Delayed occurrence of traumatic aortic dissection? Biomechanical considerations and literature.

Chronic aortic dissections and pseudoaneurysms caused by chest trauma are rare and generally have to be critically distinguished from non-traumatic dissections and aneurysms. We present a well-documented case of a post-traumatic aortic dissection that ruptured about 9 months after chest trauma. A motorcyclist sustained fractures of the forearm and chest trauma with paravertebral rib serial fractures and hemopneumothorax. Nine months after the accident, echocardiography revealed a pseudoaneurysm that ruptured 3 months later and 1 month prior to the planned surgery. An autopsy showed pericardial tamponade following a rupture of the dissected aorta. Accident scene documentation was consistent with a head-on collision of the motorcycle against the left front side of the car. The relative speed was about 55 km/h. Aggravation of unspecific symptoms after discharge, initial CT imaging, and the absence of atherosclerosis or medial necrosis hold for a post-traumatic genesis of the dissection in our case. Initially, the accident insurance company rejected the regulation. In the second instance, they revised rejection based on our interdisciplinary expert opinion.

Notch inhibition counteracts Paneth cell death in absence of caspase-8.

Opposing activities of Notch and Wnt signaling regulate mucosal barrier homeostasis and differentiation of intestinal epithelial cells. Specifically, Wnt activity is essential for differentiation of secretory cells including Wnt3-producing Paneth cells, whereas Notch signaling strongly promotes generation of absorptive cells. Loss of caspase-8 in intestinal epithelium (casp8∆int) is associated with fulminant epithelial necroptosis, severe Paneth cell death, secondary intestinal inflammation, and an increase in Notch activity. Here, we found that pharmacological Notch inhibition with dibenzazepine (DBZ) is able to essentially rescue the loss of Paneth cells, deescalate the inflammatory phenotype, and reduce intestinal permeability in casp8∆int mice. The secretory cell metaplasia in DBZ-treated casp8∆int animals is proliferative, indicating for Notch activities partially insensitive to gamma-secretase inhibition in a casp8∆int background. Our data suggest that casp8 acts in the intestinal Notch network.

Effect of Age on Liver Function in Patients Undergoing Partial Hepatectomy.

BACKGROUND: Postresectional liver failure is the most frequent cause of fatal outcome following liver surgery. Diminished preoperative liver function in the elderly might contribute to this. Therefore, the aim of the present study was to evaluate preoperative liver function in patients <60 or >70 years of age scheduled for liver resection. METHODS: All consecutive patients aged <60 or >70 years who are about to undergo elective liver surgery between 2011 and 2013 and underwent the methacetin breath liver function test (LiMAx) preoperatively were included. Histologic assessment of the resected liver gave insight into background liver disease. Correlation between age and liver function was calculated with Pearson's test. RESULTS: Fifty-nine patients were included, 31 were aged <60 and 28 were aged >70 years. General patient characteristics and liver function LiMAx values (340 (137-594) vs. 349 (191-530) µg/kg/h, p = 0.699) were not significantly different between patients aged <60 and >70 years. Moreover, no correlation between age and preoperative liver function LiMAx values was found (R = 0.04, p = 0.810). CONCLUSION: Liver function did not seem to differ between younger and older patients.

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.

Clinical and morphological aspects of adenocarcinomas of the intestinal type in the inner nose: a retrospective multicenter analysis.

Clinical and histological parameters from 117 patients with wood dust-related sinonasal adenocarcinomas of intestinal type (ITAC) were analyzed and correlated with a follow-up period of 5 years at least. The rate of survival for 5 years was 53.1 % and for 10 years 30.2 %. Only 33 patients were free of disease. 74.2 % of patients with recurrences died in relation to ITAC. As expected, tumors of T4-category had the worst prognosis. The mucus content of a tumor was the most important histological parameter. Endonasal methods of surgery had no more positive survival rates after 5 years. An effect of radiotherapy has to be in discussion. The high incidence of tumor recurrences requires control examinations consistently.

ß7-Integrin exacerbates experimental DSS-induced colitis in mice by directing inflammatory monocytes into the colon.

Leukocyte recruitment is pivotal for the initiation and perpetuation of inflammatory bowel disease (IBD) and controlled by the specificity and interactions of chemokines and adhesion molecules. Interactions of the adhesion molecules α4ß7-integrin and mucosal addressin cell-adhesion molecule-1 (MAdCAM-1) promote the accumulation of pathogenic T-cell populations in the inflamed intestine. We aimed to elucidate the significance of ß7-integrin expression on innate immune cells for the pathogenesis of IBD. We demonstrate that ß7-integrin deficiency protects recombination-activating gene-2 (RAG-2)-deficient mice from dextran sodium sulfate (DSS)-induced colitis and coincides with decreased numbers of colonic effector monocytes. We also show that ß7-integrin is expressed on most CD11b(+)CD64(low)Ly6C(+) bone marrow progenitors and contributes to colonic recruitment of these proinflammatory monocytes. Importantly, adoptive transfer of CD115(+) wild-type (WT) monocytes partially restored the susceptibility of RAG-2/ß7-integrin double-deficient mice to DSS-induced colitis, thereby demonstrating the functional importance of ß7-integrin-expressing monocytes for the development of DSS colitis. We also reveal that genetic ablation of MAdCAM-1 ameliorates experimental colitis in RAG-2-deficient mice as well. In summary, we demonstrate a previously unknown role of α4ß7-integrin-MAdCAM-1 interactions as drivers of colitis by directing inflammatory monocytes into the colon.

Metastatic behaviour of sinonasal adenocarcinomas of the intestinal type (ITAC).

The relative frequency of regional lymphogenic versus distant hematogenic metastases was evaluated in 369 patients with sinonasal adenocarcinoma of the intestinal type (ITAC). We assessed the results of neck dissections for a limited number of patients undergoing this surgical intervention. 117 ITAC patients were followed up for at least 5 years. Neck dissections were performed in 18 cases (15 primary and 3 secondary operations), 4 of which revealed carcinoma-positive lymph nodes. Metastases in lymph nodes were also diagnosed clinically in three other patients adding up to a total of seven individuals (6 % of 117) with lymphogenic metastases. In comparison, distant hematogenic metastases were identified in 15.4 % of these 117 patients. In the second group of 252 patients, the occurrence of distant hematogenic metastases and colorectal adenocarcinomas was registered but no formal follow-up procedure was applied. 50 neck dissections were performed in this group, 46 of which exhibited no histological evidence for metastases in lymph nodes, while in 1 case they were carcinoma-positive. Three additional cases showed clinical signs of metastases in regional lymph nodes. Taken together, our observations indicate that regional lymphogenic metastases are rather rare (about 2 %) in patients with sinonasal adenocarcinoma of the intestinal type. Therefore, the surgery of neck dissection appears not advised as routine intervention in these cases. ITAC patients show a normal prevalence of colorectal adenocarcinomas.

Lack of gp130 expression in hepatocytes attenuates tumor progression in the DEN model.

Chronic liver inflammation is a crucial event in the development and growth of hepatocellular carcinoma (HCC). Compelling evidence has shown that interleukin-6 (IL-6)/gp130-dependent signaling has a fundamental role in liver carcinogenesis. Thus, in the present study we aimed to investigate the role of gp130 in hepatocytes for the initiation and progression of HCC. Hepatocyte-specific gp130 knockout mice (gp130(Δhepa)) and control animals (gp130(f/f)) were treated with diethylnitrosamine (DEN). The role of gp130 for acute injury (0-144 h post treatment), tumor initiation (24 weeks) and progression (40 weeks) was analyzed. After acute DEN-induced liver injury we observed a reduction in the inflammatory response in gp130(Δhepa) animals as reflected by decreased levels of IL-6 and oncostatin M. The loss of gp130 slightly attenuated the initiation of HCC 24 weeks after DEN treatment. In contrast, 40 weeks after DEN treatment, male and female gp130(Δhepa) mice showed smaller tumors and reduced tumor burden, indicating a role for hepatocyte-specific gp130 expression during HCC progression. Oxidative stress and DNA damage were substantially and similarly increased by DEN in both gp130(f/f) and gp130(Δhepa) animals. However, gp130(Δhepa) livers revealed aberrant STAT5 activation and decreased levels of transforming growth factor-ß (TGFß), pSMAD2/3 and SMAD2, whereas phosphorylation of STAT3 at Tyr705 and Ser727 was absent. Our results indicate that gp130 deletion in hepatocytes reduces progression, but not HCC initiation in the DEN model. Gp130 deletion resulted in STAT3 inhibition but increased STAT5 activation and diminished TGF-dependent signaling. Hence, blocking gp130 in hepatocytes might be an interesting therapeutic target to inhibit the growth of HCC.

Pro-apoptotic Sorafenib signaling in murine hepatocytes depends on malignancy and is associated with PUMA expression in vitro and in vivo.

The multi-kinase inhibitor Sorafenib increases the survival of patients with advanced hepatocellular carcinoma (HCC). Current data suggest that Sorafenib inhibits cellular proliferation and angiogenesis and promotes apoptosis. However, the underlying pro-apoptotic molecular mechanisms are incompletely understood. Here we compared the pro-apoptotic and anti-proliferative properties of Sorafenib in murine hepatoma cells and syngeneic healthy hepatocytes in vitro and in animal models of HCC and liver regeneration in vivo. In vitro, we demonstrate that cell cycle activity and expression of anti-apoptotic Bcl-2 like proteins are similarly downregulated by Sorafenib in Hepa1-6 hepatoma cells and in syngeneic primary hepatocytes. However, Sorafenib-mediated activation of caspase-3 and induction of apoptosis were exclusively found in hepatoma cells, but not in matching primary hepatocytes. We validated these findings in vivo by applying an isograft HCC transplantation model and partial hepatectomy (PH) in C57BL/6 mice. Sorafenib treatment activated caspase-3 and thus apoptosis selectively in small tumor foci that originated from implanted Hepa1-6 cells but not in surrounding healthy hepatocytes. Similarly, Sorafenib did not induce apoptosis after PH. However, Sorafenib treatment transiently inhibited cell cycle progression and resulted in mitotic catastrophe and enhanced non-apoptotic liver injury during regeneration. Importantly, Sorafenib-mediated apoptosis in hepatoma cells was associated with the expression of p53-upregulated-modulator-of-apoptosis (PUMA). In contrast, regenerating livers after PH revealed downregulation of PUMA and were completely protected from Sorafenib-mediated apoptosis. We conclude that Sorafenib induces apoptosis selectively in hepatoma cells but not in healthy hepatocytes and can additionally increase non-apoptotic hepatocyte injury in the regenerating liver.

[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.

TNFR1 determines progression of chronic liver injury in the IKKγ/Nemo genetic model.

Death receptor-mediated hepatocyte apoptosis is implicated in a wide range of liver diseases including viral and alcoholic hepatitis, ischemia/reperfusion injury, fulminant hepatic failure, cholestatic liver injury, as well as cancer. Deletion of NF-κB essential modulator in hepatocytes (IKKγ/Nemo) causes spontaneous progression of TNF-mediated chronic hepatitis to hepatocellular carcinoma (HCC). Thus, we analyzed the role of death receptors including TNFR1 and TRAIL in the regulation of cell death and the progression of liver injury in IKKγ/Nemo-deleted livers. We crossed hepatocyte-specific IKKγ/Nemo knockout mice (Nemo(Δhepa)) with constitutive TNFR1(-/-) and TRAIL(-/-) mice. Deletion of TNFR1, but not TRAIL, decreased apoptotic cell death, compensatory proliferation, liver fibrogenesis, infiltration of immune cells as well as pro-inflammatory cytokines, and indicators of tumor growth during the progression of chronic liver injury. These events were associated with diminished JNK activation. In contrast, deletion of TNFR1 in bone-marrow-derived cells promoted chronic liver injury. Our data demonstrate that TNF- and not TRAIL signaling determines the progression of IKKγ/Nemo-dependent chronic hepatitis. Additionally, we show that TNFR1 in hepatocytes and immune cells have different roles in chronic liver injury-a finding that has direct implications for treating chronic liver disease.

Raising awareness about chronic intestinal pseudo-obstruction (CIPO): a case report showing CIPO as initial manifestation of atypical seronegative systemic sclerosis.

Only few case studies address pseudo-obstruction, a disorder - which often frustrates clinicians and patients due to an unclear diagnosis and limited therapeutic options. Thus, the aim of this paper is to investigate a relevant case concerning a patient presenting with symptoms of acquired chronic intestinal pseudo-obstruction (CIPO). After one year of extensive diagnostic tests and unsuccessful treatment with prokinetics, the patient underwent a subtotal ileocolectomy. The histology of the intestinal specimen revealed continuous atrophy and fibrosis mainly within the circular, inner muscle layer of muscularis propria of the ileum and colon. Even though serum markers were lacking, a subsequent skin biopsy showed signs of scleroderma supporting an initial diagnosis of intestinal involvement in systemic sclerosis. Despite treatment with steroids and methotrexate, the increasingly emaciated patient died. In conclusion, there is a bias against the publishing of pseudo-obstruction studies, in particular, due to the obscure underlying causes. To raise awareness of this problem, we call for clinicians to systematically generate comprehensive data about patients presenting these symptoms.

Doppler ultrasound of hepatic blood flow for noninvasive evaluation of liver fibrosis compared with liver biopsy and transient elastography.

BACKGROUND: Accurate quantification of liver fibrosis is essential for therapeutic decision-making and follow-up of chronic liver diseases. AIMS: To optimize the quality of non-invasive assessment of liver fibrosis in patients with chronic hepatopathy we compared Doppler ultrasound with liver histology and transient elastography (TE). METHODS: In this prospective observational study, we performed Doppler ultrasound of hepatic blood vessels as well as TE in 125 patients who underwent liver biopsy for diagnostic work-up of hepatopathy. Hepatic venous flow was evaluated by determining resistance index (HVRI) of the right hepatic vein. Doppler and TE results were compared with histological staging, grading and degree of steatosis obtained by liver biopsy. RESULTS: HVRI showed a high reliability in predicting fibrosis stage FII or higher (AUROC 93.7 %, HVRI < 1.185; sensitivity 89.66 % and specificity 86.32 %) and was superior to TE. Neither steatosis nor inflammation had significant influence on HVRI-based estimation of fibrosis (1.45 ± 0.2; 1.26 ± 0.05; 1.06 ± 0.06; 0.87 ± 0.08; 0.46 ± 0.11 for F0-FIV, respectively). HVRI differed significantly in different stages of fibrosis. In contrast, portal vein and hepatic artery only showed significant changes in higher stages of fibrosis. Hepatic artery resistance index was elevated (0.67-0.74; p < 0.05); portal vein flow maximum and undulation were significantly reduced in higher fibrosis (p < 0.05 and p < 0.01, respectively). CONCLUSIONS: Hepatic blood flow analysis, especially HVRI, provides useful information during assessment of hepatopathy and is a reliable predictor of liver fibrosis stage FII or higher as part of the non-invasive diagnostic work-up and follow-up in chronic liver disease.

[Tumors of Vater's ampulla]. / Tumoren der Papilla Vateri.

Tumors of Vater's ampulla are generally uncommon. In this location intestinal type adenomas are frequently found, followed by noninvasive papillary neoplasms of the pancreaticobiliary type and neuroendocrine tumors (carcinoids). Carcinomas of Vater's ampulla represent about 0.5% of all gastrointestinal malignancies. Intestinal type adenocarcinoma is the most common malignant epithelial tumor followed by the pancreaticobiliary type adenocarcinoma. Highly malignant neuroendocrine carcinomas of Vater's ampulla are very uncommon. Carcinomas of the ampullary region can be sporadic or a component of several disease syndromes. Designation of large carcinomas as tumors with an ampullary or extra-ampullary origin can be difficult but is of relevance for a TNM conform classification. Helpful in the decision are the relationship between the tumor centre and Vater's ampulla, the existence of premalignant lesions in the ampullary epithelium as well as histology and immunostaining of the tumor.

Deletion of gp130 in myeloid cells modulates IL-6-release and is associated with more severe liver injury of Con A hepatitis.

IL-6/gp130 dependent signaling plays an important role in modulating inflammation in acute and chronic diseases. The course of Concanavalin A- (Con A) induced hepatitis can be modulated by different immune-mediated mechanisms. IL-6/gp130-dependent signaling has been shown to be protective in hepatocytes. However, the role of this pathway in myeloid cells has not yet been studied. In our present study we used macrophage/neutrophil-specific gp130 knockout (gp130(ΔLys), KO) animals and analyzed its relevance in modulating Con A-induced hepatitis. Additionally, we performed in vitro studies with gp130(ΔLys)-macrophages. We demonstrate that gp130(ΔLys) animals are more susceptible to Con A-induced hepatitis. This is reflected by higher transaminases, higher lethality and more severe liver injury as shown by histological staining. Using flow cytometry analysis we further could show that increased liver injury of gp130(ΔLys) animals is associated with a stronger infiltration of CD11b/F4/80 double-positive cells compared to wild-type (gp130(flox/flox), WT) controls. To further characterize our observations we studied thioglycolate-elicited peritoneal macrophages from gp130(ΔLys) animals. Interestingly, the LPS-dependent IL-6 release in gp130(ΔLys) macrophages is significantly reduced (p<0.05) compared to WT macrophages. Additionally, IL-6 blood levels in vivo after Con A injection were significantly lower in gp130(ΔLys) animals compared to WT animals (p<0.05). In summary, our results suggest that gp130-deletion in macrophages and granulocytes leads to diminished IL-6 release from these cells, which is associated with more severe Con A-induced hepatitis.

Antenatal exposure to chorioamnionitis affects lipid metabolism in 7-week-old sheep.

Antenatal exposure of the fetus to inflammation may alter postnatal organ development. In our previous work, we demonstrated that the fetal liver is involved in the systemic inflammation associated with chorioamnionitis, leading to metabolic changes. On the basis of these findings, we hypothesized that chorioamnionitis can lead to postnatal inflammation-related liver injury and disturbed lipid metabolism. Chorioamnionitis was induced in sheep by intra-amniotic injection of lipopolysaccharide (LPS) or saline at 90, 100 and 110 days of gestation. Liver homeostasis and lipid metabolism were analyzed at term and at 7 weeks of age. At term, hepatic T-lymphocytes and apoptotic hepatocytes were increased. In addition, hepatic cholesterol and triglyceride levels were decreased in LPS-exposed animals compared with controls. At 7 weeks of age, no hepatic inflammation could be detected. However, liver triglycerides and plasma cholesterol levels were increased in LPS-exposed animals relative to controls. The changes in lipid levels at 7 weeks of age were associated with increased leptin receptor mRNA levels, increased lipid peroxidation, increased expression of cytochrome c oxidase subunit 4 as a marker for mitochondrial function and increased circulating ceramide levels. These findings demonstrate that chorioamnionitis-mediated antenatal inflammation-related liver disturbances have long-lasting postnatal effects on lipid metabolism.

[Primary cutaneous peripheral T-cell lymphoma (not otherwise specified)]. / Primär kutanes peripheres T-Zell-Lymphom (nicht anderweitig spezifiziert).

Peripheral cutaneous T-cell lymphoma which cannot be further classified due to high morphological and molecular variability are included into the group of "primary cutaneous peripheral T-cell lymphoma--not otherwise specified" (PCTL-NOS). PCTL-NOS represent a rare, heterogeneous group characterized by rapidly progressive nodules in the absence of typical mycosis fungoides plaques. Furthermore, therapeutic options are limited and prognosis is rather poor. We report on a 62-year-old patient presenting with asymptomatic papules in the popliteal and antecubital fossae. Based on histopathological criteria, PCTL-NOS was diagnosed. Based on recent gene expression studies, a positive reaction to tyrosine kinase and histone deacetylase inhibitors is hoped for.

Cavitating mesenteric lymph node syndrome: a rare complication of refractory celiac disease.

Celiac disease is an immune-mediated enteropathy characterized by mucosal inflammation and villous atrophy of the small bowel upon exposure to ingested gluten. Refractory celiac disease (RCD), defined as persisting villous atrophy with crypt hyperplasia despite strict gluten-free diet, is a rare form of celiac disease with poor prognosis due to a higher rate of severe complications such as life-threatening malnutrition or the development of intestinal T-cell lymphoma. The cavitating mesenteric lymph node syndrome (CMLNS) represents a rare complication of celiac disease with unknown pathogenesis which is associated with but not restricted to RCD and not necessarily associated with a malignant course. We here report a 64-year-old patient who was referred to us with a history of refractory celiac disease. During further diagnostic work-up multiple intraabdominal cystic structures were detected by a computed tomography scan and magnetic resonance imaging. A laparotomy was performed to exclude T-cell lymphoma. Histology of the intraabdominal cysts revealed the diagnosis of cavitating mesenteric lymph node syndrome as the underlying cause of the masses. Steroid therapy was initiated which led to complete regression of diarrhoea but did not induce a diminution of mesenteric lymph nodes. Three years after the diagnosis of CMLNS, the patient presented with an acute abdomen due to a small bowel perforation caused by an enteropathy associated T-cell lymphoma. We discuss the differential diagnoses of intraabdominal masses in celiac disease and review the current literature on CMLNS.