Noncanonical STAT3 activation regulates excess TGF-ß1 and collagen I expression in muscle of stricturing Crohn's disease.

Increased TGF-ß1 and TGF-ß1-dependent Collagen I production in intestinal mesenchymal cells result in fibrosis in patients with Montreal B2 fibrostenotic Crohn's disease. Numerous cytokines, including IL-6, are produced by activated mesenchymal cells themselves and activate STAT3. The aim of the current study was to determine the mechanisms by which STAT-3 activation might result in intestinal fibrosis. Cytokine levels were measured by ELISA. STAT3 and suppressor of cytokine signaling 3 protein levels were measured by immunoblot, STAT3-TGFB1 DNA-binding activity by chromatin immunoprecipitation, and TGFB1 transcriptional activity by luciferase reporter assay. TGF-ß1 (TGFB1), Collagen1α1, and connective tissue growth factor (CTGF) gene expression was measured by quantitative RT-PCR. The role of STAT3 activation was determined using STAT3 inhibitor, Stattic, and by transfection of STAT3 mutants. Autocrine production of cytokines was increased in muscle cells of B2 phenotype patients from strictures and normal intestine in the same patient and compared with other Crohn's phenotypes, ulcerative colitis, and non-Crohn's patients. A unique pattern of STAT3 phosphorylation emerged: high STAT3(S727) and low STAT3(Y705) in strictures and the opposite in unaffected intestine. TGFB1 transcriptional activity was regulated by phospho-STAT3(S727) and was decreased by Stattic or dominant-negative STAT3(S727A). TGF-ß1, COL1A1, and CTGF expression was inhibited by Stattic or dominant-negative STAT3(S727A). Treatment of normal muscle cells with IL-6 or expression of constitutively active STAT3(S727E) phenocopied muscle cells from strictured intestine. Neutralization of autocrine IL-6 reversed STAT3 phosphorylation and normalized expression of TGF-ß1 in strictured intestinal muscle. The ability of Stattic to improve development of fibrosis was confirmed in mice with 2,4,6-trinitrobenzenesulfonic acid-induced colitis. We observed a unique phospho-STAT3(S727) response in patients with Montreal B2 Crohn's disease, particularly in response to IL-6 leading to increased TGF-ß1, collagen, and CTGF production in ileal strictures.

Endogenous IGF-I and alphaVbeta3 integrin ligands regulate increased smooth muscle hyperplasia in stricturing Crohn's disease.

BACKGROUND & AIMS: Insulin-like growth factor-I (IGF-I) regulates human intestinal smooth muscle growth by stimulating proliferation and inhibiting apoptosis. IGF-I-stimulated growth is augmented when alphaVbeta3 integrin is occupied by its ligands, fibronectin and vitronectin. Increased IGF-I expression and muscle cell hyperplasia are features of stricturing Crohn's disease (CD); however, the role of IGF-I in stricture formation is unknown. The aim was to identify the functional role of endogenous IGF-I and alphaVbeta3 integrin ligands in regulating muscle cell hyperplasia in stricturing CD. METHODS: Smooth muscle cells were isolated from muscularis propria of stricturing CD or normal margins. Quantitative polymerase chain reaction, immunoblot analysis, and enzyme-linked immunosorbent assay were used to measure fibronectin, vitronectin, alphaVbeta3 integrin, and IGF-I levels. Activation of the IGF-I receptor, Erk1/2, p70S6 kinase, and GSK-3beta was measured by immunoblot. Proliferation was quantified by Ki67 immunostaining and [(3)H]thymidine incorporation. Apoptosis was measured from caspase-3 cleavage and nucleosome accumulation. RESULTS: IGF-I, vitronectin, and fibronectin RNA and protein levels were increased 1.8- to 3.4-fold in muscle cells from strictures over normal margins. Basal IGF-I receptor phosphorylation was increased 320% in strictured over normal muscle, and basal Erk1/2, p70S6 kinase, and GSK-3beta phosphorylation were increased 205%-292% in strictures. In muscle cells from strictures, Ki67 immunoreactivity and [(3)H]thymidine incorporation were increased and apoptosis was decreased compared with normal margins. Antagonists of the IGF-I receptor or alphaVbeta3 integrin reversed these changes. CONCLUSIONS: Smooth muscle cell hyperplasia in stricturing CD is regulated by increased endogenous IGF-I and alphaVbeta3 integrin ligands that regulate augmented proliferation and diminished apoptosis.

Validation that a 1-year fellowship in minimally invasive and bariatric surgery can eliminate the learning curve for laparoscopic gastric bypass.

BACKGROUND: The concept that advanced surgical training can reduce or eliminate the learning curve for complex procedures makes logical sense but is difficult to verify and has not been tested for laparoscopic Roux-en-Y gastric bypass (LRYGB). We sought to determine if minimally invasive/bariatric surgery fellowship graduates (FGs) would demonstrate complication-related outcomes (CRO) equivalent to the outcomes achieved during their training experience under the supervision of experienced bariatric surgeons. METHODS: We compared CRO for the first 100 consecutive LRYGBs performed in practice by five consecutive minimally invasive/bariatric fellows at new institutions (total 500 cases) to CRO for the 611 consecutive LRYGBs performed during their fellowship training experience under the supervision of three experienced bariatric surgeons at the host training institution. RESULTS: The two patient groups did not differ demographically. The 18 types of major and minor complications identified after LRYGB did not differ among the five fellowship graduates. The mentors' CRO were compatible with published benchmark data. As compared with the training institution data, the overall incidence of complications for the combined experience of fellowship graduates did not differ statistically from that of the mentors. The fellowship graduates' early experience included zero non-gastrojejunostomy leaks (0% versus 1.5%) and a low rate of anastomotic stricture (0.8% versus 3.0%), incisional hernia (1% versus 4.4%), bowel obstruction (0% versus 3%), wound infection (0.3% versus 3.1%), and gastrointestinal hemorrhage (0.2% versus 1.6%). The rate of gastrojejunostomy leak (1.8% versus 2.6%) and, most importantly, mortality (0.8% versus 0.7%) did not differ between the two groups. CONCLUSIONS: Fellowship graduates achieved high-quality surgical outcomes from the very beginning of their post-fellowship practices, which are comparable to those of their experienced mentors. These data validate the concept that advanced surgical training can eliminate the learning curve often associated with complex minimally invasive procedures, specifically LRYGB.

Insulin-like growth factor-binding protein-5 stimulates growth of human intestinal muscle cells by activation of G{alpha}i3.

In human intestinal smooth muscle cells, endogenous insulin-like growth factor-I (IGF-I) regulates growth and IGF-binding protein-5 (IGFBP-5) expression. The effects of IGF-I are facilitated by IGFBP-5. We previously showed that IGFBP-5 acts independently of IGF-I in human intestinal muscle to stimulate proliferation and upregulate IGF-I production by activation of Erk1/2 and p38 MAPK. Thus a positive feedback loop exists between IGF-I and IGFBP-5, whereby both stimulate muscle growth and production of the other factor. In Crohn's disease, IGF-I and IGFBP-5 expression are increased and contribute to stricture formation through this effect on muscle growth. To determine the signaling pathways coupling IGFBP-5 to MAPK activation and growth, smooth muscle cells were isolated from muscularis propria of human intestine and placed into primary culture. Erk1/2 and p38 MAPK activation and type I collagen production were measured by immunoblot. Proliferation was measured by [(3)H]thymidine incorporation. Activation of specific G proteins was measured by ELISA. AG1024, an IGF-I receptor tyrosine kinase inhibitor, was used to isolate the IGF-I-independent effects of IGFBP-5. IGFBP-5-induced phosphorylation of Erk1/2 and p38 MAPK and proliferation were abolished by pertussis toxin, implying the participation of Gi. IGFBP-5 specifically activated Gi3 but not other G proteins. Transfection of an inhibitory Galphai minigene specifically inhibited MAPK activation, proliferation, and both collagen-I and IGF-I production. Our results indicate that endogenous IGFBP-5 activates Gi3 and regulates smooth muscle growth, IGF-I production, and collagen production via the alpha-subunit of Gi3, independently of IGF-I, in normal human intestinal muscle cells.

Activation and dysregulation of the unfolded protein response in nonalcoholic fatty liver disease.

BACKGROUND & AIMS: Nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH) are associated with known triggers of the unfolded protein response (UPR). The aims were to (1) evaluate the activity of UPR in NAFL and NASH and (2) correlate expression of UPR pathways with liver histology. METHODS: Messenger RNA (mRNA) and protein expression were measured by quantitative real-time PCR and Western blot, respectively. Apoptosis was assessed by TUNEL assay. Liver histology was scored using the NASH clinical research network criteria. RESULTS: Compared with subjects with the metabolic syndrome and normal liver histology (n = 17), both NAFL (n = 21) and NASH (n = 21) were associated with increased eukaryotic initiation factor-2alpha (eIF-2alpha) phosphorylation. Activating transcription factor 4 (ATF4) mRNA and protein, C/EBP homologous protein (CHOP), and growth arrest, DNA damage-34 (GADD34) mRNA were not increased in NAFL or NASH. Whereas immunoglobulin heavy chain binding protein mRNA was significantly increased in NASH, unspliced X-box protein-1 (XBP-1) protein did not increase. Also, endoplasmic reticulum degradation-enhancing alpha-mannosidase-like protein mRNA levels were inversely related to spliced XBP-1 mRNA in NASH. NASH was specifically associated with low sXBP-1 protein and increased JNK phosphorylation. This correlated with increased TUNEL activity in NASH. The histologic severity correlated with sXBP-1 mRNA and JNK phosphorylation. CONCLUSIONS: There is a variable degree of UPR activation in NAFL and NASH. Although both NAFL and NASH are associated with eIF-2alpha phosphorylation, there is a failure to activate downstream recovery pathways, ie, ATF4-CHOP-GADD34. NASH is specifically associated with (1) failure to generate sXBP-1 protein and (2) activation of JNK.

Nonalcoholic steatohepatitis is associated with altered hepatic MicroRNA expression.

UNLABELLED: The expression of microRNA in nonalcoholic steatohepatitis (NASH) and their role in the genesis of NASH are not known. The aims of this study were to: (1) identify differentially expressed microRNAs in human NASH, (2) tabulate their potential targets, and (3) define the effect of a specific differentially expressed microRNA, miR-122, on its targets and compare these effects with the pattern of expression of these targets in human NASH. The expression of 474 human microRNAs was compared in subjects with the metabolic syndrome and NASH versus controls with normal liver histology. Differentially expressed microRNAs were identified by the muParaflo microRNA microarray assay and validated using quantitative real-time polymerase chain reaction (PCR). The effects of a specific differentially expressed miRNA (miR-122) on its predicted targets were assessed by silencing and overexpressing miR-122 in vitro. A total of 23 microRNAs were underexpressed or overexpressed. The predicted targets of these microRNAs are known to affect cell proliferation, protein translation, apoptosis, inflammation, oxidative stress, and metabolism. The miR-122 level was significantly decreased in subjects with NASH (63% by real-time PCR, P < 0.00001). Silencing miR-122 led to an initial increase in mRNA levels of these targets (P < 0.05 for all) followed by a decrease by 48 hours. This was accompanied by an increase in protein levels of these targets (P < 0.05 for all). Overexpression of miR-122 led to a significant decrease in protein levels of these targets. CONCLUSIONS: NASH is associated with altered hepatic microRNA expression. Underexpression of miR-122 potentially contributes to altered lipid metabolism implicated in the pathogenesis of NASH.

Bariatric surgery in Medicare patients: greater risks but substantial benefits.

BACKGROUND: Recent reports have documented greater mortality for bariatric surgery in Medicare (MC) patients compared with patients from other payors. METHODS: We reviewed our database for the mortality and outcomes of 282 MC and 3169 non-Medicare (NMC) patients undergoing bariatric surgery. RESULTS: Of the MC patients, 27 were >65 years of age, and 255 were receiving disability. The average age was 48.45 +/- 11.8 years, and the average BMI was 52.4 +/- 10.0 kg/m2. NMC patients had average age of 40.0 +/- 10.1 years and a BMI of 50.6 +/- 9.1 kg/m2. The co-morbidities were greater in the MC patients than in the NMC patients (hypertension 71.9% versus 48.4%, diabetes mellitus 39.72% versus 19.4%, obstructive sleep apnea 46.45% versus 28.46%, and obesity hypoventilation syndrome 9.93% versus 2.71%). The mortality rate was 2.48% in the MC patients and .76% in the NMC patients. Mortality was absent in MC patients >65 years old. The percentage of excess weight lost was less in the MC patients (60.8%) than in the NMC patients (66.5%, P <.0001). The resolution of diabetes mellitus also differed (64.86% for the MC patients and 77.18% for the NMC patients; P = .0329). The male MC patients had more prevalent co-morbidities than did the male NMC patients (hypertension 79.17% versus 58.85%; diabetes mellitus 36.11% versus 24.83%; obstructive sleep apnea 79.17% versus 54.51%; and obesity hypoventilation syndrome 26.39% versus 7.64%). The operative mortality rate was 5.6% for the male MC patients and 1.5% for the female MC patients. The weight loss was similar for the male MC and male NMC patients. The male MC patients had slightly better resolution of both hypertension (MC patients 54.8% versus NMC patients 26.7%, P = .0025) and diabetes mellitus (MC patients 30% versus NMC patients 22.5%, P = .745). When the patients were stratified into low-, intermediate-, and high-risk groups using a previously validated risk scale, patients with similar risk factors had similar mortality in both groups. CONCLUSION: The results of our study have shown that disabled MC patients have greater operative mortality than NMC patients that appears to be associated with more prevalent risk factors. However, the risk was counterbalanced by a substantial improvement in health.

Does diabetes affect weight loss after gastric bypass?

BACKGROUND: Weight loss in diabetics improves glycemic control. We investigated whether diabetes mellitus (DM) adversely affects postgastric bypass weight loss. METHODS: Our database was queried for the demographics and outcomes of patients with and without DM who had undergone gastric bypass surgery. DM was subdivided by severity: diet-controlled, oral hypoglycemic agents, and insulin. RESULTS: Of the 3193 patients, 655 (20%) had DM. The DM group was older (45.8 +/- 10.4 yr versus 39.1 +/- 9.9 yr, P <.0001), with more co-morbidities: hypertension (70.5% versus 44.2%, P <.0001), sleep apnea (36.7% versus 26.1%, P <.0001), and venous stasis (5.6% versus 2.6%, P <.0001). More men had DM (25.6% versus 19.3%, P = .0006). The age-adjusted, preoperative weight, and body mass index were equal. A direct relationship was found between DM severity and age, weight, and co-morbidities. At 1 year, the DM group had a lower percentage of excess weight loss (60.8% +/- 16.6% versus 67.6% +/- 16.7%, P <.0001) and greater body mass index (34.2 +/- 7.1 kg/m(2) versus 32.3 +/- 7.2 kg/m(2), P <.0001). The percentage of excess weight loss was 67.6% for those without DM, 63.5% for those with diet-controlled DM, 60.5% for those with DM controlled by oral hypoglycemic agents, and 57.5% for those requiring insulin. DM resolved in 89.8% of those with diet-controlled DM, 82.7% of those taking oral hypoglycemic medication, and 53.3% of those requiring insulin. Hypertension resolution was greatest in patients without DM (74.4% versus 63.5%, P <.0001). CONCLUSION: The results of our study have shown that those with DM typically have more co-morbidities, despite having no difference in preoperative weight compared with those without DM. Despite the lower weight loss, those with DM had significant resolution of their DM and hypertension and should not be deterred from undergoing gastric bypass surgery.

Effect of location and speed of diagnosis on anastomotic leak outcomes in 3828 gastric bypass cases.

INTRODUCTION: Leaks after Roux-en-Y gastric bypass are a major cause of mortality. This study attempts to define the relationship between the leak site, time from surgery to detection, and outcome. METHODS: Retrospective review of 3,828 gastric bypass procedures. RESULTS: Of the leaks (3.9% overall), 60/2,337 (2.6%) occurred after open gastric bypass, 57/1,080 (5.2%) after laparoscopic gastric bypass, and 33/411 (8.0%) after revisions. Overall leak-related mortality after Roux-en-Y gastric bypass was 0.6% (22/3,828). Mortality rate from gastrojejunostomy leaks (38 in the open gastric bypass, and 43 in the laparoscopic) was higher in the open group than the laparoscopic group (18.4 vs 2.3%, p = 0.015). Median time of detection for a gastrojejunostomy leak in the open group was longer than in the laparoscopic group (3 vs 1 days, Wilcoxon score p < 0.001). Jejunojejunostomy (JJ) leak was associated with a 40% mortality rate. Initial upper gastrointestinal series did not detect 9/10 jejunojejunostomy leaks. Median detection time was longer in the jejunojejunostomy leak group than the gastrojejunostomy leak group (4 vs 2 days, p = 0.037). DISCUSSION: Leak mortality and time of detection was higher after open gastric bypass than laparoscopic gastric bypass. GBP patients with normal upper gastrointestinal (UGI) studies may harbor leaks, especially at the JJ or excluded stomach. Normal UGI findings should not delay therapy if clinical signs suggest a leak.

Participation in 150 min/wk of moderate or higher intensity physical activity yields greater weight loss after gastric bypass surgery.

BACKGROUND: The American College of Sports Medicine's position stand on weight loss and prevention of weight regain in adults has suggested that overweight adults should participate in a minimum of 150 min/wk of moderate intensity physical activity (PA). This study compared the 3-, 6-, and 12-month postoperative weight loss between gastric bypass surgery (GBS) patients who met or exceeded the recommended 150 min/wk of moderate or higher PA and those not meeting the recommendation. METHODS: The self-administered short version of the International Physical Activity Questionnaire was used to assess moderate or higher intensity PA participation at 3 (n = 178), 6 (n = 128), and 12 months (n = 209) after GBS. The patients' height and body weight were obtained to determine the kilograms of weight lost, percentage of excess weight loss, body mass index change, and total weight loss percentage. The weight loss differences were analyzed using analysis of covariance at each point, with age and preoperative body mass index as covariates. RESULTS: Patients reporting 150 min/wk of moderate or higher PA had significantly (P <.05) greater weight lost, percentage of excess weight loss, change in body mass index, and total weight loss percentage at 6 and 12 months postoperatively. The percentage of excess weight loss was 56.0% +/- 11.5% versus 50.5% +/- 11.6% and 67.4% +/- 14.3% versus 61.7% +/- 17.0% for the group meeting and not meeting the PA requirement at 6 and 12 months after GBS, respectively. No significant difference existed at 3 months after GBS. CONCLUSION: Participation in a minimum of 150 min/wk of moderate or higher intensity PA was associated with greater postoperative weight loss at 6 and 12 months postoperatively. Patients should be encouraged to meet or exceed this recommendation until prospective, randomized studies have definitively established a link between PA and greater postoperative weight loss and maintenance.

Selective, versus routine, upper gastrointestinal series leads to equal morbidity and reduced hospital stay in laparoscopic gastric bypass patients.

BACKGROUND: The use of routine upper gastrointestinal contrast radiology series (UGIS) after laparoscopic Roux-en-Y gastric bypass surgery (LRYGB) can entail risk, expense, and patient discomfort. We have discontinued routine UGIS in favor of selective UGIS guided by patient symptoms and signs or elevations in the juxta-anastomotic drain amylase. We hypothesized that elimination of routine UGIS would not adversely affect morbidity or mortality. METHODS: We retrospectively reviewed the anastomotic leak, reoperation, and death rates and length of hospital stays for all patients who underwent LRYGB between two periods when either routine (November 2003 to December 2004) or selective (January 2005 to February 2006) postoperative UGIS were done. RESULTS: In group 1, were 267 patients who had undergone LRYGB with routine UGIS during November 2003 to December 2004. Group 2 consisted of 151 patients who had undergone LRYGB with selective UGIS during January 2005 to February 2006. The mean +/- standard error of the mean hospital stay for groups 1 and 2 was 4.3 +/- 0.3 and 3.3 +/- 0.2 days (P = .08), respectively. In group 1, 18 gastrojejunostomy leaks (6.7%) occurred compared with 6 (4.0%) in group 2 (P = .28). Also, 14 patients (5.2%) in group 1 required reoperation for anastomotic leak compared with 3 (2.0%) in group 2 (P = .13). Three patients (1.1%) in group 1 and no patients in group 2 died (P = .56). CONCLUSION: The elimination of routine UGIS did not adversely affect morbidity or mortality. The mean hospital stay in the group with selective UGIS decreased, although this decrease had not yet achieved statistical significance.

Pulmonary embolism complicating bariatric surgery: detailed analysis of a single institution's 24-year experience.

BACKGROUND: Morbidly obese patients undergoing bariatric procedures are at risk for pulmonary embolism (PE). Because large series are required to analyze low-incidence complications, factors predictive of PE have not been clearly defined. Since 1992, short-course heparin prophylaxis, beginning immediately before operation, has been used in this center. STUDY DESIGN: Prospective data on 3,861 patients undergoing bariatric procedures between 1980 and 2004 were queried. Factors analyzed included age, gender, body mass index, interval between procedure and PE, inpatient versus outpatient status, mortality, access method (open versus laparoscopic), and comorbidities. RESULTS: PE within 60 days of operation occurred in 33 patients (23 women, 10 men), for an incidence of 0.85%. No difference in incidence was noted between open (0.84%) and laparoscopic (0.88%) groups, nor did routine prophylaxis with heparin since 1992 decrease the incidence. The interval between procedure and PE was 13.2+/-2.6 (mean +/- SEM) days (open=13.0+/-3.0 days, laparoscopic 14.1+/-6.49 days, p=0.9). One-third of PEs occurred after hospital discharge. Pulmonary embolism-related mortality was 27%. A statistically greater body mass index was noted in PE patients compared with non-PE patients (57.2+/-2.4 kg.m(2) versus 49.9+/-0.2 kg/m(2), p < 0.01, Wilcoxon rank test). Multivariate logistic regression confirmed a primary role for preoperative weight as a predictor of PE; univariate analysis suggested an increased PE risk with obesity hypoventilation syndrome, anastomotic leak, and chronic venous insufficiency. CONCLUSIONS: Data demonstrated persistence of PE risk in the anticoagulation, laparoscopic-access era at a rate similar to that in the preanticoagulation, open-access era. Because one-third of PEs occur after hospital discharge, consideration should be given to continuing anticoagulants longer and to adopting a more aggressive policy of inferior vena cava filter prophylaxis, particularly in patients with high body mass index, obese hyperventilation syndrome, and venous insufficiency.

Insurance-mandated preoperative dietary counseling does not improve outcome and increases dropout rates in patients considering gastric bypass surgery for morbid obesity.

BACKGROUND: Preoperative dietary counseling (PDC) before bariatric surgery is mandated by a growing number of insurance payers. Their claim is that PDC improves outcomes and postoperative compliance. We compared outcomes of GBP patients undergoing a mandatory 13 weeks of PDC (n = 72) to a contemporaneous group of patients with no such requirement (no-PDC; n = 252) who underwent operation between January 2000 and December 2002. METHODS: The PDC and no-PDC groups were characterized by similar male:female ratios (1:4 vs 1:4.6), mean age (42 years), mean body weight (324 lb vs 309 lb), and mean body mass index (BMI) (52 kg/m2 vs 50 kg/m2). The PDC group had a higher incidence of obstructive sleep apnea compared with the no-PDC group (41% vs 28%; P < .04) but otherwise the two groups had similar incidences of obesity-related comorbidities. The presurgery dropout rate was 50% higher in the PDC group than in the no-PDC group (28% vs 19%; P < .05). RESULTS: At 1 year follow-up, the no-PDC patients had a statistically greater percentage excess weight loss (67% vs 60%; P < .0001), lower BMI (32 vs 35; P < .015), and lower body weight (197 vs 218; P < .01). Resolution of major comorbidities, complication rates, 30-day postoperative mortality, and postoperative compliance with follow-up were similar in the two groups. CONCLUSIONS: The data demonstrate that insurance-mandated PDC is an obstacle to patient access for surgical treatment of severe obesity and has no impact on weight loss outcome or postsurgical compliance. PDC should be abandoned by the insurance industry.

Physical activity stage of readiness predicts moderate-vigorous physical activity participation among morbidly obese gastric bypass surgery candidates.

BACKGROUND: Despite the ever-growing body of literature linking stage of physical activity readiness (PAR) with physical activity (PA) participation in overweight and obese populations, this relationship has not been examined among individuals seeking gastric bypass surgery (GBS). Furthermore, little is known about the specific intensity of activities undertaken by GBS candidates. Therefore, this study sought to determine whether greater PAR was associated with greater moderate-vigorous physical activity (MVPA) participation among GBS candidates. METHODS: The International Physical Activity Questionnaire (IPAQ), administered 2-weeks presurgery to 87 GBS candidates, determined MVPA participation using a formula based on metabolic equivalents (MET)-minutes/week. A stages-of-change measure categorized each candidate into one of five PAR stages: precontemplation, contemplation, preparation, action, or maintenance. RESULTS: The proportion of individuals in each PAR stage and the corresponding MVPA was as follows: contemplation (5.7%, 48.0 MET-minutes/week), preparation (46%, 394.0 MET-minutes/week), action (34.5%, 1614.0 MET-minutes/week), and maintenance (13.8%, 2056.7 MET-minutes/week). MVPA was significantly greater in candidates in the action or maintenance stages compared with those in contemplation (P =.008 and .025 for action and maintenance, respectively) or preparation (P < .0001 and .006 for action and maintenance, respectively). CONCLUSIONS: This study is the first to demonstrate a relationship between PAR and PA among GBS candidates, with 100% of the sample reporting either an intention to engage in PA or actual engagement in PA. This finding, coupled with the recent support for the importance of PA for weight loss/maintenance in GBS patients, warrants an investigation into the effectiveness of presurgical and postsurgical PA interventions matched to patients' PAR levels.

A nonneuronal 5-hydroxytryptamine receptor 3 induces chloride secretion in the rat distal colonic mucosa.

BACKGROUND: The 5-HT3 receptor is a serotonin receptor believed to reside on enteric neurons. However, several studies belie an exclusive neural localization. Our hypothesis is that the 5-HT3 receptor agonist, 2-methyl-5-HT (2Me5HT), induces chloride secretion despite neural blockade, which can be blocked by a 5-HT3 receptor antagonist. METHODS: Rat distal colon was stripped of its muscularis, mounted as mucosal sheets in Ussing chambers, and short-circuited. Adjacent sheets were pretreated with 1 micromol/L of the neurotoxin, tetrodotoxin, and incubated with 2Me5HT (50 micromol/L) alone or with a 5-HT3 (0.3 micromol/L ondansetron or 0.3 micromol/L tropisetron) or a 5-HT4 (0.3 micromol/L GR11808) receptor antagonist. Short-circuit current (I(sc)) was measured continuously. RESULTS: 2Me5HT caused an increase in I(sc), which was significantly (P <.01, repeated measures analysis of variance) inhibited by ondansetron (n = 8) and tropisetron (n = 5) but not by GR11808. CONCLUSIONS: A 5-HT3 receptor is present at the mucosal level that mediates chloride secretion by a nonneural pathway.

Impact of major co-morbidities on mortality and complications after gastric bypass.

BACKGROUND: We hypothesized that major co-morbidities affect survival and complications after gastric bypass. METHODS: A total of 1465 patients undergoing laparoscopic and open gastric bypass between 1995 and 2002 were studied. Patients with a body mass index >or= 35 kg/m(2) and major co-morbidities (group 1, n = 1045) were compared with patients with a body mass index >or= 40 kg/m(2) with minor/no co-morbidities (group 2, n = 420). RESULTS: Group 1 patients were older (43 versus 36 years, P < 0.001) and had a greater BMI (53 versus 50 kg/m(2), P < 0.001). Early postoperative complications were greater in group 1 than in group 2 and included leaks (4.1% versus 1.2%, P < 0.0032) and wound infections (3.9% versus 1.4%, P < 0.0133). Procedure-related mortality in the series was 1.7%. Mortality was 10-fold greater in group 1 (2.3% versus 0.2%, P < 0.0032). The incidence of small bowel obstruction, incisional hernia, and pulmonary embolism was similar in the two groups. Excess weight loss was significantly greater in group 2 (68% versus 62%, P < 0.001) at 1 year. Resolution of group 1 co-morbidities was great, including hypertension in 62%, diabetes in 75%, venous stasis disease in 96%, and pseudotumor cerebri in 98%. CONCLUSION: Outcomes analysis of obesity surgery requires risk stratification. The very low mortality rates in published studies are likely explained by surgical treatment of low-risk patients with minor co-morbidities, such as those seen in group 2. However, despite the increased perioperative risk, the group 1 patients (with major co-morbidities) demonstrated dramatic resolution of their co-morbid conditions, justifying the decision to go forward with surgery. The data support a radical change in treatment philosophy in which morbidly obese individuals should be offered bariatric surgery before major co-morbid conditions develop as a strategy to decrease the operative risk.

Lap-band failures: conversion to gastric bypass and their preliminary outcomes.

BACKGROUND: The LAP-BAND is designed to be an adjustable laparoscopically placed gastric restriction device for the treatment of severe obesity. The purpose of this study was to assess the outcome in patients who had failed to effectively lose weight with this device and were converted to a gastric bypass. METHODS: A retrospective chart review was performed of all LAP-BANDS placed in patients at our institution from March 1996 to June 1998. RESULTS: 36 LAP-BANDS were placed. To date, 18 of 36 (50%) have been removed. Fourteen of 18 were simultaneously converted to a gastric bypass. Indications for conversion included: failed weight loss (5), failed weight loss with esophageal dilatation (5), failed weight loss with leaking band (2), and symptomatic esophageal dilatation (1). Median time to conversion after LAP-BAND placement was 38.2 months. Median follow-up after conversion to gastric bypass was 8.3 months. Nineteen percent excess weight loss occurred after LAP-BAND placement. Forty-three percent excess weight loss occurred after conversion to gastric bypass (P =.025). CONCLUSIONS: In our experience, the LAP-BAND is associated with a high frequency of inadequate weight loss. Conversion to gastric bypass in this subset of patients is technically challenging but results in superior weight loss in a shorter time period.

Effect of cyclooxygenase inhibition on serotonin-induced chloride secretion from rat distal colon.

BACKGROUND: Serotonin is a well-known mediator of intestinal chloride secretion. The effects of exogenous 5-hydroxytryptamine (5-HT) can be demonstrated experimentally by a rise in short-circuit current, which is proportional to active electrogenic chloride secretion. Prostaglandin E2 is also an intestinal secretagogue and has been implicated in certain diarrheal illnesses. The aim of this study was to evaluate the effect of a cyclooxygenase inhibitor on 5-HT-stimulated ion transport. METHODS: Full- or partial-thickness sheets of rat colon were mounted in Ussing chambers and placed under short-circuit conditions. 5-HT or the specific 5-HT3 receptor agonist, 2-methyl-5-HT, was added in the absence and presence of the cyclooxygenase inhibitor, piroxicam. RESULTS: The overall drug effect was statistically significant at two concentrations (10(-5) and 5 x 10(-4) mol) of piroxicam when compared with 5-HT alone (P < or = .005; ANOVA, n = 8). The inhibitory effect of piroxicam (10(-5)) was statistically significant when compared to 2-methyl-5-HT alone (P < .01; ANOVA, n = 5). Piroxicam did not significantly affect baseline current. CONCLUSIONS: Exogenous 5-HT applied to an in vitro preparation of rat distal colon induces chloride secretion that is significantly inhibited by the cyclooxygenase inhibitor, piroxicam. It appears that the cyclooxygenase pathway plays a major role in the mediation of the secretory response to exogenous serotonin in vitro.

Inhibition of neural nitric oxide synthase attenuates the chloride secretory response to stroking in human jejunum.

BACKGROUND: Stroking of human jejunal mucosa induces serotonin release and a rise in short-circuit current (DeltaI(sc)). Nitric oxide is known to function as a nonadrenergic, noncholinergic neurotransmitter in response to neural serotonin receptor activation in the rat. We hypothesize that neural nitrergic mechanisms mediate the chloride secretory response to mucosal stroking in human jejunum. METHODS: Segments of normal proximal jejunum were obtained from patients having gastric bypass surgery for obesity. Muscle-stripped segments of jejunum were mounted in Ussing chambers under short-circuit conditions. The neural nitric oxide synthase inhibitor, l-thiocitrulline, was added to experimental tissues. Mucosal stroking of control and experimental segments was then performed. RESULTS: Pretreatment with l-thiocitrulline attenuated the short circuit rise seen after stroking in the experimental group when compared with the control (5.4 +/- 1.5 microA/cm(2) vs 8.0 +/- 1.6 microA/cm(2); P <.05, Student t test, paired data, n = 11), but did not affect baseline I(sc) before stroking. Serotonin released by stroking was not different in experimental versus control tissue. CONCLUSIONS: The significantly reduced DeltaI(sc) in the group pretreated with the neural nitric oxide synthase inhibitor suggests that nitric oxide liberated from enteric neurons participates in the chloride secretory response to stroking in human jejunum in vitro.