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In this work we fit an epidemiological model SEIAQR (Susceptible - Exposed - Infectious - Asymptomatic - Quarantined - Removed) to the data of the first COVID-19 outbreak in Rio de Janeiro, Brazil. Particular emphasis is given to the unreported rate, that is, the proportion of infected individuals that is not detected by the health system. The evaluation of the parameters of the model is based on a combination of error-weighted least squares method and appropriate B-splines. The structural and practical identifiability is analyzed to support the feasibility and robustness of the parameters’ estimation. We use the bootstrap method to quantify the uncertainty of the estimates. For the outbreak of March-July 2020 in Rio de Janeiro, we estimate about 90% of unreported cases, with a 95% confidence interval (85%, 93%).

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.

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.

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

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.

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.

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.

Context An increase of bile acids (BAs), fibroblast growth factor 19 (FGF19), and glucagon-like peptide 1 (GLP-1) has been implicated in metabolic improvements after Roux-en-Y gastric bypass and vertical sleeve gastrectomy. However, data are still conflicting regarding their role after laparoscopic adjustable gastric banding (LAGB). Objective To assess the fasting BA, FGF19, and GLP-1 concentrations in plasma before and after LAGB and to test for correlations with immunometabolic parameters. Furthermore, hepatic farnesoid X receptor (FXR) expression and regulation of FXR-dependent genes were analyzed. Design and Setting Observational study at the University Hospital Innsbruck. Patients Twenty obese patients. Interventions Fasting plasma samples were taken before, 3, 6, and 12 months after LAGB. Liver biopsies were obtained at surgery and after 6 months postoperatively. Main Outcome Measures BA profiles, GLP-1 and FGF19 levels, hepatic FXR expression and regulation of FXR target genes were determined. Results Total, conjugated, and secondary BAs transiently increased 3 months after LAGB (P < 0.01). Only one BA, glycolithocholic acid sulfate, remained significantly elevated throughout the whole follow-up period (P < 0.05). GLP-1 had increased transiently 3 months after surgery (P < 0.01), whereas FGF19 levels increased continuously (P < 0.05). Insulin, homeostasis model assessment index, C-reactive protein, FGF19, and GLP-1 correlated positively with different BAs. No differences were seen in hepatic FXR expression and FXR-regulated genes. Conclusions Our study results, not only identified LAGB-induced changes in BAs and BA-induced hormones, but also revealed associations between changes in BA profile with GLP-1 and FGF19.

ObjectiveAlcoholic liver disease (ALD) is a global health problem with limited therapeutic options. Intestinal barrier integrity and the microbiota modulate susceptibility to ALD. Akkermansia muciniphila, a Gram-negative intestinal commensal, promotes barrier function partly by enhancing mucus production. The aim of this study was to investigate microbial alterations in ALD and to define the impact of A. muciniphila administration on the course of ALD.DesignThe intestinal microbiota was analysed in an unbiased approach by 16S ribosomal DNA (rDNA) sequencing in a Lieber-DeCarli ALD mouse model, and faecal A. muciniphila abundance was determined in a cohort of patients with alcoholic steatohepatitis (ASH). The impact of A. muciniphila on the development of experimental acute and chronic ALD was determined in a preventive and therapeutic setting, and intestinal barrier integrity was analysed.ResultsPatients with ASH exhibited a decreased abundance of faecal A. muciniphila when compared with healthy controls that indirectly correlated with hepatic disease severity. Ethanol feeding of wild-type mice resulted in a prominent decline in A. muciniphila abundance. Ethanol-induced intestinal A. muciniphila depletion could be restored by oral A. muciniphila supplementation. Furthermore, A. muciniphila administration when performed in a preventive setting decreased hepatic injury, steatosis and neutrophil infiltration. A. muciniphila also protected against ethanol-induced gut leakiness, enhanced mucus thickness and tight-junction expression. In already established ALD, A. muciniphila used therapeutically ameliorated hepatic injury and neutrophil infiltration.ConclusionEthanol exposure diminishes intestinal A. muciniphila abundance in both mice and humans and can be recovered in experimental ALD by oral supplementation. A. muciniphila promotes intestinal barrier integrity and ameliorates experimental ALD. Our data suggest that patients with ALD might benefit from A. muciniphila supplementation.

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.

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.

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.

Validazione della versione italiana del Questionario sull’Accettazione dell’Acufene Cronico (CTAQ-I).L’acufene è un sintomo ampiamente diffuso, rappresenta una condizione cronica per circa il 10% della popolazione adulta. La maggioranza dei pazienti non si sente danneggiata dall’acufene, ma circa lo 0,5-3% della popolazione adulta sviluppa un grave disagio e si sente compromesso nella vita di tutti i giorni. Quanto grave sia il disagio provato può essere solo parzialmente spiegato dalle caratteristiche dell’acufene stesso (come intensità o durata). Le variabili psicologiche, come l’accettazione dell’acufene, sono sempre più indagate dalla ricerca. Lo scopo di questo studio è analizzare la qualità psicometrica della versione italiana del Chronic Tinnitus Acceptance Questionnaire, “Questionario sull’accettazione dell’acufene cronico” (CTAQ-I). Il CTAQ-I è un adattamento del questionario italiano sull’ accettazione del dolore cronico (CPAQ), adattato per lo scopo dello studio dell’acufene cronico. Studio multicentrico trasversale mediante questionario su 141 pazienti ambulatoriali con acufene cronico. I dati sociodemografici e clinici sono stati valutati con la Tinnitus Sample Case History (TSCH), l’accettazione dell’acufene con il “Questionario sull’accettazione dell’acufene cronico” (CTAQ-I), il disagio dell’acufene con la Tinnitus Handicap Inventory (THI) e il mini Questionnaire (TQ 12-I). Inoltre abbiamo valutato il disagio psicologico generale del paziente (Brief Symptom Inventory - BSI) e la qualità della vita correlata alla salute (SF-36). Sono state condotte valutazioni psicometriche e fattoriali del CTAQ-I. Per studiare l’influenza delle variabili sociodemografiche e numerose variabili cliniche sull’accettazione dell’acufene, abbiamo calcolato i coefficienti di correlazione, l’analisi della varianza e il test T per campioni indipendenti. L’analisi fattoriale ha rivelato una soluzione a due fattori (‘activity engagement’ e ‘tinnitus willingness’), che rappresentano il 41,1% della varianza. È stata trovata una buona coerenza interna per il punteggio totale (α = 0,84) ed entrambi i fattori (α = 0,80-0,88). Le moderate correlazioni negative con il disagio indicavano una buona validità. L’accettazione dell’acufene era ulteriormente correlata a un minore stress psicologico e minore volume dell’acufene soggettivo, oltre che ad un maggiore benessere emotivo. L’accettazione dell’acufene è considerata un’importante risorsa terapeutica di cambiamento nei trattamenti (comportamentali e di counseling professionale) per l’acufene. Il nostro studio mostra che il CTAQ-I è uno strumento affidabile e valido per misurare l’accettazione dell’acufene cronico da parte dei pazienti.Tinnitus is a widespread symptom that is chronically experienced by approximately 10% of the adult population. While the vast majority of individuals do not feel impaired by their ear noise, about 0.5-3% of the adult population develops severe distress and feels impaired in everyday life. The severity of the distress experienced can only partially be explained by the characteristics of the ear noise itself (e.g. objective tinnitus loudness or duration). Psychological variables such as tinnitus acceptance are being increasingly investigated by tinnitus research. The aim of this study was to analyse the psychometric quality of the Italian version of the “Chronic Tinnitus Acceptance Questionnaire” (CTAQ-I). The CTAQ-I is an adaption of the Italian “Chronic Pain Acceptance Questionnaire (CPAQ)” and altered for the study of tinnitus acceptance. This cross-sectional multicentre questionnaire study included 141 outpatients with chronic tinnitus. Sociodemographic and clinical data were assessed with the Tinnitus Sample Case History (TSCH), tinnitus acceptance with the Italian “Chronic Tinnitus Acceptance Questionnaire” (CTAQ-I), tinnitus distress with the Tinnitus Handicap Inventory (THI) and the Tinnitus Questionnaire Short Form (TQ 12-I). Furthermore, we assessed the patient’s general psychological distress (Brief Symptom Inventory - BSI) and Health Related Quality of Life (SF-36). Psychometric and factorial evaluation of the CTAQ-I were carried out. To investigate the influence of sociodemographic and numerous clinical variables on tinnitus acceptance we calculated correlation coefficients, analysis of variance and independent sample-t-tests. The factor analysis revealed a two-factor solution (“activity engagement” and “tinnitus willingness”), accounting for 41.1% of the variance. Good internal consistency for the total score (α = 0.84) and both factors (α = 0.80-0.88) was found. Moderate negative correlations with tinnitus distress indicated good validity. Tinnitus acceptance was further correlated with lower psychological distress and subjective tinnitus loudness, as well as increased emotional well-being. Tinnitus acceptance is considered to be an important source of therapeutic change in behavioural-based treatments as well as in professional counselling for tinnitus. Our study shows that the CTAQ-I is a reliable and valid instrument to measure the acceptance of patients suffering from chronic tinnitus.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease throughout the world. Pathophysiological insights into this disease have recently illustrated that various factors such as insulin resistance, innate immunity, metabolic inflammation, and the microbiota are of relevance. NAFLD, metabolic syndrome (MS), and type 2 diabetes (T2D) share many pathophysiological aspects, and inflammatory processes in the adipose tissue, gut, and liver have evolved to be of exceptional importance. Most of NAFLD patients are obese and encounter a high risk of developing MS and T2D. NAFLD, however, is also highly common in subjects with MS and T2D. Furthermore, reflecting its nature of a multisystem disease, NAFLD is associated with a high prevalence and incidence of cardiovascular and chronic kidney disease. These facts require screening strategies for MS/T2D in NAFLD patients and vice versa. Thus, the question of cause or effect cannot be answered as MS and NAFLD share many pathomechanisms, and at the time of either diagnosis both frequently coexist. This is also reflected by a global prevalence rate of 25% for both NAFLD and MS. For this reason, it is crucial that physicians are aware of the ‘unholy liaison' between MS, T2D, and NAFLD.

Zusammenfassung Fragestellung: Kognitiv-behaviorale Therapie (CBT) ist eine effektive Behandlung zur Reduktion von Tinnitusbelastung. Neuere Forschungsergebnisse unterstreichen den Stellenwert akzeptanzbasierter Verfahren in der Behandlung des chronischen Tinnitus. Inwiefern sich Tinnitusakzeptanz im Zuge einer CBT-Behandlung verandert, ist jedoch nicht ausreichend geklart. Das Ziel der Studie war, die Effektivitat einer kognitiv-behavioralen Gruppentherapie und die damit einhergehende Entwicklung von Tinnitusakzeptanz zu untersuchen. Methode: 68 ambulante Patienten nahmen an einer dreimonatigenCBT-Gruppentherapie teil. Mittels Effektstarken und gepaarter T-Tests wurden die Effektivitat der CBT-Gruppe sowie die Akzeptanzentwicklung untersucht. Ergebnisse: Die Ergebnisse zeigten eine signifikante Reduktion der Tinnitusbelastung sowie eine Verbesserung der Tinnitusakzeptanz mit grosen Effektstarken,welche auch uber den Follow- Up-Zeitraum von sechs Monaten konstant blieben. Diskussion: CBT kann als effektiv...

Objectives: The use of reliable and valid psychometric tools to assess subjectively experienced distress due to tinnitus is broadly recommended. The purpose of the study was the validation of the Italian version of Tinnitus Questionnaire 12 item short form (TQ 12-I) as a brief test for the assessment of patient reported tinnitus-related distress.Design: Cross-sectional multicenter questionnaire study.Setting: Tinnitus Center, European Hospital (Rome), the Department of Otorhinolaryngology, “Guglielmo da Saliceto” Hospital (Piacenza), and the Department of Audiology and Phoniatry, “Mater Domini” University Hospital (Catanzaro).Participants: One hundred and forty-three outpatients with tinnitus treated at one of the participating medical centers.Main Outcome Measures: Tinnitus Questionnaire Short Form (TQ 12-I), compared to the Tinnitus Handicap Inventory (THI), Brief Symptom Inventory (BSI), and Short Form (SF-36) Health Survey.Results: Our factor analysis revealed a two-factor solution (health anxiety, cognitive distress), accounting for 53.5% of the variance. Good internal consistency for the total score (α = 0.86) and both factors (α = 0.79–0.87) was found. Moderate correlations with the THI (r = 0.65, p < 0.001) indicated good convergent validity. Tinnitus distress was further correlated to increased psychological distress (r = 0.31, p < 0.001) and reduced emotional well-being (r = -0.34, p < 0.001).Conclusion: The study clearly showed that the TQ 12-I is a reliable and valid instrument to assess tinnitus-related distress which can be used in clinical practice as well as for research.

To assess the placental morphometry in pregnancies with hypertensive disorders of pregnancy (HDP) and its relationship with birth weight (BW).Cohort study of placental morphometry and fetal outcomes of 954 pregnancies at a university hospital in Ribeirão Preto, São Paulo, Brazil, in 2010. HDP categories were: chronic (CH), gestational (GH), preeclampsia (PRE) and pre-eclampsia superimposed on chronic hypertension (CH + PRE). Associations between BW and placental measures (PM) in pregnancies were evaluated by multiple linear regression analyses.Placental weight (PW, g), largest and smallest diameters (cm), thickness (cm), eccentricity, area (cmThe frequencies of each HDP categories were 6.5% CH; 7.6% GH; 6.1% PRE, and 2.0% CH + PRE. PW, largest and smallest diameters, area and BW/PW ratio were statistically different between HDP and the normotensive group, with the lowest values for CH + PRE; the remaining measures showed no difference. BW was lower in HDP than in the normotensive group (p = 0.016). BW and PW were highly correlated in the presence of HDP (r = 0.79, p 0.001). Sixty-seven percent of BW variability was accounted for PM (p 0.001), and increased to 81% when maternal variables, gestational age and sex were added (p 0.001).Hypertensive disorders of pregnancy significantly influence the growth of both the placenta and the fetus. PM explain 67% of BW variability, and CH + PRE was the category with the strongest association to the results.

Die intestinale Mikrobiota hat fur die Erhaltung der Gesundheit des menschlichen Organismus eine zentrale Bedeutung und dient insbesondere auch der Abwehr von intestinalen Pathogenen. Veranderungen der intestinalen Mikrobiota, auch als Dysbiose bezeichnet, spielen eine entscheidende Rolle in der Pathogenese von vielen Erkrankungen. Als fakale Mikrobiotatransplantation (FMT) oder Stuhltransplantation wird die Ubertragung von Stuhlmikroorganismen eines gesunden Spenders in den Gastrointestinaltrakt eines erkrankten Patienten bezeichnet, um ein gestortes Mikrobiom zu behandeln. Die Indikation zu dieser therapeutischen Intervention ist zumeist die rezidivierende Clostridium-difficile-Infektion (CDI). Mittlerweile gibt es bei dieser Indikation uberzeugende Daten von einigen grosen nicht kontrollierten Studien und einer kontrollierten randomisierten Studie sowie Beobachtungsstudien bei einer grosen Anzahl an Patienten. Daher wird die FMT mittlerweile von internationalen Fachgesellschaften bei rezidivierender CDI mit hoher Evidenz empfohlen. Andere potenzielle Indikationen fur die FMT sind die fulminante CDI und chronisch-entzundliche Darmerkrankungen. Bei der Anwendung der FMT bestehen vielen offene Fragen fur die Praxis v. a. bez. Voruntersuchungen des Spenders, der Aufbereitung des Stuhl- sowie des Applikationswegs. Es sind unterschiedliche Applikationsformen beschrieben worden, wobei die Verabreichung der FMT in den unteren Gastrointestinaltrakt wegen weniger Nebenwirkungen gegenuber der Gaben in den oberen Gastrointestinaltrakt zu bevorzugen ist. Die vorliegenden Publikationen berichten nur uber wenige schwere Nebenwirkungen der FMT. Trotzdem wird diese Therapieform derzeit v. a. wegen potenzieller Sicherheitsaspekte und Unklarheiten bez. des rechtlichen Status heftig in Fachkreisen diskutiert. Dieser Konsensusreport der Osterreichischen Gesellschaft fur Gastroenterologie und Hepatologie (OGGH) in Kooperation mit der Osterreichischen Gesellschaft fur Infektionskrankheiten und Tropenmedizin dient daher Arzten, die diese Methode benutzen, als eine Anleitung fur deren Anwendung basierend auf Daten der rezenten medizinischen Literatur.

TNF alpha antibodies have clearly improved the outcome of moderately to severely active ulcerative colitis. Adalimumab is the first fully human, monoclonal TNF alpha antibody, which is administered subcutaneously. Since April 2012 adalimumab is approved for the treatment of moderately to severely active ulcerative colitis in patients who have not responded despite a full and adequate course of therapy with a corticosteroid and an immunosuppressant or who are intolerant to or have medical contraindications for such therapies. Adalimumab can induce and maintain clinical remission and mucosal healing compared to placebo in moderately to severely active ulcerative colitis, can reduce the rate of ulcerative colitis related hospitalisations and improve health-related quality of life. The response can be observed after two weeks of treatment. The safety profile of adalimumab is comparable to those of other TNF alpha inhibitors. Studies on the treatment of ulcerative colitis with adalimumab did not reveal new safety aspects. The present consensus report by the Working Group Inflammatory Bowel Diseases of the Austrian Society of Gastroenterology and Hepatology presents the existing evidence of adalimumab for the treatment of ulcerative colitis and is aimed to assist as code of its practice.

Background & Aims Severe obesity is associated with a state of chronic inflammation. Sirtuins (SIRT) are a family of conserved enzymes which are able to affect many metabolic and inflammatory pathways thereby potentially improving health and increasing lifespan. Methods We investigated the effect of weight loss on subcutaneous adipose tissue and liver mRNA and immunohistochemical expression of SIRT1, SIRT3, and SIRT6. Twenty-nine severely obese patients undergoing laparoscopic adjustable gastric banding (LAGB) were studied. Tissue samples were collected before and 6months after LAGB surgery. Tissue mRNA expression levels of SIRT1 , SIRT3 , and SIRT6 were correlated with clinical, biochemical, and histological parameters. In vitro , we studied sirtuin expression in native and stimulated monocytes, adipocytes, and hepatocytes. Results SIRT1 , SIRT3 , and SIRT6 mRNA expression was higher in the subcutaneous adipose tissue than in the liver. Weight loss resulted in a significant induction of SIRT1, SIRT3, and SIRT6 expression in the subcutaneous adipose tissue. In the liver, a significant increase after weight loss was observed, particularly for SIRT3 and SIRT6 mRNA expression; immunohistochemically, SIRT1 and SIRT3 expression was upregulated. Endotoxin and tumor necrosis factor-alpha suppressed SIRT1, SIRT3, and SIRT6 expression in human monocytes. The same stimuli suppressed total sirtuin deacetylase activity again, mainly in monocytes and less in adipocytes and hepatocytes. Conclusions The relative abundance of adipose tissue mRNA expression of certain sirtuins exceeds its expression in the liver. Extensive weight loss increases sirtuin expression significantly both in adipose tissue and liver, probably as a consequence of reduced inflammation.

MicroRNA-122 (miR-122) is abundant in the liver and involved in lipid homeostasis, but its relevance to the long-term risk of developing metabolic disorders is unknown. We therefore measured circulating miR-122 in the prospective population-based Bruneck Study (n = 810; survey year 1995). Circulating miR-122 was associated with prevalent insulin resistance, obesity, metabolic syndrome, type 2 diabetes, and an adverse lipid profile. Among 92 plasma proteins and 135 lipid subspecies quantified with mass spectrometry, it correlated inversely with zinc-α-2-glycoprotein and positively with afamin, complement factor H, VLDL-associated apolipoproteins, and lipid subspecies containing monounsaturated and saturated fatty acids. Proteomics analysis of livers from antagomiR-122–treated mice revealed novel regulators of hepatic lipid metabolism that are responsive to miR-122 inhibition. In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT, n = 155), 12-month atorvastatin reduced circulating miR-122. A similar response to atorvastatin was observed in mice and cultured murine hepatocytes. Over up to 15 years of follow-up in the Bruneck Study, multivariable adjusted risk ratios per one-SD higher log miR-122 were 1.60 (95% CI 1.30–1.96; P < 0.001) for metabolic syndrome and 1.37 (1.03–1.82; P = 0.021) for type 2 diabetes. In conclusion, circulating miR-122 is strongly associated with the risk of developing metabolic syndrome and type 2 diabetes in the general population.

Background Adult non-alcoholic fatty liver disease (NAFLD) involves lobular necroinflammatory activity and fibrosis is typically centrilobular, whereas paediatric NAFLD has predominantly portal fibrosis. The reasons for these differences are unclear. We aimed to determine (a) how centrilobular and portal fibrosis in children relate to histological parameters; and (b) whether atypical fibrosis patterns exist in adults that are unexplained by current fibrogenesis models. Methods Histological features of paediatric (n=38) and adult (n=56) NAFLD were assessed using conventional scoring systems. Keratin-7 immunostaining was used to assess hepatic progenitor cell numbers and the ductular reaction. Centrilobular and portal components of fibrosis were independently scored and fibrosis patterns were classified according to accepted types. Post-treatment (rosiglitazone/gastric banding) biopsies were also examined in adults. Results Twenty-six children (68.4%) had portal-predominant fibrosis, although the typical adult pattern was seen in 11 (28.9%). Portal fibrosis was associated with a ductular reaction (P=0.021) and hepatic progenitor cell expansion (P

Obesity and obesity-related disorders have dramatically increased globally in the last decades. These entities are commonly associated with a state of insulin resistance and the relationship between extensive lipid deposition and insulin resistance is widely accepted. The underlying mechanisms for insulin resistance, however, are still incompletely understood. Evidence from experimental research and human studies in the last years has suggested that innate immune pathways and inflammatory mechanisms also might play a role. Insulin resistance in case of obesity is commonly accompanied by low-grade systemic inflammation and adipose tissue inflammation. The expression of various pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1 and IL-6 is increased in adipose tissue and its expression linked to systemic inflammation and accompanying insulin resistance. Weight loss reduces this enhanced cytokine expression in the adipose tissue and thereby improves systemic inflammation. Whereas there is also substantial evidence that pro-inflammatory cytokines, certain members of the inflammasome and various transcription factors such as nuclear factor-κB play a major role in animal models of insulin resistance and type 2 diabetes, human studies neutralizing certain pro-inflammatory cytokines suggest so far that not all pro-inflammatory cytokines are of equal clinical importance. First clinical studies favor an important role for IL-1 family members and probably IL-6 but not for TNF-α in insulin-resistant states. Although we still have missing links in the understanding of insulin resistance, certain inflammatory pathways have also evolved in humans as central players.

Diseases of the liver and the biliary tract are commonly observed in patients with inflammatory bowel diseases (IBD). Besides primary sclerosing cholangitis (PSC), drug-induced hepatotoxicity and non-alcoholic fatty liver disease (NAFLD) are the most frequent liver complications in IBD. PSC is a chronic inflammatory and commonly progressive disorder of unknown etiology associated with fibrosis and stricture development in the intrahepatic and extrahepatic biliary tree. Interestingly, this form of liver disease is mainly associated with ulcerative colitis. Development of PSC is highly relevant for IBD patients as cholestasis-associated problems increase over time resulting in biliary strictures, cholangitis, cholangiocarcinoma and importantly these patients also have a higher risk to develop colon cancer. Another major aspect regarding IBD and liver disease refers to drug-induced hepatotoxicity. Clinically, most relevant is liver toxicity caused by immunosuppressants such as azathioprine. Azathioprine and its derivate 6-mercaptopurine can cause a spectrum of liver injuries ranging from asymptomatic elevated liver enzymes to cholestasis and nodular regenerative hyperplasia. The third common IBD-associated liver disease is NAFLD, and first studies suggest that NAFLD might appear in IBD patients independent of classical risk factors such as obesity or insulin resistance. Overall, liver complications are observed in 10-20% of IBD patients, and therefore physicians have to be familiar with these complications to improve and to optimize patient care.

Diabetes & Metabolism - In Press.Proof corrected by the author Available online since mercredi 25 janvier 2017

Background & Aims Obesity and its related co-morbidities such as non-alcoholic fatty liver disease (NAFLD) are increasing dramatically worldwide. The genetic variation of Patatin-like phospholipase domain-containing protein 3 (PNPLA3), which is also called adiponutrin (ADPN), in residue 148 (I148M, rs738409) has been associated with NAFLD. However, the regulation and function of PNPLA3 in metabolic diseases remains unclear. Laparoscopic gastric banding (LAGB) of severely obese patients reduces body weight, liver and adipose tissue inflammation. In this study, we investigated whether weight loss induced by LAGB affected PNPLA3 expression in hepatic and adipose tissue. Methods Liver and subcutaneous adipose tissue samples were collected from 28 severely obese patients before and 6 months after LAGB. PNPLA3 expression was assessed by quantitative real-time PCR. To understand whether inflammatory stimuli regulated PNPLA3 expression, we studied the effect of tumour necrosis factor alpha (TNFα) and lipopolysaccharide (LPS) on PNPLA3 expression in human adipocytes and hepatocytes. Results PNPLA3 was strongly expressed in the liver and clearly detectable in subcutaneous adipose tissue of obese patients. Weight loss induced by LAGB of severely obese patients led to significantly increased adipose, but not hepatic, tissue expression of PNPLA3. Subcutaneous PNPLA3 expression negatively correlated with body-mass-index, fasting glucose and fasting insulin. TNFα potently suppressed PNPLA3 expression in adipocytes but not hepatocytes. Conclusions Weight loss induced by LAGB restored adipose tissue PNPLA3 expression which is suppressed by TNFα. Further studies will be required to determine the functional impact of PNPLA3 and its related genetic variation on adipose tissue inflammation and NAFLD. This article is protected by copyright. All rights reserved.

Adipocytokines are primarily adipocyte-derived products, although certain members are also synthesized by other cell types. These adipocytokines, similarly to classical cytokines, are characterized by very pleiotropic functions affecting biological processes throughout the body. An increasing number of adipocytokines has recently been recognized, such as adiponectin, leptin, pre-B cell colony-enhancing factor/Nampt/visfatin, resistin, progranulin, and others. Adiponectin has emerged as the most abundant circulating adipocytokine, is produced almost exclusively by adipocytes, and has mainly anti-inflammatory and anti-diabetic functions. In contrast, leptin is produced by many cell types beyond adipocytes, regulates immunity and T cell functions, and acts in a more pro-inflammatory fashion. Adipocytokines play a fundamental role in adipose tissue homeostasis (i.e. health) and disease, especially in obesity-related disorders such as non-alcoholic fatty liver diseases (NAFLD) and their complications, including hepatocellular carcinoma (HCC). Lack of adiponectin as observed in NAFLD drives steatosis and inflammation in the liver, and evidence is increasing that this adipocytokine has many anti-tumor properties and might play a rather protective role in HCC. The role of leptin in NAFLD is still unclear and this adipocytokine seems to have opposite effects in HCC, acting more as a tumor promoter. Evidence is increasing that HCC tissue produces various adipocytokines, and adiponectin expression in HCC seems to be decreased whereas leptin expression is rather increased. In conclusion, adipocytokines are increasingly recognized as pleiotropic molecules involved in the pathophysiology of HCC, which might lead to therapeutic approaches targeting these mediators.

Background Apolipoprotein A5 (apoA5) is a recently described liver-specific protein that has been shown to influence triglyceride (TG) metabolism. ApoA5 transgenic mice display dramatically reduced TG levels, while in contrast apoA5 deficiency in humans was reported to result in marked hypertriglyceridemia. ApoA5 exerts its extracellular effects by increasing lipolysis of TG-rich lipoproteins, while in vitro data suggest additional intrahepatic effects. Methods In this study the authors set out to investigate a possible role of apoA5 in non-alcoholic fatty liver disease (NAFLD). We thus determined hepatic apoA5 expression in 15 obese subjects with histologically proven NAFLD undergoing bariatric surgery. In addition, the authors established a hepatic cell culture model of apoA5 knockdown by transfecting human hepatoma cells (HepG2) with apoA5 small interfering (si) RNA, and determined intracellular TG content and expression levels of key enzymes and transcription factors of intrahepatic lipid metabolism in these cells. Results Pronounced weight loss and associated histologically verified improvement of hepatic steatosis were accompanied by significant reductions of hepatic apoA5 mRNA expression levels. Significant apoA5 knockdown in HepG2 cells resulted in a marked decrease of intracellular TG content. When HepG2 cells were co-transfected with apoA5 and peroxisome proliferator-activated receptor gamma (PPARγ), reductions in hepatic TG accumulation were significantly less pronounced when compared to apoA5 siRNA transfected HepG2 cells. Conclusions In obese subjects, hepatic apoA5 mRNA expression decreases after weight loss and improvements in hepatic steatosis. The authors9 in vitro data demonstrate that apoA5 influences intrahepatic TG metabolism and that these intracellular effects of apoA5 are accompanied by changes in PPARγ mRNA expression. In summary, the data suggest that as well as several other factors, apoA5 might be involved in the pathogenesis of hepatic steatosis.

Objectives. To determine the potential of eotaxin-3 as a diagnostic marker for active disease and genetic susceptibility factor for Churg-Strauss syndrome (CSS). Methods. A total of 37 patients with active, relapsed or inactive CSS, 123 healthy controls and 138 disease controls were studied. Clinical data were collected and serum levels of eotaxin-3 were determined. Ex vivo stability of eotaxin-3 in serum samples was tested. Furthermore, the association of single nucleotide polymorphisms (SNPs) in the eotaxin-3 gene with CSS was determined in 161 CSS patients and 124 healthy controls. Results. Serum eotaxin-3 was highly elevated in active CSS patients. Neither eosinophilic diseases nor other small-vessel vasculitides were associated with high serum eotaxin-3 levels. Receiver operating characteristic curve analysis determined a sensitivity and specificity of 87.5 and 98.6% at a cut-off level of 80 pg/ml. None of the tested SNPs within the eotaxin-3 gene influenced the susceptibility to develop CSS. Conclusions. Serum eotaxin-3 is a sensitive and specific marker for the diagnosis of active CSS suitable for routine clinical practice. Previously described SNPs in the eotaxin-3 gene do not predict the risk of developing CSS.