Outcome of behavioural treatment for idiopathic chronic constipation.

BACKGROUND/AIM: Behavioural therapy is effective in patients with chronic intractable constipation despite standard treatment, but long-term results in unselected patients are unclear. This study investigates the effects of behavioural therapy on symptoms, subjective well-being, and the physical and mental quality of life. METHODS: Patients who had failed standard care for idiopathic chronic constipation underwent behavioural therapy in a specialist clinic. Symptom severity and quality of life were assessed before and after therapy using the 'Constipation Scoring System' and the Short-Form 36 questionnaire. The primary outcome was subjective perception of improvement. Secondary outcomes were symptoms of constipation and quality of life scores. RESULTS: Of 233 consecutive patients with self-reported constipation (median symptom duration 5-10 years, median age 44 years, females 86%), 180 (77%) completed treatment in a median of three (range 1-7) sessions. One hundred and sixty-five patients (71% of all referrals or 92% of those completing treatment) reported subjective improvement. Median bowel frequency improved from once every 2-7 days to 1-3 per day (P = 0.05). Pain and bloating improved in more than 80% of patients. The Short-Form 36 physical (P < 0.05) and mental (P < 0.05) composite scores improved significantly. Patients with a longer duration of symptoms were less likely to complete treatment. Digital evacuation prior to treatment was a predictor of poor outcome. CONCLUSION: Behavioural therapy is associated with significant improvement in symptoms of chronic constipation and quality of life. Non-drug therapies that successfully treat patients with functional gut disorders resistant to standard treatment are needed in the mainstream provision of care.

Inflammatory bowel disease cancer surveillance in a tertiary referral hospital: attitudes and practice.

BACKGROUND: Physician adherence to guidelines for colorectal cancer (CRC) surveillance in inflammatory bowel disease (IBD) is often poor. This may lead to adverse patient outcomes and excess endoscopic workload. AIMS: To assess the attitudes and practice of IBD specialists in a tertiary centre towards colonoscopic surveillance. METHODS: First, a questionnaire evaluating attitudes and approach to CRC surveillance was issued to 36 clinicians at one tertiary referral hospital. Second, a retrospective audit of IBD surveillance colonoscopy practice over a 2-year period was performed. RESULTS: Questionnaire response rate was 97%. Sixty-nine per cent of respondents were aware of, and used, Australian guidelines. Surveillance was undertaken by all clinicians in patients with extensive colitis, 83% in patients with left-sided colitis and 51% in patients with proctitis. Seventy-six per cent used chromoendoscopy, and 47% took 10 to 20 random biopsies. Colectomy was considered appropriate in 0% for unifocal low-grade dysplasia, 35% for multifocal low-grade dysplasia and 83% for high-grade dysplasia. Sixty-six per cent would remove elevated dysplastic lesions endoscopically. The audit identified 103 surveillance colonoscopies in 81 patients. Chromoendoscopy was used in 21% of cases, and the median number of random biopsies was 13. Sixty-two per cent of colonoscopies were performed outside the guidelines in relation to colonoscopic frequency. Following colonoscopy, an appropriate recommendation for subsequent surveillance was documented in 40% of cases. CONCLUSIONS: Knowledge and practice of CRC surveillance in IBD vary among specialist clinicians and often deviate from guidelines. Many clinicians perform surveillance earlier and more frequently than recommended. These findings have implications for patient outcomes and workload.

Postoperative recurrence of Crohn's disease: impact of endoscopic monitoring and treatment step-up.

AIM: Eighty per cent of patients with Crohn's disease require surgery, of whom 70% will require a further operation. Recurrence occurs at the anastomosis. Although often recommended, the impact of postoperative colonoscopy and treatment adjustment is unknown. METHOD: Patients with a bowel resection over a 10-year period were reviewed and comparison made between those who did and did not have a postoperative colonoscopy within 1 year of surgery, and those who did or did not have a step-up in drug therapy. RESULTS: Of 222 patients operated on, 136 (65 men, mean age 33 years, mean disease duration 8 years, median follow-up 4 years) were studied. Of 70 patients with and 66 without postoperative colonoscopy, clinical recurrence occurred in 49% and 48% (NS) and further surgery in 9% and 5% (NS). Eighty-nine per cent of colonoscoped patients had a decision based on the colonoscopic findings: of these, 24% had a step-up of drug therapy [antibiotics (n =10), aminosalicylates (n=2), thiopurine (n=5), methotrexate (n=1)] and 76% had no step-up in drug therapy. In colonoscoped patients clinical recurrence occurred in 9 (60%) of 15 patients with, and 23 (49%) of 47 without step-up and surgical recurrence in 2 (13%) of 15 and 4 (9%) of 47 (NS). CONCLUSION: Clinical recurrence occurs in a majority of patients soon after surgery. In this cohort, there was no clinical benefit from colonoscopy or increased drug therapy within 1 year after operation. However, the response to the endoscopic findings was not standardized and immunosuppressive therapy was uncommon. Standardizing timing of colonoscopy and drug therapy, including more intense therapy, may improve outcome, although this remains to be proven.

Effect of food additives on key bacterial taxa and the mucosa-associated microbiota in Crohn's disease. The ENIGMA study.

Food additives have been linked to the pro-inflammatory microbial dysbiosis associated with Crohn's disease (CD) but the underlying ecological dynamics are unknown. Here, we examine how selection of food additives affects the growth of multiple strains of a key beneficial bacterium (Faecalibacterium prausnitzii), axenic clinical isolates of proinflammatory bacteria from CD patients (Proteus, Morganella, and Klebsiella spp.), and the consortia of mucosa-associated microbiota recovered from multiple Crohn's disease patients. Bacterial growth of the axenic isolates was evaluated using a habitat-simulating medium supplemented with either sodium sulfite, aluminum silicate, carrageenan, carboxymethylcellulose, polysorbate 80, saccharin, sucralose, or aspartame, intended to approximate concentrations found in food. The microbial consortia recovered from post-operative CD patient mucosal biopsy samples were challenged with either carboxymethylcellulose and/or polysorbate 80, and the bacterial communities compared to unchallenged consortia by 16S rRNA gene amplicon profiling. Growth of all F. prausnitzii strains was arrested when either sodium sulfite or polysorbate 80 was added to cultures at baseline or mid-exponential phase of growth, and the inhibitory effects on the Gram-negative bacteria by sodium sulfite were conditional on oxygen availability. The effects from polysorbate 80, saccharin, carrageenan, and/or carboxymethylcellulose on these bacteria were strain-specific. In addition to their direct effects on bacterial growth, polysorbate 80 and/or carboxymethylcellulose can drive profound changes in the CD mucosa-associated microbiota via niche expansion of Proteus and/or Veillonellaceae - both implicated in early Crohn's disease recurrence. These studies on the interaction of food additives with the enteric microbiota provide a basis for dietary management in Crohn's disease.

Novel strain-level resolution of Crohn's disease mucosa-associated microbiota via an ex vivo combination of microbe culture and metagenomic sequencing.

The mucosa-associated microbiota is widely recognized as a potential trigger for Crohn's disease pathophysiology but remains largely uncharacterised beyond its taxonomic composition. Unlike stool microbiota, the functional characterisation of these communities using current DNA/RNA sequencing approaches remains constrained by the relatively small microbial density on tissue, and the overwhelming amount of human DNA recovered during sample preparation. Here, we have used a novel ex vivo approach that combines microbe culture from anaerobically preserved tissue with metagenome sequencing (MC-MGS) to reveal patient-specific and strain-level differences among these communities in post-operative Crohn's disease patients. The 16 S rRNA gene amplicon profiles showed these cultures provide a representative and holistic representation of the mucosa-associated microbiota, and MC-MGS produced both high quality metagenome-assembled genomes of recovered novel bacterial lineages. The MC-MGS approach also produced a strain-level resolution of key Enterobacteriacea and their associated virulence factors and revealed that urease activity underpins a key and diverse metabolic guild in these communities, which was confirmed by culture-based studies with axenic cultures. Collectively, these findings using MC-MGS show that the Crohn's disease mucosa-associated microbiota possesses taxonomic and functional attributes that are highly individualistic, borne at least in part by novel bacterial lineages not readily isolated or characterised from stool samples using current sequencing approaches.

Adalimumab for the treatment of fistulas in patients with Crohn's disease.

OBJECTIVE: To evaluate the efficacy of adalimumab in the healing of draining fistulas in patients with active Crohn's disease (CD). DESIGN: A phase III, multicentre, randomised, double-blind, placebo controlled study with an open-label extension was conducted in 92 sites. PATIENTS: A subgroup of adults with moderate to severely active CD (CD activity index 220-450) for >or=4 months who had draining fistulas at baseline. INTERVENTIONS: All patients received initial open-label adalimumab induction therapy (80 mg/40 mg at weeks 0/2). At week 4, all patients were randomly assigned to receive double-blind placebo or adalimumab 40 mg every other week or weekly to week 56 (irrespective of fistula status). Patients completing week 56 of therapy were then eligible to enroll in an open-label extension. MAIN OUTCOME MEASURES: Complete fistula healing/closure (assessed at every visit) was defined as no drainage, either spontaneous or with gentle compression. RESULTS: Of 854 patients enrolled, 117 had draining fistulas at both screening and baseline (70 randomly assigned to adalimumab and 47 to placebo). The mean number of draining fistulas per day was significantly decreased in adalimumab-treated patients compared with placebo-treated patients during the double-blind treatment period. Of all patients with healed fistulas at week 56 (both adalimumab and placebo groups), 90% (28/31) maintained healing following 1 year of open-label adalimumab therapy (observed analysis). CONCLUSIONS: In patients with active CD, adalimumab therapy was more effective than placebo for inducing fistula healing. Complete fistula healing was sustained for up to 2 years by most patients in an open-label extension trial.

A novel population of human CD56+ human leucocyte antigen D-related (HLA-DR+) colonic lamina propria cells is associated with inflammation in ulcerative colitis.

Ulcerative colitis (UC) involves inappropriate mucosal immune responses to intestinal microbiota. Gut dendritic cells (DC) are central immunoregulators of the response to commensal bacteria, and the subset of CD11c(+) cells within the human leucocyte antigen D-related (HLA-DR(+)) lineage (lin)(-/dim) population are activated in inflammatory bowel disease. We hypothesized that CD11c(-) cells within this population may also be involved in intestinal inflammation. HLA-DR(+) lin(-/dim) cells were identified in freshly isolated lamina propria mononuclear cells by multi-colour flow cytometry in 54 UC patients and 22 controls. Proportion and number of CD11c(+) and CD11c(-) cells, and surface expression of activation markers CD40, CD86, Toll-like receptor (TLR)-2, TLR-4, and CD56(+)[natural killer (NK) marker], were determined. Cytokine production was assessed by intracellular staining. Lamina propria colonic CD11c(-) HLA-DR(+) lin(-/dim) cells were increased significantly in inflamed and 'non-inflamed' UC tissue, compared with control tissue. CD11c(+) HLA-DR(+) lin(-/dim) cells were unchanged. Fewer CD11c(-) cells expressed activation markers and produced intracellular cytokines than their CD11c(+) counterparts, and they were weakly stimulatory in mixed leucocyte reactions. Few CD11c(-) cells expressed blood plasmacytoid DC markers, but a major subset expressed high levels of CD56. CD11c(-) cells decreased after inflammation resolved. Intestinal inflammation in UC is associated with the presence of cells that share phenotypic features of both DC and NK cells. This novel population of human colonic CD56(+) HLA-DR(+) cells may play a role in immune regulation or tissue repair. Their increase in quiescent UC may be a marker of subclinical inflammation.

Improving the efficacy of sacral nerve stimulation for faecal incontinence by alteration of stimulation parameters.

BACKGROUND: Sacral nerve stimulation (SNS) is an effective treatment for faecal incontinence, but only standard stimulation parameters have been used. This study assessed the clinical impact of altering the parameters. METHODS: Twelve patients with partially improved faecal incontinence following SNS underwent acute testing to select optimal stimulation parameters; rectal compliance was used as a surrogate marker. Parameters tested were: stimulation off; frequency 14 (standard), 31 or 6.9 Hz; and pulse duration 210 (standard), 450 or 90 micros. Patients completed a 2-week bowel diary, St Mark's continence score (SMCS) and Rockwood faecal incontinence quality-of-life (FIQL) score before testing using standard settings, and after testing using optimized settings. RESULTS: Optimal settings, determined by greatest increase in rectal compliance, were shorter pulse width in five patients and higher frequency in seven. Optimized stimulation resulted in a decrease in mean episodes of incontinence from 2.3 to 1.2 per week (P = 0.031), soiling from 3.3 to 1.7 days per week (P = 0.016), faecal urgency from 31 to 18 per cent of all evacuations (P = 0.055) and SMCS from 12.3 to 8.7 (P = 0.008); the FIQL coping/behaviour score improved (P = 0.008). CONCLUSION: With a shorter pulse width and higher frequency, clinical efficacy in patients undergoing SNS for faecal incontinence can be improved.

Physiological, psychological and behavioural characteristics of men and women with faecal incontinence.

BACKGROUND: The factors leading to faecal incontinence in males are less well understood than those in females. In this prospective study we aimed to compare the physiological, anatomical, psychological and behavioural characteristics of male and female patients presenting with symptoms of faecal incontinence. METHOD: One hundred and nine patients presenting with symptoms of faecal incontinence were studied. They underwent anorectal physiological studies, endoanal ultrasonography, and completed a St Mark's Incontinence Score, a locally developed pad questionnaire, a bowel symptom questionnaire, the Short Form 36 (SF-36) Health Survey questionnaire, the Hospital Anxiety and Depression Scale and the Maudsley Obsessive Compulsive Inventory. RESULTS: Thirty-four men (mean age 59 years, SD 14 years, range 33-80) and 75 women (mean age 55 years, SD 15 years, range 21-86) participated in the study. Twenty-one patients (38% of men and 11% of women) had normal manometry and endoanal ultrasonography. There was no significant difference in the resting pressures of men compared with women, but men had significantly higher squeeze pressures. Rectal capacity was significantly higher in men but anal and rectal electrosensitivities were the same. Men placed a tissue at the anus more commonly than women while women were more likely to use a pad and to carry a spare pair of underwear around with them. Psychological profiles were very similar in the two sexes. CONCLUSIONS: Nearly 40% of men with faecal incontinence report it in the absence of a definable functional or structural sphincter abnormality. There are differences in physiological characteristics and coping behaviours of men and women with faecal incontinence.

Relationship between gut-specific autonomic testing and bowel dysfunction in spinal cord injury patients.

STUDY DESIGN: Investigation of bowel function in 55 patients and 26 healthy volunteers using radiological, anorectal physiological and laser Doppler blood flow monitoring. OBJECTIVES: Bowel dysfunction is common after spinal cord injury (SCI). We aimed to determine whether hindgut testing of autonomic innervation provides insight into presence of symptoms, altered motor function (transit) and level of injury. SETTING: St Mark's Hospital, UK and The Spinal Injuries Unit, Royal National Orthopaedic Hospital, UK. METHODS: A total of 55 patients with chronic complete SCI and 26 healthy volunteers were studied. Twenty-four patients had lesions above T5 and 31 had lesions below T5. Thirty-five patients complained of constipation: 75% (18/24) of patients with lesions above T5 and 55% (17/31) of those with lesions below T5. Gut transit, rectal electrosensitivity and rectal blood flow were measured. RESULTS: Slow gut transit occurred in 65% of patients and in all the 35 patients complaining of constipation. Delay was pancolonic. All patients had an elevated sensory threshold. The threshold was significantly higher in those with subjective constipation (P<0.01), slow transit (P<0.04) and high SCI (P=0.046). Mucosal blood flow was lower in SCI patients with constipation (P<0.04) and slow transit (P<0.03). It was higher than normal in high-SCI volunteers (P=0.056), reflecting loss of sympathetic inhibition. CONCLUSIONS: In SCI, subjective constipation correlates closely with slow gut transit. Delay is pancolonic, regardless of the site of lesion. Sensory testing provides evidence for completeness of lesion, offering further evidence for pain transmission through sympathetic pathways. Studies in SCI patients provide further evidence of mucosal blood flow as a marker of altered autonomic innervation.

Randomised trial of once- or twice-daily MMX mesalazine for maintenance of remission in ulcerative colitis.

AIM: Maintenance treatment in ulcerative colitis should be as convenient as possible, to increase the chance of compliance. MMX mesalazine is a once-daily, high-strength (1.2 g/tablet) formulation of 5-aminosalicylic acid. This study evaluated the safety and efficacy of MMX mesalazine dosed once or twice daily as maintenance therapy in patients with ulcerative colitis. METHODS: This multicentre, randomised, open-label trial enrolled patients with strictly defined clinical and endoscopic remission, immediately following an episode of mild to moderate ulcerative colitis. Patients were randomised to MMX mesalazine 2.4 g/day as a single (2x1.2 g tablet) or divided dose (1x1.2 g tablet twice daily) for 12 months. RESULTS: 174 patients (37.9%; safety population n = 459) experienced 384 adverse events, the majority of which were mild or moderate in intensity. Eighteen patients (3.9%), nine in each group, experienced a total of 22 serious adverse events (10 in the once-daily and 12 in the twice-daily group). Most serious adverse events were gastrointestinal, experienced by 5 patients in the once-daily and 4 in the twice-daily group. At month 12, 64.4% (efficacy population, n = 451) of patients in the once-daily and 68.5% of patients in the twice-daily group were in clinical and endoscopic remission (p = 0.351). At month 12, 88.9% and 93.2% in each group, respectively, had maintained clinical remission (were relapse free). CONCLUSIONS: MMX mesalazine 2.4 g/day administered as a single or divided dose demonstrated a good safety profile, was well tolerated and was effective as maintenance treatment. High clinical and endoscopic remission rates can be achieved with once-daily dosing. TRIAL REGISTRATION NUMBER: NCT00151944.

Review article: 5-aminosalicylate formulations for the treatment of ulcerative colitis--methods of comparing release rates and delivery of 5-aminosalicylate to the colonic mucosa.

BACKGROUND: Many oral 5-aminosalicylic acid (5-ASA) formulations are designed to maximize 5-ASA release in the colon where it acts topically on the colonic mucosa. Delayed-release formulations and azo-prodrugs minimize 5-ASA absorption in the upper gastrointestinal (GI) tract. AIMS: To review methods for assessing 5-ASA release and colonic distribution from oral formulations, and the potential use of this information for guiding clinical decisions. METHODS: PubMed and recent conference abstracts were searched for articles describing techniques used to assess 5-ASA release from ulcerative colitis (UC) therapies. RESULTS: In-vitro GI models, although unable to simulate more complex aspects of GI physiology, can provide useful data on 5-ASA release kinetics and bioaccessibility. Gamma-scintigraphy is useful for investigating GI disintegration of different formulations, but may not accurately reflect 5-ASA distribution. Plasma pharmacokinetic studies provide data on systemic exposure, but not on colonic distribution or mucosal uptake. Mucosal biopsies provide direct evidence of colonic distribution and may predict clinical efficacy, but must be interpreted cautiously because of considerable inter-subject variability and other confounding factors. CONCLUSION: While assessment of 5-ASA release is important, limitations of individual measurement techniques mean that randomized clinical studies in UC patients remain the best guide for dosing and treatment regimen decisions.

Economic evaluation of sacral nerve stimulation for faecal incontinence.

BACKGROUND: Sacral nerve stimulation (SNS) is an established treatment for faecal incontinence in patients who have failed conservative management. This study established the cost-effectiveness of treating patients with SNS compared with non-surgical treatment. METHODS: A decision analysis model was performed. Data from 70 patients were obtained from medical records, bowel habit diaries and Short Form 36 quality of life questionnaires. Direct medical and non-medical costs were ascertained using the 2005/2006 national tariff, national statistics, and medication, pad and device costs. Indirect non-medical costs were also estimated. RESULTS: Incontinence episodes were reduced from a median of 12 per fortnight at baseline to one per fortnight with SNS. Based on direct medical and non-medical costs, the incremental cost-effectiveness ratio (ICER) for SNS was pound25 070 per QALY gained. It cost pound1038 more per year to treat patients with SNS for a median reduction of 286 incontinence episodes, equating to pound3.63 per episode reduced. When indirect non-medical costs were included the ICER was reduced to pound12 959 per QALY gained. CONCLUSION: The ICER of pound25 070 is within the pound30 000 per QALY threshold recommended by the National Institute for Health and Clinical Excellence as an effective use of National Health Service resources with proper justification.

Life events in patients with vulvodynia.

OBJECTIVE: Vulval pain, in the absence of pathology, may have a psychological basis that relates to life events. This study aimed to determine the nature of such events. DESIGN: Structured questionnaire about patient's symptoms and early-life events. SETTING: Private practice physiotherapist specialising in pelvic floor disorders. POPULATION: Patients with vulvodynia as their primary symptom and control patients being treated for urinary tract disorder or post-childbirth routine physiotherapy who had no vulval pain on direct questioning. METHODS: Questionnaire applied to consecutive patients referred for treatment. Seventy-eight consecutive women presenting with vulvodynia (mean age 34 years, mean duration of symptoms 48 months) and 78 controls (mean age 39 years). MAIN OUTCOME MEASURES: Incidence of life events. RESULTS: A similar proportion of both groups were married. Being in a new relationship (P < 0.04), adverse current or previous relationships (39 versus 9%, P < or = 0.01), parental divorce (26 versus 9%, P < or = 0.001), history of termination of pregnancy, and adverse childbirth experiences (P < 0.04) were more common in patients than in controls. A history of sexual abuse was not more common in patients with vulvodynia compared with controls (13 versus 10%, P = not significant). Lack of libido was common in patients with vulvodynia (94 versus 29%, P < 0.0001). CONCLUSIONS: Adverse life experiences, including conflict, are common in women with vulvodynia. These factors may be important in mediating the genesis of pain through stress-related mechanisms. Sexual interest is diminished in these women. Sexual abuse is not a factor in most of these women. These findings have implications for treatment.

Pilot study of two new injectable bulking agents for the treatment of faecal incontinence.

OBJECTIVE: The use of injectable bulking agents for passive faecal incontinence appears to provide reasonable short-term results. However experience with different agents is limited. We report on the outcome of injections with new bulking agents. METHOD: Each patient received injections of either Bulkamid (hydrogel cross-linked with polyacrylamide) or Permacol (porcine dermal collagen). Assessment included clinical evaluation, anorectal physiological testing, endoanal ultrasonography and questionnaires including the St Mark's Incontinence Score, one week bowel diary card, the Faecal Incontinence Quality of Life Scale and the Short Form-36 (SF-36) health survey. Follow up was at 6 weeks and 6 months, with a further telephone review at a median of 19 months (range 14-22). RESULTS: Ten patients (nine female), median age 68 years (range 45-79), were enrolled. St Mark's incontinence score (0 = best, 24 = worst) was 15 (range 11-24) at baseline, 12.5 (range 3-18) at 6 weeks and 14 (range 6-22) at 6 months. A 1-week bowel diary and SF-36 forms also showed temporary improvement but this was not sustained beyond 6 weeks. CONCLUSION: Bulkamid and Permacol injections did not have a major effect on faecal incontinence.

Predictive factors for successful sacral nerve stimulation in the treatment of faecal incontinence: a 10-year cohort analysis.

OBJECTIVE: Sacral nerve stimulation (SNS) is an established treatment for faecal incontinence. We aimed to identify specific factors that could predict the outcome of temporary and permanent stimulation. METHOD: A cohort analysis was performed to identify potential predictive factors in 81 patients who underwent temporary SNS at a single institution over a 10-year period (June 1996 to June 2006). Data were obtained from prospectively collected patient symptom diaries and quality of life questionnaires, operation reports, anorectal physiological studies, endoanal ultrasound images and radiology of lead placement. RESULTS: Clinical outcome of temporary screening was not affected by patient gender, age, body mass index, severity or length of symptoms. The need for a repeated temporary procedure was associated with subsequent failure during screening (P = 0.008). A low threshold to obtain a motor response during temporary lead insertion was associated with improved outcome (P = 0.048). Evidence of anal sphincter trauma was associated with a greater risk of failure (P = 0.040). However, there was no difference in medium-term outcome between patients with external anal sphincter (EAS) defects and patients with intact anal sphincter muscles. CONCLUSION: Variables have been identified that help to predict the outcome of SNS. The presence of an EAS defect should not preclude treatment.

Variants in ACTG2 underlie a substantial number of Australasian patients with primary chronic intestinal pseudo-obstruction.

BACKGROUND: Primary chronic intestinal pseudo-obstruction (CIPO) is a rare, potentially life-threatening disorder characterized by severely impaired gastrointestinal motility. The objective of this study was to examine the contribution of ACTG2, LMOD1, MYH11, and MYLK mutations in an Australasian cohort of patients with a diagnosis of primary CIPO associated with visceral myopathy. METHODS: Pediatric and adult patients with primary CIPO and suspected visceral myopathy were recruited from across Australia and New Zealand. Sanger sequencing of the genes encoding enteric gamma-actin (ACTG2) and smooth muscle leiomodin (LMOD1) was performed on DNA from patients, and their relatives, where available. MYH11 and MYLK were screened by next-generation sequencing. KEY RESULTS: We identified heterozygous missense variants in ACTG2 in 7 of 17 families (~41%) diagnosed with CIPO and its associated conditions. We also identified a previously unpublished missense mutation (c.443C>T, p.Arg148Leu) in one family. One case presented with megacystis-microcolon-intestinal hypoperistalsis syndrome in utero with subsequent termination of pregnancy at 28 weeks' gestation. All of the substitutions identified occurred at arginine residues. No likely pathogenic variants in LMOD1, MYH11, or MYLK were identified within our cohort. CONCLUSIONS AND INFERENCES: ACTG2 mutations represent a significant underlying cause of primary CIPO with visceral myopathy and associated phenotypes in Australasian patients. Thus, ACTG2 sequencing should be considered in cases presenting with hypoperistalsis phenotypes with suspected visceral myopathy. It is likely that variants in other genes encoding enteric smooth muscle contractile proteins will contribute further to the genetic heterogeneity of hypoperistalsis phenotypes.

Thalidomide in luminal and fistulizing Crohn's disease resistant to standard therapies.

BACKGROUND: Thalidomide has been shown to be an effective treatment in Crohn's disease. AIM: To assess the efficacy and tolerability of thalidomide in refractory Crohn's disease patients. METHODS: Twenty-five patients were treated. Retrospective 'estimated' Crohn's Disease Activity Indices were assessed at baseline and at the end of follow-up. Clinical response was defined as symptomatic improvement and a reduction in the 'estimated' Crohn's Disease Activity Index of >100 points, > or =50% reduction in draining fistulas or clinical improvement in perianal ulcers. Clinical remission was defined as symptom resolution and an 'estimated' Crohn's Disease Activity Index <150, complete fistula closure or complete ulcer healing. RESULTS: Six of eight patients treated for luminal disease responded to thalidomide at a median follow-up of 12 months (three clinical responses, three clinical remissions). The median reduction in 'estimated' Crohn's Disease Activity Index was 212 points (P = 0.005). Nine of 11 patients with active fistulizing disease responded to thalidomide (six responses; three remissions). The four patients treated for both luminal and fistulizing disease had fistula response. Three of them had a response in luminal disease activity. One of two patients with ulcerating perianal disease responded. Twelve patients discontinued treatment because of adverse effects (three sedation; two abdominal pain; one leucopoenia; six neuropathy). CONCLUSION: Thalidomide is an effective short- to medium-term treatment in selected patients with refractory luminal and fistulizing Crohn's disease. Its long-term use is limited by toxicity.

MMX Multi Matrix System mesalazine for the induction of remission in patients with mild-to-moderate ulcerative colitis: a combined analysis of two randomized, double-blind, placebo-controlled trials.

BACKGROUND: MMX mesalazine [LIALDA (US), MEZAVANT XL (UK and Ireland) MEZAVANT (elsewhere)] utilizes MMX Multi Matrix System (MMX) technology which delivers mesalazine throughout the colon. Two phase III studies have already evaluated MMX mesalazine in patients with active, mild-to-moderate ulcerative colitis. Aim To provide more precise estimates of the efficacy of MMX mesalazine over placebo by combining the patient populations from the two phase III studies. Methods Combined data from two 8-week, double-blind, placebo-controlled trials were analyzed. Patients randomized to MMX mesalazine 2.4 g/day (once daily or 1.2 g twice daily), 4.8 g/day (once daily) or placebo were reviewed. The primary end point was clinical and endoscopic remission (modified Ulcerative Colitis-Disease Activity Index of /=1-point reduction in sigmoidoscopy score from week 0). Results Data from 517 patients were analysed. 8-week remission rates were 37.2% and 35.1% in the MMX mesalazine 2.4 g/day and 4.8 g/day groups, vs. 17.5% on placebo (P < 0.001, both comparisons). 8-week complete mucosal healing rates were 32% in both MMX mesalazine groups compared with 16% on placebo. Adverse event frequency was similar in all groups. Conclusion MMX mesalazine is effective and generally well tolerated for inducing clinical and endoscopic remission of active, mild-to-moderate ulcerative colitis.

The burden of constipation on quality of life: results of a multinational survey.

BACKGROUND: The impact of constipation on quality of life (QoL) may vary in different cultural or national settings. AIM: We studied QoL in a multinational survey to compare different social and demographic groups with and without constipation (defined according to Rome III criteria) and to detect country-specific differences among the groups studied. METHODS: Health-related QoL (HRQoL) was assessed with the Short Form 36 (SF-36) questionnaire in 2870 subjects in France, Germany, Italy, UK, South Korea, Brazil and USA. Results Respondents were mainly middle-aged, married or living together and part- or full-time employed. General health status, measured by the SF-36 questionnaire, was significantly worse in the constipated vs. non-constipated populations. RESULTS: were comparable in all countries. QoL scores correlated negatively with age. Constipated women reported more impaired HRQoL than constipated men. Brazilians were most affected by constipation as to their social functioning (35.8 constipated vs. 51.3 non-constipated) and general health perception (29.4 constipated vs. 54.4 non-constipated). CONCLUSIONS: There are significant differences in HRQoL between constipated and non-constipated individuals and a significant, negative correlation between the number of symptoms and complaints and SF-36 scores. The study detected a correlation of constipation with QoL and the influence of social and demographic factors on HRQoL in constipated people.