patients undergoing LAGB by quantitative real-time PCR. To assess the role of inflammation on GDF15 expression, we analysed Hep G2 hepatocytes stimulated with cytokines such as IL-1β, TNFα, IL-6, LPS, or cellular stressors such as tunicamycin. Results. GDF15 expression was mostly confined to the liver compared to adipose tissue in severely obese patients. Weight loss induced by LAGB was associated with reduced hepatic (but not adipose tissue) expression of GDF15. Stimulation with IL-1β or tunicamycin induced hepatic GDF15 expression in hepatocytes. In line with this, hepatic GDF15 expression directly correlated with IL-1β expression and steatosis severity in NAFLD. These data demonstrated that amelioration of metabolic inflammation and weight loss reduced hepatic GDF15 expression. Conclusion. Based on recent mechanistic findings, our data suggest that hepatic GDF15 may serve as a negative feedback mechanism to control energy balance in NAFLD.