A Nonviable Probiotic in Irritable Bowel Syndrome: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study.

BACKGROUND & AIMS: The aim of this study was to investigate the effectiveness of oral treatment with a nonviable probiotic lysate (BL) of Escherichia coli (DSM 17252) and Enterococcus faecalis (DSM 16440) in patients with irritable bowel syndrome (IBS). METHODS: A phase IV, randomized, double-blind, placebo-controlled, multicenter (30 study sites), parallel group study was conducted in 389 patients of both sexes with IBS according to Rome III criteria. The treatment period was 26 weeks. The participants were allocated to either placebo or BL after a 2-week baseline period. The primary outcome was based on the European Medicines Agency IBS guideline: improvement in global assessment (GAI) and improvement in abdominal pain. RESULTS: Patients (BL, n = 191; placebo, n = 198) had similar baseline values and dropout rates. Overall, the response was similar between BL and placebo for IBS-GAI (17.4% and 14.4%, respectively; P = ·4787) and abdominal pain (42.0% and 35.4%, respectively; P = ·1419). Some secondary outcome measures and sensitivity analyses pointed toward potentially higher sensitivity of the abdominal pain measures in diarrhea-predominant IBS (IBS-D) but not the other subtypes. For the GAI, no subgroup differences were detected. For IBS-D, post hoc analyses for abdominal pain response over time and stool consistency showed potentially promising effects of BL. Finally, the treatment with BL was well-tolerated. CONCLUSIONS: BL is not effective across all IBS subtypes. However, BL may offer a treatment option for IBS-D that needs verification by an adequately powered drug trial; EudraCT-No.: 2012-002741-38.

The alternative serotonin transporter promoter P2 impacts gene function in females with irritable bowel syndrome.

Irritable bowel syndrome (IBS) is a gut-brain disorder in which symptoms are shaped by serotonin acting centrally and peripherally. The serotonin transporter gene SLC6A4 has been implicated in IBS pathophysiology, but the underlying genetic mechanisms remain unclear. We sequenced the alternative P2 promoter driving intestinal SLC6A4 expression and identified single nucleotide polymorphisms (SNPs) that were associated with IBS in a discovery sample. Identified SNPs built different haplotypes, and the tagging SNP rs2020938 seems to associate with constipation-predominant IBS (IBS-C) in females. rs2020938 validation was performed in 1978 additional IBS patients and 6,038 controls from eight countries. Meta-analysis on data from 2,175 IBS patients and 6,128 controls confirmed the association with female IBS-C. Expression analyses revealed that the P2 promoter drives SLC6A4 expression primarily in the small intestine. Gene reporter assays showed a functional impact of SNPs in the P2 region. In silico analysis of the polymorphic promoter indicated differential expression regulation. Further follow-up revealed that the major allele of the tagging SNP rs2020938 correlates with differential SLC6A4 expression in the jejunum and with stool consistency, indicating functional relevance. Our data consolidate rs2020938 as a functional SNP associated with IBS-C risk in females, underlining the relevance of SLC6A4 in IBS pathogenesis.

[Bile acid diarrhea, stepchild of chronic diarrhea - prevalence, diagnosis and treatment. Update 2021]. / Chologene Diarrhö, Stiefkind der chronischen Diarrhö ­ Prävalenz, Diagnostik und Therapie. Update 2021.

Bile acid diarrhea is one of the most frequently undiagnosed causes of chronic diarrhea. A variety of different pathophysiologic causes can underlie chronic diarrhea. Even after exclusion of the more frequent causes, up to 5 % of the population remains affected by unexplained chronic diarrhea. In up to 50 % within this cohort, bile acid diarrhea is the underlying cause.The various pathophysiologies leading to bile acid diarrhea are well characterized. In this way, bile acid diarrhea can be divided into primary, secondary and tertiary subtypes. Common to all causes is the increased amount of bile acids in the colon and in the faeces and the resulting secretory-osmotic diarrhea, in more severe forms in combination with steatorrhea. The diagnosis of bile acid diarrhea follows a clear algorithm which, in addition to the search for the cause and possibly a therapeutic trial, recognizes the 75SeHCAT test as the reference method for the detection of an increased loss of bile acids. In view of the chronic nature of the symptoms and the need for permanent, lifelong therapy, the use of a one-time, reliable diagnostic test is justified, though the test is currently only available at a few centers. In addition to the treatment of identifiable underlying diseases, the current treatment includes the use of drugs that bind bile acids, with additional nutritional recommendations and vitamin substitutions.The present review article summarizes the pathophysiology and importance of bile acid diarrhea and discusses the current approach towards diagnosis and treatment.

[Food Allergy and Intolerance : Distinction, Definitions and Delimitation]. / Nahrungsmittelallergien und andere -unverträglichkeiten : Bedeutung, Begriffe und Begrenzung.

Immunologically mediated hypersensitivity to foods is defined as food allergy, mainly due to immunglobulins of class E (IgE) triggering immediate reactions (type I hypersensitivity) with possible involvement of mucosa, skin, airways, intestinal tract, and the vascular system. Primary food allergy is based on (early) IgE sensitization against animal (e. g., cow's milk, hen's eggs) or plant proteins (e. g. peanut, hazelnut or wheat). In the case of secondary food allergies, IgE against pollen proteins (e. g., birch) reacts to structurally related food proteins (with cross-reactions to stone and pit fruits). Non-immunological food intolerance reactions are mostly based on carbohydrate malassimilation (e. g., lactose intolerance, fructose malabsorption) and are rarely due to pseudo-allergies (e. g., flavors, dyes, preservatives) primarily in patients with chronic urticaria. Common intestinal symptoms are mainly due to functional disorders (e. g., irritable bowel disease), rarely because of inflammatory intestinal diseases (e. g., celiac disease). Histamine intolerance, gluten hypersensitivity, and so-called food type III hypersensitivities are controversial diagnoses. The aforementioned disease entities/models are of variable importance for the affected individuals, the public health system, and society in general.

Possible etiology of improvements in both quality of life and overlapping gastroesophageal reflux disease by proton pump inhibitor treatment in a prospective randomized controlled trial.

BACKGROUND: Symptoms suggestive of functional dyspepsia (FD) and irritable bowel syndrome (IBS) frequently overlap with those of gastroesophageal reflux disease. Despite the high prevalence of symptomatic overlap, the underlying etiology remains poorly defined. We assessed the correlation of symptomatic relief and health-related quality of life (HRQoL) with healing of reflux esophagitis to further derive insights into the underlying etiology. METHODS: 626 patients with reflux esophagitis were enrolled into one of two treatment groups (classical healing concept or the complete remission concept) to investigate differences in treatment intensity. Patients were treated with pantoprazole until esophageal mucosal healing. Remission was followed for up to 6 months without treatment. Gastro-intestinal symptoms and HRQoL were analyzed using disease-specific, psychometrically validated patient-reported outcome instruments (ReQuest™, GERDyzer™). RESULTS: Symptomatic burden reflected by ReQuest™ substantially decreased from baseline to end of treatment by 83% and 88% in either treatment group, respectively. ReQuest™ scores significantly decreased in patients with or without heartburn and in those with symptoms suggestive of FD and IBS, indicating response of all symptom categories to treatment (p < 0.005). Therapy-associated relief of symptoms was paralleled by substantial gains in HRQoL, which continued to stabilize post-treatment. CONCLUSIONS: Pantoprazole is effective in relieving upper and lower gastro-intestinal symptoms overlapping with erosive esophagitis, and provides sustained improvement in HRQoL post-treatment. Our results propose a link between both healing of erosive esophagitis and the slower remission of upper and lower gastro-intestinal symptoms. Since the improvement observed is likely to be multifactorial, the possibility for an immune-mediated etiology and identification of putative susceptibility factors by genome-wide association study may provide focus for future research. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00325676.

Serotonin type 3 receptor subunit gene polymorphisms associated with psychosomatic symptoms in irritable bowel syndrome: A multicenter retrospective study.

BACKGROUND: Single-nucleotide polymorphisms (SNPs) of the serotonin type 3 receptor subunit (HTR3) genes have been associated with psychosomatic symptoms, but it is not clear whether these associations exist in irritable bowel syndrome (IBS). AIM: To assess the association of HTR3 polymorphisms with depressive, anxiety, and somatization symptoms in individuals with IBS. METHODS: In this retrospective study, 623 participants with IBS were recruited from five specialty centers in Germany, Sweden, the United States, the United Kingdom, and Ireland. Depressive, anxiety, and somatization symptoms and sociodemographic characteristics were collected. Four functional SNPs - HTR3A c.-42C>T, HTR3B c.386A>C, HTR3C c.489C>A, and HTR3E c.*76G>A - were genotyped and analyzed using the dominant and recessive models. We also performed separate analyses for sex and IBS subtypes. SNP scores were calculated as the number of minor alleles of the SNPs above. The impact of HTR3C c.489C>A was tested by radioligand-binding and calcium influx assays. RESULTS: Depressive and anxiety symptoms significantly worsened with increasing numbers of minor HTR3C c.489C>A alleles in the dominant model (F depressive = 7.475, P depressive = 0.006; F anxiety = 6.535, P anxiety = 0.011). A higher SNP score (range 0-6) was linked to a worsened depressive symptoms score (F = 7.710, P-linear trend = 0.006) in IBS. The potential relevance of the HTR3C SNP was corroborated, showing changes in the expression level of 5-HT3AC variant receptors. CONCLUSION: We have provided the first evidence that HTR3C c.489C>A is involved in depressive and anxiety symptoms in individuals with IBS. The SNP score indicated that an increasing number of minor alleles is linked to the worsening of depressive symptoms in IBS.

The serotonin receptor 3E variant is a risk factor for female IBS-D.

Irritable bowel syndrome (IBS) is a gut-brain disorder of multifactorial origin. Evidence of disturbed serotonergic function in IBS accumulated for the 5-HT3 receptor family. 5-HT3Rs are encoded by HTR3 genes and control GI function, and peristalsis and secretion, in particular. Moreover, 5-HT3R antagonists are beneficial in the treatment of diarrhea predominant IBS (IBS-D). We previously reported on functionally relevant SNPs in HTR3A c.-42C > T (rs1062613), HTR3C p.N163K (rs6766410), and HTR3E c.*76G > A (rs56109847 = rs62625044) being associated with IBS-D, and the HTR3B variant p.Y129S (rs1176744) was also described within the context of IBS. We performed a multi-center study to validate previous results and provide further evidence for the relevance of HTR3 genes in IBS pathogenesis. Therefore, genotype data of 2682 IBS patients and 9650 controls from 14 cohorts (Chile, Germany (2), Greece, Ireland, Spain, Sweden (2), the UK (3), and the USA (3)) were taken into account. Subsequent meta-analysis confirmed HTR3E c.*76G > A (rs56109847 = rs62625044) to be associated with female IBS-D (OR = 1.58; 95% CI (1.18, 2.12)). Complementary expression studies of four GI regions (jejunum, ileum, colon, sigmoid colon) of 66 IBS patients and 42 controls revealed only HTR3E to be robustly expressed. On top, HTR3E transcript levels were significantly reduced in the sigma of IBS patients (p = 0.0187); more specifically, in those diagnosed with IBS-D (p = 0.0145). In conclusion, meta-analysis confirmed rs56109847 = rs62625044 as a risk factor for female IBS-D. Expression analysis revealed reduced HTR3E levels in the sigmoid colon of IBS-D patients, which underlines the relevance of HTR3E in the pathogenesis of IBS-D.

Quality of life in patients with irritable bowel syndrome.

There has been an underestimation of the impact of irritable bowel syndrome (IBS) on an individual's functioning and quality of life (QoL). The general health status of both young and elderly individuals with IBS is generally found to be poorer than that of the general population. Patients with IBS seem to have worse health-related quality of life (HRQoL) than patients with certain other conditions such as gastroesophageal reflux disease, diabetes, and end-stage renal disease. Various disease-specific instruments are now available and are widely used in clinical trials to measure changes in QoL in patients with IBS after treatment intervention. Although few such data are presently available from clinical trials, it seems that patients who have a therapeutic response to therapy for IBS have a corresponding improvement in HRQoL. There seems to be no major differences in HRQoL based on IBS subtype (constipation-dominant or diarrhea-dominant). However, the severity of bowel symptoms in IBS is associated with a corresponding impact on HRQoL and patients with worse bowel symptoms have a greater diminished QoL compared with patients with milder symptoms. Evidence also indicates that HRQoL in patients with IBS is affected by sex and psychological conditions. Careful consideration of these factors may help to individualize a therapeutic strategy to optimize long-term outcomes.

Prediction of response to PPI therapy and factors influencing treatment outcome in patients with GORD: a prospective pragmatic trial using pantoprazole.

BACKGROUND: Management of patients with gastro-oesophageal reflux disease (GORD) can be assisted by information predicting the likely response to proton pump inhibitor (PPI) treatment. The aim was to undertake a study of GORD patients designed to approximate ordinary clinical practice that would identify patient characteristics predicting symptomatic response to pantoprazole treatment. METHODS: 1888 patients with symptoms of GORD were enrolled in a multicentre, multinational, prospective, open study of 8 weeks pantoprazole treatment, 40 mg daily. Response was assessed by using the ReQuest™ questionnaire, by the investigator making conventional clinical enquiry and by asking patients about their satisfaction with symptom control. Factors including pre-treatment oesophagitis, gender, age, body mass index (BMI), Helicobacter pylori status, anxiety and depression, and concurrent IBS symptoms were examined using logistic regression to determine if they were related to response, judged from the ReQuest™-GI score. RESULTS: Poorer treatment responses were associated with non-erosive reflux disease, female gender, lower BMI, anxiety and concurrent irritable bowel syndrome symptoms before treatment. No association was found with age, Helicobacter pylori status or oesophagitis grade. Some reflux-related symptoms were still present in 14% of patients who declared themselves 'well-satisfied' with their symptom control. CONCLUSIONS: Some readily identifiable features help to predict symptomatic responses to a PPI and consequently may help in managing patient expectation. ClinicalTrial.gov identifier: NCT00312806.

First evidence for an association of a functional variant in the microRNA-510 target site of the serotonin receptor-type 3E gene with diarrhea predominant irritable bowel syndrome.

Diarrhea predominant irritable bowel syndrome (IBS-D) is a complex disorder related to dysfunctions in the serotonergic system. As cis-regulatory variants can play a role in the etiology of complex conditions, we investigated the untranslated regions (UTRs) of the serotonin receptor type 3 subunit genes HTR3A and HTR3E. Mutation analysis was carried out in a pilot sample of 200 IBS patients and 100 healthy controls from the UK. The novel HTR3E 3'-UTR variant c.*76G>A (rs62625044) was associated with female IBS-D (P = 0.033, OR = 8.53). This association was confirmed in a replication study, including 119 IBS-D patients and 195 controls from Germany (P = 0.0046, OR = 4.92). Pooled analysis resulted in a highly significant association of c.*76G>A with female IBS-D (P = 0.0002, OR = 5.39). In a reporter assay, c.*76G>A affected binding of miR-510 to the HTR3E 3'-UTR and caused elevated luciferase expression. HTR3E and miR-510 co-localize in enterocytes of the gut epithelium as shown by in situ hybridization and RT-PCR. This is the first example indicating micro RNA-related expression regulation of a serotonin receptor gene with a cis-regulatory variant affecting this regulation and appearing to be associated with female IBS-D.

The Role of Brain-Derived Neurotrophic Factor in Irritable Bowel Syndrome.

Several studies have implied a role of brain-derived neurotrophic factor (BDNF) in abdominal pain modulation in irritable bowel syndrome (IBS). The aim of this study was to establish BDNF protein expression in human colonic biopsies and to show variation in IBS compared to controls. BDNF protein and mRNA levels were correlated with IBS symptom severity based on the IBS-symptom severity score (IBS-SSS). Biopsies from the descending colon and IBS-SSS were obtained from 10 controls and 20 IBS patients. Total protein of biopsies was extracted and assessed by ELISA and Western Blot. Total mRNA was extracted and gene expression measured by nCounter analysis. In IBS patients, symptom severity scores ranged from 124 to 486 (mean ± sem: 314.2 ± 21.2, >300 represents severe IBS) while controls ranged from 0 to 72 (mean ± sem: 27.7 ± 9.0, <75 represents healthy subjects, p < 0.001). IBS patients reported significantly more food malabsorption, former abdominal surgery and psychiatric comorbidities. BDNF protein was present in all samples and did not differ between IBS and controls or sex. Subgroup analysis showed that female IBS patients expressed significantly more BDNF mRNA compared to male patients (p < 0.05) and male IBS-D patients had higher IBS symptom severity scores and lower BDNF mRNA and protein levels compared to male controls (p < 0.05). Scatter plot showed a significant negative correlation between IBS-SSS and BDNF mRNA levels in the cohort of male IBS-D patients and their male controls (p < 0.05). We detected a high proportion of gastrointestinal surgery in IBS patients and confirmed food intolerances and psychiatric diseases as common comorbidities. Although in a small sample, we demonstrated that BDNF is detectable in human descending colon, with higher BDNF mRNA levels in female IBS patients compared to males and lower mRNA and protein levels in male IBS-D patients compared to male controls. Further research should be directed toward subgroups of IBS since their etiologies might be different.

Corticotropin-releasing factor-overexpressing mice exhibit reduced neuronal activation in the arcuate nucleus and food intake in response to fasting.

Corticotropin-releasing factor (CRF) overexpressing (OE) mice are a genetic model that exhibits features of chronic stress. We investigated whether the adaptive feeding response to a hypocaloric challenge induced by food deprivation is impaired under conditions of chronic CRF overproduction. Food intake response to a 16-h overnight fast and ip injection of gut hormones regulating food intake were compared in CRF-OE and wild type (WT) littermate mice along with brain Fos expression, circulating ghrelin levels, and gastric emptying of a nonnutrient meal. CRF-OE mice injected ip with saline showed a 47 and 44% reduction of 30-min and 4-h cumulative food intake response to an overnight fast, respectively, compared with WT. However, the 30-min food intake decrease induced by ip cholecystokinin (3 microg/kg) and increase by ghrelin (300 microg/kg) were similar in CRF-OE and WT mice. Overnight fasting increased the plasma total ghrelin to similar levels in CRF-OE and WT mice, although CRF-OE mice had a 2-fold reduction of nonfasting ghrelin levels. The number of Fos-immunoreactive cells induced by fasting in the arcuate nucleus was reduced by 5.9-fold in CRF-OE compared with WT mice whereas no significant changes were observed in other hypothalamic nuclei. In contrast, fasted CRF-OE mice displayed a 5.6-fold increase in Fos-immunoreactive cell number in the dorsal motor nucleus of the vagus nerve and a 34% increase in 20-min gastric emptying. These findings indicate that sustained overproduction of hypothalamic CRF in mice interferes with fasting-induced activation of arcuate nucleus neurons and the related hyperphagic response.

Irritable bowel syndrome, mental health, and quality of life: Data from a population-based survey in Germany (SHIP-Trend-0).

BACKGROUND: Irritable bowel syndrome (IBS) is associated with reduced quality of life and high healthcare costs. This study aimed to assess the prevalence and risk factors for IBS in a general adult population. METHODS: The Study of Health in Pomerania (SHIP) is a population-based cohort study in northeastern Germany. SHIP-Trend-0 participants enrolled from 2008 to 2012 were grouped according to Rome III criteria (main criteria: abdominal discomfort or crampy or bloating pain for at least six months plus 2/3 additional criteria). Factors associated with IBS were assessed using survey-weighted backward stepwise logistic regression. KEY RESULTS: The final data set included 4194 records. IBS prevalence was 3.5% (3.0%-4.2%). Unemployment (OR: 2.02, 1.26-3.21), headaches (OR: 2.37, 1.59-3.52), mental quality of life (OR: 0.95 per unit increase, 0.93-0.97), and interactions between gender and physical quality of life (P = 0.004) and gender and alexithymia (P = 0.002) predicted IBS probability. The model resulted in a good discrimination (area under the curve = 75.4%) and model fit (F = 0.72, P = 0.69). History of depression (OR: 2.77, 1.94-3.95), back pain (OR: 2.38, 1.69-3.35), early trauma (OR: 1.03, 1.02-1.04), and duration of inpatient treatment within the last twelve months (OR: 1.02, 1.01-1.04) lost their significance in multivariable analysis. CONCLUSIONS & INFERENCES: IBS prevalence was relatively low compared to other studies. Factors predicting IBS were of biological, psychological, and social nature. The association between IBS and pain in different areas of the body indicates a potential underlying complex somatic symptom disorder.

Peripheral obestatin has no effect on feeding behavior and brain Fos expression in rodents.

Obestatin is produced in the stomach from proghrelin by post-translational cleavage. The initial report claimed anorexigenic effects of obestatin in mice. Contrasting studies indicated no effect of obestatin on food intake (FI). We investigated influences of metabolic state (fed/fasted), environmental factors (dark/light phase) and brain Fos response to intraperitoneal (ip) obestatin in rats, and used the protocol from the original study assessing obestatin effects in mice. FI was determined in male rats injected ip before onset of dark or light phase, with obestatin (1 or 5 micromol/kg), CCK8S (3.5 nmol/kg) or 0.15 M NaCl, after fasting (16 h, n=8/group) or ad libitum (n=10-14/group) food intake. Fos expression in hypothalamic and brainstem nuclei was examined in freely fed rats 90 min after obestatin (5 micromol/kg), CCK8S (1.75 nmol/kg) or 0.15 M NaCl (n=4/group). Additionally, fasted mice were injected ip with obestatin (1 micromol/kg) or urocortin 1 (2 nmol/kg) 15 min before food presentation. No effect on FI was observed after obestatin administration during the light and dark phase under both metabolic conditions while CCK8S reduced FI irrespectively of the conditions. The number of Fos positive neurons was not modified by obestatin while CCK8S increased Fos expression in selective brain nuclei. Obestatin did not influence the refeeding response to a fast in mice, while urocortin was effective. Therefore, peripheral obestatin has no effect on FI under various experimental conditions and did not induce Fos in relevant central neuronal circuitries modulating feeding in rodents.

Desacyl ghrelin inhibits the orexigenic effect of peripherally injected ghrelin in rats.

Studies showed that the metabolic unlike the neuroendocrine effects of ghrelin could be abrogated by co-administered unacylated ghrelin. The aim was to investigate the interaction between ghrelin and desacyl ghrelin administered intraperitoneally on food intake and neuronal activity (c-Fos) in the arcuate nucleus in non-fasted rats. Ghrelin (13 microg/kg) significantly increased food intake within the first 30 min post-injection. Desacyl ghrelin at 64 and 127 microg/kg injected simultaneously with ghrelin abolished the stimulatory effect of ghrelin on food intake. Desacyl ghrelin alone at both doses did not alter food intake. Both doses of desacyl ghrelin injected separately in the light phase had no effects on food intake when rats were fasted for 12h. Ghrelin and desacyl ghrelin (64 microg/kg) injected alone increased the number of Fos positive neurons in the arcuate nucleus compared to vehicle. The effect on neuronal activity induced by ghrelin was significantly reduced when injected simultaneously with desacyl ghrelin. Double labeling revealed that nesfatin-1 immunoreactive neurons in the arcuate nucleus are activated by simultaneous injection of ghrelin and desacyl ghrelin. These results suggest that desacyl ghrelin suppresses ghrelin-induced food intake by curbing ghrelin-induced increased neuronal activity in the arcuate nucleus and recruiting nesfatin-1 immunopositive neurons.

Peripheral injection of ghrelin induces Fos expression in the dorsomedial hypothalamic nucleus in rats.

Peripheral ghrelin has been shown to act as a gut-brain peptide exerting a potent orexigenic effect on food intake. The dorsomedial nucleus of the hypothalamus (DMH) is innervated by projections from other brain areas being part of the network of nuclei controlling energy homeostasis, among others NPY/AgRP-positive fibers arising from the arcuate nucleus (ARC). The aim of the study was to determine if peripherally administered ghrelin affects neuronal activity in the DMH, as assessed by Fos expression. The number of Fos positive neurons was determined in the DMH, paraventricular nucleus of the hypothalamus (PVN), ARC, ventromedial hypothalamic nucleus (VMH), nucleus of the solitary tract (NTS) and in the area postrema (AP) in non-fasted Sprague-Dawley rats in response to intraperitoneally (ip) injected ghrelin (3 nmol/rat) or vehicle (0.15 M NaCl). Peripheral ghrelin induced a significant increase in the number of Fos-ir positive neurons/section compared with vehicle in the ARC (mean+/-SEM: 49+/-2 vs. 23+/-2 neurons/section, p=0.001), PVN (69+/-5 vs. 34+/-3, p=0.001), and DMH (142+/-5 vs. 83+/-5, p<0.001). Fos-ir positive neurons were mainly localized within the ventral part of the DMH. No change in Fos expression was observed in the VMH (53+/-8 vs. 48+/-6, p=0.581), NTS (42+/-2 vs. 40+/-3, p=0.603), and in the AP (7+/-1 vs. 5+/-1, p=0.096). Additional double-labelling with anti-Fos and anti-AgRP revealed that Fos positive neurons in the DMH were encircled by a network of AgRP-ir positive fibers. These data indicate that peripheral ghrelin activates DMH neurons and that NPY-/AgRP-positive fibers may be involved in the response.

Irregular absorption profiles observed from diclofenac extended release tablets can be predicted using a dissolution test apparatus that mimics in vivo physical stresses.

The prediction of the in vivo drug release characteristics of modified release oral dosage forms by in vitro dissolution tests is a prerequisite for successful product development. A novel dissolution test apparatus that mimics the physical conditions experienced by an oral formulation during gastrointestinal transit was developed. This included the simulation of pressure forces exerted by gut wall motility, shear forces generated during propagation, and loss of water contact when the dosage form is located in an intestinal air pocket. The new apparatus was evaluated using a diclofenac extended release (ER) tablet. The in vitro dissolution profiles were compared between the novel test apparatus and a conventional dissolution apparatus (USP II). These data were compared with the profiles of plasma concentration versus time that were obtained after the administration of an ER tablet to 24 healthy volunteers under fasting conditions. Multiple peaks were observed in individual plasma concentration-time profiles after the intake of the reference ER tablet. Standard dissolution testing showed typical characteristics of an almost continuous release for this formulation; however, dissolution testing with the novel apparatus suggested that the diclofenac release from the ER tablets would be extremely variable and dependent on the applied stress. The data suggest that the observed multiple peaks of plasma concentration after dosing of the ER diclofenac tablets are most probably caused by sensitivity to physical stress events during gastrointestinal transit.

Somatic comorbidities of irritable bowel syndrome: a systematic analysis.

OBJECTIVE: A large number of irritable bowel syndrome (IBS) patients are additionally afflicted with other somatic intestinal and/or extraintestinal comorbidities. The occurrence of one or more comorbidities is correlated with enhanced medical help seeking, worse prognosis, and higher rates of anxiety and depression-all resulting in a reduced quality of life. The aims of this study were, firstly, to review the literature on comorbidities of IBS and to assess gastrointestinal and extraintestinal comorbidities, and, secondly, to evaluate explanatory hypotheses and possible common pathophysiological mechanisms. METHODS: We systematically reviewed the scientific literature in the past 25 years, as cited in MEDLINE. RESULTS: IBS patients present with a twofold increase in somatic comorbidities compared to controls, possibly caused by common pathophysiological mechanisms. Nevertheless, to date, there has been no convincing evidence for a consolidated underlying pathophysiology or somatization. Gastrointestinal disorders, such as functional dyspepsia, gastroesophageal reflux disease, functional constipation, and anal incontinence, occur in almost half of the patients. In a broad variety of extraintestinal comorbidities, fibromyalgia, chronic fatigue syndrome, and chronic pelvic pain are best documented and appear in up to 65%. CONCLUSION: The knowledge and structured assessment of comorbid somatic symptoms might allow to identify subgroups of IBS patients with special characteristics and lead to adaptation of the therapeutic concept.

Non-celiac gluten/wheat sensitivity (NCGS)-a currently undefined disorder without validated diagnostic criteria and of unknown prevalence: Position statement of the task force on food allergy of the German Society of Allergology and Clinical Immunology (DGAKI).

Within the last decade, non-celiac gluten/wheat sensitivity (NCGS) has been increasingly discussed not only in the media but also among medical specialties. The existence and the possible triggers of NCGS are controversial. Three international expert meetings which proposed recommendations for NCGS were not independently organized and only partially transparent regarding potential conflicts of interest of the participants. The present position statement reflects the following aspects about NCGS from an allergist's and nutritionist's point of view: (A) Validated diagnostic criteria and/or reliable biomarkers are still required. Currently, this condition is frequently self-diagnosed, of unknown prevalence and non-validated etiology. (B) Gluten has not been reliably identified as an elicitor of NCGS because of high nocebo and placebo effects. Double-blind, placebo-controlled provocation tests are of limited value for the diagnosis of NCGS and should be performed in a modified manner (changed relation of placebo and active substance). (C) Several confounders hamper the assessment of subjective symptoms during gluten-reduced or gluten-free diets. Depending on the selection of food items, e.g., an increased vegetable intake with soluble fibers, diets may induce physiological digestive effects and can modify gastrointestinal transit times independent from the avoidance of gluten. (D) A gluten-free diet is mandatory in celiac disease based on scientific evidence. However, a medically unjustified avoidance of gluten may bear potential disadvantages and risks. (E) Due to a lack of diagnostic criteria, a thorough differential diagnostic work-up is recommended when NCGS is suspected. This includes a careful patient history together with a food-intake and symptom diary, if necessary an allergy diagnostic workup and a reliable exclusion of celiac disease. We recommend such a structured procedure since a medically proven diagnosis is required before considering the avoidance of gluten.

The construction of a new evaluative GERD questionnaire--methods and state of the art.

Gastroesophageal reflux disease (GERD) is one of the most prevalent diseases worldwide, and it is becoming increasingly important to monitor the effect of various interventions on GERD symptoms. There can be rapid temporal changes in the severity and frequency of patients' symptoms as well as their health status and well-being, all of which could, theoretically, be monitored using diaries or questionnaires. However, current GERD monitoring instruments are not appropriate because they do not assess symptoms daily, they are not sufficiently responsive to short-term changes in health status or they are not adequately validated. To address these problems, the conceptual and psychometric requirements for a GERD symptom assessment questionnaire were identified. A dimension-based scale was designed to reduce the number of symptoms monitored on a daily basis, and the validation process was defined to produce parallel long and short forms of a scale for patients' self-assessment of their GERD symptom response to therapy. These basic principles which underlie the successful development of a new, self-assessed symptomatic reflux questionnaire (ReQuest) are also applicable to the development of validated questionnaires for daily symptom self-assessment in other disease areas.