Classification of acute appendicitis (CAA): treatment directed new classification based on imaging (ultrasound, computed tomography) and pathology.

PURPOSE: Acute appendicitis (AA) is amongst the most common causes of acute abdominal pain. In spite of progress based on risk stratifications, "negative" appendectomies are performed in up to 30% of patients whilst the appendix perforates in others. Preoperative classification of AA based on imaging is therefore recommended. The aim was to classify AA based on imaging (ultrasound/US, computed tomography/CT), surgical pathology, and/or histopathology in order to differentiate between complicated and uncomplicated AA. A new classification of acute appendicitis (CAA) shall be illustrated by typical US and CT images and be employed in a diagnostic and therapeutic algorithm. METHODS: Medline, Embase, and the Cochrane Library were searched. Any study after 1970, which investigated clinical scores, pathology, US, CT, magnetic resonance imaging, and treatment of AA, was included. Typical images were taken from the author's image database. RESULTS: Five main types of AA are defined, normal appendix (type 0), nonvisualised appendix (type X), uncomplicated AA (type 1), complicated AA without perforation (type 2), and complicated AA with perforation (type 3). The imaging modality is indicated by an additional letter, e.g., type p3b for free perforation on pathology. Standardised reporting of the appendix evaluation by US and CT is presented, as well as algorithms for AA management. Imaging features indicating imminent perforation, as well as likely recurrence, were both classified as complicated AA. CONCLUSION: Imaging is mandatory in suspected AA. The CAA clearly separates uncomplicated from complicated forms of AA allowing nonoperative management in selected patients with uncomplicated forms of AA.

Improving treatment of patients with inflammatory bowel diseases: a controlled trial of a multifaceted intervention in two German cities.

PURPOSE: Many recommendations from clinical practice guidelines are not implemented. We aimed to develop and evaluate a multifaceted strategy for the implementation of guidelines for Crohn's disease (CD) and ulcerative colitis (UC). METHODS: In the intervention region (Berlin, Germany), a continuing medical education course was held, brief guidelines for practice were distributed to all family physicians and gastroenterologists, and patient guidelines were distributed to all surveyed patients. Educational outreach visits with local opinion leaders were also conducted. No specific interventions were performed in the control region (Hamburg, Germany). Prior to the intervention and 1 year later, 1900 members of three statutory sickness funds were asked about their treatment according to guidelines with (1) long-term aminosalicylates and (2) immunosuppressants, (3) whether they took long-term glucocorticoids for maintenance of remission, (4) if they smoked, in CD patients, and (5) about the surveillance colonoscopies, in UC patients. RESULTS: Response rate after implementation was 20.1%. Responders differed between intervention and control region by age and by distribution between patients with UC or CD. After 1 year, more patients were treated according to clinical practice guidelines in the control region than in the intervention region. More patients in the intervention region took immunosuppressants after 1 year, and fewer had a surveillance colonoscopy. However, no before-after comparison was statistically significant. CONCLUSIONS: This implementation strategy of UC and CD guidelines did not result in a statistically significant effect. Future implementation of guidelines for inflammatory bowel disease might need thorough evaluation of barriers and the support of theory-based concepts.

Guideline recommendations for treatment of patients with inflammatory bowel diseases are not implemented in clinical practice-results of a non-representative survey.

PURPOSE: There is a growing evidence for over-, under-, or misuse of health care in patients with inflammatory bowel disease. Most studies looked at treatment variability or used quality measures, which mostly capture supportive interventions rather than treatment of IBD in itself. We aimed to evaluate if current recommendations in clinical practice guidelines regarding the medical treatment of patients with inflammatory bowel diseases are being followed in Germany. METHODS: A questionnaire was sent to 1901 patients insured with two large German statutory sickness funds and an ICD 10 diagnosis of Crohn's disease (CD) or ulcerative colitis (UC). The questionnaire asked about drug treatment, indications for drug treatment, provision of surveillance endoscopies in ulcerative colitis patients, and smoking status in Crohn's disease patients. RESULTS: Out of 460 evaluable patients, 62.4% of UC patients and 53.9% of CD patients were treated with mesalamine according to guidelines, 91.3% of all patients were treated with glucocorticoids according to guideline recommendations, while only 75.6% received recommended immunosuppressive treatment. Of UC patients, 94.5% had surveillance colonoscopies at the recommended interval and 58.8% of CD patients were non-smokers. No predictor for overall treatment according to guidelines could be found while being of age older than 60 or being treated outside of a dedicated IBD clinic was associated with less immunosuppressive treatment. CONCLUSIONS: A large proportion of patients with IBD do not receive drug treatment in accordance with clinical practice guidelines. Quality improvement measures are much needed.

Targeting human CD2 by the monoclonal antibody CB.219 reduces intestinal inflammation in a humanized transfer colitis model.

The cell adhesion molecule CD2 facilitates antigen-independent T-cell activation and CD2 deficiency or blockade reduces intestinal inflammation in murine models. We here aimed to evaluate the therapeutic potential of monoclonal antibodies (mAb) specific for human CD2 in colitis treatment. Transfer colitis induced by naïve CD4(+) T cells expressing human CD2 was treated with anti-human CD2 mAb. The mAb CB.219 protected from severe colitis in a preventive treatment regimen, while therapeutic treatment ameliorated intestinal inflammation. Diminished intestinal tissue damage was paralleled by a profound suppression of lamina propria lymphocytes to produce pro-inflammatory cytokines and tumor necrosis factor α as well as the neutrophil chemoattractant CXC motif ligand 1 and the CC chemokine ligand 3. Furthermore, infiltration with macrophages and T cells was low. Thus, reduced intestinal inflammation in our humanized colitis model by targeting CD2 on T cells with the mAb CB.219 suggests a novel approach for colitis treatment.

Gadofluorine M-enhanced magnetic resonance imaging of inflammatory bowel disease: quantitative analysis and histologic correlation in a rat model.

OBJECTIVES: : To determine the colonic mural enhancement in a rat model of inflammatory bowel disease (IBD) using gadofluorine M- and diethylenetriamine pentaacetic acid (Gd-DTPA)-enhanced magnetic resonance (MR) imaging, and to correlate the degree of enhancement with the histopathologic severity of the disease. MATERIALS AND METHODS: : This study was approved by our hospital's institutional animal care and use committee. A total of 44 rats with 2 grades (mild, n = 17; and severe, n = 27) of dinitrobenzene sulfonic acid (DNBS)-induced IBD and 13 rats without IBD, were examined using a 2.4-T, small animal MR scanner. T2- and T1-weighted MR images were acquired, and sequential T1-weighted MR imaging was then performed immediately and again 15, 45, 60, and 90 minutes, and 24 hours after intravenous -injection of either gadofluorine M- or Gd-DTPA (0.1 mmol Gd/kg body weight). The signal-to-noise ratios and enhancement ratios (ER) of the colon wall were measured. For paired and group comparisons of the histopathology and MR imaging data, the Wilcoxon- and the Mann-Whitney U tests were used, and the multifactorial analysis of variance test was used to compare the time courses of the ERs. RESULTS: : Gadofluorine M injection resulted in significant differences in the ER of noninflamed, mildly inflamed, and severely inflamed colon wall at any time up to 24 hours after contrast injection (ER at 24 hours 2.0 ± 1.2; 10.1 ± 4.3; and 49.7 ± 10.8, respectively; P < 0.01). After Gd-DTPA injection, significant differences were observed in the ER of inflamed and noninflamed bowel at 15, 45, and 60 minutes (P < 0.01); however, no significant differences in mildly and severely inflamed bowel were observed at any time. In contrast to Gadofluorine M, there was no prolonged contrast enhancement in the inflamed colon wall after intravenous injection of Gd-DTPA (ER at 24 hours 1.6 ± 1.3; 3.4 ± 2.7; and 3.3 ± 1.6, respectively; n.s.). CONCLUSIONS: : Gadofluorine M-enhanced MR imaging shows a higher correlation of the wall enhancement and histopathology grading in an IBD rat model than does Gd-DTPA-enhanced imaging.

Helicobacter pylori and gastroduodenal ulcer disease.

BACKGROUND: Helicobacter pylori-associated diseases and gastroduodenal ulcer disease are common conditions of major clinical and economic importance. There is thus a need for a guideline that incorporates the scientific knowledge gained in recent years and that takes specific aspects of the situation in Germany into account with regard to epidemiology, resistance status, diagnostic evaluation, and treatment. METHODS: This level-S3 consensus guideline was developed in accordance with the recommendations of the Association of Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF). It was commissioned by the German Association for Digestive and Metabolic Diseases (Deutsche Gesellschaft für Verdauungs- und Stoffwechselkrankheiten, DGVS) and prepared in cooperation with other scientific societies. After search terms were compiled, a systematic, IT-supported literature search was performed in the PubMed and Cochrane databases. The search was restricted to articles that appeared in German or English from 2000 onward. RESULTS: H. pylori infection can be accurately diagnosed either non-invasively (with a (13)C-urea breath test or a stool antigen test) or invasively (with a rapid urease test, by histology, or by culture). Gastric and duodenal ulcer and gastric MALT lymphoma are absolute indications for eradication therapy; relative indications include functional dyspepsia, the prevention of gastric cancer in persons at risk, the initiation of long-term treatment with non-steroidal anti-inflammatory drugs (NSAID), and the prior occurrence of gastroduodenal complications with the use of either NSAID or acetylsalicylic acid (ASA). First-line therapy consists of a proton-pump inhibitor (PPI) and clarithromycin combined with either metronidazole or amoxicillin, given for at least one week. CONCLUSION: This guideline enables the structured, evidence-based diagnosis and treatment of H. pylori infection and associated conditions, as well as of gastroduodenal ulcer disease.

Human peripheral gammadelta T cells possess regulatory potential.

Deficiency in gammadelta T cells aggravates colitis in animal models suggesting that gammadelta T cells have regulatory properties. Therefore, proliferation, suppression and cytokine secretion of human gammadelta T cells were determined in vitro. Human peripheral gammadelta T cells were isolated from the whole blood of healthy donors by magnetic antibody cell sorting technology. The proliferation after CD3/CD28 stimulation was measured by (3)[H]thymidine incorporation. Interferon-gamma (IFN-gamma), interleukin-2 (IL-2), transforming growth factor-beta (TGF-beta) and IL-10 concentrations were measured by enzyme-linked immunosorbent assay; TGF-beta messenger RNA was also measured by reverse transcription-polymerase chain reaction. The expression of latency associated peptide (LAP), a TGF-beta complex component, intracellular cytokine content and T helper cell proliferation were measured by flow cytometry. Human gammadelta T cells showed poor proliferation upon CD3/CD28 stimulation and suppressed T helper cell growth stronger than CD4(+) CD25(+) T cells, although gammadelta T cells were FOXP3 negative. They secreted little IL-2 but high concentrations of IFN-gamma, IL-10 and TGF-beta. When looking at LAP expression the Vdelta1 subset was found to be the main TGF-beta producer compared to Vdelta2 T cells. Taken together, peripheral gammadelta T cells have in vitro a more potent regulatory potential than CD4(+) CD25(+) cells regarding T helper cell suppression. This is most likely the result of strong TGF-beta secretion, particularly by the Vdelta1 subset.

[Clinical practice guideline on diagnosis and treatment of Crohn's disease - summary for the general practitioner]. / Leitlinie "Diagnostik und Therapie des Morbus Crohn" - Kurzfassung für Internisten und Hausärzte.

The German clinical practice guideline on diagnosis and therapy of Crohn's disease is the result of an evidence-based consensus conference under the auspices of the German Gastroenterologic Society and the Competence Network IBD. This article will summarize the recommendations most important for the general practitioner.Crohn's disease is diagnosed in cooperation with a gastroenterologist who is performing endoscopy and possibly ultrasound. Uncomplicated relapses can nevertheless be successfully treated at the office of a family physician - mostly with steroids. Steroids are not appropriate for long-term treatment though. In those cases an early treatment with immunosuppressants in collaboration with a gastroenterologist is required. Cooperation with several different sub specialists is necessary when surgery is required as well as for the treatment of fistula, psychosomatic aspects and extraintestinal manifestations.

Magnetic resonance imaging of experimental inflammatory bowel disease: quantitative and qualitative analyses with histopathologic correlation in a rat model using the ultrasmall iron oxide SHU 555 C.

OBJECTIVES: To quantitatively and qualitatively characterize the MR findings of inflammatory bowel disease in a rat model after i.v. injection of the reticuloendothelial system cell specific ultrasmall iron oxide SHU 555 C. MATERIALS AND METHODS: Colitis was induced in 15 rats using dinitrobenzene sulfonic acid instillation. Five rats served as controls. T1- and T2-weighted spin-echo- and T2*-weighted gradient-echo-sequences were acquired at 2.4 Tesla before and immediately, 15, 45, 60, and 90 minutes, and 24 hours after i.v.-injection of SHU 555 C (0.1 mmol Fe/kg). MR images were evaluated quantitatively regarding thickness and signal-to-noise ratio (SNR) of the bowel wall and qualitatively regarding overall bowel wall signal intensity and the occurrence of bowel wall ulcerations. MR findings were correlated to histology. RESULTS: The inflamed bowel wall was significantly thicker than the noninflamed bowel wall and 90 minutes after contrast injection it showed a significant reduction of SNR in T1- (94 +/- 27 vs. 61 +/- 29; P < 0.01), T2- (67 +/- 26 vs. 28 +/- 17; P < 0.05), and T2*- (92 +/- 57 vs. 10 +/- 7; P < 0.05) weighted images as compared with unenhanced images. At 24 hours, the respective SNR values remained significantly reduced. The signal loss was homogeneous in 12 and focal in 3 of the 15 rats with colitis. Nine rats showed colonic wall ulcerations. In all but one animal (missed focal ulceration) MR findings correlated to the histologic findings. CONCLUSIONS: SHU 555 C leads to a significant signal intensity loss of the inflamed bowel wall in T1-, T2- and T2*-weighted images. SHU 555 C enhanced MRI findings correlate well with histologic findings.

Gammadelta T lymphocytes: a new type of regulatory T cells suppressing murine 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced colitis.

BACKGROUND: The intestinal immune system is continuously challenged by antigen without becoming dysregulated. However, injury of the mucosa by, i.e. dextran sulphate sodium causes severe inflammation in gammadelta T-cell-deficient mice. We therefore asked whether gammadelta T cells have regulatory functions. MATERIALS AND METHODS: gammadelta T cells were isolated from spleens and mesenteric lymph nodes of C57BL/6 wild-type (wt) mice. Proliferation and cytokine secretion of gammadelta T cells were quantified by [(3)H] thymidine incorporation and ELISA. Additionally, proliferation of carboxyfluorescein diacetate succinimidylester-labelled CD4(+) T cells cocultured with gammadelta T cells was analysed by flow cytometry. Finally, gammadelta T cells from wt or interleukin-10 transgenic (IL-10tg) mice were transferred into congenic mice with 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced colitis. RESULTS: gammadelta T cells were hyporesponsive to CD3/CD28 stimulation and suppressed CD4(+) T-cell proliferation (up to 66+/-7% suppression) in vitro. Further, the preventive transfer of wt or IL-10tg gammadelta T cells ameliorated TNBS-induced colitis resulting in prolonged survival and reduced histological damage (1.5+/-0.4 and 1.3+/-0.2, respectively vs. 3.8+/-0.3 in untransferred mice, p<0.05). This was accompanied by reduced TNF-alpha and increased IL-10 and TGF-beta secretion from intestinal and splenic lymphocytes. CONCLUSIONS: Murine gammadelta T cells are a new type of regulatory T cells in vitro and act protective on mouse TNBS-induced colitis in vivo. Future studies have to define the underlying mechanism and to investigate whether gammadelta T cells can be used for immunotherapy of human inflammatory bowel disease.

Through the endoscope balloon dilation of ileocolonic strictures: prognostic factors, complications, and effectiveness.

BACKGROUND/AIMS: About half of all Crohn's disease (CD) patients undergo surgery at some point, many because of strictures. An alternative possibility is to dilate strictures endoscopically. However, little is known about prognostic factors. PATIENTS AND METHODS: Thirty-two patients with primary CD (n=2), radiogenic strictures (n=1), or postoperative strictures (27 because of CD; 2 after resection because of cancer), were planned to undergo colonoscopic dilatation of which 25 patients were dilated (10 men; 15 women; median age 48). Length of stenosis, diameter of stricture, balloon size, smoking status, ulcer in the stricture, passage postdilatation, hemoglobin level, complications, redilatation, and subsequent surgery were recorded. Only patients with at least 6 months follow up were included. RESULTS: Five out of 32 patients had no stenosis, marked inflammation, or fistulas adjacent to the stricture. One patient each had a long stricture (8 cm) or a filiform stenosis ruling out dilatation [technical success, 25/27 (92.6%)]. Among these 25 patients, 39 colonoscopies with 51 dilatations were performed. After a single dilatation, 52% were asymptomatic while 48% needed another intervention, half of them surgery. Bleeding without need for transfusion occurred in 3 out of 39 colonoscopies and one perforation required surgery. Significant prognostic factors were smoking and ulcers in the stricture (P<0.05 each). Some ulcers led to intussusception requiring surgery in spite of good dilatation results. CONCLUSION: Through the endoscope balloon stricture dilatation is a relatively safe and often effective treatment modality in ileocolonic strictures. The presence of ulcers in the stricture have a worse outcome as do smokers.

Aggravation of different types of experimental colitis by depletion or adhesion blockade of neutrophils.

BACKGROUND & AIMS: Neutrophils are generally thought to play an important proinflammatory role in the pathogenesis of inflammatory bowel disease. The objective of this study was to evaluate whether blocking the invasion of neutrophils by anti-L-selectin monoclonal antibodies modulates chemically induced colitis and how this modulation is accomplished. METHODS: Trinitrobenzene sulfonic acid/dinitrobenzene sulfonic acid (TNBS/DNBS)-induced colitis was studied in rats on treatment with anti-L-selectin monoclonal antibodies (mAb) or antineutrophil antiserum. Different anti-L-selectin mAb, either blocking or nonblocking, as well as F(ab)(2) fragments were evaluated. Additionally, leukocyte migration was examined using intravital microscopy. Furthermore, the effect of neutrophil depletion in rat TNBS-induced colitis was studied either prior to or after colitis induction as well as murine CD4(+)CD45RB(high) transfer colitis. Finally, bacterial translocation during DNBS-induced colitis was studied in neutrophil-depleted and control rats. RESULTS: Anti-L-selectin mAb treatment resulted in increased mortality and bowel inflammation as well as hemorrhagic eye secretion. No clear difference was found between blocking and nonblocking mAb or F(ab)(2) fragments. For all investigated antibodies/fragments, either complete blockade of leukocyte invasion or marked neutrophil depletion was found. Accordingly, neutrophil depletion by antiserum resulted in aggravation of rat DNBS-induced colitis as well as murine transfer colitis. CONCLUSIONS: Adhesion blockade or neutrophil depletion aggravates rat TNBS/DNBS-induced colitis together with extraintestinal manifestations of the eyes. Therefore, neutrophils appear to have an important role in mucosal repair processes. Importantly, adhesion blockade as a therapeutic concept can be detrimental in inflammatory bowel disease.