Unusual onset of adult still's disease due to a systemic reaction to artificial breast implants.

In this manuscript, we report an exceptional observation study of a young woman suffering from an autoimmune syndrome induced by adjuvants (ASIA). Until today only seven cases of adult-onset Still's disease (AOSD) induced by breast implants have been published. This may be due to the fact that this illness itself is very rare; however, the reason might also be that the community is not sensitized to the case-specific symptoms. Within this article, we show for the first time highly detailed diagnostic test procedures such as PET-CT scans and specific histological staining of the breast tissue, displaying proinflammatory macrophages that are a well-known activator and booster of autoimmune diseases. We hope to give new insights into the clinical picture and pathogenesis of AOSD in order to improve the challenging diagnosis.

c-Jun N-terminal kinase 2 promotes enterocyte survival and goblet cell differentiation in the inflamed intestine.

c-Jun N-terminal kinases (JNKs) contribute to immune signaling but their functional role during intestinal mucosal inflammation has remained ill defined. Using genetic mouse models, we characterized the role of JNK1 and JNK2 during homeostasis and acute colitis. Epithelial apoptosis, regeneration, differentiation, and barrier function were analyzed in intestinal epithelium-specific (ΔIEC) or complete JNK1 and bone marrow chimeric or complete JNK2 deficient mice as well as double-knockout animals (JNK1ΔIECJNK2-/-) during homeostasis and acute dextran sulfate sodium (DSS)-induced colitis. Results were confirmed using human HT-29 cells and wild-type or JNK2-deficient mouse intestinal organoid cultures. We show that nonhematopoietic JNK2 but not JNK1 expression confers protection from DSS-induced intestinal inflammation reducing epithelial barrier dysfunction and enterocyte apoptosis. JNK2 additionally enhanced Atonal homolog 1 expression, goblet cell and enteroendocrine cell differentiation, and mucus production under inflammatory conditions. Our results identify a protective role of epithelial JNK2 signaling to maintain mucosal barrier function, epithelial cell integrity, and mucus layer production in the event of inflammatory tissue damage.

Mouse models of metabolic liver injury.

Metabolic liver injury is one of the fastest growing health problems worldwide. Alcoholic and non-alcoholic fatty livers have been shown to be associated with progression to end-stage liver diseases, as well as to liver cancers, in humans. More importantly, there are no validated therapies for these disorders, therefore intensive research is required in this area. This review of standard operation procedures focuses on the experimental models of fatty liver disease in the mouse. Firstly, use of these experimental models might improve understanding of underlying mechanisms, and secondly this might help to test potential therapeutic options. This article includes, besides a short historic background, an insight into the pathobiochemical mechanisms and detailed experimental procedures as well as the practical implementation of these models.

[Diagnostic value of routine ileum biopsy in patients with chronic diarrhoea--a prospective monocentric study]. / Die diagnostische Bedeutung der Ileumbiopsie bei chronischer Diarrhö--eine prospektive monozentrische Studie.

BACKGROUND AND AIMS: In patients with chronic diarrhoea of unknown origin, colonoscopy with intubation of the terminal ileum and performance of biopsies are standard in the diagnostic work-up. While the importance of random biopsies in the colon even in cases with normal endoscopic appearance has been proven in several studies, the role of biopsies in the terminal ileum under these circumstances is not well defined. PATIENTS AND METHODS: In this prospective observational 24-month study patients with chronic diarrhoea of unknown cause were included. All patients underwent colonoscopy with intubation and biopsy of the terminal ileum. These biopsies have been analysed, their diagnostic value has been compared to the endoscopic appearance and the clinical diagnosis was investigated. RESULTS: In 159 patients, the terminal ileum showed a pathological endoscopic appearance in 27 cases (17 %). In 22 (81.5 %) of these 27 patients diagnostic pathological findings were present, in 4 cases (14.8 %) non-specific histological changes were detected and in one patient (3.7 %), histology was normal. In contrast, only in one of 132 cases with normal endoscopic appearance, did histopathology show a significant pathology (celiac disease). In 30 of the 132 patients (22.7 %) with a normal endoscopic appearance, distinctive histological features were detected (slight eosinophilia or elevated mucosal immune cell count), but not classified as diagnostic. In all cases, these features were also present in simultaneously performed colonic biopsies. CONCLUSIONS: Routine biopsy of the terminal ileum, when normal endoscopic appearance is documented, does not give any additional information and cannot be recommended as a standard procedure in endoscopic work-up of chronic diarrhoea.

[Acute liver failure. Diagnosis and therapy]. / Akutes Leberversagen. Übersicht zur aktuellen Diagnostik und Therapie.

Although acute liver failure is a rare disease with a prevalence of 5 per 1 million people, it has a considerablely high mortality rate of 34 %. The main causes in western civilizations are drug overdose (acetaminophen) and viral hepatitis. Patients are affected by the loss of liver synthesis function and are at risk of developing hepatic encephalopathy and possible multiorgan failure. Specific therapies consisting of the administration of N-acetylcysteine (acetaminophen) or of nucleotide/nucleoside analogs (hepatitis B) are possible, but are often not adequate. Orthotopic liver transplantation is, therefore, frequently the only remaining effective therapy for severe acute liver failure. Due to organ shortage, new prognostic tools, e.g., the Acute Liver Failure Study Group (ALFSG) score, have been developed to improve patient selection using sufficiently stringent selection criteria.

[Abnormal liver function tests in the intensive care unit]. / Leberwerterhöhung auf der Intensivstation.

Abnormal liver biochemical and function tests are found in the majority of critically ill patients and are associated with increased mortality. Frequent causes for elevated liver function tests in the intensive care unit (ICU) are acute hepatic dysfunction due to acute hepatitis, acute liver failure (ALF), and drug-induced liver injury (DILI). Furthermore, exacerbations of pre-existing liver diseases (acute on chronic) and secondary liver injury during critical diseases such as sepsis, right heart failure, or cardiogenic shock, resulting in ischemic or hypoxic hepatitis, need to be considered. Elevated liver enzymes may also reflect a complication of ICU treatment measures like drug-related hepatotoxicity, secondary sclerosing cholangitis in critically ill patients (SC-CIP), or related to parenteral nutrition. Comprehensive diagnostic evaluation is essential to identify the underlying etiology of abnormal liver function tests and to initiate the appropriate therapeutic strategies.

[Management of decompensated liver cirrhosis in the intensive care unit]. / Management der dekompensierten Leberzirrhose auf der Intensivstation.

Liver cirrhosis is the end-stage of long-standing chronic liver diseases. The occurrence of complications from liver cirrhosis increases the mortality risk, but the prognosis can be improved by optimal management in the intensive care unit (ICU). Defined diagnostic algorithms allow the etiology and presence of typical complications upon presentation to the ICU to be identified. Acute variceal bleeding requires endoscopic intervention, vasoactive drugs, antibiotics, supportive intensive care measures and, where necessary, urgent transjugular intrahepatic portosystemic shunt (TIPS) procedure. Spontaneous bacterial peritonitis needs to be diagnosed and immediately treated in patients with ascites. Hepatorenal syndrome should be treated by albumin and terlipressin. In case of respiratory failure, differential diagnosis should not only consider pneumonia, pulmonary embolism and cardiac failure, but also hepatic hydrothorax, portopulmonary hypertension and hepatopulmonary syndrome. The feasibility of liver transplantation should be always discussed in patients with decompensated cirrhosis. Artificial liver support devices may only serve as a bridging procedure until transplant.

Endoscopic ultrasound as an early diagnostic tool for primary sclerosing cholangitis: a prospective pilot study.

BACKGROUND AND STUDY AIMS: Primary sclerosing cholangitis (PSC) is a rare, chronic cholestatic liver disease, which typically affects middle-aged men and is frequently associated with inflammatory bowel disease. Early recognition and accurate diagnosis remains a clinical challenge. Invasive diagnostic procedures, such as endoscopic retrograde cholangiography or liver biopsy are needed when magnetic resonance cholangiopancreatography remains inconclusive. As these procedures are associated with significant risks, the current study sought to determine whether endoscopic ultrasound (EUS) of the biliary tract is a useful diagnostic tool in cases of suspected PSC. PATIENTS AND METHODS: In a prospective pilot study, 138 patients presenting with chronic cholestatic hepatopathy were screened and 32 patients with possible PSC were evaluated further. In addition to all routine measures, EUS was included in the diagnostic work-up.  The following parameters were evaluated and compared with the definitive diagnosis: wall thickening ( ≥ 1.5  mm), irregular wall structure, significant changes of caliber of the common bile duct, and perihilar lymphadenopathy. RESULTS: In the 138 patients screened, a PSC prevalence of 13 % was found. Of the 32 patients included in the study, 17 had large-duct PSC diagnosed. When two of the aforementioned four parameters showed PSC-like features, sensitivity and specificity of predicting PSC were 76.4 % and 100 %, with positive and negative predictive values of 100 % and 79 %, respectively. In four patients presenting with strictly intrahepatic disease, EUS was not diagnostic. CONCLUSIONS: EUS proved to be a valuable tool in suspected PSC and accurately predicted extrahepatic disease. EUS should be evaluated further as an early procedure in routine diagnostic measurements. This approach promises a significant improvement in disease detection as well as a reduction in high risk invasive procedures.

[Treatment of inflammatory bowel disease in intensive care medicine]. / Behandlung chronisch entzündlicher Darmerkrankungen in der Intensivmedizin.

In patients with inflammatory bowel disease (IBD) complications of both IBD and immunosuppressive therapy may be life-threatening conditions requiring intensive care therapy. These patients oftentimes present themselves with severe bloody diarrhoea, and infectious colitis, pseudomembranous colitis or intestinal ischemia must be included in the differential diagnosis. Steroids, immunosuppressants such as azathioprine, 6-mercaptopurine, methotraxate or ciclosporine, as well as biologicals, which act as TNF-alpha antagonists, are commonly used for maintenance therapy and treatment of acute exacerbations of IBD. Due to immunosuppressive therapy potentially life-threatening infections and reactivations of latent infections like tuberculosis or cytomegalovirus (CMV) can occur. Fistulas, abscesses, perforations and intestinal obstructions are typical complications of Crohn's disease in the intensive care setting, whereas clinical presentation in ulcerative colitis is characterised by its acute exacerbation and the toxic dilatation of the colon, potentially resulting in toxic megacolon with high risk of perforation or severe bleeding. Most important for an effective therapy in the critically ill patient with inflammatory bowel disease are the control of the underlying disease, the empiric antibiotic therapy in case of infectious complications, transcutaneous drainage of abscesses, bowel decompression in toxic megacolon and the early interdisciplinary assessment of the abdomen.

Value of magnifying endoscopy in classifying colorectal polyps based on vascular pattern.

BACKGROUND AND STUDY AIMS: Narrow-band imaging (NBI) has been developed as a new technique to differentiate tissue patterns in vivo. The aim of this study was to evaluate the diagnostic accuracy of NBI endoscopy with and without high magnification for the differentiation of neoplastic from non-neoplastic colorectal polyps. PATIENTS AND METHODS: Among 200 colorectal polyps from 131 patients, 100 lesions were classified according to vascular patterns by NBI endoscopy with high optical magnification and 100 lesions by high-definition endoscopy without high magnification. Additionally, the clarity of the vessel network was assessed. Histologic analysis was performed on all lesions. RESULTS: NBI endoscopy with high magnification resulted in a sensitivity of 92.1 % and a specificity of 89.2 % for the differentiation of neoplastic versus non-neoplastic lesions. This performance was statistically comparable to high-definition NBI endoscopy without high magnification, which showed a sensitivity of 87.9 % and specificity of 90.5 %. However, vessel network was significantly better visualized by NBI endoscopy with optical magnification compared with high-definition NBI endoscopy without high magnification. In comparison with NBI endoscopy, white-light endoscopy, with or without magnification, resulted in inferior discrimination between neoplastic and non-neoplastic polyps. CONCLUSION: The results demonstrate that the superior visibility of capillary vessels by the NBI technique allows the evaluation of colorectal lesions - based on the vascular patterns - with high diagnostic accuracy. In clinical routine, high-definition NBI endoscopy without high magnification may be used to sufficiently predict colorectal polyp histology, and high magnification can additionally facilitate visualization of vascular networks.

[The value of duodenal biopsy within routine upper endoscopy: a prospective study in 1000 patients]. / Die Wertigkeit der tiefen Duodenalbiopsie im Rahmen der Routineendoskopie: Eine prospektive Studie mit 1000 Patienten.

BACKGROUND AND AIM: Several gastrointestinal diseases are localised in the small bowel and are confirmed by duodenal biopsies upon upper gastrointestinal endoscopy. However, the clinical value of routine duodenal biopsies during endoscopy has not been satisfactorily defined and was assessed in the current study. METHODS: In 1000 consecutive patients duodenal biopsies were performed during routine upper gastrointestinal endoscopy. Endoscopic diagnoses, symptoms and the prevalence of anaemia were correlated with the histological diagnoses. RESULTS: Coeliac disease and giardiasis was diagnosed in 18 and two patients, respectively (2.0 % of all cases). In 11 (55 %) patients the diagnosis was already made macroscopically during endoscopy. The sensitivity for endoscopic diagnosis of coeliac disease MARSH III was 84.6 %. There was no correlation between clinical symptoms, the prevalence of anaemia and the diagnosis of coeliac disease or giardiasis in our cohort. CONCLUSION: Endoscopic diagnosis of advanced celiac disease (MARSH III) can be made with high sensitivity and specifity. Nevertheless, duodenal biopsy is necessary for the diagnosis of early coeliac disease or giardiasis. However, the routine duodenal sampling of normal mucosa during gastrointestinal endoscopy cannot be recommended.

Type testing the Model 6600 plus automatic TLD reader.

The Harshaw Model 6600 Plus is a reader with a capacity for 200 TLD cards or 800 extremity cards. The new unit integrates more functionality, and significantly automates the QC and calibration process compared to the Model 6600. The Model 6600 Plus was tested against the IEC 61066 (1991-2012) procedures using Harshaw TLD-700H and TLD-600H, LiF:Mg,Cu,P based TLD Cards. An overview of the type testing procedures is presented. These include batch homogeneity, detection threshold, reproducibility, linearity, self-irradiation, residue, light effects on dosemeter, light leakage to reader, voltage and frequency, dropping and reader stability. The new TLD reader was found to meet all the IEC criteria by large margins and appears well suited for whole body, extremity and environmental dosimetry applications, with a high degree of dosimetric performance.

Acute CMV-colitis in a patient with a history of ulcerative colitis.

A symptomatic cytomegalovirus (CMV) infection usually occurs in patients with debilitating diseases, immunosuppression, transplantations and acquired immunodeficiency syndrome (AIDS). Gastrointestinal infections with CMV, especially colitis, are usually found in immunocompromised patients and rarely affect immunocompetent subjects. Here we report the case of a young female patient with a history of ulcerative colitis (UC) who presented with an acute attack of colitis caused by CMV infection. This was documented by the presence of CMV early antigen, antibodies and evidence of CMV in the colonic mucosa. After combined anti-inflammatory and antiviral treatment the patient recovered completely. As most attention is given to CMV-pathogeneity in immunocompromised patients, here we discuss the relationship to inflammatory bowel diseases.

Mediators of inflammation and acute phase response in the liver.

The acute phase response is a generalized response of the organism to multiple disturbances of its physiological homeostasis. It consists of local and systemic reactions. Inflammatory processes are the main causes for the initiation of these defence mechanisms. Responsible mediators for the acute phase response are predominantly cytokines, whereby the liver is the predominant target organ. Changes in hepatocyte gene expression profiles result in dramatic changes in serum concentrations of specific plasma proteins, called acute phase proteins. IL-6 was identified as the principal mediator of this reaction. Via its cellular signal transducer gp130 IL-6 induces DNA-binding of STAT transcription factors on regulatory elements of target genes. While IL-6 dependent processes are mainly conferred to be protective other inflammatory cytokines are attributed to be cytotoxic for the liver. TNF-alpha was shown to be involved in several models of liver failure as a mediator for both cytotoxicity and cell proliferation. TNF-alpha leads via caspases to the onset of apoptosis, the so-called programmed cell death. On the other hand it activates NF-kappaB thereby triggering inflammatory processes. In this review we display the relevance for intracellular actions of both cytokines in several models of liver injury. Especially we refer to the T-cell mediated Concanavalin A induced liver failure and to liver regeneration induced by CCL4 and partial hepatectomy. Both cytokines contribute in concert to a cellular balance during these pathophysiological conditions.

Induction of Mdr1b expression by tumor necrosis factor-alpha in rat liver cells is independent of p53 but requires NF-kappaB signaling.

The multidrug resistance protein Mdr1b in rats is up-regulated during liver regeneration after partial hepatectomy or after endotoxin treatment. We hypothesize that up-regulation of Mdr1b in these models is TNF-alpha-dependent. The mechanism of Mdr1b activation by TNF-alpha is unknown as TNF-alpha can signal through various pathways, including NF-kappaB and p53, transcription factors for which binding sites in the Mdr1b promoter have been identified. We aimed to elucidate the mechanism of up-regulation of Mdr1b by TNF-alpha. We selectively used constructs expressing dominant negative Fas-associated death domain protein (FADD), TNF receptor associated factor-2 (TRAF2) or IkappaB to inhibit pathways downstream of the TNF receptor. Further, the proteasome inhibitor MG-132 was used, which prevents the breakdown of IkappaB. We show a critical role for NF-kappaB in activation of Mdr1b gene expression both in primary rat hepatocytes and in rat hepatoma H-4-II-E cells. Because p53 is up-regulated by TNF-alpha in an NF-kappaB-dependent manner and the Mdr1b promoter contains a p53 binding site, we used liver cells expressing a dominant negative p53 to show that TNF-alpha up-regulation of Mdr1b is independent of functional p53. Using transient transfection assays, we show that Mdr1b up-regulation correlates with activation of the promoter. Mutation of the NF-kappaB site in the Mdr1b promoter prevents its induction by TNF-alpha. In conclusion our results show that activation of the rat Mdr1b gene by TNF-alpha is a result of NF-kappaB signaling and independent of p53.

Dissection of the intracellular pathways in hepatocytes suggests a role for Jun kinase and IFN regulatory factor-1 in Con A-induced liver failure.

Con A administration results in dose-dependent immune-mediated liver injury. Cytokines are important to determine the outcome of liver failure in this model, and especially TNF-alpha and IFN-gamma directly contribute to hepatocyte damage. The intracellular pathways of these two cytokines, which eventually result in tissue destruction, are not well defined. Here we used anti-IFN-gamma Abs and adenoviral vectors that express molecules inhibiting distinct TNF-alpha-dependent pathways in hepatocytes to better understand the relevance of specific intracellular signaling cascades for Con A-induced liver failure. We show that activation of TNF-alpha- and IFN-gamma-dependent intracellular pathways occurs prior to the influx of immune-activated cells into the liver and that anti-TNF-alpha and anti-IFN-gamma neutralizing Abs cannot block infiltration of these cells. Blocking experiments with Abs and adenoviral vectors showed that NF-kappaB activation and the Fas-associated death domain protein/caspase 8 cascade in hepatocytes during Con A-induced liver failure have no impact on tissue injury. Additionally, STAT1 activation alone after Con A injection in liver cells does not result in liver damage. In contrast, IFN-gamma-dependent expression of IFN regulatory factor-1 and TNF-alpha-dependent activation of c-Jun N-terminal kinase in liver cells correlates with liver cell damage after Con A injection. Therefore, our experiments indicate that 11418690

Interleukin-6-induced tethering of STAT3 to the LAP/C/EBPbeta promoter suggests a new mechanism of transcriptional regulation by STAT3.

LAP/C/EBPbeta is a member of the C/EBP family of transcription factors and contributes to the regulation of the acute phase response in hepatocytes. Here we show that IL-6 controls LAP/C/EBPbeta gene transcription and identify an IL-6 responsive element in the LAP/C/EBPbeta promoter, which contains no STAT3 DNA binding motif. However, luciferase reporter gene assays showed that STAT3 activation through the gp130 signal transducer molecule is involved in mediating IL-6-dependent LAP/C/EBPbeta transcription. Southwestern analysis indicated that IL-6 induces binding of a 68-kDa protein to the recently characterized CRE-like elements in the LAP/C/EBPbeta promoter. Transfection experiments using promoter constructs with mutated CRE-like elements revealed that these sites confer IL-6 responsiveness. Further analysis using STAT1/STAT3 chimeras identified specific domains of the protein that are required for the IL-6-dependent increase in LAP/C/EBPbeta gene transcription. Overexpression of the amino-terminal domain of STAT3 blocked the IL-6-mediated response, suggesting that the STAT3 amino terminus has an important function in IL-6-mediated transcription of the LAP/C/EBPbeta gene. These data lead to a model of how tethering STAT3 to a DNA-bound complex contributes to IL-6-dependent LAP/C/EBPbeta gene transcription. Our analysis describes a new mechanism by which STAT3 controls gene transcription and which has direct implication for the acute phase response in liver cells.