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Abstract: BACKGROUND: . Angiogenesis has been suggested as an integral part of inflammatory bowel disease pathology. Vascular endothelial growth factor has long been considered to play a central, specific role in angiogenesis. Endothelial junction adhesion molecules, such as CD146, have recently been suggested to play a potent role in angiogenesis. CD34 is expressed on vascular endothelium, and it has been reported to be upregulated on endothelium in IBD. We investigated the expression of tissue vascular endothelial growth factor, CD34 and CD146 in the inflamed mucosa of patients with active inflammatory bowel disease compared with no inflamed mucosa of healthy controls. METHODS.: Forty-two IBD patients [23 ulcerative colitis, 19 Crohn's disease] and ten healthy controls were included in the study. In colonoscopically obtained biopsies, CD34, CD146 and vascular endothelial growth factor expression were evaluated by immunohistochemistry. RESULTS.: Vascular endothelial growth factor was detected in the mucosa of all groups, and its expression was significantly higher in both Crohn's disease and ulcerative colitis compared with controls (p<0.05). Immunohistochemical staining for CD146 in the inflamed mucosa was significantly higher in both Crohn's disease and ulcerative colitis compared with controls (p=0.002). A trend of higher CD34 expression in Crohn's disease and ulcerative colitis compared with controls was also found, but the difference among the three groups was not statistically significant (p=0.09). CONCLUSIONS: . Inflamed mucosa of patients with active Crohn's disease and ulcerative colitis showed a markedly enhanced expression of VEGF and CD146, than normal mucosa of controls, indicating a possible role of angiogenesis in the pathogenesis of inflammatory bowel disease.

Abstract: BACKGROUND: Patients with inflammatory bowel disease (IBD) have an increased risk of thromboembolic events. Imbalance of fibrinolysis has been suggested as one of the possible pathogenetic mechanisms. As plasminogen activator inhibitor-1 (PAI-1) and thrombin-activatable fibrinolysis inhibitor (TAFI) are inhibitors of fibrinolysis, we studied TAFI as well as PAI-1 plasma levels in IBD patients compared with healthy controls. METHODS: A total of 132 IBD patients [68 ulcerative colitis (UC) and 64 Crohn's disease (CD)] and 50 healthy controls were enrolled. PAI-1 and TAFI plasma levels were assessed by commercially available enzyme-linked immunosorbent assay kits. Their relationship with clinical parameters of UC and CD was assessed. RESULTS: Mean plasma PAI-1 levels were significantly higher in both UC patients (3.9+/-1.3 IU/ml) and CD patients (4.0+/-1.5 IU/ml) compared with healthy controls (3.1+/-1.1 IU/ml) (P=0.01). On the other hand, mean plasma TAFI levels were significantly lower in both UC patients (14.7+/-3.1 microg/ml) and CD patients (13.3+/-3.4 microg/ml) compared with healthy controls (17.4+/-3.0 microg/ml) (P<0.0001). Patients with active disease had significantly higher PAI-1 levels compared with patients with inactive disease for both diseases (P=0.03 and P=0.01, respectively). No significant association between plasma TAFI levels and disease activity was also found. Plasma TAFI levels were significantly lower in patients with ileal CD compared with patients with colonic CD. CONCLUSION: PAI-1 plasma levels are increased whereas TAFI levels are decreased in IBD patients. These results suggest an imbalance of fibrinolysis in IBD.

Abstract: Inflammatory bowel disease (IBD) is characterized by anorexia, malnutrition, altered body composition, and development of mesenteric white adipose tissue (WAT) hypertrophy. Increasing evidence suggests that adipokines synthesized either in WAT or in immune cells, are involved in these manifestations of IBD. Among adipokines leptin, adiponectin and resistin hold a fundamental role while the role of ghrelin in inflammation is not well established. Preliminary studies have shown overexpression of leptin, adiponectin, and resistin in mesenteric WAT of patients with Crohn's disease (CD) and significant alterations of circulating serum levels of these adipokines in IBD. It has also been demonstrated that intestinal inflammation causes an increase in endogenous ghrelin production. In animal models of intestinal inflammation, existing data suggest that leptin, adiponectin, and resistin are pivotal mediators of inflammation. Interesting therapeutic interventions based on these data have been suggested. A specific role for hypertrophic WAT has also been implicated in CD. Further efforts with experimental and clinical studies are needed to better understand the role of adipokines in IBD.

Abstract: AIM: To evaluate the role of pentavalent Tc-99m dimercaptosuccinic acid [Tc-99m (V) DMSA] in the diagnosis of ischemic colitis. METHODS: Fourteen patients with endoscopically and histologically confirmed ischemic colitis were included in the study. Tc-99m (V) DMSA scintigraphy was performed within 2 d after colonoscopy. Images were considered positive when an area of increased activity was observed in the region of interest and negative when no abnormal tracer uptake was detected. RESULTS: In 3 out of the 14 patients, Tc-99m (V) DMSA images showed moderate activity in the bowel. The scintigraphic results corresponded with the endoscopic findings. In the other 11 patients, no abnormal tracer uptake was detected in the abdomen. CONCLUSION: Besides the limited number of patients, Tc-99m (V) DMSA could not be considered as a useful imaging modality for the evaluation of ischemic colitis.

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Abstract: Thromboembolism is a significant cause of morbidity and mortality in patients with inflammatory bowel disease (IBD). Recent data suggest thromboembolism as a disease-specific extraintestinal manifestation of IBD, which is developed as the result of multiple interactions between acquired and genetic risk factors. There is evidence indicating an imbalance of procoagulant, anticoagulant and fibrinolitic factors predisposing in thrombosis in patients with IBD. The genetic factors that have been suggested to interfere in the thrombotic manifestations of IBD include factor V Leiden, factor II (prothrombin, G20210A), methylenetetrahydrofolate reductase gene mutation (MTHFR, 6777T), plasminogen activator inhibitor type 1 (PAI-1) gene mutation and factor XIII (val34leu). In this article we review the current data and future prospects on the role of genetic risk factors in the development of thromboembolism in IBD.

Abstract: BACKGROUND & AIMS: Although ischemic colitis (IC) usually occurs in old people with concomitant illnesses, an increasing frequency of this disease among young people has been reported. Inherited risk factors have been suggested to play an important role in the pathogenesis of IC. The aim of this study was to investigate the prevalence and possible role of mutations associated with cardiovascular morbidity in young patients with IC. METHODS: Patients younger than 55 years old with nonocclusive colon ischemia who were conservatively treated were included in the study. The diagnosis of definite IC was based on established clinical, endoscopic, and histologic criteria. Twelve polymorphisms of thrombophilic and vasoactive genes were evaluated in a group of 19 young patients with IC compared with 52 matched healthy controls (HC) by using commercially available kit. RESULTS: The frequency of the 506 Q allele of the factor V (FV) 506 RQ (Leiden) mutation was significantly higher in patients with IC than in HC (P = .005). The allele frequency of the mutant 4G allele of plasminogen activator inhibitor (PAI) polymorphism was significantly higher in patients with IC compared with HC (P = .006). The frequencies of the genotypes and mutant alleles of the other 10 polymorphisms were not statistically different in the 2 groups (P > .05). CONCLUSIONS: Our results suggest that FV R506Q and PAI-1 gene polymorphisms might be associated with the development of IC in young patients without other serious illness. Genetic predisposition might play an important role in the pathogenesis of IC in young patients.

Abstract: There is evidence that thromboembolism as a disease-specific extraintestinal manifestation of inflammatory bowel disease (IBD) is developed as the result of multiple interactions between acquired and genetic risk factors. An imbalance of procoagulant, anticoagulant, and fibrinolitic factors predisposing to thrombosis has been reported by several studies in patients with IBD. The study by Nguyen and Sam demonstrates that hospitalized IBD patients have higher prevalence of venous thromboembolism and a more than two-fold excess of mortality compared with non-IBD hospitalized patients. When the findings from this large study are combined with previous data, they suggest that thromboembolism is a significant cause of extraintestinal morbidity and mortality in IBD patients with a higher risk during hospitalization.

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Abstract: PURPOSE: Evaluation and comparison between pentavalent 99mTc dimercaptosuccinic acid (99mTc(V)-DMSA) and 99mTc-hexamethylpropylene amine oxime white blood cell (99mTc-HMPAO WBC) scintigraphy in the detection and assessment of disease activity in patients with active inflammatory bowel disease (IBD). MATERIALS AND METHODS: 99mTc(V)-DMSA scintigraphy was performed in 23 patients with active IBD and true positive 99mTc-HMPAO WBC scintigraphy. Images were considered positive when an area of increased uptake was observed. To assess severity of IBD, semi-quantitative analysis was included with reference to the uptake in the iliac crest. Comparison with endoscopic, radiological and clinical data was performed. RESULTS: The diagnostic accuracy of 99mTc-HMPAO WBC and 99mTc(V)-DMSA was 91% and 84%, respectively. A significant correlation between the findings of both radioisotopic methods and scintigraphy score was demonstrated. Endoscopic findings were significantly correlated with scintigraphic results. Kappa statistics showed a moderate to good agreement between the two scintigraphic methods. Two patients (8.8%) had negative findings with 99mTc(V)-DMSA scintigraphy (false negative results). CONCLUSION: 99mTc(V)-DMSA compared to 99mTc-HMPAO WBC could provide a simple, non-invasive alternative method for the assessment of disease activity, although it is slightly inferior to 99mTc-HMPAO WBC scintigraphy especially in the evaluation of disease localization in IBD patients.

Abstract: Anemia is a frequent complication in patients with inflammatory bowel disease (IBD), and is associated with decreased quality of life and increased rate of hospitalization. The primary therapeutic targets of IBD-associated anemia are iron deficiency and anemia of chronic disease. An important prognostic parameter of the success or failure of therapy is the outcome of the underlying disease. Iron deficiency should be appropriately managed with iron supplementation. However, the use of oral iron therapy is limited by several problems, the most important being gastrointestinal side effects leading occasionally to disease relapse and poor iron absorption. Intravenous iron preparations are more reliable, with iron sucrose demonstrating the best efficacy and tolerability. Treatment with erythropoietin or darbepoetin has been proven to be effective in patients with anemia, who fail to respond to intravenous iron. Patients with ongoing inflammation have anemia of chronic disease and may require combination therapy comprising of intravenous iron sucrose and erythropoietin. After initiating treatment, careful monitoring of hemoglobin levels and iron parameters is needed in order to avoid recurrence of anemia. In conclusion, anemia in the setting of IBD should be aggressively diagnosed, investigated, and treated. Future studies should define the optimal dose and schedule of intravenous iron supplementation and appropriate erythropoietin therapy in these patients.

Abstract: The management of patients with persistent perianal fistulae depends on thorough evaluation by clinical history and examination, assessment of intestinal disease and assessment of perianal disease. The main therapeutic options are medical and surgical treatment and their appropriate integration is essential for the optimal management of the patients. Medical treatment includes antibiotics, azathioprine or 6-mercaptopurine, infliximab and tacrolimus or cyclosporine. Surgical treatment includes fistulotomy, placement of setons, endorectal advancement flaps, fecal diversion and proctectomy. Fistula recurrence often occurs, possibly due to early discontinuation of medication or premature removal of setons. Using anorectal endoscopic ultrasound or magnetic resonance imaging to guide therapy, the healing rates of perianal fistula can be increased. In persistent complex perianal fistulae where medical treatment initially fails, examination under anaesthesia and placement of non-cutting setons, when necessary, combined with medical treatment results in higher healing rates.

Abstract: BACKGROUND: Tumour necrosis factor alpha is a critical mediator of inflammation-related altered metabolism in inflammatory bowel disease (IBD), possibly through its interaction with adipokines, which play an important role in IBD. Infliximab is a well established antitumour necrosis factor alpha treatment in IBD. AIM AND METHODS: We studied serum levels of leptin, adiponectin and resistin in 20 IBD patients before and after infliximab treatment using commercially available enzyme-linked immunosorbent assays. The results were correlated with alterations of disease activity, BMI and C-reactive protein. RESULTS: Infliximab induced clinical response or remission in 18 out of 20 treated IBD patients. Mean serum-leptin levels were 4.6+/-0.5 and 5.1+/-0.5 ng/ml (P=0.41), mean serum-adiponectin levels were 10513.9+/-1216.9 and 9653.5+/-1031.5 ng/ml (P=0.36) and mean serum-resistin levels were 26.3+/-4.1 and 13.9+/-1.4 ng/ml (P=0.004), before and after infliximab treatment, respectively. No significant correlation between the changes of BMI, C-reactive protein or the clinical indices of activity and alterations of the examined adipokines was found. CONCLUSIONS: Serum levels of leptin and adiponectin had no significant alterations, whereas serum-resistin levels are significantly decreased after infliximab therapy in IBD patients, suggesting a possible proinflammatory status for resistin in IBD and a role as a marker of successful therapy.

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Abstract: BACKGROUND: Inherited risk factors have been suggested to play an important role in the pathogenesis of vascular complications of inflammatory bowel disease (IBD). The aim of the present study was to investigate the role of mutations associated with cardiovascular disease in IBD patients with or without vascular complications compared with thrombotic and healthy controls (HC). METHODS: Twelve polymorphisms of thrombophilic and vasoactive genes were evaluated in a group of 30 IBD patients with vascular complications (IBD-VC) compared with 60 IBD patients without vascular complications, 30 thrombotic controls (TC), and 54 healthy controls, using a commercially available kit. RESULTS: No significant differences between IBD-VC and TC concerning the carriage of these mutations were found. The frequencies of the factor V (FV) 506 RQ (Leiden) genotype and the 506Q allele were significantly higher in these groups than in HC (P < 0.05) but not IBD controls (P > 0.05). The allele frequency of the mutant 4G allele of the plasminogen activator inhibitor (PAI) polymorphism, similar in the IBD-VC and TC groups, was significantly higher in these groups compared with the IBD group (P = 0.03) and the HC (P = 0.001). It is noteworthy that there was a trend of association of FV R506Q polymorphism with venous thrombosis and PAI-1 gene polymorphism with arterial thrombosis. CONCLUSIONS: Our results suggest that the investigated gene polymorphisms do not differ in patients with IBD-VC and TC. FV R506Q and PAI-1 gene polymorphisms might be associated with the increased risk of development of vascular complications in IBD.

Abstract: Anemia is a common complication of inflammatory bowel diseases. An international working party has formed and developed guidelines for evaluation and treatment of anemia and iron deficiency that should serve practicing gastroenterologists. Within a total of 16 statements, recommendations are made regarding diagnostic measures to screen for iron- and other anemia-related deficiencies regarding the triggers for medical intervention, treatment goals, and appropriate therapies. Anemia is a common cause of hospitalization, prevents physicians from discharging hospitalized patients, and is one of the most frequent comorbid conditions in patients with inflammatory bowel disease. It therefore needs appropriate attention and specific care.

Abstract: The researchers' view regarding the role of white adipose tissue (WAT) in inflammation has been greatly transformed over the last 10 years. WAT is now considered as an active organ producing many crucial molecules called adipokines. Resistin is a recently discovered cysteine-rich adipokine that has emerged during this decade as a promising inflammatory marker in various diseases. It is synthesized either from adipocytes or from immune cells, and exerts a pro-inflammatory profile in a variety of different experimental settings. Inflammatory bowel disease (IBD) is characterized by anorexia, malnutrition, altered body composition and the development of mesenteric WAT hypertrophy. The study by Konrad-Zerna et al. in this issue of the journal demonstrates an increased serum resistin in IBD patients, this being in agreement with previous IBD studies in mesenteric WAT and serum. Interesting aspects like the true validity of resistin as a marker of disease activity, the role of its different molecular isoforms, the cells that predominantly produce this molecule, and the possible use of resistin as a guide for therapeutic interventions, arise.

Abstract: The purpose of this study was to compare MR enteroclysis (MRE) with conventional enteroclysis (CE) in patients with small intestinal Crohn's disease. Fifty-two consecutive patients with known or suspected Crohn's disease underwent MR and conventional enteroclysis, which was considered the gold standard. Eleven imaging features, classified in three groups, mucosal, transmural and extraintestinal, were subjectively evaluated by two experienced radiologists. MRE and CE were in full agreement in revealing, localizing and estimating the length of all involved segments of the small bowel. The sensitivity of MRE for the detection of superficial ulcers, fold distortion and fold thickening was 40, 30 and 62.5%, respectively. The sensitivity of MRE for the detection of deep ulcers, cobble-stoning pattern, stenosis and prestenostic dilatation was 89.5, 92.3, 100 and 100%, respectively. Additional findings demonstrated on MRE images included fibrofatty proliferation in 15 cases and mesenteric lymphadenopathy in 19 cases. MRE strongly correlates with CE in the detection of individual lesions expressing small intestinal Crohn's disease. It provides additional information from the mesenteries; however, its capability to detect subtle lesions is still inferior to conventional enteroclysis.

Abstract: BACKGROUND: In Crohn's disease (CD), studies associating phenotype at diagnosis and subsequent disease activity are important for patient counselling and health care planning. AIMS: To calculate disease recurrence rates and to correlate these with phenotypic traits at diagnosis. METHODS: A prospectively assembled uniformly diagnosed European population based inception cohort of CD patients was classified according to the Vienna classification for disease phenotype at diagnosis. Surgical and non-surgical recurrence rates throughout a 10 year follow up period were calculated. Multivariate analysis was performed to classify risk factors present at diagnosis for recurrent disease. RESULTS: A total of 358 were classified for phenotype at diagnosis, of whom 262 (73.2%) had a first recurrence and 113 patients (31.6%) a first surgical recurrence during the first 10 years after diagnosis. Patients with upper gastrointestinal disease at diagnosis had an excess risk of recurrence (hazard ratio 1.54 (95% confidence interval (CI) 1.13-2.10)) whereas age >/=40 years at diagnosis was protective (hazard ratio 0.82 (95% CI 0.70-0.97)). Colonic disease was a protective characteristic for resective surgery (hazard ratio 0.38 (95% CI 0.21-0.69)). More frequent resective surgical recurrences were reported from Copenhagen (hazard ratio 3.23 (95% CI 1.32-7.89)). CONCLUSIONS: A mild course of disease in terms of disease recurrence was observed in this European cohort. Phenotype at diagnosis had predictive value for disease recurrence with upper gastrointestinal disease being the most important positive predictor. A phenotypic North-South gradient in CD may be present, illustrated by higher surgery risks in some of the Northern European centres.

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Abstract: Several studies have shown alterations in vascular anatomy and physiology in inflammatory bowel disease (IBD). These findings, together with the observed upregulation of the mediators of angiogenesis in IBD patients, suggest that angiogenesis possibly contributes to the initiation and perpetuation of IBD. There is considerable evidence of an interrelationship between the mechanisms of angiogenesis and chronic inflammation in IBD. The increased expression of endothelial junction adhesion molecules found in IBD patients indicates the presence of active angiogenesis. Evidence that angiogenesis is involved in IBD was also obtained from animal models of colitis, most notably from studies of angiogenesis inhibition. Serum levels of vascular endothelial growth factor (VEGF) correlate with disease activity in human IBD and fall with the use of steroids, thalidomide, or infliximab. Pharmacological inhibition of angiogenesis, therefore, has the potential to be a therapeutic strategy in IBD. This review outlines the evidence that the rate of angiogenesis is increased in the inflamed intestine in IBD and proposes lines for future research in this field.

Abstract: BACKGROUND: The combination of intravenous iron and recombinant human erythropoietin has been proved to be effective in the treatment of refractory anaemia in patients with inflammatory bowel disease (IBD). Darbepoetin-alpha (DPO) has a three-fold longer terminal half-life than erythropoietin. The purpose of this pilot study was to determine whether darbepoetin-alpha is also effective for the treatment of refractory anaemia in IBD. METHODS: Twenty IBD patients (nine ulcerative colitis and 11 Crohn's disease) and refractory anaemia received intravenous iron sucrose (total iron dose 1.3+/-0.5 g, range 0.7-1.9) and darbepoetin-alfa at the single, weekly dose of 0.9 microg/kg subcutaneously for 4 weeks. Serum erythropoietin, ferritin, transferrin, soluble transferrin receptor, C-reactive protein and interleukin-6 were measured at baseline and after treatment. RESULTS: Haematopoietic response (increase of haemoglobin > or = 2.0 g/dl) was observed in 15 out of the 20 patients (75%). The mean haemoglobin concentrations increased from 9.48+/-0.82 g/dl at baseline to 12.71+/-1.12 g/dl after treatment (P<0.0001). Mean corpuscular volume and serum ferritin levels were also significantly increased whereas mean C-reactive protein levels and endogenous erythropoietin levels significantly decreased after treatment. CONCLUSIONS: In IBD patients with refractory anaemia the administration of darbepoetin in combination with intravenous iron sucrose can raise haemoglobin levels.

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Abstract: BACKGROUND: Angiogenesis has been suggested to play an important role in inflammatory bowel disease (IBD). The aim of the study was to evaluate the serum markers of angiogenesis angiopoietin-2 (Ang-2) and soluble angiopoietin receptor Tie-2 in patients with ulcerative colitis (UC) and Crohn's disease (CD). MATERIALS AND METHODS: Serum Ang-2 and Tie-2 serum levels were measured in 160 IBD patients (79 UC and 81 CD) and in 80 matched healthy controls using commercially available enzyme-linked immunosorbent assays. Serum Ang-2 and Tie-2 levels were correlated with the disease activity, as well as the type, localization and treatment of the disease. RESULTS: Median serum Ang-2 and Tie-2 levels were significantly higher in both the UC patients and the CD patients compared with the healthy controls (P < 0.05 and P < 0.001, respectively). The IBD patients with early disease (diagnosis < 2 years) had significantly higher (P = 0.04) median serum Ang-2 levels but significantly lower (P = 0.02) median serum Tie-2 levels as compared with IBD patients with late disease (diagnosis > 2 years). The CD patients with active disease had significantly higher levels of Ang-2 compared with non-active disease (P = 0.02). Serum levels of both Ang-2 and Tie-2 were not correlated with laboratory markers such as ESR, CRP, white blood cell count, platelet count and albumin. CONCLUSIONS: Serum Ang-2 and Tie-2 levels are elevated in patients with IBD. These markers may mediate angiogenesis and vascular permeability in the mucosa of patients with IBD.

Abstract: BACKGROUND: There is evidence that adipocytokines play an important role in metabolism and in inflammation. Because human metabolism dramatically changes in inflammatory bowel disease (IBD) and chronic inflammation is the hallmark of the disease, we studied serum levels of leptin, adiponectin, resistin, and ghrelin in patients with ulcerative colitis (UC) and Crohn's disease (CD) in comparison with healthy controls (HC). METHODS: Leptin, adiponectin, resistin, and active ghrelin serum levels were measured in 100 IBD patients (46 UC and 54 CD) and in 60 matched HC using commercially available enzyme-linked immunosorbent assays. Leptin, adiponectin, resistin, and ghrelin levels were correlated with disease activity, type, localization, and treatment. RESULTS: Mean serum leptin levels were 10.6+/-2.0 ng/mL in UC patients, 12.5+/-2.6 ng/mL in CD patients, and 15.0+/-1.8 ng/mL in HC (P=.01). Mean serum adiponectin levels were 9514.8+/-787.8 ng/mL in UC patients, 7651.1+/-613 ng/mL in CD patients, and 7270.6+/-559.4 ng/mL in HC (P=.05). Mean serum resistin levels were 21.2+/-2.2 ng/mL in UC patients, 18.7+/-1.6 ng/mL in CD patients and 11.8+/-0.6 ng/mL in HC (P=.0002). Mean serum ghrelin levels were 48.2+/-4.2 pg/mL in UC patients, 49.4+/-4.6 pg/mL in CD patients and 14.8+/-3.0 pg/mL in HC (P<.0001). Serum levels of these adipocytokines were not correlated with either C-reactive protein levels or the clinical indices of activity. No association between serum adipocytokines levels and disease localization in both UC and CD patients was found. Only serum ghrelin was significantly higher in ileal compared with colonic CD (P=.04). CONCLUSIONS: Serum levels of adiponectin, resistin, and active ghrelin are increased whereas serum levels of leptin are decreased in patients with IBD. Further studies are needed to elucidate the role of adipocytokines in IBD.

Abstract: Anorexia, malnutrition, altered body composition and development of mesenteric obesity are well known features of inflammatory bowel disease (IBD). Recent data suggest that dysregulation of protein secretion by white adipose tissue is involved in these manifestations of patients with IBD. Adipocytes are recently recognized as endocrine cells that secrete a variety of bioactive substances known as adipocytokines. There is evidence that adipocytokines are involved in inflammatory and metabolic pathways in human beings. Overexpression of adipocytokines such as leptin, adiponectin and resistin in mesenteric adipose tissue of operated patients with Crohn's disease has recently been reported, suggesting that mesenteric adipocytes in IBD may act as immunoregulating cells. Therefore, it could be suggested that adipocytokines play an important role in the disease pathogenesis. Moreover, modulators of mesenteric adipose function have been suggested as potential therapeutic drugs in IBD. In this review, the importance of white adipose tissue function and adipocytokines, is discussed with respect to IBD.

Abstract: Pancreatic autoantibodies (PAbs) have been suggested as a specific but not sensitive marker for Crohn's disease (CD). The aim of this study was to assess the value of detecting PAbs in Greek patients with ulcerative colitis (UC) and CD. Sera were collected from 150 patients with IBD (73 with UC and 77 with CD), 31 cases with non-IBD intestinal inflammation, 16 cases with other autoimmune diseases, and 104 healthy controls. Determination of PAbs was performed by a standard indirect immunofluorescence technique. PAbs were detected in 18 of 73 (24.7%) samples from UC patients and in 32 of 77 (41.6%) samples from CD patients. The prevalence of positive PAbs was significantly higher in CD than in UC (P = 0.04). None of the 104 samples from healthy controls and the 31 cases with non-IBD intestinal inflammation had detectable PAbs. One patient with Sjogren's syndrome was PAbs positive. No association of PAbs with IBD activity, IBD localization, or medical treatment was found. Patients with stenotic CD had a significantly higher prevalence of PAbs positivity (60%) compared with patients with inflammatory (28.6%) and fistulizing (41.2%) disease (P = 0.02). The prevalence of PAbs in Greek CD patients was found to be similar to that in previous reports. In contrast to these studies we found also increased prevalence of PAbs in UC patients. These findings suggest that PAbs should be considered as a specific marker for IBD rather than for CD.

Abstract: Inflammatory bowel disease (IBD) is associated with an increased risk of vascular complications. The most important of these complications are arterial and venous thromboembolism, which represent a significant cause of morbidity and mortality in IBD patients. Recent data suggest that thromboembolism is a disease-specific extraintestinal manifestation of IBD. The most common thrombotic manifestations in IBD are deep vein thrombosis of the leg and pulmonary emboli. It has been suggested that disease activity and the extent of colonic localization are correlated with the risk of developing thromboembolism. The occurrence of thrombosis in patients with IBD is partially attributed to the existing hypercoagulable state in IBD. Both coagulation and fibrinolysis are activated in patients with IBD; this is especially true for those with active disease. The most common risk factors for thrombophilia in IBD patients with venous thromboembolism are Leiden mutation in the gene encoding factor V, hyperhomocysteinemia, and antiphospholipid antibodies. The main genetic defects that have been established as risk factors for venous thrombosis are rather uncommon in IBD, but when present increase the risk of thromboembolism. Screening for coagulation defects seems justified only in IBD patients with a history of thrombosis or a family history of venous thromboembolic events. Antithrombotic treatment of IBD patients with venous thromboembolism is similar to that of thrombotic non-IBD patients.

Abstract: BACKGROUND: Segmental colitis associated with diverticulosis (SCAD) has been defined as chronic colonic inflammation surrounding diverticula with rectal sparing. Distinguishing this condition from inflammatory bowel disease may be difficult. Our aim was to evaluate the epidemiological and clinical characteristics of SCAD in our area. METHODS: Retrospective case identification with prospective follow-up was done. Patients with endoscopic findings suggestive of SCAD were enrolled. The epidemiological, clinical, and histological characteristics of these patients were analyzed. RESULTS: Out of 605 patients with diverticulosis, 23 cases of SCAD were identified (3.8%). Four patients had histological characteristics suggestive of ulcerative colitis, in 1 case the histology was suggestive of ischemic colitis, 6 patients had histology compatible with SCAD, and the remaining patients had either transitional mucosa or minimal lesions. Four cases were refractory to conservative treatment (mesalamine and antibiotics) and surgery was required. No cases of extension of colonic inflammation in diverticula-free areas were found. CONCLUSIONS: Segmental colitis associated with diverticulosis is not a rare disorder. It may occur with a spectrum of clinical and histologic features and may be confused with ulcerative colitis. The majority of the cases respond to medical therapy with antibiotics and/or mesalamine, whereas few cases are refractory and need surgery. No evolution to inflammatory bowel disease was observed.

Abstract: Oxidative stress and depletion of antioxidants may play a key role in the pathogenesis of inflammatory bowel disease (IBD)-related intestinal damage. A new automated assay for the determination of blood total antioxidant capacity (TAC), based on the crocin bleaching method, has been used for the measurement of TAC and corrected TAC (cTAC) in patients with ulcerative colitis (UC) and Crohn's disease (CD) in comparison to healthy controls (HC). Ninety-four patients with UC, 97 patients with CD, and 72 HC were included in this study. Serum TAC was measured in all patients and controls on an Olympus AU-600 chemistry analyzer using a TAC kit. cTAC was calculated from TAC after subtraction of the interactions due to endogenous uric acid, bilirubin and albumin. Mean serum TAC as well as cTAC levels were significantly lower in both UC and CD patients compared with HC (P < 0.0001). Patients with active UC had no different TAC and cTAC compared to those with inactive disease. Patients with active CD had significantly lower mean TAC compared to those with inactive disease but cTAC was not different between the two phases of disease activity. Patients with proctitis had significantly higher TAC and cTAC compared to patients with left-sided colitis and total colitis. In CD patients no association between disease localization and these markers was found. TAC and cTAC are significantly reduced in IBD patients compared with controls irrespective of disease activity. The decreased antioxidant defenses may be a primary phenomenon severely compromising the mucosa and therefore increase susceptibility to oxidative tissue damage.

Abstract: Angiogenesis-promoting cytokines have been suggested to play an important role in inflammatory bowel disease (IBD) since they promote inflammation by increasing vascular permeability and mediate tissue repair by activating fibroblasts. The aim of the present study was to evaluate the serum levels of angiogenin, a potent angiogenic factor, in patients with ulcerative colitis (UC) and Crohn's disease (CD). Angiogenin serum levels were measured in 154 IBD patients (78 UC and 76 CD), in 18 cases with other causes of intestinal inflammation, and in 84 matched healthy controls using a commercially available enzyme-linked immunosorbent assay. Angiogenin levels were assessed in terms of disease activity, type, localization, and treatment. Mean (+/-SD) serum angiogenin levels were 526.5+/-224.1 ng/ml in UC patients, 508.8+/-228.5 ng/ml in CD patients, 394.6+/-137.6 ng/ml in healthy controls, and 448.1+/-167.8 ng/ml in patients with non-IBD intestinal inflammation. A statistically significant difference among the mean levels of angiogenin in the four groups was found (P = 0.0003). IBD patients with early disease had a significantly lower mean serum angiogenin compared with patients with late disease (P = 0.03). No significant association between angiogenin levels and disease activity, localization, disease type, or treatment was found. Serum angiogenin is elevated in patients with IBD. The increased serum angiogenin suggests that angiogenin may mediate angiogenesis and vascular permeability in the mucosa of patients with IBD.

Abstract: BACKGROUND: Inflammatory bowel disease is associated with an increased incidence of thromboembolic complications. The aim of this study was to investigate the role of the soluble CD40 ligand (sCD40L), which displays prothrombotic properties, in patients with ulcerative colitis (UC) and Crohn's disease (CD) in comparison with inflammatory and healthy controls. METHODS: Plasma levels of sCD40L, prothrombin fragment 1+2 (F1+2), thrombin-antithrombin (TAT) complex and soluble P-selectin were measured in 104 inflammatory bowel disease patients (54 ulcerative colitis and 50 Crohn's disease), in 18 cases with other causes of intestinal inflammation and in 80 healthy controls using commercially available enzyme-linked immunosorbent assays. Plasma levels of sCD40L were correlated with disease activity, type, localization and treatment as well as with the measured thrombophilic parameters. RESULTS: CD patients had significantly higher sCD40L levels than both groups of controls (CD vs HC P < 0.001; CD vs non-IBD P < 0.05). UC patients had higher but not significantly different sCD40L levels compared with the controls. Both UC and CD patients with active disease had significantly higher sCD40L levels in comparison with patients with inactive disease. Plasma levels of sCD40L were correlated with platelet count (r = 0.27, P = 0.001). They also showed a correlation with prothrombin F1+2 (r = 0.16, r = 0.03) and TAT (r = 0.15, r = 0.04) as well as with P-selectin (r = 0.19, P = 0.01). CONCLUSIONS: The increased sCD40L plasma levels may represent, at least in some degree, a molecular link between inflammatory bowel disease and the procoagualant state.

Abstract: Hepatocellular carcinoma (HCC) patients have an increased risk for venous thromboembolism, mainly portal venous thrombosis (PVT). The aim of this study was to assess the role of acquired and hereditary thrombotic risk factors in HCC patients. Thirty-one patients with HCC, 30 patients with cirrhosis but without HCC or PVT, and 48 matched healthy controls were studied. Mean levels of plasma protein C, protein S, antithrombin, and serum lipoprotein (a) were significantly lower in patients with HCC and in the cirrhotic group compared to the healthy controls. Mean serum homocysteine levels were significantly higher in patients with HCC compared to cirrhotics and healthy controls. The prevalence of activated protein C resistance, factor V Leiden mutation, prothrombin gene mutation G20210GA, and C677T methylenetetrahydrofolate reductase polymorphism was not significantly different among the three groups. In conclusion, thrombophilic defects are common in HCC patients and they might contribute to the observed thrombotic complications in this malignancy.

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Abstract: PURPOSE: To evaluate the use of pentavalent (V) technetium 99m (99mTc) dimercaptosuccinic acid (DMSA) scintigraphy for the assessment of disease activity in patients with inflammatory bowel disease (IBD). MATERIALS AND METHODS: 99mTc (V) DMSA scintigraphy was performed in 76 patients. There were 36 patients with active IBD (11 with ulcerative colitis, 25 with Crohn disease), 28 patients with inactive disease (eight with ulcerative colitis, 20 with Crohn disease), and 12 patients with miscellaneous bowel disease. Sensitivity and specificity of 99mTc (V) DMSA scintigraphy in the diagnosis of IBD were calculated. In the group with active IBD, the disease activity and laboratory indices, as well as the endoscopic and histologic activity, were compared with the scanning activity index. Correlation coefficients between them were calculated with the Spearman rank test. RESULTS: 99mTc (V) DMSA scintigraphy had a 92% (33 of 36) sensitivity and an 86% (24 of 28) specificity in the detection of active IBD. A significant correlation between disease activity indices and scintigraphy score was demonstrated. Endoscopic and histologic activity was significantly correlated (P =.005 and.02, respectively, overall disease activity) with the scanning activity score. Of the group of patients with miscellaneous bowel disease, three with ischemic colitis had negative findings at scintigraphy. CONCLUSION: 99mTc (V) DMSA scintigraphy provides a noninvasive, practical, and accurate assessment of IBD activity.

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Abstract: BACKGROUND AND AIMS: Initiation of a fibrotic process has been suggested as part of the intestinal response to chronic inflammation in inflammatory bowel disease. YKL-40 has been proposed as a new serum marker of fibrosis. We studied compared the serum levels of YKL-40 in patients with ulcerative colitis or Crohn's disease with inflammatory and healthy controls. PATIENTS AND METHODS: YKL-40 serum levels were measured in 179 patients with inflammatory bowel disease (94 ulcerative colitis, 85 Crohn's disease), in 23 with intestinal inflammation of other causes, and 70 matched healthy controls using a commercially available enzyme-linked immunosorbent assay. YKL-40 levels were assessed in terms of disease activity, type and localization. RESULTS: Mean serum YKL-40 levels were 102.6+/-82.7 ng/ml in ulcerative colitis patients and 112.2+/-83.7 ng/ml in Crohn's disease patients, significantly higher than in healthy controls (64.1+/-21.4 ng/ml) but not significantly different from inflammatory controls (77.8+/-23.1 ng/ml). Disease activity and C-reactive protein levels were significantly correlated with YKL-40 levels in both ulcerative colitis and Crohn's disease. Crohn's disease patients with ileum localization had significantly higher YKL-40 levels than those with ileocolonic or colonic disease. Patients with stenotic disease had mean YKL-40 levels not significantly different than those with nonstenotic disease. CONCLUSION: Serum levels of YKL-40 are increased in patients with inflammatory bowel disease, and this is associated with the inflammatory process rather than with the degree of fibrosis.

Abstract: BACKGROUND: Although endometriosis with sigmoid serosal involvement is not uncommon in women of childbearing age, the mucosal involvement is rare and differential diagnosis from colon cancer may be difficult due to the lack of pathognomonic symptoms and the poor diagnostic yield of colonoscopy and colonic biopsies. CASE PRESENTATION: We present a case of a young woman with sigmoid endometriosis, in which the initial diagnostic workup suggested colon cancer. Histologic evidence, obtained from a second colonoscopy, along with pelvic ultrasound findings led to the final diagnosis of intestinal endometriosis which was confirmed by laparoscopy. CONCLUSION: Colonic endometriosis is often a diagnostic challenge and should be considered in young women with symptoms from the lower gastrointestinal tract.

Abstract: Hypercoagulable states have been suggested to play an important role in the pathogenesis of ischemic colitis. Since protein Z is, as recently demonstrated, important in the regulation of coagulation, we investigated the plasma levels of protein Z in connection to factor V Leiden (FVL) and anti-phospholipid antibodies in patients with a definite diagnosis of ischemic colitis. The plasma levels of protein Z were measured using a commercially available enzyme-linked immunosorbent assay in 33 patients with ischemic colitis, 13 patients with diverticulitis, and 33 healthy controls. Mean plasma protein Z levels were 1.38 +/- 0.52 microg/ml in patients with ischemic colitis and were significantly lower compared to healthy controls (1.86 +/- 0.49 microg/ml) and patients with diverticulitis (1.72 +/- 0.53 microg/ml) (P = 0.001). Protein Z deficiency was found in patients cases with ischemic colitis (18.2%) compared to one with diverticulitis (7.7%) and one healthy control (3.0%). In conclusion, our results suggest that low plasma protein Z levels may play a role in the disease development in some cases with ischemic colitis.

Abstract: BACKGROUND:/Aims: Laminin and collagen IV have been proposed as extracellular matrix serum markers. Because fibrosis is a major complication of inflammatory bowel disease, serum concentrations of laminin and collagen IV were measured in patients with ulcerative colitis (UC) and Crohn's disease (CD) and compared with inflammatory and healthy controls. METHODS: Laminin and collagen IV serum concentrations were measured in 170 patients with inflammatory bowel disease (86 UC and 84 CD), in 23 patients with other causes of intestinal inflammation, and in 80 matched healthy controls using commercially available enzyme linked immunosorbent assays. Laminin and collagen IV concentrations were correlated with disease activity, type, localisation, and treatment. RESULTS: Mean (SD) serum laminin concentrations were 281.0 (110.1) ng/ml in patients with UC, 275.6 (106.7) ng/ml in patients with CD, 192.0 (17.8) ng/ml in healthy controls, and 198.5 (32.5) ng/ml in inflammatory controls. Mean (SD) serum collagen IV concentrations were 72.8 (22.9) ng/ml in patients with UC, 71.0 (18.2) in patients with CD, 79.8 (12.2) ng/ml in healthy controls, and 88.9 (24.6) ng/ml in inflammatory controls. There was a significant difference among the four groups (p < 0.0001) for both markers. There was a strong correlation between serum laminin, but not collagen IV, and disease activity in both diseases. No significant association was found between these markers and disease localisation or disease type. CONCLUSIONS: Serum concentrations of laminin are increased, whereas serum concentrations of collagen IV are decreased, in patients with inflammatory bowel disease. They may be useful surrogate markers for sustained inflammation and tissue remodelling.

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Abstract: OBJECTIVES: To study the frequency and specificity of acquired coagulation inhibitors in inflammatory and malignant gastrointestinal diseases. METHODS: In a 10-year period, 511 patients from the island of Crete in Greece were studied, 302 with ulcerative colitis, 112 with Crohn's disease, 82 with gastrointestinal carcinoma and 15 with gastrointestinal lymphoma. Prothrombin time and activated partial thromboplastin time were measured by routine methods. When prothrombin time and/or activated partial thromboplastin time were found to be prolonged, mixture experiments with 25%, 50% and 75% pooled normal human plasma were performed. If clotting times were inadequately corrected, the presence of an acquired inhibitor against a coagulation factor was suggested. Specific coagulation factor assays were then performed with deficient plasmas. RESULTS: Fifteen patients acquired inhibitors to the following coagulation factors within the 10-year observation period: factor IX (four patients); factor X (three patients); factor XII (three patients); factor VIII (two patients); factor XI (two patients); and factor V (one patient). The activity of the above factors varied from < 1% to 10%. Five patients with ulcerative colitis, six with Crohn's disease, two with gastrointestinal lymphoma and two with gastrointestinal carcinoma developed an inhibitor. Only one patient with factor VIII inhibitor presented with severe bleeding and was treated with recombinant human activated factor VII, while the others had no complications. Remission was obtained in all patients after immunosuppressive therapy, chemotherapy or tumour resection. CONCLUSION: An increased incidence of coagulation factor inhibitors was found in patients with gastrointestinal inflammatory and malignant diseases compared to the healthy population. In addition, an increased incidence of these inhibitors was also found in the common population of Crete compared to that found in other areas.

Abstract: OBJECTIVE: A dysregulated local immune defence with a constant influx of leucocytes provides a basis for continuous intestinal inflammation in ulcerative colitis and Crohn's disease. Since vascular adhesion protein 1 (VAP-1) is one of the adhesion molecules that mediates lymphocyte binding to endothelium, we investigated the levels of soluble VAP-1 (sVAP-1) in the sera of inflammatory bowel disease (IBD) patients compared with healthy controls. METHODS: sVAP-1 serum levels were measured in 161 IBD patients (90 ulcerative colitis, 71 Crohn's disease) and 93 controls using a commercially available enzyme-linked immunosorbent assay (ELISA). sVAP-1 levels were correlated with disease activity and localization. In 42 patients, sVAP-1 levels were measured in both the active and inactive phases of the disease. RESULTS: sVAP-1 serum levels were detected in all control and IBD subjects. Mean sVAP-1 levels were 365.5 +/- 153.5 ng/ml in ulcerative colitis patients, 336.4 +/- 172.8 ng/ml in Crohn's disease patients, and 344.7 +/- 150.4 ng/ml in healthy controls. The differences between the groups were not significant. No association between disease activity or disease localization and sVAP-1 was found. CONCLUSIONS: sVAP-1 serum concentrations are not significantly different in IBD and healthy control subjects. sVAP-1 serum levels are of no value in the assessment of disease activity or severity of inflammation in patients with IBD.

Abstract: BACKGROUND: Intestinal tuberculosis is a rare disease in western countries, affecting mainly immigrants and immunocompromised patients. Intestinal tuberculosis is a diagnostic challenge, especially when active pulmonary infection is absent. It may mimic many other abdominal diseases. CASE PRESENTATION: Here, we report a case of isolated colonic tuberculosis where the initial diagnostic workup was suggestive of Crohn's disease. Computed tomography findings however, raised the possibility of colonic tuberculosis and the detection of acid-fast bacilli in biopsy specimens confirmed the diagnosis. CONCLUSIONS: In conclusion, this case highlights the need for awareness of intestinal tuberculosis in the differential diagnosis of chronic intestinal disease

Abstract: Besides a genetic predisposition, a causal role of various environmental factors has been considered in the etiology of ulcerative colitis (UC). The association between appendectomy and UC has recently been the subject of intense scrutiny in the hope that it may lead to the identification of important pathogenetic mechanisms. Published data from animal models of colitis demonstrated reduction in experimental colitis after appendectomy, especially if performed at an early age. Several epidemiological case control and cohort studies have shown a strong and consistent relationship. The metaanalysis of 17 case-controlled studies showed an overall odds ratio 0.312 (95% confidence intervals = 0.261-0.373) in favor of appendectomy (p < 0.0001). One of the two recent large cohort studies is in agreement with these results, but the other failed to confirm them. All these studies have suggested that alterations in mucosal immune responses leading to appendicitis or resulting from appendectomy may negatively affect the pathogenetic mechanisms of UC. Further investigation of the role of appendectomy in UC is expected to open new fields for basic scientific research and may lead to the improvement of our understanding for the disease pathogenesis.

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Abstract: BACKGROUND & AIMS: Hypercoagulable states may play an important role in the pathogenesis of colon ischemia. Aim of this study was to assess this hypothesis investigating the role of acquired and hereditary thrombotic risk factors in patients with definite diagnosis of colon ischemia. METHODS: We compared the frequency of antiphospholipid antibodies, protein C, protein S, and antithrombin deficiencies, factor V Leiden, prothrombin gene mutation G20210GA, and methylenetetrahydrofolate reductase C677T in 36 patients (23 men, 13 women; mean age, 64.8 years) with colon ischemia, 18 patients with diverticulitis, and 52 healthy controls. RESULTS: The prevalence of antiphospholipid antibodies was significantly higher in patients with colon ischemia compared with inflammatory and healthy controls (19.4% vs. 0% and 1.9%). Among genetic factors, only factor V Leiden was significantly associated with colon ischemia (22.2% vs. 0% and 3.8%). A combination of thrombophilic disorders was found in 25% of the cases. Overall, one or several prothrombotic abnormalities were present in 26 patients (72%). CONCLUSIONS: A comprehensive thrombophilic screening in colon ischemia reveals a congenital or acquired thrombophilic state in 72% of patients. Hereditary and acquired thrombotic risk factors may play an important role in the disease pathogenesis.

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Abstract: OBJECTIVES: The combined measurement of perinuclear antineutrophil cytoplasmic autoantibodies (pANCA) and anti-Saccharomyces cerevisiae mannan antibodies (ASCA) has recently been suggested as a valuable diagnostic approach in inflammatory bowel disease (IBD). The aim of this study was to assess the value of detecting pANCA and ASCA in the differentiation between ulcerative colitis (UC) and Crohn's disease (CD) in a Greek population with IBD. METHODS: Sera were collected from 157 patients with IBD (97 with UC, 56 with CD, and four with indeterminate colitis) and 150 healthy controls. Determination of pANCA was performed by a standard indirect immunofluorescence technique on ethanol-fixed granulocytes and ASCA by an ELISA assay. RESULTS: In patients with UC, sensitivity, specificity, positive predictive value, and negative predictive value of the pANCA test was 67%, 84%, 93%, and 46% respectively. These values did not change significantly when the combination of positive pANCA and negative ASCA was used. ASCA test in diagnosing CD yielded a sensitivity, specificity, positive predictive value, and negative predictive value of 39%, 89%, 54%, and 81%. The combination of pANCA negative and ASCA positive increased the positive predictive value to 77% and it was associated with small bowel disease. CONCLUSIONS: A positive pANCA test in Greek patients has a diagnostic value in confirming a diagnosis of UC. Measurement of pANCA and ASCA together has a rather limited value in the differential diagnosis between UC and CD but may be of help in studying disease heterogeneity.

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Abstract: OBJECTIVES: We investigated whether the mean platelet volume would be a useful marker in the evaluation of inflammatory bowel disease activity. METHODS: Complete blood count, C-reactive protein, erythrocyte sedimentation rate, serum thrombopoietin and erythropoietin, plasma beta-thromboglobulin, and platelet factor 4 were measured in 93 patients with ulcerative colitis, 66 patients with Crohn's disease, and 38 healthy blood donors. Disease activity was assessed by the Clinical Colitis Activity Index in patients with ulcerative colitis and by the Crohn's Disease Activity Index in patients with Crohn's disease. RESULTS: Mean platelet count was increased in patients with active compared to inactive ulcerative colitis (p < 0.05), and in patients with active compared to inactive Crohn's disease (p = 0.0002) or healthy controls (p < 0.0001). On the other hand, mean platelet volume was significantly decreased in patients with active compared to inactive ulcerative colitis (p = 0.02) or healthy controls (p < 0.0001), and in patients with active compared to inactive Crohn's disease (p = 0.0005) or healthy controls (p < 0.0001). Mean platelet volume was inversely correlated with the white blood cell count (r = -0.17, p = 0.02), C-reactive protein (r = -0.46, p = 0.009) and erythrocyte sedimentation rate (r = -0.28, p = 0.008). No significant correlations were found between mean platelet volume and serum thrombopoietin or erythropoietin levels; however, a strong negative correlation between mean platelet volume and beta-thromboglobulin (r = -0.34, p < 0.0001) and platelet factor 4 (r = -0.30, p = 0.0002) was observed. CONCLUSIONS: Mean platelet volume is significantly reduced in active inflammatory bowel disease and is negatively correlated with the known inflammatory bowel disease activity markers and the platelet activation products. We propose that mean platelet volume provides a useful marker of activity in inflammatory bowel disease.

Abstract: The objective of this study was to measure the concentrations of tumor necrosis factor-alpha (TNFalpha) in pleural and peritoneal effusions of different causes and to verify whether TNFalpha, alpha-1-antitrypsin (alpha1AT), and complement factors C3 and C4 can be used in the differential diagnosis of serous effusion. One hundred forty-five serous effusions of various origins were analyzed. TNFalpha, alpha1AT, and complement factors C3 and C4 concentrations were measured simultaneously in blood and serous effusion using commercially available methods. Serous effusions were classified as follows: 102 exudates and 43 transudates. All variables were found to have good diagnostic value in the differential diagnosis of serous effusion. In the stepwise discriminant analysis, four variables were selected, producing a significant discriminant function (p < 0.001). Their order of selection was alpha1AT effusion, C4 serum, TNFalpha-effusion, and C3 effusion. Combined use of these variables increased remarkably the diagnostic value (in diagnosing exudates versus transudates) giving sensitivity = 93.14%; specificity = 90.70%; positive predictive value = 95.96%; negative predictive value = 84.78%. Determination of TNFalpha, complement factors C3 and C4, and alpha1AT may be a significant parameter in the differential diagnosis of serous effusions, particularly in those patients with malignant disease. Moreover, the combination of them significantly increased their diagnostic power.

Abstract: OBJECTIVE: Lipoprotein (a) is recognized as a risk factor for arterial and venous thrombosis, a property that might be related to its structural similarity to plasminogen. Since patients with inflammatory bowel disease frequently suffer from thromboembolic events, we studied the role of lipoprotein (a) in conjunction with lipids and apolipoproteins in Greek patients with ulcerative colitis and Crohn's disease. METHODS: Lipoprotein (a), total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, apolipoprotein A-1 and apolipoprotein B-100 were determined in sera from 129 consecutive fasting Greek patients with inflammatory bowel disease (66 with ulcerative colitis and 63 with Crohn's disease) and from 66 matched healthy controls. RESULTS: In Crohn's disease patients, the mean serum lipoprotein (a) level was significantly higher than in control patients (41.2 mg/dl vs 22.9 mg/dl; P = 0.005). Mean apolipoprotein A-1 and apolipoprotein B-100 levels were significantly lower in Crohn's disease patients than in the controls. In ulcerative colitis patients the mean levels of lipoprotein (a) and apolipoprotein A-1 were not significantly different to the controls, but the levels of apolipoprotein B-100 were significantly lower. Raised levels of lipoprotein (a) of > 30 mg/dl were found in 29 Crohn's disease patients (46%), 15 ulcerative colitis patients (23%) and 11 control patients (17%). Patients with active Crohn's disease had significantly higher mean lipoprotein (a) and lower apolipoprotein A-1 than patients with non-active disease. CONCLUSIONS: Our results suggest that Crohn's disease patients have different lipoprotein (a) and apolipoprotein patterns compared to ulcerative colitis patients and healthy controls. These changes in Crohn's disease patients may possibly expose them to a higher risk of thrombosis.

Abstract: Idiopathic fibrosing pancreatitis is an uncommon condition in children and adolescents of unknown aetiology. This syndrome has been reported in 36 cases so far. To our knowledge none of these cases was definitively associated with Crohn's disease. In this report we describe a young female patient who developed Crohn's disease of the colon 5 years after having been diagnosed with idiopathic fibrosing pancreatitis. The differential diagnosis between this syndrome associated with Crohn's disease and pancreatic Crohn's disease or fibrosing colonopathy, an entity related to pancreatic enzyme therapy, is discussed.

Abstract: OBJECTIVE: Patients with inflammatory bowel disease (IBD) frequently suffer from thromboembolic events. A recently identified mechanism for thrombophilia, the poor anticoagulant response to activated protein C, has been suggested as one of the leading risk factors for thrombosis. The aim of this study was to evaluate the frequency of thrombophilic abnormalities, including activated protein C-resistance (APCR), in Greek patients with ulcerative colitis (UC) and Crohn's disease (CD). METHODS: Forty-eight patients with UC, 36 with CD, and 61 matched healthy controls (HC) were studied. Cases with presence of lupus anticoagulant, use of anticoagulants or heparin, and pregnancy were excluded. Disease activity in CD was evaluated by use of the Crohns Disease Activity Index (CDAI) score and in UC by the Truelove-Witts grading system. Plasma levels of protein C, free protein S, antithrombin III (AT-III), activated protein C resistance (APCR), and fibrinogen were determined in IBD patients, as well as in HC. All the cases and controls with abnormal APCR were further studied by genetic testing for the factor V Leiden mutation. RESULTS: Mean fibrinogen levels in UC and CD patients were significantly elevated (p<0.0001), compared with HC. The mean values of free protein S, as well as mean APCR, were significantly lower in UC and CD patients than in the HC (p<0.0001). Seven (five UC and two CD) of 84 IBD patients (8.3%) and three of the HC (4.9%) had the factor V Leiden mutation. No significant difference was observed for the other thrombophilic parameters. Fibrinogen levels and profound free protein S deficiency were found related to disease activity. CONCLUSIONS: Thrombophilic defects are common in Greek patients with IBD and they could interfere either in the disease manifestation or in the thrombotic complications.

Abstract: OBJECTIVES: Elevated platelet count is a well recognized marker of inflammatory bowel disease (IBD) activity. Thrombopoietin (TPO) is a critical cytokine in the physiological regulation of thrombopoiesis. The aim of this study was to investigate the serum levels of endogenous TPO in patients with IBD, the relationship between platelet counts and TPO levels, and the correlation of TPO with the clinical characteristics of the patients. METHODS: TPO levels in 40 patients with Crohn's disease (CD), 63 patients with ulcerative colitis (UC), and in 42 healthy blood donors were assessed by ELISA. Platelet and white blood cell counts as well as C-reactive protein, and erythrocyte sedimentation rate were measured. RESULTS: TPO levels were significantly elevated in patients with CD (mean 124.3 +/- SD 58.0 pg/ml, p < 0.0001) and in patients with UC (mean 152.2 +/- SD 142.3 pg/ml, p < 0.0001), compared to controls (mean 53.4 +/- SD 45.7 pg/ml). TPO levels remained significantly elevated in remission (mean 144.7 +/- SD 131.1 pg/ml, p < 0.0001 compared to controls). Platelets were significantly elevated only in active CD, being normal in inactive disease as well as in all patients with UC. There was no significant correlation between TPO levels and various clinical characteristics of patients with IBD. No significant correlation was found between TPO levels and either platelet counts or white blood cell counts, erythrocyte sedimentation rate, and C-reactive protein. CONCLUSIONS: TPO levels are increased in IBD, irrespective of disease activity, platelet counts, and clinical characteristics of the patients. These observations indicate that TPO, apart from being a platelet producer, might have additional functions, probably related to the procoagulant state of IBD.

Abstract: In recent years hyperhomocysteinemia has been established as a new risk factor for arterial and venous thrombosis. Since patients with inflammatory bowel disease (IBD) frequently suffer from thromboembolic events, we studied the prevalence and clinical significance of hyperhomocysteinemia in Greek patients with ulcerative colitis (UC) and Crohn's disease (CD). In 108 consecutive fasting IBD patients (53 UC and 55 CD) and 74 healthy controls (HC), a standard record of various clinical thrombotic risk factors was completed by interview, and fasting serum concentrations of total homocysteine (tHcy), folate, cobalamin, creatinine, cholesterol, HDL, LDL, and triglycerides were measured. The concentration (mean +/- SD) of serum tHcy was significantly higher in UC (15.9 +/- 10.3 micromol/liter) and CD patients (13.6 +/- 6.5) than in controls (9.6 +/- 3.4, P < 0.05). Both UC and CD patients had lower levels of folate than HC (P < 0.05). Covariance analysis of age, gender, and all clinical variables indicated that the differences in homocysteine levels between IBD patients and HC remain significant even after adjustment for these covariates. In conclusion, mild hyperhomocysteinemia is common in Greek IBD patients and may account for the increased thrombotic risk of these patients.

Abstract: OBJECTIVE: Numerous epidemiological studies have been performed to determine risk factors that might contribute to the development of ulcerative colitis (UC). Recent studies have focused on the role of appendectomy in the disease's pathogenesis. This report aims to review and analyze the degree of evidence from recent published studies. METHODS: Medline and Embase databases were scrutinized for studies published between 1987 and January 1999. Reference lists from published articles, reviews, and abstracts from major gastrointestinal (GI) meetings were also reviewed. All studies specifically designed to evaluate the association between appendectomy and UC were selected. Thirteen studies that satisfied our selection criteria were evaluated by metaanalysis. RESULTS: The 13 case-control studies collectively gathered evidence from 2770 patients with UC and 3352 controls. Combining the results of the individual studies gave an overall odds ratio of 0.307 (95% confidence interval [CI] = 0.249-0.377) in favor of appendectomy (p<0.0001). This suggests that appendectomy gives a 69% reduction in the risk of developing UC (95% CI = 62%-75%). The test for heterogeneity (of all 13 studies) was not significant (chi2 = 16.213, d.f. = 12, p>0.10). The influence of potential confounding factors (mainly smoking) on these results could be excluded. CONCLUSIONS: The review of the literature and the metaanalysis of the selected studies suggest that the inverse association between appendectomy and UC is strong and consistent. Further studies are needed to establish whether a causal relationship exists.

Abstract: Thromboembolic disease is a significant cause of morbidity and mortality in patients with inflammatory bowel disease (IBD). It is recognized that a hypercoagulable state exists in IBD which involves all components of the clotting system. It has been suggested that this hypercoagulable state is closely linked to the disease pathogenesis. Recent studies have shown that genetic defects such as factor V Leiden mutation and C677T methylenetetrahydrofolate reductase polymorphism associated with hyperhomocysteinemia seem to interfere in the thrombotic manifestations of IBD. Acquired factors such as antiphospholipid antibodies could also participate in the development of the thrombotic process. Deficiencies of other anticoagulant factors play a less important role in the thrombosis, and therefore it is not surprising that the results on these factors in IBD are contradictory. In conclusion the resultant gene-gene and gene-environment interactions between risk factors are the key to the understanding of why an IBD patient develops thrombosis at a specific point in time.

Abstract: Primary biliary cirrhosis and ulcerative colitis are two diseases with many features of autoimmunity. Thirteen cases of coexistence of the two diseases have been reported in the literature so far. Patients are usually younger and more often males than the ordinary primary biliary cirrhosis patient, while the colitis is mild and easily controllable. In a homogeneous population of 550,000 inhabitants of the island of Crete, 412 cases of ulcerative colitis and 82 individuals with primary biliary cirrhosis or autoimmune cholangitis have been identified. In two cases, coexistence of the two diseases was found. Immunological screening for AMA positivity in 150 ulcerative colitis sera disclosed no further cases. Prevalence of primary biliary cirrhosis in ulcerative colitis patients seems at least 30 times higher than in the general population in our area. A possible immunological link between the two diseases is discussed.

Abstract: PURPOSE: Appendectomy has been suggested as a possible protective factor in ulcerative colitis and as a risk factor in Crohn's disease. Tonsillectomy has also been associated with Crohn's disease. We performed a case-controlled study to investigate these associations in a homogeneous Greek population. METHODS: One hundred thirty-four consecutive cases of ulcerative colitis and 76 cases of Crohn's disease were included in the study. For each inflammatory bowel disease patient and a corresponding healthy control subject, matched for gender, age, and educational level, a standard record on various risk factors was completed by interview. The association between disease status and risk factors was assessed by Pearson's chi-squared test and the independent contribution of each risk factor was analyzed by means of logistic regression analysis. RESULTS: Appendectomy had been performed in 11 (8.2 percent) patients with ulcerative colitis, in 18 (13.4 percent) of their matched healthy control cases, in 19 (25.0 percent) patients with Crohn's disease, and in 10 (13.2 percent) of their matched healthy control cases. Odds ratio for development of ulcerative colitis after appendectomy was 0.6 (95 percent confidence interval, 0.26-1.27). Odds ratio for Crohn's disease was 2.2 (95 percent confidence interval, 0.94-5.12). Odds ratio for development of ulcerative colitis or Crohn's disease after tonsillectomy was 0.95 (95 percent confidence interval, 0.49-1.82) and 3.29 (95 percent confidence interval, 1.29-8.37), respectively. The logistic regression analysis showed that appendectomy and tonsillectomy have no independent association with the risk of developing ulcerative colitis, whereas in Crohn's disease both appendectomy and tonsillectomy have positive associations. Well-established risk factors, such as family history and smoking status, were also verified in this study. CONCLUSIONS: This case-control study, using multivariate logistic regression analysis, showed a less pronounced association between ulcerative colitis and appendectomy than previous reports. Our data also support the conclusion that tonsillectomy is a risk factor for developing Crohn's disease.

Abstract: OBJECTIVES: To investigate the effect of somatostatin in acute severe bleeding from portal hypertensive gastropathy in 26 cirrhotic patients. METHODS: All patients with signs of acute gastrointestinal bleeding and an upper GI endoscopy (during the first 24 h) indicating overt bleeding from portal hypertensive gastropathy were included in the study. Somatostatin (or the synthetic tetradecapeptide, octreotide) was administered in all cases. Eleven patients received somatostatin and 15 patients received octreotide. An initial injection of 250 microg bolus somatostatin was followed by a continuous infusion of 250 microg/h for 3 days (100 microg and 50 microg/h for octreotide). RESULTS: Somatostatin arrested bleeding in all 26 patients and in 23 there was no hospital relapse. In the remaining three patients the bleeding recurred each time somatostatin infusion was discontinued and arrested again on reinstitution of treatment. In two there was a control of haemorrhage, while the third required a total gastrectomy after repeated episodes. The rebleeding rate in our study is much lower compared to untreated patients of other series. There were no differences between the somatostatin and octreotide group. There were no significant side effects. Gastroscopy at the end of the therapy showed improvement of the endoscopic appearance. CONCLUSIONS: This open study suggests that somatostatin is a safe and effective treatment of acute severe bleeding from portal hypertensive gastropathy.

Abstract: BACKGROUND: Common aetiopathogenic factors may explain the association of ulcerative colitis with autoimmune disorders such as systemic lupus erythematosus. PATIENTS: We report two cases of ulcerative colitis associated with idiopathic systemic lupus erythematosus: one patient who developed ulcerative colitis 11 years after having been diagnosed as a case of systemic lupus erythematosus and one case of simultaneous appearance of the two diseases. The lupus clinical manifestations were in neither case correlated with the treatment of ulcerative colitis. CONCLUSION: The association between ulcerative colitis and systemic lupus erythematosus is rare. Although a chance occurrence cannot be excluded it is possible that both conditions share some genetic or immunological defects.

Abstract: Patients with ulcerative colitis have an increased risk for developing colon cancer compared to the general population. The risk is related to the extension of the disease and its duration. This risk is the same for Crohn's colitis patients of equal extension and duration. By chemoprevention we mean the use of specific natural or synthetic chemical agents to reverse, suppress or prevent progression to invasive cancer. The chemopreventive agents for colon cancer are either of natural origin (vitamins, minerals, food constituents) or synthetic chemicals (difluoromethyl ornithine) and pharmaceutical agents (aspirin, oltipraz). Apart from folate, no other agent has so far been used in vivo for the prevention of colon cancer in long-standing inflammatory bowel disease. The use of folate was, however, not primarily intended to prevent cancer but to enhance folate absorption in ulcerative colitis. From retrospective studies, within the framework of cancer surveillance programmes, it became evident that folate supplementation may play a positive role as a chemopreventive agent against colorectal cancer in patients with long-standing, extensive ulcerative colitis. There is also evidence suggesting that folate supplementation may contribute to regulation of rectal cell proliferation in ulcerative colitis patients. There is a real need for multicentre, randomized, prospective clinical studies in order to evaluate the promising role of folate in preventing colorectal cancer in patients with long-standing inflammatory bowel disease.

Abstract: Patients with inflammatory bowel disease (IBD) frequently suffer from thromboembolic events. Anti-cardiolipin (aCL) antibodies have been shown to be associated with thrombosis. Recently, the antibodies against the anti-cardiolipin cofactor beta2-glycoprotein I (a(beta2)GPI) have been found with higher specificity for thrombosis. The presence of these antibodies was assessed in 128 patients with IBD [83 with ulcerative colitis (UC) and 45 with Crohn's disease (CD)] and 100 healthy controls (blood donors). Patients with UC and CD had a significantly higher prevalence of aCL (18.1% and 15.6%, respectively) than healthy controls (HC) (3%). Eleven IBD patients (8.6%) but no HC had a(beta2)GPI. None of the IBD patients with a history of thrombosis had aCL and only one of them (a UC patient with deep vein thrombosis of the right leg) had a high titer of IgG a(beta2)GPI. In conclusion, these data show that both aCL and a(beta2)GPI are significantly associated with IBD but further studies are needed to determine the significance of our findings.

Abstract: OBJECTIVE: To study the incidence of ulcerative colitis and to analyse the pattern of the disease in the prefecture of Heraklion, Crete. PARTICIPANTS: The population at risk comprised 263,670 inhabitants in the prefecture of Heraklion (2641 km2). The two regional hospitals, five health centres, 109 private family doctors and 145 specialists participated in the study. METHODS: A prospective and population-based epidemiological study of ulcerative colitis over five years from 1990 to the end of 1994. RESULTS: Overall, 117 patients with ulcerative colitis (75 males and 42 females) were newly diagnosed during the study period. The mean annual incidence of the disease for the years 1990-1994 was 8.9 per 10(5) inhabitants (95% CI 7.2-10.4). The male to female ratio was 1.8:1. There were no significant difference between the age-specific incidences of the age groups. The majority (51.3%) of the patients were exsmokers and one-third had never smoked. A family history of first-degree relatives positive for inflammatory bowel disease was obtained in 9.6% of our patients. CONCLUSION: Ulcerative colitis is common in Crete; its incidence is as high as in Northern Europe.

Abstract: BACKGROUND: There has been an impression from published work that Crohn's disease is less common in southern than in northern Europe. A low incidence of Crohn's disease has been observed in Greece, but conclusive data are still lacking. METHOD: A 5-year prospective and population-based epidemiologic study of Crohn's disease was carried out in a well-defined area of Crete. RESULTS: The mean annual incidence of the disease for the years 1990-94 was 3.0 per 10(5) inhabitants. During the study period the incidence increased from 1.9/10(5) in 1990 to 3.8/10(5) in 1994. The male to female ratio was 2.4:1. The age group 25-34 years had the highest age-adjusted incidence (6.3/10(5)). The incidence of Crohn's disease was also found to be higher in smokers, in urban areas, and in people with high educational level. CONCLUSION: Crohn's disease is common in Heraklion, Crete. The findings of the study are discussed in relation to those of other European countries.

Abstract: In 153 patients with IBD, 64 with Crohn's disease (CD), and 89 with ulcerative colitis (UC), as well as in 54 healthy controls (HC), the frequencies of four known di-allelic polymorphisms in the genes for TNF-alpha and lymphotoxin alpha (LTalpha) were investigated. In the Dutch population, the alleles of these four polymorphisms are present in only five combinations, called TNF haplotypes: TNF-C, -E, -H, -I, -P. Furthermore, the relation with the presence of perinuclear anti-neutrophil cytoplasmic autoantibodies (P-ANCA) was studied. A small, but statistically significant, association between the polymorphism at position -308 in the promoter region of the TNF-alpha gene and UC was found. The frequency of the uncommon TNF-alpha -308 allele 2 was found to be decreased in patients with UC compared with HC (allele frequency of allele 2 in UC patients 0-15 versus 0.25 in HC, P=0.044). No significant differences in distribution of the TNF haplotypes were found between IBD patients and HC, although there was a tendency towards a higher frequency of the TNF-C haplotype in UC patients compared with controls (haplotype frequency 22% versus 13%; P=0.19). No statistically significant differences in distribution of the TNF haplotypes were observed between P-ANCA-positive and P-ANCA-negative UC patients. The strength of the associations indicates that TNF genes are not markers for the predisposition to suffer from IBD. They may, however, be markers of subsets of patients with UC and CD.

Abstract: Besides a genetic predisposition, a causal role of various environmental factors have been taken into consideration in the etiology of inflammatory bowel disease (IBD). The most consistent association of environmental factors so far identified is the association between non smoking and ulcerative colitis (UC) as well a between smoking and Crohn's disease (CD). Other factors such as oral contraceptives, refined sugar, perinatal events, childhood infections, microbial agents, and domestic hygiene have been found to be associated with ulcerative colitis and Crohn's disease but further evaluation is required to confirm the consistency and to define the strength of the association. Recent data also suggest that measles virus may persist in intestinal tissue and early exposure to the virus may be a risk factor for development of CD. The further investigation of environmental factors on IBD and the explanation of their role is expected to open new avenues for basic scientific research and may lead to the development of a more rational approach to the prevention and treatment of IBD. The available data suggest that UC and CD are heterogeneous disorders of multifactorial etiology in which hereditary and environmental factors interact to produce the disease.

Abstract: OBJECTIVE: To investigate a polymorphism within intron 2 of the interleukin-1 receptor antagonist (IL-1ra) gene in a Dutch white population of patients with ulcerative colitis and Crohn's disease. DESIGN: Genotype and allele frequencies of the polymorphic region in the IL-1ra gene were determined in 111 unrelated patients with ulcerative colitis, 92 patients with Crohn's disease, and 86 healthy controls. METHODS: The polymorphic region on the IL-1ra gene was amplified by the polymerase chain reaction (PCR). The resultant products were analyzed by electrophoresis on 2% agarose gels and stained with ethidium bromide. Amplification of the second exon of HLA-DRB1, HLA-DQA1, and HLA-DQB1 genes was performed by PCR, and Dot-blot analysis with biotin-labelled sequence-specific oligonucleotide probes was used for HLA typing. The standard perinuclear antineutrophil cytoplasmic antibodies (pANCA) indirect immunofluorescence assay was performed according to the protocol described by the First International Workshop on ANCA. RESULTS: The frequency of allele 2 of the IL-1ra gene in ulcerative colitis (27.0%) and Crohn's disease patients (25.5%) did not differ significantly from healthy controls (23.8%). However, the estimate of the relative risk for carriers of allele 2 for ulcerative colitis [odds ratio (OR): 1.35, 95%-confidence interval (CI) from 0.73 to 2.49] was in agreement with a previous British study. The exact test for homogeneity of odds ratios provided no evidence for heterogeneity between both populations (P = 0.35) and therefore confirmed the genetic associated between ulcerative colitis and the IL-1ra allele 2 in a different population. Our data confirm that, in ulcerative colitis, the presence of this allele is a genetic marker for severity of the disease. A significant association was demonstrated between the carriership of allele 2 of the IL-1ra gene and the trend over the three localizations in ulcerative colitis (P = 0.023). The same approach for Crohn's disease when compared with healthy controls did not provide evidence for a similar association. The meta-analysis, based on the British data and our data, yielded: OR = 1.06, 95%-CI from 0.71 to 1.59, and P = 0.767. No association between IL-1ra gene polymorphism, and pANCA and the HLA-DR2 allele was found in ulcerative colitis.

Abstract: Recent reports have shown that allele 2 of the IL-1 receptor antagonist (IL-1Ra) gene is over-represented in ulcerative colitis (UC). Healthy individuals carrying allele 2 of this gene have increased production of IL-1Ra protein. Since the final outcome of the biological effects of IL-1 beta may depend on the relative proportion of these two cytokines, we have studied if a TaqI polymorphism in the IL-1 beta gene, which is relevant to IL-1 beta protein production, may be involved in the genetic susceptibility to UC and Crohn's disease (CD), in association with the established IL-1Ra gene polymorphism. Polymorphisms in the closely linked genes for IL-1 beta and IL-1Ra were typed in 100 unrelated Dutch patients with UC, 79 with CD, and 71 healthy controls. The polymorphic regions in exon 5 of the IL-1 beta gene and in intron 2 of the IL-1Ra gene, were studied by polymerase chain reaction (PCR)-based methods. The IL-1 beta allele frequencies in UC and CD patients did not differ from those in healthy controls. In order to study if the IL-1 beta gene polymorphism might participate synergistically with the IL-1Ra gene polymorphism in susceptibility to UC and CD, individuals were distributed into carriers and non-carriers of allele 2 of the genes encoding IL-1 beta and IL-1Ra, in each of the patient groups and controls. Results indicated a significant association of this pair of genes, estimated by the odds ratio (OR) after performing Fisher's exact test, in the UC group (P = 0.023, OR = 2.81), as well as in the CD group (P = 0.01, OR = 3.79). Thus, non-carriers of IL-1 beta allele 2 were more often present in the subgroup of patients carrying the IL-1Ra allele 2. By contrast, no association of these alleles was detected in the group of healthy controls (P = 1.00, OR = 0.92). These results suggest that the IL-1 beta/IL-1Ra allelic cluster may participate in defining the biological basis of predisposition to chronic inflammatory bowel diseases.

Abstract: