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Patient: Female, 13 Final Diagnosis: Multiorgan failure as a sequelae of advanced liver disease Symptoms: A lysosomal enzyme defect • abnormal bilirubin level • abnormal lipid profile • cardiovascular complications • Child-Pugh A/B • cholestasis and/or gallbladder dysfunction • chronic and florid fibroplastic cholecystitis • frequent diarrhoea • greatly elevated hepatic content of cholesteryl esters • hepatic fibrosis • hepatomegaly • hepatosplenomegaly with thrombocytopenia • increasing jaundice • increasing transaminases • Lab-MELD 14 cirrhosis • malabsorption • oesophageal varices (Grade III) • orange-yellow liver • pressure in the right epigastrium • steatorrhoea • symptomatic gallstones • Vitamin D deficiency Medication: — Clinical Procedure: — Specialty: Gastroenterology and Hepatology Objective: Rare disease Background: Cholesteryl ester storage disease (CESD), also known as lysosomal acid lipase deficiency (LAL-D), is a rare autosomal-recessive inheritable lysosomal storage disease. Since 2015, a causal treatment with sebelipase alfa, which replaces the missing LAL enzyme, has been approved. We report a fatal course of LAL-D in a female patient. Case Report: In 1979, CESD was first diagnosed in a 13-year-old female with marked hepatomegaly. At that time, no specific treatment for CESD was available and the spontaneous course of the disease had to be awaited. In 2013, a laparoscopic cholecystectomy for symptomatic gallstones was performed. The patient’s CESD had caused a Child-Pugh A/B and Lab-MELD 14 cirrhosis with esophageal varices (grade III), a solitary fundal varix, as well as hepatosplenomegaly with thrombocytopenia. In 2016, the patient was admitted with compensated cirrhosis and splenomegaly for a ligature of esophageal varices which was complicated by vomiting of blood followed by severe coagulopathy and hemorrhagic shock. The dried blood test showed reduced acid lipase (0.03 nmol/spot*3 hours; reference range 0.2–2) and beta-galactosidase (0.08 nmol/spot*21 hours; reference range 0.5–3.2). Then 15 days after the esophageal varices bleed, the patient died due to multiorgan failure as a sequelae of advanced liver disease. Conclusions: LAL-D should be included in the differential diagnosis of lipid metabolism disorder, hepatomegaly, and non-alcoholic fatty liver disease with fibrosis or cirrhosis. Causal treatment with sebelipase alfa should be introduced even in patients who have LAL-D and many years of clinically mild symptoms of this disease to prevent the serious sequelae of cirrhosis or cardiovascular complications.

Aim Physical exercise is important in the prevention and treatment of cardiovascular diseases. Nevertheless, controversy remains around type and intensity of effort required for significant biochemical protective changes. This study investigates two exercise protocols on ventricular oxidative parameters in rats post-infarction. Main methods Thirty-six 2-month-old male Wistar rats were divided in two groups (n = 18): Sham and acute myocardial infarction (AMI) conducted by blocking the coronary artery. Thirty days after AMI, animals were divided in 6 subgroups (n = 6): sham, sham + continuous training (60 min), sham + interval training, AMI, AMI + continuous training, and AMI + interval training. Training was conducted in water (30–32 °C) 5 times a week for 6 weeks. Animals were sacrificed 48 h after the last exercise routine. Left ventricles were used for oxidative stress analyses (antioxidant enzyme activity and level, oxidative damage) and HIF1α and cit c oxidase expression. Key findings After AMI, both exercise models decreased superoxide levels significantly. Training routines did not alter SOD expression and activity, though CAT expression increased with continuous training and GPX level diminished in both training groups, which coincided with the increase in GPX activity. Lipid damage decreased only in the continuous training group, while protein damage decreased only in the interval training group. Cytochrome C increased in both groups, while HIF-1 α dropped significantly after both exercise protocols. Significance Significant improvement occurred in myocardium redox status in rats challenged with AMI after different training routines. However, continuous training seems to be more efficient in improving the parameters analyzed.

Background: Mesalamine suppositories are first-line therapy in active ulcerative proctitis; the standard regime still recommends multiple doses per day. The primary objective of this study was to show the noninferiority of once-daily administration of a novel 1 g mesalamine suppository versus thrice-daily administration of the 0.5 g mesalamine suppository. Methods: This was a single-blind (investigator-blinded), randomized, multicenter, comparative, Phase III clinical trial. Patients with mild to moderately active ulcerative proctitis inserted either one mesalamine 1 g suppository at bedtime or one mesalamine 0.5 g suppository thrice daily over a 6-week period. The primary endpoint was rate of remission (Disease Activity Index below 4). Results: In all, 354 patients were evaluable for safety and per-protocol analysis. The new regimen demonstrated noninferiority: The percentage of patients with remission was 87.9% for the once-daily 1 g mesalamine suppository and 90.7% for the thrice-daily 0.5 g mesalamine suppository. Each regimen resulted in prompt cessation of clinical symptoms (e.g., median time to ≤3 stools per day (all without blood): 5 days in the 1 g mesalamine once-daily and 7 days in the 0.5 g mesalamine thrice-daily group). Patients preferred applying suppositories once a day. Conclusions: In active ulcerative proctitis the once-daily administration of a 1 g mesalamine suppository is as effective and safe, yet considerably more convenient, than the standard thrice-daily administration of a 0.5 g mesalamine suppository. (Inflamm Bowel Dis 2010)

To analyze the dosimetric and clinical benefit of a forward planned technique to optimize dose distribution in whole-breast irradation (WBI) using additional partial-volume segments (PVSeg).: In two separate treatment periods, 265 breast cancer patients received tangential-field WBI and were retrospectively analyzed. Between 02/2004 and 03/2006, 96 patients were treated with one to two additional low-weighted PVSeg to reduce dose peaks within the target volume. 169 patients treated between 01/2000 and 12/2001 before implementation of this PVSeg technique served as comparison group. Total dose was 50-50.4 Gy (single dose, 1.8-2 Gy). The planning target volume (PTV) receiving at least 95%, 105% and 110% of the reference dose (V(95-110%)) and frequency of moist skin desquamation during radiotherapy were compared uni- and multivariately with patient- and treatment-related variables.: The mean PTV was 1,144 ml (range, 235-2,365 ml). Moist skin desquamations developed in 16 patients (17%) with PVSeg compared to 30 patients (18%) without PVSeg (p = 0.482). In breast volumes1,100 ml, the corresponding figures were 19% versus 29% (p = 0.133). V(105%) was significantly reduced by the use of PVSeg (82 +/- 51 ml vs. 143 +/- 129 ml; p0.0001). In univariate analysis, the following variables had significant influence on the development of moist skin desquamation: V(95%) (p0.0001), V(105%) (p0.001), V(110%) (p = 0.012) adjuvant chemotherapy (p = 0.02), and single dose (p = 0.009). In multivariate analysis, only V(95%) (p = 0.002) remained significant.: The use of PVSeg in WBI reduced dose peaks within the PTV while breast volumes1,100 ml benefited most. V(95%) was strongly correlated to the risk of developing moist skin desquamations.

History and clinical findings A 18-year-old girl suffered from chronic active ulcerative colitis for ten years with growth retardation, primary amenorrhoea and osteopenia, so that total colectomy had been discussed as a possible treatment option. However, clinical remission was reached using a medication with budesonide (9 mg), mesalazine (3 g) and azathioprine (100 mg) when a painful ulcer occurred at the right lower leg. Investigations The clinical examination revealed an ulcer of 7 cm diameter with a red-bluish margin at the right lower leg. The typical clinical features led to the diagnosis of pyoderma gangrenosum. Treatment and course High doses of orally administered prednisolone induced the healing of the pyoderma gangrenosum within 2 months. After another 2 months systemic steroids were discontinued. Further laboratory tests confirmed secondary adrenal and ovarian failure (negative CRH-GnRH-test). Change of drug therapy to hydrocortisone (25 mg) in combination with mesalazine (3 g) and azathioprine (100 mg) improved the clinical course. Hydrocortisone was gradually reduced until CRH-GnRH-response returned to normal. Conclusion Drug therapy with azathioprine can be regarded as a treatment option in pediatric patients with chronic active inflammatory bowel disease. It can be concluded from this case report that faced with controversial therapeutic options in adolescent patients the decision mainly depends on the clinical experience of the physician than on the results of controlled clinical trials.

An investigation was conducted on 21 patients (16 men and five women; mean age 48.2 [34-67] years) with cirrhosis of the liver of various aetiologies to determine whether molsidomine, which selectively reduces pre-load with-out the development of tolerance, effects portal and cardiac haemodynamics in liver cirrhosis and portal hypertension. Intravenous injection of 2 mg molsidomine reduced the hepatic vein closing pressure after 30 min by 8% (P less than 0.05) and the hepatic vein closing pressure gradient by 13.4% (P less than 0.002). The cardiac output fell by 5.8% (P less than 0.02) and the mean systemic arterial pressure by 4.2% (P less than 0.003). The reduction in hepatic venous closing pressure gradient did not correlate with the fall in cardiac output and mean arterial pressure. In 15 of 21 patients the hepatic venous pressure fell, but in six patients (28.6%) the pressure was not reduced (non-responders). The latter failure of response was associated with marked ascites, significant functional liver decompensation and alcoholic liver cirrhosis. Preliminary long-term observations with molsidomine point to a reduction in portal pressure by as much as 40%. This suggests that the drug is suitable for preventing bleeding from oesophageal varices.

The acute effect of metoclopramide on oesophageal motility was investigated prospectively in 33 consecutive patients (20 men and 13 women; mean age 60.5 +/- 12.6 years) with type I (n = 8) or type II (n = 25) diabetes. 15 patients had a peripheral sensory-motor polyneuropathy only and three just an autonomic cardial neuropathy. Both lesions were present in ten, none in five. No patient had oesophago-gastroduodenal lesions. Sphincter pressure, relaxation time, contraction amplitude and propulsion velocity of bolus-induced oesophageal peristalsis were measured manometrically after intravenous administration of 10 mg metoclopramide. Resting pressure in the lower oesophageal sphincter rose significantly by 26.7%, contraction amplitude in the tubular portion of the oesophagus by more than 30%, and propulsion velocity by more than 20% (P for each < 0.05). At the same time the amount of segmental and aperistaltic oesophageal contractions regressed significantly. The effect of metoclopramide was demonstrated regardless of the type of diabetes, duration of diabetes and any manifestation of autonomic cardial or peripheral sensory-motor neuropathy.

In 124 patients with Crohn's disease (69 women, 55 men; mean age 33.7 [11-66] years) and 53 with ulcerative colitis (30 women, 23 men; mean age 36.2 [19-74] years) the incidence of lactose intolerance, as measured by the H2 breath test and blood sugar concentration, was determined prospectively. To exclude abnormal bacterial colonization of the small intestine or rapid small-intestine transit after partial resection of the small intestine as a cause of lactose intolerance, the oro-caecal transit time for lactulose (H2 breath test) was measured. While 21 of 124 patients with Crohn's disease (16.9%) had the expected incidence of lactose intolerance, this was present in only 2 of 53 patients with ulcerative colitis (3.8%; P < 0.05). The lactose intolerance was independent of the site of any inflammatory changes, disease activity and extent of small-intestine resection. Oro-caecal transit time for lactose was similar for all patients. There was no lactose intolerance in two patients with abnormal small-intestinal bacterial colonization.--Because of their considerable diagnostic and prognostic significance, tests for lactose intolerance should be performed routinely in all cases of Crohn's disease or ulcerative colitis.

Background Collagenous colitis is clinically characterized by watery diarrhoea and can histologically be diagnosed by a thickening of the subepithelial collagen layer and an inflammatory infiltrate in the lamina propria. So far, the pathogenesis of collagenous colitis and the role of luminal factors remain unclear. Methods This clinical pilot investigation was conducted with an open-label design to monitor the clinical effects of EcN on stool frequency and stool consistency in 14 patients (11 female, 3male; age: 58.1 +/- 9.6 years). Due to the open-label protocol EcN was administered at different doses (1 - 6 capsules/day containing 2.5 - 25 x 10 (9) viable bacteria each). Except for two patients who discontinued treatment, therapy duration was at least 4 weeks. Results The results indicate a marked clinical response to the oral administration of EcN with a reduction of the stool frequency > or = 50 % in 9/14 (64 %) patients. Stool frequency clearly (p = 0.034) decreased from 7.6 +/- 4.8/day to 3.7 +/- 5.8/day at the end of therapy (between 4 and 18 weeks). Moreover, stool consistency changed in 7/14 patients from watery or slimy to soft (6 pts) and normal (1 pt), respectively. Conclusion With respect to the preliminary data from this trial, the probiotic E. coli strain Nissle 1917 (EcN) seems to be of therapeutic clinical benefit in collagenous colitis. This may be explained with the recently shown antagonistic effect of EcN against Yersinia species, since a relevant number of patients suffering from collagenous colitis showed positive titres of serum IgG and IgA antibodies against Yersinia species. Further studies on the effects of EcN on mucosal collagen metabolism and long-term follow-up are warranted.

Nuclear factor kappa-B (NFkappaB) plays a crucial role in diseases associated with dysregulated immune response. NFkappaB inhibitor alpha downregulates the activity of NFkappaB.To evaluate the contribution of the NFkappaB inhibitor alpha gene in Crohn's disease single nucleotide polymorphisms in the 3'-UTR and at position -420 in the promoter were studied in 259 patients with Crohn's disease genotyped for the variations of the CARD15 gene in comparison to 441 healthy controls. Additionally we screened the coding region of the NFkappaB inhibitor alpha gene for polymorphisms by SSCP analysis.In comparison to controls the A allele and the AA genotype frequencies of the single nucleotide polymorphisms in the 3'-UTR were significantly increased only in Crohn's disease patients without a variation in the CARD15 gene. Similarly, the difference between patients harboring no predisposing CARD15 alleles and patients harboring such a variation was significant.The findings indicate that the phenotype Crohn's disease is to be substructured with respect to genetic susceptibility.

Anamnese und klinischer Befund: Ein 61-jahriger Patient stellte sich mit diffusen Oberbauchbeschwerden und den Symptomen einer progredienten Belastungsdyspnoe stationar vor. Klinisch imponierten die Zeichen einer Rechtsherzbelastung und eine ausgepragte Kyphoskoliose. Therapie und Verlauf: Mittels Einschwemmkatheteruntersuchung konnte eine pulmonale Hypertonie mit Ausschluss einer kardialen Genese diagnostiziert werden. Eine obstruktive Atemwegserkrankung und eine Lungenembolie wurden durch eine Lungenfunktionsanalyse bzw. durch eine Spiralcomputertomographie des Thorax ausgeschlossen. Die Kyphoskoliose blieb somit als alleinige Ursache der pulmonalen Hypertonie bestehen. Da der Patient einer nichtinvasiven Beatmung als Therapie der Wahl ablehnend gegenuberstand, konnte alternativ unter einer medikamentosen Therapie mit Calciumantagonisten und ACE-Hemmern und nachfolgender Sauerstofftherapie der pulmonalvaskulare Widerstand effektiv gesenkt werden (746 vs. 332 dyn*s*cm−5). Schlussfolgerung: Eine Kyphoskoliose kann eine betrachtliche pulmonalarterielle Widerstandserhohung hervorrufen. Diese lasst sich durch eine medikamentose Therapie und eine Sauerstofftherapie effektiv senken.

Collagenous colitis is an idiopathic microscopic colitis characterized by chronic watery diarrhea, a typical subepithelial collagen layer, and lymphoplasmacellular infiltration. We investigated the effect of budesonide on symptoms and histology in patients with collagenous colitis in a randomized, double-blind, placebo-controlled multicenter trial.Patients with chronic diarrhea and histologically proven collagenous colitis were randomized to receive either oral budesonide (Entocort capsules; AstraZeneca, Sodertalje, Sweden) 9 mg/day for 6 weeks or placebo. Complete colonoscopy was performed before and after treatment. Histopathology was assessed by a single pathologist blinded to the patients' treatment. Clinical symptoms were assessed by standardized questionnaires.Fifty-one patients were randomized; 45 patients were available for per protocol analysis. The rate of clinical remission was significantly higher (P0.001) in the budesonide group than in the placebo group (per protocol 86.9% vs. 13.6%, respectively; intention-to-treat 76.9% vs. 12.0%, respectively). Histologic improvement was observed in 14 patients of the budesonide group (60.9%) and in 1 patient of the placebo group (4.5%; P0.001). Two patients in the budesonide group (7.7%) and 1 patient in the placebo group (4.0%) discontinued treatment prematurely because of side effects.Oral budesonide (Entocort capsules) is an effective and safe treatment modality for patients with collagenous colitis. Long-term follow-up of these patients is necessary to investigate whether clinical and histologic remission is sustained.

Studies have confirmed an increased prevalence for developing microscopic colitis in patients with sprue, and vice versa (1– 3). For collagenous colitis, the reported prevalence of sprue is 3.46% (1). In patients with confirmed sprue who continue to have symptoms in spite of adherence to their restriction diet, collagenous colitis and lymphocytic colitis should always be excluded.

UNLABELLED Numerous extraintestinal manifestations in various organ systems have been reported to be associated with inflammatory bowel disease (IBD). Aim of the present paper was to evaluate the frequency of cutaneous manifestations in Crohn's disease (CD) and ulcerative colitis (UC) with respect to their location, the activity and location of the underlying disease, the treatment options and the time to remission. METHODS The medical records of 1043 inpatients with CD and UC were screened retrospectively for extraintestinal symptoms with special regard to cutaneous manifestations. RESULTS The prevalence of cutaneous manifestations in IBD was 22/1043 (2.1%; 18 women, 4 men; age: 31.41 +/- 9.9 [21-51] yrs.). In 15/22 patients (68.2%) the cutaneous manifestations were associated with CD, in 7/22 patients (31.8%) UC was confirmed. In 6/22 patients (27.3%) pyoderma gangrenosum (PG) was diagnosed, in 16/22 patients (72.7%) erythema nodosum (EN). EN and PG predominately occurred at the lower legs: in 68.1% the tibia was the main affection site. Other locations like breast or anus were rare. In 16/22 patients (72.7%) an acute phase of the underlying disease was evident, in 6/22 patients (27.3%) CD or UC were in remission. In patients with CD a colonic involvement was found in 86.7%. Arthritis was the most frequent coexisting extraintestinal manifestation in CD (53.3%) and UC (28.8%). Drug treatment was performed with high doses of glucocorticoids and salicylates. The time to remission in patients with EN was significantly shorter as compared to PG (5.3 +/- 1.8 vs. 19.6 +/- 14.2 weeks; p < 0.001). In 5/22 patients (22.7%) cutaneous manifestations reoccurred after a symptom-free interval. All efflorescenses reoccurred during an active phase of the underlying disease at the same manifestation site as the initial presentation. CONCLUSION In this series the prevalence of cutaneous manifestations in IBD was 22/1043 (2.1%). EN and PG were more frequent in women with IBD, in CD, and during the acute phases of the underlying disease. EN and PG predominately affect the lower legs. Cutaneous manifestations respond well to an acute phase therapy of the underlying disease. The time to remission was significantly shorter in EN as compared to PG. However, relapses have to be considered in a relevant subgroup of patients.

Although genetic predisposition for inflammatory bowel disease (IBD) is well established, little is known about the accountable genes. The pathogenesis of IBD is characterized by an imbalanced activation of Th1- and Th2-lymphocytes. IL-10 represents an anti-inflammatory cytokine which downregulates the production of Th1-derived cytokines. To evaluate the role of the IL-10 gene in IBD, two polymorphisms in the promoter region (G/A at position -1082 and C/A at position -592) were genotyped in 142 patients with Crohn's disease (CD), 104 patients with ulcerative colitis (UC), and 400 healthy controls. Significant differences were not apparent, neither in the allele frequencies of either polymorphism, nor in the haplotype frequencies. Screening of the coding region of the IL-10 gene by polymerase chain reaction--single strand conformation polymorphism (PCR-SSCP) analysis revealed a rare sequence variation in exon 1 leading to an amino acid exchange (G-->A; G15R) in two patients with CD and five healthy controls. Therefore, polymorphisms of the IL-10 gene are not demonstrably involved in the predisposition of IBD in our cohorts of patients.

The overlap syndrome between autoimmune hepatitis and primary sclerosing cholangitis is a rare condition and only few cases have been published, partly associated with ulcerative colitis, but not with Crohn's disease. We report an autoimmune hepatitis/primary sclerosing cholangitis overlap syndrome in a female patient with Crohn's disease. In addition, a second case of overlap syndrome is reported in a man without inflammatory bowel disease. A 24-year-old woman was referred with a 10-month history of diarrhoea and biochemical changes including elevated serum levels of alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase and immunoglobulin G. Enzyme linked immunosorbent assay showed that antinuclear autoantibodies were elevated. Immunofluorescence for perinuclear-staining antineutrophil cytoplasmatic antibodies was positive. Diagnostic criteria of definite autoimmune hepatitis according to the International Autoimmune Hepatitis Group were fulfilled. Liver biopsy simultaneously showed criteria of autoimmune hepatitis and primary sclerosing cholangitis. Endoscopic retrograde cholangiography demonstrated features of primary sclerosing cholangitis. Colonoscopy and colonoscopic biopsies indicated an active Crohn's disease affecting the terminal ileum and the ascending and transverse colon. Furthermore, we report the case of a 28-year-old man with known primary sclerosing cholangitis for the previous 6 years, and who developed jaundice and a marked increase of aspartate aminotransferase, alanine aminotransferase and immunoglobulin G, leading to the diagnosis of definite autoimmune hepatitis. A review of the literature revealed only 16 cases of an autoimmune hepatitis/primary sclerosing cholangitis syndrome in patients without inflammatory bowel disease or in association with ulcerative colitis. We report two additional cases, one case showing an association with Crohn's disease.

OBJECTIVE: Collagenous colitis is a chronic watery diarrhea disorder characterized by a subepithelial collagen layer and a lymphoplasmacytic infiltration within the lamina propria. However, no standard treatment has been introduced by controlled clinical trials. Aim of the present pilot trial was to investigate the clinical effects of orally administered budesonide (3 mg t.i.d.) in 7 patients with collagenous colitis. In addition, the histomorphological changes after budesonide treatment were described in a group of 3 patients. METHODS: The study was performed as an open label pilot trial. Study end point was the clinical remission of collagenous colitis defined by stool frequency and stool consistency. RESULTS: The results indicate a rapid and sustained clinical response in all patients. Stool frequency significantly decreased (p < 0.001) from 10.43 ± 5.56 per day (4–20 per day) to 3.3 ± 1.2 (1–5 per day) after 10 days and to 1.86 ± 0.69 per day (1–3 per day) after 10 wk. Moreover stool consistency changed from watery (6 patients) or soft (1 patient) to soft (1 patient) or solid (6 patients). Clinical improvement was achieved within the first 10 days in all patients and maintained after dose reduction. In 3 patients no diarrhea recurred within 7, 12, or 15 months after treatment with budesonide was terminated. In these patients control biopsies were taken and showed a marked regression of both characteristics, the collagen band and the lymphoplasmacytic infiltration. CONCLUSIONS: With respect to the preliminary data from this pilot trial, budesonide with its high topical and low systemic effects seems to be of therapeutic clinical benefit in collagenous colitis. A therapeutic effect could be demonstrated for both therapeutic goals, the clinical response and morphological changes. Further studies on the effects of budesonide on mucosal collagen metabolism and long-term follow-up are warranted.

Recently, increased serum levels of vascularendothelial growth factor (VEGF) have been shown inpatients with inflammatory bowel disease. The origins ofthe circulating VEGF are still not described. Monocytes play an important role in the inflammatoryprocess. VEGF binding to monocytes mediates monocyterecruitment and activation. The present studyinvestigates the VEGF production of peripheral bloodmononuclear cells and the ability of peripheral monocytesto bind VEGF165 in patients with Crohn'sdisease. Nineteen patients with Crohn's disease and 10healthy volunteers were studied. VEGF165labeling of CD14+ monocytes was measured using two-color flow cytometry.Density of VEGF labeling was expressed as the meanfluorescence intensity (MFI). Furthermore, VEGF levelswere determined in culture supernatants of unstimulated peripheral blood mononuclear cells. VEGF inculture supernatants was measured using a solid-phaseenzyme-linked immunosorbent assay. There was asignificantly decreased VEGF165 labeling ofmonocytes of patients with active Crohn's disease (MFI:369.9 ± 121.6, N = 7, P < 0.002) compared topatients with inactive disease (MFI: 457.7 ±74.5, N = 6) and healthy controls (MFI: 542.9 ±96.2, N = 10). Unstimulated peripheral blood mononuclear cellsof patients with active Crohn's disease producedsignificantly higher amounts of VEGF (1142.6 ±483.9 pg/ml, N = 12, P < 0.001) compared withperipheral blood mononuclear cells of healthy volunteers(113.4 ± 101.8 pg/ml, N = 10). VEGF production byperipheral blood mononuclear cells of patients withactive disease was significantly increased compared to patients with quiescent disease (261.6± 254.8 pg/ml, N = 7, P < 0.001). Inconclusion, our data describe peripheral bloodmononuclear cells as one of the origins of the elevatedVEGF serum levels in patients with active Crohn's disease.Furthermore, a decrease in VEGF165 bindingsites on peripheral monocytes of patients with activeCrohn's disease has been shown. The study underlines theimportant role of VEGF in Crohn's disease.

Vascular endothelial growth factor (VEGF) is a potent angiogenic, vascular permeability-enhancing, and calcium-dependent enzyme-modulating cytokine with overexpression in various pathologic disorders, including granulomatous inflammation, tissue repair, delayed hypersensitivity reactions, rheumatoid arthritis, and tissue ischemia. The present study investigates the role of VEGF in chronic inflammatory bowel disease.Thirty-one patients with Crohn's disease, 15 patients with ulcerative colitis, and 9 healthy volunteers were studied. VEGF serum levels were measured with a solid-phase enzyme-linked immunosorbent assay.Significantly increased VEGF serum levels were observed in both active Crohn's disease and active ulcerative colitis when compared with healthy controls. Patients with active Crohn's disease and active ulcerative colitis showed significantly higher VEGF serum levels than patients with quiescent disease. No difference was observed between inactive disease and healthy controls. In addition, strongly increased VEGF serum levels were found in patients with Crohn's disease with fistulas in the absence of clinical, endoscopic, histologic, and laboratory findings of disease activity.Significantly increased VEGF serum levels were observed in patients with active Crohn's disease and ulcerative colitis, which suggests that VEGF has an important role in chronic inflammatory bowel disease. Its possible association with fistulas has yet to be determined.

Background and aims. Linkage of inflammatory bowel diseases to chromosome 12p13.2–q24.1 (IBD2) has been confirmed in several genome wide screens. The STAT6 gene is located within this chromosomal region. The transcription factor STAT6 is involved in the regulation of the TH1/TH2 immune response. Increased production of TH1 cytokines is crucial in the pathogenesis of Crohn's disease. Patients and methods. Therefore, we genotyped a single nucleotide polymorphism in the 3′ untranslated region of the STAT6 gene (G2964A) in 243 patients with Crohn's disease, 100 patients with ulcerative colitis and 548 healthy controls. Results. In comparison to controls, the G allele and the GG genotype frequencies were significantly increased only in Crohn's disease patients without a variation in the CARD15 gene (p Conclusions. Alterations in the STAT6 pathway may play a crucial role in the pathogenesis of distinct subgroups of patients with Crohn's disease.

Inflammatory bowel diseases (IBD) are multifactorial disorders characterised by the host's inability to limit the inflammatory response to luminal antigens. The association of polymorphisms in the CARD15 gene with Crohn's disease (CD) demonstrates the relevance of activated transcription factor NF(kappa)B in mononuclear cells. Interleukin 11 (IL11) mediates anti-inflammatory effects and is able to downregulate LPS-induced NF(kappa)B activation. The IL11 gene is therefore a good candidate involved in genetic predisposition to IBD. To evaluate the role of the IL11 gene in IBD, two polymorphisms, including a dinucleotide repeat in the promoter region, have been genotyped in 222 patients with CD, 152 patients with ulcerative colitis (UC) and 400 healthy controls. PCR-SSCP analysis of the coding region revealed a single polymorphism in exon 4 leading to an amino acid exchange (G335A; R112H), not significantly associated with either disease. Dinucleotide repeat frequencies of the IL11.A1 allele and of IL11.A1 homozygous individuals were significantly increased among the patients with UC (P0.002 and (P0.003, respectively) but not with CD. Altered expression of IL11 appears to be involved in the genetic predisposition of UC.

Background : Inflammatory bowel diseases (IBD) are multifactorial disorders, characterized by failure to limit the inflammatory response to luminal antigens. Although genetic factors play an important role in the pathogenesis, little is known about the genes accountable. Immune response to intestinal bacteria seems to be crucial in the pathogenesis of IBD. Methods : To evaluate the role of the CD14 gene in IBD, a functionally relevant polymorphism in the promoter region (T/C at position-159) has been genotyped in 219 patients with Crohn disease (CD), 142 patients with ulcerative colitis (UC) and 410 healthy controls by RFLP analysis. Results : T allele and TT genotype frequencies were found increased in CD patients compared to controls ( P c = 0.044 and 0.005, respectively). Conclusion : An altered immune response to LPS seems to play a role in the genetic predisposition to CD but not to UC.

To investigate the effects physical training exerts on markers of oxidative stress in rats with chronic kidney disease (CKD).Twenty-four male Wistar rats were divided into four groups (n=6): sham, CKD, exercise-sham and exercise-CKD. Surgical reduction of the renal mass was performed (5/6 nephrectomized) and exercise was conducted on a treadmill (50 min/day up to 1 km/h for, 5 days/week for eight weeks). Forty-eight hours after the last exercise session, blood (1 mL) was collected from the abdominal aorta and animals were decapitated. The left kidney was surgically removed and stored at -70 °C for subsequent analysis.An increase was observed in creatinine and urea levels, superoxide production, antioxidant enzymes, and oxidative damage in the CKD group, as compared to sham animals (p0.05). Physical training made superoxide production and oxidative damage decrease in the CKD group (p0.05), increasing SOD and GPX activity, though it did not increase the antioxidant effects of CAT, and renal parameters.Even without altering renal function in animals induced to CKD model, the results show that physical training is an important component in the treatment of CKD, because it exerted a positive influence on oxidative stress parameters, especially on the reduction in superoxide production and oxidative damage, as well as an improvement in the antioxidant defense system, like SOD and GPX.

Background & Aims Comparative data on budesonide vs mesalamine for the treatment of mild-to-moderately active Crohn's disease (CD) are sparse. We assessed the efficacy and safety of each therapy in patients with mildly to moderately active CD. Methods We performed a randomized, double-blind, double-dummy, 8-week, multicenter study in which 309 patients with mildly to moderately active CD received pH-modified-release oral budesonide (9 mg/day once daily or 3 mg/day 3 times daily) or Eudragit-L–coated oral mesalamine (4.5 g/day). Results The primary efficacy variable, clinical remission (defined as Crohn's Disease Activity Index ≤150), at the final visit occurred in 69.5% (107 of 154) of patients given budesonide vs 62.1% (95 of 153) of patients given mesalamine (difference, 7.4%; 95% repeated confidence interval, −4.6% to 18.0%; P = .001 for noninferiority). Clinical remission rates did not differ significantly between the 2 budesonide groups. Treatment response, defined as Crohn's Disease Activity Index of 150 or less and/or a decrease of 70 or more (Δ70) or 100 or more (Δ100) points from baseline to final visit, did not differ significantly between patients given budesonide vs mesalamine (Δ70, P = .11; Δ100, P = .15), or between the 2 budesonide groups (Δ70, P = .38; Δ100, P = .78). No other efficacy end points differed significantly between groups. Discontinuation because of adverse events occurred in 3% and 5% of budesonide- and mesalamine-treated patients, respectively. There were no clinically relevant differences in adverse events between the 2 budesonide groups. Conclusions Budesonide (9 mg/day) was numerically, but not statistically, more effective than Eudragit-L–coated mesalamine (4.5 g/day) in patients with mildly to moderately active CD. Budesonide (9 mg/day), administered once daily, was as effective as the standard (3 times daily) regimen.

Imbalances in the regulation of Th1 and Th2 lymphocytes are crucial in inflammatory bowel diseases. Interleukin-4 is secreted by Th2 lymphocytes and downregulates cytokine production from Th1 lymphocytes. Functionally relevant polymorphisms have been described in the interleukin-4 and the interleukin-4 receptor alpha genes. Association of inflammatory bowel diseases with these polymorphisms has been reported recently suggesting high transcription and enhanced signalling activity in Crohn's disease. Our study, comprising 211 patients with Crohn's disease, 147 patients with ulcerative colitis and 446 healthy controls revealed significant association of Crohn's disease with the -590 T allele of the interleukin-4 gene (P = 0.03). This allele entails reduced expression of IL-4. The reason for these contrasting findings may be discussed in the context of a putatively predisposing allele in linkage disequilibrium with the alleles of the interleukin-4 gene.

Objective Inflammatory bowel diseases (IBD) are multifactorial disorders, characterized by failure to limit the inflammatory response to luminal antigens. Genetic factors play an important role in the pathogenesis, but little is known about the accountable genes. Increased secretion of pro-inflammatory cytokines appears crucial in the initiation of the inflammatory response. Methods To evaluate the role of the IL-6 gene in IBD, a functionally relevant polymorphism in the promoter region (G/C at position -174) has been genotyped in 169 patients with Crohn's disease (CD), 133 patients with ulcerative colitis (UC) and 440 healthy controls by using restriction fragment length polymorphism (RFLP) analysis. Results No significant differences were apparent in the allele, genotype and carrier frequencies between patients and controls. Conclusion High secretion of IL-6 does not seem to play a major role in the genetic predisposition to IBD.

In a prospective study we compared the usefulness of various laboratory tests (albumin, alpha-1-proteinase inhibitor (A1PI), cholinesterase (CHE), C-reactive protein, erythrocyte sedimentation rate, hematocrit) and activity indices (CDAI, VHAI) in relation to the disease activity by endoscopic criteria. Except for hematocrit highly significant differences (p less than 0.0005) of the mean values of all test results were found for patients without or with slight mucosal lesions compared with patients with severe inflammation of the mucosa. Further analysis of the data indicates the highest test efficiency (84%), sensitivity (80%), and specificity (88.6%) for CHE. CHE showed good correlations to all other tests; the highest correlation was found between CHE and VHAI (r = -0.78). We suggest that a suppression of CHE synthesis mediated by endotoxins and cytokines rather than an increased intestinal loss explains the decreased CHE in severe Crohn's disease. It is concluded from the data that CHE is a useful test to assess the inflammatory activity of Crohn's disease.

An example of acute pancreatitis developing five weeks after initial treatment with 5-aminosalicylic acid (5-ASA) and methylprednisolone for severe Crohn's disease is reported in a 37 year old female patient. She had undergone cholecystectomy for gall stones some years earlier. There was no evidence of acute or chronic pancreatitis. No morphological changes of the upper gastrointestinal tract were found except for some irregularity of the main pancreatic duct and the secondary ducts on endoscopic retrograde pancreatography. Rechallenge with 5-ASA did not induce recurrent pancreatitis or changes in pancreatic enzymes. This case report supports the concept of an association between acute pancreatitis and Crohn's disease.

The efficacy of a therapy with interferon-α-2b and ribavirin in patients with hepatitis C not responding to the initial treatment remains controversial. Objective of the present study was to determine the efficacy of a combination therapy with 3 MU interferon-α thrice weekly and 1,000-1,200 mg ribavirin daily for six months in an open label trial. Methods: 44 consecutive patients (genotype 1: 79.5%) who had been previously treated with a minimum dose of 3 MU interferon-α thrice weekly for at least three months were monitored. Sustained response was defined as virological response with clearance of HCV-RNA after a follow-up period of six months after the end of therapy. Results: A significant decrease of the mean levels of AST (34.3 ± 27.6 vs. 16.4 ± 13.5 U/L) and ALT (59.6 ± 48.8 vs. 23.2 ± 20.7 U/L) was observed. In 15/44 patients (34.1%) a virological end-of-treatment response was evident. 8/44 patients (18.2%) achieved a sustained response. In 33.3% of the previous non-responders biochemical response with normal aminotransferases, but no virological response was evident. A significant decrease of the mean hemoglobin level was observed during therapy (12.0 ± 1.7 vs, 14.6 ± 1.0 g/dl; p

Myositis of the skeletal muscle is a rare complication of inflammatory bowel disease. We report about a 33-year-old woman with quiescent ulcerative colitis known since 1995. She had suffered from recurring fever and pain in the thighs for about 4 weeks. Electromyography of quadriceps and deltoid muscles revealed myopathic changes. Diagnosis of polymyositis was confirmed by magnetic resonance imaging indicating edematous changes in the distal extremity muscles. The symptoms rapidly responded to high doses of steroids. Review of the literature indicates only a few cases describing an association of ulcerative colitis and myositis, most of them during acute exacerbations of the disease. In contrast, the present patient was in remission. Diagnosis of myositis should be considered in inflammatory bowel disease patients complaining of myalgia or muscular weakness. Magnetic resonance imaging may show specific features and can be used in addition to laboratory investigations and muscle biopsy for diagnosis of polymyositis.

Background: The bactericidal/permeability increasing protein (BPI) is involved in the elimination of gram-negative bacteria. A functionally relevant single nucleotide polymorphism of the BPI gene causes an amino acid exchange (Glu216Lys). Study: To evaluate whether this single nucleotide polymorphism contributes to the predisposition to inflammatory bowel disease, we compared the allele frequencies of 265 patients with Crohn's disease, 207 patients with ulcerative colitis, and 608 healthy controls. Results: The Glu/Glu genotype frequency was decreased significantly in Crohn's disease patients as compared with controls (P < 0.027). No differences were obvious in patients with ulcerative colitis. Conclusions: Failure of the innate intestinal immune system could be involved in the pathogenesis of Crohn's disease via reduced/impaired defense against gram-negative bacteria.

Collagenous colitis is a chronic inflammatory bowel disease with a band-like subepithelial deposition of immature extracellular matrix. Because the extracellular matrix deposition is potentially reversible, an imbalance between fibrogenesis and fibrolysis with reduced matrix degradation has been suspected. Vascular endothelial growth factor plays a central role in extracellular matrix degradation. Therefore, we investigated the expression of vascular endothelial growth factor in the colonic mucosa of patients with collagenous colitis before and after long-term treatment with oral budesonide.A quantitative immunohistochemical method was used to measure the amount of immunoreactive vascular endothelial growth factor, tenascin and leucocyte common antigen within the epithelium and the lamina propria of colonic biopsies by area morphometry.Strong immunostaining for vascular endothelial growth factor within the epithelium and the lamina propria, and for tenascin, was seen in patients with collagenous colitis compared with normal controls. The enhanced immunostaining for vascular endothelial growth factor within the lamina propria was accompanied by the accumulation of leucocytes, detected by staining for leucocyte common antigen. After long-term treatment with oral budesonide, the amount of immunostaining for leucocyte-derived vascular endothelial growth factor within the lamina propria decreased significantly to normal levels. In contrast, staining for vascular endothelial growth factor within the epithelium remained significantly increased.Our data suggest an important role of vascular endothelial growth factor in counteracting the local imbalance of fibrogenesis and fibrolysis, leading to an accumulation of immature subepithelial matrix in collagenous colitis.

Background The aim of the present study was to evaluate the protective effect of concurrent exercise in the degree of the insulin resistance in mice fed with a high-fat diet, and assess adiponectin receptors (ADIPOR1 and ADIPOR2) and endosomal adaptor protein APPL1 in different tissues. Methods Twenty-four mice were randomized into four groups (n = 6): chow standard diet and sedentary (C); chow standard diet and simultaneous exercise training (C-T); fed on a high-fat diet and sedentary (DIO); and fed on a high-fat diet and simultaneous exercise training (DIO-T). Simultaneously to starting high-fat diet feeding, the mice were submitted to a swimming exercise training protocol (2 x 30 minutes, with 5 minutes of interval/day), five days per week, for twelve weeks (90 days). Animals were then euthanized 48 hours after the last exercise training session, and adipose, liver, and skeletal muscle tissue were extracted for an immunoblotting analysis. Results IR, IRs, and Akt phosphorylation decreased in the DIO group in the three analyzed tissues. In addition, the DIO group exhibited ADIPOR1 (skeletal muscle and adipose tissue), ADIPOR2 (liver), and APPL1 reduced when compared with the C group. However, it was reverted when exercise training was simultaneously performed. In parallel, ADIPOR1 and 2 and APPL1 protein levels significantly increase in exercised mice. Conclusions Our findings demonstrate that exercise training performed concomitantly to a high-fat diet reduces the degree of insulin resistance and improves adipoR1-2/APPL1 protein levels in the hepatic, adipose, and skeletal muscle tissue.