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Einleitung: Bei der idiopathischen Achalasie handelt es sich um eine multifaktorielle Krankheit, an deren Entstehung genetische und nicht-genetische Risikofaktoren beteiligt sind. Es wird davon ausgegangen, dass bei der Achalasie autoimmunologische Vorgänge bei Personen mit genetischem Risikoprofil[for full text, please go to the a.m. URL], 129. Kongress der Deutschen Gesellschaft für Chirurgie

In various models vagus nerve activation has been shown to ameliorate intestinal inflammation, via nicotinic acetylcholine receptors (nAChRs) expressed on immune cells. As the alpha7 nAChR has been put forward to mediate this effect, we studied the effect of nicotine and two selective alpha7 nAChR agonists (AR-R17779, (-)-spiro[1-azabicyclo[2.2.2] octane-3,5'-oxazolidin-2'-one and GSK1345038A) on disease severity in two mouse models of experimental colitis.Colitis was induced by administration of 1.5% dextran sodium sulphate (DSS) in drinking water or 2 mg 2,4,6-trinitrobenzene sulphonic acid (TNBS) intrarectally. Nicotine (0.25 and 2.50 micromol.kg(-1)), AR-R17779 (0.6-30 micromol.kg(-1)) or GSK1345038A (6-120 micromol.kg(-1)) was administered daily by i.p. injection. After 7 (DSS) or 5 (TNBS) days clinical parameters and colonic inflammation were scored.Nicotine and both alpha7 nAChR agonists reduced the activation of NF-kappaB and pro-inflammatory cytokines in whole blood and macrophage cultures. In DSS colitis, nicotine treatment reduced colonic cytokine production, but failed to reduce disease parameters. Reciprocally, treatment with AR-R17779 or GSK1345038A worsened disease and led to increased colonic pro-inflammatory cytokine levels in DSS colitis. The highest doses of GSK1345038A (120 micromol.kg(-1)) and AR-R17779 (30 micromol.kg(-1)) ameliorated clinical parameters, without affecting colonic inflammation. Neither agonist ameliorated TNBS-induced colitis.Although nicotine reduced cytokine responses in vitro, both selective alpha7 nAChR agonists worsened the effects of DSS-induced colitis or were ineffective in those of TNBS-induced colitis. Our data indicate the need for caution in evaluating alpha7 nAChR as a drug target in colitis.

International audience; Background: Transient lower esophageal sphincter relaxations (TLESRs) are a major mechanism behind gastroesophageal reflux disease (GERD). Aim: To assess the effect of lesogaberan (AZD3355) – a novel peripherally active GABAB receptor agonist – on TLESRs. Methods: Twenty-four healthy men were enrolled in this single-blind, placebo-controlled, randomized, single-centre, three-period crossover phase 1 study. Subjects were randomized to receive single oral doses of lesogaberan (0.8 mg/kg), baclofen (40 mg) and placebo, separated by washout periods of ≤ 7 days. Subjects finished a meal 1 hour after the dose. Esophageal manometry and pH-metry measurements were taken during the 3 hours after the meal. Results: Twenty-one subjects completed the study. Compared with placebo, lesogaberan 0.8 mg/kg significantly reduced the number of TLESRs by 36% (geometric mean ratio [GMR]: 0.64; 95% confidence interval [CI]: 0.51–0.82) and significantly reduced the number of acid reflux episodes (mean reduction: 1.6; 95% CI: 0.34–2.9). Lesogaberan also significantly increased lower esophageal sphincter (LES) pressure by 39% compared with placebo (GMR: 1.39; 95% CI: 1.18–1.64). Comparable results were observed with baclofen. Similar numbers of adverse events were reported by subjects taking lesogaberan and placebo. Conclusions: Compared with placebo, lesogaberan significantly reduced TLESRs and acid reflux episodes, and increased LES pressure.

Defined pharmacologically by its insensitivity to the GABA(A) antagonist bicuculline and sensitivity to the GABA analogue baclofen, the G protein-linked gamma-aminobutyric acid type B (GABA(B)) receptor couples to adenylyl cyclase, voltage-gated calcium channels, and inwardly-rectifying potassium channels. On the basis of a wealth of preclinical data in conjunction with early clinical observations that baclofen improves symptoms of gastroesophageal reflux disease (GERD), the GABA(B) receptor has been proposed as a therapeutic target for a number of diseases including GERD. Subsequently, there has been a significant effort to develop a peripherally-restricted GABA(B) agonist that is devoid of the central nervous system side effects that are observed with baclofen. In this article we review the in vitro and in vivo pharmacology of the peripherally-restricted GABA(B) receptor agonists and the preclinical and clinical development of lesogaberan (AZD3355, (R)-(3-amino-2-fluoropropyl) phosphinic acid), a potent and predominately peripherally-restricted GABA(B) receptor agonist with a preclinical therapeutic window superior to baclofen

1 Intestinal manipulation (IM) during abdominal surgery triggers the influx of inflammatory cells, leading to postoperative ileus. Prevention of this local muscle inflammation, using intercellular adhesion molecule-1 ( ICAM-1) and leukocyte function-associated antigen-1-specific antibodies, has been shown to shorten postoperative ileus. However, the therapeutic use of antibodies has considerable disadvantages. 2 The aim of the current study was to evaluate the effect of ISIS-3082, a mouse-specific ICAM-1 antisense oligonucleotide, on postoperative ileus in mice. 3 Mice underwent a laparotomy or a laparotomy combined with IM after treatment with ICAM-1 antibodies, 0.1-10 mg kg(-1) ISIS-3082, saline or ISIS-8997 ( scrambled control antisense oligonucleotides, 1 and 3 mg kg(-1)). At 24 h after surgery, gastric emptying of a (TC)-T-99m labelled semi-liquid meal was determined using scintigraphy. Intestinal inflammation was assessed by myeloperoxidase ( MPO) activity in ileal muscle whole mounts. 4 IM significantly reduced gastric emptying compared to laparotomy. Pretreatment with ISIS-3082 ( 0.1-1 mg kg(-1)) as well as ICAM-1 antibodies ( 10 mg kg(-1)), but not ISIS-8997 or saline, improved gastric emptying in a dose-dependent manner. This effect diminished with higher doses of ISIS-3082 ( 3-10 mg kg(-1)). 5 Similarly, ISIS-3082 ( 0.1-1 mg kg(-1)) and ICAM-1 antibodies, but not ISIS-8997 or higher doses of ISIS-3082 ( 3-10mg kg(-1)), reduced manipulation-induced inflammation. Immunohistochemistry showed reduction of ICAM-1 expression with ISIS-3082 only. 6 ISIS-3082 pretreatment prevents postoperative ileus in mice by reduction of manipulation-induced local intestinal muscle inflammation. Our data suggest that targeting ICAM-1 using antisense oligonucleotides may represent a new therapeutic approach to the prevention of postoperative ileus

The gastric accommodation response to a meal is impaired in conditions such as functional dyspepsia. At present, a barostat study is the gold standard to assess fundic relaxation in response to a meal. However, this method is invasive and possibly induces artifacts as a result of positive intraluminal balloon pressure. A noninvasive scintigraphic test has been developed to measure gastric accommodation in humans. The aim of this study was to refine this method, increasing the imaging time span and limiting the radiation dose applied without losing image quality, so that repeated measurements within 1 subject are possible without increasing radiation risk. Methods: Thirteen healthy volunteers without gastrointestinal symptoms were recruited from a student population. Each volunteer had previously undergone a barostat study. After an overnight fast, volunteers were scanned twice on separate days after intravenous injection of 200 MBq Tc-99m-pertechnetate. On 1 occasion, volunteers were pretreated with a proton pump inhibitor. Thirty minutes after injection, sequential, 7-min SPECT scans (72 views, 10 s/view, 128 matrix) were acquired on a dual-head -gamma-camera system before and up to 2 h after ingestion of a test meal. After reconstruction (filtered backprojection, ramp-Butterworth filter; order, 10; cutoff, 0.45 Nyquist), fundus volume was calculated semiautomatically by means of a threshold voxel volume tool. Results: Limiting injection dose from 370-740 MBq to 200 MBq Tc-99m-pertechnetate resulted in good-quality images, with high target-to-background ratio up to 150 min after injection. This represents a significant dose reduction, from 4.6-9.3 to 2.5 mSv. There was no significant difference between SPECT fundic volumes or accommodation response with or without proton pump inhibitor pretreatment. Volume kinetics were similar to those with barostat studies, but gastric volumes were inferior. Conclusion: Refining the methodology yields an improved noninvasive test for the assessment of gastric accommodation without unnecessarily increasing radiation burden. This technique enables repeated and serial measurement of gastric accommodation to a test meal, a process that is potentially useful for characterization and follow-up of dyspeptic patients with and without drug intervention

Gastric emptying in small laboratory animals is a useful parameter to assess gastrointestinal motility for physiologic, pharmacologic, or other research purposes. In mice, phenol red recovery is considered the gold standard for determination of gastric emptying. However, this method requires sacrifice of the animal and yields data of gastric emptying at only 1 time point. Gastric-emptying scintigraphy, the gold standard technique in humans, allows sequential and serial measurements in the same subject. In this study, we developed and validated a novel method of gastric-emptying scintigraphy applied in mice, by comparing it with phenol red photospectrometry. Methods: A dedicated animal pinhole gamma camera was equipped with a specially designed mouse application device. Gastric emptying was measured in unanesthetized mice using pinhole scintigraphy. First, gastric emptying determined with scintigraphy was compared with gastric phenol red recovery simultaneously within the same population. Subsequently, normal values for gastric emptying of solids and liquids in mice were established, and finally, the effects of handling stress and the late effects of frequently used anesthetics or sedatives on gastric emptying were assessed by scintigraphy. Results: Gastric emptying of liquids measured by pinhole scintigraphy did not significantly differ from that measured by phenol red recovery. For the same information, 80% fewer animals were needed for the scintigraphic method. More stress-related delay in gastric emptying was induced by multiple handling of the mice, compared with the less frequent handling that was associated with taking measurements every 10 min or more (P

Primary follicular lymphoma of the gastrointestinal tract (GI-FL) is a rare so far poorly studied entity. We analyzed four FL cases located in the small intestine and duodenum to gain insight in their pathogenesis and to find an explanation for their low tendency to disseminate outside the GI tract. GI-FLs resemble nodal FLs with respect to morphology and expression of typical GC markers such as CD10, CD38, and BCL-6. We established that the high levels of the anti-apoptosis protein BCL-2 in the tumor cells are in all cases due to a t(14;18) involving the immunoglobulin heavy chain and BCL-2 loci. Detailed immunoglobulin gene analyses on microdissected tissue samples further supported the GC-cell derivation: GI-FLs carry extensively mutated variable heavy-chain genes. The mutation patterns indicated that at some time point in development stringent antigen receptor-based selection processes must have occurred. Interestingly, three of four neoplasms expressed surface IgA, an immunoglobulin class typical of the mucosal immune system and seldom found in nodal FL. In contrast to nodal FLs, the GI-FLs expressed the alpha4beta7 integrin, an established mucosa-homing receptor also expressed by normal intestinal B and T lymphocytes and by low-grade mucosa-associated lymphoid tissue lymphomas. However, the chemokine receptor CXCR3, expressed on low-grade mucosa-associated lymphoid tissue lymphomas, was not detected on the GI-FLs or on nodal FLs. The combined data suggests that primary FL of the small intestine is a distinct entity that originates from local antigen-responsive B cells

Background & Aims: Postoperative ileus after abdominal surgery largely contributes to patient morbidity and prolongs hospitalization. We aimed to study its pathophysiology in a murine model by determining gastric emptying after manipulation of the small intestine. Methods: Gastric emptying was determined at 6, 12, 24, and 48 hours after abdominal surgery by using scintigraphic imaging. Intestinal or gastric inflammation was assessed by immune-histochemical staining and measurement of tissue myeloperoxidase activity. Neuromuscular function of gastric and intestinal muscle strips was determined in organ baths. Results: Intestinal manipulation resulted in delayed gastric emptying up to 48 hours after surgery; gastric half-emptying time 24 hours after surgery increased from 16.0 +/- 4.4 minutes after control laparotomy to 35.6 +/- 5.4 minutes after intestinal manipulation. The sustained delay in gastric emptying was associated with the appearance of leukocyte infiltrates in the muscularis of the manipulated intestine, but not in untouched stomach or colon. The delay in postoperative gastric emptying was prevented by inhibition of intestinal leukocyte recruitment. In addition, postoperative neural blockade with hexamethonium (I mg/kg intraperitoneally) or guanethidine (50 mg/kg intra peritoneally) normalized gastric emptying without affecting small-intestinal transit. The appearance of intestinal infiltrates after intestinal manipulation was associated with increased c-fos protein expression in sensory neurons in the lumbar spinal cord. Conclusions: Sustained postoperative gastroparesis after intestinal manipulation is mediated by an inhibitory enterogastric neural pathway that is triggered by inflammatory infiltrates recruited to the intestinal muscularis. These findings show new targets to shorten the duration of postoperative ileus pharmacologically

1 The effects of addition of Cu2+ and chelation of Cu2+ were studied on relaxations in response to S-nitrosothiols and on relaxations to non-adrenergic non-cholinergic (NANC) nerve stimulation, nitric oxide (NO) and glyceryl trinitrate (GTN) in the rat gastric fundus. 2 The S-nitrosothiols S-nitroso-L-cysteine (NOCys, 1-300 nM), S-nitrosoglutathione (GSNO, 0.01-3 mu M) and S-nitroso-N-acetyl-D,L-penicillamine (SNAP, 0.01-3 mu M) induced concentration-dependent relaxations of the rat gastric fundus muscle strip. The relaxant potencies of the S-nitrosothiols were NOCys>SNAP>GSNO. Relaxations to NOCys were transient and comparable to those to NANC nerve stimulation and NO whereas relaxations to GSNO and SNAP were sustained. The relaxations to NOCys, GSNO and SNAP were significantly and concentration-dependently enhanced by CuSO4 (330 mu M). The order of relaxant potency in the presence of CuSO4 was reversed to GSNO approximate to SNAP> NOCys. 3 In the presence but not in the absence of 0.1 mu M GSNO, CuSO4 (1 mu M) induced a rapid and transient relaxation which was inhibited by the superoxide radical generator, pyrogallol (30 mu M). CuCl2 but not FeSO4 mimicked the effect of CuSO4. 4 Electrical stimulation (0.5-8 Hz) of the rat gastric fundus strips induced frequency-dependent relaxations which were previously shown to be nitrergic in nature and which were not affected by CuSO4 (3-30 mu M). Relaxations to NO (3-100 nM) and GTN (0.01-1 mu M) were not affected by 3 and 10 mu M CuSO4 but were inhibited by 30 mu M CuSO4. 5 The Cu2+ chelator, bathocuproine (3-30 mu M) significantly and concentration-dependently inhibited the relaxations to NOCys (0.01-3 mu M), GSNO (0.01-10 mu M) and SNAP (0.01-3 mu M). The inhibitory effect of 10 mu M bathocuproine was reversed by 3 mu M CuSO4. 6 Bathocuproine (3-30 mu M) had no effect on the relaxations to NANC nerve stimulation (0.5-8 Hz) or on the concentration-response curve to NO (0.01-0.3 mu M), whereas relaxations to GTN (0.01-1 mu M) were significantly inhibited by 30 mu M bathocuproine. 7 From these results we conclude that relaxations to S-nitrosothiols and to nitrergic stimulation of the rat gastric fundus are differentially affected by addition and chelation of Cu2+, suggesting that the nitrergic NANC neurotransmitter in the rat gastric fundus is not an S-nitrosothiol but is more likely to be free nitric oxide.

Idiopathic achalasia is a severe motility disorder of the esophagus and is characterized by a failure of the lower esophageal sphincter to relax due to a loss of neurons in the myenteric plexus. Most recently, we identified an eight-amino-acid insertion in the cytoplasmic tail of HLA-DQβ1 as strong achalasia risk factor in a sample set from Central Europe, Italy and Spain. Here, we tested whether the HLA-DQβ1 insertion also confers achalasia risk in the Polish and Swedish population. We could replicate the initial findings and the insertion shows strong achalasia association in both samples (Poland P=1.84 × 10(-04), Sweden P=7.44 × 10(-05)). Combining all five European data sets - Central Europe, Italy, Spain, Poland and Sweden - the insertion is achalasia associated with Pcombined=1.67 × 10(-35). In addition, we observe that the frequency of the insertion shows a geospatial north-south gradient. The insertion is less common in northern (around 6-7% in patients and 2% in controls from Sweden and Poland) compared with southern Europeans (~16% in patients and 8% in controls from Italy) and shows a stronger attributable risk in the southern European population. Our study provides evidence that the prevalence of achalasia may differ between populations.European Journal of Human Genetics advance online publication, 6 January 2016; doi:10.1038/ejhg.2015.262. ispartof: European Journal of Human Genetics vol:24 issue:8 pages:1228-1231 ispartof: location:England status: published