Search

To use information from the referral letters to assess the appropriateness of colonoscopies in a primary open-access referral center, according to the criteria from the European Panel on the Appropriateness of Gastrointestinal Endoscopy (EPAGE) II, and to compare with the first EPAGE guidelines. Second, to evaluate how the appropriateness and other patient- or doctor-related factors affected the diagnostic yield (DY).A set of variables; symptoms, referring physician and final diagnosis, for 323 referrals accepted for colonoscopy were recorded prospectively and later on assessed using the EPAGE and EPAGE II criteria, respectively. Patients with incomplete visualization of the entire colon or colonoscopic findings as indication were excluded.EPAGE and EPAGE II criteria were applicable in 287 (95.3%) and 295 (98.0%) referrals, respectively. A total of 166 (57.8%) patients were considered appropriate by EPAGE and 240 (81.4%) patients were considered appropriate by EPAGE II. DY for appropriate versus uncertain/inappropriate referrals was 34.9% versus 17.4% for EPAGE (odds ratio [OR] = 2.5, 95% confidence interval [CI]: 1.8-4.4, p = 0.003) and 31.3% versus 10.9% for EPAGE II (OR = 3.5, 95% CI: 1.4-8.9, p = 0.007). Sensitivity was higher for EPAGE II (92.6% vs. 73.4%). According to EPAGE II, 68 (23.1%) patients were referred due to lesions identified on other diagnostic procedures, producing a DY of 39.7%. In this group, 70% presented symptoms appropriate for a primary referral to colonoscopy.The majority of colonoscopies were found appropriate by EPAGE II. There was a clear association between high appropriateness of the indication and a high DY. EPAGE II is a guideline-improvement that may be useful for both referring physicians and gastroenterologists when considering referrals.

Neurologic complications are common after hematopoietic stem cell transplantation (HSCT) and solid organ transplantation (SOT) and affect 30-60% of transplant recipients. The aim of this article is to provide a practical imaging approach based on the timeline and etiology of CNS abnormalities, and neurologic complications related to transplantation of specific organs. The lesions will be classified based upon the interval from HSCT procedure: pre-engraftment period30 days, early post-engraftment period 30-100 days, late post-engraftment period100 days, and the interval from SOT procedure: postoperative phase 1-4 weeks, early posttransplant syndromes 1-6 months, late posttransplant syndromes6 months. Further differentiation will be based on etiology: infections, drug toxicity, metabolic derangements, cerebrovascular complications, and posttransplantation malignancies. In addition, differentiation will be based on complications specific to the type of transplantation: allogeneic and autologous hematopoietic stem cells (HSC), heart, lung, kidney, pancreas, and liver. Thus, in this article we emphasize the strategic role of neuroradiology in the diagnosis and response to treatment by utilizing a methodical approach in the work up of patients with neurologic complications after transplantation.

The molecular mechanisms that drive expression of the alarmin interleukin-33 (IL-33) in endothelial cells are unknown. Because nuclear IL-33 is a marker of endothelial cell quiescence (corroborated in this study by coexpression of cyclin-dependent kinase inhibitor p27 Kip1 ), we hypothesized that Notch signaling might be involved in regulating IL-33 expression. Activation of Notch1 by immobilized Notch ligands was sufficient to induce nuclear IL-33 expression in cultured endothelial cells. Conversely, IL-33 expression was inhibited by the γ-secretase inhibitor DAPT or by inhibiting the function of Dll4, Jagged1, Notch1, or the canonical Notch transcription factor RBP-Jκ. Insensitivity to cycloheximide indicated that IL-33 was a direct target of Notch signaling, well in line with the identification of several conserved RBP-Jκ binding sites in the IL33 gene. The in vivo expression of Dll4 but not of Jagged1 was well correlated with expression of IL-33 in quiescent vessels, and subcutaneous injection of DAPT in healthy skin reduced IL-33 expression, indicating that Notch signaling was involved. On the other hand, loss of IL-33 during angiogenesis occurred despite sustained Dll4 and Notch1 expression, suggesting that other signals may override the IL-33-driving signal in this context. Taken together, our data demonstrate that endothelial nuclear IL-33 is induced by Notch and that Dll4 may be the dominant ligand responsible for this signaling in vivo .

The present population based adult cohort was part of a new prospective study of patients with inflammatory bowel disease (IBD) in South-Eastern Norway, the Inflammatory Bowel South-Eastern Norway II study, investigating disease characteristics in an attempt to improve our knowledge regarding factors related to early clinical phenotype and disease activity.Patients suspected to have IBD on the basis of predefined symptoms, including abdominal pain, diarrhea, and/or blood in stool for more than 10 days were examined at the local hospital. Colonoscopy with biopsies was performed and blood and stool samples were taken.In ulcerative colitis (UC) patients, the median Simple Clinical Colitis Activity Index (SCCAI) was 4 (range 0-10) in mild and 6 (range 0-14) in patients with moderate or severe endoscopic activity of inflammation (p = 0.002). The calprotectin concentration in feces was significantly related to the SCCAI (p = 0.034) and the Mayo endoscopic subscore (p = 0.031). There was a significant association between the C-reactive protein (CRP) value, leucocytes and thrombocytes and the SCCAI, but only leucocytes were significantly associated with the Mayo endoscopic subscore. In Crohn's disease (CD) patients, there was no statistical significant association between the Harvey-Bradshaw Index (HBI) and the endoscopic grade of mucosal inflammation (p = 0.8). The calprotectin concentration in feces was significantly related to the endoscopic activity score (p = 0.004), but not to the HBI (p = 0.5). HBI was significantly related to the CRP value (p = 0.047) and thrombocytes (p = 0.03).In UC, both biochemical and fecal markers are related to disease activity and extent of disease, whereas in CD, the fecal calprotectin concentration is a reliable marker of mucosal affection, but not for systemic disease activity.

Interleukin-33 (IL-33) is a novel member of the interleukin-1 family that induces mucosal pathology in vivo and may drive fibrosis development and angiogenesis. To address its potential role in inflammatory bowel disease, we explored its tissue expression in biopsy specimens from untreated ulcerative colitis patients, observing a 2.6-fold up-regulation of IL-33 mRNA levels, compared to controls. Immunohistochemical analyses of surgical specimens showed that a prominent source of IL-33 in ulcerative colitis lesions were ulceration-associated myofibroblasts that co-expressed the fibroblast marker heat shock protein 47, platelet-derived growth factor receptor (PDGFR)β, and, in part, the myofibroblast marker α-smooth muscle actin (SMA). In contrast, IL-33-positive myofibroblasts were almost absent near the deep fissures seen in Crohn's disease. A screen of known and putative activators of IL-33 in cultured fibroblasts revealed that the Toll-like receptor-3 agonist poly (I:C) was among the strongest inducers of IL-33 and that it synergized with transforming growth factor-β, a combination also known to boost myofibroblast differentiation. Experimental wound healing in rat skin revealed that the de novo induction of IL-33 in pericytes and the possible activation of scattered, tissue-resident IL-33(+)PDGFRβ(+)αSMA(-) fibroblast-like cells were early events that preceded the later appearance of IL-33(+)PDGFRβ(+)αSMA(+) cells. In conclusion, our data point to a novel role for IL-33 in mucosal healing and wound repair and to an interesting difference between ulcerative colitis and Crohn's disease.

Cholangiocytes express antigen-presenting molecules, but it has been unclear whether they can present antigens. Natural killer T (NKT) cells respond to lipid antigens presented by the major histocompatibility complex class I-like molecule CD1d and are abundant in the liver. We investigated whether cholangiocytes express CD1d and present lipid antigens to NKT cells and how CD1d expression varies in healthy and diseased bile ducts. Murine and human cholangiocyte cell lines as well as human primary cholangiocytes expressed CD1d as determined by flow cytometry and western blotting. Murine cholangiocyte cell lines were able to present both exogenous and endogenous lipid antigens to invariant and noninvariant NKT cell hybridomas and primary NKT cells in a CD1d-dependent manner. A human cholangiocyte cell line, cholangiocarcinoma cell lines, and human primary cholangiocytes also presented exogenous CD1d-restricted antigens to invariant NKT cell clones. CD1d expression was down-regulated in the biliary epithelium of patients with late primary sclerosing cholangitis, primary biliary cirrhosis, and alcoholic cirrhosis compared to healthy controls. Conclusions Cholangiocytes express CD1d and present antigens to NKT cells and CD1d expression is down-regulated in diseased biliary epithelium, findings which show that the biliary epithelium can activate an important lymphocyte subset of the liver. This is a potentially important immune pathway in the biliary system, which may be capable of regulating inflammation in the context of biliary disease.

IL-33 is a novel IL-1 family member with a putative role in inflammatory skin disorders and a complex biology. Therefore, recent conflicting data regarding its function in experimental models justify a close assessment of its tissue expression and regulation. Indeed, we report here that there are strong species differences in the expression and regulation of epidermal IL-33. In murine epidermis, IL-33 behaved similar to an alarmin, being constitutively expressed in keratinocyte nuclei and rapidly lost during acute inflammation. By contrast, human and porcine IL-33 were weakly expressed or absent in keratinocytes of noninflamed skin but induced during acute inflammation. To this end, we observed that expression of IL-33 in human keratinocytes but not murine keratinocytes was strongly induced by IFN-γ, and this upregulation completely depended on the presence of EGFR ligands. Accordingly, IFN-γ increased the expression of IL-33 in the basal layers of the epidermis in human ex vivo skin cultures only, despite good evidence of IFN-γ activity in cultures from both species. Together these findings demonstrate that a full understanding of IL-33 function in clinical settings must take species-specific differences into account.

Objective— Interleukin (IL)-33 is a nuclear protein that is released from stressed or damaged cells to act as an alarmin. We investigated the effects of IL-33 on endothelial cells, using the prototype IL-1 family member, IL-1β, as a reference. Methods and Results— Human umbilical vein endothelial cells were stimulated with IL-33 or IL-1β, showing highly similar phosphorylation of signaling molecules, induction of adhesion molecules, and transcription profiles. However, intradermally injected IL-33 elicited significantly less proinflammatory endothelial activation when compared with IL-1β and led us to observe that quiescent endothelial cells (ppRb low p27 high ) were strikingly resistant to IL-33. Accordingly, the IL-33 receptor was preferentially expressed in nonquiescent cells of low-density cultures, corresponding to selective induction of adhesion molecules and chemokines. Multiparameter phosphoflow cytometry confirmed that signaling driven by IL-33 was stronger in nonquiescent cells. Manipulation of nuclear IL-33 expression by siRNA or adenoviral transduction revealed no functional link between nuclear, endogenous IL-33, and exogenous IL-33 responsiveness. Conclusion— In contrast to other inflammatory cytokines, IL-33 selectively targets nonquiescent endothelial cells. By this novel concept, quiescent cells may remain nonresponsive to a proinflammatory stimulus that concomitantly triggers a powerful response in cells that have been released from contact inhibition.

Cytokines are thought to exert biological effects through their specific cell surface membrane receptors but increasing evidence suggests that some also function within the nucleus. Here, we review current knowledge of such cytokines, including the novel interleukin (IL)-1 family member IL-33. Its extracellular function has attracted much recent attention as a ligand for the Th2-associated ST2 receptor, but the discoveries of its nuclear functions and modes of secretion are only just beginning to surface. We review the currently available data on IL-33 regulation, nuclear function and release and discuss them in the context of other intranuclear cytokines and the prototype alarmin HMGB1, considering to what extent IL-33 can be seen as a novel member of the alarmin family.

Interleukin (IL)-33 is a novel member of the IL-1 family of cytokines that promotes Th2 responses in lymphocytes as well as the activation of both mast cells and eosinophils via the ST2 receptor. Additionally, IL-33 has been proposed to act as a chromatin-associated transcriptional regulator in both endothelial cells of high endothelial venules and chronically inflamed vessels. Here we show that nuclear IL-33 is expressed in blood vessels of healthy tissues but down-regulated at the earliest onset of angiogenesis during wound healing; in addition, it is almost undetectable in human tumor vessels. Accordingly, IL-33 is induced when cultured endothelial cells reach confluence and stop proliferating but is lost when these cells begin to migrate. However, IL-33 expression was not induced by inhibiting cell cycle progression in subconfluent cultures and was not prevented by antibody-mediated inhibition of VE-cadherin. Conversely, IL-33 knockdown did not induce detectable changes in either expression levels or the cellular distribution of either VE-cadherin or CD31. However, activation of endothelial cell cultures with either tumor necrosis factor-alpha or vascular endothelial growth factor and subcutaneous injection of these cytokines led to a down-regulation of vascular IL-33, a response consistent with both its rapid down-regulation in wound healing and loss in tumor endothelium. In conclusion, we speculate that the proposed transcriptional repressor function of IL-33 may be involved in the control of endothelial cell activation.

Background: IL-33, a recently described member of the IL-1-family, is an important player in a variety of inflammatory settings and is thought to be released from damaged or necrotic cells. Little work has so far been published on the cellular expression and regulation of IL-33 in inflammatory lesions. Results: In normal mouse skin IL-33 showed a nuclear expression in non-proliferating keratinocytes (Ki67-) and periglandular myoepithelial cells. After injection with Staphylococcus aureus (6h i.d.) we observed that nuclear IL-33 disappeared from keratinocytes in the center of the lesion and instead appeared in fibroblasts at the periphery. The keratinocyte layer remained intact and expressed nuclear HMGB1, revealing no evidence of overt necrosis at this time point, thus indicating possible secretion. Wound lesions of the ear showed a similar picture at the margins. At later time points IL-33 reappeared in keratinocytes, initially in a hyperproliferative, multilayer structure in which IL33 and Ki-67 remained minimally co-localized. Similarly, in cultured human keratinocytes there was constitutive expression of nuclear IL-33 in non-proliferating cells and in contrast to endothelial cells, expression levels appeared unaffected by cell density or pro-inflammatory activation (TNF-a or IL1b) Conclusion: The regulation of IL-33 in keratinocytes appears to involve molecular signals different from the regulation seen in vascular endothelial cells and deserves further investigation.

The molecular mechanisms that induce and maintain expression of the alarming interleukin-33 (IL-33) in endothelial cells are unknown. Based on the observation that IL-33 is also a marker of endothelial cell quiescence, we hypothesized that the Notch signaling pathway might be involved in regulation of IL-33 expression. Here we show that activation of Notch1 by immobilized Notch ligands was sufficient to induce nuclear IL-33 expression in human umbilical vein endothelial cells (HUVECs). Furthermore, IL-33 expression in confluent HUVECs was inhibited by the γ-secretase inhibitor DAPT or by blocking antibodies to Dll4, Jagged1 or Notch1, as well as by knockdown of the transcription factor RBP-Jκ. In vivo, expression of Dll4 but not Jagged1 was generally observed in all segments of quiescent vessels in healthy organs in both human and rat tissue, and therefore well correlated with expression of IL-33. Moreover, subcutaneous injections of DAPT markedly reduced expression of vascular IL-33, compatible with a role for Notch signaling in driving vascular IL-33 expression in vivo. Taken together, our data demonstrate that the alarmin IL-33 is a target of Notch and serve to further establish Notch signaling in innate immune defense.