Anthocyanins Prevent Colorectal Cancer Development in a Mouse Model.

BACKGROUND: Colorectal cancer is the main leading cause of cancer-related deaths worldwide. Present data suggest that plant-derived anthocyanins have anti-inflammatory and chemopreventive properties. This study was aimed at evaluating the effect of an anthocyanin-rich extract from bilberries on colorectal tumour development and growth in the administration of azoxymethan (AOM)/dextran sodium sulfate (DSS) mouse model. METHODS: Colonic carcinogenesis was induced by AOM and DSS 3 or 5%, respectively, in 50 female Balb/c mice. Mice received either normal food (controls) or a diet containing either 10 or 1% anthocyanin-rich bilberry extract. Colonoscopy took place at week 4 and 9 after initiation of carcinogenesis. After termination at week 9, colon samples were analysed macroscopically and microscopically. RESULTS: Mice receiving 10% anthocyanins showed significantly (p < 0.004) less reduced colon length (12.1 cm [8.5-14.4 cm]) as compared to controls (11.2 cm [9.8-12.3]) indicating less inflammation. Mice fed with 10% anthocyanin-rich extract revealed significantly less mean tumour numbers (n = 1.2) compared to control (n = 14) and anthocyanin 1% treated mice (n = 10.6, p < 0.001). CONCLUSION: Anthocyanins prevented the formation and growth of colorectal cancer in AOM/DSS-treated Balb/c mice. Further studies should investigate the mechanisms of how anthocyanins influence the development of colorectal cancer.

Feasibility and acceptability of couple counselling and pelvic floor muscle training after operation for prostate cancer.

BACKGROUND: Radical prostatectomy is often followed by long-lasting erectile dysfunction and urinary incontinence, with adverse effects on the quality of life and intimate relationship of patients and partners. We developed the ProCan intervention to ameliorate sexual and urological dysfunction after radical prostatectomy and examined its feasibility, acceptability and changes in sexual function. MATERIAL AND METHODS: Between May 2014 and October 2014, seven couples attending the Department of Urology, Rigshospitalet, were included 3-4 weeks after radical prostatectomy in the ProCan intervention, which consists of up to six couple counselling sessions, group instruction in pelvic floor muscle training (PFMT), up to three individual PFMT sessions and a DVD home training program. We examined its feasibility on the basis of the recruitment rate, adherence to and acceptability of the intervention, the response rate and changes in erectile and sexual functioning measured on the International Index of Erectile Function at baseline and at eight and 12 months. RESULTS: The recruitment rate was 14%. One couple withdrew, six couples attended 1-4 counselling sessions, and all patients attended PFMT until continence was achieved. The response rate on outcomes was 85% for patients and 71% for partners. The couples reported that counselling improved their sex life but it did not improve their ability to talk openly about sex. Most patients found that the physiotherapist improved their motivation and the quality and intensity of PFMT. Erectile dysfunction improved from severe at baseline to moderate at eight months' follow-up, and mean sexual functioning improved from 18.4 to 37.1 points at eight months' follow-up, but decreased slightly to 31.4 at 12 months. CONCLUSION: Our results suggest that the recruitment procedure should be adapted and minor revisions are needed in the intervention. The key components, couple counselling and PFMT, were well accepted and achievable for the patients.

Galectin-3 Modulates Experimental Colitis.

BACKGROUND: We recently identified galectin-3 (gal-3) as a new and strong fibroblast activator produced by colonic epithelial cells. Very little is known about the influence of gal-3 in inflammatory bowel disease. We, therefore, investigated the impact of gal-3 on dextran sodium sulfate (DSS)-induced colitis in a mouse model. METHODS: Colonic lamina propria fibroblasts of healthy controls were used for co-incubation studies of gal-3 with gal-1, TGF-ß1, IFNγ, IL-4 and IL-10. Acute and chronic DSS colitis was induced by 3% DSS in drinking water in female Balb/c mice weighing 20-22 g. Recombinant gal-3 was expressed by the pET vector system and used for a 5-day treatment in different concentrations intraperitoneally. The distal third of the colon was used for histologic analysis. Colonic cytokine expression was determined by quantitative RT-PCR. RESULTS: In vitro, gal-3 induced IL-8 secretion was significantly reduced by co-incubation with IL-10 (5 ng/ml) and IL-4 (10 ng/ml). Acute DSS-induced colitis was ameliorated by gal-3 treatment as indicated by increased colonic length and reduced weight loss compared to that of controls. In acute and chronic colitis, gal-3 treatment resulted in a significant suppression of colonic IL-6. CONCLUSION: Gal-3 significantly reduces inflammation in acute and chronic DSS colitis in mice indicating a potential role in intestinal inflammation.

Gastrointestinal endoscopy in patients aged 75 years and older: risks, complications, and findings--a retrospective study.

PURPOSE: Endoscopy of the gastrointestinal tract offers simultaneously diagnostic and therapeutic options and is increasingly performed in elderly patients due to a continuously growth of this population segment. Whereas safety data of diagnostic and interventional endoscopy in patients younger than 65 years are well characterized, only scarce data exist for elderly patients older than 75 years. METHODS: We analyzed outcomes and complications of endoscopic procedures with focus on colonoscopy in patients aged 75 and older at a single tertiary referral center in Germany between 1996 and 2006. RESULTS: A total of 3770 endoscopies (2270 gastroscopies, 735 colonoscopies, 765 ERCP) were performed in 1841 patients with a mean age of 79 years (range 75 to 97 years). Seventy-four percent of all patients suffered from relevant comorbidities. Therapeutic interventions were carried out in 43 % of colonoscopies. Complications were observed in approximately 1 %. CONCLUSION: The observed complication rate in diagnostic and therapeutic endoscopic procedures is not increased in elderly patients compared to the reported complication rates in younger patients.

Golimumab in unresponsive ulcerative colitis.

Ulcerative colitis (UC) is a chronic inflammation mainly affecting the colon mucosa. It predominantly occurs in younger patients. Until recently, the main goals in the treatment of UC were to temper the symptoms, such as diarrhea, pain, and weight loss, by using mesalazine and steroids. With newer medications, such as immunomodulators (thiopurines) and the biologics providing blockade of tumor necrosis factor (TNF), the goals of the therapy in UC have changed to long-term remission and mucosal healing. The first available anti-TNF therapy in UC included infusion therapy with infliximab every few weeks. In 2012, subcutaneously administered adalimumab gained approval for the treatment of UC in Germany. In patients with a mild disease, therapy with mesalazine, orally or topically, can be sufficient. In patients with moderate to severe disease, therapy with azathioprine or anti-TNF is often required to reach disease control; however, this is only efficient in about two-thirds of patients. Some patients either show no response or a lost response while on treatment. So, further medical options are warranted in the treatment of UC. With golimumab, a new approach in the treatment of mild to moderate UC recently became available in Germany and is a promising new option in the therapy regimen for patients with UC.

Physiologic TLR9-CpG-DNA interaction is essential for the homeostasis of the intestinal immune system.

BACKGROUND: Cytosine-guanosine dinucleotide (CpG) motifs are immunostimulatory components of bacterial DNA and activators of innate immunity through Toll-like receptor 9 (TLR9). Administration of CpG oligodeoxynucleotides before the onset of experimental colitis prevents intestinal inflammation by enforcement of regulatory mechanisms. It was investigated whether physiologic CpG/TLR9 interactions are critical for the homeostasis of the intestinal immune system. METHODS: Mesenteric lymph node cell and lamina propria mononuclear cell (LPMC) populations from BALB/c wild-type (wt) or TLR9 mice were assessed by flow cytometry and proteome profiling. Cytokine secretion was determined and nuclear extracts were analyzed for nuclear factor kappa B (NF-κB) and cAMP response-element binding protein activity. To assess the colitogenic potential of intestinal T cells, CD4-enriched cells from LPMC of wt or TLR9 donor mice were injected intraperitoneally in recipient CB-17 SCID mice. RESULTS: TLR9 deficiency was accompanied by slight changes in cellular composition and phosphorylation of signaling proteins of mesenteric lymph node cell and LPMC. LPMC from TLR9 mice displayed an increased proinflammatory phenotype compared with wt LPMC. NF-κB activity in cells from TLR9 mice was enhanced, whereas cAMP response-element binding activity was reduced compared with wt. Transfer of lamina propria CD4-enriched T cells from TLR9 mice induced severe colitis, whereas wt lamina propria CD4-enriched T cells displayed an attenuated phenotype. CONCLUSIONS: Lack of physiologic CpG/TLR9 interaction impairs the function of the intestinal immune system indicated by enhanced proinflammatory properties. Thus, physiologic CpG/TLR interaction is essential for homeostasis of the intestinal immune system as it is required for the induction of counterregulating anti-inflammatory mechanisms.

Colonic bowel wall thickening: is there a need for endoscopic evaluation?

PURPOSE: Clinical relevance of colonic bowel wall thickening seen on abdominal CT scans is unknown. Recommendations for further diagnostic procedures are lacking. The aim of this retrospective study was to evaluate detecting of bowel wall thickening on CT scan and findings that were seen in case of endoscopical evaluation. METHODS: The radiological database was retrospectively reviewed for all reports of CT scans from 2003 to 2009 at the University Hospital Regensburg, Germany. Patients with underlying diseases for suspected bowel wall thickening were excluded. RESULTS: Sixty-two patients with bowel wall thickening were detected. Twenty-one percent (13/62) had generalized bowel wall thickening. In 58%, bowel wall thickening was limited to one segment of the colon (36/62), mostly left sided (25/62). Forty-four percent of patients (27/62) were sent to endoscopy. In 15% (4/27), malignancy was suspected, and it could be histologically confirmed in two patients. Nineteen percent (5/27) had normal endoscopy, and 67% (18/62) showed benign findings. CONCLUSION: Colonic bowel wall thickening is not a common finding on CT scan in this study. Consequential endoscopic evaluation was performed in less than 50% of patients. Pathological findings were detected in 80% of these patients. We recommend endoscopical evaluation if bowel wall thickening is reported on CT scan.

Fibrin glue in the endoscopic treatment of fistulae and anastomotic leakages of the gastrointestinal tract.

BACKGROUND: Fistulae or leakages of anastomotic junctions of the gastrointestinal tract used to be an indication for surgery. However, patients often are severely ill and endoscopic therapeutic options have been suggested to avoid surgical intervention. PURPOSE: This is a retrospective analysis of fibrin glue application in the treatment of gastrointestinal fistulae or anastomotic leakages. AIM: The aim of this study was to investigate the value of fibrin glue in the treatment of gastrointestinal fistulae and leakages. METHODS: From September 1996 to November 2002, 52 patients with gastrointestinal fistulae or insufficiencies have been treated endoscopically including the use of fibrin glue (Tissucol Duo S®, Baxter, Unterschleissheim, Germany). Clinical data comprising concomitant therapies and results were analysed by chart review. RESULTS: Twenty-six lesions were located in the oesophagus or gastroesophageal junction, 4 in the stomach, 7 in the small intestine, 13 colorectal and 2 in the pancreas. The duration of treatment ranged from 12 to 1,765 days. Two to 81 ml fibrin glue (median 8.5) was used in 1-40 sessions (median 4). All patients received antibiotics; additional endoscopic options were frequently applied. Endoscopic therapy cured 55.7% patients (n = 29); 36.5% (n = 19) were cured with fibrin glue as sole endoscopic option. In 23.1% (n = 12), surgical intervention became necessary. Patients without major infectious complications tended to have a higher cure rate without surgery (87.5% vs. 50%). Eleven patients died (21.1%). CONCLUSION: Endoscopic therapy is a valuable option in the treatment of fistulae and anastomotic insufficiencies of the gastrointestinal tract. It usually is applied repeatedly. Fibrin glue is a mainstay of this procedure. Major infectious complications seem to define a subgroup of patients with poorer outcome.

Expression of growth factor receptors and targeting of EGFR in cholangiocarcinoma cell lines.

BACKGROUND: Cholangiocarcinoma (CC) is a malignant neoplasm of the bile ducts or the gallbladder. Targeting of growth factor receptors showed therapeutic potential in palliative settings for many solid tumors. The aim of this study was to determine the expression of seven growth factor receptors in CC cell lines and to assess the effect of blocking the EGFR receptor in vitro. METHODS: Expression of EGFR (epithelial growth factor receptor), HGFR (hepatocyte growth factor receptor) IGF1R (insulin-like growth factor 1 receptor), IGF2R (insulin-like growth factor 2 receptor) and VEGFR1-3 (vascular endothelial growth factor receptor 1-3) were examined in four human CC cell lines (EGI-1, HuH28, OZ and TFK-1). The effect of the anti-EGFR-antibody cetuximab on cell growth and apoptosis was studied and cell lines were examined for KRAS mutations. RESULTS: EGFR, HGFR and IGFR1 were present in all four cell lines tested. IGFR2 expression was confirmed in EGI-1 and TFK-1. No growth-inhibitory effect was found in EGI-1 cells after incubation with cetuximab. Cetuximab dose-dependently inhibited growth in TFK-1. Increased apoptosis was only seen in TFK-1 cells at the highest cetuximab dose tested (1 mg/ml), with no dose-response-relationship at lower concentrations. In EGI-1 a heterozygous KRAS mutation was found in codon 12 (c.35G>A; p.G12D). HuH28, OZ and TFK-1 lacked KRAS mutation. CONCLUSION: CC cell lines express a pattern of different growth receptors in vitro. Growth factor inhibitor treatment could be affected from the KRAS genotype in CC. The expression of EGFR itself does not allow prognoses on growth inhibition by cetuximab.

Gnotobiotic IL-10; NF-kappaB mice develop rapid and severe colitis following Campylobacter jejuni infection.

Limited information is available on the molecular mechanisms associated with Campylobacter jejuni (C. jejuni) induced food-borne diarrheal illnesses. In this study, we investigated the function of TLR/NF-kappaB signaling in C. jejuni induced pathogenesis using gnotobiotic IL-10(-/-); NF-kappaB(EGFP) mice. In vitro analysis showed that C. jejuni induced IkappaB phosphorylation, followed by enhanced NF-kappaB transcriptional activity and increased IL-6, MIP-2alpha and NOD2 mRNA accumulation in infected-mouse colonic epithelial cells CMT93. Importantly, these events were blocked by molecular delivery of an IkappaB inhibitor (Ad5IkappaBAA). NF-kappaB signalling was also important for C.jejuni-induced cytokine gene expression in bone marrow-derived dendritic cells. Importantly, C. jejuni associated IL-10(-/-); NF-kappaB(EGFP) mice developed mild (day 5) and severe (day 14) ulcerating colonic inflammation and bloody diarrhea as assessed by colonoscopy and histological analysis. Macroscopic analysis showed elevated EGFP expression indicating NF-kappaB activation throughout the colon of C. jejuni associated IL-10(-/-); NF-kappaB(EGFP) mice, while fluorescence microscopy revealed EGFP positive cells to be exclusively located in lamina propria mononuclear cells. Pharmacological NF-kappaB inhibition using Bay 11-7085 did not ameliorate C. jejuni induced colonic inflammation. Our findings indicate that C. jejuni induces rapid and severe intestinal inflammation in a susceptible host that correlates with enhanced NF-kappaB activity from lamina propria immune cells.

Primary human colonic epithelial cells are transiently protected from anoikis by a Src-dependent mechanism.

Complete loss of cell anchorage triggers apoptosis in primary human colonic epithelial cells (CEC), a phenomenon known as anoikis. Besides the induction of pro-apoptotic events, activation of survival pathways was observed in detached intestinal epithelial cell lines, providing a transient apoptosis protection. However, nothing is known about molecular mechanisms protecting primary CEC from anoikis. In this study intact CEC crypts were isolated and kept in suspension, a condition which leads to the loss of cell-cell anchorage and induces anoikis. To reconstitute cell-cell contacts, cells were centrifuged to form cell aggregates. Induction of apoptosis was assessed by caspase-3 activity assay; activation of survival pathways was analyzed by Western blot. Immediately after loss of cell anchorage a rapid activation of survival proteins was observed before active caspase-3 could be detected. Src hyperactivation significantly contributed to transient protection from anoikis in CEC because its inhibition reversed the protecting effect of re-establishment of cell contacts. Basal levels of active Src in CEC from patients with inflammatory bowel disease were markedly reduced compared to control patients. These results demonstrate that loss of cell anchorage activates survival pathways in primary human CEC providing transient anoikis protection. Src is an important mediator of this mechanism and therefore constitutes a key regulatory molecule coordinating survival signals mediated by cell adhesion in primary human CEC.

Enterocyte-derived TAK1 signaling prevents epithelium apoptosis and the development of ileitis and colitis.

Recent studies have revealed that TAK1 kinase is an essential intermediate in several innate immune signaling pathways. In this study, we investigated the role of TAK1 signaling in maintaining intestinal homeostasis by generating enterocyte-specific constitutive and inducible gene-deleted TAK1 mice. We found that enterocyte-specific constitutive TAK1-deleted mice spontaneously developed intestinal inflammation as observed by histological analysis and enhanced expression of IL-1beta, MIP-2, and IL-6 around the time of birth, which was accompanied by significant enterocyte apoptosis. When TAK1 was deleted in the intestinal epithelium of 4-wk-old mice using an inducible knockout system, enterocytes underwent apoptosis and intestinal inflammation developed within 2-3 days following the initiation of gene deletion. We found that enterocyte apoptosis and intestinal inflammation were strongly attenuated when enterocyte-specific constitutive TAK1-deleted mice were crossed to TNF receptor 1(-/-) mice. However, these mice later (>14 days) developed ileitis and colitis. Thus, TAK1 signaling in enterocytes is essential for preventing TNF-dependent epithelium apoptosis and the TNF-independent development of ileitis and colitis. We propose that aberration in TAK1 signaling might disrupt intestinal homeostasis and favor the development of inflammatory disease.

Nursing documentation audit--the effect of a VIPS implementation programme in Denmark.

AIM AND OBJECTIVES: The aim of this paper is to present a study describing nurses' adherence to the VIPS model by evaluating the quality of nursing assessment, and the quantity of completed nursing care plans. BACKGROUND: Numerous efforts have been made over the years to improve nursing documentation in Denmark. Hospitals have traditionally based nurses' charting on a rudimentary version of the nursing process and on Virginia Henderson's theory of human needs. In 2002-2004 the Copenhagen University Hospital, Rigshospitalet, introduced the Swedish VIPS model for nursing documentation. VIPS is an acronym for well being, integrity, prevention and safety, all of which are seen as major goals for nursing care. The model organizes nursing data according to a system of keywords, which facilitates storage and retrieval of data. DESIGN AND METHODS: The design in this part of the study was retrospective, wherein 50 journals from each of the departments of cardiology, neurology, oncology and urology were audited annually for three years using the Cat-ch-Ing instrument (n=600). All nursing journals were randomly selected by including the first 50 journals at each site given a specific date. RESULTS: The nursing documentation significantly improved during the course of the study. After the second year the participants used the keywords appropriately and correctly according to the VIPS model. Application of primary nursing increased during the study. Initial, ongoing and discharge patient status improved. The nurses' familiarity with nursing diagnoses, goals and interventions increased. CONCLUSIONS: The structured implementation programme significantly improved nursing documentation, and the simultaneous training of the entire nursing staff shows promise. The VIPS model has prepared the nurses for more complex computerized taxonomies and classification systems in the future by improving the nurses' analytical skills. Relevance to clinical practice. New strategies for improving nursing documentation have been demonstrated.

The effect of a VIPS implementation programme on nurses' knowledge and attitudes towards documentation.

The Copenhagen University Hospital decided to adhere to the standards of the Joint Commission of International Accreditation in 2000. These standards require systematic assessment of patient care needs and include the use of written nursing care plans. In order to meet these standards, the hospital management decided to introduce the Swedish VIPS model, which is a model designed to structure nursing documentation (VIPS is an acronym for well-being, integrity, prevention and safety). The present study explores the nurses' knowledge and attitudes towards documentation and addresses the research questions: (a) what are the nurses' attitudes towards documentation of nursing care? and (b) do nurses have sufficient knowledge of the documentation system to systematically document their patient assessment and clinical decisions? The research design was prospective, comparative, and quasi-experimental (nonrandomized), including a study group (n=72) and a control group (n=57). A questionnaire was used to compare nurses' self-evaluated attitudes towards documentation, and a multiple-choice test was given in order to assess nurses' knowledge of the documentation system. The study group participated in a special implementation programme (response rate 82%), while the control group attended the regular 3-day documentation course at the hospital (response rate 79%). The study showed that the two groups responded similarly, but the nurses in the study group were significantly stronger in their conviction that they had the knowledge to make care plans and that they routinely made them. The study group demonstrated slightly less motivation than the control group, while the two groups shared a positive attitude towards nursing documentation. The study group did consistently better on the knowledge tests. The findings show that the implementation programme had a positive impact on nursing documentation, and that the VIPS model increased the nurses' understanding of the nursing process.