Crohn's disease is a chronic inflammatory disorder of the gastrointestinal tract, which is thought to result from the effect of environmental factors in a genetically predisposed host. A gene location in the pericentromeric region of chromosome 16, IBD1, that contributes to susceptibility to Crohn's disease has been established through multiple linkage studies, but the specific gene(s) has not been identified. NOD2, a gene that encodes a protein with homology to plant disease resistance gene products is located in the peak region of linkage on chromosome 16 (ref. 7). Here we show, by using the transmission disequilibium test and case-control analysis, that a frameshift mutation caused by a cytosine insertion, 3020insC, which is expected to encode a truncated NOD2 protein, is associated with Crohn's disease. Wild-type NOD2 activates nuclear factor NF-kappaB, making it responsive to bacterial lipopolysaccharides; however, this induction was deficient in mutant NOD2. These results implicate NOD2 in susceptibility to Crohn's disease, and suggest a link between an innate immune response to bacterial components and development of disease.

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A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease

Increasing Incidence and Prevalence of the Inflammatory Bowel Diseases With Time, Based on Systematic Review

https://www.ualberta.ca/~loewen/Medicine/GIM%20Residents%20Core%20Reading/IBD,%20CROHN'S%20AND%20U.C/accent%20i%20trial.pdf

Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial

Vertebrates achieve internal homeostasis during infection or injury by balancing the activities of proinflammatory and anti-inflammatory pathways. Endotoxin (lipopolysaccharide), produced by all gram-negative bacteria, activates macrophages to release cytokines that are potentially lethal. The central nervous system regulates systemic inflammatory responses to endotoxin through humoral mechanisms. Activation of afferent vagus nerve fibres by endotoxin or cytokines stimulates hypothalamic-pituitary-adrenal anti-inflammatory responses. However, comparatively little is known about the role of efferent vagus nerve signalling in modulating inflammation. Here, we describe a previously unrecognized, parasympathetic anti-inflammatory pathway by which the brain modulates systemic inflammatory responses to endotoxin. Acetylcholine, the principle vagal neurotransmitter, significantly attenuated the release of cytokines (tumour necrosis factor (TNF), interleukin (IL)-1beta, IL-6 and IL-18), but not the anti-inflammatory cytokine IL-10, in lipopolysaccharide-stimulated human macrophage cultures. Direct electrical stimulation of the peripheral vagus nerve in vivo during lethal endotoxaemia in rats inhibited TNF synthesis in liver, attenuated peak serum TNF amounts, and prevented the development of shock.

Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin

Background Infliximab, a chimeric monoclonal antibody directed against tumor necrosis factor α, is an established treatment for Crohn's disease but not ulcerative colitis. Methods Two randomized, double-blind, placebo-controlled studies — the Active Ulcerative Colitis Trials 1 and 2 (ACT 1 and ACT 2, respectively) — evaluated the efficacy of infliximab for induction and maintenance therapy in adults with ulcerative colitis. In each study, 364 patients with moderate-to-severe active ulcerative colitis despite treatment with concurrent medications received placebo or infliximab (5 mg or 10 mg per kilogram of body weight) intravenously at weeks 0, 2, and 6 and then every eight weeks through week 46 (in ACT 1) or week 22 (in ACT 2). Patients were followed for 54 weeks in ACT 1 and 30 weeks in ACT 2. Results In ACT 1, 69 percent of patients who received 5 mg of infliximab and 61 percent of those who received 10 mg had a clinical response at week 8, as compared with 37 percent of those who received placebo (P<0...

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Infliximab for induction and maintenance therapy for ulcerative colitis.

The formation of calcium oxalate (CaOx) kidney stones is extremely common, 1 and evidence suggests that minimal, perhaps transient, elevations in urinary oxalate concentration may be important factors in at least a subgroup of these patients with ‘idiopathic’ CaOx urolithiasis. 2 In the case of enteric hyperoxaluria, the pathogenic role of oxalate is clear, and renal scarring can also be observed as a consequence of oxalate exposure and CaOx crystal deposition. 3–6 Unfortunately, few satisfactory specific treatments for hyperoxaluria are available. Dietary restriction is commonly advised, but is difficult for patients to follow effectively without extensive education, in part because oxalate content is not listed on food labels. 7 Typical treatment strategies for enteric hyperoxaluria also include low-fat diets to limit malabsorption and effects of fatty acids and bile acids on oxalate absorption in the distal colon, 8,9 oral calcium to bind oxalate, 10 and bile acid sequestrants such as cholestyramine. 8,11 These more intensive strategies have not been widely employed for patients with CaOx stones and, even if effective, they do not seem likely to be accepted by the majority of patients with mild hyperoxaluria and idiopathic CaOx stone disease. Previous studies have shown that components of the endogenous digestive microbiota can utilize oxalate, potentially limiting its absorption from the intestinal lumen. 12 A recent preliminary study demonstrated that a preparation of lactic acid bacteria degraded oxalate in vitro and reduced urinary oxalate excretion when given by mouth. 13 We previously demonstrated that the same preparation of lactic acid bacilli (Oxadrop, VSL Pharmaceuticals, Gaithersburg, MD, USA) can reduce urinary oxalate excretion in patients with enteric hyperoxaluria. 14 Agri-King Synbiotic (AKSB) is a candidate synbiotic preparation extensively studied at Mayo Clinic that might have beneficial effects on gastrointestinal health, although there is no evidence it should influence oxalate metabolism directly. In this study, we tested the effect of these two preparations on oxalate excretion in subjects

Diet, but not oral probiotics, effectively reduces urinary oxalate excretion and calcium oxalate

Collagenous and lymphocytic colitis: subject review and therapeutic alternatives.

Background We sought to identify clinical and demographic features influencing hospitalization and colectomy in a population-based inception cohort of ulcerative colitis. Methods Between 1970 and 2004, a total of 369 patients (58.5% males) from Olmsted County, MN, were followed from diagnosis for 5401 person-years. The cumulative probability of hospitalization and colectomy were estimated using the Kaplan-Meier method. Cox proportional hazards regression was used to identify factors associated with hospitalization and colectomy. Results The cumulative probability of first hospitalization was 29.4% at 5 years (95% confidence interval [CI], 24.5%-34.1%), 38.7% at 10 years (33.1%-43.8%), 49.2% at 20 years (42.7%-55.2%), and 52.3% at 30 years (45.1%-59.7%). The incidence rate of hospitalizations decreased over the last 4 decades, although cumulative probability of first hospitalization increased with successive decades of diagnosis. Early need for corticosteroids (hazard ratio [HR], 1.8; 95% CI, 1.1%-2.7%) and early need for hospitalization (HR, 1.5; 95% CI, 1.02-2.4) were independent predictors of hospitalization after 90 days of illness. The cumulative probability of colectomy from the time of diagnosis was 13.1% at 5 years (95% CI, 9.4%-16.6%), 18.9% at 10 years (95% CI, 14.4%-23.2%), and 25.4% at 20 years (95% CI, 19.8%-30.8%). Male gender (HR, 2.1; 95% CI, 1.3-3.5), diagnosis in the 1990s (HR, 2.0; 95% CI, 1.01-4.0), and diagnosis in 2000 to 2004 (HR, 3.7; 95% CI, 1.7-8.2) were significantly associated with colectomy risk. Conclusions Colectomy rates were comparable to reports from northern Europe. The numbers of hospitalizations show a decreasing trend. Male gender and being diagnosed in the 2000 to 2004 period predicted colectomy while extensive colitis predicted future hospitalizations.

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Cumulative incidence and risk factors for hospitalization and surgery in a population-based cohort of ulcerative colitis

Internal fistulas occur in 5-10% of patients with Crohn's disease. The clinical presentation of each of the three main types of internal fistulas--enteroenteric, enterovaginal, and enterovesical fistulas--is important in determining the best management. Asymptomatic fistulas usually require no treatment, but fistulas that cause severe or persistent symptoms necessitate intervention. Previously regarded as a surgical condition requiring resection, some internal fistulas are amenable to a more conservative approach involving medical therapy, surgical repair, or both. So far, there have not been any prospective studies designed specifically to assess the efficacy of a medical treatment of internal fistulas, and information about treatment results is gleaned from trials in which patients with internal fistulas have been included and from retrospective reports. Drugs that have been reported to close internal fistulas partially or completely include azathioprine, 6-mercaptopurine, mycophenolate mofetil, cyclosporine A, tacrolimus, and infliximab. Reparative surgical techniques include transrectal and transvaginal mucosal advancement flaps, cutaneous advancement flap, and anal stricturectomy in combination with a rectal mucosal advancement sleeve. Prospective trials of medical therapy and combination medical and surgical therapy for internal fistulas are needed to provide evidence to support the use of these new therapeutic approaches.

William J. Tremaine

Papers

Diet, but not oral probiotics, effectively reduces urinary oxalate excretion and calcium oxalate

Collagenous and lymphocytic colitis: subject review and therapeutic alternatives.

Cumulative incidence and risk factors for hospitalization and surgery in a population-based cohort of ulcerative colitis

Management of internal fistulas in Crohn's disease.

Budesonide CIR capsules (once or twice daily divided-dose) in active Crohn's disease: a randomized placebo-controlled study in the United States.