IL-1beta signaling in cat lower esophageal sphincter circular muscle.
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In a cat model of acute experimental esophagitis, resting in vivo lower esophageal sphincter (LES) pressure and in vitro tone are lower than in normal LES, and the LES circular smooth muscle layer contains elevated levels of IL-1beta that decrease the LES tone of normal cats. We now examined the mechanisms of IL-1beta-induced reduction in LES tone. IL-1beta significantly reduced acetylcholine-induced Ca(2+) release in Ca(2+)-free medium, and this effect was partially reversed by catalase, demonstrating a role of H(2)O(2) in these changes. IL-1beta significantly increased the production of H(2)O(2), and the increase was blocked by the p38 MAPK inhibitor SB-203580, by the cytosolic phospholipase A(2) (cPLA(2)) inhibitor AACOCF3, and by the NADPH oxidase inhibitor apocynin, but not by the MEK1 inhibitor PD-98059. IL-1beta significantly increased the phosphorylation of p38 MAPK and cPLA(2). IL-1beta-induced cPLA(2) phosphorylation was blocked by SB-203580 but not by AACOCF3, suggesting sequential activation of p38 MAPK-phosphorylating cPLA(2). The IL-1beta-induced reduction in LES tone was partially reversed by AACOCF3 and by the Ca(2+)-insensitive PLA(2) inhibitor bromoenol lactone (BEL). IL-1beta significantly increased cyclooxygenase (COX)-2 and PGE(2) levels. The increase in PGE(2) was blocked by SB-203580, AACOCF3, BEL, and the COX-2 inhibitor NS-398 but not by PD-98059 or the COX-1 inhibitor valeryl salicylate. The data suggested that IL-1beta reduces LES tone by producing H(2)O(2), which may affect Ca(2+)-release mechanisms and increase the synthesis of COX-2 and PGE(2). Both H(2)O(2) and PGE(2) production depend on sequential activation of p38 MAPK and cPLA(2). cPLA(2) activates NADPH oxidases, producing H(2)O(2), and may produce arachidonic acid, converted to PGE(2) via COX-2. (+info)
The relationship between somatic growth and in vivo esophageal segmental and sphincteric growth in human neonates.
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BACKGROUND: Measurement of aerodigestive tract length is an important determinant for accurate placement of esophageal probes and gavage tubes at the desired location. The relationship of esophageal body, upper esophageal sphincter (UES) and lower esophageal sphincter (LES) lengths with somatic growth in neonates is not well understood. OBJECTIVES: Our objectives were to (1) evaluate a relationship between segmental esophageal lengths and somatic growth parameters and (2) ascertain the relationship between segmental esophageal lengths and gestational age (GA) and postmenstrual age (PMA) in preterm and full-term born human neonates. DESIGN/METHODS: One hundred esophageal manometry studies were performed in 75 infants (30-60 weeks PMA) and the high-pressure zones of LES and UES identified. The distance from nares to LES and from nares to UES, esophageal body length, length of UES and LES derived from the manometry studies were correlated with somatic growth parameters. Growth rate of different esophageal segments was also determined in 26 subjects that underwent longitudinal studies. Analysis of variance and linear regression analysis were performed. RESULTS: Seventy-five neonates of 23.0-40.6 weeks gestational age (0.6-4.4 kg) were studied at 29.1-58.6 weeks PMA (1.0-6.4 kg). Significant correlation (P < 0.001) of PMA and physical growth parameters with the growth of nares-LES (R = 0.8), esophageal body length (R = 0.6) and nares-UES (R = 0.4) were noted. Nares-to-LES length increased at a rate of 0.25 cm/wk PMA during 33.0-36.0 weeks of age. CONCLUSIONS: In vivo esophageal segmental lengths correlated strongly with somatic growth parameters and PMA in neonates. We speculate that this approach has many practical applications with the use of esophageal probes and catheters. (+info)
Review article: the management of achalasia - a comparison of different treatment modalities.
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BACKGROUND: Achalasia is an uncommon primary oesophageal motor disorder with an unknown aetiology. Therapeutic options for achalasia are aimed at decreasing the lower oesophageal sphincter pressure, improving the oesophageal empting, and most importantly, relieving the symptoms of achalasia. Modalities for treatment include pharmacologic, endoscopic, pneumatic dilatation and surgical. The decision of which modality to use involves the consideration of multiple clinical and economic factors. AIM: To review the management strategies currently available for achalasia. METHODS: A Medline search identified the original articles and reviews the published in the English language literature between 1966 and 2006. RESULTS: The results reveal that pharmacotherapy, injection of botulinum toxin, pneumatic dilatation and minimally invasive surgical oesophagomyotomy are variably effective at controlling the symptoms of achalasia but that each modality has specific strengths and weaknesses which make them each suitable in certain populations. Overall, pharmacologic therapy results in the shortest lived, least durable response followed by botulinum toxin injection, pneumatic dilatation and surgery, respectively. CONCLUSION: The optimal treatment for achalasia remains an area of controversy given our lack of complete understanding about the pathophysiology of the disease as well as the high numbers of clinical relapse after treatment. Further research focusing on optimal dosing of botulinum toxin injection and optimal timing of repeated graduated pneumatic dilatations could add to our knowledge regarding long-term therapy. (+info)
Injection of botulinum toxin before pneumatic dilatation in achalasia treatment: a randomized-controlled trial.
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BACKGROUND: Pneumatic dilatation is the first line therapy in achalasia, but half of patients relapse within 5 years of therapy and require further dilatations. AIM: To assess whether botulinum toxin injection before pneumatic dilatation is superior to pneumatic dilatation alone in achalasia patients. METHODS: Newly diagnosed achalasia patients were randomly assigned to receive botulinum toxin 1 month before pneumatic dilatation (botulinum toxin-pneumatic dilatation group: 27 patients with median age of 38) or to undergo pneumatic dilatation alone (pneumatic dilatation group: 27 patients with median age of 30). Response to therapy was assessed by clinical and objective methods at various intervals. RESULTS: One-year remission rate of patients in botulinum toxin-pneumatic dilatation group was 77% compared with 62% in pneumatic dilatation group (P = 0.1). In pneumatic dilatation group, the oesophageal barium volume significantly (P < 0.001) decreased at 1 month, but this reduction did not persist over 1-year follow-up. Botulinum toxin-pneumatic dilatation group showed a significant (P < 0.001) reduction in barium volume at the various times intervals post-treatment. In the botulinum toxin-pneumatic dilatation group, 10/11 (91%) patients over 40 were in remission at 1 year, comparing with only five of nine (55%) cases in pneumatic dilatation group (P = 0.07). CONCLUSION: Injection of botulinum toxin before pneumatic dilatation does not significantly enhance the efficacy of pneumatic dilatation. (+info)
Treatment of esophageal achalasia with Heller myotomy: retrospective evaluation of patient satisfaction and disease-specific quality of life.
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BACKGROUND: Prospective randomized studies have suggested that surgery palliates esophageal achalasia more effectively than pneumatic dilatation, but for some dilatation is still the procedure of choice for initial treatment. We decided to compare achalasia symptoms before and after Heller myotomy by means of postoperative questionnaires. METHODS: The study included 22 patients who underwent Heller myotomy for achalasia at the Hotel Dieu Hospital, Queen's University, Kingston, Ont., since July 1990; 5 of them required repeat myotomy for symptom recurrence, for a total of 9 open and 18 laparoscopic procedures. Median follow-up was 43 (range 6-109) months. Preoperative and postoperative data regarding dysphagia, regurgitation, chest pain and overall patient satisfaction were gathered. Symptom scores were calculated by adding severity (0 = none, 2 = mild, 4 = moderate, 6 = severe) to frequency (0 = never, 1 = occasionally, 2 = once a month, 3 = every week, 4 = twice a week, 5 = daily). Patients having a repeat procedure were instructed to evaluate symptoms with respect to their initial myotomy. RESULTS: Seventeen (77%) patients were successfully contacted, 4 of them had subsequent repeat myotomy for symptom recurrence. Initially, overall symptom scores decreased for all but 1 patient, with mean preoperative and postoperative values of 23.1 and 7.3 respectively (p < 0.001). The patient in whom symptoms did not improve is a candidate for a repeat procedure. Repeat myotomy was performed after a median of 38 (range 23-75) months, corresponding to an overall 3-year positive outcome in 13 (76%) of the 17 patients. Fifteen (88%) patients considered their myotomies a success and 16 (94%) would choose to have this procedure again given the outcome. CONCLUSION: Heller myotomy appears to be effective in alleviating the symptoms of achalasia. Repeat myotomy is occasionally required. (+info)
Peripheral versus central modulation of gastric vagal pathways by metabotropic glutamate receptor 5.
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Metabotropic glutamate receptors (mGluR) are classified into group I, II, and III mGluR. Group I (mGluR1, mGluR5) are excitatory, whereas group II and III are inhibitory. mGluR5 antagonism potently reduces triggering of transient lower esophageal sphincter relaxations and gastroesophageal reflux. Transient lower esophageal sphincter relaxations are mediated via a vagal pathway and initiated by distension of the proximal stomach. Here, we determined the site of action of mGluR5 in gastric vagal pathways by investigating peripheral responses of ferret gastroesophageal vagal afferents to graded mechanical stimuli in vitro and central responses of nucleus tractus solitarius (NTS) neurons with gastric input in vivo in the presence or absence of the mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP). mGluR5 were also identified immunohistochemically in the nodose ganglia and NTS after extrinsic vagal inputs had been traced from the proximal stomach. Gastroesophageal vagal afferents were classified as mucosal, tension, or tension-mucosal (TM) receptors. MPEP (1-10 microM) inhibited responses to circumferential tension of tension and TM receptors. Responses to mucosal stroking of mucosal and TM receptors were unaffected. MPEP (0.001-10 nmol icv) had no major effect on the majority of NTS neurons excited by gastric distension or on NTS neurons inhibited by distension. mGluR5 labeling was abundant in gastric vagal afferent neurons and sparse in fibers within NTS vagal subnuclei. We conclude that mGluR5 play a prominent role at gastroesophageal vagal afferent endings but a minor role in central gastric vagal pathways. Peripheral mGluR5 may prove a suitable target for reducing mechanosensory input from the periphery, for therapeutic benefit. (+info)
Anatomy of reflux: a growing health problem affecting structures of the head and neck.
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Gastroesophageal reflux disease (GERD) and laryngopharyngeal reflux (LPR) are sibling diseases that are a modern-day plague. Millions of Americans suffer from their sequelae, ranging from subtle annoyances to life-threatening illnesses such as asthma, sleep apnea, and cancer. Indeed, the recognized prevalence of GERD alone has increased threefold throughout the 1990s. Knowledge of the precise etiologies for GERD and LPR is becoming essential for proper treatment. This review focuses on the anatomical, physiological, neurobiological, and cellular aspects of these diseases. By definition, gastroesophageal reflux (GER) is the passage of gastric contents into the esophagus; when excessive and damaging to the esophageal mucosa, GERD results. Reflux that advances to the laryngopharynx and, subsequently, to other regions of the head and neck such as the larynx, oral cavity, nasopharynx, nasal cavity, paranasal sinuses, and even middle ear results in LPR. While GERD has long been identified as a source of esophageal disease, LPR has only recently been implicated in causing head and neck problems. Recent research has identified four anatomical/physiological "barriers" that serve as guardians to prevent the cranial incursion of reflux: the gastroesophageal junction, esophageal motor function and acid clearance, the upper esophageal sphincter, and pharyngeal and laryngeal mucosal resistance. Sequential failure of all four barriers is necessary to produce LPR. While it has become apparent that GER must precede both GERD and LPR, the head and neck distribution of the latter clearly separates these diseases as distinct entities warranting specialized focus and treatment. (+info)
An experimental model of prolonged esophagitis with sphincter failure in the rat and the therapeutic potential of gastric pentadecapeptide BPC 157.
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We report a simple novel rat model that combines prolonged esophagitis and parallel sphincters failure. The anti-ulcer gastric pentadecapeptide BPC 157, which was found to be stable in gastric juice, and is being evaluated in inflammatory bowel disease trials, is an anti-esophagitis therapy that recovers failed sphincters. Twelve or twenty months after the initial challenge (tubes sutured into sphincters for one week and then spontaneously removed by peristalsis), rats exhibit prolonged esophagitis (confluent hemorrhagic and yellowish lesions, thinner epithelium and superficial corneal layer, with stratification derangement); constantly lowered pressure of both sphincters (assessed by using a water manometer connected to the drainage port of a Foley catheter implanted into the stomach either through esophageal or duodenal incision); and both lower esophageal and pyloric sphincter failure. Throughout the esophagitis experiment, BPC 157 was given at either 10 micro g/kg, i.p., once a day (last application 24 h before assessment) or alternatively, it was given continuously in drinking water at 0.16 micro g/ml (12 ml/rat). This treatment recovers i) esophagitis (macroscopically and microscopically, at either region or investigated time period) and ii) pressure in both sphincters (cmH2O). In addition, BPC 157 (10 micro g/kg) or saline (1 ml/rat, 5 ml/kg) was specifically given directly into the stomach; pressure assessment was performed at 5 min thereafter. The effect of BPC 157 is specific because in normal rats, it increases lower esophageal sphincter-pressure, but decreases pyloric sphincter-pressure. Ranitidine, given as the standard drug using the same protocol (50 mg/kg, i.p., once daily; 0.83 mg/ml in drinking water; or 50 mg/kg directly into the stomach) had no effect. (+info)