Truncated neurokinin-1 receptor is increased in colonic epithelial cells from patients with colitis-associated cancer.

Patients with chronic ulcerative colitis (UC) are at high risk for developing colorectal cancer. In this study, archival formalin-fixed paraffin-embedded colonic tissue from patients with UC who developed carcinoma (CA) or high-grade dysplasia (HGD) was examined for changes in expression of the proinflammatory and mitogenic neurokinin-1 receptor (NK-1R). Laser capture microscopy was used to microdissect epithelia from areas of colons that showed histologic evidence of CA, HGD, and epithelia that were not dysplastic or cancerous but did contain evidence of prior inflammation (quiescent colitis). mRNA was extracted from the dissected tissue, and PCR array analysis was performed on extracted mRNA. Two antibodies were necessary to separately estimate the protein levels of the truncated (tr-NK-1R) and full-length (fl-NK-1R) receptors by immunohistochemistry. mRNA expression of tr-NK-1R increased 14-fold (P = 0.02) when comparing the HGD and CA groups. In contrast, the fl-NK-1R transcript showed no significant differences among groups. The protein levels of the total NK-1R increased by 40% (P = 0.02) in HGD and 80% (P = 0.0007) in CA compared with quiescent colitis. There were no significant changes in protein levels of the fl-NK-1R. We conclude that the increase in total NK-1R protein in HGD and CA is attributable to an increase in tr-NK-1R, suggesting there may be a functional role for tr-NK-1R in malignant transformation in colitis-associated cancer. The tr-NK-1R could prove useful as a diagnostic marker to identify patients at risk for neoplasia and may serve as a useful therapeutic target in the treatment of colitis-associated cancer.

Substance P is an early mediator of peritoneal fibrinolytic pathway genes and promotes intra-abdominal adhesion formation.

BACKGROUND: The substance P (SP) or neurokinin-1 receptor pathway has been implicated in intra-abdominal adhesion formation, in large part through its effects on peritoneal fibrinolysis. This study investigates the role of SP as an early mediator of the messenger RNA (mRNA) expression of key components of the peritoneal fibrinolytic system and other fundamental adhesiogenic pathways. MATERIALS AND METHODS: Intra-abdominal adhesions were surgically induced in 28 rats using the ischemic button model. mRNA levels of tissue plasminogen activator (tPA), plasminogen activator inhibitor 1 (PAI-1), hypoxia-inducible factors (HIFs) 1α and 2α, and vascular endothelial growth factor A (VEGF-A) were measured in adhesive button tissue taken at time 0 and 1, 3, 6, 12, and 24h after surgery in rats receiving an intraoperative peritoneal bolus (25mg/kg) of a neurokinin-1 receptor antagonist (NK-1RA) or saline. Peritoneal fluid fibrinolytic activity was measured in peritoneal lavages taken at the same time points. RESULTS: SP levels increased (P≤0.05) within 1h postoperatively followed by an increase (P≤0.05) in tPA mRNA expression from 3 to 6h after surgery along with a striking increase (P≤0.05) in PAI-1 mRNA expression from 3 to 12h. NK-1RA administration further increased (P≤0.05) tPA mRNA expression and significantly blunted the increase in PAI-1 mRNA levels. The NK-1RA increased (P≤0.05) fitbrinolytic activity in peritoneal fluid at 3, 12, and 24h after surgery. HIF-1α and VEGF-A mRNA expressions increased from 3 to 12h (P≤0.05) and from 1 to 3h (P≤0.05) after surgery, respectively, whereas HIF-2α mRNA expression steadily decreased. NK-1RA delayed the rise in HIF-1α mRNA and ablated the changes in HIF-2α and VEGF-A mRNAs. CONCLUSIONS: SP is a pleiotropic early regulator of mRNA levels of key adhesiogenic mediators after surgery, suggesting that it may be a viable therapeutic target.

Is pyloric gland metaplasia in ileal pouch biopsies a marker for Crohn's disease?

BACKGROUND: Approximately 5-10 % of ulcerative colitis (UC) patients who undergo ileal pouch-anal anastomosis (IPAA) will develop postoperative complications such as refractory pouchitis or a change in diagnosis to Crohn's disease (CD). Serological markers and histologic aspects of the pouch such as pyloric gland metaplasia (PGM) have been associated with a risk for these complications. METHODS: Twenty-eight IPAA patients with either CD of the pouch or chronic pouchitis (cases) and 36 IPAA controls who experienced a normal postoperative course were originally consented. Of these 64 subjects, 22 cases and 17 controls had histopathologic and serologic data available and were subsequently enrolled. Demographic and clinical data were entered into a database, blood analyzed for serological markers (Prometheus Labs, San Diego, CA) and biopsies of the pouch and the afferent limb reviewed by two GI pathologists. RESULTS: Of the cases, 55 % (12/22) had evidence of PGM in their pouch and/or small bowel biopsies, as compared to 12 % (2/17) of the controls (p = 0.006). Of 13 subjects with CD, 77 % (10/13) were found to have PGM versus subjects with chronic pouchitis in which 22 % (2/9) were found to have PGM (p = 0.03). There was a trend of ASCA positivity (both IgG and IgA, p = 0.20) and of higher ASCA titer levels (p = 0.07) with postoperative complications. CONCLUSION: This study suggests that the presence of ileal pouch PGM is associated with postoperative complications and favors a diagnosis of CD over UC with chronic pouchitis.

ASCA IgG and CBir antibodies are associated with the development of Crohn's disease and fistulae following ileal pouch-anal anastomosis.

BACKGROUND: For ulcerative colitis (UC) patients undergoing ileal pouch-anal anastomosis (IPAA), postoperative complications include chronic pouchitis and development of Crohn's disease (CD) of the pouch. AIMS: The aim of this study was to determine if serologic markers obtained postoperatively are associated with the development of complications in UC patients after IPAA. METHODS: A retrospective chart review was conducted of UC patients with IPAA were tested for expression of serologic markers. Complications abstracted from medical records included postoperative fistula, CD of the pouch, chronic pouchitis, and diversion or excision of the pouch. RESULTS: 142 patients were enrolled, 44 of whom developed complications. Positive serologic profiles for ASCA IgG and anti-CBir1 markers were found to be associated with the development of any complication, (P = 0.017 and P = 0.002, respectively). A positive anti-CBir1 test was also found to be associated with CD of the pouch and/or fistula formation (P < 0.001). Similarly, both ASCA IgG and anti-CBir1 titers were significantly associated with postoperative IPAA complications (P = 0.034 and P = 0.001, respectively), and anti-CBir1 titers were associated with CD of the pouch and/or fistula formation (P < 0.001). Complications developed after a median follow-up of 216 months (range 1-264). CONCLUSIONS: ASCA IgG and anti-CBir1 markers were associated with the development of complications after IPAA, specifically fistulae and/or CD of the pouch. The ability to identify patients at high risk for adverse outcomes may allow for early aggressive therapy, which may decrease the rate of pouch failure. A prospective study of patients with preoperative serology is ongoing.

Stasis predisposes ileal pouch inflammation in a rat model of ileal pouch-anal anastomosis.

BACKGROUND: While restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) has become the definitive surgical treatment for patients suffering from chronic ulcerative colitis (CUC), pouchitis still remains a major late complication. Fecal stasis has been implicated in the etiology of ileal inflammation; however, the mechanism(s) remain unclear, in part due to the lack of an animal model. Our goal was to surgically mimic the IPAA procedure in a rat to investigate the hypothesis that stasis leads to biochemical changes that predispose the ileal pouch to inflammation. MATERIALS AND METHODS: Thirty-two Sprague-Dawley rats underwent total colectomy with either straight ileorectal (IRA) or IPAA, and 11 nonoperated rats served as controls (Controls). Twenty-one d postoperatively, 48 h serial barium radiographs and 12 h charcoal transit follow-through studies were performed. Following sacrifice, ileal tissue was harvested for the measurement of myeloperoxidase activity (MPO) activity, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) mRNA levels, and histology. RESULTS: Serial barium radiographs showed stasis in the ileal pouch compared with IRA animals, and charcoal transit times that were two times longer (P ≤ 0.05) than that in the straight IRA rats. Ileal pouch MPO levels were significantly elevated in the IPAA rats compared with the straight IRA rats. ICAM-1 and VCAM-1 mRNA levels were not associated with neutrophil infiltration. CONCLUSIONS: These studies showed that ileal pouch stasis predisposes biochemical and histological evidence of ileal pouch mucosal inflammation. Studies such as this may provide the rationale for novel, adjunct therapies for the management of pouchitis in patients having undergone IPAA for CUC.

Carcinoembryonic antigen-stimulated THP-1 macrophages activate endothelial cells and increase cell-cell adhesion of colorectal cancer cells.

The liver is the most common site for metastasis by colorectal cancer, and numerous studies have shown a relationship between serum carcinoembryonic antigen (CEA) levels and metastasis to this site. CEA activates hepatic macrophages or Kupffer cells via binding to the CEA receptor (CEA-R), which results in the production of cytokines and the up-regulation of endothelial adhesion molecules, both of which are implicated in hepatic metastasis. Since tissue macrophages implicated in the metastatic process can often be difficult to isolate, the aim of this study was to develop an in vitro model system to study the complex mechanisms of CEA-induced macrophage activation and metastasis. Undifferentiated, human monocytic THP-1 (U-THP) cells were differentiated (D-THP) to macrophages by exposure to 200 ng/ml phorbol myristate acetate (PMA) for 18 h. Immunohistochemistry showed two CEA-R isoforms present in both U- and D-THP cells. The receptors were localized primarily to the nucleus in U-THP cells, while a significant cell-surface presence was observed following PMA-differentiation. Incubation of D-THP-1 cells with CEA resulted in a significant increase in tumor necrosis factor-alpha (TNF-alpha) release over 24 h compared to untreated D-THP-1 or U-THP controls confirming the functionality of these cell surface receptors. U-THP cells were unresponsive to CEA. Attachment of HT-29 cells to human umbilical vein endothelial cells significantly increased at 1 h after incubation with both recombinant TNF-alpha and conditioned media from CEA stimulated D-THP cells by six and eightfold, respectively. This study establishes an in vitro system utilizing a human macrophage cell line expressing functional CEA-Rs to study activation and signaling mechanisms of CEA that facilitate tumor cell attachment to activated endothelial cells. Utilization of this in vitro system may lead to a more complete understanding of the expression and function of CEA-R and facilitate the design of anti-CEA-R therapeutic modalities that may significantly diminish the metastatic potential of CEA overexpressing colorectal tumors.

The effectiveness of a single intraperitoneal infusion of a neurokinin-1 receptor antagonist in reducing postoperative adhesion formation is time dependent.

BACKGROUND: Current methods to prevent intraabdominal adhesions are not uniformly effective. We recently showed in rats that a neurokinin-1 receptor (NK-1R) antagonist is capable of reducing adhesion formation. To determine the clinical feasibility of using an NK-1R antagonist to reduce adhesions, this study examined the time dependence for the effectiveness of NK-1R antagonist administration and its effects on wound healing. METHODS: Adhesions were surgically induced in rats receiving a single intraperitoneal infusion of the NK-1R antagonist, CJ-12,255, during or 1, 5, 12, or 24 hours after surgery. Adhesion formation was assessed 7 days later. In a subset of animals, tissue plasminogen activator (tPA) activity, which is a measure of peritoneal fibrinolytic activity, was determined in peritoneal fluid 24 hours after surgery (48 hours for animals infused at 24 hours). The tPA activity was also determined in nonoperated animals 24 hours after peritoneal injection of the NK-1R antagonist. Colonic burst pressures were measured 7 days after creation of anastomoses in rats that were administered the antagonist at surgery. RESULTS: The NK-1R antagonist significantly reduced (P=.003) intraabdominal adhesions when administered during or 1 hour after surgery, only moderately reduced (P=.08) adhesions when administered at 5 hours, and had no effect at 12 or 24 hours. Peritoneal tPA activity was significantly increased (P<.05) in peritoneal fluid 24 hours after administration of the NK-1R antagonist regardless of the surgical procedure. The NK-1R antagonist did not alter colonic anastomotic healing. CONCLUSIONS: These data show that some of the events critical to adhesion formation occur within the first 5 hours following an abdominal operation in this model. The fact that the NK-1R antagonist does not impair colonic anastomotic healing enhances its usefulness as a therapeutic agent to inhibit adhesion formation.

Time series analysis of variables associated with daily mean emergency department length of stay.

STUDY OBJECTIVE: We measure the effect of various input, throughput, and output factors on daily emergency department (ED) mean length of stay per patient (daily mean length of stay). METHODS: The study was a retrospective review of 93,274 ED visits between April 15, 2002, and December 31, 2003. The association between the daily mean length of stay and the independent variables was assessed with autoregressive moving average time series analysis (ARIMA). The following independent variables were measured per 24-hour period: number of elective surgical admissions, ED volume, number of ED admissions, number of ED ICU admissions, number of ED clinical attending hours, hospital medical-surgical occupancy (hospital occupancy), and day of the week. RESULTS: Three factors were independently associated with daily mean length of stay in time series analysis: number of elective surgical admissions, number of ED admissions, and hospital occupancy. The daily mean length of stay increased by 0.21 minutes for every additional elective surgical admission, 2.2 minutes for every additional admission, and 4.1 minutes for every 5% increase in hospital occupancy. Elective surgical admissions were associated with a maximum of 35 hours of additional ED dwell time. The model accounted for 31.5% of the variability in daily mean length of stay. The final model parameters for the ARIMA analysis were autoregressive term (1) moving average (1). CONCLUSION: Hospital occupancy and the number of ED admissions are associated with daily mean length of stay. Every additional elective surgical admission prolonged the daily mean length of stay by 0.21 minutes per ED patient. Autocorrelation exists between the daily mean length of stay of the current day and the previous day.

Prognostic significance of superficial fissuring ulceration in patients with severe "indeterminate" colitis.

Some colectomy specimens from patients with severe colitis contain superficial fissuring-type ulcers but do not have any other features of Crohn's disease (CD). This finding may cause difficulty with regard to distinguishing ulcerative colitis (UC) from CD and, thus, lead to a diagnosis of "indeterminate" colitis. The aim of this study was to evaluate the clinical and pathologic features, and outcome, of a cohort of patients with colitis and superficial fissuring ulcers, but without any other features that may suggest a diagnosis of CD. We retrospectively identified 21 patients (male-to-female ratio, 10/11; mean age, 38 years) with severe chronic active colitis, all of whom had at least one (range, 1-3) superficial fissuring ulcer in their colectomy specimens (but without any other features of CD), as well as a control group of 18 patients (male-to-female ratio, 10/8; mean age, 41 years) with equally severe disease, but without fissuring ulcers. Both groups were evaluated for a variety of clinical and pathologic features, such as clinical presentation, degree, extent, and duration of colitis, and follow-up information, such as the development of pouchitis, pouch fistulae, and any other features of CD. Overall, 81% of the study patients presented clinically with fulminant colitis and underwent an emergent or urgent colectomy, compared with only 41% of the control patients (P = 0.02). Nine (43%) study patients had active serositis in their colectomy specimens, whereas only 1 (6%) control patient had this finding (P = 0.002). However, no significant differences were noted in either the extent or severity of disease or the presence of active ("backwash") ileitis, between the study and control groups. Upon follow-up (mean, 42 months; range, 4-121 months), the study patients with superficial fissuring ulcers developed pouchitis significantly more often (68% vs. 20%, P = 0.007) than the control group following an ileal pouch-anal anastomosis (IPAA) procedure. One patient from each group developed an anal fissure and another from each group developed an anastomotic stricture. In addition, 1 study patient developed a pouch-cutaneous fistula, and 1 control patient developed an enterocutaneous fistula to a loop ileostomy. Finally, 1 control patient ultimately had her pouch excised because of recurrent intractable pouchitis. However, none of the other study or control patients developed any clinical or pathologic manifestations of CD. We conclude that superficial fissuring ulcers may occur in patients with severe chronic active UC, particularly those who present with fulminant disease. Affected individuals should not be considered to have CD or "indeterminate" colitis and should not be denied an IPAA procedure. Nevertheless, the presence of superficial fissuring-type ulcers in patients with severe chronic active UC denotes a subgroup with a higher risk of pouchitis following surgical resection.

Anti-Saccharomyces cerevisiae antibodies are associated with the development of postoperative fistulas following ileal pouch-anal anastomosis.

Although serologic testing for perinuclear antineutrophil cytoplasmic antibodies (pANCA) and anti-Saccharomyces cerevisiae antibodies (ASCA) is reportedly useful in distinguishing ulcerative colitis (UC) from Crohn's disease (CD), there are few and conflicting reports assessing their utility in predicting postoperative complications after ileal pouch-anal anastomosis (IPAA). We examined the associations between postoperative complications such as pouchitis or fistulas and pANCA and ASCA antibodies in a group of patients who underwent IPAA for UC. We conducted a retrospective chart review of 34 patients initially diagnosed with UC (four of these patients had a diagnosis of indeterminate colitis) who underwent IPAA by a single surgeon, and who had pANCA and ASCA antibody levels measured during their clinical course. Study patients were assigned to four groups based on the pattern of antibody reactivity: pANCA+/ASCA- (16 patients), pANCA-/ASCA+ (nine patients), pANCA+/ASCA+ (five patients), and pANCA-/ASCA- (four patients). The median length of follow-up was 16 months (3-144 months). None of the patients (0 of 16) who were pANCA+/ASCA- had their preoperative diagnosis of UC changed after a median follow-up of 14 months (3-118 months). Of the nine patients with a preoperative diagnosis of UC who were pANCA-/ASCA+, four patients (44%) had their diagnosis changed postoperatively to CD based on clinical findings, with a median follow-up: 15 months (5-98 months). Of 16 patients who underwent IPAA and who were pANCA+/ASCA-, 15 of 16 (93.75%), were free of fistulas postoperatively, with a median follow-up of 14 months (3-118 months). Of nine patients with a preoperative diagnosis of UC who underwent IPAA and who were pANCA-/ASCA+, four of nine (44%; p = 0.04) developed fistulas postoperatively, with a median length of follow-up of 55 months (15-67 months). No relationship between serologic profiles or antibody titer levels and the development of pouchitis was identified. In a cohort of patients undergoing IPAA for UC, serologic profiles may be useful in identifying patients at risk of postoperative fistula formation. Patients who were pANCA-/ASCA+ were at increased risk for the development of fistulas postoperatively compared to patients who were pANCA+/ASCA-, and were also more likely to have their diagnosis changed postoperatively to CD. A larger study is needed to validate these observations.

MRI of complicated pouchitis.

OBJECTIVE: The purpose of this study is to assess the ability of MRI to identify the presence of inflammation related to the pouch reservoir in symptomatic patients with an ileal pouch-anal anastomosis who present with clinically suspected complicated pouchitis. CONCLUSION: Initial results suggest that MRI should be considered in patients who have undergone ileal pouch-anal anastomosis and present a clinical impression of complicated pouchitis. MRI showed abnormalities consistent with complicated pouchitis in seven of nine examinations, with findings including pouch wall thickening, abnormal wall enhancement, peripouch fluid collection, sinus and fistula tract formation, lymphadenopathy, and peripouch stranding and fatty proliferation. MRI findings of complicated pouchitis should raise the suspicion of Crohn's disease and should prompt further investigation.

Pathologic features and clinical significance of "backwash" ileitis in ulcerative colitis.

Patients with ulcerative colitis (UC) may develop inflammation in the distal ileum thought to be due to "backwash" of cecal contents ("backwash ileitis"). However, a systematic analysis of ileal changes in UC has never been performed, and the prevalence and criteria for "backwash" ileitis have not been defined. The aim of this study was to evaluate the prevalence and spectrum of inflammatory changes in the ileum in patients with UC and to correlate ileal changes with outcome after total proctocolectomy and ileal pouch-anal anastomosis. Routinely processed ileocolonic resection specimens from 200 consecutive patients with clinically and pathologically confirmed UC were evaluated for a wide variety of pathologic features in the ileum and colon. The ileal data were correlated with both the clinical features and the pathologic findings in the colon. Follow-up data were obtained to confirm absence of Crohn's disease and to evaluate outcome of ileo-anal pouches. Overall, 34 of 200 (17%) UC patients had inflammatory changes in the ileum (male/female ratio, 16/18; mean age, 42 years); 32 of 34 (94%) had pancolitis, which was significantly higher than the rate of pancolitis (39%) in patients without ileal disease (N = 166) (P < 0.001), but there were no other differences between patients with or without ileal pathology. In the colon, 22 of 34 (65%) patients had severe activity. Ileal changes included villous atrophy and crypt regeneration without increased inflammation (N = 3), increased neutrophilic and mononuclear inflammation in the lamina propria (N = 6), patchy cryptitis and crypt abscesses (N = 21) and focal superficial surface erosions (N = 4), some with pyloric metaplasia (N = 2 of 4). In general, the severity of ileal changes paralleled the severity of colonic activity. However, 2 of 4 (50%) patients with superficial erosions in the ileum had subtotal or left-sided colitis only, and had only mild colonic activity. Other cases showed only mild to moderate colonic activity and patchy or discontinuous involvement of the distal ileum. Upon follow-up of patients with erosions (mean, 48.5 months; range, 26-102 months), none developed manifestations of Crohn's disease anywhere in the gastrointestinal tract. The presence of inflammatory changes in the ileum had no effect on the prevalence of pouch complications or on the occurrence of dysplasia or cancer. Ileal changes in UC are not uncommon (prevalence, 17%), are generally mild in nature (villous atrophy, increased inflammation, scattered crypt abscesses), and are not associated with an increased rate of ileo-anal pouch complications, dysplasia, or carcinoma. In some cases, our findings are consistent with a backwash etiology. However, rarely, ileal erosions may occur in patients without cecal involvement, which may indicate that other pathogenetic mechanisms should be considered in the etiology of ileitis in UC patients.

Histologic predictors of pouchitis in patients with chronic ulcerative colitis.

Inflammation of ileal reservoir mucosa ("pouchitis") is a common sequelae in ulcerative colitis (UC) patients who have had a colectomy with ileal pouch anal-anastomosis (IPAA). Although several clinical, genetic, and laboratory parameters have been evaluated, reliable pathologic predictors for the development of pouchitis are lacking. The purpose of this case-control study was to determine whether there are any pathologic features in UC colectomy specimens that may help predict the subsequent development of pouchitis after an IPAA procedure. The study group consisted of 39 UC patients (male/female ratio: 21/18, mean age: 35 years), who had at least 1 episode of pouchitis after an IPAA procedure during the follow-up period (mean: 57 months, range: 12-121 months). There were 26 control patients (male/female ratio: 11/15, mean age: 37 years), all of whom also underwent a total colectomy and IPAA procedure for UC, but did not develop pouchitis during the follow-up period (mean: 78 months, range: 14-223 months). Routinely processed tissues from each colectomy specimen were evaluated for a variety of histologic features, such as extent of colitis, severity of colitis, extent of severe colitis, type and extent of ulceration, presence and severity of appendiceal inflammation, and the presence of active ileitis, and compared between the study and control patients. Pathologic features that were associated with the subsequent development of pouchitis included the presence of severe colitis that extended into the cecum (severe pancolitis), which was present in 7/39 (18%) pouchitis patients, but in none (0%) of the control patients (P = 0.03), early fissuring ulcers [9/39 (23%) pouchitis cases versus 1/26 (4%) controls (P = 0.04)], active inflammation of the appendix [20/32 (63%) pouchitis patients versus 7/19 (31%) controls (P = 0.03)], and appendiceal ulceration [13/32 (41%) pouchitis patients versus none (0%) of the controls (P = 0.002)]. No significant differences in patient gender or age, depth or extent of ulceration, or the presence or absence of "backwash ileitis" were identified between the 2 groups. In conclusion, there are several histologic features in colectomy specimens from UC patients who have undergone an IPAA procedure that may help predict the subsequent development of pouchitis. Of these features, appendiceal ulceration is highly associated with pouchitis.

Pouchitis in a rat model of ileal J pouch-anal anastomosis.

Endorectal ileal pouch-anal anastomosis (IPAA) has become the operation of choice for patients with chronic ulcerative colitis. Although this procedure improves the quality of life, pouchitis remains a significant postoperative complication. Because our understanding of the pathophysiology of pouchitis may, in part, be due to the lack of small animal model, our aim was to develop a model of IPAA in a rat that mimics its clinical counterpart. Colectomy, proctectomy, construction of an ileal J pouch, and ileal pouch-rectal anastomosis as a model of IPAA was performed in Sprague-Dawley and Lewis rats. Radiographic contrast studies were performed to quantitate intestinal transit. The presence of activated neutrophils was quantified by measuring mucosal myeloperoxidase (MPO) activity. Oxidative stress was quantitated by measuring urinary 8-isoprostane (8-IP) levels. Anaerobic and aerobic bacterial counts were determined on Brucella and tryptic soy agar plates, respectively. Dextran sulfate sodium (DSS) was used to exacerbate ileal J pouch inflammation. Mortality was low, and animals gained weight normally after recovery. Stasis was documented radiographically. MPO levels were elevated (p < 0.05) in the ileal J pouch 30 and 60 days after IPAA, indicating an inflammation that was associated with stasis and bacterial overgrowth. 8-IP levels were elevated by 80% compared with controls. Oral administration of 5% DSS to IPAA rats with further elevated MPO and 8-IP levels in concert with a pouchitis-like syndrome that included the physical, gross, and histologic characteristics of clinical pouchitis. An understanding of the pathophysiology of pouchitis is essential to the future development of new therapeutic modalities. This model is applicable to investigating several key etiologic mechanisms purportedly related to pouchitis.

Colonic metaplasia in the ileal pouch is associated with inflammation and is not the result of long-term adaptation.

Ileal pouch-anal anastomosis (IPAA) is the preferred surgical therapy for chronic ulcerative colitis (CUC) and familial adenomatous polyposis (FAP). Previous studies have demonstrated morphologic changes in pouch mucosa such as villous atrophy and crypt hyperplasia. These changes have been labeled "colonic metaplasia." The aims of this study were to determine whether these changes represent "normal" long-term adaptation of the nondiseased pouch or instead are present only in the setting of inflammation. Twenty-four patients were identified, greater than 5 years status post-IPAA for CUC, who underwent pouchoscopy for surveillance and had no history of pouchitis. Thirty-one patients were identified greater than 5 years status post-IPAA for CUC, who had a history of pouchitis and had undergone pouchoscopy at least 5 years status post-IPAA. Eight patients status post-IPAA for FAP were also identified. Biopsy specimens were reevaluated by a single, blinded pathologist for degree of inflammation, the presence of villous atrophy and crypt hyperplasia, and evidence of dysplasia. Among the patients with CUC, the inflammation score was greater in the pouchitis group, 13.2 +/- 1.2, compared to the nonpouchitis group, 4.0 +/- 0.5 (P < 0.0001). Median colonic metaplasia score was greater in the pouchitis group (4 [range 2 to 6]) vs. 2 (9 [range 0 to 6]; P < 0.0001). The colonic metaplasia score correlated with the inflammation score (Spearman coefficient r = 0.83; P < 0.0001). In the eight patients with FAP, the inflammation score was 5.1 +/- 0.9 and the median colonic metaplasia score was 1 (range 0 to 4). There was no evidence of dysplasia in any of the biopsy specimens. Patients without a history of pouchitis or symptoms of pouchitis have only a minimal degree of villous atrophy and crypt hyperplasia. These morphologic changes in the ileal pouch are found primarily in the setting of inflammation, and likely represent a reparative response.

Distribution of polycyclic aromatic hydrocarbons in soils and terrestrial biota after a spill of crude oil in Trecate, Italy.

Ecological and human health exposures from soil-based petroleum-derived contaminants commonly are estimated by using soil-to-biota transfer factors that usually are based on octanol-water partitioning. Few studies of biota have been conducted in relation to spills of crude oils in terrestrial environments. After a large blowout of crude oil in northern Italy in 1994, the distribution of polycyclic aromatic hydrocarbons (PAHs) was examined over time and space in soils, uncultivated wild vegetation, insects, mice, and frogs in the area. Within two years of the blowout, PAH concentrations declined to background levels over much of the area where initial concentrations were within an order of magnitude above background, but had not declined to background in areas where starting concentrations exceeded background by two orders of magnitude. Octanol-water partitioning and extent of alkylation explained much of the variance in uptake of PAHs by plants and animals. The PAHs with lower octanol-water partition coefficients (K(ow)s) and higher-alkylated PAHs had higher biota-soil accumulation factors (BSAFs) than did high-K(ow) and unalkylated forms. The BSAFs for PAHs with higher K(ow)s were very low for plants, but much higher for animals, with frogs accumulating more of these compounds than other species.

Gastric outlet obstruction as a consequence of a duodenal web masquerading as gastrinoma in an adult.

We present the case of a 24-year-old man with recurrent peptic ulcers and hypergastrinemia, in whom a multidisciplinary investigation for gastrinoma revealed a duodenal web. The affected duodenal segment was excised, and a gastroduodenostomy with highly selective vagotomy was performed. Postoperative serum gastrin levels returned to the normal range over the next 6 weeks. Congenital duodenal anomalies are unusual causes of gastric outlet obstruction in adults. Chronic gastric outlet obstruction secondary to an adult duodenal web can induce neurohumoral changes in gastric function, which enhance both acid output and gastrin secretion. This case reminds clinicians to consider congenital anomalies in adults presenting with recurrent peptic ulcers and hypergastrinemia.