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1.  Caspase-8 controls the gut response to microbial challenges by Tnf-α-dependent and independent pathways 
Gut  2014;64(4):601-610.
Intestinal epithelial cells (IEC) express toll-like receptors (TLR) that facilitate microbial recognition. Stimulation of TLR ligands induces a transient increase in epithelial cell shedding, a mechanism that serves the antibacterial and antiviral host defence of the epithelium and promotes elimination of intracellular pathogens. Although activation of the extrinsic apoptosis pathway has been described during inflammatory shedding, its functional involvement is currently unclear.
We investigated the functional involvement of caspase-8 signalling in microbial-induced intestinal cell shedding by injecting Lipopolysaccharide (LPS) to mimic bacterial pathogens and poly(I:C) as a probe for RNA viruses in vivo.
TLR stimulation of IEC was associated with a rapid activation of caspase-8 and increased epithelial cell shedding. In mice with an epithelial cell-specific deletion of caspase-8 TLR stimulation caused Rip3-dependent epithelial necroptosis instead of apoptosis. Mortality and tissue damage were more severe in mice in which IECs died by necroptosis than apoptosis. Inhibition of receptor-interacting protein (Rip) kinases rescued the epithelium from TLR-induced gut damage. TLR3-induced necroptosis was directly mediated via TRIF-dependent pathways, independent of Tnf-α and type III interferons, whereas TLR4-induced tissue damage was critically dependent on Tnf-α.
Together, our data demonstrate an essential role for caspase-8 in maintaining the gut barrier in response to mucosal pathogens by permitting inflammatory shedding and preventing necroptosis of infected cells. These data suggest that therapeutic strategies targeting the cell death machinery represent a promising new option for the treatment of inflammatory and infective enteropathies.
PMCID: PMC4392221  PMID: 25379949
Apoptosis; TNF; Cell Biology; Cell Death; Intestinal Epithelium
2.  Activation of Intestinal Epithelial Stat3 Orchestrates Tissue Defense during Gastrointestinal Infection 
PLoS ONE  2015;10(3):e0118401.
Gastrointestinal infections with EHEC and EPEC are responsible for outbreaks of diarrheal diseases and represent a global health problem. Innate first-line-defense mechanisms such as production of mucus and antimicrobial peptides by intestinal epithelial cells are of utmost importance for host control of gastrointestinal infections. For the first time, we directly demonstrate a critical role for Stat3 activation in intestinal epithelial cells upon infection of mice with Citrobacter rodentium – a murine pathogen that mimics human infections with attaching and effacing Escherichia coli. C. rodentium induced transcription of IL-6 and IL-22 in gut samples of mice and was associated with activation of the transcription factor Stat3 in intestinal epithelial cells. C. rodentium infection induced expression of several antimicrobial peptides such as RegIIIγ and Pla2g2a in the intestine which was critically dependent on Stat3 activation. Consequently, mice with specific deletion of Stat3 in intestinal epithelial cells showed increased susceptibility to C. rodentium infection as indicated by high bacterial load, severe gut inflammation, pronounced intestinal epithelial cell death and dissemination of bacteria to distant organs. Together, our data implicate an essential role for Stat3 activation in intestinal epithelial cells during C. rodentium infection. Stat3 concerts the host response to bacterial infection by controlling bacterial growth and suppression of apoptosis to maintain intestinal epithelial barrier function.
PMCID: PMC4370566  PMID: 25799189
3.  Investigating the motivational behavior of pupils during outdoor science teaching within self-determination theory 
This paper presents data from a mixed-method pilot study (n = 84) searching into learning psychological aspects of an outdoor science teaching program. We use data from qualitative explorations into the pupils' learning motivation during field observation, a group interview, and open questionnaires, in order to understand quantitative measures from the Self-Determination Index (SDI), and the Practical Orientation (PO) of the program. Our data suggest that lower self-regulated pupils in “normal” science classes show a significantly higher self-regulated learning motivational behavior in the outdoor educational setting (p < 10−4), and that the outdoor-teaching has generally been perceived as more practical than teaching at the normal school context (p < 10−4), irrespective of gender or school culture. We are going to provide in-depth analyses of all quantitative findings with our qualitative data and thus explain the findings logically, with respect to the direction of the statistical interpretation, and substantially, with respect to the meaning of the discoveries. We conclude that outdoor programming appears to be a suitable tool to trigger interest in science in youngsters, especially for less motivated pupils.
PMCID: PMC4331641  PMID: 25741301
outdoor teaching; science teaching; self-determination theory; motivation
4.  FDG-PET/CT pitfalls in oncological head and neck imaging 
Insights into Imaging  2014;5(5):585-602.
Positron emission tomography-computed tomography (PET/CT) with fluorine-18-fluorodeoxy-D-glucose (FDG) has evolved from a research modality to an invaluable tool in head and neck cancer imaging. However, interpretation of FDG PET/CT studies may be difficult due to the inherently complex anatomical landmarks, certain physiological variants and unusual patterns of high FDG uptake in the head and neck. The purpose of this article is to provide a comprehensive approach to key imaging features and interpretation pitfalls of FDG-PET/CT of the head and neck and how to avoid them.
We review the pathophysiological mechanisms leading to potentially false-positive and false-negative assessments, and we discuss the complementary use of high-resolution contrast-enhanced head and neck PET/CT (HR HN PET/CT) and additional cross-sectional imaging techniques, including ultrasound (US) and magnetic resonance imaging (MRI).
The commonly encountered false-positive PET/CT interpretation pitfalls are due to high FDG uptake by physiological causes, benign thyroid nodules, unilateral cranial nerve palsy and increased FDG uptake due to inflammation, recent chemoradiotherapy and surgery. False-negative findings are caused by lesion vicinity to structures with high glucose metabolism, obscuration of FDG uptake by dental hardware, inadequate PET scanner resolution and inherent low FDG-avidity of some tumours.
The interpreting physician must be aware of these unusual patterns of FDG uptake, as well as limitations of PET/CT as a modality, in order to avoid overdiagnosis of benign conditions as malignancy, as well as missing out on actual pathology.
Teaching points
• Knowledge of key imaging features of physiological and non-physiological FDG uptake is essential for the interpretation of head and neck PET/CT studies.
• Precise anatomical evaluation and correlation with contrast-enhanced CT, US or MRI avoid PET/CT misinterpretation.
• Awareness of unusual FDG uptake patterns avoids overdiagnosis of benign conditions as malignancy.
PMCID: PMC4195840  PMID: 25154759
Positron emission tomography-computed tomography (PET/CT); Pitfalls; Head and neck tumours
5.  Determination of Split Renal Function Using Dynamic CT-Angiography: Preliminary Results 
PLoS ONE  2014;9(3):e91774.
To determine the feasibility of a dynamic CT angiography-protocol with regard to simultaneous assessment of renal anatomy and function.
7 healthy potential kidney donors (58±7 years) underwent a dynamic computed tomography angiography (CTA) using a 128-slice CT-scanner with continuous bi-directional table movement, allowing the coverage of a scan range of 18 cm within 1.75 sec. Twelve scans of the kidneys (n = 14) were acquired every 3.5 seconds with the aim to simultaneously obtain CTA and renal function data. Image quality was assessed quantitatively (HU-measurements) and qualitatively (grade 1–4, 1 = best). The glomerular filtration rate (GFR) was calculated by a modified Patlak method and compared with the split renal function obtained with renal scintigraphy.
Mean maximum attenuation was 464±58 HU, 435±48 HU and 277±29 HU in the aorta, renal arteries, and renal veins, respectively. The abdominal aorta and all renal vessels were depicted excellently (grade 1.0). The image quality score for cortex differentiation was 1.6±0.49, for the renal parenchyma 2.4±0.49. GFR obtained from dynamic CTA correlated well with renal scintigraphy with a correlation coefficient of r = 0.84; P = 0.0002 (n = 14). The average absolute deviation was 1.6 mL/min. The average effective dose was 8.96 mSv.
Comprehensive assessment of renal anatomy and function is feasible using a single dynamic CT angiography examination. The proposed protocol may help to improve management in case of asymmetric kidney function as well as to simplify evaluation of potential living kidney donors.
PMCID: PMC3950217  PMID: 24618919
6.  Respiratory-Gated MRgHIFU in Upper Abdomen Using an MR-Compatible In-Bore Digital Camera 
BioMed Research International  2014;2014:421726.
Objective. To demonstrate the technical feasibility and the potential interest of using a digital optical camera inside the MR magnet bore for monitoring the breathing cycle and subsequently gating the PRFS MR thermometry, MR-ARFI measurement, and MRgHIFU sonication in the upper abdomen. Materials and Methods. A digital camera was reengineered to remove its magnetic parts and was further equipped with a 7 m long USB cable. The system was electromagnetically shielded and operated inside the bore of a closed 3T clinical scanner. Suitable triggers were generated based on real-time motion analysis of the images produced by the camera (resolution 640 × 480 pixels, 30 fps). Respiratory-gated MR-ARFI prepared MRgHIFU ablation was performed in the kidney and liver of two sheep in vivo, under general anaesthesia and ventilator-driven forced breathing. Results. The optical device demonstrated very good MR compatibility. The current setup permitted the acquisition of motion artefact-free and high resolution MR 2D ARFI and multiplanar interleaved PRFS thermometry (average SNR 30 in liver and 56 in kidney). Microscopic histology indicated precise focal lesions with sharply delineated margins following the respiratory-gated HIFU sonications. Conclusion. The proof-of-concept for respiratory motion management in MRgHIFU using an in-bore digital camera has been validated in vivo.
PMCID: PMC3925565  PMID: 24716196
7.  An experimental model to investigate the targeting accuracy of MR-guided focused ultrasound ablation in liver 
Magnetic Resonance-guided High Intensity Focused Ultrasound (MRgHIFU) is a hybrid technology that aims to offer non-invasive thermal ablation of targeted tumors or other pathological tissues. Acoustic aberrations and non-linear wave propagating effects may shift the focal point significantly away from the prescribed (or, theoretical) position. It is therefore mandatory to evaluate the spatial accuracy of ablation for a given HIFU protocol and/or device. We describe here a method for producing a user-defined ballistic target as an absolute reference marker for MRgHIFU ablations.
The investigated method is based on trapping a mixture of MR contrast agent and histology stain using radiofrequency (RF) ablation causing cell death and coagulation. A dedicated RF-electrode was used for the marker fixation as follows: a RF coagulation (4 W, 15 seconds) and injection of the mixture followed by a second RF coagulation. As a result, the contrast agent/stain is encapsulated in the intercellular space. Ultrasonography imaging was performed during the procedure, while high resolution T1w 3D VIBE MR acquisition was used right after to identify the position of the ballistic marker and hence the target tissue. For some cases, after the marker fixation procedure, HIFU volumetric ablations were produced by a phased-array HIFU platform. First ex vivo experiments were followed by in vivo investigation on four rabbits in thigh muscle and six pigs in liver, with follow-up at Day 7.
At the end of the procedure, no ultrasound indication of the marker’s presence could be observed, while it was clearly visible under MR and could be conveniently used to prescribe the HIFU ablation, centered on the so-created target. The marker was identified at Day 7 after treatment, immediately after animal sacrifice, after 3 weeks of post-mortem formalin fixation and during histology analysis. Its size ranged between 2.5 and 4 mm.
Experimental validation of this new ballistic marker method was performed for liver MRgHIFU ablation, free of any side effects (e.g. no edema around the marker, no infection, no bleeding). The study suggests that the absolute reference marker had ultrasound conspicuity below the detection threshold, was irreversible, MR-compatible and MR-detectable, while also being a well-established histology staining technique.
PMCID: PMC3901025  PMID: 24433332
MR guided HIFU; Ballistic marker; Tracer encapsulation; Targeting; Pre-clinical quality assurance
8.  Detection and quantification of focal uptake in head and neck tumours: 18F-FDG PET/MR versus PET/CT 
Our objectives were to assess the quality of PET images and coregistered anatomic images obtained with PET/MR, to evaluate the detection of focal uptake and SUV, and to compare these findings with those of PET/CT in patients with head and neck tumours.
The study group comprised 32 consecutive patients with malignant head and neck tumours who underwent whole-body 18F-FDG PET/MR and PET/CT. PET images were reconstructed using the attenuation correction sequence for PET/MR and CT for PET/CT. Two experienced observers evaluated the anonymized data. They evaluated image and fusion quality, lesion conspicuity, anatomic location, number and size of categorized (benign versus assumed malignant) lesions with focal uptake. Region of interest (ROI) analysis was performed to determine SUVs of lesions and organs for both modalities. Statistical analysis considered data clustering due to multiple lesions per patient.
PET/MR coregistration and image fusion was feasible in all patients. The analysis included 66 malignant lesions (tumours, metastatic lymph nodes and distant metastases), 136 benign lesions and 470 organ ROIs. There was no statistically significant difference between PET/MR and PET/CT regarding rating scores for image quality, fusion quality, lesion conspicuity or anatomic location, number of detected lesions and number of patients with and without malignant lesions. A high correlation was observed for SUVmean and SUVmax measured on PET/MR and PET/CT for malignant lesions, benign lesions and organs (ρ = 0.787 to 0.877, p < 0.001). SUVmean and SUVmax measured on PET/MR were significantly lower than on PET/CT for malignant tumours, metastatic neck nodes, benign lesions, bone marrow, and liver (p < 0.05). The main factor affecting the difference between SUVs in malignant lesions was tumour size (p < 0.01).
In patients with head and neck tumours, PET/MR showed equivalent performance to PET/CT in terms of qualitative results. Comparison of SUVs revealed an excellent correlation for measurements on both modalities, but underestimation of SUVs measured on PET/MR as compared to PET/CT.
PMCID: PMC3913851  PMID: 24108458
PET/MR; PET/CT; Hybrid imaging; Head and neck tumours; SUV
9.  N-acetylcysteine does not prevent contrast nephropathy in patients with renal impairment undergoing emergency CT: a randomized study 
BMC Nephrology  2013;14:119.
Patients admitted to the emergency room with renal impairment and undergoing a contrast computed tomography (CT) are at high risk of developing contrast nephropathy as emergency precludes sufficient hydration prior to contrast use. The value of an ultra-high dose of intravenous N-acetylcysteine in this setting is unknown.
From 2008 to 2010, we randomized 120 consecutive patients admitted to the emergency room with an estimated clearance lower than 60 ml/min/1.73 m2 by MDRD (mean GFR 42 ml/min/1.73 m2) to either placebo or 6000 mg N-acetylcysteine iv one hour before contrast CT in addition to iv saline. Serum cystatin C and creatinine were measured one hour prior to and at day 2, 4 and 10 after contrast injection. Nephrotoxicity was defined either as 25% or 44 μmol/l increase in serum creatinine or cystatin C levels compared to baseline values.
Contrast nephrotoxicity occurred in 22% of patients who received placebo (13/58) and 27% of patients who received N-acetylcysteine (14/52, p = 0.66). Ultra-high dose intravenous N-acetylcysteine did not alter creatinine or cystatin C levels. No secondary effects were noted within the 2 groups during follow-up.
An ultra-high dose of intravenous N-acetylcysteine is ineffective at preventing nephrotoxicity in patients with renal impairment undergoing emergency contrast CT.
Trial registration
The study was registered as Clinical trial (NCT01467154).
PMCID: PMC3682900  PMID: 23731573
Computerized Tomography; Contrast media; Emergency medicine; N-acetylcysteine; Nephrotoxicity
10.  Confocal Laser Endomicroscopy for In Vivo Diagnosis of Clostridium difficile Associated Colitis — A Pilot Study 
PLoS ONE  2013;8(3):e58753.
Clostridium difficile infection (CDI) is one of the most dreaded causes of hospital-acquired diarrhea. Main objective was to investigate whether confocal laser endomicroscopy (CLE) has the capability for in vivo diagnosis of C. difficile associated histological changes. Second objective was to prove the presence of intramucosal bacteria using CLE.
80 patients were prospectively included, 10 patients were diagnosed with CDI based on toxigenic culture. To validate the presence of intramucosal bacteria ex vivo, CLE was performed in pure C. difficile culture; additionally fluorescence in situ hybridization (FISH) was performed. Finally, CLE with fluorescence labelled oligonucleotide probe specific for C. difficile was performed ex vivo in order to prove the presence of bacteria.
CLE identified CDI-associated histological changes in vivo (sensitivity and accuracy of 88.9% and 96.3%). In addition, intramucosal bacteria were visualized. The presence of these bacteria could be proven by CLE with labeled, specific molecular C. difficile probe and FISH-technique. Based on comparison between CLE and FISH analyses, sensitivity and specificity for the presence of intramucosal bacteria were 100%.
CLE has the potential for in vivo diagnosis of CDI associated colitis. In addition, CLE allowed the detection of intramucosal bacteria in vivo.
PMCID: PMC3602426  PMID: 23527018
11.  Tumor fibroblast–derived epiregulin promotes growth of colitis-associated neoplasms through ERK 
The Journal of Clinical Investigation  2013;123(4):1428-1443.
Molecular mechanisms specific to colitis-associated cancers have been poorly characterized. Using comparative whole-genome expression profiling, we observed differential expression of epiregulin (EREG) in mouse models of colitis-associated, but not sporadic, colorectal cancer. Similarly, EREG expression was significantly upregulated in cohorts of patients with colitis-associated cancer. Furthermore, tumor-associated fibroblasts were identified as a major source of EREG in colitis-associated neoplasms. Functional studies showed that Ereg-deficient mice, although more prone to colitis, were strongly protected from colitis-associated tumors. Serial endoscopic studies revealed that EREG promoted tumor growth rather than initiation. Additionally, we demonstrated that fibroblast-derived EREG requires ERK activation to induce proliferation of intestinal epithelial cells (IEC) and tumor development in vivo. To demonstrate the functional relevance of EREG-producing tumor-associated fibroblasts, we developed a novel system for adoptive transfer of these cells via mini-endoscopic local injection. It was found that transfer of EREG-producing, but not Ereg-deficient, fibroblasts from tumors significantly augmented growth of colitis-associated neoplasms in vivo. In conclusion, our data indicate that EREG and tumor-associated fibroblasts play a crucial role in controlling tumor growth in colitis-associated neoplasms.
PMCID: PMC3613905  PMID: 23549083
12.  Autologous Bone Marrow Mononuclear Cell Transplantation in Patients with Decompensated Alcoholic Liver Disease: A Randomized Controlled Trial 
PLoS ONE  2013;8(1):e53719.
Impaired liver regeneration is associated with a poor outcome in patients with decompensated alcoholic liver disease (ALD). We assessed whether autologous bone marrow mononuclear cell transplantation (BMMCT) improved liver function in decompensated ALD.
58 patients (mean age 54 yrs; mean MELD score 19, all with cirrhosis, 81% with alcoholic steatohepatitis at baseline liver biopsy) were randomized early after hospital admission to standard medical therapy (SMT) alone (n = 30), including steroids in patients with a Maddrey’s score ≥32, or combined with G-CSF injections and autologous BMMCT into the hepatic artery (n = 28). Bone marrow cells were harvested, isolated and reinfused the same day. The primary endpoint was a ≥3 points decrease in the MELD score at 3 months, corresponding to a clinically relevant improvement in liver function. Liver biopsy was repeated at week 4 to assess changes in Ki67+/CK7+ hepatic progenitor cells (HPC) compartment.
Both study groups were comparable at baseline. After 3 months, 2 and 4 patients died in the BMMCT and SMT groups, respectively. Adverse events were equally distributed between groups. Moderate alcohol relapse occurred in 31% of patients. The MELD score improved in parallel in both groups during follow-up with 18 patients (64%) from the BMMCT group and 18 patients (53%) from the SMT group reaching the primary endpoint (p = 0.43 (OR 1.6, CI 0.49–5.4) in an intention to treat analysis. Comparing liver biopsy at 4 weeks to baseline, steatosis improved (p<0.001), and proliferating HPC tended to decrease in both groups (−35 and −33%, respectively).
Autologous BMMCT, compared to SMT is a safe procedure but did not result in an expanded HPC compartment or improved liver function. These data suggest either insufficient regenerative stimulation after BMMCT or resistance to liver regenerative drive in patients with decompensated alcoholic cirrhosis.
Trial Registration ISRCTN83972743.
PMCID: PMC3544843  PMID: 23341981
13.  SPECT myocardial perfusion imaging as an adjunct to coronary calcium score for the detection of hemodynamically significant coronary artery stenosis 
Coronary artery calcifications (CAC) are markers of coronary atherosclerosis, but do not correlate well with stenosis severity. This study intended to evaluate clinical situations where a combined approach of coronary calcium scoring (CS) and nuclear stress test (SPECT-MPI) is useful for the detection of relevant CAD.
Patients with clinical indication for invasive coronary angiography (ICA) were included into our study during 08/2005-09/2008. At first all patients underwent CS procedure as part of the study protocol performed by either using a multidetector computed tomography (CT) scanner or a dual-source CT imager. CAC were automatically defined by dedicated software and the Agatston score was semi-automatically calculated. A stress-rest SPECT-MPI study was performed afterwards and scintigraphic images were evaluated quantitatively. Then all patients underwent ICA. Thereby significant CAD was defined as luminal stenosis ≥75% in quantitative coronary analysis (QCA) in ≥1 epicardial vessel. To compare data lacking Gaussian distribution an unpaired Wilcoxon-Test (Mann–Whitney) was used. Otherwise a Students t-test for unpaired samples was applied. Calculations were considered to be significant at a p-value of <0.05.
We consecutively included 351 symptomatic patients (mean age: 61.2±12.3 years; range: 18–94 years; male: n=240) with a mean Agatston score of 258.5±512.2 (range: 0–4214). ICA verified exclusion of significant CAD in 66/67 (98.5%) patients without CAC. CAC was detected in remaining 284 patients. In 132/284 patients (46.5%) with CS>0 significant CAD was confirmed by ICA, and excluded in 152/284 (53.5%) patients. Sensitivity for CAD detection by CS alone was calculated as 99.2%, specificity was 30.3%, and negative predictive value was 98.5%. An additional SPECT in patients with CS>0 increased specificity to 80.9% while reducing sensitivity to 87.9%. Diagnostic accuracy was 84.2%.
In patients without CS=0 significant CAD can be excluded with a high negative predictive value by CS alone. An additional SPECT-MPI in those patients with CS>0 leads to a high diagnostic accuracy for the detection of CAD while reducing the number of patients needing invasive diagnostic procedure.
PMCID: PMC3527199  PMID: 23206557
Computed tomography coronary calcium scoring; Single photon emission computed tomography myocardial perfusion imaging; Invasive coronary angiography; Coronary artery disease
14.  Evaluation of a handheld creatinine measurement device for real-time determination of serum creatinine in radiology departments 
World Journal of Radiology  2012;4(7):328-334.
AIM: To assess the feasibility/accuracy of a commercial handheld device in the context of increased demand for point-of-care serum creatinine (SCr) determination.
METHODS: In this institutional review board-approved, prospective study, 401 patients referred for contrast-enhanced computed tomography were included at two centres. Capillary (c)SCr was determined using two devices A+B and venous (v)SCr was determined in the centre’s laboratory. Method comparison statistics for both centres and for vSCr<>1.2 mg/dL, receiver operating characteristic analysis, negative predictive values (NPV), sensitivity and specificity were calculated pre-/post-curve offset correction with vSCr.
RESULTS: Pearson’s coefficients for cSCr vs vSCr were: centre 1-A:0.93/B:0.92; centre 2-A:0.85/B:0.82 (all P < 0.0001). Overall correlation was better for vSCr > 1.2 mg/dL. The area under the receiver operating characteristic curves showed a high accuracy for cSCr, but the device underestimated SCr, which was confirmed by Bland-Altman plot. Addition of the offset correction factor to the original data from centre 1 resulted in an improvement in sensitivity for detecting patients at risk (> 1.2 mg/dL), whilst maintaining acceptable specificity and improving NPV.
CONCLUSION: This study showed the feasibility of SCr determination using the evaluated handheld device in a routine clinical setting. The device showed high sensitivity and high NPV, but may significantly underestimate SCr without offset correction to local laboratories.
PMCID: PMC3419870  PMID: 22900135
Contrast-medium-induced nephropathy; Nephrogenic systemic fibrosis; Point of care testing; Serum creatinine determination; StatSensor
15.  Colovesical fistula causing an uncommon reason for failure of computed tomography colonography: a case report 
Computed tomography colonography, or virtual colonoscopy, is a good alternative to optical colonoscopy. However, suboptimal patient preparation or colon distension may reduce the diagnostic accuracy of this imaging technique.
Case presentation
We report the case of an 83-year-old Caucasian woman who presented with a five-month history of pneumaturia and fecaluria and an acute episode of macrohematuria, leading to a high clinical suspicion of a colovesical fistula. The fistula was confirmed by standard contrast-enhanced computed tomography. Optical colonoscopy was performed to exclude the presence of an underlying colonic neoplasm. Since optical colonoscopy was incomplete, computed tomography colonography was performed, but also failed due to inadequate colon distension. The insufflated air directly accumulated within the bladder via the large fistula.
Clinicians should consider colovesical fistula as a potential reason for computed tomography colonography failure.
PMCID: PMC3423059  PMID: 22823906
16.  Caspase-8 regulates TNF-alpha induced epithelial necroptosis and terminal ileitis 
Nature  2011;477(7364):335-339.
Dysfunction of the intestinal epithelium is believed to result in excessive translocation of commensal bacteria into the bowel wall that drives chronic mucosal inflammation in Crohn's disease; an incurable inflammatory bowel disease in humans characterized by inflammation of the terminal ileum1. Beside the physical barrier established by the tight contact of cells, specialized epithelial cells such as Paneth cells and goblet cells provide innate immune defence functions by secreting mucus and antimicrobial peptides which hamper access and survival of bacteria adjacent to the epithelium2. Epithelial cell death is a hallmark of intestinal inflammation and has been discussed as a pathogenic mechanism driving Crohn's disease (CD) in humans3. However, the regulation of epithelial cell death and its role in intestinal homeostasis remains poorly understood.
Here we demonstrate a critical role for caspase-8 in regulating necroptosis of intestinal epithelial cells (IEC) and terminal ileitis. Mice with a conditional deletion of caspase-8 in the intestinal epithelium (Casp8ΔIEC) spontaneously developed inflammatory lesions in the terminal ileum and were highly susceptible to colitis. Casp8ΔIEC mice lacked Paneth cells and showed reduced numbers of goblet cells suggesting dysregulated anti-microbial immune cell functions of the intestinal epithelium. Casp8ΔIEC mice showed increased cell death in the Paneth cell area of small intestinal crypts. Epithelial cell death was induced by tumor necrosis factor (TNF) -α, was associated with increased expression of receptor-interacting protein 3 (RIP3) and could be inhibited upon blockade of necroptosis. Finally, we identified high levels of RIP3 in human Paneth cells and increased necroptosis in the terminal ileum of patients with Crohn's disease, suggesting a potential role of necroptosis in the pathogenesis of this disease. Taken together, our data demonstrate a critical function of caspase-8 in regulating intestinal homeostasis and in protecting IEC from TNF-α induced necroptotic cell death.
PMCID: PMC3373730  PMID: 21921917
17.  Pancreatic magnetic resonance imaging after manganese injection distinguishes type 2 diabetic and normoglycemic patients 
Islets  2012;4(3):243-248.
A non-invasive method to image the mass and/or function of human pancreatic islets is needed to monitor the progression of diabetes, and the effect of therapeutic interventions. As yet, no method is available for this purpose, which could be applied to in situ human islets. Animal and in vitro studies have documented that manganese infusion could improve the magnetic resonance imaging (MRI) of the endocrine pancreas. Here, we have tested whether a similar approach could discriminate diabetic and non-diabetic patients. In vitro, human isolated islets readily incorporated manganese. In vivo, 243 manganese-enhanced magnetic resonance imaging (MEMRI) examinations were reviewed, including 41 examinations which were run on 24 patients with type 2 diabetes and 202 examinations which were run on 119 normoglycemic patients. The results show that MEMRI discriminates type 2 diabetics from non-diabetic patients, based on the signal enhancement of pancreas.
PMCID: PMC3442822  PMID: 22722479
MEMRI; MRI; diabetes; imaging; manganese
18.  Lack of Intestinal Epithelial Atg7 Affects Paneth Cell Granule Formation but Does Not Compromise Immune Homeostasis in the Gut 
Genetic polymorphisms of autophagy-related genes have been associated with an increased risk to develop inflammatory bowel disease (IBD). Autophagy is an elementary process participating in several cellular events such as cellular clearance and nonapoptotic programmed cell death. Furthermore, autophagy may be involved in intestinal immune homeostasis due to its participation in the digestion of intracellular pathogens and in antigen presentation. In the present study, the role of autophagy in the intestinal epithelial layer was investigated. The intestinal epithelium is essential to maintain gut homeostasis, and defects within this barrier have been associated with the pathogenesis of IBD. Therefore, mice with intestinal epithelial deletion of Atg7 were generated and investigated in different mouse models. Knockout mice showed reduced size of granules and decreased levels of lysozyme in Paneth cells. However, this was dispensable for gut immune homeostasis and had no effect on susceptibility in mouse models of experimentally induced colitis.
PMCID: PMC3265132  PMID: 22291845
19.  VEGF receptor signaling links inflammation and tumorigenesis in colitis-associated cancer 
The Journal of Experimental Medicine  2010;207(13):2855-2868.
Inflammation drives expression of VEGFR2, which is expressed on and drives growth of tumor cells in colitis-associated cancer.
Whereas the inhibition of vascular endothelial growth factor (VEGF) has shown promising results in sporadic colon cancer, the role of VEGF signaling in colitis-associated cancer (CAC) has not been addressed. We found that, unlike sporadic colorectal cancer and control patients, patients with CAC show activated VEGFR2 on intestinal epithelial cells (IECs). We then explored the function of VEGFR2 in a murine model of colitis-associated colon cancer characterized by increased VEGFR2 expression. Epithelial cells in tumor tissue expressed VEGFR2 and responded to VEGF stimulation with augmented VEGFR2-mediated proliferation. Blockade of VEGF function via soluble decoy receptors suppressed tumor development, inhibited tumor angiogenesis, and blocked tumor cell proliferation. Functional studies revealed that chronic inflammation leads to an up-regulation of VEGFR2 on IECs. Studies in conditional STAT3 mutant mice showed that VEGFR signaling requires STAT3 to promote epithelial cell proliferation and tumor growth in vivo. Thus, VEGFR-signaling acts as a direct growth factor for tumor cells in CAC, providing a molecular link between inflammation and the development of colon cancer.
PMCID: PMC3005238  PMID: 21098094
20.  Critical role of the disintegrin metalloprotease ADAM17 for intestinal inflammation and regeneration in mice 
The Journal of Experimental Medicine  2010;207(8):1617-1624.
The protease a disintegrin and metalloprotease (ADAM) 17 cleaves tumor necrosis factor (TNF), L-selectin, and epidermal growth factor receptor (EGF-R) ligands from the plasma membrane. ADAM17 is expressed in most tissues and is up-regulated during inflammation and cancer. ADAM17-deficient mice are not viable. Conditional ADAM17 knockout models demonstrated proinflammatory activities of ADAM17 in septic shock via shedding of TNF. We used a novel gene targeting strategy to generate mice with dramatically reduced ADAM17 levels in all tissues. The resulting mice called ADAM17ex/ex were viable, showed compromised shedding of ADAM17 substrates from the cell surface, and developed eye, heart, and skin defects as a consequence of impaired EGF-R signaling caused by failure of shedding of EGF-R ligands. Unexpectedly, although the intestine of unchallenged homozygous ADAM17ex/ex mice was normal, ADAM17ex/ex mice showed substantially increased susceptibility to inflammation in dextran sulfate sodium colitis. This was a result of impaired shedding of EGF-R ligands resulting in failure to phosphorylate STAT3 via the EGF-R and, consequently, in defective regeneration of epithelial cells and breakdown of the intestinal barrier. Besides regulating the systemic availability of the proinflammatory cytokine TNF, our results demonstrate that ADAM17 is needed for vital regenerative activities during the immune response. Thus, our mouse model will help investigate ADAM17 as a potential drug target.
PMCID: PMC2916135  PMID: 20603312
21.  The T‐box transcription factor eomesodermin controls CD8 T cell activity and lymph node metastasis in human colorectal cancer 
Gut  2007;56(11):1572-1578.
An efficient cytolytic T cell function is essential for immune mediated rejection of colorectal cancer. However, the molecular mechanisms driving T cell mediated cancer rejection are still poorly understood. Here, we assessed the relevance of the T‐box transcription factor eomesodermin in colorectal cancer.
By analysing tissue probes from 88 different colorectal tumours, a significant (p<0.02) inverse correlation between eomesodermin expression in colorectal cancers and the presence of lymph node metastases could be shown, whereas no such correlation was noted for the master transcription factor of regulatory T cells, FoxP3 and CD8alpha expression. To evaluate whether this effect might be due to effects of eomesodermin on tumour infiltrating CD8 T cells, we subsequently analysed the regulated expression and function of this transcription factor in human T cells. Whereas overexpression of this factor induced perforin but not granzyme expression, siRNA mediated suppression of eomesodermin expression led to significantly reduced IFN‐γ production, perforin levels and cytolytic activity of CD8 T cells. Furthermore, TGF‐β and IL4 could be identified as important inducer of eomesodermin expression.
These data define for the first time a regulatory role of eomesodermin for CD8 T cell activity in humans. Our findings are consistent with a model in which eomesodermin expression in tumour infiltrating T cells regulates cytolytic functions of CD8 T cells via perforin expression. These data provide novel insights into control mechanisms governing the functional activity of human CD8 T lymphocytes via T‐box transcription factors in cancer.
PMCID: PMC2095672  PMID: 17566017
cytokines; eomesodermin; colorectal cancer
22.  Computed tomography of complicated Meckel’s diverticulum in adults: a pictorial review 
Insights into Imaging  2010;1(2):53-61.
To show various CT aspects of complicated Meckel’s diverticulum in adult patients to facilitate the preoperative diagnosis of this rare pathology in emergency settings.
A computer search of medical records over a 15 year period identified 23 adult patients who underwent surgery for acute abdomen generated by a complicated Meckel’s diverticulum. CT images available for review were analyzed, and some specific patterns leading to the diagnosis of complicated Meckel’s diverticulum are presented in this review.
Complications were related to inflammation (14 patients), bleeding (5 patients), intestinal obstruction (3 patients), and penetrating foreign body (1 patient). The presence of a Meckel’s diverticulum was usually suggested at CT scan by an abnormal outpouching, blind-ending digestive structure connected to the terminal ileum by a neck of variable caliber. Depending on the type of complications, the diverticulum was surrounded by mesenteric inflammatory changes, or presented as a localized fluid or air-fluid collection contiguous with the terminal ileum. The diverticulum was also the source of active bleeding or acted as the lead point to intestinal obstruction or intussusception.
CT findings of complicated Meckel’s diverticulum are polymorphic and should be considered in the evaluation of adult patients with acute abdomen.
PMCID: PMC3259399  PMID: 22347905
Meckel’s diverticulum; Computed tomography; Acute abdomen; Complications; Bowel
23.  Computed tomography of complicated Meckel’s diverticulum in adults: a pictorial review 
Insights into Imaging  2010;1(2):53-61.
To show various CT aspects of complicated Meckel’s diverticulum in adult patients to facilitate the preoperative diagnosis of this rare pathology in emergency settings.
A computer search of medical records over a 15 year period identified 23 adult patients who underwent surgery for acute abdomen generated by a complicated Meckel’s diverticulum. CT images available for review were analyzed, and some specific patterns leading to the diagnosis of complicated Meckel’s diverticulum are presented in this review.
Complications were related to inflammation (14 patients), bleeding (5 patients), intestinal obstruction (3 patients), and penetrating foreign body (1 patient). The presence of a Meckel’s diverticulum was usually suggested at CT scan by an abnormal outpouching, blind-ending digestive structure connected to the terminal ileum by a neck of variable caliber. Depending on the type of complications, the diverticulum was surrounded by mesenteric inflammatory changes, or presented as a localized fluid or air-fluid collection contiguous with the terminal ileum. The diverticulum was also the source of active bleeding or acted as the lead point to intestinal obstruction or intussusception.
CT findings of complicated Meckel’s diverticulum are polymorphic and should be considered in the evaluation of adult patients with acute abdomen.
PMCID: PMC3259399  PMID: 22347905
Meckel’s diverticulum; Computed tomography; Acute abdomen; Complications; Bowel
24.  Smad7 in T cells drives T helper 1 responses in multiple sclerosis and experimental autoimmune encephalomyelitis 
Brain  2010;133(4):1067-1081.
Autoreactive CD4+ T lymphocytes play a vital role in the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. Since the discovery of T helper 17 cells, there is an ongoing debate whether T helper 1, T helper 17 or both subtypes of T lymphocytes are important for the initiation of autoimmune neuroinflammation. We examined peripheral blood CD4+ cells from patients with active and stable relapsing–remitting multiple sclerosis, and used mice with conditional deletion or over-expression of the transforming growth factor-β inhibitor Smad7, to delineate the role of Smad7 in T cell differentiation and autoimmune neuroinflammation. We found that Smad7 is up-regulated in peripheral CD4+ cells from patients with multiple sclerosis during relapse but not remission, and that expression of Smad7 strongly correlates with T-bet, a transcription factor defining T helper 1 responses. Concordantly, mice with transgenic over-expression of Smad7 in T cells developed an enhanced disease course during experimental autoimmune encephalomyelitis, accompanied by elevated infiltration of inflammatory cells and T helper 1 responses in the central nervous system. On the contrary, mice with a T cell-specific deletion of Smad7 had reduced disease and central nervous system inflammation. Lack of Smad7 in T cells blunted T cell proliferation and T helper 1 responses in the periphery but left T helper 17 responses unaltered. Furthermore, frequencies of regulatory T cells were increased in the central nervous system of mice with a T cell-specific deletion and reduced in mice with a T cell-specific over-expression of Smad7. Downstream effects of transforming growth factor-β on in vitro differentiation of naïve T cells to T helper 1, T helper 17 and regulatory T cell phenotypes were enhanced in T cells lacking Smad7. Finally, Smad7 was induced during T helper 1 differentiation and inhibited during T helper 17 differentiation. Taken together, the level of Smad7 in T cells determines T helper 1 polarization and regulates inflammatory cellular responses. Since a Smad7 deletion in T cells leads to immunosuppression, Smad7 may be a potential new therapeutic target in multiple sclerosis.
PMCID: PMC2850583  PMID: 20354004
EAE; multiple sclerosis; immune regulation; T cell responses; T helper 1
25.  Spontaneous dissection of the superior mesenteric artery and the right hepatic artery: a case report 
Isolated spontaneous dissection of the superior mesenteric artery is a very rare condition. Endovascular stent placement has been proposed recently for selected cases, which has led to some good clinical results.
Case presentation
We report a case of spontaneous dissection of the superior mesenteric artery spreading to the origin of a right hepatic artery in a 48-year-old Chinese man. He benefited from the placement of an endovascular stent that yielded excellent results.
Endovascular stent placement is a good alternative treatment for dissection of the superior mesenteric artery. We propose an algorithm for the management of this rare condition.
PMCID: PMC2848679  PMID: 20233417

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