Proteomics Highlights Common and Distinct Pathophysiological Processes Associated with Ileal and Colonic Ulcers in Crohn's Disease.

BACKGROUND AND AIMS: Based on genetics and natural history, Crohn's disease can be separated into two entities, an ileal and a colonic disease. Protein-based approaches are needed to elucidate whether such subphenotypes are related to distinct pathophysiological processes. METHODS: The proteome of ulcer edges was compared with that of paired control tissue samples [n = 32 biopsies] by differential proteomics in the ileum and the colon of Crohn's disease patients [n = 16]. The results were analysed using a hypothesis-driven approach [based on the literature] and a hypothesis-free approach [pathway enrichment analyses] to determine common and segment-specific pathophysiological processes associated with ileal and colonic CD ulcer edges. To confirm the involvement of a key pathway highlighted by proteomics, two proteins were also studied by immunochemistry. RESULTS: In the ileum and the colon, 4428 and 5204 proteins, respectively, were identified and quantified. Ileal and colonic ulcer edges differed in having a distinct distribution of proteins associated with epithelial-mesenchymal transition, neutrophil degranulation, and ribosomes. Ileal and colonic ulcer edges were similarly characterized by an increase in the proteins implicated in the endoplasmic reticulum protein-processing pathway and a decrease in mitochondrial proteins. Immunochemistry confirmed the presence of endoplasmic reticulum stress in the mucosa of ileal and colonic ulcer edges. CONCLUSION: This study provides protein-based evidence for partially distinct pathophysiological processes being associated with ileal and colonic ulcer edges in Crohn's disease patients. This could constitute a first step toward the development of gut segment-specific diagnostic markers and therapeutics.

Diagnostic challenge of the non-specific presentation of adult intussusception.

The following report will discuss the diagnosis and management of non-specific abdominal pain in a 77-year-old woman who presented to a district general hospital in South London. CT imaging demonstrated ileo-colic intussusception with free air and fluid indicating perforation. The images of the specimen clearly show the ileal tumour within the intussusception. Thus, the patient underwent an emergency right hemicolectomy and formation of a double-barrelled ileostomy. Histology subsequently confirmed this was secondary to a colonic adenocarcinoma. This case report is unique as it highlights that intussusception in adults is very difficult to accurately diagnose based on clinical features (due to non-specific findings) and even with radiology can be challenging. This is also the first documented case of the site of perforation not being directly involved with the site of intussusception. The perforation site was in fact distal to the intussusception. At the time of surgery, it was noted that the patient had significantly faecal loading up to her rectum. The resulting closed loop was the cause of her perforation.

Outpatient management of intussusception: a systematic review and meta-analysis.

BACKGROUND: Variability in management of intussusception after enema reduction exists. Historically, inpatient observation was recommended; however, there is a lack of evidence-based guidelines for this practice. METHODS: A systematic review and meta-analysis evaluating outcomes between inpatient (IP) and outpatient (OP) management after enema reduction was performed. The following databases were searched: PubMed, EBSCOhost CINAHL, EMBASE, Web of Science, and Cochrane Database. Data from an institutional review were included in the meta-analysis. RESULTS: Ten studies of patients aged 0-18 years with intussusception who underwent successful enema reduction that reported outcomes of outpatient management were included. Overall recurrence rates were 6% for IP and 8% for OP (p = 0.20). Recurrences within 24 (IP: 1% vs OP: 0%, p = 0.90) and 48 h (IP: 1% vs OP: 2%, p = 0.11) were similar. There was no significant difference in the rate of return to the emergency department (IP: 6% vs OP: 14%, p = 0.11). Both groups had a similar rate of requiring an operation (IP: 2% vs OP: 1%, p = 0.84). CONCLUSIONS: Outpatient management of intussusception after enema reduction results in a shorter hospital stay with no difference in the rate of return to the emergency department, recurrence, need for operation, or mortality. The findings of the meta-analysis suggest that outpatient management may be safe and could reduce hospital resource utilization. TYPE OF STUDY: Treatment study. LEVEL OF EVIDENCE: III.

PATTERNS AND SEASONAL VARIATION OF INTUSSUSCEPTION IN CHILDREN: A RETROSPECTIVE ANALYSIS OF CASES OPERATED IN A TERTIARY HOSPITAL IN ETHIOPIA.

BACKGROUND: Intussusception is one of the frequent causes of bowel obstruction in infants and toddlers (1). It involves invagination of a portion of intestine into another(2-4). The peak age of occurrence is between the age of 4 and 8 months. The aim of this study is to review the pattern of clinical presentation and seasonal variation of intussusception in our hospital, and to analyze the mode and outcomes of treatment. PATIENTS AND METHODS: This is a four-year retrospective study of children aged 13 years and below who were admitted and treated for intussusception between January 2011 and December 2014 at the pediatric surgery unit of Tikur Anbesa Specialized Hospital (TAH) in Ethiopia. Information on the patients' demographic characteristics, clinical presentation, and month of occurrence as well as the operative findings and outcome were obtained from the pediatric surgery unit record book, patient charts, and the operating theatre registry. RESULTS: One hundred and thirty six cases of intussusception were admitted to TAH, Addis Ababa over a four year period, of which 130 charts were retrieved and analyzed. Males dominated in the series. Age distribution showed that 59.2% of the cases were ≤ one year old, and 77.7 % were ≤ two years old. Abdominal pain, vomiting, bloody mucoid diarrhea and a mass palpated abdominally and/or rectally were the most common modes of presentations, with the classic triad of abdominal pain, vomiting and bloody mucoid diarrhea occurring in nearly two third of cases. The highest peak of presentation was in the month of June with 18 (13.9%) cases. The mean duration of symptoms before presentation to our hospital was 5.2 days with a range of 1-21 days. Intraoperatively, it was found that ileocolic intussusception was the most common type. Simple reduction without bowel resection was possible in 70.8% of cases. There were 44 (33.9 %) complications, wound site infection being the most common occurring in 20 (15.4%) cases and there were 6 deaths. CONCLUSION: Intussusception was more common in the wet season. There was delayed presentation with a higher rate of operative management and bowel resection. The mortality rate has decreased significantly compared with a previous study from this institution.

Transient and Non-Transient Intussusceptions of the Large Bowel in Adults: Two Case Reports.

BACKGROUND: Intussusception of the large bowel in adults is a very rare pathological condition. However, it has its clinical importance because intussusception is very often associated with an intraluminal lesion. CASE REPORT: We report two cases of the large bowel intussusception, ileocolic and colorectal. Both intussusceptions were associated with a malignant tumor. However, the clinical presentation was different. One of the intussusceptions was of non-transient character, while the second one resolved spontaneously before operation. Both patients underwent surgery and malignant tumors were found and removed. RESULTS: The purpose of the article is to draw attention to intussusception and emphasize that intussusception, either transient or non-transient, should be further examined. CONCLUSIONS: The intussusception may be the first and the only signal of the existence of a malignant tumor, very often colorectal carcinoma.

Vagus Nerve Mediates the Neural Stem Cell Response to Intestinal Injury.

BACKGROUND: Intestinal ischemia and reperfusion injury results in damage to elements critical to maintaining intestinal barrier function, including neurons and glia cells, which are part of the enteric nervous system (ENS). To limit inflammation, the ENS must be restored or replaced, yet the process by which this occurs is poorly understood. Multipotent progenitor cells called enteric nervous stem cells (ENSC) can differentiate into neurons or glia when stimulated. The ability of this cell population to respond to intestinal injury is unknown. In this study, we hypothesized that resolution of intestinal barrier injury would be associated with vagus nerve-mediated expansion of ENSCs. STUDY DESIGN: Ischemia and reperfusion injury was reproduced in male mice by occluding the superior mesenteric artery for 30 minutes. Abdominal vagotomy was performed in a separate cohort to study the effects of the vagus nerve. Terminal ileum was harvested at various time points after reperfusion and analyzed with histology, flow cytometry, and immunohistochemistry. RESULTS: Enteric nervous stem cell expansion occurs at 2, 4, and 8 hours after injury compared with sham (4.6% vs 2.1%; p < 0.001) and correlated with increased glial fibrillary acidic protein on immunohistochemistry. Vagotomy prevented both ENSC expansion and increased glial fibrillary acidic protein staining after injury. Intestinal permeability was restored to baseline by 48 hours after injury, but remained elevated in the vagotomy group compared with sham and injury alone at 48 hours (3.25 mg/mL vs 0.57 mg/mL and 0.26 mg/mL, respectively; p < 0.05). CONCLUSIONS: Vagal-mediated expansion of ENSCs occurs after ischemia and reperfusion injury and results in improved kinetics of injury resolution.

Cytomegalovirus-related necrotising vasculitis mimicking Henoch-Schönlein syndrome.

Viral vasculitides have been previously reported in the literature, the role of infections in their pathogenesis ranging from direct cause to trigger event. Here we report the case of a 3-year-old immunocompetent girl who developed a systemic vasculitis leading to ileal perforation, mimicking a full blown picture of Henoch-Schönlein purpura. High dosage steroid treatment was started, with good response. The anatomopathological examination of the resected gastrointestinal tract showed features of necrotising vasculitis and cytomegalovirus (CMV)-related inclusion bodies in the endothelial cells, with direct correlation to vascular damage. The causative role of viral infection was revealed by the presence of CMV DNA in patient's blood and positive IgG titer against the virus. Steroid therapy was then tapered: the patient achieved clinical remission, which still persists after a six-months follow-up. Our report suggests that CMV vasculitis is probably more frequent than previously thought, even in immunocompetent patients, with a protean clinical presentation, mimicking other types of vasculitides.

In vitro smooth muscle contractility before and after relief of experimental obstruction in the rat: application to the surgical management of ileal dilatation.

PURPOSE: Bowel dilatation occurs proximal to an obstruction and predisposes to intestinal dysmotility. The present study sought to determine whether or not changes in smooth muscle contractility and the thickness of the proximal, dilated bowel wall can be reversed following relief of the obstruction. MATERIALS AND METHODS: Three groups of seven male Wistar rats were studied. In 8-week-old animals in a control group and a sham-operated group, a small segment of bowel (designated as R1 for controls and R2 for shams) was resected 5.0 cm from the cecum. In the third (operated) group, a narrow, isoperistaltic intestinal loop was created proximal to an end-to-end anastomosis of the ileum in 4-week-old animals. When these animals were 6 weeks old, the loop was re-anastomosed to the distal small bowel (after resection of the loop's distal portion, referred to as R3). Two weeks later, a small segment of bowel was resected proximal to the anastomosis (R4). We evaluated the thickness of the smooth muscle layers and the in vitro contractile responses of circular smooth muscle ileal strips (R1-R4) to electrical stimulation and pharmacological stimulation (with KCl, acetylcholine (ACh), substance P, N(G)-nitro-l-arginine methyl ester (L-NAME) and histamine). RESULTS: The amplitudes of contraction in response to electrical and Ach-mediated stimulation were higher for R3 than for R4 (P<0.001), R1 and R2 (both P<0.05). Compared with R1 and R2, the smooth muscle layer was three times as thick in R3 (P<0.001) and 2.5 times as thick in R4 (P<0.01). CONCLUSION: Our study provides evidence of the possible recovery of intestinal motility (in response to neurotransmitters involved in gut function) after the relief of an obstruction. If ileal motility can conceivably return to normal values, conservative surgical procedures in pediatric patients should be preferred (in order to leave a sufficient length of bowel and avoid short bowel syndrome).

Glucose absorption in small intestinal diseases.

Recent developments in the field of diabetes and obesity management have established the central role of the gut in glucose homeostasis; not only is the gut the primary absorptive site, but it also triggers neurohumoral feedback responses that regulate the pre- and post-absorptive phases of glucose metabolism. Structural and/or functional disorders of the intestine have the capacity to enhance (e.g.: diabetes) or inhibit (e.g.: short-gut syndrome, critical illness) glucose absorption, with potentially detrimental outcomes. In this review, we first describe the normal physiology of glucose absorption and outline the methods by which it can be quantified. Then we focus on the structural and functional changes in the small intestine associated with obesity, critical illness, short gut syndrome and other malabsorptive states, and particularly Type 2 diabetes, which can impact upon carbohydrate absorption and overall glucose homeostasis.

Gastrointestinal manifestations of Behçet's disease in Japan: a study of 43 patients.

We analyzed the clinical gastrointestinal (GI) characteristics of Behçet's disease (BD) patients in Japan. We retrospectively reviewed the clinical charts of 412 patients who fulfilled the 1987 Japanese criteria for BD and were treated in two university hospitals from July 1991 to December 2007. Forty-three patients (10.4 %) had BD-related GI lesions, which were shown by imaging examinations. Median age at BD diagnosis and onset of GI episodes were 29.6 and 31.0 years, respectively. The patients suffered from abdominal pain (30/43) and GI bleeding (18/43), while they had lower frequency of eye involvement and higher incidence of arthritis and vascular involvement than BD patients without GI lesions. The lesions were prevalent in the ileum (32/43) followed by cecum (21/43) and esophagus (9/43). The patients were treated with mesalazine and sulfasalazine (41/43), corticosteroids (32/43), immunosuppressants (13/43), and infliximab for 7 patients having refractory lesions, while 10 patients had surgical operation. Two patients died due to non-GI events during the observation. The diagnosis of BD was often difficult because of lack of eye involvement. Surgery is required for some patients in spite of intensive immunosuppressive therapies. Appropriate use of anti-TNF agents may be promising for the GI involvement.

[Diagnostics and surgical treatment of biliary ileal obstruction].

7 patients with biliary ileal obstruction were operated on during the past 2 years. The article focuses on the features of the clinical presentation and the efficacy of diagnostic means. The surgical tactics and volume of the intervention is suggested. Recommendations on the prevention of the biliary ileus were worked out.

Comparison of different methods of intestinal obstruction in a rat model.

AIM: To investigate different methods of creating incomplete intestinal obstruction in a rat model and to compare their electrophysiologic, morphologic and histologic characteristics. METHODS: Rat ileum was partially obstructed by the respective application of: braided silk (penetrated the mesentery and surrounded intestine); half ligation (penetrated directly and ligated 1/2 cross-section of the intestine); wide pipe (6 mm in width, surrounded the intestine); narrow pipe (2 mm in width, surrounded the intestine). A control was also included (no obstruction). Various behavioral and electrophysiologic variables, as well as morphologic and immunohistochemical observations were recorded by blinded investigators at different time points (12, 24, 48, 72 h), including daily general condition, ileal wet weight and circumference, macromorphous and micromorphous intestine, bowel movement capability in vivo and in vitro, slow wave and neural electrical activity, and the number of c-Kit positive interstitial cells of Cajal (ICC). RESULTS: Despite being of a similar general condition, these methods resulted in different levels of obstruction in each group compared with the control at different time points (12, 24, 48, 72 h). However, these fields of the wide pipe rat showed significantly differences when compared with the other three obstructed groups at 12 to 72 h, including macroscopic and histological presentation, intestinal transit ratio and contractility, circumference and wet weight, amplitude and frequency of nerve electrical discharge and slow wave, and ICC numbers (all P < 0.01). CONCLUSION: The wide pipe rat method is significantly more reliable and stable than the other methods of obstruction, demonstrating that use of the wide pipe method can be a useful model of incomplete intestinal obstruction.

Accommodation and peristalsis are functional responses to obstruction in rat hypertrophic ileum.

AIM: To investigate the effects of chronic obstruction on enteric reflexes evoked by electrical stimulation (EFS) or intraluminal distension of the rat hypertrophic ileum. METHODS: Motor responses to EFS and to intraluminal distension were studied in the absence and in the presence of various inhibitors of enteric mediators. Ileum segments from operated (chronic ileal obstruction), sham-operated (control) and normal rats were horizontally mounted, connected to a pressure transducer and intraluminally perfused. The effects of selective serotonin receptor (5-HTR) blockers were investigated on distension-induced responses. The cellular localization of 5-HT3Rs was also examined in control and hypertrophic tissues through confocal microscopy. RESULTS: In non-obstructed segments, EFS elicited tetrodotoxin (TTX)-sensitive responses with high amplitude contraction followed by weak relaxation. In hypertrophic tissues, EFS lowered the baseline pressure and evoked TTX-sensitive contractions significantly larger than normal (P < 0.01) or control (P < 0.05), and devoid of any relaxation phase (P < 0.01 vs normal). Incubation with atropine and guanethidine [non-adrenergic non-cholinergic (NANC) conditions] did not modify intestinal tone in normal and control preparations, but reversed the accommodation produced by EFS in hypertrophic tissues, and depressed the amplitude of contractions in all types of tissues. L-NAME and α-chymotrypsin blocked residual NANC motility in all tissues and augmented intraluminal pressure in hypertrophic segments (P < 0.05 vs NANC conditions). Intraluminal distension of the intestinal wall evoked non-propulsive cycles of contractions and relaxations in non-obstructed tissues. In all hypertrophic segments, strong propulsive strokes, markedly wider (P < 0.001), and larger than normal (P < 0.001) or control (P < 0.05) were elicited. Both motor patterns were blocked under NANC conditions and with simultaneous incubation with L-NAME and α-chymotrypsin. In all types of tissues, incubation with ketanserin or GR125487 did not modify distension-induced motility. In contrast, blockade of 5-HT3Rs by ondansetron concentration-dependently inhibited motor responses in normal and control tissues, but only slightly impaired enteric reflexes in the hypertrophic preparations. Finally, confocal microscopy did not reveal a different cellular distribution of 5-HT3Rs in control and hypertrophic ileum. CONCLUSION: Accommodation and distension-induced peristalsis of rat hypertrophic ileum are controlled by cholinergic and peptidergic transmission and are negligibly affected by 5-HT3Rs, which modulate distension-induced motility in non-obstructed tissues.

Dietary long-chain PUFA enhance acute repair of ischemia-injured intestine of suckling pigs.

Infant formula companies have been fortifying formulas with long-chain PUFA for 10 y. Long-chain PUFA are precursors of prostanoids, which stimulate recovery of intestinal barrier function. Supplementation of milk with PUFA increases the content of arachidonic acid (ARA) in enterocyte membranes; however, the effect of this enrichment on intestinal repair is not known. The objective of these experiments was to investigate the effect of supplemental ARA on intestinal barrier repair in ischemia-injured porcine ileum. One-day-old pigs (n = 24) were fed a milk-based formula for 10 d. Diets contained no PUFA (0% ARA), 0.5% ARA, 5% ARA, or 5% EPA of total fatty acids. Following dietary enrichment, ilea were subjected to in vivo ischemic injury by clamping the local mesenteric blood supply for 45 min. Following the ischemic period, control (nonischemic) and ischemic loops were mounted on Ussing chambers. Transepithelial electrical resistance (TER) was measured over a 240-min recovery period. Ischemia-injured ileum from piglets fed 5% ARA (61.0 ± 14%) exhibited enhanced recovery compared with 0% ARA (16 ± 14) and 0.5% ARA (22.1 ± 14)-fed pigs. Additionally, ischemia-injured ileum from 5% EPA (51.3 ± 14)-fed pigs had enhanced recovery compared with 0% ARA-fed pigs (P < 0.05). The enhanced TER recovery response observed with ischemia-injured 5% ARA supplementation was supported by a significant reduction in mucosal-to-serosal flux of (3)H-mannitol and (14)C-inulin compared with all other ischemia-injured dietary groups (P < 0.05). A histological evaluation of ischemic ilea from piglets fed the 5% ARA showed reduced histological lesions after ischemia compared with the other dietary groups (P < 0.05). These data demonstrate that feeding elevated levels of long-chain PUFA enhances acute recovery of ischemia-injured porcine ileum.