Exploring associations between lower urinary tract symptoms (LUTS) and gastrointestinal (GI) problems in women: a study in women with urological and GI problems vs a control population.

OBJECTIVES: To study the prevalence of self-reported lower urinary tract symptoms (LUTS) in women consulting a Gastroenterology clinic with complaints of functional constipation (FC), fecal incontinence (FI) or both, compared with a female control population. Also, to study the influence of FC, FI, or both on self-reported LUTS in women attending a Urology clinic. PATIENTS AND METHODS: We present a retrospective study of data collected through a validated self-administered bladder and bowel symptom questionnaire in a tertiary referral hospital from three different female populations: 104 controls, 159 gastroenterological patients and 410 urological patients. Based on the reported bowel symptoms, patients were classified as having FC, FI, a combination of both, or, no FC or FI. LUTS were compared between the control population and the gastroenterological patients, and between urological patients with and without concomitant gastroenterological complaints. Results were corrected for possible confounders through logistic regression analysis. RESULTS: The prevalence of LUTS in the control population was similar to large population-based studies. Nocturia was significantly more prevalent in gastroenterological patients with FI compared with the control population [odds ratio (OR) 9.1]. Female gastroenterological patients with FC more often reported straining to void (OR 10.3), intermittency (OR 5.5), need to immediately re-void (OR 3.7) and feeling of incomplete emptying (OR 10.5) compared with the control population. In urological patients, urgency (94%) and urgency urinary incontinence (UUI, 54% of UI) were reported more often by patients with FI than by patients without gastroenterological complaints (58% and 30% of UI respectively), whereas intermittency (OR 3.6), need to immediately re-void (OR 2.2) and feeling of incomplete emptying (OR 2.2) were reported more often by patients with FC than by patients without gastroenterological complaints. CONCLUSION: As LUTS are reported significantly more often by female gastroenterological patients than by a control population, and as there is a difference in self-reported LUTS between female urological patients with different concomitant gastroenterological complaints, we suggest that general practitioners, gastroenterologists and urologists should always include the assessment of symptoms of the other pelvic organ system in their patient evaluation. The clinical correlations between bowel symptoms and LUTS may be explained by underlying neurological mechanisms.

CD4+ROR γ t++ and Tregs in a Mouse Model of Diet-Induced Nonalcoholic Steatohepatitis.

BACKGROUND AND AIMS: Inflammatory mediators that cross-talk in different metabolically active organs are thought to play a crucial role in the pathogenesis of Nonalcoholic Steatohepatitis (NASH). This study was aimed at investigating the CD4+RORγt+ T-helper cells and their counterpart, the CD4+CD25+FOXP3+ regulatory T cells in the liver, subcutaneous adipose tissue (SAT), and abdominal adipose tissue (AAT) in a high fat diet (HFD) mouse model. METHODS: C57BL6 mice were fed a HFD or a normal diet (ND). Liver enzymes, metabolic parameters, and liver histology were assessed. The expression of CD4+RORγt+ cells and regulatory T cells in different organs (blood, liver, AAT, and SAT) were analyzed by flow cytometry. Cytokine and adipokine tissue expression were studied by RT-PCR. RESULTS: Mice fed a HFD developed NASH and metabolic alterations compared to normal diet. CD4+RORγt++ cells were significantly increased in the liver and the AAT while an increase of regulatory T cells was observed in the SAT of mice fed HFD compared to ND. Inflammatory cytokines were also upregulated. CONCLUSIONS: CD4+RORγt++ cells and regulatory T cells are altered in NASH with a site-specific pattern and correlate with the severity of the disease. These site-specific differences are associated with increased cytokine expression.

Histamine H4 and H1 receptors contribute to postinflammatory visceral hypersensitivity.

OBJECTIVES: Substantial evidence implicates mast cells and their main constituent histamine in the pathogenesis of visceral hypersensitivity. We explored the specific contribution of histamine H4 (H4R) and H1 (H1R) receptors to visceral hypersensitivity in a postinflammatory rat model. DESIGN: Trinitrobenzenesulfonic acid (TNBS)-colitis was monitored individually by colonoscopy: first on day 3 to confirm the presence of colitis and then every 4 days, starting from day 10, to monitor convalescence and determine the exact timepoint of endoscopic healing in each rat. Experiments were performed 3 days after endoscopic resolution of colitis. Visceral sensitivity was assessed by quantifying visceromotor responses (VMRs) to colorectal distension. Colonic mast cell numbers, histamine release and H4R and H1R mRNA expression were quantified. JNJ7777120 (H4R antagonist) and/or levocetirizine (H1R antagonist) were administered 30 min prior to VMR assessment or histamine release assay. RESULTS: Postcolitis rats displayed a higher number of colonic mast cells, excessive histamine release and significantly enhanced VMRs. Heightened VMRs were dose-dependently reduced by JNJ7777120 and levocetirizine; combined administration of JNJ7777120 and levocetirizine potentiated the antinociceptive effect. In the colon, both H4R and H1R mRNA were present; in the dorsal root ganglia, only H1R mRNA was found. Only colonic H4R mRNA expression was increased in postcolitis rats. Excessive histamine release in postcolitis rats was attenuated by the highest dose of JNJ7777120. CONCLUSIONS: H4R and H1R antagonists dose-dependently reduce and even normalise postinflammatory visceral hypersensitivity via different underlying mechanisms but with a synergistic effect. Both receptor subtypes represent promising targets for the treatment of postinflammatory visceral hypersensitivity.

The effect of chemically induced colitis, psychological stress and their combination on visceral pain in female Wistar rats.

Visceral sensitivity is of pathophysiological importance in abdominal pain disorders and can be modulated by inflammation and stress. However, it is unclear whether inflammation and stress alter visceral perception independently of each other or in conjunction through neuroendocrine interactions. Therefore, we compared the short- and long-term effects of experimental colitis and water avoidance stress (WAS), alone or in combination, on visceral sensitivity in female Wistar rats. Colitis was induced by trinitrobenzene sulfonic acid (TNBS) and colonoscopically confirmed. During WAS, rats were placed on a platform surrounded by water for 1 h. Visceral sensitivity was assessed by quantifying the visceromotor responses (VMRs) to colorectal distension. Activation of the hypothalamic-pituitary-adrenal axis was determined by measuring serum corticosterone in a separate protocol. TNBS instillation resulted in overt colitis, associated with significant visceral hypersensitivity during the acute inflammatory phase (3 days post-TNBS; n = 8/group); after colitis had subsided (28 days post-TNBS), hypersensitivity was resolved (n = 4-8/group). Single WAS was associated with increased VMRs of a magnitude comparable to acute TNBS-induced hypersensitivity (n = 8/group). However, after repetitive WAS no significant hypersensitivity was present (n = 8/group). No additive effect of colitis and stress was seen on visceral pain perception (n = 6-8/group). Corticosterone levels were only increased in acute TNBS-colitis, acute WAS and their combination. To conclude, both colitis and stress successfully induced short-term visceral hypersensitivity and activated the hypothalamic-pituitary-adrenal axis, but long-term effects were absent. In addition, our current findings do not support an additive effect of colitis and stress on visceral sensitivity in female Wistar rats.

Mechanisms of pelvic organ crosstalk: 1. Peripheral modulation of bladder inhibition by colorectal distention in rats.

PURPOSE: Bladder activity can be inhibited by afferent input from the colorectum (inhibitory rectovesical reflex). We evaluated the functional response of the rat bladder to nonnoxious and noxious colorectal distention, and investigated the mechanical and pharmacological peripheral modulation of this response. MATERIALS AND METHODS: In 70 female Sprague-Dawley® rats we evaluated the effect of nonnoxious (20 mm Hg) and noxious (40 and 60 mm Hg) colorectal distention on the micturition volume threshold and on bladder activity in a filled bladder. We also studied the effect of rectal balloon size (1.5 vs 3.5 cm long), and rectal administration of 2% lidocaine jelly or 1 mM allyl isothiocyanate solution on the inhibitory rectovesical reflex. RESULTS: Colorectal distention at 60 mm Hg increased the micturition volume threshold (mean ± SE 0.640 ± 0.056 vs 0.448 ± 0.035 ml in controls, p <0.001). Bladder contraction frequency was significantly decreased by 40 and 60 mm Hg colorectal distention vs controls (mean 0.62 ± 0.06 and 0.33 ± 0.05 per minute, respectively, vs 0.77 ± 0.03, each p <0.001). These effects were reversible and pressure dependent (p <0.001), and more pronounced using a large rectal balloon (mean 40 vs 60 mm Hg colorectal distention 0.35 ± 0.12 vs 0.07 ± 0.04 per minute, p = 0.004). We noted no significant graded inhibition of bladder contraction amplitude or duration. The inhibitory rectovesical reflex was reversibly abolished by intrarectal lidocaine administration. Intrarectal allyl isothiocyanate administration significantly increased the effect of noxious colorectal distention on bladder contraction frequency. CONCLUSIONS: Only noxious levels of colorectal distention initiated the inhibitory rectovesical reflex. The effect increased with rectal balloon size and with intrarectal administration of allyl isothiocyanate. It was reversibly abolished by lidocaine. Results suggest that spinal interneurons are the mechanism behind the inhibitory rectovesical reflex.

Renewed attention for overtube-assisted colonoscopy to prevent incomplete endoscopic examination of the colon.

BACKGROUND: Colonoscopy is the standard examination to detect mucosal pathology in the colon. However, failure to complete colonoscopy may reach more than 10% in population-based endoscopy practices. The reasons for incomplete conventional colonoscopy are diverse and result in missed diagnosis of colonic polyps and carcinoma. OBJECTIVE: Recent endoscopic developments have shown that the use of specialized overtubes may help to reach the cecum in the case of a difficult colonoscopy, even with less discomfort. Several types of overtubes are currently available, whereas other types are being developed and clinically evaluated. The current review highlights the development of overtubes for colonoscopy and the available clinical data on overtube-assisted colonoscopy in the case of incomplete conventional colonoscopy. DATA SOURCES: Data were derived from a PubMed search through November 2012. STUDY SELECTION: Available clinical literature data on recent developments in overtube-assisted colonoscopy were studied. INTERVENTION: A descriptive comparison was made of currently available endoscopy systems used for overtube-assisted colonoscopy. MAIN OUTCOME MEASURES: The primary outcomes measured were the feasibility and safety of different endoscopy systems to perform overtube-assisted colonoscopy. RESULTS: Several overtube-assisted colonoscopy systems have recently been developed to complete colonoscopy in the case of difficult conventional colonoscopy. Literature data show excellent feasibility to reach the cecum with very low complication rates and good patient tolerance for the different overtube systems. LIMITATIONS: The majority of available studies are uncontrolled case series describing 7 to 110 patients undergoing overtube-assisted colonoscopy with only 1 direct comparison between 2 overtube systems. CONCLUSIONS: Overtube-assisted colonoscopy has been shown to be useful in performing colonoscopy by increasing the cecal intubation rate and patient tolerance and by decreasing the need for sedation. There is no standardized superior overtube system at this moment.

Increased intrahepatic resistance in severe steatosis: endothelial dysfunction, vasoconstrictor overproduction and altered microvascular architecture.

Non-alcoholic fatty liver disease can progress to steatohepatitis and fibrosis, and is also associated with impaired liver regeneration. The pathophysiology remains elusive. We recently showed that severe steatosis is associated with an increase in portal pressure, suggesting liver flow impairment. The objective of this study is to directly assess total intrahepatic resistance and its potential functional and structural determinants in an in situ perfusion model. Male Wistar rats fed a control (n = 30) or a methionine-choline-deficient (MCD) diet (n = 30) for 4 weeks were compared. Liver tissue and serum analysis, in vivo haemodynamic measurements, in situ perfusion experiments and vascular corrosion casts were performed. The MCD group showed severe steatosis without inflammation or fibrosis on histology. Serum levels and liver tissue gene expression of interleukin (IL)-6, tumour necrosis factor-α, IL-1ß and interferon-γ, liver tissue myeloperoxidase activity and liver immunohistochemistry with anti-CD68 and anti-α smooth muscle actin were comparable between groups, excluding significant inflammation. Flow-pressure curves were significantly different between groups for all flows (slope values: 0.1636 ± 0.0605 mm Hg/ml/min in controls vs 0.7270 ± 0.0408 mm Hg/ml/min in MCD-fed rats, P < 0.001), indicating an increased intrahepatic resistance, which was haemodynamically significant (portocaval pressure gradient 2.2 ± 1.1 vs 8.2 ± 1.3 mm Hg in controls vs MCD, P<0.001). Dose-response curves to acetylcholine were significantly reduced in MCD-fed rats (P < 0.001) as was the responsiveness to methoxamine (P<0.001). Vascular corrosion casts showed a replacement of the regular sinusoidal anatomy by a disorganized pattern with multiple interconnections and vascular extensions. Liver phosphorylated endothelial NO synthase (eNOS)/eNOS and serum nitrite/nitrate were not increased in severe steatosis, whereas liver thromboxane synthase expression, liver endothelin-1 (ET-1) expression and serum andothelin-1 concentration were significantly increased. Severe steatosis induces a haemodynamically significant increase in intrahepatic resistance, which precedes inflammation and fibrogenesis. Both functional (endothelial dysfunction and increased thromboxane and ET-1 synthesis) and structural factors are involved. This phenomenon might significantly contribute to steatosis-related disease.

Noninvasive assessment of nonalcoholic fatty liver disease in obese or overweight patients.

BACKGROUND & AIMS: Reliable noninvasive tools are needed for staging nonalcoholic fatty liver disease (NAFLD). Published scoring systems have not been validated in prospective assessments of unselected patients. We aimed to identify factors that predicted development of nonalcoholic steatohepatitis (NASH) in a large group of overweight or obese patients and compared these with established factors. METHODS: We performed a prospective analysis of factors associated with the development and severity of NAFLD in patients at a single obesity center. We evaluated liver involvement in 542 patients by a large set of routine and non-routine parameters, including ultrasound and genetic testing. Those suspected of having NAFLD underwent liver biopsy (57.7%). Patients were divided into design cohort (n = 200) and validation cohort (n = 113) to identify factors associated with the presence and severity of NAFLD and NASH. RESULTS: Factors independently associated with development of NASH included increased levels of alanine aminotransferase (ALT), fasting levels of C-peptide, and ultrasound steatosis scores (USSs), with area under the receiver operating curve (AUROC) values of 0.854 in the design cohort and 0.823 in the validation cohort. NASH activity scores also correlated with level of ALT, USS, and fasting level of C-peptide (R(2) = 0.491). Independent predictors of advanced fibrosis included waist circumference and level of aspartate aminotransferase (AUROC values of 0.839 and 0.846 for design and validation cohorts, respectively; negative predictive values of 98% and 97%, respectively, for a cutoff of -2.14). Previously published scoring systems had significantly lower AUROC values. Levels of CK18 and PNPLA3 polymorphisms correlated with development of NASH but did not add value. CONCLUSIONS: Parameters routinely analyzed in assessing obese patients can be used to determine the presence of NASH and advanced fibrosis. Non-routine tests do not increase diagnostic accuracy. Previously published scores are significantly less accurate.

Safety of pull-type and introducer percutaneous endoscopic gastrostomy tubes in oncology patients: a retrospective analysis.

BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) allows long-term tube feeding. Safety of pull-type and introducer PEG placement in oncology patients with head/neck or oesophageal malignancies is unknown. METHODS: Retrospective analysis of 299 patients undergoing PEG tube placement between January 2006 and December 2008 revealed 57 oncology patients. All patients with head/neck or oesophageal malignancy were treated with chemo- and radiotherapy. In case of high-grade stenosis introducer Freka® Pexact PEG tube was placed (n = 24) and in all other patients (n = 33) conventional pull-type PEG tube. Short-term complications and mortality rates were compared. RESULTS: Patients' characteristics and clinical status were comparable in both groups. Short-term complications were encountered in 11/24 (48%) introducer PEG patients as compared to only 4/33 (12%) pull-type PEG patients (P < 0.05). Accidental removal of the introducer PEG tube occurred in 4/24 (17%) with need for surgical intervention in 1 vs. 0/33 (0%, P < 0.05). Wound infection occurred in 3/24 (12%) leading to septic shock and admission to intensive care unit (ICU) in 1 vs. 3/33 (9%, NS). Finally, 3/24 gastrointestinal perforations (12%) resulted from a difficult placement procedure vs. 1/33 (3%), leading to urgent surgical intervention and admission to ICU. Two introducer PEG patients died at ICU, resulting in an overall mortality rate of 8% vs. 0% (P = 0.091). CONCLUSION: The introducer Freka® Pexact PEG procedure for long-term tube feeding may lead to significantly higher complication and mortality rates in patients with head/neck or oesophageal malignancies treated with chemo- and radiotherapy. It is suggested to use the conventional pull-type PEG tube placement in this group of patients, if possible.

Lower bowel function in urinary incontinent women, urinary continent women and in controls.

AIMS: The anorectum and the lower urinary tract (LUT) are closely related. Clinically, it is important for caregivers to identify the presence of concomitant pathology as early in the diagnostic process as possible. This study evaluates lower bowel symptoms (LBS) in women with different types of urinary incontinence (UI), and compares the outcome with continent women and with a female control group. METHODS: Female patients, consulting at the Functional Unit of our Urology Department, with or without UI, were included in the study (URO patients). A female control group was recruited at the Orthopedic and the General Internal Medicine Consultation and among co-workers from the hospital (CONTROL group). All were asked to complete a validated, self-administered questionnaire, which identified the possible presence of UI, allowed categorization by type of UI, and questioned LBS. RESULTS: URO patients had, regardless of presence and type of UI, more complaints of fecal incontinence (FI) and of constipation than the CONTROL group. Patients with Urge UI and Mixed UI had significantly more difficulty postponing defecation and significantly more FI than Stress UI (SUI) patients and than continent URO patients (27% vs. 8%). More SUI patients reported straining during defecation. CONCLUSIONS: Our data confirm that in patients with functional problems of the LUT, the prevalence of LBS is high. Bowel symptoms differ in different types of UI.

Treatment of infants and toddlers with cystic fibrosis-related pancreatic insufficiency and fat malabsorption with pancrelipase MT.

BACKGROUND: Pancreatic enzyme replacement therapy (PERT) improves nutritional status and growth in patients with cystic fibrosis (CF) with pancreatic insufficiency (PI). The current recommendation for infants and young children, who are not able to swallow the whole capsule, is to open the capsule and mix the beads in a spoon with some applesauce; however, the efficacy and safety data of this approach are currently lacking. The aim of this study was to assess the efficacy, palatability (ease of swallowing), and safety of 4 dose levels of pancrelipase microtablets (Pancrease MT) in infants and young children with CF-related PI. PATIENTS AND METHODS: This study was a phase II randomized, investigator-blinded, parallel-group pilot study in DNA-proven infants with CF and PI. The study design included a run-in period (days 1-5) and an experimental period (days 6-11). Pancrelipase microtablets (2-mm, enteric coated) were provided orally. Sixteen subjects, 6 to 30 months of age, were provided 500 U lipase/kg/meal for 5 days (baseline period). Subsequently, subjects were randomly assigned to 1 of 4 treatment groups (each n = 4), receiving 500, 1000, 1500, or 2000 U (Ph. EUR) of lipase/kg/meal, respectively, for 5 days (experimental period). The primary endpoint was medication efficacy assessed by the 72-hour fecal fat excretion, expressed as coefficient of fecal fat absorption (CFA), and 13C mixed triglyceride breath test. Secondary endpoints were safety and palatability. RESULTS: Overall compliance, defined as used study medication, was 89% to 99% for the entire study. None of the 4 dose regimens significantly influenced the CFA, relative to the baseline period (median range 83%-93%). During the run-in period the median cumulative % 13C was 11 (range -8 to 59). After randomization the median cumulative % 13C was 18 (range 14-23) in the 500-U, 14 (range -1 to 17) in the 1000-U, 10 (range 10-27) in the 1500-U, and 3 (range 1-49) in the 2000-U groups. Palatability was scored fair to good by the parents in each of the treatment groups. Gastrointestinal symptoms were reported in some patients, including common adverse events reported in clinical trials involving pancreatic enzyme therapy. No serious or other adverse events were reported. CONCLUSION: Treatment with Pancrease MT at a dosage of 500 U lipase/kg/meal resulted in a CFA of approximately 89% in pediatric subjects ages 6 to 30 months with PI resulting from CF. Pancrease MT doses were well tolerated and mean palatability was scored as fair to good. Present results do not indicate that a dosage higher than 500 U (Ph. EUR) lipase/kg/meal increases the coefficient of fat absorption in a cohort of infants 6 to 30 months of age.

Non-alcoholic steatohepatitis induces non-fibrosis-related portal hypertension associated with splanchnic vasodilation and signs of a hyperdynamic circulation in vitro and in vivo in a rat model.

INTRODUCTION: Steatosis, without fibrosis, may lead to changes in liver blood flow, which are poorly understood, and to date have not been correlated to portal pressure and related haemodynamics. AIMS: To study the temporal relation between progressive steatosis, portal pressure, systemic haemodynamics, vascular responsiveness, mesenteric and portal blood flow in methionine-choline-deficient diet (MCDD)-fed rats. METHODS: Male Wistar rats fed the MCDD were examined at week (w) 0-1-2-3-4-5-6-7-8, respectively, including systemic haemodynamics and portal pressure. At w0-4-8, in vivo blood flow was measured in the portal vein and the superior mesenteric artery. Dose-response curves to phenylephrine (PE) were established in abdominal aortic rings. RESULTS: Histology showed 100% steatosis from w3 on. Fibrosis was absent. Significant inflammation was nearly absent upon w4. Portal pressure slightly increased at w2, reached a maximum at w4 [9.4 +/- 0.3 vs 2.9 +/- 0.6 mmHg at w0 (P=0.003)] and remained stable upon w8. Mean arterial blood pressure (MABP) decreased from w2 on [98.7 +/- 5.7 mmHg on w4 compared with 123.8 +/- 1.8 on w0 (P=0.002)]. Portal flow increased from 1.85 +/- 0.11 to 3.07 +/- 0.44 ml/min/100 g on w0 and w8 respectively (P=0.039). Mesenteric artery flow increased from 3.40 +/- 0.26 to 4.56 +/- 0.30 ml/min/100 g on w0 and w8 respectively (P=0.043). Vascular responsiveness to PE gradually decreased from 138 +/- 3% on w0 to 110 +/- 5% on w4 (P=0.013). CONCLUSION: Steatohepatitis induces significant portal hypertension (PHT) in the absence of fibrosis, associated with an increase in mesenteric arterial and portal venous flow, arterial hyporesponsiveness to vasoconstrictors and a decrease in MABP, indicating the presence of splanchnic vasodilation and hyperdynamic circulation. These alterations resemble those seen in cirrhotic PHT.

Cecal intubation rate with the double-balloon endoscope after incomplete conventional colonoscopy: a study in 45 patients.

BACKGROUND AND AIM: Conventional colonoscopy is the gold standard for colorectal cancer screening. However, a failure rate to complete conventional colonoscopy of more than 10% is reported in the literature. We evaluated whether the therapeutic Fujinon double-balloon endoscope EN-450T5/20 is a valuable tool to intubate the cecum and to carry out all conventional endoscopic procedures after incomplete conventional colonoscopy. METHODS: Forty-five consecutive patients with prior incomplete conventional colonoscopy were prospectively enrolled. All but three procedures were carried out under conscious sedation with the patient in the left lateral decubitus position without fluoroscopic guidance. RESULTS: The cecum was reached in 42 of 45 patients (93%) and in 62% additional therapeutic interventions were carried out. Double-balloon colonoscopy required less conscious sedation compared to conventional colonoscopy. No external abdominal compression nor fluoroscopic control was used. The insertion depth of the double-balloon endoscope did not exceed the working length of a conventional colonoscope. CONCLUSIONS: The present study illustrates that the concept of double-balloon endoscopy is a valuable alternative to reach the cecum after prior incomplete conventional colonoscopy, especially due to redundant colon and colonic loop formation. The procedure requires less conscious sedation and no fluoroscopic control, but allows all conventional endoscopic interventions.

Effect of genetic SSTR4 ablation on inflammatory peptide and receptor expression in the non-inflamed and inflamed murine intestine.

The recently suggested pivotal role of somatostatin (SOM) receptor 4 (SSTR4) in inflammation and nociception in several non-intestinal organs and in gastrointestinal (GI) physiology, necessitates exploration of the role of SSTR4 in GI pathophysiology. Therefore, the role of SSTR4 in GI activity was explored by investigating the effects of SSTR4 deficiency on intestinal motility, smooth muscle contractility and on the expression of SSTRs and neuropeptides in the healthy and Schistosoma mansoni-infected murine small intestine. Functional experiments revealed no differences in intestinal motility or smooth muscle cell contractility between wild-type and SSTR4 knockout (SSTR4(-/-)) mice in physiological conditions. As revealed by multiple immunofluorescent labellings, RT-PCR and quantitative real time RT-PCR (qPCR), genetic deficiency of SSTR4 considerably altered the expression of SOM and SSTRs in non-inflamed and inflamed conditions, affecting both extrinsic and intrinsic components of the intestinal innervation, along with SSTR expression in several non-neuronal cell types. Moreover, substance P and calcitonin gene-related peptide expression were significantly elevated in SSTR4(-/-) mice, confirming the modulatory role of SSTR4 on intestinal pro-inflammatory neuropeptide expression. These data suggest that SSTR4 plays a previously unexpected modulatory role in the regulation of intestinal SSTR expression. Moreover, in addition to the recently described inhibitory effects of SSTR4 on the neuronal release of pro-inflammatory peptides, SSTR4 appears also to be involved in the neuronal expression of both pro- and anti-inflammatory peptides in the murine small intestine.

Diagnostic and therapeutic double-balloon enteroscopy after small bowel Roux-en-Y reconstructive surgery.

BACKGROUND: Roux-en-Y reconstruction excludes the afferent limb and the biliopancreatic system from conventional endoscopic access. Postoperative problems in these excluded gastrointestinal systems are therefore often dealt with surgically. We investigated the usefulness of the therapeutic double-balloon enteroscope to perform interventional endoscopic procedures in the excluded segment of the gastrointestinal tract after Roux-en-Y reconstruction. METHODS: 30 procedures were performed in 22 patients with Roux-en-Y reconstruction after enterobiliary anastomosis, gastrectomy or bariatric gastric bypass. All procedures were performed with the therapeutic double-balloon enteroscope, under general anesthesia and with fluoroscopic control. RESULTS: ERCP at the enterobiliary anastomosis was successful in 90% (n = 10) of the procedures. ERCP at the intact papilla was successful in 60% (n = 5). Enterocutaneous fistula closure after (sub)total gastrectomy was performed in 2 procedures. Successful diagnostic procedures encompassed intubation of the excluded stomach after bariatric gastric bypass (89%, n = 9) or the afferent limb after Roux-en-Y reconstruction (75%, n = 4). The overall success rate in accessing the aimed excluded segment with the double-balloon enteroscope was 87%. Interventional procedures were able to avoid surgery in 65%. One retroperitoneal perforation occurred during ERCP which was conservatively treated. CONCLUSIONS: Excluded gastrointestinal segments after Roux-en-Y reconstruction can be accessed with a substantial success rate using double-balloon enteroscopy. Therapeutic interventions like ERCP can prevent surgery in the majority of patients.

Worms and the treatment of inflammatory bowel disease: are molecules the answer?

The lack of exposure to helminth infections, as a result of improved living standards and medical conditions, may have contributed to the increased incidence of IBD in the developed world. Epidemiological, experimental, and clinical data sustain the idea that helminths could provide protection against IBD. Studies investigating the underlying mechanisms by which helminths might induce such protection have revealed the importance of regulatory pathways, for example, regulatory T-cells. Further investigation on how helminths influence both innate and adaptive immune reactions will shed more light on the complex pathways used by helminths to regulate the hosts immune system. Although therapy with living helminths appears to be effective in several immunological diseases, the disadvantages of a treatment based on living parasites are explicit. Therefore, the identification and characterization of helminth-derived immunomodulatory molecules that contribute to the protective effect could lead to new therapeutic approaches in IBD and other immune diseases.

The role of tachykinins in circular muscle contractility of the murine ileum: a functional investigation.

We investigated the participation of different tachykinin receptors in contractility of circular muscle strips of the mouse ileum using selective NK receptor agonists and antagonists. The NK1 receptor agonist septide (1-100 nM) induced dose-dependent contractions which were reduced by atropine and augmented by L-NNA. L-NNA increased and TTX consecutively reduced contractions to the NK2 receptor agonist beta-A-NKA (1-100 nM). Senktide, agonist of NK3 receptors, failed to induce contractions. NANC contractions to EFS were decreased after NK1 receptor blockade with RP67580. This inhibitory effect was more pronounced after additional blockade of NK2 and NK3 receptors. NK3 receptor antagonism alone reduced contractions at higher frequencies of stimulation. When the duration of the EFS stimulus was increased, the participation of all NK receptor subtypes became more evident. Our results suggest that excitatory NANC transmission in the circular muscle layer of the mouse ileum is mediated by tachykinins acting principally on NK1 receptors on cholinergic nerves and smooth muscle cells. Also NK2 receptors, located on smooth muscle cells and nitrergic neurons, and NK3 receptors on enteric neurons are involved.

Gastrointestinal parasites: potential therapy for refractory inflammatory bowel diseases.

Crohn's disease and ulcerative colitis are chronic relapsing inflammatory bowel diseases (IBDs). Different pharmacological agents are currently used in several combinations to control the inflammatory process. Recently, antibodies against the proinflammatory cytokine tumor necrosis factor-alpha appeared to be very effective in treating patients with Crohn's disease. However, due to the fact that the pathogen causing IBD is still unknown, no causative treatment is currently available that is able to make the disease disappear. Recently, the hygiene hypothesis of the development of immunological diseases was proposed, stating that raising children in extremely hygienic environments with less exposure to parasite infections may negatively affect the development of the immune system, predisposing them to immunologic diseases such as IBD. This hypothesis is supported by experimental data showing that helminthic parasites protect against T helper (TH) type 1 cell-mediated gastrointestinal inflammations like Crohn's disease. Both TH-2 cells and regulatory T cells may be involved in this immunomodulatory mechanism. Here, we review the experimental and clinical studies in favor of the hygiene hypothesis, opening perspectives on new therapies for IBD.