The American Journal of Gastroenterology, May 1, 2006
Inflammatory bowel disease (IBD), comprising primarily of Crohn&a... more Inflammatory bowel disease (IBD), comprising primarily of Crohn's disease (CD) and ulcerative colitis (UC), is increasingly prevalent in racial and ethnic minorities. This study was undertaken to characterize racial differences in disease phenotype in a predominantly adult population. Phenotype data on 830 non-Hispanic white, 127 non-Hispanic African American, and 169 Hispanic IBD patients, recruited from six academic centers, were abstracted from medical records and compiled in the NIDDK-IBD Genetics Consortium repository. We characterized racial differences in family history, disease location and behavior, surgical history, and extraintestinal manifestations (EIMs) using standardized definitions. African American CD patients were more likely than whites to develop esophagogastroduodenal CD (OR = 2.8; 95% CI: 1.4-5.5), colorectal disease (OR = 1.9; 95% CI: 1.1-3.4), perianal disease (OR = 1.7; 95% CI: 1.03-2.8), but less likely to have ileal involvement (OR = 0.55; 95% CI: 0.32-0.96). They were also at higher risk for uveitis (OR = 5.5; 95% CI: 2.3-13.0) and sacroiliitis (OR = 4.0; 95% CI: 1.55-10.1). Hispanics had higher prevalence of perianal CD (OR = 2.9; 95% CI: 1.8-4.6) and erythema nodosum (3.3; 95% CI: 1.7-6.4). Among UC patients, Hispanics had more proximal disease extent. Both African American and Hispanic CD patients, but not UC patients, had lower prevalences of family history of IBD than their white counterparts. There are racial differences in IBD family history, disease location, and EIMs that may reflect underlying genetic variations and have important implications for diagnosis and management of disease. These findings underscore the need for further studies in minority populations.
Clinical Gastroenterology and Hepatology the Official Clinical Practice Journal of the American Gastroenterological Association, Jan 7, 2006
Onercept is a recombinant, soluble human p55 receptor to tumor necrosis factor-alpha. A randomize... more Onercept is a recombinant, soluble human p55 receptor to tumor necrosis factor-alpha. A randomized, double-blind, placebo-controlled, dose-ranging trial was performed to evaluate the efficacy of onercept induction therapy in patients with Crohn's disease (CD). Patients (n = 207) with moderate-to-severe acute or chronic active CD were randomized to receive subcutaneous onercept (10, 25, 35, or 50 mg) or placebo 3 times weekly for 8 weeks. Primary analysis was induction of remission (defined as a CD activity index score < or = 150) at week 8. A total of 104 patients had acute active CD. Remission rates at week 8 were 23.5% for placebo (n = 17), and 34.8%, 20.0%, 26.1%, and 28.6% for onercept 10 mg (n = 23), 25 mg (n = 20), 35 mg (n = 23), and 50 mg (n = 21), respectively (P = .98). A total of 103 patients had chronic active CD. Remission rates at week 8 were 23.8% for placebo (n = 21), and 23.8%, 9.1%, 35.3%, and 13.6% for onercept 10 mg (n = 21), 25 mg (n = 22), 35 mg (n = 17), and 50 mg (n = 22), respectively (P = .66). There were no differences between treatment groups in the incidence of adverse events. However, mild-to-moderate injection-site reactions occurred in up to 12% of onercept-treated patients. Onercept was well tolerated but was not effective at the doses studied in patients with active CD.
ABSTRACT The IBD5 locus is a genetic risk factor for IBD, particularly Crohn's Disease, c... more ABSTRACT The IBD5 locus is a genetic risk factor for IBD, particularly Crohn's Disease, coding for the organic cation/carnitine transporters (OCTN1 and 2). Two variants of OCTN are associated with susceptibility to Crohn's Disease. Modified transport of carnitine in vitro has been reported for a polymorphism of OCTN1. The aim was to investigate the function of intestinal OCTNs in IBD in relation to genetic polymorphisms. Intestinal tissue was obtained from endoscopic biopsies and surgical resections from IBD patients (n=33 and 14, resp.) and controls (n=22 and 14, resp.). OCTN protein levels were measured in intestinal biopsies and carnitine transport was quantified in intestinal resections. OCTN1 protein levels were significantly higher in ileal versus colonic tissue (2.95% ± 0.4 vs 0.66% ± 0.2, resp.; p<0.0002). OCTN1 expression was higher in Crohn's disease patients with mutant homozygous or heterozygous genotypes (0.6% ± 0.1 vs 3% ± 0.8, resp., p<0.02). Carnitine transport was very rapid and Na+ dependent (10s). It was not different comparing Crohn's Disease and control groups (0.45 ± 0.12 vs 0.51 ± 0.12 nM carnitine/mg prot/min, resp.). Carnitine transport tended to be higher in subjects with mutant homozygous and heterozygous OCTN1 and OCTN2 genotypes (0.19 vs 0.59 and 0.25 vs 0.6, respectively). The present data reveal that OCTN protein levels appear to be similar in intestinal tissue from Crohn's Disease patients and controls. Overall, ileal carnitine transport appears to as well equal in Crohn's Disease and control groups. However, there was a trend towards higher carnitine transport in subjects with OCTN1 and OCTN2 mutations.
Inflammatory bowel disease (IBD), comprising primarily of Crohn's disease (CD) and ulcerative... more Inflammatory bowel disease (IBD), comprising primarily of Crohn's disease (CD) and ulcerative colitis (UC), is increasingly prevalent in racial and ethnic minorities. This study was undertaken to characterize racial differences in disease phenotype in a predominantly adult population. Phenotype data on 830 non-Hispanic white, 127 non-Hispanic African American, and 169 Hispanic IBD patients, recruited from six academic centers, were abstracted from medical records and compiled in the NIDDK-IBD Genetics Consortium repository. We characterized racial differences in family history, disease location and behavior, surgical history, and extraintestinal manifestations (EIMs) using standardized definitions. African American CD patients were more likely than whites to develop esophagogastroduodenal CD (OR = 2.8; 95% CI: 1.4-5.5), colorectal disease (OR = 1.9; 95% CI: 1.1-3.4), perianal disease (OR = 1.7; 95% CI: 1.03-2.8), but less likely to have ileal involvement (OR = 0.55; 95% CI: 0.32...
... Review Intestinal tight junctions and their importance in health and disease: role of dietary... more ... Review Intestinal tight junctions and their importance in health and disease: role of dietary lipids G. Wild, K. Madsen,* and ABR ... well, the cytoskeleton may participate in such mechanisms .23 On activation, PLC converts PIP2 into IP3 (1,4,5triphosphate) and diacylglycerol (DAG). ...
BACKGROUND/OBJECTIVES: Since the first use of azathioprine (AZA) in the treatment of chronic ulce... more BACKGROUND/OBJECTIVES: Since the first use of azathioprine (AZA) in the treatment of chronic ulcerative colitis (UC), there have been several open studies reporting benefit but few controlled trials. The aim of this study was to compare the efficacy of AZA and oral 5-ASA in the treatment of steroid-dependent UC.METHODS:52 patients with steroid-dependent UC (29F, 23M, mean age 42, range 18-72), were admitted to this investigator blind study. Steroiddependence was defined as a requirement of steroid therapy at -> 10 mg/day during the preceding 6 months, with at least 2 attempts to discontinue the medication. The disease had to be clinically and endoscopicelly active at study entry, and all patients were taking systemic prednisolone (40 mg/day). Patients were randomised to receive AZA 2 mg/Kg/day or oral 5-ASA 3.2 g/day, for a 6-month follow-up period. Clinical and endoscopic activity was monitored by PowelI-Tuck and Baron indeces, respectively. Physician Global Assessment (PGA)(from 1 = very much improved to 6 = much worse) was evaluated after 6 months. The outcome of the treatment was defined as (1) success = induction of clinical and endoscopic remission and steroid discontinuation, (2) failure = need of at least 1 further cycle of systemic steroids to control symptoms, apart from that initial one or colectomy. RESULTS: 27 patients were treated wit AZA and 25 with 5-ASA.3 patients (1 in AZA and 2 in 5-ASA group) were lost to follow-up. After 6 months, significantly more patients in the AZA than in the 5-ASA group obtained success of therapy.Two patients in the AZA and 2 in the 5-ASA treatment groups had colectomy. PGA was b~er in AZA than in 5-ASA treatment at month 6 (AZA vs 5-ASA = 2.84_+1.75 vs 4.21_+1.80, p<O.01). CONCLUSIONS:AZA therapy is significantly more effective than 5-ASA in inducing clinical and endoscopic remission and avoiding steroid requirement in the treatment of steroid-dependent UC. AZA 5-ASA Success Failure 15 (58 %) 6 (26 %) 11 (42%} 17/74%) p = 0.042 (Fisher's test) (C1~.5 % -57 %).
Lipid-binding proteins have been identified in the enterocyte, including the cytosolic intestinal... more Lipid-binding proteins have been identified in the enterocyte, including the cytosolic intestinal and liver fatty acid binding proteins (I-FABP and L-FABP, respectively) as well as the brush border membrane fatty acid transporter (FAT). It is unclear whether variations in the type of dietary lipids or diabetes modify the RNA abundance of these proteins. Diabetes is associated with an increased intestinal lipid uptake, and the lipid uptake is greater in rats fed a semisynthetic saturated fatty acid (SFA) as compared with a polyunsaturated fatty acid (PUFA) diet. Male Sprague-Dawley rats were injected with streptozotocin or control vehicle and fed chow or either SFA or PUFA for 2 weeks. Northern blotting was performed on RNA isolated from jejunal and ileal tissues. In controls, feeding SFA as compared with PUFA reduced the jejunal abundance of I-FABP and L-FABP RNA. In diabetic rats, feeding SFA increased the ileal FAT RNA. Feeding PUFA reduced jejunal L-FABP and ileal FAT RNA in diabetic rats as compared with controls. The enhanced lipid uptakes reported with feeding an SFA diet or with diabetes were not associated with parallel alterations in lipid-binding proteins. We speculate that these lipid-binding proteins act as a storage mechanism for lipids in enterocytes and are not directly involved in lipid uptake.
Onercept is a recombinant, soluble human p55 receptor to tumor necrosis factor-alpha. A randomize... more Onercept is a recombinant, soluble human p55 receptor to tumor necrosis factor-alpha. A randomized, double-blind, placebo-controlled, dose-ranging trial was performed to evaluate the efficacy of onercept induction therapy in patients with Crohn&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (CD). Patients (n = 207) with moderate-to-severe acute or chronic active CD were randomized to receive subcutaneous onercept (10, 25, 35, or 50 mg) or placebo 3 times weekly for 8 weeks. Primary analysis was induction of remission (defined as a CD activity index score &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; or = 150) at week 8. A total of 104 patients had acute active CD. Remission rates at week 8 were 23.5% for placebo (n = 17), and 34.8%, 20.0%, 26.1%, and 28.6% for onercept 10 mg (n = 23), 25 mg (n = 20), 35 mg (n = 23), and 50 mg (n = 21), respectively (P = .98). A total of 103 patients had chronic active CD. Remission rates at week 8 were 23.8% for placebo (n = 21), and 23.8%, 9.1%, 35.3%, and 13.6% for onercept 10 mg (n = 21), 25 mg (n = 22), 35 mg (n = 17), and 50 mg (n = 22), respectively (P = .66). There were no differences between treatment groups in the incidence of adverse events. However, mild-to-moderate injection-site reactions occurred in up to 12% of onercept-treated patients. Onercept was well tolerated but was not effective at the doses studied in patients with active CD.
Glucagon-like peptide (GLP)-2 enhances nutrient uptake in adult animals. Glucocorticosteroids acc... more Glucagon-like peptide (GLP)-2 enhances nutrient uptake in adult animals. Glucocorticosteroids accelerate intestinal ontogeny and increase nutrient uptake in adult animals. We hypothesized that administering GLP-2 and dexamethasone (DEX) to suckling rats will enhance sugar uptake and that this effect persists into the postweaning period. Suckling rats were treated for 10 days with GLP-2 (0.1 microg/g/d, twice daily), DEX (0.128 microg/g/d, once daily), GLP-2 + Dex (same doses as above), or placebo. The rate of intestinal uptake of glucose and fructose in sucklings (19-21 days old) and weanlings (49 days old) was assessed using an in vitro ring technique. DEX reduced body weight in weanlings, whereas GLP-2 + DEX prevented this effect. In sucklings, GLP-2 + DEX increased ileal villous height and jejunal and ileal villous width and crypt depth. In sucklings, GLP-2 + DEX increased the maximal transport rate (Vmax) for jejunal glucose uptake, whereas DEX reduced the ileal Vmax. In weanlings, GLP-2 + DEX increased jejunal villous height, whereas ileal villous width and crypt depth were reduced. DEX increased the ileal Vmax and apparent affinity constant for glucose in weanlings. The combination of these hormones may be useful in stimulating glucose uptake in the developing intestine, and giving DEX to sucklings may enhance glucose uptake in later life.
Selective blockade of lymphocyte–vascular endothelium interactions in the gastrointestinal tract ... more Selective blockade of lymphocyte–vascular endothelium interactions in the gastrointestinal tract is a promising therapeutic strategy for inflammatory bowel disease. This randomized, double-blind, controlled trial assessed the efficacy and safety of MLN0002, a monoclonal antibody targeting the α4β7 integrin, in patients with active Crohn's disease.Patients were randomized to receive MLN0002 2.0 mg/kg (n = 65), MLN0002 0.5 mg/kg (n = 62), or placebo (n = 58) by intravenous infusion on days 1 and 29. The primary efficacy end point was clinical response (≥70-point decrement in the Crohn's Disease Activity Index [CDAI] score) on day 57. Secondary end points were the proportions of patients with clinical remission (CDAI score ≤150) and with an enhanced clinical response (≥100-point decrement in CDAI). Human anti-human antibody levels were measured.Clinical response rates at day 57 were 53%, 49%, and 41% in the MLN0002 2.0 mg/kg, MLN0002 0.5 mg/kg, and placebo groups. Clinical remission rates at day 57 were 37%, 30%, and 21%, respectively (P = .04 for the 2.0 mg/kg vs placebo comparison). At day 57, 12% and 34% of patients in the 2.0- and 0.5-mg/kg groups had clinically significant human anti-human antibody levels (titers > 1:125). There was one infusion-related hypersensitivity reaction. The most common serious adverse event was worsening of Crohn's disease.This phase 2 study was suggestive of a dose-dependent beneficial effect of MLN0002 therapy on clinical remission. MLN0002 was well tolerated in patients with active Crohn's disease.
In the past year there have been many advances in the area of small bowel physiology and patholog... more In the past year there have been many advances in the area of small bowel physiology and pathology and therapy. In preparation for this review, over 1500 papers were assessed. The focus is on presenting clinically useful information for the practicing gastroenterologist. Selected important clinical learning points include the following: (1) glutamine may restore the AIDs-associated increased intestinal permeability to normal; (2) substance P is a major mediator of diarrhea caused by Costridium difficile toxin A, acting by binding to a G-proteincoupled receptor, and represents a possible 2therapeutic target; (3) the serological diagnosis of celiac disease has been greatly enhanced with the use of anti-endomysial antibody testing, and the recent antitransglutaminase; (4) a quarter of patients with celiac disease may have secondary pancreatic insufficiency and require enzyme replacement therapy; (5) in the patient with unexplained elevation in the serum transaminase concentration, consider celiac disease as an obscure possibility; (6) bosentan and endothelin receptor agonist may prove to be useful in reducing gut ischemia in patients with septic shock; and (7) the administration of recombinant human fibroblast growth factor-2 may prove to be useful to prevent radiation damage to the gastrointestinal tract.
In the past 18 months there have been many advances in the areas of small bowel physiology, patho... more In the past 18 months there have been many advances in the areas of small bowel physiology, pathology, and clinical management. In preparation for this three part review, over 1000 papers were assessed; some have been selected and reviewed here, with a focus on presenting clinically useful information for the practicing gastroenterologist. This is new material which represents a rolling review, an update on advances in the small bowel and physiology and pathology since last reviewed and published in Digestive
The aim of this study was to identify determinants of nonadherence to medication in outpatients w... more The aim of this study was to identify determinants of nonadherence to medication in outpatients with established inflammatory bowel disease (IBD). Ten gastroenterologists and 153 of their IBD patients participated in this prospective study. Demographic, clinical, and psychosocial characteristics, as well as patient-physician discordance, were assessed at an office visit. Nonadherence to medication was assessed 2 wk later. Separate generalized estimating equations were used to identify determinants of nonadherence. Physicians averaged 47.9 yr in age (range 30.1-57.5 yr), and 90% were male. Patients averaged 37.0 yr (SD = 15.1), and 87 (56.9%) were female. In all, 63 patients (41.2%) were nonadherent to medication; of these, 51 (81.0%) indicated unintentional nonadherence, 23 (36.5%) intentional nonadherence, and 11 (17.5%) both. Overall nonadherence was predicted by disease activity (OR = 0.55, p = 0.0022), new patient status (OR = 2.14, p = 0.0394), disease duration (OR = 0.50, p = ...
The aim of this study was to identify the independent psychosocial correlates of patient-physicia... more The aim of this study was to identify the independent psychosocial correlates of patient-physician discordance in adult outpatients with inflammatory bowel disease. This cross-sectional study was conducted in three university-affiliated tertiary care settings. Psychological distress, social support, perceived stress, and negative life events were assessed, as were demographic, lifestyle, and clinical characteristics. Patient-physician discordance was assessed with 10-item questionnaires. Ten gastroenterologists and 200 of their patients participated. Patients and their physicians disagreed most on discussion of personal issues. Patients with Crohn's disease had statistically significantly higher discordance on disease activity and physical limitation, as well as higher average overall discordance scores than patients with ulcerative colitis. Mean discordance levels were similar across different physicians. Higher psychological distress and more perceived stress were independentl...
The American Journal of Gastroenterology, May 1, 2006
Inflammatory bowel disease (IBD), comprising primarily of Crohn&amp;amp;amp;amp;amp;amp;amp;a... more Inflammatory bowel disease (IBD), comprising primarily of Crohn&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (CD) and ulcerative colitis (UC), is increasingly prevalent in racial and ethnic minorities. This study was undertaken to characterize racial differences in disease phenotype in a predominantly adult population. Phenotype data on 830 non-Hispanic white, 127 non-Hispanic African American, and 169 Hispanic IBD patients, recruited from six academic centers, were abstracted from medical records and compiled in the NIDDK-IBD Genetics Consortium repository. We characterized racial differences in family history, disease location and behavior, surgical history, and extraintestinal manifestations (EIMs) using standardized definitions. African American CD patients were more likely than whites to develop esophagogastroduodenal CD (OR = 2.8; 95% CI: 1.4-5.5), colorectal disease (OR = 1.9; 95% CI: 1.1-3.4), perianal disease (OR = 1.7; 95% CI: 1.03-2.8), but less likely to have ileal involvement (OR = 0.55; 95% CI: 0.32-0.96). They were also at higher risk for uveitis (OR = 5.5; 95% CI: 2.3-13.0) and sacroiliitis (OR = 4.0; 95% CI: 1.55-10.1). Hispanics had higher prevalence of perianal CD (OR = 2.9; 95% CI: 1.8-4.6) and erythema nodosum (3.3; 95% CI: 1.7-6.4). Among UC patients, Hispanics had more proximal disease extent. Both African American and Hispanic CD patients, but not UC patients, had lower prevalences of family history of IBD than their white counterparts. There are racial differences in IBD family history, disease location, and EIMs that may reflect underlying genetic variations and have important implications for diagnosis and management of disease. These findings underscore the need for further studies in minority populations.
Clinical Gastroenterology and Hepatology the Official Clinical Practice Journal of the American Gastroenterological Association, Jan 7, 2006
Onercept is a recombinant, soluble human p55 receptor to tumor necrosis factor-alpha. A randomize... more Onercept is a recombinant, soluble human p55 receptor to tumor necrosis factor-alpha. A randomized, double-blind, placebo-controlled, dose-ranging trial was performed to evaluate the efficacy of onercept induction therapy in patients with Crohn&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (CD). Patients (n = 207) with moderate-to-severe acute or chronic active CD were randomized to receive subcutaneous onercept (10, 25, 35, or 50 mg) or placebo 3 times weekly for 8 weeks. Primary analysis was induction of remission (defined as a CD activity index score &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; or = 150) at week 8. A total of 104 patients had acute active CD. Remission rates at week 8 were 23.5% for placebo (n = 17), and 34.8%, 20.0%, 26.1%, and 28.6% for onercept 10 mg (n = 23), 25 mg (n = 20), 35 mg (n = 23), and 50 mg (n = 21), respectively (P = .98). A total of 103 patients had chronic active CD. Remission rates at week 8 were 23.8% for placebo (n = 21), and 23.8%, 9.1%, 35.3%, and 13.6% for onercept 10 mg (n = 21), 25 mg (n = 22), 35 mg (n = 17), and 50 mg (n = 22), respectively (P = .66). There were no differences between treatment groups in the incidence of adverse events. However, mild-to-moderate injection-site reactions occurred in up to 12% of onercept-treated patients. Onercept was well tolerated but was not effective at the doses studied in patients with active CD.
ABSTRACT The IBD5 locus is a genetic risk factor for IBD, particularly Crohn&#39;s Disease, c... more ABSTRACT The IBD5 locus is a genetic risk factor for IBD, particularly Crohn&#39;s Disease, coding for the organic cation/carnitine transporters (OCTN1 and 2). Two variants of OCTN are associated with susceptibility to Crohn&#39;s Disease. Modified transport of carnitine in vitro has been reported for a polymorphism of OCTN1. The aim was to investigate the function of intestinal OCTNs in IBD in relation to genetic polymorphisms. Intestinal tissue was obtained from endoscopic biopsies and surgical resections from IBD patients (n=33 and 14, resp.) and controls (n=22 and 14, resp.). OCTN protein levels were measured in intestinal biopsies and carnitine transport was quantified in intestinal resections. OCTN1 protein levels were significantly higher in ileal versus colonic tissue (2.95% ± 0.4 vs 0.66% ± 0.2, resp.; p&lt;0.0002). OCTN1 expression was higher in Crohn&#39;s disease patients with mutant homozygous or heterozygous genotypes (0.6% ± 0.1 vs 3% ± 0.8, resp., p&lt;0.02). Carnitine transport was very rapid and Na+ dependent (10s). It was not different comparing Crohn&#39;s Disease and control groups (0.45 ± 0.12 vs 0.51 ± 0.12 nM carnitine/mg prot/min, resp.). Carnitine transport tended to be higher in subjects with mutant homozygous and heterozygous OCTN1 and OCTN2 genotypes (0.19 vs 0.59 and 0.25 vs 0.6, respectively). The present data reveal that OCTN protein levels appear to be similar in intestinal tissue from Crohn&#39;s Disease patients and controls. Overall, ileal carnitine transport appears to as well equal in Crohn&#39;s Disease and control groups. However, there was a trend towards higher carnitine transport in subjects with OCTN1 and OCTN2 mutations.
Inflammatory bowel disease (IBD), comprising primarily of Crohn's disease (CD) and ulcerative... more Inflammatory bowel disease (IBD), comprising primarily of Crohn's disease (CD) and ulcerative colitis (UC), is increasingly prevalent in racial and ethnic minorities. This study was undertaken to characterize racial differences in disease phenotype in a predominantly adult population. Phenotype data on 830 non-Hispanic white, 127 non-Hispanic African American, and 169 Hispanic IBD patients, recruited from six academic centers, were abstracted from medical records and compiled in the NIDDK-IBD Genetics Consortium repository. We characterized racial differences in family history, disease location and behavior, surgical history, and extraintestinal manifestations (EIMs) using standardized definitions. African American CD patients were more likely than whites to develop esophagogastroduodenal CD (OR = 2.8; 95% CI: 1.4-5.5), colorectal disease (OR = 1.9; 95% CI: 1.1-3.4), perianal disease (OR = 1.7; 95% CI: 1.03-2.8), but less likely to have ileal involvement (OR = 0.55; 95% CI: 0.32...
... Review Intestinal tight junctions and their importance in health and disease: role of dietary... more ... Review Intestinal tight junctions and their importance in health and disease: role of dietary lipids G. Wild, K. Madsen,* and ABR ... well, the cytoskeleton may participate in such mechanisms .23 On activation, PLC converts PIP2 into IP3 (1,4,5triphosphate) and diacylglycerol (DAG). ...
BACKGROUND/OBJECTIVES: Since the first use of azathioprine (AZA) in the treatment of chronic ulce... more BACKGROUND/OBJECTIVES: Since the first use of azathioprine (AZA) in the treatment of chronic ulcerative colitis (UC), there have been several open studies reporting benefit but few controlled trials. The aim of this study was to compare the efficacy of AZA and oral 5-ASA in the treatment of steroid-dependent UC.METHODS:52 patients with steroid-dependent UC (29F, 23M, mean age 42, range 18-72), were admitted to this investigator blind study. Steroiddependence was defined as a requirement of steroid therapy at -> 10 mg/day during the preceding 6 months, with at least 2 attempts to discontinue the medication. The disease had to be clinically and endoscopicelly active at study entry, and all patients were taking systemic prednisolone (40 mg/day). Patients were randomised to receive AZA 2 mg/Kg/day or oral 5-ASA 3.2 g/day, for a 6-month follow-up period. Clinical and endoscopic activity was monitored by PowelI-Tuck and Baron indeces, respectively. Physician Global Assessment (PGA)(from 1 = very much improved to 6 = much worse) was evaluated after 6 months. The outcome of the treatment was defined as (1) success = induction of clinical and endoscopic remission and steroid discontinuation, (2) failure = need of at least 1 further cycle of systemic steroids to control symptoms, apart from that initial one or colectomy. RESULTS: 27 patients were treated wit AZA and 25 with 5-ASA.3 patients (1 in AZA and 2 in 5-ASA group) were lost to follow-up. After 6 months, significantly more patients in the AZA than in the 5-ASA group obtained success of therapy.Two patients in the AZA and 2 in the 5-ASA treatment groups had colectomy. PGA was b~er in AZA than in 5-ASA treatment at month 6 (AZA vs 5-ASA = 2.84_+1.75 vs 4.21_+1.80, p<O.01). CONCLUSIONS:AZA therapy is significantly more effective than 5-ASA in inducing clinical and endoscopic remission and avoiding steroid requirement in the treatment of steroid-dependent UC. AZA 5-ASA Success Failure 15 (58 %) 6 (26 %) 11 (42%} 17/74%) p = 0.042 (Fisher's test) (C1~.5 % -57 %).
Lipid-binding proteins have been identified in the enterocyte, including the cytosolic intestinal... more Lipid-binding proteins have been identified in the enterocyte, including the cytosolic intestinal and liver fatty acid binding proteins (I-FABP and L-FABP, respectively) as well as the brush border membrane fatty acid transporter (FAT). It is unclear whether variations in the type of dietary lipids or diabetes modify the RNA abundance of these proteins. Diabetes is associated with an increased intestinal lipid uptake, and the lipid uptake is greater in rats fed a semisynthetic saturated fatty acid (SFA) as compared with a polyunsaturated fatty acid (PUFA) diet. Male Sprague-Dawley rats were injected with streptozotocin or control vehicle and fed chow or either SFA or PUFA for 2 weeks. Northern blotting was performed on RNA isolated from jejunal and ileal tissues. In controls, feeding SFA as compared with PUFA reduced the jejunal abundance of I-FABP and L-FABP RNA. In diabetic rats, feeding SFA increased the ileal FAT RNA. Feeding PUFA reduced jejunal L-FABP and ileal FAT RNA in diabetic rats as compared with controls. The enhanced lipid uptakes reported with feeding an SFA diet or with diabetes were not associated with parallel alterations in lipid-binding proteins. We speculate that these lipid-binding proteins act as a storage mechanism for lipids in enterocytes and are not directly involved in lipid uptake.
Onercept is a recombinant, soluble human p55 receptor to tumor necrosis factor-alpha. A randomize... more Onercept is a recombinant, soluble human p55 receptor to tumor necrosis factor-alpha. A randomized, double-blind, placebo-controlled, dose-ranging trial was performed to evaluate the efficacy of onercept induction therapy in patients with Crohn&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (CD). Patients (n = 207) with moderate-to-severe acute or chronic active CD were randomized to receive subcutaneous onercept (10, 25, 35, or 50 mg) or placebo 3 times weekly for 8 weeks. Primary analysis was induction of remission (defined as a CD activity index score &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; or = 150) at week 8. A total of 104 patients had acute active CD. Remission rates at week 8 were 23.5% for placebo (n = 17), and 34.8%, 20.0%, 26.1%, and 28.6% for onercept 10 mg (n = 23), 25 mg (n = 20), 35 mg (n = 23), and 50 mg (n = 21), respectively (P = .98). A total of 103 patients had chronic active CD. Remission rates at week 8 were 23.8% for placebo (n = 21), and 23.8%, 9.1%, 35.3%, and 13.6% for onercept 10 mg (n = 21), 25 mg (n = 22), 35 mg (n = 17), and 50 mg (n = 22), respectively (P = .66). There were no differences between treatment groups in the incidence of adverse events. However, mild-to-moderate injection-site reactions occurred in up to 12% of onercept-treated patients. Onercept was well tolerated but was not effective at the doses studied in patients with active CD.
Glucagon-like peptide (GLP)-2 enhances nutrient uptake in adult animals. Glucocorticosteroids acc... more Glucagon-like peptide (GLP)-2 enhances nutrient uptake in adult animals. Glucocorticosteroids accelerate intestinal ontogeny and increase nutrient uptake in adult animals. We hypothesized that administering GLP-2 and dexamethasone (DEX) to suckling rats will enhance sugar uptake and that this effect persists into the postweaning period. Suckling rats were treated for 10 days with GLP-2 (0.1 microg/g/d, twice daily), DEX (0.128 microg/g/d, once daily), GLP-2 + Dex (same doses as above), or placebo. The rate of intestinal uptake of glucose and fructose in sucklings (19-21 days old) and weanlings (49 days old) was assessed using an in vitro ring technique. DEX reduced body weight in weanlings, whereas GLP-2 + DEX prevented this effect. In sucklings, GLP-2 + DEX increased ileal villous height and jejunal and ileal villous width and crypt depth. In sucklings, GLP-2 + DEX increased the maximal transport rate (Vmax) for jejunal glucose uptake, whereas DEX reduced the ileal Vmax. In weanlings, GLP-2 + DEX increased jejunal villous height, whereas ileal villous width and crypt depth were reduced. DEX increased the ileal Vmax and apparent affinity constant for glucose in weanlings. The combination of these hormones may be useful in stimulating glucose uptake in the developing intestine, and giving DEX to sucklings may enhance glucose uptake in later life.
Selective blockade of lymphocyte–vascular endothelium interactions in the gastrointestinal tract ... more Selective blockade of lymphocyte–vascular endothelium interactions in the gastrointestinal tract is a promising therapeutic strategy for inflammatory bowel disease. This randomized, double-blind, controlled trial assessed the efficacy and safety of MLN0002, a monoclonal antibody targeting the α4β7 integrin, in patients with active Crohn's disease.Patients were randomized to receive MLN0002 2.0 mg/kg (n = 65), MLN0002 0.5 mg/kg (n = 62), or placebo (n = 58) by intravenous infusion on days 1 and 29. The primary efficacy end point was clinical response (≥70-point decrement in the Crohn's Disease Activity Index [CDAI] score) on day 57. Secondary end points were the proportions of patients with clinical remission (CDAI score ≤150) and with an enhanced clinical response (≥100-point decrement in CDAI). Human anti-human antibody levels were measured.Clinical response rates at day 57 were 53%, 49%, and 41% in the MLN0002 2.0 mg/kg, MLN0002 0.5 mg/kg, and placebo groups. Clinical remission rates at day 57 were 37%, 30%, and 21%, respectively (P = .04 for the 2.0 mg/kg vs placebo comparison). At day 57, 12% and 34% of patients in the 2.0- and 0.5-mg/kg groups had clinically significant human anti-human antibody levels (titers > 1:125). There was one infusion-related hypersensitivity reaction. The most common serious adverse event was worsening of Crohn's disease.This phase 2 study was suggestive of a dose-dependent beneficial effect of MLN0002 therapy on clinical remission. MLN0002 was well tolerated in patients with active Crohn's disease.
In the past year there have been many advances in the area of small bowel physiology and patholog... more In the past year there have been many advances in the area of small bowel physiology and pathology and therapy. In preparation for this review, over 1500 papers were assessed. The focus is on presenting clinically useful information for the practicing gastroenterologist. Selected important clinical learning points include the following: (1) glutamine may restore the AIDs-associated increased intestinal permeability to normal; (2) substance P is a major mediator of diarrhea caused by Costridium difficile toxin A, acting by binding to a G-proteincoupled receptor, and represents a possible 2therapeutic target; (3) the serological diagnosis of celiac disease has been greatly enhanced with the use of anti-endomysial antibody testing, and the recent antitransglutaminase; (4) a quarter of patients with celiac disease may have secondary pancreatic insufficiency and require enzyme replacement therapy; (5) in the patient with unexplained elevation in the serum transaminase concentration, consider celiac disease as an obscure possibility; (6) bosentan and endothelin receptor agonist may prove to be useful in reducing gut ischemia in patients with septic shock; and (7) the administration of recombinant human fibroblast growth factor-2 may prove to be useful to prevent radiation damage to the gastrointestinal tract.
In the past 18 months there have been many advances in the areas of small bowel physiology, patho... more In the past 18 months there have been many advances in the areas of small bowel physiology, pathology, and clinical management. In preparation for this three part review, over 1000 papers were assessed; some have been selected and reviewed here, with a focus on presenting clinically useful information for the practicing gastroenterologist. This is new material which represents a rolling review, an update on advances in the small bowel and physiology and pathology since last reviewed and published in Digestive
The aim of this study was to identify determinants of nonadherence to medication in outpatients w... more The aim of this study was to identify determinants of nonadherence to medication in outpatients with established inflammatory bowel disease (IBD). Ten gastroenterologists and 153 of their IBD patients participated in this prospective study. Demographic, clinical, and psychosocial characteristics, as well as patient-physician discordance, were assessed at an office visit. Nonadherence to medication was assessed 2 wk later. Separate generalized estimating equations were used to identify determinants of nonadherence. Physicians averaged 47.9 yr in age (range 30.1-57.5 yr), and 90% were male. Patients averaged 37.0 yr (SD = 15.1), and 87 (56.9%) were female. In all, 63 patients (41.2%) were nonadherent to medication; of these, 51 (81.0%) indicated unintentional nonadherence, 23 (36.5%) intentional nonadherence, and 11 (17.5%) both. Overall nonadherence was predicted by disease activity (OR = 0.55, p = 0.0022), new patient status (OR = 2.14, p = 0.0394), disease duration (OR = 0.50, p = ...
The aim of this study was to identify the independent psychosocial correlates of patient-physicia... more The aim of this study was to identify the independent psychosocial correlates of patient-physician discordance in adult outpatients with inflammatory bowel disease. This cross-sectional study was conducted in three university-affiliated tertiary care settings. Psychological distress, social support, perceived stress, and negative life events were assessed, as were demographic, lifestyle, and clinical characteristics. Patient-physician discordance was assessed with 10-item questionnaires. Ten gastroenterologists and 200 of their patients participated. Patients and their physicians disagreed most on discussion of personal issues. Patients with Crohn's disease had statistically significantly higher discordance on disease activity and physical limitation, as well as higher average overall discordance scores than patients with ulcerative colitis. Mean discordance levels were similar across different physicians. Higher psychological distress and more perceived stress were independentl...
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Papers by Gary Wild