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Background Low-grade immune activation in the gut is a potential treatment target in irritable bowel syndrome (IBS). Aims To determine improvement in IBS symptoms after mesalazine treatment, and the utility of measures of immune activity in the rectal mucosa Methods This was a randomised, double-blind, placebo-controlled, parallel-arm, multicentre trial in subjects with IBS (Rome III criteria), with an eight-week treatment period of mesalazine 2400 mg or plcebo once-daily. The primary endpoint was the global assessment of satisfactory relief of IBS symptoms in ≥50% of weeks during intervention. IBS symptoms were also measured with the IBS severity scoring system; immune activity was measured by mucosal patch technology. A post hoc meta-analysis of randomised placebo-controlled trials of mesalazine in IBS was added. Results Of 181 included patients, 91 received mesalazine and 90 received placebo. The primary endpoint was met by 32 (36%) patients after mesalazine and 27 (30%) after placebo (p = 0.40). There were no differences in response rates related to IBS subtype or post-infection symptom onset. More reduction of abdominal bloating was noted in the mesalazine group (p = 0.02). The meta-analysis showed no effect of mesalazine on IBS symptoms. No mucosal patch technology measure could predict response to mesalazine, and found no differences in the effects of intervention on levels of immune markers. Conclusions Mesalazine is ineffective in reducing IBS symptoms. Rectal measures of immune activity by the mucosal patch technology cannot predict a higher chance of response to mesalazine. publishedVersion

Pancreatic exocrine insufficiency (PEI) results in maldigestion of fat, leading to steatorrhea, malabsorption and weight loss. Sjögren's syndrome (SS) is a chronic autoimmune rheumatic disease with unknown etiology. The exocrine pancreas and the salivary glands are functionally and histologically comparable, and pancreatic dysfunction in SS has been hypothesized.Patients were recruited from the Department for Rheumatology at the Karolinska University Hospital in Stockholm, Sweden, between June and December 2019. PEI was assessed by fecal elastase-1 (FE-1) andFifty-seven patients with primary SS were included in the study, comprising 92% females with a median age of 63 years. In total, 87% of SS patients were tested for FE-1 and all had normal results. All patients who underwent aIn our study, most SS patients suffered from irritable bowel syndrome (IBS)-like GI symptoms that could not be attributed to PEI.

Background & Aims IgA exerts its primary function at mucosal surfaces, where it binds microbial antigens to regulate bacterial growth and epithelial attachment. One third of individuals with IgA deficiency (IgAD) suffers from recurrent mucosal infections, possibly related to an altered microbiota. We aimed to delineate the impact of IgAD and the IgA-autoantibody status on the composition and functional capacity of the gut microbiota. Methods We performed a paired, lifestyle-balanced analysis of the effect of IgA on the gut microbiota composition and functionality based on fecal samples from individuals with IgAD and IgA-sufficient household members (n = 100), involving quantitative shotgun metagenomics, species-centric functional annotation of gut bacteria, and strain-level analyses. We supplemented the data set with 32 individuals with IgAD and examined the influence of IgA-autoantibody status on the composition and functionality of the gut microbiota. Results The gut microbiota of individuals with IgAD exhibited decreased richness and diversity and was enriched for bacterial species encoding pathogen-related functions including multidrug and antimicrobial peptide resistance, virulence factors, and type III and VI secretion systems. These functional changes were largely attributed to Escherichia coli but were independent of E coli strain variations and most prominent in individuals with IgAD with IgA-specific autoreactive antibodies. Conclusions The microbiota of individuals with IgAD is enriched for species holding increased proinflammatory potential, thereby potentially decreasing the resistance to gut barrier–perturbing events. This phenotype is especially pronounced in individuals with IgAD with IgA-specific autoreactive antibodies, thus warranting a screening for IgA-specific autoreactive antibodies in IgAD to identify patients with IgAD with increased risk for gastrointestinal implications.

Background: Enteroendocrine cells (EEC) have been suggested to have a role in the pathogenesis of irritable bowel syndrome (IBS). Although many studies have analysed possible numeric changes of EEC in IBS, the results differ between different studies. One reason might be due to difficulties in standardising the morphometric method.Aim: The aim of this study was to compare two different methods for counting EEC in jejunum biopsies from patients with IBS and healthy controls.Method: Fifty-one patients with IBS and 35 healthy controls were included in the study. Jejunum mucosa was procured using a Watson capsule. Slides were immunostained for serotonin and chromogranin A and then scanned digitally. The morphometry was done by counting cells per high power field (hpf) and per mm2 after defining area of the mucosa. The two methods were compared using Bland Altman analysis.Results: There was no difference in the number of EEC in patients with IBS compared to healthy controls. The number of cells detected by per mm2 area of mucosa were higher than number of cells per hpf. Counting EEC per high power field systematically underestimated the number of cells in the mucosal area.Conclusions: Counting cells per mm2 mucosal area gives a better representation of the number of EEC in small bowel mucosa. The finding of no difference in EEC numbers does not imply an equal function and further studies are needed to evaluate the role, if any of EEC, in IBS.

PROBIOTICS—THE CONCEPTHistory and DefinitionsA century ago, Elie Metchnikoff (a Russian scientist, Nobel laureate, and professor at the Pasteur Institute in Paris) postulated that lactic acid bacteria (LAB) offered health benefits capable of promoting longevity. He suggested that “intestinal autoint

The aim of our study was to compare patients with irritable bowel syndrome (IBS) and healthy controls regarding the expression of toll-like receptors 2, 4, 5, and 9 (TLR2, TLR4, TLR5, and TLR9), the primary mucosal receptors of bacterial components, in small and large bowel mucosa.Methods.We analysed biopsies from jejunum and sigmoid colon of 22 patients (17 females) with IBS aged 18–66 (median: 39) years and 14 healthy volunteers (12 females) aged 22–61 (median: 42) years. Eight patients had constipation-predominant IBS (C-IBS), 7 had diarrhoea-predominant IBS (D-IBS), and 7 had IBS without predominance of constipation or diarrhoea. We analysed mRNA levels for TLRs using quantitative PCR and distribution of TLRs in mucosa using immunohistochemistry.Results.We found increased mRNA expression of TLR4 (mean fold change1.85±0.31versus1.0±0.20;p<0.05), TLR5 (1.96±0.36versus1.0±0.20;p<0.05) and TLR9 (2.00±0.24versus1.0±0.25;p<0.01) but not of TLR2 in the small bowel mucosa from patients with IBS compared to the controls. There was no significant difference in mRNA levels for TLRs in colon mucosa between patients and controls.Conclusion.Upregulation of TLR4, TLR5, and TLR9 suggests the involvement of bacteria or dysregulation of the immune response to commensal flora in small bowel mucosa in IBS patients.

International audience; Background: Gastric electrical stimulation (GES) is used in both the US and Europe, but little research has investigated the demographics of gastroparesis patients receiving GES by geographic location.Methods: We compared data from 380 patients, 296 female and 84 males, mean age 42 years, 246 idiopathic (ID), 107 diabetic (DM), and 27 post-surgical (PS). The statistical significance was calculated by Chi-square test and a P-value obtained for ID, DM, and PS. The statistical significance was calculated by Fischer exact test and a P-value obtained comparing male vs. female.Results: European centers had 61 GES patients compared to 319 from the US. In Europe, 100% of patients had gastric emptying test (GET) values available; in the US, it was 75% of patients. European centers had more DM patients (59%) than the US (22%), and a smaller proportion of ID patients (25%) than the US (72%). There was a statistical difference between the causes of gastroparesis in the patients receiving GES (P-value < 0.00001). There was also significant difference in the gender of the patients receiving GES, with a greater proportion of women in the US (P value = 0.0023).Conclusions: Comparing GES in US vs. Europe demonstrated significant differences in gastroparesis demographics and percentage of patients with GET data. After analyzing the previously discussed results and reviewing recent updates in evidence-based medicine guidelines, the discrepancy and variance in patient populations in the US and Europe emphasizes the need for a database that allows better analysis and treatment of gastroparesis patients worldwide including stimulation therapies.

BACKGROUND & AIMS: Genetic factors are believed to affect risk for irritable bowel syndrome (IBS), but there have been no sufficiently powered and adequately sized studies. To identify DNA variants associated with IBS risk, we performed a genome-wide association study (GWAS) of the large UK Biobank population-based cohort, which includes genotype and health data from 500,000 participants. METHODS: We studied 7,287,191 high-quality single nucleotide polymorphisms in individuals who self-reported a doctor's diagnosis of IBS (cases; n = 9576) compared to the remainder of the cohort (controls; n = 336,499) (mean age of study subjects, 40-69 years). Genome-wide significant findings were further investigated in 2045 patients with IBS from tertiary centers and 7955 population controls from Europe and the United States, and a small general population sample from Sweden (n = 249). Functional annotation of GWAS results was carried out by integrating data from multiple biorepositories to obtain biological insights from the observed associations. RESULTS: We identified a genome-wide significant association on chromosome 9q31.2 (single nucleotide polymorphism rs10512344; P = 3.57 × 10-8) in a region previously linked to age at menarche, and 13 additional loci of suggestive significance (P < 5.0×10-6). Sex-stratified analyses revealed that the variants at 9q31.2 affect risk of IBS in women only (P = 4.29 × 10-10 in UK Biobank) and also associate with constipation-predominant IBS in women (P = .015 in the tertiary cohort) and harder stools in women (P = .0012 in the population-based sample). Functional annotation of the 9q31.2 locus identified 8 candidate genes, including the elongator complex protein 1 gene (ELP1 or IKBKAP), which is mutated in patients with familial dysautonomia. CONCLUSIONS: In a sufficiently powered GWAS of IBS, we associated variants at the locus 9q31.2 with risk of IBS in women. This observation may provide additional rationale for investigating the role of sex hormones and autonomic dysfunction in IBS. ispartof: GASTROENTEROLOGY vol:155 issue:1 pages:168-179 ispartof: location:United States status: published

Background: Gastrointestinal complications are common in hereditary transthyretin amyloid (ATTRm) amyloidosis. The underlying mechanisms have not been fully elucidated, and the patients' small bowel function remains largely unexplored. The aim of the present study was to compare the small bowel motility in ATTRm amyloidosis patients with that in non-amyloidosis patient controls. Methods: ATTRm amyloidosis patients undergoing evaluation for liver transplantation were consecutively investigated with 24-hour duodenojejunal manometry (n=19). The somatostatin analogue octreotide was used to induce fasting motility. Patients with age at onset of 50years were defined as late-onset cases. For each patient, three age- and sex-matched patient controls (n=57) were selected from the total pool of investigated patients. Key Results: Manometry was judged as abnormal in 58% of the patients and in 26% of the patient controls (P=.01). Patients displayed significantly more daytime phase III migrating motor complexes than patient controls (median 4 vs 2, P

Patients with irritable bowel syndrome (IBS) often associate their symptoms to certain foods. In congenital sucrase-isomaltase deficiency (CSID), recessive mutations in the SI gene (coding for the disaccharidase digesting sucrose and 60% of dietary starch)1 cause clinical features of IBS through colonic accumulation of undigested carbohydrates, triggering bowel symptoms.2 Hence, in a previous study,3 we hypothesized that CSID variants reducing SI enzymatic activity may contribute to development of IBS symptoms. We detected association with increased risk of IBS for 4 rare loss-of-function variants typically found in (homozygous) CSID patients, because carriers (heterozygous) of these rare variants were more common in patients than in controls.1,4 Through a 2-step computational and experimental strategy, the present study aimed to determine whether other (dys-)functional SI variants are associated with risk of IBS in addition to known CSID mutations. We first aimed to identify all SI rare pathogenic variants (SI-RPVs) on the basis of integrated Mendelian Clinically Applicable Pathogenicity (M-CAP) and Combined Annotation Dependent Depletion (CADD) predictive (clinically relevant) scores; next, we inspected genotype data currently available for 2207 IBS patients from a large ongoing project to compare SI-RPV case frequencies with ethnically matched population frequencies from the Exome Aggregation Consortium (ExAC). ispartof: CLINICAL GASTROENTEROLOGY AND HEPATOLOGY vol:16 issue:10 pages:1673-1676 ispartof: location:United States status: published

ObjectiveIBS is a common gut disorder of uncertain pathogenesis. Among other factors, genetics and certain foods are proposed to contribute. Congenital sucrase–isomaltase deficiency (CSID) is a rare genetic form of disaccharide malabsorption characterised by diarrhoea, abdominal pain and bloating, which are features common to IBS. We tested sucrase–isomaltase (SI) gene variants for their potential relevance in IBS.DesignWe sequenced SI exons in seven familial cases, and screened four CSID mutations (p.Val557Gly, p.Gly1073Asp, p.Arg1124Ter and p.Phe1745Cys) and a common SI coding polymorphism (p.Val15Phe) in a multicentre cohort of 1887 cases and controls. We studied the effect of the 15Val to 15Phe substitution on SI function in vitro. We analysed p.Val15Phe genotype in relation to IBS status, stool frequency and faecal microbiota composition in 250 individuals from the general population.ResultsCSID mutations were more common in patients than asymptomatic controls (p=0.074; OR=1.84) and Exome Aggregation Consortium reference sequenced individuals (p=0.020; OR=1.57). 15Phe was detected in 6/7 sequenced familial cases, and increased IBS risk in case–control and population-based cohorts, with best evidence for diarrhoea phenotypes (combined p=0.00012; OR=1.36). In the population-based sample, 15Phe allele dosage correlated with stool frequency (p=0.026) and Parabacteroides faecal microbiota abundance (p=0.0024). The SI protein with 15Phe exhibited 35% reduced enzymatic activity in vitro compared with 15Val (pConclusionsSI gene variants coding for disaccharidases with defective or reduced enzymatic activity predispose to IBS. This may help the identification of individuals at risk, and contribute to personalising treatment options in a subset of patients.

Background Innate immune responses to conserved microbial products such as lipopolysaccharide (LPS) and flagellin are likely important in microbial–host interactions and intestinal homeostasis. We hypothesized that bacterial translocation and activation of mucosal immunity against common microbial antigens might be involved in the development of irritable bowel syndrome (IBS). We therefore compared serum levels of LPS, soluble CD14 (sCD14), and flagellin antibodies between patients with different subtypes of IBS and healthy controls. Methods We analyzed serum obtained from 88 patients (74 females) aged 19(43)–73 years and 106 healthy volunteers (77 females) aged 19(38)–62 years. Diarrhea-predominant IBS (D-IBS) was present in 32 patients (36%), 23 patients (26%) had constipation-predominant IBS (C-IBS), and 33 patients (38%) had A-IBS. We used ELISA for sCD14 and antiflagellin immunoglobulin G and limulus amebocyte assay for LPS. Abdominal symptoms and psychiatric comorbidities were assessed using validated questionnaires. Key Results We found a significantly higher serum level of LPS in patients with D-IBS compared to controls (p = 0.0155). The level of antibodies to flagellin was higher in patients with IBS than in controls (mainly driven by higher levels in D-IBS, p = 0.0018). The levels of sCD14 were lower in D-IBS patients compared to controls (p = 0.0498). We found a weak, but significant correlation between the levels of antiflagellin antibodies and anxiety among IBS patients (ρ = 0.38; p = 0.0045). Conclusions & Inferences Our results support the concept that immune reactivity to luminal antigens may have a role in the development of D-IBS. The serum level of antiflagellin antibodies was found to correlate with patients’ self-reported anxiety score.

Recently in Gut , genetic variation affecting ion channels activity has been highlighted in relation to bowel function and the biology of stool frequency.1 It is also known that 2% of patients with IBS carry functional missense mutations in the voltage-gated channel NaV1.5 ( SCN5A gene).2 Hence, channelopathies represent potential abnormalities underlying GI dysfunction and IBS. We inspected data from our previous genome-wide association study (GWAS) of IBS,3 in relation to 27 genes whose ion channel products contribute to GI sensorimotor development and function, visceral sensation and GI motility (see online supplementary table S1). Significant (uncorrected) results were detected for four genes (calcium voltage-gated channels CACNA1A and CACNA1E , and transient receptor potential channels TRPV3 and TRPM8 ; see online supplementary figure S1), which were selected for replication analyses in an independent set of IBS cases (N=386) and controls (N=357) (see online supplementary material methods). A sex-adjusted logistic regression analysis of genotype data from this cohort (see online supplementary material methods) detected significant associations for …

BACKGROUND & AIMS: SCN5A encodes the α-subunit of the voltage-gated sodium channel NaV1.5. Many patients with cardiac arrhythmias caused by mutations in SCN5A also have symptoms of irritable bowel syndrome (IBS). We investigated whether patients with IBS have SCN5A variants that affect the function of Nav1.5. METHODS: We performed genotype analysis of SCN5A in 584 persons with IBS and 1380 without (controls). Mutant forms of SCN5A were expressed in HEK-293 cells, and functions were assessed by voltage clamp analysis. A genome-wide association study (GWAS) was analyzed for an association signal for the SCN5A gene, and replicated in 1745 patients in 4 independent cohorts of IBS patients and controls. RESULTS: Missense mutations were found in SCN5A in 13/584 patients (2.2%, probands). Diarrhea-predominant IBS (IBS-D) was the most prevalent form of IBS in the overall study population (25%). However, a greater percentage of individuals with SCN5A mutations had constipation-predominant IBS (IBS-C, 31%) than IBS-D (10%, P

New diagnostic techniques have advanced our knowledge about the irritable bowel syndrome. The majority of patients that we believed to have a psychosomatic disorder have received other diagnoses explaining their symptoms. Endoscopy makes it possible to diagnose celiac disease before it leads to malnutrition and allows the detection of microscopic colitis as a cause of watery diarrhea. At the severe end of the symptom spectrum enteric dysmotility marks the border at which IBS ceases to be a functional disorder and becomes a genuine motility disorder. Joint hypermobility or Ehlers-Danlos syndrome is present in a substantial proportion of patients with enteric dysmotility. Chronic intestinal pseudo-obstruction is the end-stage of a large number of very rare disorders in which failed peristalsis is the common denominator. Nutritional needs and symptom control are essential in the management of pseudo-obstruction. Home parenteral nutrition is life saving in more than half of patients with chronic intestinal pseudo-obstruction.

The wireless motility-recording capsule, "SmartPill", is an ingested one-time use electronic capsule that measures gastrointestinal luminal pressure, pH and temperature along the whole gastrointestinal tract. The pH profile and the pressure patterns define the time at which the capsule moves from the stomach to the duodenum and from the ileum to the caecum, whereas changes in temperature define the times of ingestion and expulsion. The recordings from the wireless motility capsule are sent from a radio transmitter in the capsule to a receiver carried around the waist. Wireless motility recordings have several advantages over imaging and manometry that have been used previously. Primarily the simplicity by which motility recordings are done, as well as the tolerability for the patient and limited need of assistance are valuable aspects. The wireless motility capsule provides standardized measures of transit with relevant normal values for the clinical work-up of patients with motility disturbances.

The fundamental gastrointestinal functions include motility, sensation, absorption, secretion, digestion and intestinal barrier function. Digestion of food and absorption of nutrients normally occurs without conscious perception. Symptoms of functional gastrointestinal disorders are often triggered by meal intake suggesting abnormalities in the physiological processes are involved in the generation of symptoms. In this manuscript, normal physiology and pathophysiology of gastrointestinal function, and the processes underlying symptom generation are critically reviewed. The functions of each anatomical region of the digestive tract are summarized. The pathophysiology of perception, motility, mucosal barrier, and secretion in functional gastrointestinal disorders as well as effects of food, meal intake and microbiota on gastrointestinal motility and sensation are discussed. Genetic mechanisms associated with visceral pain and motor functions in health and functional gastrointestinal disorders are reviewed. Understanding the basis for digestive tract functions is essential to understand dysfunctions in the functional gastrointestinal disorders.

OBJECTIVE: This 1-year study aimed to assess low-dose budesonide therapy for maintenance of clinical remission in patients with collagenous colitis.DESIGN: A prospective, randomised, placebo-controlled study beginning with an 8-week open-label induction phase in which patients with histologically confirmed active collagenous colitis received budesonide (Budenofalk, 9 mg/day initially, tapered to 4.5 mg/day), after which 92 patients in clinical remission were randomised to budesonide (mean dose 4.5 mg/day; Budenofalk 3 mg capsules, two or one capsule on alternate days) or placebo in a 12-month double-blind phase with 6 months treatment-free follow-up. Primary endpoint was clinical remission throughout the double-blind phase.RESULTS: Clinical remission during open-label treatment was achieved by 84.5% (93/110 patients). The median time to remission was 10.5 days (95% CI (9.0 to 14.0 days)). The maintenance of clinical remission at 1 year was achieved by 61.4% (27/44 patients) in the budesonide group versus 16.7% (8/48 patients) receiving placebo (treatment difference 44.5% in favour of budesonide; 95% CI (26.9% to 62.7%), pCONCLUSIONS: Budesonide at a mean dose of 4.5 mg/day maintained clinical remission for at least 1 year in the majority of patients with collagenous colitis and preserved health-related quality of life without safety concerns. Treatment extension with low-dose budesonide beyond 1 year may be beneficial given the high relapse rate after budesonide discontinuation.TRIAL REGISTRATION NUMBERS: http://www.clinicaltrials.gov (NCT01278082) and http://www.clinicaltrialsregister.eu (EudraCT: 2007-001315-31).

Irritable bowel syndrome (IBS) is common in western Europe and North America, and many aspects of its epidemiology, risk factors, and natural history have been described in these regions. Recent data suggest, however, that IBS is also common in the rest of the world and there has been some evidence to suggest some differences in demographics and presenting features between IBS in the west and as it is experienced elsewhere. The World Gastroenterology Organization, therefore, established a Task Force comprising experts on the topic from all parts of the world to examine IBS from a global perspective. IBS does, indeed, seem to be common worldwide though with some significant variations in prevalence rates between regions and countries and there may well be some potentially interesting variations in presenting symptoms and sex distribution. The global map of IBS is far from complete; community-based prevalence data is not available from many areas. Furthermore, while some general trends are evident in terms of IBS impact and demographics, international comparisons are hampered by differences in diagnostic criteria, study location and methodology; several important unanswered questions have been identified that should form the basis for future collaborative research and have the potential to shed light on this challenging disorder. © 2012 by Lippincott Williams & Wilkins.

Early therapeutic decision-making is crucial in patients with higher-risk MDS where median survival is only around one year. Azacitidine prolongs survival for these patients (Fenaux et al, Lancet Oncology 2009) but clinically relevant biomarkers remain to be identified. We evaluated retrospectively, the impact of clinical parameters and mutational profiles in 134 consecutive patients treated with a median number of 7 cycles of Azacitidine (range 1-45), in accordance to European guidelines. The vast majority (n=114) had higher-risk disease i.e. MDS with IPSS int-2 or high, AML with multilinear dysplasia and 20-30% blasts or CMML-II. We combined an initial cohort from Karolinska University Hospital (n=89) with a validating cohort from King's College Hospital, London (n=45). Studied endpoints were response, as defined by the IWG criteria, and survival. Since prolonged survival is the main goal for this cohort of patients, we believe that survival is the most relevant endpoint, supported by the fact that even non-responding patients have a survival benefit from Azacitidine (Gore et al, Haematologica, 2013). While neither clinical parameters nor mutations had a significant impact on response rate, both karyotype and mutational profile were strongly associated with survival from the start of treatment, see Table 1 and Figure 1-2. IPSS high-risk cytogenetics was negatively associated with survival (median 20 vs 10 months; p Table 1. Variables associated with survival. Univariate analyses used the log-rank test. The cox model included all listed variables except response rate in a multivariate analyses. Estimated median survival (months) Univariate p-value Cox regression p-value Hazard ratio (95% CI) Response rate: CR / mCR vs PR/HI vs SD/PD 20 vs 20 vs 10 Figure 1. Kaplan-Meier estimated survival stratified for response and pre-treatment parameters Figure 1. Kaplan-Meier estimated survival stratified for response and pre-treatment parameters Figure 2. Forest plot indicating hazard ratio including confidence interval for all pre-treatment variables. The hazard ratios were retrieved using cox univariate regression models for each variable analyzed separately. Figure 2. Forest plot indicating hazard ratio including confidence interval for all pre-treatment variables. The hazard ratios were retrieved using cox univariate regression models for each variable analyzed separately. Figure 3. Kaplan-Meier estimated survival stratified for the two dominant predictors in the cox regression model: Adverse cytogenetics and histone modulator mutations Figure 3. Kaplan-Meier estimated survival stratified for the two dominant predictors in the cox regression model: Adverse cytogenetics and histone modulator mutations Disclosures McLornan: Novartis: Research Funding, Speakers Bureau. Jädersten:Celgene: Other: speakers fee. Kulasekararaj:Alexion: Consultancy. Mufti:Celgene: Consultancy, Other: Speakers fee. Hellström-Lindberg:Celgene Corporation: Research Funding.

Taken together, the above examples indicate that physiology-based diagnosis has a substantial overlap with symptom-based diagnosis. Neither symptomatic treatment nor therapy aimed at restoring normal physiology has had much success. It is still uncertain if measurement of physiologic parameters facilitates the doctor-patient relationship, whether results are abnormal or normal. However, the addition of physiology parameters to the evaluation of therapeutic interventions aimed at symptom reduction in FGIDs can possibly facilitate the identification of subgroups with a higher probability of treatment success. Unfortunately, our experience from clinical trials in this area is that physiology testing usually disappears as a new drug moves from phase II to phase III trials. In the ideal situation, the development of measurement methods with better availability and standardization, like different ingestible capsules, will help us to merge physiology and symptoms regarding both diagnosis and treatment evaluation.

Background Irritable bowel syndrome (IBS) is a widespread gastrointestinal disorder of unknown etiology. Recently, our group detected chlamydial antigens in enteroendocrine cells (EEC) of jejunum biopsies from patients with IBS. Impairment of EEC secretion upon Chlamydia infection might lead to disturbances of gut functions. We have therefore studied the interaction between Chlamydia and EEC in vitro. Methods Two different human enteroendocrine cell lines were studied: LCC-18 from a neuroendocrine colonic tumour and CNDT2 from a small intestinal carcinoid. Cell lines were infected with C. trachomatis serovar LGV II strain 434. We used Penicillin G for inducing persistent infection. The ultrastructure of infected cells was studied using transmission electron microscopy and immunofluorescence and we used RT-PCR analysis for studying changes in gene expression at different stages of infection. Key Results We found that both cell lines could be infected with C. trachomatis yielding productive infections and persistence could be induced using penicillin G. Immunofluorescence showed different cellular distributions of serotonin and chromogranin A in non-infected (cytoplasmatic distribution) compared with infected cells (serotonin and chromogranin mostly in chlamydial inclusions). In line with the microscopical findings, we found a significant down-regulation of the gene coding for the vesicular monoamine transporter (VMAT1) in infected compared with non-infected EEC (P

Conflicting data exist on whether discontinuation of proton pump inhibitors (PPIs) is associated with rebound secretion of gastric acid.A total of 48 healthy Helicobacter pylori-negative volunteers (24 females) were randomized in a double-blinded manner to treatment with either pantoprazole 40 mg or placebo once daily for 28 days. Dyspeptic symptoms were registered daily using the Glasgow dyspepsia score (GDS) 2 weeks before, during, and 6 weeks after treatment. Plasma levels of gastrin and serum levels of chromogranin-A levels were measured before, during, and after treatment.During the 2 weeks before treatment, the placebo group had a mean GDS of 0.20 + or - 0.7 compared with the pantoprazole group score of 0.54 + or - 1.3 (NS). No significant differences between the symptom severity scores of the two groups were shown during the treatment period. During the first week after discontinuation of treatment, the pantoprazole group had a mean symptom score of 5.7 + or - 11.7 vs. 0.74 + or - 2.6 in the placebo group (P0.01). A total of 11 out of 25 (44%) subjects in the pantoprazole group developed dyspepsia compared with 2 out of 23 (9%) in the placebo group (P0.01). During the second week of follow-up, the pantoprazole group had a mean symptom score of 1.6 + or - 3.4 compared with 0 + or - 0 in the placebo group (P0.05). There were no significant differences in the mean symptom score for the pantoprazole group (1.1 + or - 0.6) compared with the placebo group (0.4 + or - 0.3) during the third week of follow-up. Symptom scores during the first week after treatment correlated with basal (P0.01) and meal-stimulated (P0.01) gastrin levels at the end of treatment.A 4-week course of pantoprazole seems to induce dyspeptic symptoms in previously asymptomatic healthy H. pylori-negative subjects. The correlation between symptom score and gastrin levels suggests that these symptoms are due to acid rebound hypersecretion and seem to be related to the degree of acid inhibition.

The long-term survival of subjects with nonalcoholic fatty liver disease (NAFLD) in comparison with both individuals with elevated transaminases attributable to other causes and the general poulation is poorly characterized. This study was undertaken to determine the frequency of NAFLD in a cohort of subjects who underwent liver biopsy from 1980 to 1984 because of elevated liver enzymes, and to assess mortality among subjects with NAFLD in comparison with the general Swedish population. The 256 subjects (61% men) had a mean age of 45 ± 12 years at the inclusion. Liver biopsies were blindly scored for NAFLD and nonalcoholic steatohepatitis (NASH). Causes of death were ascertained from the national Swedish Cause of Death Registry. Fatty liver was detected in 143 of the 256 subjects, including 25 (10%) with alcoholic fatty liver disease and 118 (46%) exhibiting NAFLD. Of those, 51 (20%) were classified as NASH and 67 (26%) as nonalcoholic bland steatosis. Cirrhosis was present in 9% at inclusion. During the follow-up period, 113 (44%) of the total population and 47 (40%) of the 118 subjects diagnosed with NAFLD died. Of the 113 deaths, 37 were of cardiovascular disease and 16 of liver diseases. Compared with the total Swedish population, adjusted for sex, age, and calendar period, subjects with NAFLD exhibited a 69% increased mortality (standardized mortality ratio [SMR] = 1.69; 95% confidence interval [CI], 1.24–2.25); subjects with bland steatosis, a 55% increase (SMR, 1.55; 95% CI, 0.98–2.32; P = 0.062); and subjects with NASH, 86% (SMR, 1.86; 95% CI, 1.19–2.76; P = 0.007). Conclusion: Patients with NASH are at increased risk of death compared with the general population. Liver disease is the third most common cause of death among patients with NAFLD. (HEPATOLOGY 2009.)

Background and Aims: Small bowel manometry is increasingly used in the clinical investigation of patients with symptoms of intestinal motor dysfunction. Enteric dysmotility (ED) has been suggested as a new diagnostic term for patients with abnormal intestinal motor activity but no radiological signs of chronic intestinal pseudo-obstruction (CIP). Histopathological features of adult patients with ED and CIP have been compared in a large case series to study differences and similarities between the two diagnostic groups. Methods: Routine staining and an extensive panel of immunohistochemical stains on transversal and tangential cuts from full-thickness biopsies of the small bowel were used. Results: 39 females and 11 males with CIP and 58 females and 7 males with ED were investigated. The underlying lesion was more often a visceral myopathy (22% vs 5%) or neuromyopathy (30% vs 12%) in patients with CIP than in those with ED, whereas the predominant lesion in ED was neuropathy with inflammation. Conclusion: CIP in adults is associated with very different underlying pathology, whereas ED is more homogeneously associated with neuropathy in the enteric nervous system. Neuropathy of enteric ganglia with inflammation seems to be the most common cause for measurable disturbances of intestinal motor function.

Objective. To investigate whether patients with chronic intestinal pseudo-obstruction (CIP) differ from those with enteric dysmotility (ED) regarding self-reported measures of functional status, he ...

Chronic intestinal pseudo-obstruction (CIP) is the most severe form of intestinal dysmotility. Enteric dysmotility (ED) has been proposed as a new diagnostic label for patients with disturbed intestinal motility and severe symptoms but no radiological signs of pseudo-obstruction. The purpose of this study was to compare the clinical features, small-bowel manometry findings and long-term survival in patients with CIP and ED.Data collected during a 16-year period from 1987 to 2002 were retrospectively analysed and followed-up through 2007 in a tertiary referral centre. The study comprised 55 patients (41 F, median age 42 years, range 23-76) with CIP and 70 patients (63 F, median age 39 years, range 18-71) with ED.The median observation time was 9.9 years (range 5.2-20.1). Nineteen patients with CIP (35%) and 9 patients with ED (13%) died. Survival among patients with ED was significantly better (p0.05). Patients with CIP (49%) needed parenteral nutrition more often than patients with ED (14%). Small-bowel manometry showed similar abnormalities in the two groups but absence of a fed motor response to meals was seen in 16/43 patients with CIP compared to none with ED (p0.001), sustained periods of uncoordinated phasic activity were more common (p0.05) in CIP patients (23/45) than in ED patients (19/70) and severe hypomotility was only seen in 7 patients with CIP.CIP and ED differ with respect to severity of measurable physiological derangement, nutritional needs and long-term prognosis. Our findings indicate that CIP and ED are different entities that require different approaches to management.

This paper shows that an algorithm for differential diagnosis of jaundice developed in Denmark has been successfully transferred for use in a Swedish hospital. The algorithm, which is based on data from nearly 1000 patients, utilises 21 items of information from the medical history, physical examination and blood chemistry. The algorithm recognises four diagnostic groups: benign obstructive jaundice, malignant obstructive jaundice, acute non-obstructive jaundice, and chronic non-obstructive jaundice. To each item of information, a score is attached reflecting its weight of evidence. Summing the scores for the symptoms and signs that are present leads to a probabilistic statement about the diagnosis. Because of missing data in the Swedish patient material, three of the items were excluded from the original algorithm. Corrections were made for differences in the distribution of diseases. In reclassification of 985 Danish patients the modified algorithm's "best bid", i.e. the diagnosis given the highest probability, was correct in 78% of cases. More important, 93% of the cases given a "confident" diagnosis (probability greater than 0.80) were correct. The corresponding figures when the algorithm was applied to Swedish patients were 76% and 93%, respectively. In both series the predicted probabilities were matched by a corresponding proportion of actual diagnostic hits. It is concluded that the algorithm leads to reliable estimates of diagnostic probabilities in jaundice and that the algorithm seems to work well in Sweden also.

Patients with chronic intestinal dysmotility (CID) have a lifelong disease, and no curative treatment is available. Interventions are needed to improve the care and support of the patients. The aim of this study was to measure health-care consumption in adult patients with CID before and after the introduction of a specialized day-care unit.Retrospective analysis was made of medical and nursing records from 3 different health-care delivery systems: period I, traditional care (1987-1996); period II, outpatient clinic (1997-1999); and period III, specialized day-care unit (2000-2002). There were 54 patients (44 women) with a median age of 47 years (range, 22-80 years).The need for admissions to hospital care decreased from 80% to 35% of the patients after the introduction of the specialized day-care unit (P.002). Also, the mean number of days in hospital care per patient and year was reduced from 39.4 to 3.3 days. The number of outpatient visits remained unaltered. The average cost per patient-year decreased from $32,698 during traditional health-care services to $9,681 after introducing the specialized day-care unit (P.002). Irrespective of the form of care delivery, the majority of patients (67%-77%) needed daily treatment with analgesics, and 81%-84% needed nutritional support on a regular basis.Individually tailored care at a specialized day-care unit leads to substantially decreased needs for hospital stays and lower costs in patients with CID.

Advances in minimally invasive surgery have made laparoscopy and full-thickness bowel biopsy possible in the investigation of patients with suspected gastrointestinal neuromuscular disorders. The safety and diagnostic yield of this investigation have not been formally reported. A prospective study was undertaken of 124 patients with clinico-physiological diagnoses of chronic intestinal pseudo-obstruction, enteric dysmotility and severe irritable bowel syndrome undergoing LFTB in three European teaching centres with expertise in the management of gastrointestinal neuromuscular disorders. Perioperative data were collected including complications. Diagnostic yield was expressed as proportion with well-established specific neuromuscular abnormalities based on a protocol of routine and immunohistochemical techniques. The majority of patients underwent a laparoscopically assisted procedure with extracorporeal biopsy. Median operating time was 50 min, conversion rate 2% and length of stay 1 day. There was an 8% readmission rate for obstructive symptoms but minimal other morbidity and no mortality. Overall specific diagnostic yield was 81%, being high for jejunal biopsies (89%) but low for a small number of ileal and colonic biopsies. Laparoscopy and full-thickness biopsy of the bowel appears acceptable in terms of safety. It should be performed in a jejunal site to achieve a high diagnostic yield.

BACKGROUND: Opioids have inhibitory effects on gastric motility, but the mechanism is far from clear. Electrical slow waves in the stomach determine the frequency and the peristaltic nature of gast ...

Dyspeptic symptoms related to the upper gastrointestinal tract are often diffusely related to specific diseases. Nausea, vomiting, early satiety, fullness, epigastric pain and bloating can all be s...

Chronic disturbances of gastrointestinal function encompass a wide spectrum of clinical disorders that range from common conditions with mild-to-moderate symptoms to rare diseases characterized by a severe impairment of digestive function, including chronic pain, vomiting, bloating and severe constipation. Patients at the clinically severe end of the spectrum can have profound changes in gut transit and motility. In a subset of these patients, histopathological analyses have revealed abnormalities of the gut innervation, including the enteric nervous system, termed enteric neuropathies. This Review discusses advances in the diagnosis and management of the main clinical entities--achalasia, gastroparesis, intestinal pseudo-obstruction and chronic constipation--that result from enteric neuropathies, including both primary and secondary forms. We focus on the various evident neuropathologies (degenerative and inflammatory) of these disorders and, where possible, present the specific implications of histological diagnosis to contemporary treatment. This knowledge could enable the future development of novel targeted therapeutic approaches.

Several studies have indicated that colonic microbiota may exhibit important differences between patients with irritable bowel syndrome (IBS) and healthy controls. Less is known about the microbiota of the small bowel. We used massive parallel sequencing to explore the composition of small bowel mucosa-associated microbiota in patients with IBS and healthy controls. We analysed capsule biopsies from the jejunum of 35 patients (26 females) with IBS aged 18-(36)-57 years and 16 healthy volunteers (11 females) aged 20-(32)-48 years. Sequences were analysed based on taxonomic classification. The phyla with the highest total abundance across all samples were: Firmicutes (43%), Proteobacteria (23%), Bacteroidetes (15%), Actinobacteria (9.3%) and Fusobacteria (7.0%). The most abundant genera were: Streptococcus (19%), Veillonella (13%), Prevotella (12%), Rothia (6.4%), Haemophilus (5.7%), Actinobacillus (5.5%), Escherichia (4.6%) and Fusobacterium (4.3%). We found no difference among major phyla or genera between patients with IBS and controls. We identified a cluster of samples in the small bowel microbiota dominated by Prevotella, which may represent a common enterotype of the upper small intestine. The remaining samples formed a gradient, dominated by Streptococcus at one end and Escherichia at the other.

none 44 si IBS shows genetic predisposition, but adequately powered gene-hunting efforts have been scarce so far. We sought to identify true IBS genetic risk factors by means of genome-wide association (GWA) and independent replication studies. open Ek, Weronica E; Reznichenko, Anna; Ripke, Stephan; Niesler, Beate; Zucchelli, Marco; Rivera, Natalia V; Schmidt, Peter T; Pedersen, Nancy L; Magnusson, Patrik; Talley, Nicholas J; Holliday, Elizabeth G; Houghton, Lesley; Gazouli, Maria; Karamanolis, George; Rappold, Gudrun; Burwinkel, Barbara; Surowy, Harald; Rafter, Joseph; Assadi, Ghazaleh; Li, Ling; Papadaki, Evangelia; Gambaccini, Dario; Marchi, Santino; Colucci, Rocchina; Blandizzi, Corrado; Barbaro, Raffaella; Karling, Pontus; Walter, Susanna; Ohlsson, Bodil; Tornblom, Hans; Bresso, Francesca; Andreasson, Anna; Dlugosz, Aldona; Simren, Magnus; Agreus, Lars; Lindberg, Greger; Boeckxstaens, Guy; Bellini, Massimo; Stanghellini, Vincenzo; Barbara, Giovanni; Daly, Mark J; Camilleri, Michael; Wouters, Mira M; D'Amato, Mauro Ek, Weronica E; Reznichenko, Anna; Ripke, Stephan; Niesler, Beate; Zucchelli, Marco; Rivera, Natalia V; Schmidt, Peter T; Pedersen, Nancy L; Magnusson, Patrik; Talley, Nicholas J; Holliday, Elizabeth G; Houghton, Lesley; Gazouli, Maria; Karamanolis, George; Rappold, Gudrun; Burwinkel, Barbara; Surowy, Harald; Rafter, Joseph; Assadi, Ghazaleh; Li, Ling; Papadaki, Evangelia; Gambaccini, Dario; Marchi, Santino; Colucci, Rocchina; Blandizzi, Corrado; Barbaro, Raffaella; Karling, Pontus; Walter, Susanna; Ohlsson, Bodil; Tornblom, Hans; Bresso, Francesca; Andreasson, Anna; Dlugosz, Aldona; Simren, Magnus; Agreus, Lars; Lindberg, Greger; Boeckxstaens, Guy; Bellini, Massimo; Stanghellini, Vincenzo; Barbara, Giovanni; Daly, Mark J; Camilleri, Michael; Wouters, Mira M; D'Amato, Mauro

BACKGROUND & AIMS: Chronic intestinal pseudo-obstruction (CIPO) is characterized by severe intestinal dysmotility that mimics a mechanical subocclusion with no evidence of gut obstruction. We searched for genetic variants associated with CIPO to increase our understanding of its pathogenesis and to identify potential biomarkers. METHODS: We performed whole-exome sequencing of genomic DNA from patients with familial CIPO syndrome. Blood and lymphoblastoid cells were collected from patients and controls (individuals without CIPO); levels of messenger RNA (mRNA) and proteins were analyzed by quantitative reverse-transcription polymerase chain reaction, immunoblot, and mobility shift assays. Complementary DNAs were transfected into HEK293 cells. Expression of rad21 was suppressed in zebrafish embryos using a splice-blocking morpholino (rad21a). Gut tissues were collected and analyzed. RESULTS: We identified a homozygous mutation (p.622, encodes Ala>Thr) in RAD21 in patients from a consanguineous family with CIPO. Expression of RUNX1, a target of RAD21, was reduced in cells from patients with CIPO compared with controls. In zebrafish, suppression of rad21a reduced expression of runx1; this phenotype was corrected by injection of human RAD21 mRNA, but not with the mRNA from the mutated p.622 allele. rad21a Morpholino zebrafish had delayed intestinal transit and greatly reduced numbers of enteric neurons, similar to patients with CIPO. This defect was greater in zebrafish with suppressed expression of ret and rad21, indicating their interaction in the regulation of gut neurogenesis. The promoter region of APOB bound RAD21 but not RAD21 p.622 Ala>Thr; expression of wild-type RAD21 in HEK293 cells repressed expression of APOB, compared with control vector. The gut-specific isoform of APOB (APOB48) is overexpressed in sera from patients with CIPO who carry the RAD21 mutation. APOB48 also is overexpressed in sporadic CIPO in sera and gut biopsy specimens. CONCLUSIONS: Some patients with CIPO carry mutations in RAD21 that disrupt the ability of its product to regulate genes such as RUNX1 and APOB. Reduced expression of rad21 in zebrafish, and dysregulation of these target genes, disrupts intestinal transit and the development of enteric neurons. Background Aims Chronic intestinal pseudo-obstruction (CIPO) is characterized by severe intestinal dysmotility that mimics a mechanical subocclusion with no evidence of gut obstruction. We searched for genetic variants associated with CIPO to increase our understanding of its pathogenesis and to identify potential biomarkers. Methods We performed whole-exome sequencing of genomic DNA from patients with familial CIPO syndrome. Blood and lymphoblastoid cells were collected from patients and controls (individuals without CIPO); levels of messenger RNA (mRNA) and proteins were analyzed by quantitative reverse-transcription polymerase chain reaction, immunoblot, and mobility shift assays. Complementary DNAs were transfected into HEK293 cells. Expression of rad21 was suppressed in zebrafish embryos using a splice-blocking morpholino (rad21a). Gut tissues were collected and analyzed. Results We identified a homozygous mutation (p.622, encodes Ala>Thr) in RAD21 in patients from a consanguineous family with CIPO. Expression of RUNX1, a target of RAD21, was reduced in cells from patients with CIPO compared with controls. In zebrafish, suppression of rad21a reduced expression of runx1; this phenotype was corrected by injection of human RAD21 mRNA, but not with the mRNA from the mutated p.622 allele. rad21a Morpholino zebrafish had delayed intestinal transit and greatly reduced numbers of enteric neurons, similar to patients with CIPO. This defect was greater in zebrafish with suppressed expression of ret and rad21, indicating their interaction in the regulation of gut neurogenesis. The promoter region of APOB bound RAD21 but not RAD21 p.622 Ala>Thr; expression of wild-type RAD21 in HEK293 cells repressed expression of APOB, compared with control vector. The gut-specific isoform of APOB (APOB48) is overexpressed in sera from patients with CIPO who carry the RAD21 mutation. APOB48 also is overexpressed in sporadic CIPO in sera and gut biopsy specimens. Conclusions Some patients with CIPO carry mutations in RAD21 that disrupt the ability of its product to regulate genes such as RUNX1 and APOB. Reduced expression of rad21 in zebrafish, and dysregulation of these target genes, disrupts intestinal transit and the development of enteric neurons.

Interdigestive human small bowel motility is characterized by the migrating motor complex (MMC). The aims of this study were to: (i) establish the normal range of variables of the nocturnal jejunal MMC and (ii) incorporate these data in a subsequent meta-analysis. Eighty-one recordings were performed by prolonged (24 h) ambulatory manometry in 51 subjects in two centres. Quantitative analysis was undertaken of 419 Phase III and 332 Phase II episodes. Adjusted mean values of seven variables were calculated using a mixed-effects model. Meta-analysis of pooled published data to generate a reliable 95% reference range was also performed. Adjusted mean values and confidence intervals are presented for all seven variables. Intrasubject variances were large in comparison with intersubject. Meta-analysis of 19 studies (356 pooled patients) meeting inclusion criteria produced wide reference ranges. At least five such ranges are useful for the detection of abnormality in the individual. This is the largest study of normal volunteers presented to date, with ranges for many variables produced using appropriate statistical methodology. A model for definition of abnormality has been proposed. We recommend that these data may be used by investigators in this field as a complement to other existing indicators of small bowel dysmotility.

The aim of this study was to record gastric myoelectric activity using multichannel electrogastrography (EGG) and to determine if there are differences due to age, gender, body mass, and study location. In 61 normal subjects from four centers, fasting multichannel EGG was recorded for 1 h, followed by two 1-h postprandial recordings after a test meal. Variables assessed included dominant frequency (DF) and its power, percentage time in 2- to 4-cpm frequency, and percentage slow-wave coupling (%SWC). There were no significant differences in EGG parameters with respect to gender or age. Subjects with a BMI >25 had a decrease in the absolute DF power but a similar increase in the postprandial DF power. Subjects with a BMI >25 had a postprandial decrease in the %SWC compared to those with a BMI

PURPOSE: A significant proportion of patients with slow-transit constipation have abnormal small-bowel motility. It is unclear whether abnormal small-bowel motility indicates worse results after surgery for slow-transit constipation. We studied the results of colectomy with ileorectal anastomosis in patients with normal and abnormal antroduodenal manometry findings. METHODS: Seventeen, consecutive patients who had been referred for intractable constipation and who were found to suffer from slow-transit constipation underwent subtotal colectomy. All patients underwent a set of diagnostic investigations, including whole gut transit time, anorectal manometry, antroduodenal manometry, electromyography of the anal sphincter, balloon expulsion test, and defecography. Patients were followed up after five years. RESULTS: Patients’ median age at the time of the operation was 46 (range, 23–70) years, and the median duration of constipation was 31 (range, 11–65) years. One patient died 21 days after the operation. Three patients developed intestinal pseudo-obstruction after the operation, and two of these died during the follow-up period. Fourteen patients were available for follow-up after a median of five (range, 4–7) years. Bowel frequency was significantly increased from a median of 0 (range, 0–2) times per week to a median of 30 (range, 10–102) times per week after surgery (P < 0.001). The incidence of abdominal pain decreased from 94 to 43 percent. Seven of 13 patients (54 percent) continued to have bloating. At long-term follow-up, 12 of 14 patients (86 percent) reported that they had an overall improvement after surgery, despite continuing pain and bloating in a significant proportion of them. The outcome of surgery was good or excellent in seven of seven patients with normal findings on antroduodenal manometry, but only five of nine patients with abnormal manometry findings attained a good result after surgery. We found a trend (P = 0.09) toward better long-term results after surgery for slow-transit constipation in patients with a normal antroduodenal manometry before the operation.

In this prospective randomized multicenter trial 93 patients, median age 72 years, with RAEB-t (n=25) and myelodysplastic syndrome (MDS)-AML (n=68) were allocated to a standard induction chemotherapy regimen (TAD 2+7) with or without addition of granulocyte-macrophage-CSF (GM-CSF). The overall complete remission (CR) rate was 43% with no difference between the arms. Median survival times for all patients, CR patients, and non-CR patients were 280, 550, and 100 days, respectively, with no difference between the arms. Response rates were significantly better in patients with serum lactate dehydrogenase (S-LDH) levels

We have published previously a prototype of a decision model for anaemic patients with myelodysplastic syndromes (MDS), in which transfusion need and serum erythropoietin (S-Epo) were used to define three groups with different probabilities of erythroid response to treatment with granulocyte colony-stimulating factor (G-CSF) + Epo. S-Epo 500 U/l and >/= 2 units/month for a poor response, whereas the presence of only one negative prognostic marker predicted an intermediate response. A total of 53 patients from a prospective study were included in our evaluation sample. Patients with good or intermediate probability of response were treated with G-CSF + Epo. The overall response rate was 42% with 28.3% achieving a complete and 13.2% a partial response to treatment. The response rates were 61% and 14% in the good and intermediate predictive groups respectively. The model retained a significant predictive value in the evaluation sample (P < 0.001). Median duration of response was 23 months. Scores for global health and quality of life (QOL) were significantly lower in MDS patients than in a reference population, and fatigue and dyspnoea was significantly more prominent. Global QOL improved in patients responding to treatment (P = 0.01). The validated decision model defined a subgroup of patients with a response rate of 61% (95% confidence interval 48-74%) to treatment with G-CSF + Epo. The majority of these patients have shown complete and durable responses.

Evidence for the effectiveness of existing treatments of patients with eating disorders is weak. Here we describe and evaluate a method of treatment in a randomized controlled trial. Sixteen patients, randomly selected out of a group composed of 19 patients with anorexia nervosa and 13 with bulimia nervosa, were trained to eat and recognize satiety by using computer support. They rested in a warm room after eating, and their physical activity was restricted. The patients in the control group ( n = 16) received no treatment. Remission was defined by normal body weight (anorexia), cessation of binge eating and purging (bulimia), a normal psychiatric profile, normal laboratory test values, normal eating behavior, and resumption of social activities. Fourteen patients went into remission after a median of 14.4 months (range 4.9–26.5) of treatment, but only one patient went into remission while waiting for treatment ( P = 0.0057). Relapse is considered a major problem in patients who have been treated to remission. We therefore report results on a total of 168 patients who have entered our treatment program. The estimated rate of remission was 75%, and estimated time to remission was 14.7 months (quartile range 9.6 ≥ 32). Six patients (7%) of 83 who were treated to remission relapsed, but the others (93%) have remained in remission for 12 months (quartile range 6–36). Because the risk of relapse is maximal in the first year after remission, we suggest that most patients treated with this method recover.