European guidelines on achalasia: United European Gastroenterology and European Society of Neurogastroenterology and Motility recommendations.

INTRODUCTION: Achalasia is a primary motor disorder of the oesophagus characterised by absence of peristalsis and insufficient lower oesophageal sphincter relaxation. With new advances and developments in achalasia management, there is an increasing demand for comprehensive evidence-based guidelines to assist clinicians in achalasia patient care. METHODS: Guidelines were established by a working group of representatives from United European Gastroenterology, European Society of Neurogastroenterology and Motility, European Society of Gastrointestinal and Abdominal Radiology and the European Association of Endoscopic Surgery in accordance with the Appraisal of Guidelines for Research and Evaluation II instrument. A systematic review of the literature was performed, and the certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation methodology. Recommendations were voted upon using a nominal group technique. RESULTS: These guidelines focus on the definition of achalasia, treatment aims, diagnostic tests, medical, endoscopic and surgical therapy, management of treatment failure, follow-up and oesophageal cancer risk. CONCLUSION: These multidisciplinary guidelines provide a comprehensive evidence-based framework with recommendations on the diagnosis, treatment and follow-up of adult achalasia patients.

Histamine-mediated potentiation of transient receptor potential (TRP) ankyrin 1 and TRP vanilloid 4 signaling in submucosal neurons in patients with irritable bowel syndrome.

Previously, we showed histamine-mediated sensitization of transient receptor potential (TRP) vanilloid 1 (TRPV1) in patients with irritable bowel syndrome (IBS). Sensitization of TRP ankyrin 1 (TRPA1) and TRP vanilloid 4 (TRPV4) are also involved in aberrant pain perception in preclinical models of somatic pain. Here, we hypothesize that in parallel with TRPV1, histamine sensitizes TRPA1 and TRPV4, contributing to increased visceral pain in patients with IBS. Rectal biopsies were collected from patients with IBS and healthy subjects (HS) to study neuronal sensitivity to TRPA1 and TRPV4 agonists (cinnamaldehyde and GSK1016790A) using intracellular Ca2+ imaging. In addition, the effect of supernatants of rectal biopsies on patients with IBS and HS was assessed on TRPA1 and TRPV4 responses in murine dorsal root ganglion (DRG) sensory neurons. Finally, we evaluated the role of histamine and histamine 1 receptor (H1R) in TRPA1 and TRPV4 sensitization. Application of TRPA1 and TRPV4 agonists evoked significantly higher peak amplitudes and percentage of responding submucosal neurons in biopsies of patients with IBS compared with HS. In HS, pretreatment with histamine significantly increased the Ca2+ responses to cinnamaldehyde and GSK1016790A, an effect prevented by H1R antagonism. IBS supernatants, but not of HS, sensitized TRPA1 and TRPV4 on DRG neurons. This effect was reproduced by histamine and prevented by H1R antagonism. We demonstrate that the mucosal microenvironment in IBS contains mediators, such as histamine, which sensitize TRPV4 and TRPA1 via H1R activation, most likely contributing to increased visceral pain perception in IBS. These data further underscore H1R antagonism as potential treatment for IBS. NEW & NOTEWORTHY We provide evidence for histamine-mediated transient receptor potential (TRP) ankyrin 1 and TRP vanilloid 4 sensitization in irritable bowel syndrome (IBS) via histamine 1 receptor (H1R) activation, most likely contributing to increased visceral pain perception. Our results reveal a general role of sensory TRP channels as histamine effectors in the pathophysiology of IBS and provide novel mechanistic insights into the therapeutic potential of H1R antagonism in IBS.

INPP4B overexpression and c-KIT downregulation in human achalasia.

BACKGROUND: Achalasia is a rare motility disorder characterized by myenteric neuron and interstitial cells of Cajal (ICC) abnormalities leading to deranged/absent peristalsis and lack of relaxation of the lower esophageal sphincter. The mechanisms contributing to neuronal and ICC changes in achalasia are only partially understood. Our goal was to identify novel molecular features occurring in patients with primary achalasia. METHODS: Esophageal full-thickness biopsies from 42 (22 females; age range: 16-82 years) clinically, radiologically, and manometrically characterized patients with primary achalasia were examined and compared to those obtained from 10 subjects (controls) undergoing surgery for uncomplicated esophageal cancer (or upper stomach disorders). Tissue RNA extracted from biopsies of cases and controls was used for library preparation and sequencing. Data analysis was performed with the "edgeR" option of R-Bioconductor. Data were validated by real-time RT-PCR, western blotting and immunohistochemistry. KEY RESULTS: Quantitative transcriptome evaluation and cluster analysis revealed 111 differentially expressed genes, with a P ≤ 10-3 . Nine genes with a P ≤ 10-4 were further validated. CYR61, CTGF, c-KIT, DUSP5, EGR1 were downregulated, whereas AKAP6 and INPP4B were upregulated in patients vs controls. Compared to controls, immunohistochemical analysis revealed a clear increase in INPP4B, whereas c-KIT immunolabeling resulted downregulated. As INPP4B regulates Akt pathway, we used western blot to show that phospho-Akt was significantly reduced in achalasia patients vs controls. CONCLUSIONS & INFERENCES: The identification of altered gene expression, including INPP4B, a regulator of the Akt pathway, highlights novel signaling pathways involved in the neuronal and ICC changes underlying primary achalasia.

Evidence for long-term sensitization of the bowel in patients with post-infectious-IBS.

Post-infectious irritable bowel syndrome (PI-IBS) is a common gastrointestinal disorder characterized by persistent abdominal pain despite recovery from acute gastroenteritis. The underlying mechanisms are unclear, although long-term changes in neuronal function, and low grade inflammation of the bowel have been hypothesized. We investigated the presence and mechanism of neuronal sensitization in a unique cohort of individuals who developed PI-IBS following exposure to contaminated drinking water 7 years ago. We provide direct evidence of ongoing sensitization of neuronal signaling in the bowel of patients with PI-IBS. These changes occur in the absence of any detectable tissue inflammation, and instead appear to be driven by pro-nociceptive changes in the gut micro-environment. This is evidenced by the activation of murine colonic afferents, and sensitization responses to capsaicin in dorsal root ganglia (DRGs) following application of supernatants generated from tissue biopsy of patients with PI-IBS. We demonstrate that neuronal signaling within the bowel of PI-IBS patients is sensitized 2 years after the initial infection has resolved. This sensitization appears to be mediated by a persistent pro-nociceptive change in the gut micro-environment, that has the capacity to stimulate visceral afferents and facilitate neuronal TRPV1 signaling.

Abdominal vagus nerve stimulation as a new therapeutic approach to prevent postoperative ileus.

BACKGROUND: Electrical stimulation of the cervical vagus nerve (VNS) prevents postoperative ileus (POI) in mice. As this approach requires an additional cervical procedure, we explored the possibility of peroperative abdominal VNS in mice and human. METHODS: The effect of cervical and abdominal VNS was studied in a murine model of POI and lipopolysaccharide (LPS)-induced sepsis. Postoperative ileus was quantified by assessment of intestinal transit of fluorescent dextran expressed as geometric center (GC). Next, the effect of cervical and abdominal VNS on heart rate was determined in eight Landrace pigs to select the optimal electrode for VNS in human. Finally, the effect of sham or abdominal VNS on LPS-induced cytokine production of whole blood was studied in patients undergoing colorectal surgery. KEY RESULTS: Similar to cervical VNS, abdominal VNS significantly decreased LPS-induced serum tumor necrosis factor-α (TNFα) levels (abdominal VNS: 366±33 pg/mL vs sham: 822±105 pg/mL; P<.01). In line, in a murine model of POI, abdominal VNS significantly improved intestinal transit (GC: sham 5.1±0.2 vs abdominal VNS: 7.8±0.6; P<.01) and reduced intestinal inflammation (abdominal VNS: 35±7 vs sham: 80±8 myeloperoxidase positive cells/field; P<.05). In pigs, heart rate was reduced by cervical VNS but not by abdominal VNS. In humans, abdominal VNS significantly reduced LPS-induced IL8 and IL6 production by whole blood. CONCLUSIONS & INFERENCES: Abdominal VNS is feasible and safe in humans and has anti-inflammatory properties. As abdominal VNS improves POI similar to cervical VNS in mice, our data indicate that peroperative abdominal VNS may represent a novel approach to shorten POI in man.

Postoperative Ileus: Pathophysiology, Current Therapeutic Approaches.

Postoperative ileus, which develops after each abdominal surgical procedure, is an iatrogenic disorder characterized by a transient inhibition of gastrointestinal motility. Its pathophysiology is complex involving pharmacological (opioids, anesthetics), neural, and immune-mediated mechanisms. The early neural phase, triggered by activation of afferent nerves during the surgical procedure, is short lasting compared to the later inflammatory phase. The latter starts after 3-6 h and lasts several days, making it a more interesting target for treatment. Insight into the triggers and immune cells involved is of great importance for the development of new therapeutic strategies. In this chapter, the pathogenesis and the current therapeutic approaches to treat postoperative ileus are discussed.

Neuroimmune factors in functional gastrointestinal disorders: A focus on irritable bowel syndrome.

BACKGROUND: Abnormal abdominal pain perception is the most bothersome and difficult to treat symptom of functional gastrointestinal disorders (FGIDs). Visceral pain stimuli are perceived and transmitted by afferent neurons residing in the dorsal root ganglia that have sensory nerve endings in the gut wall and mesentery. Accumulating evidence indicates that peripheral activation and sensitization of these sensory nerve endings by bioactive mediators released by activated immune cells, in particular mast cells, can lead to aberrant neuroimmune interactions and the development and maintenance of visceral hypersensitivity. Besides direct neuronal activation, low concentrations of proteases, histamine, and serotonin can chronically sensitize nociceptors, such as TRP channels, leading to persistent aberrant pain perception. PURPOSE: This review discusses the potential mechanisms underlying aberrant neuroimmune interactions in peripheral sensitization of sensory nerves. A better understanding of the cells, mediators, and molecular mechanisms triggering persistent aberrant neuroimmune interactions brings new insights into their contribution to the physiology and pathophysiology of visceral pain perception and provides novel opportunities for more efficient therapeutic treatments for these disorders.

Phenotyping of subjects for large scale studies on patients with IBS.

BACKGROUND: Irritable bowel syndrome (IBS) is a complex condition with multiple factors contributing to its aetiology and pathophysiology. Aetiologically these include genetics, life-time events and environment, and physiologically, changes in motility, central processing, visceral sensitivity, immunity, epithelial permeability and gastrointestinal microflora. Such complexity means there is currently no specific reliable biomarker for IBS, and thus IBS continues to be diagnosed and classified according to symptom based criteria, the Rome Criteria. Carefully phenotyping and characterisation of a 'large' pool of IBS patients across Europe and even the world however, might help identify sub-populations with accuracy and consistency. This will not only aid future research but improve tailoring of treatment and health care of IBS patients. PURPOSE: The aim of this position paper is to discuss the requirements necessary to standardize the process of selecting and phenotyping IBS patients and how to organise the collection and storage of patient information/samples in such a large multi-centre pan European/global study. We include information on general demographics, gastrointestinal symptom assessment, psychological factors, quality of life, physiological evaluation, genetic/epigenetic and microbiota analysis, biopsy/blood sampling, together with discussion on the organisational, ethical and language issues associated with implementing such a study. The proposed approach and documents selected to be used in such a study was the result of a thoughtful and thorough four-year dialogue amongst experts associated with the European COST action BM1106 GENIEUR (www.GENIEUR.eu).

Smooth muscle and neural dysfunction contribute to different phases of murine postoperative ileus.

BACKGROUND: Postoperative ileus (POI) is characterized by a transient inhibition of gastrointestinal (GI) motility after abdominal surgery mediated by the inflammation of the muscularis externa (ME). The aim of this study was to identify alterations in the enteric nervous system that may contribute to the pathogenesis of POI. METHODS: Gastrointestinal transit, contractility of isolated smooth muscle strips and inflammatory parameters were evaluated at different time points (1.5 h to 10 days) after intestinal manipulation (IM) in mice. Immune-labeling was used to visualize changes in myenteric neurons. KEY RESULTS: Intestinal manipulation resulted in an immediate inhibition of GI transit recovering between 24 h and 5 days. In vitro contractility to K(+) (60 mM) or carbachol (10(-9) to 10(-4) M) was biphasically suppressed over 24 h after IM (with transient recovery at 6 h). The first phase of impaired myogenic contractility was associated with increased expression of TNF-α, IL-6 and IL-1α. After 24 h, we identified a significant reduction in electrical field stimulation-evoked contractions and relaxations, lasting up to 10 days after IM. This was associated with a reduced expression of chat and nos1 genes. CONCLUSIONS & INFERENCES: Intestinal manipulation induces two waves of smooth muscle inhibition, most likely mediated by inflammatory cytokines, lasting up to 3 days after IM. Further, we here identify a late third phase (>24 h) characterized by impaired cholinergic and nitrergic neurotransmission persisting after recovery of muscle contractility. These findings illustrate that POI results from inflammation-mediated impaired smooth muscle contraction, but also involves a long-lasting impact of IM on the enteric nervous system.

Effect of genetic background and postinfectious stress on visceral sensitivity in Citrobacter rodentium-infected mice.

BACKGROUND: Infectious gastroenteritis is a major risk factor to develop postinfectious irritable bowel syndrome (PI-IBS). It remains unknown why only a subgroup of infected individuals develops PI-IBS. We hypothesize that immunogenetic predisposition is an important risk factor. Hence, we studied the effect of Citrobacter rodentium infection on visceral sensitivity in Th1-predominant C57BL/6 and Th2-predominant Balb/c mice. METHODS: Eight-week-old mice were gavaged with C. rodentium, followed by 1 h of water avoidance stress (WAS) at 5 weeks PI. At 10, 14 days, and 5 weeks PI, samples were assessed for histology and inflammatory gene expression by RT-qPCR. Visceral sensitivity was evaluated by visceromotor response recordings (VMR) to colorectal distension. KEY RESULTS: Citrobacter rodentium evoked a comparable colonic inflammatory response at 14 days PI characterized by increased crypt length and upregulation of Th1/Th17 cytokine mRNA levels (puncorrected  < 0.05) in both C57BL/6 and Balb/c mice. At 5 weeks PI, inflammatory gene mRNA levels returned to baseline in both strains. The VMR was maximal at 14 days PI in C57BL/6 (150 ± 47%; p = 0.02) and Balb/c mice (243 ± 52%; p = 0.03). At 3 weeks PI, the VMR remained increased in Balb/c (176 ± 23%; p = 0.02), but returned to baseline in C57BL/6 mice. At 5 weeks PI, WAS could not re-introduce visceral hypersensitivity (VHS). CONCLUSIONS & INFERENCES: Citrobacter rodentium infection induces transient VHS in C57BL/6 and Balb/c mice, which persisted 1 week longer in Balb/c mice. Although other strain-related differences may contribute, a Th2 background may represent a risk factor for prolonged PI-VHS. As PI-VHS is transient, other factors are crucial for persistent VHS development as observed in PI-IBS.

The pig as preclinical model for laparoscopic vagus nerve stimulation.

PURPOSE: Cervical vagus nerve stimulation (VNS) prevents manipulation-induced intestinal inflammation and improves intestinal transit in a mouse model of postoperative ileus (POI). Cervical VNS, however, is accompanied by cardiovascular and respiratory side effects. In view of potential clinical application, we therefore evaluated the safety and feasibility of abdominal VNS via laparoscopic approach in a porcine model. METHODS: Six pigs were used in a non-survival study for both cervical and abdominal VNS. Two cardiac pacing electrodes were positioned around the right cervical and posterior abdominal vagus nerve and connected to an external stimulator. VNS was performed using four different settings (5 and 20 Hz, 0.5 and 1 ms pulse width) during 2 min with ECG recording. Laparoscopic VNS was timed and videotaped, and technical difficulties were noted. A validated National Aeronautics and Space Administration Task Load Index (NASA-TLX) questionnaire was used to evaluate the task and workload. RESULTS: The procedure was completed in all pigs with 4-port laparoscopic technique. Cervical and abdominal VNS were performed after correct identification and isolation of the nerve, and positioning of the electrodes around the nerve. Median laparoscopic operating time was 16 min (range 8-33 min), and median NASA-TLX was 31 (range 11-74). No major complications were encountered. Reduction of heart rate was between 5.5 and 14% for cervical VNS and undetectable for abdominal VNS. CONCLUSION: In a porcine model, laparoscopic VNS is feasible and safe with cardiac pacing electrodes and may lead to a similar novel approach in humans in the near future.

Is there a causal link between psychological disorders and functional gastrointestinal disorders?

Psychological disorders, most notably anxiety and depressive disorders, somatization and catastrophizing, often precede or exacerbate functional gastrointestinal disorder (FGID) symptoms and correlate with symptom severity and health outcomes. Mounting evidence shows that psychological distress alters gut immunity, in particular mast cell activation, leading to a potentiation of sensory nerves and aberrant visceral pain perception. On the other hand, psychological stressors modulate the processing of incoming sensory signals by the brain, thereby contributing to FGID symptom development. A better understanding of the molecular mechanisms underlying stress-induced changes in the immune system or brain processing is crucial for the development of novel beneficial therapeutic strategies.

Ghrelin receptor modulates T helper cells during intestinal inflammation.

BACKGROUND: The orexigenic peptide ghrelin has anti-inflammatory properties in colitis, however, the mechanism of action and the immune cells targeted remain still to be elucidated. Here, we assessed the possible effect of ghrelin on T helper (Th) cells in a T cell transfer model of chronic colitis. METHODS: Disease was induced in the recombination activating gene 1 knockout mice (Rag1(-/-) ) by adoptive transfer of naïve Th cells from ghrelin receptor knockout mice (GRLN-R(-/-) ) or littermate wild-type (WT) mice. The course and severity of colitis was assessed by monitoring body weight, diarrhea score, histological analysis, gene expression, and flow cytometry analysis. The possible effects of ghrelin on Th cell proliferation, polarization, and apoptosis was examined in vitro. KEY RESULTS: Our data showed that Rag1(-/-) mice injected with GRLN-R(-/-) Th cells displayed increased severity of colitis compared to mice injected with WT Th cells. In addition, Rag1(-/-) mice injected with GRLN-R(-/-) Th cells had significantly higher intestinal inflammation and increased accumulation of Th1 and Th17 cells in the colon. In vitro, ghrelin directly affected proliferation of Th cells and induced apoptosis whereas it did not influence Th cell polarization. CONCLUSION & INFERENCES: Our observations suggest that ghrelin modulates Th effector cells in the gut controlling proliferation and inducing apoptosis. Our findings further support the use of ghrelin as a novel therapeutic option to treat intestinal inflammatory diseases.

Endogenous vagal activation dampens intestinal inflammation independently of splenic innervation in postoperative ileus.

Postoperative ileus is encountered by patients undergoing open abdominal surgery and is characterized by intestinal inflammation associated with impaired gastrointestinal motility. We recently showed that inflammation of the gut muscularis triggered activation of the vagal efferent pathway mainly targeting the inflamed zone. In the present study we investigate further the modulatory role of endogenous activation of the vagal motor pathway on the innate immune response. Intestinal or splenic denervation was performed two weeks prior to intestinal manipulation (IM) or laparotomy (L). Twenty-four hour post-surgery, the gastrointestinal transit, immune cell influx, and pro-inflammatory cytokine levels were measured in the gut muscularis. Manipulation of the small intestine led to a delay in intestinal transit, an influx of leukocytes and increased pro-inflammatory cytokine expression. Surgical lesion of the vagal branch that selectively innervates the small intestine did not further delay the intestinal transit but significantly enhanced the expression levels of the pro-inflammatory cytokines IL-1ß and IL-6 in the gut muscularis. Splenic denervation did not affect intestinal inflammation or gastrointestinal transit after intestinal manipulation. Our study demonstrates that selective vagotomy, leaving the splenic innervation intact, increases surgery-induced intestinal inflammation. These data suggest that endogenous activation of the vagal efferent pathway by intestinal inflammation directly dampens the local immune response triggered by intestinal manipulation independently of the spleen.

Using human intestinal biopsies to study the pathogenesis of irritable bowel syndrome.

BACKGROUND: Although animal models of the irritable bowel syndrome (IBS) have provided important insights, there are no models that fully express the features of this complex condition. One alternative approach is the use of human intestinal biopsies obtained during endoscopic procedures to examine peripheral mechanisms in this disorder. These studies have served to confirm the existence of peripheral pathways in humans with IBS and have provided many new mechanistic insights. Two general approaches have been employed; one approach has been to examine the biological activity of mediators within the mucosal tissue of IBS patients and the other has been to examine changes in the structural properties of key signaling pathways contained within the biopsies. Using these approaches, important changes have been discovered involving the enteric nervous system and the extrinsic sensory pathway (dorsal root ganglia neurons), the immune system, and epithelial signaling in IBS patients compared to healthy subjects. PURPOSE: This review will systematically explore these mechanistic pathways, highlight the implications of these novel findings and discuss some of the important limitations of this approach.

Inter- and intra-rater reproducibility of automated and integrated pressure-flow analysis of esophageal pressure-impedance recordings.

BACKGROUND: Automated impedance manometry pressure-flow analysis (AIM analysis) determines pressure measurements relative to bolus flow and has to date shown subtle variations in esophageal motility in relation to dysphagia. In this study, we assessed intra- and inter-rater reproducibility of AIM metrics derived using purpose designed software. METHODS: Fifty patients referred for evaluation of gastro-esophageal reflux symptoms (33 men, age 52 ± 1.9 years) underwent combined high-resolution impedance manometry and completed a dysphagia questionnaire. From 10 liquid and 10 viscous swallows, a subset of four swallows (two saline and two viscous) was systematically selected from each patient for manual and AIMplot analysis, which was performed twice by five observers (two experts, three non-experts). Intra- and inter-rater agreement were determined using intraclass correlation coefficients. KEY RESULTS: AIMplot-based analysis showed high intra-rater and inter-rater reproducibility for all metrics (mean ICCs of 0.95 and 0.94, respectively). Reproducibility of metrics derived for liquid and viscous did not differ (ICCs of 0.96 and 0.91 for liquid and viscous, respectively). In addition, metrics derived by experts had an equivalent level of reproducibility compared to non-experts (ICCs of 0.96 and 0.94, respectively). Variables that could be derived with commercial software (ManoView™) correlated highly with variables from AIMplot-based analysis, such as 4-s integrated relaxation pressure (r = 0.85) and the 20-mmHg isobaric contour defect (r = 0.92). CONCLUSIONS & INFERENCES: Esophageal AIM analysis is highly reproducible, independent of an observer's level of experience in esophageal motility. Therefore, AIM analysis produces data that are reliable for clinical and research purposes.

Susceptibility to stress induced visceral hypersensitivity in maternally separated rats is transferred across generations.

BACKGROUND: In irritable bowel syndrome (IBS), familial clustering and transfer across generations may largely depend on environmental factors but this is difficult to establish in the human setting. Therefore, we aimed to set up a relevant animal model. We investigated whether susceptibility to stress induced visceral hypersensitivity in maternally separated (MS) Long Evans rats can be transferred across generations without further separation protocols and, if so, whether this depends on maternal care. METHODS: At adult age, we evaluated pre- vs post water avoidance (WA) changes in visceromotor response to distension in non-handled second filial generation offspring (NH-F2) of previously separated MS-F1 dams. Furthermore, the role of maternal care was evaluated by cross-fostering F2 offspring of NH-F1 and MS-F1 dams and subsequent sensitivity measurements at adult age. Involvement of mast cells in post stress hypersensitivity of NH-F2 rats was evaluated by mast cell stabilization. KEY RESULTS: In adult NH-F2 offspring of MS-F1 dams, post-WA hypersensitivity to colorectal distension was observed in 80% of rats compared with 19% in offspring of NH-F1 dams. Cross-fostered pups adapted to the phenotype of the foster mother: pups of NH-F1 dams nursed by MS-F1 dams showed post-WA hypersensitivity to distension at adult age and vice versa (100% and 20% respectively). In NH-F2 rats, post-WA hypersensitivity was reversed by mast cell stabilizer doxantrazole. CONCLUSIONS & INFERENCES: Maternal separated-induced susceptibility to stress-triggered visceral hypersensitivity is transferred across generations and this transfer depends on maternal care. Thus, MS is a suitable model to evaluate environmental triggers relevant to IBS clustering in families.

Systemic inflammation with enhanced brain activation contributes to more severe delay in postoperative ileus.

BACKGROUND: The severity of postoperative ileus (POI) has been reported to result from decreased contractility of the muscularis inversely related to the number of infiltrating leukocytes. However, we previously observed that the severity of POI is independent of the number of infiltrating leukocytes, indicating that different mechanisms must be involved. Here, we hypothesize that the degree of tissue damage in response to intestinal handling determines the upregulation of local cytokine production and correlates with the severity of POI. METHODS: Intestinal transit, the inflammatory response, I-FABP (marker for tissue damage) levels and brain activation were determined after different intensities of intestinal handling. KEY RESULTS: Intense handling induced a more pronounced ileus compared with gentle intestinal manipulation (IM). No difference in leukocytic infiltrates in the handled and non-handled parts of the gut was observed between the two intensities of intestinal handling. However, intense handling resulted in significantly more tissue damage and was accompanied by a systemic inflammation with increased plasma levels of pro-inflammatory cytokines. In addition, intense but not gentle handling triggered enhanced c-Fos expression in the nucleus of the solitary tract (NTS) and area postrema (AP). In patients, plasma levels of I-FABP and inflammatory cytokines were significantly higher after open compared with laparoscopic surgery, and were associated with more severe POI. CONCLUSIONS & INFERENCES: Not the influx of leukocytes, rather the manipulation-induced damage and subsequent inflammatory response determine the severity of POI. The release of tissue damage mediators and pro-inflammatory cytokines into the systemic circulation most likely contribute to the impaired motility of non-manipulated intestine.

Esophageal stasis on a timed barium esophagogram predicts recurrent symptoms in patients with long-standing achalasia.

OBJECTIVES: In achalasia, early recognition of the need for retreatment is of crucial importance to reduce morbidity and long-term complications such as esophageal decompensation. In clinical practice, symptoms and parameters of esophageal function including lower esophageal sphincter (LES) pressure and esophageal emptying are used to decide whether additional treatment is required. However, which of these tests performs best remains unclear. METHODS: A cohort of 41 patients with long-standing achalasia (median 17 years), underwent esophageal manometry, timed barium esophagogram and symptom evaluation. Patients were followed up for 10 years, and were regarded as a therapeutic failure if Eckardt score was >3 or when retreatment was needed. Predictors of therapeutic failure were evaluated. RESULTS: Of the 41 included patients, 7 patients had an elevated LES pressure (>10 mm Hg) and 26 had esophageal stasis >5 cm on timed barium esophagogram. During follow-up, 25 patients had recurrence of symptoms and were considered therapeutic failures. Of the 25 patients, 5 had an elevated LES pressure, whereas 22 had esophageal stasis on barium esophagogram. Hence, the sensitivity to predict the need of retreatment is higher for esophageal stasis (88%) compared with LES pressure (20%). A total of 16 patients (39%) were in long-term remission, of which 12 patients (75%) did not have stasis at their initial visit. CONCLUSIONS: In contrast to LES pressure, esophageal stasis is a good predictor of treatment failure in patients with long-standing achalasia. Based on these findings, we propose to use timed barium esophagogram rather than esophageal manometry as test to decide on retreatment.