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.

Increased activation of latent TGF-ß1 by αVß3 in human Crohn's disease and fibrosis in TNBS colitis can be prevented by cilengitide.

BACKGROUND: Strictures develop in >30% of patients affected with Crohn's disease. No available medication prevents stricture development in susceptible patients. In Crohn's strictures, but not adjacent normal intestine, TGF-ß1 increases in muscularis smooth muscle, increasing collagen I production and strictures. Muscle cells express αVß3 integrin containing an Arg-Gly-Asp (RGD) binding domain. The aim was to determine whether increased TGF-ß1 levels in strictures were the result of latent TGF-ß1, which contains an RGD sequence, binding to and activation by αVß3; and whether cilengitide, which is an RGD-containing αVß3 integrin inhibitor, decreases TGF-ß1 activation and development of fibrosis in chronic 2,4,6 trinitrobenzene sulfonic acid (TNBS)-induced colitis. DESIGN: Muscle cells isolated from Crohn's disease strictures and normal resection margin and from the colon of rats after 42 days of chronic TNBS-induced colitis were used to prepare RNA and protein lysates and to initiate primary cultures. The mechanisms leading to increased TGF-ß1 activation, collagen I production, and fibrosis were examined in human muscle and in rats. Human cultured cells in vitro and rats in vivo were treated with cilengitide to determines it efficacy to decrease TGF-ß1-activation, collagen production, and decrease the development of fibrosis. RESULTS: Latent TGF-ß1 is activated by the αVß3 RGD domain in human and rat intestinal smooth muscles. Increased activation of TGF-ß1 in Crohn's disease and in TNBS-induced colitis causes increased collagen production, and fibrosis that could be inhibited by cilengitide. CONCLUSIONS: Cilengitide, an αVß3 integrin RGD inhibitor, could be a novel treatment to diminish excess TGF-ß1 activation, collagen I production, and development of fibrosis in Crohn's disease.

Endogenous IGFBP-3 regulates excess collagen expression in intestinal smooth muscle cells of Crohn's disease strictures.

BACKGROUND: Stricture formation occurs in ≈30% of patients with Crohn's disease (CD) and is a significant cause of morbidity. Strictures are characterized by intestinal smooth muscle cell hyperplasia, smooth muscle cell hypertrophy, and fibrosis due to excess net extracellular matrix production, including collagen. Transforming growth factor-ß1 (TGF-ß1) has profibrotic effects in many tissues due to its ability to regulate collagen expression and extracellular matrix dynamics. We previously showed that both insulin-like growth factor (IGF) binding protein-3 (IGFBP-3) and TGF-ß1 are expressed by normal human intestinal smooth muscle cells, bind to, and activate TGF-ßRII/I receptors in these cells. METHODS: Smooth muscle cells isolated from the muscularis propria of patients were used to prepare RNA, protein lysates, or placed into primary culture. IGFBP-3, TGF-ß1, and collagen IαI expression was measured with quantitative reverse-transcription polymerase chain reaction (RT-PCR) and protein levels by enzyme-linked immunosorbent assay (ELISA) or immunoblot. RESULTS: Expression and production of IGFBP-3, TGF-ß1, and collagen IαI were significantly increased specifically in smooth muscle cells isolated from regions of strictured intestine in CD compared to nonstrictured histologically normal resection margin. IGFBP-3 and TGF-ß1 regulated collagen IαI expression and production via a TGF-ßRII/I-dependent and Smad2/3-dependent mechanism. Upregulated (excess) collagen IαI expression and production in smooth muscle cells of strictures and basal collagen IαI in smooth muscle cells of normal margin were inhibited by immunoneutralization of IGFBP-3 or TGF-ß1. CONCLUSIONS: The findings indicate that upregulated endogenous IGFBP-3 and TGF-ß1 expression regulates excess collagen IαI production and contributes to fibrosis and stricture formation in CD.

Long-term results of malabsorptive distal Roux-en-Y gastric bypass in superobese patients.

BACKGROUND: The purpose of the present study was to evaluate the safety, efficacy, and nutritional outcomes of malabsorptive distal Roux-en-Y gastric bypass (D-RYGB) 20-25 years later at a university hospital. METHODS: From 1985 to 1989, 49 mostly superobese (body mass index >50 kg/m(2)) patients had undergone D-RYGB. D-RYGB consisted of open laparotomy with a 50-mL proximal gastric pouch and gastroenterostomy performed 250 cm proximal to the ileocecal junction, with common channels of 50-150 cm. These 49 patients were compared with a similar group of 92 consecutive patients who had undergone long-limb RYGB, with a 75-cm biliopancreatic limb and 150-cm alimentary limb. RESULTS: The mean ± SD preoperative body mass index was 58.9 ± 9.3 kg/m(2). After 1 perioperative death secondary to pulmonary embolism, limb-lengthening revisions were required in 21 (43.7%) of the 48 remaining patients for protein-calorie malnutrition. Of the 23 with a 50-cm common channel, 13 required revision compared with 8 of 25 with ≥100-cm common channel (P <.05, chi-square). Of the 48 patients who had undergone D-RYGB, 8 had died 6-19 years after D-RYGB. Of the nonrevised patients, 19 (70.4%) of 27 had >5 years of follow-up. In these, the latest body mass index was 34.2 kg/m(2) at 10 ± 6.1 years. The percentage of excess weight loss was 66.8% ± 14%. The lowest late serum albumin level was 3.4 ± .5 g/dL (range 2.3-4.4). The mean 25-hydroxy vitamin D level was 14.6 ± 11.3 ng/mL. Compared with patients who had undergone long-limb RYGB, the D-RYGB patients had a significantly greater percentage of excess weight loss after 5 years but significantly lower albumin, hemoglobin, iron, and calcium levels. CONCLUSION: Although D-RYGB afforded superior long-term weight loss, it caused protein-calorie malnutrition requiring frequent revision. The nonrevised patients had frequent severe metabolic derangements. Thus, D-RYGB should not be the primary operation for morbid or superobese patients.

Analysis of factors associated with durable remission of diabetes after Roux-en-Y gastric bypass.

BACKGROUND: Data on the durability of remission of type 2 diabetes mellitus (T2DM) after gastric bypass are limited. Our purpose was to identify the rate of long-term remission of T2DM and the factors associated with durable remission. METHODS: A total of 177 patients with T2DM who had undergone Roux-en-Y gastric bypass from 1993 to 2003 had 5-year follow-up data available. T2DM status was determined by interview and evaluation of the diabetic medications. Patients with complete remission or recurrence of T2DM were identified. RESULTS: Follow-up ranged from 5 to 16 years. Of the 177 patients, 157 (89%) had complete remission of T2DM with a decrease in their mean body mass index from baseline (50.2 +/- 8.2 kg/m(2)) to 31.3 +/- 7.2 kg/m(2) postoperatively (mean percentage of excess weight loss 70.0% +/- 18.6%). However, 20 patients (11.3%) did not have T2DM remission despite a mean percentage of excess weight loss of 58.2% +/- 12.3% (P <.0009). Of the 157 patients with initial remission of their T2DM, 68 (43%) subsequently developed T2DM recurrence. Remission of T2DM was durable in 56.9%. Durable (>5-year) resolution of T2DM was greatest in the patients who originally had either controlled their T2DM with diet (76%) or oral hypoglycemic agents (66%). The rate of T2DM remission was more likely to be durable in men (P = .00381). Weight regain was a statistically significant, but weak predictor, of T2DM recurrence. CONCLUSION: Early remission of T2DM occurred in 89% of patients after Roux-en-Y gastric bypass. T2DM recurred in 43.1%. Durable remission correlated most closely with an early disease stage at gastric bypass.

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.

Drain amylase levels are an adjunct in detection of gastrojejunostomy leaks after Roux-en-Y gastric bypass.

BACKGROUND: Because anastomotic leaks after gastric bypass surgery can have devastating consequences for the patient, early detection is highly desirable. This and many other bariatric surgical centers have discontinued routine use of upper gastrointestinal contrast x-ray because of the lack of cost-effectiveness, discomfort to the patient, and the failure of the study to detect some leaks. We postulated that drain amylase levels from a juxta-anastomotic drain would detect the presence of salivary amylase and be a sensitive test for gastrojejunostomy leak. STUDY DESIGN: Routine measurement of amylase levels from a drain adjacent to the gastrojejunostomy was instituted in 2005. Leak was defined as anastomotic incompetence documented either by confirmatory upper gastrointestinal contrast x-rays, CT scans, or reoperation. RESULTS: On postoperative day 1, the drain amylase levels of 350 patients were tested. Seventeen patients had postoperative leaks (4.8%); 14 of the 17 had leaks at the gastrojejunal anastomosis (82%). The median peak value for patients without leak was 79.5 IU/L+/-1,436.2 SD; for patients with leak it was 6,307 IU/L+/-50,166 (p < 0.0001, Wilcoxon rank sum test). All patients but one with a leak had a drain amylase > 400 IU/L. A drain amylase value of 400 IU/L empirically defines gastrojejunostomy leaks with a sensitivity of 94.1% and a specificity of 90.0%. Negative predictive value of a drain amylase level < 400 IU/L in excluding leak was 99.6%. Positive predictive value of a drain amylase > 400 IU/L in predicting leak was 33.3%. Of the 17 leaks, 7 required reoperation at a median of 1 day (mean, 1.6+/-1.1 days). There was no perioperative mortality. CONCLUSIONS: Drain amylase levels are a simple, low-cost adjunct with high sensitivity and specificity that can help to identify patients who may have a leak after gastric bypass surgery.

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.

Becoming physically active after bariatric surgery is associated with improved weight loss and health-related quality of life.

The purpose of this study was to determine whether pre- to postoperative increases in physical activity (PA) are associated with weight loss and health-related quality of life (HRQoL) following bariatric surgery. Participants were 199 Roux-en-Y gastric bypass (RYGB) surgery patients. The International Physical Activity Questionnaire (IPAQ) was used to categorize participants into three groups according to their preoperative and /1-year postoperative PA level: (i) Inactive/Active (<200-min/week/>or=200-min/week), (ii) Active/Active (>or=200-min/week/>or=200-min/week) and (iii) Inactive/Inactive (<200-min/week/<200-min/week). The Medical Outcomes Study Short Form-36 (SF-36) was used to assess HRQoL. Analyses of covariance were conducted to examine the effects of PA group on weight and HRQoL changes. Inactive/Active participants, compared with Inactive/Inactive individuals, had greater reductions in weight (52.5 +/- 15.4 vs. 46.4 +/- 12.8 kg) and BMI (18.9 +/- 4.6 vs. 16.9 +/- 4.2 kg/m(2)). Weight loss outcomes in the Inactive/Active and Active/Active groups were similar to each other. Inactive/Active and Active/Active participants reported greater improvements than Inactive/Inactive participants on the mental component summary (MCS) score and the general health, vitality and mental health domains (P < 0.01). Although the direction of causation is not clear, these findings suggest that RYGB patients who become active postoperatively achieve weight losses and HRQoL improvements that are greater than those experienced by patients who remain inactive and comparable to those attained by patients who stay active. Future randomized controlled trials should examine whether assisting patients who are inactive preoperatively to increase their PA postoperatively contributes to optimization of weight loss and HRQoL outcomes.

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.

Four hundred fifty consecutive laparoscopic Roux-en-Y gastric bypasses with no mortality and declining leak rates and lengths of stay in a bariatric training program.

BACKGROUND: We reviewed our obesity surgery database for 2 experienced bariatric surgeons since their last patient death in October 2003 through July 2007. STUDY DESIGN: Data on all patients undergoing planned laparoscopic Roux-en-Y gastric bypass (L-GBP) by the two attending bariatric surgeons at the Medical College of Virginia Hospitals were reviewed. The operations were performed by fellows in minimally invasive surgery, assisted by the 2 attending physicians in more than 90% of patients. Surgical technique included a handsewn imbrication of a gastrojejejunostomy and jejunojejunostomy, each performed with a linear stapler. Routine sampling of a juxtaanastamotic drain for amylase levels was substituted for routine upper gastrointestinal contrast studies during the study period. RESULTS: All patients, except those who had earlier extensive upper abdominal surgery in that time period, were offered a laparoscopic approach (5.7% were converted to open procedures). The mean (+/- SD) age was 42.4+/-11 years; body mass index was 49.5+/-9 kg/m(2). Women represented 80.5% of patients. The leak rate declined from 9.7% in 2004 to 2.0% in 2006 (p < 0.05, chi-square test); there have been no leaks in any patient since July 2006, including the 40 patients in 2007. Hospital length of stay declined from 4.7+/-5.7 days in 2004 to 2.9+/-3.3 days in 2006 (p < 0.05, Wilcoxon rank test). At 1-year followup, 270 patients had lost 66.1%+/-17% of initial excess weight, which was similar to that in our open gastric bypasses. Comorbid conditions improved or resolved in 67.6% of patients with diabetes, 56.1% of those with hypertension, 75% of those with sleep apnea, 87.8% of those with urinary stress incontinence, 95.9% of those with gastroesophageal reflux disease, and in 100% of those with stasis ulcers. Overall complication rates of wound infection (1.5%), incisional hernia (1.7%), internal hernia (0.2%), and intestinal obstruction (1.7%) were low. CONCLUSIONS: Results for laparoscopic Roux-en-Y gastric bypass improve with experience and can be taught in an academic training program, with low morbidity and mortality. Routine postoperative upper gastrointestinal contrast studies are unnecessary and may lengthen hospital stay.

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.

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.

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.

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.