[Management of thyroid carcinoma arising from thyroglossal duct cyst]. / Vorgehen bei Schilddrüsenkarzinomen in einer medianen Halszyste.

Thyroid carcinoma presenting within thyroglossal duct remnants is rarely reported. Mostly diagnosis is received postoperatively after resection of the cyst. No definite agreement exists regarding the therapeutical management after excision of the cyst especially concerning the necessity of total thyroidectomy and radioiodine therapy. A series of five cases is presented and relevant literature is reviewed.A retrospective review of all patients with thyroglossal duct cyst carcinoma treated between 2002 und 2017 was performed. Out of 578 patients with a thyroglossal duct cyst in five (3 women and 2 men) in the age of 16-73 years (mean: 51, median: 56 years) a thyroidal carcinoma could be identified. All of them presented with a painless hyoidal swelling. Diagnosis was made in all cases after surgery, but in one case, malignancy was presumed in the preoperative MRI. Papillary thyroid carcinoma was found in all samples. Four of the patients underwent total thyroidectomy and radioiodine therapy, in two of them a neck dissection of medial and lateral compartment was performed. The last patient withdrew from further diagnostics and therapy.In all four samples, no carcinoma of the thyroidal gland or nodal metastasis was found. Due to the rare occurrence of thyroidal carcinoma in thyroglossal duct cysts, therapeutical management is controversial.Stratification of patients to risk groups should be used to identify patients, who would benefit from an additional thyroidectomy. Prognosis is excellent.

Novel score predicts risk for cytomegalovirus infection in ulcerative colitis.

BACKGROUND: Cytomegalovirus (CMV) infection is associated with relapse and exacerbation of ulcerative colitis (UC), especially in immunosuppressed patients. OBJECTIVES: The aim of this study was to identify risk factors for CMV colitis and to develop a predictive risk score to estimate the probability of CMV colitis in UC patients supporting clinical decision making. STUDY DESIGN: A cohort of 239 UC-patients was retrospectively analyzed. Univariate and multivariate regression analysis identified several independent risk factors for CMV colitis and a predictive risk score was established using ROC analysis. RESULTS: CMV colitis is common in patients with severe ulcerative colitis. Clinical UC activity, disease duration and extent as well as the use of steroids and anti-TNF-α agents were identified as risk factors (p < 0.05 each). Based on five predictive parameters, a web-based risk score was developed. A strong correlation between the predicted and actual rates of CMV colitis was found (AUC: 0.855; 95% CI 0.79-0.92; p < 0.0001). CONCLUSIONS: Our study supports the pathogenic relevance of CMV in UC. The predictive risk score estimates the risk of CMV colitis and might aid in clinical decision making, especially when timely modifications of therapeutic regimens are needed and reliable diagnostic tools are not readily available.

Detection and characterization of murine colitis and carcinogenesis by molecularly targeted contrast-enhanced ultrasound.

AIM: To study mucosal addressin cellular adhesion molecule-1 (MAdCAM-1) and vascular endothelial growth factor (VEGF)-targeted contrast enhanced ultrasound (CEUS) for the assessment of murine colitis and carcinogenesis. METHODS: C57BL/6 mice were challenged with 3% dextran sodium-sulfate (DSS) for three, six or nine days to study the development of acute colitis. Ultrasound was performed with and without the addition of unspecific contrast agents. MAdCAM-1-targeted contrast agent was used to detect and quantify MAdCAM-1 expression. Inflammatory driven colorectal azoxymethane (AOM)/DSS-induced carcinogenesis was examined on day 42 and 84 using VEGF-targeted contrast agent. Highly specific tissue echogenicity was quantified using specialized software. Sonographic findings were correlated to tissue staining, western blot analysis and immunohistochemistry to quantify the degree of inflammation and stage of carcinogenesis. RESULTS: Native ultrasound detected increased general bowel wall thickening that correlated with more progressed and more severe DSS-colitis (healthy mice: 0.3 mm ± 0.03 vs six days DSS: 0.5 mm ± 0.2 vs nine days DSS: 0.6 mm ± 0.2, P < 0.05). Moreover, these sonographic findings correlated well with clinical parameters such as weight loss (r2 = 0.74) and histological damage (r2 = 0.86) (P < 0.01). In acute DSS-induced murine colitis, CEUS targeted against MAdCAM-1 detected and differentiated stages of mild, moderate and severe colitis via calculation of mean pixel contrast intensity in decibel (9.6 dB ± 1.6 vs 12.9 dB ± 1.4 vs 18 dB ± 3.33, P < 0.05). Employing the AOM/DSS-induced carcinogenesis model, tumor development was monitored by CEUS targeted against VEGF and detected a significantly increased echogenicity in tumors as compared to adjacent healthy mucosa (healthy mucosa, 1.6 dB ± 1.4 vs 42 d, 18.2 dB ± 3.3 vs 84 d, 18.6 dB ± 4.9, P < 0.01). Tissue echogenicity strongly correlated with histological analysis and immunohistochemistry findings (VEGF-positive cells in 10 high power fields of healthy mucosa: 1 ± 1.2 vs 42 d after DSS start: 2.4 ± 1.6 vs 84 d after DSS start: 3.5 ± 1.3, P < 0.01). CONCLUSION: Molecularly targeted CEUS is a highly specific and non-invasive imaging modality, which characterizes murine intestinal inflammation and carcinogenesis in vivo.

Multimodal Quantitative Phase Imaging with Digital Holographic Microscopy Accurately Assesses Intestinal Inflammation and Epithelial Wound Healing.

The incidence of inflammatory bowel disease, i.e., Crohn's disease and Ulcerative colitis, has significantly increased over the last decade. The etiology of IBD remains unknown and current therapeutic strategies are based on the unspecific suppression of the immune system. The development of treatments that specifically target intestinal inflammation and epithelial wound healing could significantly improve management of IBD, however this requires accurate detection of inflammatory changes. Currently, potential drug candidates are usually evaluated using animal models in vivo or with cell culture based techniques in vitro. Histological examination usually requires the cells or tissues of interest to be stained, which may alter the sample characteristics and furthermore, the interpretation of findings can vary by investigator expertise. Digital holographic microscopy (DHM), based on the detection of optical path length delay, allows stain-free quantitative phase contrast imaging. This allows the results to be directly correlated with absolute biophysical parameters. We demonstrate how measurement of changes in tissue density with DHM, based on refractive index measurement, can quantify inflammatory alterations, without staining, in different layers of colonic tissue specimens from mice and humans with colitis. Additionally, we demonstrate continuous multimodal label-free monitoring of epithelial wound healing in vitro, possible using DHM through the simple automated determination of the wounded area and simultaneous determination of morphological parameters such as dry mass and layer thickness of migrating cells. In conclusion, DHM represents a valuable, novel and quantitative tool for the assessment of intestinal inflammation with absolute values for parameters possible, simplified quantification of epithelial wound healing in vitro and therefore has high potential for translational diagnostic use.

The 5A apolipoprotein A-I (apoA-I) mimetic peptide ameliorates experimental colitis by regulating monocyte infiltration.

BACKGROUND AND PURPOSE: New therapies for inflammatory bowel disease (IBD) are highly desirable. As apolipoprotein (apo)A-I mimetic peptides are beneficial in several animal models of inflammation, we hypothesized that they might be effective at inhibiting murine colitis. EXPERIMENTAL APPROACH: Daily injections of 5A peptide, a synthetic bihelical apoA-I mimetic dissolved in PBS, or PBS alone were administered to C57BL/6 mice fed 3% (w v(-1) ) dextran sodium sulfate (DSS) in drinking water or healthy controls. KEY RESULTS: Daily treatment with 5A peptide potently restricted DSS-induced inflammation, as indicated by improved disease activity indices and colon histology, as well as decreased intestinal tissue myeloperoxidase levels and plasma TNFα and IL-6 concentrations. Additionally, plasma levels of monocyte chemoattractant protein-1 and the monocyte expression of adhesion-mediating molecule CD11b were down-regulated, pro-inflammatory CD11b(+) /Ly6c(high) monocytes were decreased, and the number of intestinal monocytes was reduced in 5A peptide-treated animals as determined by intravital macrophage-related peptide-8/14-directed fluorescence-mediated tomography and post-mortem immunhistochemical F4/80 staining. Intravital fluorescence microscopy of colonic microvasculature demonstrated inhibitory effects of 5A peptide on leukocyte adhesion accompanied by reduced plasma levels of the soluble adhesion molecule sICAM-1. In vitro 5A peptide reduced monocyte adhesion and transmigration in TNFα-stimulated monolayers of human intestinal microvascular endothelial cells. Increased susceptibility to DSS-induced inflammation was noted in apoA-I(-/-) mice. CONCLUSIONS AND IMPLICATIONS: The 5A peptide is effective at ameliorating murine colitis by preventing intestinal monocyte infiltration and activation. These findings point to apoA-I mimetics as a potential treatment approach for IBD.

Hepatorenal syndrome: outcome of response to therapy and predictors of survival.

Aim. Treatment of hepatorenal syndrome (HRS) in patients with liver cirrhosis is still challenging and characterized by a very high mortality. This study aimed to delineate treatment patterns and clinical outcomes of patients with HRS intravenously treated with terlipressin. Methods. In this retrospective single-center cohort study, 119 patients (median [IQR]; 56.50 [50.75-63.00] years of age) with HRS were included. All patients were treated with terlipressin and human albumin intravenously. Those with response to treatment (n = 65) were compared to the patient cohort without improvement (n = 54). Patient characteristics and clinical parameters (Child stage, ascites, hepatic encephalopathy, HRS type I/II, and initial MELD score) were retrieved. Univariate analysis of factors influencing the success of terlipressin therapy and Cox regression analysis of factors influencing survival was carried out. Results. One-month survival was significantly longer in the group of responders (p = 0.048). Cox regression analysis identified age [Hazard ratio, 95% confidence interval (CI); 1.05, 1.01-1.09, resp.], alcohol abuse [HR 3.05, 95% CI 1.11-8.38], duration of treatment [HR 0.92, 95% CI 0.88-0.96], and MELD score [HR 1.08, 95% CI 1.02-1.14] to be independent predictors of survival. Conclusions. Survival of HRS patients after treatment depends on age, etiology of liver disease, and the duration of treatment.

Giant cell arteritis exclusively detected by 18F-fluorodeoxyglucose positron emission tomography: a case report.

INTRODUCTION: This case of giant cell arteritis is noteworthy because it evaded standard diagnostic criteria and only emerged as fever of unknown origin. In this regard, we present 18F-fluorodeoxyglucose positron emission tomography as a valid diagnostic method. CASE PRESENTATION: This case report describes a 58-year-old Caucasian woman who is a cigarette smoker with a 10-week history of fever of unknown origin, night sweats and weight loss of 12 kg. Initially, clinical presentation was suspicious of malignant disease. Laboratory findings detected significantly elevated inflammatory blood parameters including C-reactive protein and elevated erythrocyte sedimentation rate (110 mm/hour). Extensive diagnostic workup including microbiological and rheumatological assessment, ultrasonography, endoscopy and computed tomography of abdomen and thorax did not indicate any septic or malignant focus. Eventually, 18F-fluorodeoxyglucose positron emission tomography was able to reveal arteritis of her aortic arch and supraaortic branches. Subsequently, she commenced steroid and methotrexate therapy that led to sustained remission. CONCLUSIONS: This case of giant cell arteritis may promote discussion regarding a more specific classification for this disease entity. Furthermore, it confirms that 18F-fluorodeoxyglucose positron emission tomography might serve as a valuable tool for diagnosis of giant cell arteritis, because it could facilitate an accurate and non-invasive detection of lesions of large vessels.

Regulated expression of leukocyte-specific transcript (LST) 1 in human intestinal inflammation.

INTRODUCTION: Leukocyte-specific transcript 1 (LST1) encoded peptides are involved in immunomodulation and nanotube-mediated cell-cell communication. The aim of this study was to assess the expression of LST1 in colonic epithelium and endothelium during intestinal inflammation. METHODS: LST1 expression was evaluated by RT-PCR, FACS, western blot analysis, and immunohistochemistry in intestinal epithelial Caco-2 cells, human intestinal microvascular endothelial cells and in human histological specimens from inflammatory bowel disease (IBD) patients and non-IBD colitis patients. RESULTS: LST1 expression was significantly increased upon proinflammatory stimulation in intestinal epithelial and endothelial cells. Furthermore, LST1 tissue expression was significantly enhanced in macroscopically inflamed colonic mucosal biopsies as compared to non-affected mucosal areas. CONCLUSIONS: This is the first report demonstrating regulated LST1 expression in human intestinal epithelial and microvascular endothelial cells and in inflamed colonic tissue from IBD patients. Proinflammatory expression of LST1 occurs in the setting of human IBD and is not restricted to immune cell populations. Future studies are needed to further elucidate the role of soluble and membrane-expressed LST1 in the regulation of mucosal intestinal immunity and inflammation as well as to reveal possible therapeutic implications.

Nicotinamide treatment ameliorates the course of experimental colitis mediated by enhanced neutrophil-specific antibacterial clearance.

SCOPE: In previous studies, we could show that the B vitamin nicotinamide (NAM) enhanced antimicrobial activity of neutrophils. Here, we assessed the effects of NAM in two models of experimental colitis. METHODS AND RESULTS: Colitis was induced in C57BL/6 mice either by oral infection with Citrobacter rodentium or by DSS (dextran sodium sulphate) administration, and animals were systemically treated with NAM. Ex vivo bacterial clearance was assessed in murine and human whole blood, as well as isolated human neutrophils. In C. rodentium-induced colitis, NAM treatment resulted in markedly decreased systemic bacterial invasion, histological damage and increased fecal clearance of C. rodentium by up to 600-fold. In contrast, NAM had no effect when administered to neutrophil-depleted mice. Ex vivo stimulation of isolated human neutrophils, as well as murine and human whole blood with NAM led to increased clearance of C. rodentium and enhanced expression of antimicrobial peptides in neutrophils. Moreover, NAM treatment significantly ameliorated the course of DSS colitis, as assessed by body weight, histological damage and myeloperoxidase activity. CONCLUSION: Pharmacological application of NAM mediates beneficial effects in bacterial and chemically induced colitis. Future studies are needed to explore the clinical potential of NAM in the context of intestinal bacterial infections and human inflammatory bowel disease (IBD).

Crohn's disease complicated by intestinal infection with methicillin-resistant Staphylococcus aureus.

We report on a 24-year-old male patient with history of bloody diarrhea, abdominal pain and vomiting. Endoscopy revealed massive ulcerative discontinuous proctosigmoiditis with deep, sharply demarcated epithelial denudations and enterotoxigenic methicillin-resistant Staphylococcus aureus (MRSA) was detected in mucosal biopsies. After treatment with linezolide and steroids, a significant amelioration of colitis was detected and testing for MRSA became negative. In face of the case presented here, we suggest that in patients with refractory inflammatory bowel disease (IBD), microbiological assessment should be performed to detect a possible Staphylococcus aureus infection in order to initiate an antimicrobial treatment in addition to IBD-specific treatment.

Translational 18F-FDG PET/CT imaging to monitor lesion activity in intestinal inflammation.

UNLABELLED: In patients with inflammatory bowel disease (IBD) and in murine IBD models, mucosal disease activity is routinely assessed by endoscopy and histologic evaluation. This information is valuable for monitoring treatment response, with mucosal healing being a major treatment goal. The aim of this study was to evaluate the translational potential of noninvasive (18)F-FDG PET/CT for the assessment of mucosal damage in murine dextran sodium sulfate (DSS) colitis and human IBD. METHODS: After induction of DSS colitis, (18)F-FDG uptake was serially assessed from colonic volumes of interest defined on PET/CT scans and intraindividually correlated to histologic findings and to infiltrating cell types. In addition, (18)F-FDG PET/CT scans of 25 Crohn disease patients were analyzed, and colonic (18)F-FDG uptake was correlated to endoscopically assessed damage. RESULTS: At days 4 and 7 after DSS induction, colonic (18)F-FDG uptake was significantly increased, with a distinct peak in the medial colon. (18)F-FDG uptake strongly correlated with histologic epithelial damage. Additionally, (18)F-FDG uptake increased in the bone marrow in the course of the disease, correlating with an increase in intestinal (18)F-FDG uptake. Histology and fluorescence-activated cell sorting analysis of the bone marrow of DSS mice revealed an increased number of immature neutrophils, whereas mucosal polymerase chain reaction suggested a correlation of (18)F-FDG uptake to T cell infiltration. In accordance with the results of (18)F-FDG PET/CT in DSS colitis, an increased (18)F-FDG uptake was found in 87% of deep mucosal ulcerations in IBD patients, whereas mild endoscopic lesions were detected only by (18)F-FDG PET/CT in about 50% of patients assessed. CONCLUSION: (18)F-FDG PET/CT is a noninvasive method for evaluation of both experimental colitis and Crohn disease patients and thereby offers promising translational potential.

Improving relapse prediction in inflammatory bowel disease by neutrophil-derived S100A12.

BACKGROUND: Prediction of inflammatory bowel disease relapse has important implications for therapeutic strategies. Fecal S100A12 has been reported as a novel marker of intestinal inflammation. The objective was to investigate the utility of S100A12 as a marker for the confirmation of stable remission and prediction of relapses. METHODS: We consecutively included 147 adults and 34 children with Crohn's disease (n = 61) or ulcerative colitis (n = 120). Over a 3-year period, we collected 686 stool samples and 861 serum samples during regular follow-up visits. S100A12 and calprotectin levels were measured by an enzyme-linked immunoassay. RESULTS: Fecal S100A12 correlated with S100A12 serum levels, other laboratory markers, as well as disease activity, location, and behavior. Fecal S100A12 levels in the relapse group differed significantly from those of the nonrelapse group. A baseline fecal S100A12 level of >0.5 mg/kg was significantly associated with disease relapse within 18 months. Time course analysis of fecal S100A12 before and after relapse showed a clear increase of S100A12 concentrations up to 6 months before clinical relapse. At 0.43 mg/kg, the sensitivity and specificity of S100A12 for predicting relapse already 8 to 12 weeks earlier were 70% and 83%, respectively. CONCLUSIONS: Regular measurements of fecal S100A12 levels reliably detect inflammatory bowel disease relapse at an early stage, which makes the test a promising noninvasive tool for monitoring and optimizing therapy, and may reduce the need for invasive investigations during disease follow-up.

Detection and differentiation of inflammatory versus fibromatous Crohn's disease strictures: prospective comparison of 18F-FDG-PET/CT, MR-enteroclysis, and transabdominal ultrasound versus endoscopic/histologic evaluation.

BACKGROUND: Differentiation between inflammatory and fibromatous strictures in Crohn's disease (CD) is difficult but crucial for therapeutic decisions. The aim of this study was to assess the best noninvasive imaging method for the detection and differentiation of inflammatory and fibromatous stenoses in CD in comparison to endoscopic and histologic evaluation. METHODS: Patients with suspected CD strictures were included. According to a formalized endoscopic and histologic protocol, strictures were classified as inflammatory, mixed, and fibrostenotic. Strictures were further analyzed using fluorine 18-labeled fluoro-2-deoxy-D-glucose ((18) FDG) / positron emission tomography (PET) low-dose computed tomography (CT), magnetic resonance (MR) enteroclysis and transabdominal ultrasound using standardized scoring systems. RESULTS: Thirty patients with 37 strictures were evaluated (inflamed n = 22; mixed n = 12, fibromatous n = 3). (18) FDG-PET/CT detected 81%, MR-enteroclysis 81%, and ultrasound 68% of the strictures. Correct differentiation rates of strictures were 57% for MRE, 53% for (18) FDG-PET/CT, and 40% for ultrasound. Differences of detection rates and differentiation rates were not statistically significant. When combining transabdominal ultrasound with (18) FDG-PET/CT or MR-enteroclysis all strictures that required invasive treatment were detected. CONCLUSIONS: Detection rates of the strictures were not significantly different between (18) FDG-PET/CT, MR-enteroclysis, and ultrasound. Despite good stricture detection rates relating to our gold standard, (18) FDG-PET/CT nor MR-enteroclysis nor ultrasound can accurately differentiate inflamed from fibrotic strictures. A combination of MR-enteroclysis and ultrasound as well as a combination of (18) FDG-PET/CT and ultrasound resulted in a 100% detection rate of strictures requiring surgery or endoscopic dilation therapy, suggesting the combination of these methods as an alternative to endoscopy at least in the group of patients not able to perform an adequate bowel preparation.

Cytomegalovirus (CMV)-Specific Perforin and Granzyme B ELISPOT Assays Detect Reactivation of CMV Infection in Inflammatory Bowel Disease.

The role of cytomegalovirus (CMV) infection in the pathogenesis and exacerbation of Inflammatory Bowel Disease (IBD) has been unresolved. Typically, the CMV genome remains dormant in infected cells, but a breakdown of immune surveillance can lead to re-activation of viral replication in the gut mucosa, which is not necessarily associated with viremia or changes in antibody titers. We hypothesized that the detection of CMV-specific CD8 effector T cells should permit the distinction between dormant and active CMV infection. As CD8 effector T cells, unlike memory CD8 T cells, have perforin (PFN) and granzyme B (GzB) preformed in their cytoplasmic granules, we employed single cell resolution ELISPOT assays to measure the CMV antigen-triggered release of these molecules by CD8 T cells isolated from subjects with IBD, and age-matched healthy controls. The frequencies of CMV-specific (GzB) and PFN-producing CD8 T cells were increased in IBD patients compared to healthy controls. Furthermore, the increased CMV reactivity was associated with active IBD disease and with longer disease duration. Notably, PCR on serum frequently failed to detect CMV DNA during flares. The data show that during active IBD there is a flare of CD8 T cell activity against CMV in a substantial proportion of IBD patients, suggesting CMV reactivation that serum PCR does not detect. While it remains open whether CMV reactivation is a cause or consequence of IBD, our data suggest that monitoring CMV antigen-specific effector CD8 T cells with GzB and PFN ELISPOT analysis can provide novel insights into the role of CMV infection in IBD. Additionally, our data have implications for the fields of transplantation, HIV, cancer, and autoimmune diseases, in all of which patient care critically depends on sensitive and reliable detection of a reactivation of CMV infection.

Enoxaparin improves the course of dextran sodium sulfate-induced colitis in syndecan-1-deficient mice.

Syndecan-1 (Sdc1) plays a major role in wound healing and modulates inflammatory responses. Sdc1 expression is reduced in lesions of patients with ulcerative colitis. The aim of this study was to investigate the role of Sdc1 in murine dextran sodium sulfate (DSS)-induced colitis. DSS colitis was induced in Sdc1-deficient (knockout (KO)) and wild-type mice by oral administration of 3% DSS. KO mice exhibited a significantly increased lethality as compared with wild-type controls (61 versus 5%, P < 0.05). Impaired mucosal healing and prolonged recruitment of inflammatory cells in KO mice were accompanied by significant up-regulation of tumor necrosis factor-alpha, CC chemokine ligand 3/macrophage inflammatory protein-1alpha, and vascular cell adhesion molecule-1, as determined by histological correlation between 0 and 15 days after colitis induction, TaqMan low-density array analysis, and quantitative real-time PCR. Treatment from days 7 through 14 with enoxaparin, a functional analogue of the Sdc1 heparan sulfate chains, significantly reduced lethality of KO mice due to DSS-induced colitis, which was correlated with improved mucosal healing. In vitro, Sdc1-deficient polymorphonuclear cells displayed increased adhesion to endothelial cells and intercellular adhesion molecule-1, and enoxaparin reverted adhesion to wild-type levels. Small interfering RNA-mediated knockdown of Sdc1 expression resulted in reduced basic fibroblast growth factor-mediated mitogen-activated protein kinase signaling and reduced Caco-2 cell proliferation. We conclude that Sdc1 has a protective effect during experimental colitis. The modification of missing Sdc1 function by heparin analogues may emerge as a promising anti-inflammatory approach.

Vascular cell adhesion molecule-1 expression in human intestinal microvascular endothelial cells is regulated by PI 3-kinase/Akt/MAPK/NF-kappaB: inhibitory role of curcumin.

Endothelial activation and surface expression of cell adhesion molecules (CAMs) is critical for binding and recruitment of circulating leukocytes in tissues during the inflammatory response. Endothelial CAM expression plays a critical role in the intestinal microvasculature in inflammatory bowel disease (IBD), as blockade of leukocyte alpha4-integrin binding by gut endothelial CAM ligands has therapeutic benefit in IBD. Mechanisms underlying expression of vascular cell adhesion molecule (VCAM)-1, a ligand for alpha4-integrin in primary cultures of human intestinal microvascular endothelial cells (HIMEC) has not been defined. We investigated the effect of curcumin, phosphatidylinositol 3-kinase (PI 3-kinase)/protein kinase B (Akt), and mitogen-activated protein kinase (MAPK) inhibitors on VCAM-1 expression and function in HIMEC. CAM expression was assessed and HIMEC-leukocyte adhesion was visualized under static and flow conditions. Western blotting and in vitro kinase assays were used to assess Akt and MAPK activation. Nuclear factor-kappaB (NF-kappaB) activation and nuclear translocation of its p65 subunit were determined. Tumor necrosis factor (TNF)-alpha/lipopolysaccharide (LPS)-induced VCAM-1 expression in HIMEC was suppressed by Akt small-interfering RNA, curcumin, and inhibitors of NF-kappaB (SN-50), p38 MAPK (SB-203580) and PI 3-kinase/Akt (LY-294002). VCAM-1 induction was partially suppressed by p44/42 MAPK (PD-098059) but unaffected by c-Jun NH2-terminal kinase (SP-600125) inhibition. Curcumin inhibited Akt/MAPK/NF-kappaB activity and prevented nuclear translocation of the p65 NF-kappaB subunit following TNF-alpha/LPS. At physiological shear stress, curcumin attenuated leukocyte adhesion to TNF-alpha/LPS-activated HIMEC monolayers. In conclusion, curcumin inhibited the expression of VCAM-1 in HIMECs through blockade of Akt, p38 MAPK, and NF-kappaB. Curcumin may represent a novel therapeutic agent targeting endothelial activation in IBD.

Constrictive pericarditis, still a diagnostic challenge: comprehensive review of clinical management.

The diagnosis of constrictive pericarditis (CP) continues to be a challenge in the modern era. Understanding the pathophysiology and integrating the results of invasive and non-invasive techniques are important in the differential diagnosis of CP and e.g. restrictive cardiomyopathy. New echocardiographic techniques such as tissue Doppler imaging (TDI) and 2D-speckle tracking, dual-source CT (computed tomographic imaging) and especially tagged cine-MRI (magnetic resonance imaging) with the analysis of phase contrast angiography sequences are promising novel approaches. Pericardiectomy in experienced centers with complete decortication (if technically feasible) is the treatment of choice for CP and it results in symptomatic relief in most patients. However, some patients may not benefit from pericardiectomy and this may be due to myocardial compliance abnormalities, myocardial atrophy after prolonged constriction, residual constriction or other myocardial processes. An important predictor of long-term outcome after pericardiectomy is the etiology of the pericardial disease. The overall mortality in the current literature is nearly 5-6%. Survival with post-surgical CP is worse than with idiopathic CP, but significantly better than with post-radiation CP.