Factors Associated with Anxiety About Colonoscopy: The Preparation, the Procedure, and the Anticipated Findings.

BACKGROUND: Previous research has assessed anxiety around colonoscopy procedures, but has not considered anxiety related to different aspects related to the colonoscopy process. AIMS: Before colonoscopy, we assessed anxiety about: bowel preparation, the procedure, and the anticipated results. We evaluated associations between patient characteristics and anxiety in each area. METHODS: An anonymous survey was distributed to patients immediately prior to their outpatient colonoscopy in six hospitals and two ambulatory care centers in Winnipeg, Canada. Anxiety was assessed using a visual analog scale. For each aspect, logistic regression models were used to explore associations between patient characteristics and high anxiety. RESULTS: A total of 1316 respondents completed the questions about anxiety (52% female, median age 56 years). Anxiety scores > 70 (high anxiety) were reported by 18% about bowel preparation, 29% about the procedure, and 28% about the procedure results. High anxiety about bowel preparation was associated with female sex, perceived unclear instructions, unfinished laxative, and no previous colonoscopies. High anxiety about the procedure was associated with female sex, no previous colonoscopies, and confusing instructions. High anxiety about the results was associated with symptoms as an indication for colonoscopy and instructions perceived as confusing. CONCLUSIONS: Fewer people had high anxiety about preparation than about the procedure and findings of the procedure. There are unique predictors of anxiety about each colonoscopy aspect. Understanding the nuanced differences in aspects of anxiety may help to design strategies to reduce anxiety, leading to improved acceptance of the procedure, compliance with preparation instructions, and less discomfort with the procedure.

Markedly increased incidence of critical illness in adults with Type 1 diabetes.

AIMS: To compare the incidence of and mortality after intensive care unit admission in adults with paediatric-onset Type 1 diabetes vs the general population. METHODS: Using population-based administrative data from Manitoba, Canada, we identified 814 cases of paediatric-onset Type 1 diabetes, and 3579 general population controls matched on age, sex and region of residence. We estimated the incidence of intensive care unit admission in adulthood, and compared the findings between populations using incidence rate ratios and multivariable Cox proportional hazards regression, adjusting for age, sex, comorbidity and socio-economic status. We estimated age- and sex-standardized mortality rates after intensive care unit admission. RESULTS: Between January 2000 and October 2009, the average annual incidence of intensive care unit admission among prevalent cohorts was 910 per 100 000 in the Type 1 diabetes population, and 106 per 100 000 in matched controls, an eightfold increased risk (incidence rate ratio 8.6; 95% CI 5.5, 14.0). The adjusted risk of intensive care unit admission was elevated to a greater extent among women with Type 1 diabetes compared with matched women (hazard ratio 14.7; 95% CI 7.2, 29.4) than among men with Type 1 diabetes compared with matched men (hazard ratio 4.92; 95% CI 10.3, 2.36) The most common reasons for admission in the diabetes cohort were diabetic ketoacidosis, infection and ischaemic heart disease. At 30%, 5-year mortality was higher in the diabetes cohort than in the matched cohort (relative risk 5.7; 95% CI 1.2, 8.9). CONCLUSIONS: Compared with the general population, the risk of intensive care unit admission was higher in adults with paediatric-onset Type 1 diabetes, and mortality after admission was also higher.

Endoscopic and chemopreventive management of familial adenomatous polyposis syndrome.

Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome predisposing affected individuals to gastrointestinal (GI) cancers through a high burden of polyposis. Colorectal cancer rates reach 100% by the age of 45, making early colectomy a mainstay of treatment. While most patients undergo colectomy at an early age, ongoing screening and surveillance of the upper gastrointestinal tract and rectal pouch must continue throughout adulthood. Endoscopic therapy of gastric, duodenal, ampullary and rectal pouch polyps is critical to reduce morbidity and cancer related mortality. Management of these lesions is not uniform, and is dependent on their location, size, histology, and risk of malignant potential. Medical therapies targeting pathways that reduce the malignant progression of pre-cancerous lesions have been studied for many years. While studies on the use of aspirin and non-steroidal anti-inflammatories (NSAIDs) in chemoprevention have shown encouraging results in Lynch syndrome and primary colorectal cancer, the potential benefits of these medications have not been duplicated in FAP cohorts. While data remains limited on chemoprevention in FAP, a number of randomized trials are currently underway examining targeted therapies with the potential to slow the progression of the disease. This review aims to provide an in-depth review of the literature on current endoscopic options and chemopreventive therapies targeting FAP. While the endoscopic management has robust data for its use, chemoprevention in FAP is still in its infancy. The complementary use of chemopreventive agents and endoscopic therapy for FAP patients is quickly becoming a growing and exciting area of research.

Non-HLA genes modulate the risk of rheumatoid arthritis associated with HLA-DRB1 in a susceptible North American Native population.

Most of the genetic risk for rheumatoid arthritis (RA) is conferred by 'shared epitope' (SE), encoding alleles of HLA-DRB1. Specific North American Native (NAN) populations have RA prevalence rates of 2-5%, representing some of the highest rates estimated worldwide. As many NAN populations also demonstrate a high background frequency of SE, we sought to determine whether other genetic factors contribute to disease risk in this predisposed population. RA patients (n=333) and controls (n=490) from the Cree/Ojibway NAN population in Central Canada were HLA-DRB1 typed and tested for 21 single-nucleotide polymorphisms (SNPs) that have previously been associated with RA, including PTPN22, TRAF1-C5, CTLA4, PADI4, STAT4, FCRL3, CCL21, MMEL1-TNFRSF14, CDK6, PRKCQ, KIF5A-PIP4K2C, IL2RB, TNFAIP3, IL10-1082G/A and REL. Our findings indicate that SE is prevalent and represents a major genetic risk factor for RA in this population (82% cases versus 68% controls, odds ratio=2.2, 95% confidence interval 1.6-3.1, P<0.001). We also demonstrate that in the presence of SE, the minor allele of MMEL1-TNFRSF14 significantly reduces RA risk in a dominant manner, whereas TRAF1-C5 increases the risk. These findings point to the importance of non-HLA genes in determining RA risk in a population with a high frequency of disease predisposing HLA-DRB1 alleles.

Does conventional early life academic excellence predict later life scientific discovery? An assessment of the lives of great medical innovators.

BACKGROUND: Perhaps, as never before, we need innovators. With our growing population numbers, and with increasing pressures on our education systems, are we in danger of becoming more rigid and formulaic and increasingly inhibiting innovation? When young can we predict who will become the great innovators? For example, in medicine, who will change clinical practice? AIMS: We therefore determined to assess whether the current academic excellence approach to medical school entrance would have captured previous great innovators in medicine, assuming that they should all have well fulfilled current entrance requirements. METHODS: The authors assembled a list of 100 great medical innovators which was then approved, rejected or added to by a jury of 12 MD fellows of the Royal Society of Canada. Two reviewers, who had taken both the past and present Medical College Admission Test as part of North American medical school entrance requirements, independently assessed each innovator's early life educational history in order to predict the innovator's likely success at medical school entry, assuming excellence in all entrance requirements. RESULTS: Thirty-one percent of the great medical innovators possessed no medical degree and 24% would likely be denied entry to medical school by today's standards (e.g. had a history of poor performance, failure, dropout or expulsion) with only 24% being guaranteed entry. Even if excellence in only one topic was required, the figure would only rise to 41% certain of medical school entry. CONCLUSION: These data show that today's medical school entry standards would have barred many great innovators and raise questions about whether we are losing medical innovators as a consequence. Our findings have important implications for promoting flexibility and innovation for medical education, and for promoting an environment for innovation in general.

Detecting colorectal cancer by 1H magnetic resonance spectroscopy of fecal extracts.

Colorectal cancer is one of the most common cancers in the western world. Its early detection has been found to improve the prognosis of the patient, providing a wide window of opportunity for successful therapeutic interventions. However, current diagnostic techniques all have some limitations; there is a need to develop a better technique for routine screening purposes. We present a new methodology based on magnetic resonance spectroscopy of fecal extracts for the non-invasive detection of colorectal cancer. Five hundred twenty-three human subjects (412 with no colonic neoplasia and 111 with colorectal cancer, who were scheduled for colonoscopy or surgery) were recruited to donate a single sample of stool. One-dimensional (1)H magnetic resonance spectroscopy (MRS) experiments were performed on the supernatant of aqueous dispersions of the stool samples. Using a statistical classification strategy, several multivariate classifiers were developed. Applying the preprocessing, feature selection and classifier development stages of the Statistical Classification Strategy led to approximately 87% average balanced sensitivity and specificity for both training and monitoring sets, improving to approximately 92% when only crisp results, i.e. class assignment probabilities > or =75%, are considered. These results indicate that (1)H magnetic resonance spectroscopy of human fecal extracts, combined with appropriate data analysis methodology, has the potential to detect colorectal neoplasia accurately and reliably, and could be a useful addition to the current screening tools.

Canadian Association of Gastroenterology Clinical Practice Guidelines: The use of tumour necrosis factor-alpha antagonist therapy in Crohn's disease.

BACKGROUND: Guidelines regarding the use of infliximab in Crohn's disease were previously published by the Canadian Association of Gastroenterology in 2004. However, recent clinical findings and drug developments warrant a review and update of these guidelines. OBJECTIVE: To review and update Canadian guidelines regarding the use of tumour necrosis factor-alpha antibody therapy in both luminal and fistulizing Crohn's disease. METHODS: A consensus group of 25 voting participants developed a series of recommendation statements that addressed pertinent clinical questions and gaps in existing knowledge. An iterative voting and feedback process was used in advance of the consensus meeting in conjunction with a systematic literature review to refine the voting statements. These statements were brought to a formal consensus meeting held in Montreal, Quebec (March 2008), wherein each statement underwent discussion, reformulation, voting and subsequent revision until group consensus was obtained (at least 80% agreement). OUTCOME: The 47 voting statements addressed three themes: induction therapy, maintenance therapy and safety issues. As a result of the iterative process, 23 statements achieved consensus and were submitted for publication. CONCLUSION: In the past five years, tumour necrosis factor-alpha antagonist therapy has become a cornerstone in the management of moderate-to-severe Crohn's disease refractory to conventional treatment algorithms. The evidentiary base supporting the use of these drugs in Crohn's disease is substantial and strengthened by results from longterm clinical and molecular studies. However, significant gaps in knowledge exist, particularly with regard to treatment failure. Confidence in the safety of these drugs is increasing, provided that therapy is administered in a clinical setting in which potential complications can be readily recognized and treated.

Rising incidence of psychiatric disorders before diagnosis of immune-mediated inflammatory disease.

AIMS: After the diagnosis of immune-mediated inflammatory diseases (IMID) such as inflammatory bowel disease (IBD), multiple sclerosis (MS) and rheumatoid arthritis (RA), the incidence of psychiatric comorbidity is increased relative to the general population. We aimed to determine whether the incidence of psychiatric disorders is increased in the 5 years before the diagnosis of IMID as compared with the general population. METHODS: Using population-based administrative health data from the Canadian province of Manitoba, we identified all persons with incident IBD, MS and RA between 1989 and 2012, and cohorts from the general population matched 5 : 1 on year of birth, sex and region to each disease cohort. We identified members of these groups with at least 5 years of residency before and after the IMID diagnosis date. We applied validated algorithms for depression, anxiety disorders, bipolar disorder, schizophrenia, and any psychiatric disorder to determine the annual incidence of these conditions in the 5-year periods before and after the diagnosis year. RESULTS: We identified 12 141 incident cases of IMID (3766 IBD, 2190 MS, 6350 RA) and 65 424 matched individuals. As early as 5 years before diagnosis, the incidence of depression [incidence rate ratio (IRR) 1.54; 95% CI 1.30-1.84) and anxiety disorders (IRR 1.30; 95% CI 1.12-1.51) were elevated in the IMID cohort as compared with the matched cohort. Similar results were obtained for each of the IBD, MS and RA cohorts. The incidence of bipolar disorder was elevated beginning 3 years before IMID diagnosis (IRR 1.63; 95% CI 1.10-2.40). CONCLUSION: The incidence of psychiatric comorbidity is elevated in the IMID population as compared with a matched population as early as 5 years before diagnosis. Future studies should elucidate whether this reflects shared risk factors for psychiatric disorders and IMID, a shared final common inflammatory pathway or other aetiology.

An SNP linkage scan identifies significant Crohn's disease loci on chromosomes 13q13.3 and, in Jewish families, on 1p35.2 and 3q29.

Inflammatory bowel disease (IBD) is a complex genetic disorder of two major phenotypes, Crohn's disease (CD) and ulcerative colitis (UC), with increased risk in Ashkenazi Jews. Twelve genome-wide linkage screens have identified multiple loci, but these screens have been of modest size and have used low-density microsatellite markers. We, therefore, performed a high-density single-nucleotide polymorphism (SNP) genome-wide linkage study of 993 IBD multiply affected pedigrees (25% Jewish ancestry) that contained 1709 IBD-affected relative pairs, including 919 CD-CD pairs and 312 UC-UC pairs. We identified a significant novel CD locus on chromosome 13p13.3 (peak logarithm of the odds (LOD) score=3.98) in all pedigrees, significant linkage evidence on chromosomes 1p35.1 (peak LOD score=3.5) and 3q29 (peak LOD score=3.19) in Jewish CD pedigrees, and suggestive loci for Jewish IBD on chromosome 10q22 (peak LOD score=2.57) and Jewish UC on chromosome 2q24 (peak LOD score=2.69). Nominal or greater linkage evidence was present for most previously designated IBD loci (IBD1-9), notably, IBD1 for CD families at chromosome 16q12.1 (peak LOD score=4.86) and IBD6 in non-Jewish UC families at chromosome 19p12 (peak LOD score=2.67). This study demonstrates the ability of high information content adequately powered SNP genome-wide linkage studies to identify loci not observed in multiple microsatellite-based studies in smaller cohorts.

Review and clinical perspectives for the use of infliximab in ulcerative colitis.

Infliximab is a chimeric, monoclonal anti-tumour necrosis factor-alpha antibody. It has been previously demonstrated to be an effective treatment for patients with Crohn's disease who do not achieve the desired response with conventional treatments. Although the etiology of ulcerative colitis (UC) differs from that of Crohn's disease, randomized controlled trials have demonstrated that infliximab is also beneficial for the treatment of moderate to severe UC in patients who are either intolerant of or refractory to immunosuppressant agents or steroids, or those who are steroid-dependent. A review of the literature is followed by practical recommendations regarding infliximab that address the needs of clinicians and UC patients. Where there is a lack of evidence-based information, the expert panel provides its combined opinion derived from the members' clinical experiences.

Independent Validation of a Self-Report Version of the IBD Disability Index (IBDDI) in a Population-Based Cohort of IBD Patients.

Introduction: A new clinician-administered inflammatory bowel disease (IBD) Disability Index (IBDDI) was recently developed and validated among a population in France. We aimed to validate the IBDDI in a North American setting and adapt for use as a self-report tool. Methods: Persons 18-65 years old from the population-based University of Manitoba IBD Research Registry were mailed a self-administered survey. This survey included the IBDDI and several scales that should correlate with a disability measure- the World Health Organization (WHO) Disability Assessment Scale (WHODAS) 2.0, Work and Social Adjustment Scale (WSAS), the Inflammatory Bowel Disease Questionnaire (IBDQ), and the K6-Kessler Emotional Distress Scale. We used Pearson correlation coefficients to assess construct validity, Cronbach's alpha to assess internal consistency, and Factor analysis to assess which of the IBDDI items likely belonged to a single IBD-related disability factor. Results: In response to the survey request,1143 (46% of those contacted) participated (61% female, mean age 51, 52% with Crohn's disease). On an index scale from 0-100, 14% had a score ≥50 (extreme disability, 18% of those with Crohn's disease; 10% of those with ulcerative colitis). There were strong correlations between IBDDI and WSAS (0.76), WHODAS (0.76), K6 (0.73), and an inverse correlation with IBDQ (-0.86). The Cronbach's alpha was high (0.88). All but 2 items (number of liquid stools in the past week and arthritis/arthralgia) of the 14 identified for IBDDI loaded highly onto a single factor (factor loading > 0.40). Conclusions: The findings support the validity of this new self-report version of the IBDDI as a sound measure of disability in IBD.

Predictors of patient reluctance to wake early in the morning for bowel preparation for colonoscopy: a precolonoscopy survey in city-wide practice.

INTRODUCTION: Many endoscopists do not use split-dose bowel preparation (SDBP) for morning colonoscopies. Despite SDBP being recommended practice, they believe patients will not agree to take early morning bowel preparation (BP). We assessed patients' opinions about waking early for BP. METHODS: A self-administered survey was distributed between 08/2015 and 06/2016 to patients in Winnipeg, Canada when they attended an outpatient colonoscopy. Logistic regression was performed to determine predictors of reluctance to use early morning BP. RESULTS: Of the 1336 respondents (52 % female, median age 57 years), 33 % had used SDBP for their current colonoscopy. Of the 1336, 49 % were willing, 24 % neutral, and 27 % reluctant to do early morning BP. Predictors of reluctant versus willing were number of prior colonoscopies (OR 1.20; 95 %CI: 1.07 - 1.35), female gender (OR 1.65; 95 %CI: 1.19 - 2.29), unclear BP information (OR 1.86; 95 %CI: 1.21 - 2.85), high BP anxiety (OR 2.02; 95 %CI: 1.35 - 3.02), purpose of current colonoscopy being bowel symptoms (OR 1.40; 95 %CI: 1.00 - 1.97), use of 4 L of polyethylene glycol laxative (OR 1.45; 95 %CI: 1.02 - 2.06), not having SDBP (OR 1.96; 95 %CI: 1.31 - 2.93), and not having finished the laxative for the current colonoscopy (OR 1.66; 95 %CI: 1.01 - 2.73). Most of the same predictors were identified when reluctance was compared to willing or neutral, and in ordinal logistic regression. CONCLUSIONS: Almost three-quarters of patients do not express reluctance to get up early for BP. Among those who are reluctant, improving BP information, allaying BP-related anxiety, and use of low volume BP may increase acceptance of SDBP.

An assessment of endoscopic and concomitant management of acute variceal bleeding at a tertiary care centre.

BACKGROUND: Several therapies have been demonstrated to be beneficial in the management of acute variceal bleeding (AVB). The aim of the present study was to characterize the use of these therapies at a Canadian tertiary care centre. PATIENTS AND METHODS: A comprehensive chart review was performed to assess the management of all adult cirrhotic patients with AVB who were admitted to a university-affiliated, tertiary care centre between April 2001 and March 2004. RESULTS: A total of 81 AVB patients were identified with a mean age of 53.7+/-13.2 years and a median model for end-stage liver disease score of 14. Endoscopy was performed within 8.2+/-7.6 h of admission. Variceal banding was performed for 87% of patients with esophageal varices, which were the most common source of bleeding (80%). Octreotide was used in 82% of patients for a mean duration of 74.3+/-35.4 h; prophylactic antibiotics were used in 25% of patients and beta-blockers were used in 24% of patients without any contraindications. Follow-up endoscopy was arranged for 46 of 71 (65%) survivors. Prophylactic antibiotic use was associated with the presence of ascites, while beta-blockers were used more often in the last year of the study. CONCLUSIONS: There is a disconnection between the use of evidence-based recommendations and routine clinical practices in the management of AVB. Deficiencies identified include the lack of use of prophylactic antibiotics and beta-blockers, variable use of octreotide and inadequate follow-up recommendations. There is a need to identify measures to improve the process of care for patients with AVB which would ensure optimal management of these patients.

Review article: changes in the epidemiology of inflammatory bowel disease-clues for aetiology.

BACKGROUND: The changing epidemiology of inflammatory bowel disease (IBD) in both the developed and developing worlds may provide insights into disease aetiology. Factors that impact on the gut microbiome are leading aetiological candidates. AIM: To review epidemiological studies and trends that identify risk factors for the development of IBD. METHODS: Studies that identified factors associated with the development of IBD differentially in children and adults were reviewed. There was a focus on epidemiological studies and on studies that involve the gut microbiome. RESULTS: Use of antibiotics has been shown to be associated with development of Crohn's disease in childhood (odds ratio, OR = 2.75, 95% CI 1.72-4.38). Breastfeeding has been protective against developing IBD (OR=0.69, 95% CI 0.51-0.94), but there is a paucity of data exploring duration of breastfeeding and timing of introduction of bottled milk or table food. Antibiotics and diet changes can also impact on adults enhancing the risk for IBD. Both smoking (OR=1.76, 95% CI 1.40-2.22) and oral contraceptives (relative risk=1.46, 95% CI 1.26-1.70) increase the risk for Crohn's disease and their use is associated with worse outcomes in Crohn's disease. It is unclear if their impact is mediated through the gut microbiome. CONCLUSIONS: A leading aetiological clue for IBD based on epidemiological studies is the antecedent use of antibiotics both for children and adults. Some dietary changes may be a risk for adults but there is a paucity of dietary data in children prior to IBD development. Both antibiotic use and dietary changes have the potential to impact the gut microbiome, which in turn can alter the gut immune response.

A comparison of the gut microbiome between long-term users and non-users of proton pump inhibitors.

BACKGROUND: Proton pump inhibitor (PPI) use is associated with an increased risk of Clostridium difficile infection (CDI), though the mechanism is unclear. PPI induced alterations to the gut microbiome may facilitate the emergence of CDI, though the effects of PPIs on gut microbiota are not well characterised. [Correction added on 10 March 2016, after first online publication: microflora has been changed to microbiota throughout the article.] AIM: To compare the faecal microbiomes of long-term PPI users to those with no history of PPI use. METHODS: We used a population-based database to identify individuals with ≥5 years of continuous PPI use along with non-PPI using controls. Stool samples were subjected to microbiological analysis, with hierarchical clustering at genus level, along with alpha and beta diversity measures comparing the two groups. Metadata was accounted for using quantile regression to eliminate potential confounding variables in taxonomic abundance comparisons. RESULTS: Sixty-one subjects (32 PPI, 29 controls) were analysed. While no significant differences in alpha diversity were found between the PPI users and controls, a moderate shift of the PPI users away from the non-PPI user cluster in the beta diversity was observed. After controlling for pertinent confounders, we discovered a decrease in Bacteroidetes and an increase in Firmicutes at the phylum level. We also performed species classifications and found Holdemania filiformis and Pseudoflavonifractor capillosus to be increased and decreased in the PPI cohort, respectively. CONCLUSIONS: Long-term PPIs use has an effect on the gut microbiome. The alteration in the ratio of Firmicutes to Bacteroidetes may pre-dispose to the development of CDI.

Systematic review and meta-analysis of interventions for depression and anxiety in persons with multiple sclerosis.

BACKGROUND: Depression and anxiety are common in persons with multiple sclerosis (MS), and adversely affect fatigue, medication adherence, and quality of life. Though effective treatments for depression and anxiety exist in the general population, their applicability in the MS population has not been definitively established. OBJECTIVE: To determine the overall effect of psychological and pharmacological treatments for depression or anxiety in persons with MS. METHODS: We searched the Medline, EMBASE, PsycINFO, PsycARTICLES Full Text, Cochrane Central Register of Controlled Trials, CINAHL, Web of Science, and Scopus databases using systematic review methodology from database inception until March 25, 2015. Two independent reviewers screened abstracts, extracted data, and assessed risk of bias and strength of evidence. We included controlled clinical trials reporting on the effect of pharmacological or psychological interventions for depression or anxiety in a sample of persons with MS. We calculated standardized mean differences (SMD) and pooled using random effects meta-analysis. RESULTS: Of 1753 abstracts screened, 21 articles reporting on 13 unique clinical trials met the inclusion criteria. Depression severity improved in nine psychological trials of depression treatment (N=307; SMD: -0.45 (95%CI: -0.74, -0.16)). The severity of depression also improved in three pharmacological trials of depression treatment (SMD: -0.63 (N=165; 95%CI: -1.07, -0.20)). For anxiety, only a single trial examined psychological therapy for injection phobia and reported no statistically significant improvement. CONCLUSION: Pharmacological and psychological treatments for depression were effective in reducing depressive symptoms in MS. The data are insufficient to determine the effectiveness of treatments for anxiety.

A randomized, double-blind, placebo-controlled trial of CDP571, a humanized monoclonal antibody to tumour necrosis factor-alpha, in patients with corticosteroid-dependent Crohn's disease.

AIM: To evaluate CDP571, a humanized monoclonal antibody to tumour necrosis factor-alpha, for the treatment of corticosteroid-dependent Crohn's disease. METHODS: Patients with corticosteroid-dependent Crohn's disease (use of prednisolone 15-40 mg/day or budesonide 9 mg/day for at least 8 weeks, a previous failed attempt to discontinue corticosteroids within 8 weeks, and Crohn's Disease Activity Index score 150 points or less) were enrolled in a 16-week, randomized, double-blind, placebo-controlled trial. The patients received intravenous CDP571 (20 mg/kg at week 0 and 10 mg/kg at week 8) or placebo. Corticosteroid therapy was decreased following a predefined schedule. The primary efficacy end-point was the percentage of patients with corticosteroid-sparing [i.e. no disease flare (Crohn's Disease Activity Index score > or =220 points) and no longer requiring corticosteroid therapy] at week 10. The major secondary efficacy end-point was corticosteroid-sparing at week 16. RESULTS: Seventy-one patients received treatment. Corticosteroid-sparing was achieved by 19 of 39 (48.7%) CDP571 patients and 13 of 42 (40.6%) placebo patients (P = 0.452) at week 10, and by 18 of 39 (46.2%) CDP571 patients and seven of 32 (21.9%) placebo patients (P = 0.032) at week 16. CDP571 therapy was well-tolerated and the incidence of serious adverse events was similar to placebo. CONCLUSIONS: The CDP571 was effective for corticosteroid-sparing at week 16 but not week 10, and was well-tolerated in patients with corticosteroid-dependent Crohn's disease.

Decreased bone density in inflammatory bowel disease is related to corticosteroid use and not disease diagnosis.

Although corticosteroid therapy is associated with the development of osteopenia, it is unclear whether the cause of osteopenia in inflammatory bowel disease (Crohn's disease and ulcerative colitis) is related to corticosteroid therapy or other disease-related variables. Patients with Crohn's disease (a diffuse gastrointestinal disease) could have greater osteopenia than patients with ulcerative colitis because of small bowel disease and secondary malabsorption of calcium and vitamin D. A cross-sectional analysis of consecutive patients with Crohn's disease and ulcerative colitis was undertaken. Bone density was determined by measurements of the L2-L4 spine, the total hip, and Ward's triangle using dual energy X-ray absorptiometry (DXA). A number of clinical parameters were recorded prior to bone density evaluation and analyzed by univariate and subsequently multivariate analysis to determine possible predictors of osteopenia. Of the 26 patients with Crohn's disease, diminished bone density (a Z score of at least -1) was found at the hip in 64% and at the spine in 44%; and of the 23 patients with ulcerative colitis diminished bone density was found at the hip in 43% and at the spine in 48%. Among all the variables tested, only corticosteroid use was a statistically significant predictor of diminished bone density (p = 0.025 for the spine and hip and p = 0.005 for Ward's triangle). Disease diagnosis (Crohn's disease compared with ulcerative colitis) did not predict or correlate with diminished bone density. No obvious associations were seen between the measurements of any serum hormones or biochemistries and bone density, although the patients using corticosteroids had lower serum calcium levels than the nonusers.(ABSTRACT TRUNCATED AT 250 WORDS)

Rectal afferent function in patients with inflammatory and functional intestinal disorders.

Chronic symptoms of abdominal pain and discomfort are reported by patients with inflammatory bowel disease (IBD) and functional disorders of the gut, such as Irritable Bowel Syndrome (IBS). It has recently been suggested that transient inflammatory mucosal events may result in long-lasting sensitization of visceral afferent pathways. To determine the effect of recurring intestinal tissue irritation on lumbosacral afferent pathways, and to identify a plausible mechanism that could account for the overlap in symptomatology between IBD and IBS, we compared rectal afferent mechanisms in patients with Crohn's disease (inflammation limited to the ileum) with those observed in patients with diarrhea-predominant IBS. Continuous volume ramp and phasic pressure step distension of a rectal balloon were performed in 9 healthy male control subjects, 12 male patients with isolated ileal Crohn's disease and 9 male patients with diarrhea-predominant IBS using an electronic visceral stimulation device. The response of rectal afferents to distension was evaluated by measuring thresholds for the perception of physiological (stool) and aversive (discomfort) sensations, viscerosomatic referral patterns, skin conductance responses, receptive relaxation, and rectoanal reflex responses. In response to slow ramp distension, thresholds for aversive sensations were significantly higher in Crohn's disease patients, but similar between the two other groups. In response to rapid phasic distension, IBS patients reported discomfort at lower distension pressures, while all other thresholds were similar between groups. Skin conductance responses to aversive distension were greatly reduced in Crohn's disease patients while IBS patients had greater responses when compared to normals. Changes in viscerosomatic referral patterns and receptive relaxation rate were similar in Crohn's disease and IBS patients. These findings demonstrate that chronic ileal inflammation is associated with increased thresholds for discomfort and greatly diminished systemic autonomic reflex responses. In contrast, IBS patients show lowered thresholds for discomfort associated with increased autonomic responses. The findings in Crohn's patients may result from descending bulbospinal inhibition of sacral dorsal horn neurons in response to chronic intestinal tissue irritation.