A. J. Kroesen

Expression of catalytic proteasome subunits in the gut of patients with Crohn's disease

Background and purposeActivation of the transcription factor NF-κB by proteasomes and subsequent nuclear translocation of cytoplasmatic complexes play a crucial role in the intestinal inflammation. Proteasomes have a pivotal function in NF-κB activation by mediating degradation of inhibitory IκB proteins and processing of NF-κB precursor proteins. This study aims to analyze the expression of the human proteasome subunits in colonic tissue of patients with Crohn’s disease.Materials and methodsThirteen patients with Crohn’s disease and 12 control patients were studied. The expression of immunoproteasomes and constitutive proteasomes was examined by Western blot analysis, immunoflourescence and quantitative real-time PCR. For real-time PCR, AK2C was used as housekeeping gene.ResultsThe results indicate the influence of the intestinal inflammation on the expression of the proteasomes in Crohn’s disease. Proteasomes from inflamed intestine of patients with Crohn’s disease showed significantly increased expression of immunosubunits on both protein and mRNA levels. Especially, the replacement of the constitutive proteasome subunit β1 by inducible immunosubunit β1i was observed in patients with active Crohn’s disease. In contrast, relatively low abundance of immunoproteasomes was found in control tissue.ConclusionsOur data demonstrate that in contrast to normal colonic tissue, the expression of immunoproteasomes was evidently increased in the inflamed colonic mucosa of patients with Crohn’s disease. Thus, the chronic intestinal inflammation process in Crohn’s disease leads to significant alterations of proteasome subsets.

Impairment of epithelial transport but not of barrier function in idiopathic pouchitis after ulcerative colitis

Background and aims: Little is known of the permeability of ileoanal pouches. Hence the aim of the present study was to determine changes in permeability and mucosal function after ileo-pouchanal anastomosis (IPAA) in patients with ulcerative colitis. Materials and methods: Biopsies were taken from 43 patients (male:female ratio 28:15; mean age 35.2 (12.5) years) prior to colectomy (ileum prior to pouch), prior to closure of ileostomy (deviation), and after closure of ileostomy (intact pouch) in the case of pouchitis, and from 14 healthy controls. Tissues were mounted in a miniaturised Ussing chamber. Epithelial and subepithelial resistance was determined by transmural impedance analysis. Active Na+-glucose cotransport was measured as change in short circuit current after stepwise addition of glucose, and active Cl− secretion was measured after stimulation with theophylline and prostaglandin E2. Results: Neither epithelial resistance nor mannitol fluxes were significantly altered compared with intact controls, indicating no barrier defect in pouchitis. Subepithelial resistances of intact pouches and pouchitis were increased compared with deviation (18.2 (1.6) and 24.3 (1.5) v 13.6 (1.0) Ω×cm2) consistent with an adaptive thickening of the subepithelial layer. In contrast, active Cl− secretion of pouchitis tissues was reduced versus intact pouch and controls (1.4 (0.3) v 4.3 (0.7) and 4.6 (0.7) μmol/h/cm2), and Na+-glucose cotransport of pouchitis was reduced compared with intact pouch and controls (1.8 (0.5) v 4.2 (0.8) and 8.8 (1.3) μmol/h/cm2). Conclusions: Ileal mucosa in pouchitis and terminal ileum prior to IPAA exhibit impaired secretory and absorptive transport functions whereas the epithelial barrier function remains unchanged. This differs from findings in ulcerative colitis. Thus the hypothesis that pouchitis represents a remanifestation of ulcerative colitis has to be questioned.

Acute sigmoid diverticulitis. Are operations more frequent since the introduction of laparoscopy and CT scanning

INTRODUCTION Sigmoid resection is now considered as a standard procedure for acute and recurrent sigmoid diverticulitis (SD). In the last decade significant changes in preoperative diagnosis with computed tomography (CT) scanning and surgical access (laparoscopy) have been implemented. The aim of this study was to examine whether this has led to changes in the indications for surgical therapy. PATIENTS AND METHODS Consecutive admissions of 1,154 patients from January 1995 to December 2009 with acute SD were prospectively included. In terms of pre-operative and intraoperative findings and postoperative course 3 treatment periods (TP) were distinguished: TP I 1995-1999, TP II 2000-2004 and TP III 2005-2009. RESULTS CT scanning was used in more than 90% of cases since TP II compared to 51% during TP I (p<0.001). The ratio of emergency versus elective surgery significantly increased in favor of elective surgery (p<0.001). The rate of laparoscopy-assisted sigmoid resections showed a continuous increase from 53% in TP I to 71% in TP III (p<0.001) while the rate of Hartmanns procedures decreased over time (p<0.001). Overall, the rate of surgically treated patients decreased during the time periods studied despite an increase in the total number of patients with SD (TP III versus TP I +41%.) The rate of conservatively treated patients increased significantly (p<0.001). The morbidity rate decreased (p<0,001) whereas mortality rates remained at a constantly low level (p=0.175). CONCLUSION The increasing use of CT diagnosis and the laparoscopic approach led to a shift from emergency surgery with a high complication rate to elective surgery with a high rate of primary restoration of continuity and low morbidity. However, the indications for surgery and therefore the overall rate of patients who underwent surgery did not increase due to these changes.

Therapy of complicated Crohn's disease during pregnancy--an interdisciplinary challenge.

BackgroundSevere courses of Crohn’s disease (CD) during pregnancy are rare. However, if occurring, the risk of miscarriage and low birth weight is increased. At present, only limited data is available on the treatment of CD during pregnancy. In particular, there are no standard guidelines for surgical therapy. Nevertheless, surgery is often unavoidable if complications during the course of the disease arise.PurposeThis study provides a critical overview of conventional and interventional treatment options for CD complications during pregnancy and analyses the surgical experience gained thus far. For illustrative purposes, clinical cases of three young women with a severe clinical course during pregnancy are presented.MethodsAfter treatment-refractory for conservative and interventional measures, surgery remained as the only treatment option. In all cases, a split stoma was created after resection to avoid anastomotic leaks that would endanger the lives of mother and child. The postoperative course of all three patients was uneventful, and pregnancy remained intact until delivery. No further CD specific medication was required before birth.ConclusionsThe management of CD patients during pregnancy requires close interdisciplinary co-operation between gastroenterologists, obstetricians, anaesthetists and visceral surgeons. For the protection of mother and child treatment should thus be delivered in a specialised centre. This article demonstrates the advantages of surgical therapy by focusing on alleviating CD complaints and preventing postoperative complications.

Therapierefraktäre Proktocolitis Crohn

BACKGROUND Laparoscopic colorectal surgery is nowadays also widely used in surgery of inflammatory bowel disease. With the correct indications laparoscopic surgery is an attractive cosmetic alternative for the predominantly juvenile patients. Refractory fistulizing Crohns proctocolitis is a very severe disease with a maximal limitation on the quality of life. Proctocolectomy with a Brooke ileostomy represents a very effective option for these patients. The laparoscopic technique can at least spare the patients a salvage laparotomy incision. We report about our preliminary experiences PATIENTS AND METHOD A total of 8 patients (mean age 25 years, range 19 Background 31 years, female:male ratio 5:3) were operated on. The mean preoperative time course of the disease was 28 months (range 12 Background 156 months). All patients had received long-term prednisolone therapy of >15mg, 2 patients received azathioprine medication, 2 underwent anti TNF-alpha therapy and 6 received 5-aminosalicylic acid (5-ASA). The mean preoperative BMI was 19 (range 15 Background 21). All patients suffered from Crohns pancolitis with anorectal fistulas. Laparoscopic proctocolectomy was performed using 4 trocars place in a semicircular fashion. The resected tissue was salvaged transanally and the Brooke ileostomy was drained via the right lateral trocar. The terminal exit of the rectum occurred transanally with preservation of the pelvic floor and the anal sphincter and the anal fistulas were separated. The small pelvis was filled by a transanally fixed omentum. RESULTS The median time for surgery was 236.5 mins (range 220-330 mins). A complication of postoperative paralysis of the bowel occurred in two patients and 4 patients could be discharged problem-free according to the fast-track concept. Cosmetic results were excellent in all cases. Perianal and perirectal manifestations healed completely after a median of 4 weeks. CONCLUSIONS Incisionless proctocolectomy represents a good and realizable alternative to open surgery. The main advantages are excellent cosmetic results and a better preservation of the external integrity of the abdomen.

[Therapy of refractory proctocolitis and Crohn's disease. Incisionless laparoscopic proctocolectomy with a Brooke ileostomy].

BACKGROUND Laparoscopic colorectal surgery is nowadays also widely used in surgery of inflammatory bowel disease. With the correct indications laparoscopic surgery is an attractive cosmetic alternative for the predominantly juvenile patients. Refractory fistulizing Crohns proctocolitis is a very severe disease with a maximal limitation on the quality of life. Proctocolectomy with a Brooke ileostomy represents a very effective option for these patients. The laparoscopic technique can at least spare the patients a salvage laparotomy incision. We report about our preliminary experiences PATIENTS AND METHOD A total of 8 patients (mean age 25 years, range 19 Background 31 years, female:male ratio 5:3) were operated on. The mean preoperative time course of the disease was 28 months (range 12 Background 156 months). All patients had received long-term prednisolone therapy of >15mg, 2 patients received azathioprine medication, 2 underwent anti TNF-alpha therapy and 6 received 5-aminosalicylic acid (5-ASA). The mean preoperative BMI was 19 (range 15 Background 21). All patients suffered from Crohns pancolitis with anorectal fistulas. Laparoscopic proctocolectomy was performed using 4 trocars place in a semicircular fashion. The resected tissue was salvaged transanally and the Brooke ileostomy was drained via the right lateral trocar. The terminal exit of the rectum occurred transanally with preservation of the pelvic floor and the anal sphincter and the anal fistulas were separated. The small pelvis was filled by a transanally fixed omentum. RESULTS The median time for surgery was 236.5 mins (range 220-330 mins). A complication of postoperative paralysis of the bowel occurred in two patients and 4 patients could be discharged problem-free according to the fast-track concept. Cosmetic results were excellent in all cases. Perianal and perirectal manifestations healed completely after a median of 4 weeks. CONCLUSIONS Incisionless proctocolectomy represents a good and realizable alternative to open surgery. The main advantages are excellent cosmetic results and a better preservation of the external integrity of the abdomen.

Simplified placement and management of cutting setons in the treatment of transsphincteric anal fistula

A. J. Kroesen ()) Department of Surgery, Charit , Universit tsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany e-mail: kroesen@medizin.fu-berlin.de Tel.: +49-30-84452541 Fax: +49-30-84452740 Anal fistula are, from the very beginning of fistula surgery, a difficultto-treat entity. There are many therapeutical options to treat them. For idiopathic anorectal fistulas, most coloproctological societies have established a standardized strategy for the different fistula types. Simple submucosal and low transsphincteric fistulas can be surgically divided without a major risk for faecal incontinence. High transsphincteric and supralevatoric fistulas are priorly excised in the same way as exstrasphincteric fistula course. The intrasphincteric course is excised as well, but followed by a muscle suture. The intraanal or intrarectal covering of the internal fistula opens by a flap formed out of anoderm, rectal mucosa or a mucosa muscle flap. With this concept, idiopathic fistulas can be healed with a success rate up to 90% [1, 2, 3]. Also, drainage setons play an important role in the treatment of anal fistulas. In very extensive fistulas with accompanying abscesses, they can be used to clean the wound prior to a definitive closure of the internal fistula opening [4]. Especially in Crohn’s-disease-associated fistulas, setons are even more important [5]. Due to the high recurrence rates of a plastic closure of Crohn fistulas, drainage setons are frequently used as a definitive treatment of the fistula. The coloproctological group of Hamel et al. is now introducing a technical note for a simplified placement of cutting setons. The placement technique is very simple and nice and many surgeons might introduce this technique in their own daily routine. As far as setons are used for a long-term drainage, there is nothing to dispute about this article. The technique of a cutting seton, on the other hand, is abandoned by almost all leading coloproctological units [3, 6, 7]. The arguments against cutting setons are numerous:

Metaplastische Paneth Zellen bei chronisch-entzündlichen Darmerkrankungen

The pathogenesis of the inflammatory bowel disease comes out to be complex and multifactor event. Pathological changes seem to occur already in gene pool. The existent term of IBD genetics suggest several known susceptibility genes like NOD2, IL23R, PTPN2 for Crohn’s disease (CD), or IBD5 and ARG16L1 for ibd. Recent studies suggest reduced TCF4 expression in paediatric patients with CD [1]. The mucosal wall plays a pivotal role as high immune-competent barrier. Its function depends on the integrity of the epithelia, tide junctions, submucosal macrophages and dendritic cells. Particular interest merits the Paneth cells, as they are able to produce specific constitutive α-5 and α-6 defensins with antimicrobial activity. Next to the secretor function Paneth cells might participate in the regulation mucosal immunity, these functions are poor understood. The β-catenin/TFC signalling way regulates the epithelial cell differentiation in the crypt-villus-axis. The position and orientation of the Paneth cells depends on availability of the WNT-receptor-frizzled-5. In IBD Paneth cells occur in atypical gut segments of colon and show increased count in ileum in Crohn’s disease. The multiprotein complexes NALP are involved in activating MHC and seem to be novel track in the studies of IBD immunity disorder. NALP1 is promoting through caspase-1 activation the building of proinflammatory cytokine IL-1β, well known to be increased in Crohn’s disease and is usually expressed next to NALP3 and NOD2 in antigen presenting cells. NALP 8 is believed to have antiviral activity in reproductive cells, though no further details are known about NAPL’s 7, 8 or 11 [2].

Enhanced activity of immunoproteasomes in patiens with Crohn’s disease

The eukaryotic 20S proteasome is the main protease in the cytoplasm and nucleus composed of seven different α and seven different β subunits which form four rings stacked on top of each other. It is now known that the constitutive proteasome is the predominant form in most tissue. Our current study demonstrates that the second form, inducible immunoproteasome is more abundant in inflamed ileum and colon of Crohn’s disease. Especially, immunosubunit β1 i is increasingly expressed in the inflamed intestinal tissue of patients with Crohn’s disease. We show here that this subunit exchange alters the cleavage pattern of proteasomes in the inflamed intestine of patients with Crohn’s disease contributing directly to the activation of NF-kB by increasing the processing of p105 and degradation of IkBα. Thus, the immunoproteasome is involved in the enhanced activity of NF.-kB which is one of the most important regulators of proinflammatory gene expression in intestinal inflammation.

Therapierefraktäre Proktocolitis Crohn@@@Therapy of refractory proctocolitis and Crohn’s disease: Bergeinzisionslose laparoskopische Proktokolektomie mit Brooke-Ileostoma@@@Incisionless laparoscopic proctocolectomy with a Brooke ileostomy

BACKGROUND Laparoscopic colorectal surgery is nowadays also widely used in surgery of inflammatory bowel disease. With the correct indications laparoscopic surgery is an attractive cosmetic alternative for the predominantly juvenile patients. Refractory fistulizing Crohns proctocolitis is a very severe disease with a maximal limitation on the quality of life. Proctocolectomy with a Brooke ileostomy represents a very effective option for these patients. The laparoscopic technique can at least spare the patients a salvage laparotomy incision. We report about our preliminary experiences PATIENTS AND METHOD A total of 8 patients (mean age 25 years, range 19 Background 31 years, female:male ratio 5:3) were operated on. The mean preoperative time course of the disease was 28 months (range 12 Background 156 months). All patients had received long-term prednisolone therapy of >15mg, 2 patients received azathioprine medication, 2 underwent anti TNF-alpha therapy and 6 received 5-aminosalicylic acid (5-ASA). The mean preoperative BMI was 19 (range 15 Background 21). All patients suffered from Crohns pancolitis with anorectal fistulas. Laparoscopic proctocolectomy was performed using 4 trocars place in a semicircular fashion. The resected tissue was salvaged transanally and the Brooke ileostomy was drained via the right lateral trocar. The terminal exit of the rectum occurred transanally with preservation of the pelvic floor and the anal sphincter and the anal fistulas were separated. The small pelvis was filled by a transanally fixed omentum. RESULTS The median time for surgery was 236.5 mins (range 220-330 mins). A complication of postoperative paralysis of the bowel occurred in two patients and 4 patients could be discharged problem-free according to the fast-track concept. Cosmetic results were excellent in all cases. Perianal and perirectal manifestations healed completely after a median of 4 weeks. CONCLUSIONS Incisionless proctocolectomy represents a good and realizable alternative to open surgery. The main advantages are excellent cosmetic results and a better preservation of the external integrity of the abdomen.