The management of patients undergoing colorectal surgery has changed in recent decades. Efforts have been made to show that perioperative physiological stress to the patient can be minimised with standardised care programmes and thus improve short term outcome after colorectal surgery. Mechanical bowel preparation (MBP), for instance, has been questioned as part of standard management. There are studies highlighting the effect of cancer treatment and its side effects in the elderly, showing that geriatric patients benefit from oncological therapy in much the same way as younger patients. The impact of this information on surgical and oncological practice in Sweden today is not known. To assess the effectiveness of colorectal surgery we need both randomised controlled trials and population-based cohort studies. We have performed a trial on colonic surgery with and without preoperative mechanical bowel preparation, as well as a nation-wide register study comparing treatment and outcome of rectal cancer in two age groups. In a randomised controlled trial 1505 patients from 21 hospitals were randomised to MBP or no-MBP prior to open elective colonic resection. There were no differences in overall complication rates between the groups: cardiovascular 5.1% with MBP vs. 4.6% without MBP; general infection 7.9% vs. 6.8%; and surgical site complications 15.1% vs. 16.1%. The proportion of patients reaching at least one primary endpoint was 24.5% vs. 23.7% respectively. The patients experience of and postoperative recovery after MBP or no-MBP was evaluated in 105 of the patients in the bowel preparation trial at three of the participating hospitals. Sixty-five patients received MBP and 40 patients did not. In the MBP group 52% needed assistance with bowel preparation. Day 4 postoperatively patients in the no-MBP group perceived more discomfort than patients in the MBP group, p<0.05. Bowel emptying occurred significantly earlier in the no-MBP group than in the MBP group, p<0.05. In an experimental study the effect of MBP on intramucosal bacterial count was evaluated. Macroscopically normal colon mucosa was collected from 37 patients (20 MBP and 17 No-MBP) undergoing elective colorectal surgery at three hospitals. MBP did not influence the median colony count of E. coli, Bacteroides, or total median colony count, information that was previously unknown. These three studies imply that MBP can be omitted before elective colonic resection. In a population-based register study, treatment for rectal cancer in patients ≥ 75 years and those < 75 years was evaluated using data from the Swedish Rectal Cancer Register 1995-2004 (N=15104). This study revealed that preoperative radiotherapy was used less in patients > 75 years. There was also a higher threshold for surgery in this group, and they more often received a permanent stoma compared to younger patients. Outcome in terms of 5-year local recurrence rate and 5-year cancer-specific survival differed very little between the older and younger patient groups who underwent abdominal tumour resection with curative intent. We suggest future studies focusing on ways of reducing surgical and perioperative stress and on quality of life when assessing suitable treatment modalities for rectal cancer.

El objetivo de nuestro estudio fue evaluar si el fallo de la función intestinal absortiva observado después del trasplante de intestino delgado se debe a cambios en el tamaño de la superficie epitelial o bien proviene de un fallo en la función celular de los enterocitos. MATERIAL Y MÉTODOSSe realizaron trasplantes de intestino delgado (SBT) en ratas de acuerdo con la técnica de Monchik y Russell. Los animales fueron distribuidos en tres grupos (n=15 cada uno): Grupo A (control): asa simple de Thiry Vella; Grupo B: isotransplante heterotópico LEW-LEW; Grupo C: alotransplante heterotópico LBN-LEW. Se utilizó como solución de preservación Ringer lactato heparinizado a 4º C. Las ratas del grupo C se trataron con Ciclosporina (15mg/kg/24h IM). A los 21 dias del transplante heterotòpico, en 5 animales de cada grupo se realizó un segundo procedimiento quirúrgico para colocar el segmento de intestino transplantado en posición ortotópica. Mediante microscopía òptica y tinción H/E se observó la evolución micromorfológica de la mucosa intestinal, tomando muestras del intestino donante in situ antes de la perfusión y tras el transplante a los 7,14,21 y 36 dias. Estas muestras fueron procesadas mediante un sistema de analisis morfométrico de imagenes para quantificar cambios en el tamaño de las vellosidades en cuanto altura y anchura y asi determinar una posible modificacion en la superficie epitelial absortiva. En las series con transplante ortotópico, las muestras de intestino se estudiaron además por Microscopía Electrónica de Transmisión (TEM). Para determinar la evolución de la función absortiva del intestino transplantado se efectuaron pruebas de absorción de glucosa en los mismos intervalos de tiempo que las biopsias.RESULTADOS El estudio morfométrico muestra una disminución progresiva en la altura de las vellosidades tras el transplante, siendo más pronunciado en el grupo C. Una tendencia al aumento se observó en el ancho de las vellosidades. La superficie epitelial absortiva mostró una tendencia a la reducción, recuperando los valores iniciales tras la interposición ortotópica. Una reducción progresiva significativa de la absorción de glucosa se observó en ambos grupos de animales trasplantados respecto al grupo control. El estudio por TEM mostró la presencia de vacuolas citoplasmáticas en los enterocitos, así como una leve alteración en la morfología de las microvellosidades, mitocondrias y retículo endoplásmico. DISCUSIÓN Y CONCLUSIONES Una alteración de la fisiología celular parece ser la causa del fallo de la función de absorción intestinal después de SBT y este fracaso no dependería del tamaño de la superficie epitelial. Las alteraciones ultraestructurales observadas al TEM sugieren un daño celular grave que podría ser la causa de la insuficiencia absortiva. Pero el origen de estas alteraciones intracelulares sigue siendo desconocido pudiendo provenir tanto del efecto isquemia-reperfusión como de la respuesta inmunológica o de la toxicidad del propio tratamiento inmunosupresor. / The aim of our study was to asses if the failure of the absortive intestinal function observed after small bowel transplantation is due either to changes in the size of epithelial surface or caused by a failure in the cellular function of enterocytes.MATERIALS AND METHODSSmall bowel transplants (SBT) were performed in rats according to Monchik and Russell's technique. Animals were distributed into three groups (n=15 each):Group A (control):simple Thiry-Vella loop; Group B:heterotopic isograft LEW-LEW; Group C:heterotopic allograft LBN-LEW. Heparinized lactated Ringer's at 4ºC was a cold preservation solution. Cyclosporine dose 15mg/kg/24h IM was administered to group C rats. At day 21 of the initial surgery, a second operative procedure was carried out on 5 of the transplanted animals of each group to place the transplanted small bowel in orthotopic position.To asses the micromorphology of intestinal mucosa by light microscopy (LM), biopsy specimens of the donor small bowel were taken in situ before perfusion and after transplant at 7,14,21 and 36 days. In those series with orthotopic transplantation bowel samples were studied, in addition, by Transmision Electron Microscopy (TEM).The absortive function of the transplanted bowel was observed by Glucose absorption test performed at same time points of the biopsies. Histomorphometric determinations of size of villus height and width, and total epithelial surface was performed by LM H/E and Image Processing and Analysis System.RESULTSMorphometrical study shows a progressive shortening of villus in both groups of transplanted animals, being more pronounced in the group C at the end of study. A tendency to increase was observed in the villus width. The absorptive epithelial surface showed an initial reduction followed of return to normal state after orthotopical interposition.A significative progressive reduction of glucose absorption was observed in both groups of transplanted animals than in the control group.Study by TEM showed cytoplasmic vacuoles in the absorptive cells. There was also a slight alteration on morphology of microvilli, mitochondries and endoplasmic reticulum.DISCUSSION/CONCLUSIONSAn alteration of cellular physiology underlies the failure of intestinal absorptive function after SBT and this failure does not depend on the size of epithelial surface. The findings of TEM suggest a severe ultrastructural damage could be the cause of cellular absorptive failure, but the cause of this cellular damage remains unkown.

This study investigated the association between flavonoid profiles of different cowpea (Vigna Unguiculata) varieties with anti-inflammatory properties as a possible benefit against inflammatory bowel disease. Cowpea, a drought tolerant annual herbaceous legume that originated in Africa, is known to possess high levels of polyphenolics, which have demonstrated anti-inflammatory, immunoregulatory and antioxidant properties. Black, red, white, brown and light brown cowpeas were investigated for phenolic content and composition using UV-Visible Spectroscopy and HPLC; antioxidant activation mechanism (AOX) by oxygen radical absorbance capacity (ORAC). Anti-inflammatory activity was measured via NF-κB activation in Raw 264.7 macrophages challenged with a lipo-polysaccharide. Phenols, tannins and AOX activity were generally similar within phenotypes; however among light brown varieties, 09FCV-CC-27M, had among the highest phenols, tannins and AOX, whereas IAR-48 had among the lowest. White cowpea (EARLY ACRE) variety showed the least amount of total phenol content (78.2 mg GAE/g) and condensed tannin content (4.1 mg CE/g); whereas the red varieties (IT82D-889, IT97K-1042-3) contained the highest amounts of tannins (242 and 132 mg CE/g), and phenols (431 and 454 mg GAE/g) respectively. Antioxidant activity correlated with phenol content data. Anthocyanins were only found in the black cowpea. The red varieties had the highest levels of flavonols, which were mostly quercetin derivatives; the white and light brown (IAR-48) varieties had quercetin-3-O-diglucoside as the dominantcompound. The light brown variety (09FCV-CC-27M) had the highest amount of flavan-3-ols while in the white variety no flavan-3-ols were detected. Unexpectedly, the cowpea extracts with lower phenolic and tannins content, the white and light brown (IAR-48) varieties, showed significant (p<0.05) anti-inflammatory properties in the LPS induced macrophages, inhibiting the activation of NF-κB at different concentrations (0.33, 1.67 and 3.33 μg extract/mL). Conversely, extracts with higher phenolic and tannin content did not induce anti-inflammatory response at similar concentrations, suggesting that tannins or other phenolics interfered with anti-inflammatory response at these concentrations. These results suggest that cowpea composition is an important determinant of anti-inflammatory response in inflammatory bowel disease.

Inflammatory bowel diseases (IBD) are associated with an elevated risk of colorectal cancer that increases with disease duration and severity. Tumor necrosis factor (TNF) is a major therapeutic target in IBD, but long-term anti-TNF therapy is associated with increased risks of infection and lymphoma, therefore we asked whether TNF signaling through its receptors TNFR1 and TNFR2 could impact colitis and colitis-associated cancer (CAC). In acute dextran sulphate sodium (DSS)-colitis, no major inflammatory differences were found between wildtype (WT), TNFR1- and TNFR2-deficient mice, with the exception of reduced macrophage infiltration into inflamed tissue in TNFR1-/- mice. Chronic colitis and tumor development was assessed in these mice using the carcinogen azoxymethane and 4 cycles of DSS. TNFR1-/- mice were protected against colorectal tumor development compared to WT and TNFR2-/- mice, while inflammation was similar between strains. Hematopoietic TNFR1 deficiency resulted in reduced inflammation and tumor incidence, while stromal/epithelial TNFR1 deficiency reduced indices of cancer without affecting inflammation. 8-OHDG was significantly lower in TNFR1-/- mice compared to other strains, suggesting that TNF could contribute to oxidative stress within the colon. Mice lacking leukocyte NADPH oxidase were protected against clinical illness and CAC despite similar histological inflammation, indicating that inflammation-associated oxidative stress can play a role in CAC. In conclusion, TNF signaling through TNFR1 contributes significantly to the development of colorectal cancer in a model of CAC in a manner that involves both stromal/epithelial and hematopoietic TNFR1. This is significant because anti-TNF therapies may be effective at reducing CAC in the absence of a clinical reduction of IBD symptoms.

This thesis explored the effects of cooked whole asparagus and its purified bioactive, rutin, on colitis symptoms and disease progression in mice using a chemically-induced model of colitis. This model mimics active colitis and recovery states of ulcerative colitis. C57BL/6 mice were fed a basal diet supplemented with 2% asparagus or 0.025% rutin for 3 weeks. Colitis was induced by 2% dextran sodium sulfate in drinking water for 7 days. Asparagus diet was determined to contain higher antioxidant capacities than rutin diet through antioxidant assays. During active colitis, consumption of asparagus alleviated some clinical symptoms (stool consistency, stool blood, and spleen hypertrophy) of colitis. In recovery, asparagus-fed mice were improving in terms of regenerating crypts, surface epithelial, and goblet cells, potentially due to its rutin content. Overall, these findings advocate that asparagus can be therapeutic in treating symptoms during active colitis and recovery phases of ulcerative colitis.

This study assesses generic and disease-specific Health-Related Quality of Life (HRQOL) in children and adolescents with Inflammatory Bowel Disease (IBD). More specifically, the purpose of the study is to address the relationship between disease- specific indicators, both on a symptom-by-symptom basis and as a whole, to overall HRQOL. Self- and proxy-report versions of the Pediatric Quality of Life Inventory™ (PedsQL™) Generic Core Scales and the newly developed Pediatric Quality of Life Inventory™ Gastrointestinal Symptoms Module were administered to 187 parent-child dyads at ten study sites across the United States. Disease-specific indicators included: stomach pain, stomach upset, trouble swallowing, heartburn and reflux, gas and bloating, constipation, and diarrhea. It was hypothesized that caregiver- and child-reported disease-specific HRQOL would be positively correlated with generic HRQOL, and that physical disease-specific indicators would contribute the greatest variance in total generic HRQOL scores, for both self and proxy report. Results confirmed the hypothesis that disease-specific HRQOL would be positively correlated with generic HRQOL for children and caregivers. Multivariate regression results revealed that the Stomach Pain and Hurt, Worry, Medicines, and Communication scales contributed the most variance to overall HRQOL scores for children. The same analysis performed for parent ratings yielded one statistically significant scale: Worry. In essence, intervention efforts aimed at reducing the influence of worry and anxiety may prove more effective in improving HRQOL outcomes than interventions targeting reduction of physical symptoms.

Inflammatory bowel disease (IBD) alters neuronal regulation of the gastrointestinal (GI) tract. The superior mesenteric ganglia (SMG) contain sympathetic neurons that modulate GI functions such, as motility and blood flow. IBD reduces the release of noradrenaline, a sympathetic neurotransmitter. We hypothesized that the reduction in NA release is due to inhibition of voltage-gated calcium current (ICa), as calcium influx is a regulator of neurotransmitter release. We also hypothesized that tumor necrosis factor α (TNFα), a proinflammatory cytokine elevated during IBD, can also inhibit the ICa of SMG neurons. Therefore, we compared ICa amplitude in neurons from normal mice and mice with dextran sulphate sodium (DSS; 5% w/v)-induced colitis. Neurons dissociated from the SMG were cultured overnight and changes to ICa were investigated using electrophysiological, Ca2+ imaging, PCR and neurotransmitter release techniques. Colitis significantly reduced ICa of SMG neurons by selectively inhibiting N-type Ca2+ channels. This was accompanied by a reduction in mRNA encoding the N-type channel alpha subunit (CaV 2.2) and a rightward shift in the voltage dependence of activation of ICa. Colitis reduced the NA release from the colon and jejunum. Depolarization-induced release of tritiated-NA was inhibited by ω-Conotoxin GVIA (300 nM). These results suggest that the changes in VGCC observed at the cell bodies of SMG neurons were also occurring at the nerve terminals during colitis. Similar experimental techniques were performed using SMG neurons incubated overnight in TNFα (1nM). TNFα decreased ICa and depolarization-induced Ca2+ influx in SMG neurons. Similar to DSS-induced colitis, the reduction in ICa was limited to N-type Ca2+ channels. Preincubation of neurons with SC 514 (20μM) and Bay 11 7082 (1µM), inhibitors of nuclear factor kappa B signaling, prevented the reduction in ICa. Preincubation with the p38 MAPK inhibitor, PD 169316 (30µM), recovered a smaller portion of the reduction in Ca2+ influx. These data suggest that DSS colitis and TNFα inhibit N-type VGCC ICa in sympathetic neurons and identify a novel role for NF-κB and p38 MAPK in the regulation of neurotransmitter release. These findings also suggest that DSS colitis inhibits NA release by altering sympathetic N-type VGCC in the colon and jejunum. / Thesis (Master, Physiology) -- Queen's University, 2008-09-02 12:06:20.438

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