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1.
Artigo em Inglês | MEDLINE | ID: mdl-32267559

RESUMO

BACKGROUND AND AIM: Several studies observed alterations in the gut microbiota in patients with non-alcoholic fatty liver disease (NAFLD). However, analyzed patient populations and methods strongly differ among these studies. The aim of this study was to prove the reproducibility of published results and to provide a detailed overview of all findings in our NAFLD cohort using next generation sequencing methods. METHODS: The individual taxonomic microbiota composition of fecal samples from 90 NAFLD patients and 21 healthy controls was analyzed using 16S rRNA gene sequencing. Study participants were grouped according to their disease stage and compared regarding their gut microbiota composition. Studies were identified from PubMed listed publications, and the results were compared with the findings in our cohort. RESULTS: Results from 13 identified studies were compared with our data. A decreased abundance of the Bacteroidetes and Ruminococcaceae as well as an increased abundance of Lactobacillaceae and Veillonellaceae and Dorea were the most frequently reported changes among NAFLD patients in 4/13, 5/13, 4/13, 2/13, and 3/13 studies, respectively. Even though these alterations in the gut microbiota composition were also observed in our patient cohort, the majority of published differences could not be reproduced, neither in our own nor in other NAFLD cohort studies. CONCLUSION: Despite repeatedly reproduced abundance patterns of specific bacteria, the heterogeneous study results did not reveal a consistent disease specific gut microbiota signature. Further prospective studies with homogenous patient cohorts and standardized methods are necessary to phenotype NAFLD by the gut microbiota.

2.
Liver Int ; 40(4): 860-865, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31943701

RESUMO

Several studies show associations between gut bacterial dysbiosis and chronic liver diseases, but causative mechanisms are largely unclear. We recently identified cytolysin, a bacterial exotoxin expressed and secreted by Enterococcus faecalis to cause liver damage in the setting of alcohol-related liver disease. Cytolysin was increased and highly correlated with liver disease severity and mortality in alcoholic hepatitis patients. In this study, we investigated if faecal cytolysin-positivity can be linked to non-alcoholic fatty liver disease, a highly prevalent disease where new biomarkers and treatment targets are urgently needed. In contrast to what we observed in alcoholic hepatitis, only seven out of 96 non-alcoholic fatty liver disease patients were cytolysin-positive, and these patients did not have increased liver disease activity compared with cytolysin-negative patients. These results indicate that the association of cytolysin carriage with worse clinical outcome might be specific for alcoholic hepatitis.

3.
Scand J Gastroenterol ; 55(2): 222-227, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31990240

RESUMO

Objective: International guidelines recommend hepatocellular carcinoma (HCC) surveillance with ultrasound in high-risk patients with chronic liver diseases. However, there is low-strength evidence about the effects on mortality. The aim of our study was to assess the impact of surveillance on the clinical course and survival of HCC patients seen at a tertiary referral center in Germany.Material and methods: We retrospectively evaluated the data of 401 HCC patients, who presented to our clinic between 1997 and 2015. Two groups were compared regarding patient and disease outcomes: one group included patients who received at least two ultrasound examinations for surveillance purposes prior to first diagnosis (n = 111). The other group consisted of patients with HCC at first presentation without foregoing HCC surveillance (n = 290).Results: Median follow-up in the surveillance group was 76 months (range 4-310 months). Patients in the surveillance group had smaller median tumor sizes (3.5 cm vs. 4.5 cm; p < .001), fulfilled more often Milan criteria (64% vs. 42%; p < .001) and received more often liver transplantation (27% vs. 9%, p < .001) when compared with the non-surveillance group. However, HCC surveillance was not associated with an improved survival (14 months in the surveillance group vs. 12 months in the non-surveillance group, p = .375), hazard ratio regarding overall mortality for the surveillance group: 0.80 (95% CI: 0.62-1.04, p = .09).Conclusions: HCC surveillance with ultrasound led to the detection of earlier disease stages but was not significantly associated with improved survival. Further prospective and long-term studies are needed to clarify benefits and harms of HCC surveillance programs on mortality.

4.
Hepatology ; 71(2): 522-538, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31228214

RESUMO

Chronic alcohol consumption causes increased intestinal permeability and changes in the intestinal microbiota composition, which contribute to the development and progression of alcohol-related liver disease. In this setting, little is known about commensal fungi in the gut. We studied the intestinal mycobiota in a cohort of patients with alcoholic hepatitis, patients with alcohol use disorder, and nonalcoholic controls using fungal-specific internal transcribed spacer amplicon sequencing of fecal samples. We further measured serum anti-Saccharomyces cerevisiae antibodies (ASCA) as a systemic immune response to fungal products or fungi. Candida was the most abundant genus in the fecal mycobiota of the two alcohol groups, whereas genus Penicillium dominated the mycobiome of nonalcoholic controls. We observed a lower diversity in the alcohol groups compared with controls. Antibiotic or steroid treatment was not associated with a lower diversity. Patients with alcoholic hepatitis had significantly higher ASCA levels compared to patients with alcohol use disorder and to nonalcoholic controls. Within the alcoholic hepatitis cohort, patients with levels of at least 34 IU/mL had a significantly lower 90-day survival (59%) compared with those with ASCA levels less than 34 IU/mL (80%) with an adjusted hazard ratio of 3.13 (95% CI, 1.11-8.82; P = 0.031). Conclusion: Patients with alcohol-associated liver disease have a lower fungal diversity with an overgrowth of Candida compared with controls. Higher serum ASCA was associated with increased mortality in patients with alcoholic hepatitis. Intestinal fungi may serve as a therapeutic target to improve survival, and ASCA may be useful to predict the outcome in patients with alcoholic hepatitis.

5.
J Hepatol ; 72(3): 391-400, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31606552

RESUMO

BACKGROUND & AIMS: Alcohol-associated liver disease is a leading indication for liver transplantation and a leading cause of mortality. Alterations to the gut microbiota contribute to the pathogenesis of alcohol-associated liver disease. Patients with alcohol-associated liver disease have increased proportions of Candida spp. in the fecal mycobiome, yet little is known about the effect of intestinal Candida on the disease. Herein, we evaluated the contributions of Candida albicans and its exotoxin candidalysin in alcohol-associated liver disease. METHODS: C. albicans and the extent of cell elongation 1 (ECE1) were analyzed in fecal samples from controls, patients with alcohol use disorder and those with alcoholic hepatitis. Mice colonized with different and genetically manipulated C. albicans strains were subjected to the chronic-plus-binge ethanol diet model. Primary hepatocytes were isolated and incubated with candidalysin. RESULTS: The percentages of individuals carrying ECE1 were 0%, 4.76% and 30.77% in non-alcoholic controls, patients with alcohol use disorder and patients with alcoholic hepatitis, respectively. Candidalysin exacerbates ethanol-induced liver disease and is associated with increased mortality in mice. Candidalysin enhances ethanol-induced liver disease independently of the ß-glucan receptor C-type lectin domain family 7 member A (CLEC7A) on bone marrow-derived cells, and candidalysin does not alter gut barrier function. Candidalysin can damage primary hepatocytes in a dose-dependent manner in vitro and is associated with liver disease severity and mortality in patients with alcoholic hepatitis. CONCLUSIONS: Candidalysin is associated with the progression of ethanol-induced liver disease in preclinical models and worse clinical outcomes in patients with alcoholic hepatitis. LAY SUMMARY: Candidalysin is a peptide toxin secreted by the commensal gut fungus Candida albicans. Candidalysin enhances alcohol-associated liver disease independently of the ß-glucan receptor CLEC7A on bone marrow-derived cells in mice without affecting intestinal permeability. Candidalysin is cytotoxic to primary hepatocytes, indicating a direct role of candidalysin on ethanol-induced liver disease. Candidalysin might be an effective target for therapy in patients with alcohol-associated liver disease.

6.
Nature ; 575(7783): 505-511, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31723265

RESUMO

Chronic liver disease due to alcohol-use disorder contributes markedly to the global burden of disease and mortality1-3. Alcoholic hepatitis is a severe and life-threatening form of alcohol-associated liver disease. The gut microbiota promotes ethanol-induced liver disease in mice4, but little is known about the microbial factors that are responsible for this process. Here we identify cytolysin-a two-subunit exotoxin that is secreted by Enterococcus faecalis5,6-as a cause of hepatocyte death and liver injury. Compared with non-alcoholic individuals or patients with alcohol-use disorder, patients with alcoholic hepatitis have increased faecal numbers of E. faecalis. The presence of cytolysin-positive (cytolytic) E. faecalis correlated with the severity of liver disease and with mortality in patients with alcoholic hepatitis. Using humanized mice that were colonized with bacteria from the faeces of patients with alcoholic hepatitis, we investigated the therapeutic effects of bacteriophages that target cytolytic E. faecalis. We found that these bacteriophages decrease cytolysin in the liver and abolish ethanol-induced liver disease in humanized mice. Our findings link cytolytic E. faecalis with more severe clinical outcomes and increased mortality in patients with alcoholic hepatitis. We show that bacteriophages can specifically target cytolytic E. faecalis, which provides a method for precisely editing the intestinal microbiota. A clinical trial with a larger cohort is required to validate the relevance of our findings in humans, and to test whether this therapeutic approach is effective for patients with alcoholic hepatitis.

7.
Dig Dis Sci ; 64(7): 1878-1892, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31076986

RESUMO

BACKGROUND: Alcohol-related liver disease is one of the most prevalent chronic liver diseases worldwide. Mechanisms involved in the pathogenesis of alcohol-related liver disease are not well understood. Oxylipins play a crucial role in numerous biological processes and pathological conditions. Nevertheless, oxylipins are not well studied in alcohol-related liver disease. AIMS: (1) To characterize the patterns of bioactive ω-3 and ω-6 polyunsaturated fatty acid metabolites in alcohol use disorder and alcoholic hepatitis patients and (2) to identify associations of serum oxylipins with clinical parameters in patients with alcohol-related liver disease. METHODS: We performed a comprehensive liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis of serum and fecal oxylipins derived from ω-6 arachidonic acid, ω-3 eicosapentaenoic acid, and docosahexaenoic acid in a patient cohort with alcohol-related liver disease. RESULTS: Our results show profound alterations in the serum oxylipin profile of patients with alcohol use disorder and alcoholic hepatitis compared to nonalcoholic controls. Spearman correlation of the oxylipins with clinical parameters shows a link between different serum oxylipins and intestinal permeability, aspartate aminotransferase, bilirubin, albumin, international normalized ratio, platelet count, steatosis, fibrosis and model for end-stage liver disease score. Especially, higher level of serum 20-HETE was significantly associated with decreased albumin, increased hepatic steatosis, polymorphonuclear infiltration, and 90-day mortality. CONCLUSIONS: Patients with alcohol-related liver disease have different oxylipin profiles. Future studies are required to confirm oxylipins as disease biomarker or to connect oxylipins to disease pathogenesis.


Assuntos
Alcoolismo/sangue , Ácidos Graxos Ômega-3/sangue , Ácidos Graxos Ômega-6/sangue , Fezes/química , Hepatite Alcoólica/sangue , Oxilipinas/sangue , Adulto , Idoso , Alcoolismo/diagnóstico , Biomarcadores/sangue , Cromatografia Líquida de Alta Pressão , Cromatografia de Fase Reversa , Feminino , Hepatite Alcoólica/diagnóstico , Humanos , Masculino , Metabolômica/métodos , Pessoa de Meia-Idade , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem
8.
Z Gastroenterol ; 56(12): 1475-1480, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30536252

RESUMO

HINTERGRUND: Die bisher veröffentlichte Studienlage zur Assoziation von Kolondivertikeln und kolorektalen Polypen einschließlich des kolorektalen Karzinoms (KRK) ist konträr. Ziel der Studie war es, die Assoziation für sämtliche relevanten histologischen Polypensubtypen, d. h. hyperplastische Polypen (HP), sessil und traditionell serratierte Adenome (SSA und TSA), klinisch relevante serratierte Polypen (krSP), tubuläre Adenome und fortgeschrittene Adenome in einer ausschließlichen Vorsorgekoloskopie-Kohorte zu untersuchen. MATERIAL UND METHODEN: Wir führten eine retrospektive Analyse von Personen ≥ 50 Jahre und einem durchschnittlichen Risiko für ein KRK, die eine Vorsorgekoloskopie zwischen dem 01.01.2012 und dem 14.12.2016 in einer Universitätsklinik und 6 gastroenterologischen Schwerpunktpraxen erhalten haben, durch. Ausschlusskriterien waren Erkrankungen mit einem erhöhten KRK-Risiko (z. B. chronisch-entzündliche Darmerkrankungen, KRK in der Vorgeschichte, hereditäre Karzinomsyndrome), eine vorherige Koloskopie und eine unvollständige Untersuchung. ERGEBNISSE: 4196 Koloskopien wurden eingeschlossen (mittleres Alter 63,4 Jahre, Standardabweichung ±â€Š7,6 Jahre, 48,6 %). Bei Vorliegen von Divertikeln zeigten sich nach Adjustierung für Alter und Geschlecht erhöhte Odds-Ratios (OR) für den Nachweis von HP im gesamten (OR 1,340, 95 %-Konfidenzintervall 1,133 - 1,584, p = 0,001) und im distalen Kolon (OR 1,459, 95 %-KI 1,208 - 1,763, p < 0,001) sowie von tubulären Adenomen im distalen Kolon (OR 1,355, 95 %-KI 1,144 - 1,604, p < 0,001). Die mittlere Polypenanzahl pro Untersuchung mit dem Nachweis von mindestens einem Polypensubtypen unterschied sich nicht zwischen beiden Gruppen. SCHLUSSFOLGERUNG: Die Untersucher sollten beim Vorliegen einer Divertikulose wachsam für den Nachweis von vor allem distal gelegenen Adenomen sein.


Assuntos
Adenoma , Pólipos do Colo , Neoplasias Colorretais , Divertículo do Colo , Adenoma/complicações , Adenoma/epidemiologia , Idoso , Pólipos do Colo/complicações , Pólipos do Colo/epidemiologia , Colonoscopia , Neoplasias Colorretais/complicações , Neoplasias Colorretais/epidemiologia , Divertículo do Colo/complicações , Feminino , Humanos , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade
9.
Endoscopy ; 50(10): 993-1000, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29727905

RESUMO

BACKGROUND: Serrated polyps have been recognized as precursors of colorectal cancer (CRC) via the serrated pathway. Endoscopic detection and histopathological evaluation of serrated polyps are challenging. The aims of this study were to determine detection rates of the recently proposed entity of clinically relevant serrated polyps (crSPs) and to identify factors that influence their detection in a primary colonoscopy screening cohort. METHODS: We retrospectively analyzed average-risk screening colonoscopies performed at a tertiary academic hospital and six community-based private practices in Germany between 01/01/2012 and 14/12/2016. Exclusion criteria were age < 50 years, conditions with increased risk for CRC (e. g. inflammatory bowel disease, history of CRC, hereditary cancer syndromes), and incomplete procedures. CrSPs were defined as serrated polyps ≥ 10 mm and/or > 5 mm located proximally to the splenic flexure. Conventional adenomas were defined as adenomas excluding serrated polyps. RESULTS: A total of 4161 colonoscopies from average-risk individuals were included (median age 62 years [interquartile range 56 - 69]; 48.6 % male). CrSPs were detected in 6.9 %, with a mean detection rate of 4.7 % (95 % confidence interval 2.3 % - 7.2 %). Detection rates ranged from 0 % to 16.2 %. In multivariate analysis, simultaneous detection of conventional adenomas and an endoscopist adenoma detection rate of ≥ 25 % were significantly associated with increased detection of crSPs, with odds ratios of 1.43 (95 %CI 1.11 - 1.85; P = 0.01) and 7.35 (95 %CI 4.43 - 12.19; P < 0.001). The individual endoscopist's detection rate for conventional adenomas and crSPs were significantly correlated (r = 0.54, P = 0.02). CONCLUSION: Detection rates for crSPs differed between participating endoscopists. However, individual skills to detect polypoid lesions have a relevant bearing on the detection rate of crSPs.


Assuntos
Adenoma/diagnóstico por imagem , Pólipos do Colo/diagnóstico por imagem , Pólipos do Colo/patologia , Colonoscopia , Neoplasias Colorretais/diagnóstico por imagem , Detecção Precoce de Câncer , Idoso , Feminino , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
10.
Eur J Gastroenterol Hepatol ; 29(11): 1235-1240, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28885276

RESUMO

BACKGROUND AND AIM: The aim of the study was to analyze the diagnostic performance and clinical utility of simple noninvasive tests for the detection of advanced fibrosis in patients with chronic hepatitis B (CHB) infection seen at a tertiary referral center in Germany. PATIENTS AND METHODS: We retrospectively analyzed 239 adult CHB patients with available liver biopsies. Patient demographics, hepatitis B markers, antiviral treatment, laboratory parameters, results from liver imaging, and histology were recorded. The sensitivity, specificity, and positive and negative predictive values were determined along with the area under receiver operating characteristic curves (AUROC) using published formulas and cut-off values for fibrosis index based on the four factors, aspartate aminotransferase-alanine aminotransferase ratio index (AAR), aspartate aminotransferase-to-platelet ratio index (APRI), and age-platelet index. RESULTS: The median documented duration of CHB infection was 31 months (range: 6-340 months); 86% of the patients were Caucasian and 71% were men. The AUROCs for the detection of advanced fibrosis were 0.75 [95% confidence interval (CI): 0.67-0.82], 0.72 (95% CI: 0.64-0.80), 0.48 (95% CI: 0.39-0.56), and 0.73 (95% CI: 0.66-0.81) for fibrosis index the four factors, APRI, AAR, and age-platelet index, respectively. Patients with advanced fibrosis on biopsy were misclassified as having mild fibrosis in 35% (APRI) to 82% (AAR) of cases. CONCLUSION: Because of their moderate test performance (AUROCs: 0.48-0.75) and their high misclassification rate, we could not confirm a reliable clinical utility for the analyzed noninvasive fibrosis scoring systems for the prediction of advanced fibrosis in mostly Caucasian CHB patients.


Assuntos
Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Hepatite B Crônica/complicações , Cirrose Hepática/sangue , Cirrose Hepática/diagnóstico , Adulto , Fatores Etários , Área Sob a Curva , Feminino , Humanos , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Valor Preditivo dos Testes , Curva ROC , Estudos Retrospectivos , Índice de Gravidade de Doença
12.
Medicine (Baltimore) ; 95(38): e4602, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27661015

RESUMO

We aimed to validate the liver fibrosis index FIB-4 as a model for risk stratification of hepatocellular carcinoma development in predominantly non-Asian patients with chronic hepatitis B infection seen at a tertiary referral center in Germany.We retrospectively analyzed 373 adult patients with chronic hepatitis B infection. Patient demographics, hepatitis B markers, antiviral treatment, laboratory parameters, results from liver imaging and histology were recorded. Patients were divided into 2 groups according to their FIB-4 levels and their hazard ratios for developing hepatocellular carcinoma were analyzed adjusted for age, sex, body mass index, alcohol consumption, and antiviral medication.Median follow-up was 8.7 years (range 1-21.3 years), 93% of patients were of non-Asian origin, and 64% were male. Compared with patients with a low FIB-4 (<1.25) patients with FIB-4 ≥1.25 showed a hazard ratio for incidence of hepatocellular carcinoma of 3.03 (95% confidence interval (CI): 1.24-7.41) and an adjusted hazard ratio of 1.75 (95% CI: 0.64-4.74). Notably, 68% of patients with liver cirrhosis and 68% of those who developed HCC during observation had a low FIB-4 (<1.25).We could not confirm that a FIB-4 value ≥1.25 is a reliable clinical indicator for incidence of hepatocellular carcinoma in predominantly non-Asian patients with chronic hepatitis B. Further studies in geographically and ethnically diverse populations are needed to prove its utility as a predictive tool.


Assuntos
Carcinoma Hepatocelular/etiologia , Hepatite B Crônica/sangue , Cirrose Hepática/sangue , Neoplasias Hepáticas/etiologia , Índice de Gravidade de Doença , Adulto , Fatores Etários , Alanina Transaminase/sangue , Antivirais/uso terapêutico , Aspartato Aminotransferases/sangue , Biomarcadores Tumorais/sangue , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/virologia , Feminino , Seguimentos , Alemanha/epidemiologia , Hepatite B Crônica/complicações , Humanos , Incidência , Cirrose Hepática/complicações , Cirrose Hepática/virologia , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Modelos de Riscos Proporcionais , Valores de Referência , Reprodutibilidade dos Testes , Estudos Retrospectivos , Medição de Risco , Fatores de Risco
13.
J Dig Dis ; 16(10): 541-57, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26406351

RESUMO

Nonalcoholic fatty liver disease (NAFLD) has emerged as the most common chronic liver disease worldwide with a reported prevalence ranging 6-33%, depending on the studied populations. It encompasses a spectrum of liver manifestations ranging from simple steatosis (also known as nonalcoholic fatty liver, NAFL) to nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis, which may ultimately progress to hepatocellular carcinoma. NAFLD is strongly associated with the components of metabolic syndrome, mainly obesity and type 2 diabetes mellitus. NAFLD patients are at increased risk of liver-related as well as cardiovascular mortality. Current paradigm suggests a benign course for NAFL whereas NASH is considered to be the progressive phenotype. Although previously under-recognized accumulating evidence suggests that NAFL may also progress, suggesting a higher number of patients at risk than previously appreciated. Liver biopsy remains the gold standard for definitive diagnosis, but the majority of patients can be diagnosed accurately by noninvasive methods. Approved therapies for NAFLD are still lacking and lifestyle modifications aiming at weight loss remain the mainstay of NAFLD treatment. Intensive research could identify insulin resistance, lipotoxicity and dysbiosis of the gut microbiota as major pathophysiological mechanisms, leading to the development of promising targeted therapies which are currently investigated in clinical trials. In this review we summarized the current knowledge of NAFLD epidemiology, natural history, diagnosis, pathogenesis and treatment and considered future directions.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Previsões , Humanos , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/terapia
14.
Angiogenesis ; 16(4): 921-37, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23881168

RESUMO

Notch is an intercellular signaling pathway related mainly to sprouting neo-angiogenesis. The objective of our study was to evaluate the angiogenic mechanisms involved in the vascular augmentation (sprouting/intussusception) after Notch inhibition within perfused vascular beds using the chick area vasculosa and MxCreNotch1(lox/lox) mice. In vivo monitoring combined with morphological investigations demonstrated that inhibition of Notch signaling within perfused vascular beds remarkably induced intussusceptive angiogenesis (IA) with resultant dense immature capillary plexuses. The latter were characterized by 40 % increase in vascular density, pericyte detachment, enhanced vessel permeability, as well as recruitment and extravasation of mononuclear cells into the incipient transluminal pillars (quintessence of IA). Combination of Notch inhibition with injection of bone marrow-derived mononuclear cells dramatically enhanced IA with 80 % increase in vascular density and pillar number augmentation by 420 %. Additionally, there was down-regulation of ephrinB2 mRNA levels consequent to Notch inhibition. Inhibition of ephrinB2 or EphB4 signaling induced some pericyte detachment and resulted in up-regulation of VEGFRs but with neither an angiogenic response nor recruitment of mononuclear cells. Notably, Tie-2 receptor was down-regulated, and the chemotactic factors SDF-1/CXCR4 were up-regulated only due to the Notch inhibition. Disruption of Notch signaling at the fronts of developing vessels generally results in massive sprouting. On the contrary, in the already existing vascular beds, down-regulation of Notch signaling triggered rapid augmentation of the vasculature predominantly by IA. Notch inhibition disturbed vessel stability and led to pericyte detachment followed by extravasation of mononuclear cells. The mononuclear cells contributed to formation of transluminal pillars with sustained IA resulting in a dense vascular plexus without concomitant vascular remodeling and maturation.


Assuntos
Neovascularização Patológica/fisiopatologia , Receptores Notch/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Animais , Transplante de Medula Óssea , Quimiocina CXCL12/biossíntese , Quimiocina CXCL12/genética , Embrião de Galinha , Regulação da Expressão Gênica , Leucócitos Mononucleares/transplante , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neovascularização Patológica/genética , Neovascularização Patológica/prevenção & controle , Oligopeptídeos/farmacologia , Pericitos/patologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Receptor EphB2/biossíntese , Receptor EphB2/genética , Receptor EphB4/biossíntese , Receptor EphB4/genética , Receptor Notch1/deficiência , Receptor TIE-2/biossíntese , Receptor TIE-2/genética , Receptores CXCR4/biossíntese , Receptores CXCR4/genética , Receptores Notch/fisiologia , Receptores de Fatores de Crescimento do Endotélio Vascular/biossíntese , Receptores de Fatores de Crescimento do Endotélio Vascular/genética , Transdução de Sinais/fisiologia
15.
PLoS One ; 8(3): e58360, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23555578

RESUMO

AIMS: To develop, validate and compare a non-invasive fibrosis scoring system for non-alcoholic fatty liver disease (NAFLD) derived from routinely obtained clinical and biochemical parameters. METHODS: 267 consecutive patients with biopsy proven fatty liver or non-alcoholic steatohepatitis were randomly assigned to the estimation (2/3) or validation (1/3) group to develop a model for the prediction of advanced fibrosis. Univariate statistics were performed to compare patients with and without advanced fibrosis, and following a multivariate logistic regression analysis a new scoring system was constructed. This non-invasive Koeln-Essen-index (NIKEI) was validated and compared to the FIB-4 index by calculating the area under the receiver operating characteristic curve (AUC). We evaluated a stepwise combination of both scoring systems for the precise prediction of advanced fibrosis. To set in contrast, we additionally tested the diagnostic accuracy of the AST/ALT ratio, BARD score and the NAFLD fibrosis score in our cohort. RESULTS: Age, AST, AST/ALT ratio, and total bilirubin were identified as significant predictors of advanced fibrosis and used to construct the NIKEI with an AUC of 0.968 [0.937; 0.998] compared to 0.929 [0.869; 0.989] for the FIB-4 index. The absence of advanced fibrosis could be confirmed with excellent accuracy (99-100%). The positive predictive value of the FIB-4 index was higher (100% vs. 60%), however, the false negative rate was also high (33%). With a stepwise combination of both indices 82%-84% of biopsies would have been avoidable without a single misclassification. The AUROC for AST/ALT ratio, the NAFLD fibrosis score, and the BARD score were 0.81 (95% CI, 0.72-0.90), 0.96 (95% CI 0.92-0.99), and 0.67 (95% CI 0.55-0.78), respectively. CONCLUSION: The NIKEI can reliably exclude advanced fibrosis in subjects with NAFLD. In combination with the FIB-4 index misclassification with inadequate clinical management can be avoided while the need for liver biopsies can be reduced.


Assuntos
Fígado Gorduroso , Cirrose Hepática , Modelos Biológicos , Índice de Gravidade de Doença , Adulto , Fígado Gorduroso/diagnóstico , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Fígado Gorduroso/fisiopatologia , Feminino , Humanos , Cirrose Hepática/diagnóstico , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Cirrose Hepática/fisiopatologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica , Valor Preditivo dos Testes , Estudos Retrospectivos
16.
J Clin Gastroenterol ; 47(8): 719-26, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23442837

RESUMO

OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease ranging from simple fatty liver to steatohepatitis, fibrosis, and cirrhosis. We aimed to analyze the diagnostic performance and clinical utility of simple noninvasive tests alone or in combination for the detection of advanced fibrosis in patients with NAFLD. DESIGN AND SUBJECTS: Data from 323 patients with biopsy-proven NAFLD/NASH who presented to the Clinic for Gastroenterology and Hepatology, University Hospital of Cologne between July 1998 and November 2009, were analyzed retrospectively. Sensitivity, specificity, positive predictive values, and negative predictive values were determined along with the area under receiver operating characteristic curves (AUROC) using published formulas for NAFLD, FIB-4, and BARD fibrosis scores. RESULTS: The area under receiver operating characteristic curves were as follows: NAFLD fibrosis score 0.96 [95% confidence interval (CI), 0.92-0.99], FIB-4 0.95 (95% CI, 0.91-1.00), BARD 0.82 (95% CI, 0.71-0.92) with negative predictive values for advanced fibrosis of 96%, 98%, and 96%, respectively. When applying the NAFLD, FIB-4, or BARD scoring systems 25%, 15%, or 26% of cases with advanced fibrosis would have been missed. Combining FIB-4 and BARD in a stepwise fashion, patients would have been correctly classified without biopsy in 67% of cases without missing a single case of advanced fibrosis. CONCLUSIONS: The FIB-4 and NAFLD fibrosis scores perform better than the BARD scoring system. Liver biopsy can securely be replaced only with a stepwise combination of simple noninvasive tests, otherwise the assessment of risk due to advanced fibrosis may be misleading in a clinically meaningful proportion of patients.


Assuntos
Fígado Gorduroso/diagnóstico , Cirrose Hepática/diagnóstico , Adulto , Biópsia , Fígado Gorduroso/patologia , Feminino , Hospitais Universitários , Humanos , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica , Valor Preditivo dos Testes , Curva ROC , Estudos Retrospectivos , Sensibilidade e Especificidade
17.
New Microbiol ; 35(3): 349-52, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22842606

RESUMO

After field dressing a rabbit in the state of Upper Austria, Austria two members of a family were infected with tularemia in November 2010. The patients were a man in his forties and his father-in-law in his sixties. Tularemia is a rare disease in Austria. In the last 10 years between 2 and 8 cases have been reported annually. Of the total of 40 cases none was reported in the state of Upper Austria. Thus, this case report documents the reemergence of tularemia in Upper Austria.


Assuntos
Francisella tularensis/isolamento & purificação , Coelhos/microbiologia , Tularemia/epidemiologia , Adulto , Animais , Áustria , Axila/microbiologia , Axila/patologia , Vetores de Doenças , Doxiciclina/uso terapêutico , Francisella tularensis/patogenicidade , Humanos , Masculino , Pessoa de Meia-Idade , Tularemia/tratamento farmacológico
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