Upper esophageal sphincter abnormalities and high-resolution esophageal manometry findings in patients with laryngopharyngeal reflux.

Background: The association between laryngopharyngeal reflux (LPR) and abnormalities of upper esophageal sphincter (UES) and esophageal motility is not clearly known. High-resolution esophageal manometry (HREM) has allowed accurate measurement and evaluation of UES and esophageal function.

Goals: To evaluate the UES function and esophageal motility using HREM in patients with LPR and compare them to patients with typical gastroesophageal reflux disease (GERD).

Current and Emerging Medical Therapies for Gastroparesis.

Gastroparesis likely involves various pathophysiological disorders and is increasingly prevalent as complications of surgeries, medications, and chronic diabetes. Key to diagnosis is evidence of delayed gastric emptying, generally based on standardized scintigraphy, and ruling out distal obstruction or other dysmotilities. Initial medical management includes reviewing potentially exacerbating medications and ruling out other reversible causes, achieving tighter glucose control in diabetics, and implementing dietary and lifestyle changes.

Stretta Radiofrequency Treatment for GERD: A Safe and Effective Modality.

Gastroesophageal reflux disease is one of the leading gastrointestinal disorders. Current treatments include lifestyle modifications, pharmacological therapies, surgical fundoplications, and, more recently, endoscopic procedures. The rising concern of long-term side effects of the popular proton-pump inhibitors and the more recent evidence raising doubts about the durability of fundoplication have spurred reinterest in endoscopic procedures to treat reflux disorders.

Structure activity relationship of synaptic and junctional neurotransmission.

Chemical neurotransmission may include transmission to local or remote sites. Locally, contact between 'bare' portions of the bulbous nerve terminal termed a varicosity and the effector cell may be in the form of either synapse or non-synaptic contact. Traditionally, all local transmissions between nerves and effector cells are considered synaptic in nature.

CaMKII inhibition hyperpolarizes membrane and blocks nitrergic IJP by closing a Cl(-) conductance in intestinal smooth muscle.

The ionic basis of nitrergic "slow'" inhibitory junction potential (sIJP) is not fully understood. The purpose of the present study was to determine the nature and the role of calmodulin-dependent protein kinase II (CaMKII)-dependent ion conductance in nitrergic neurotransmission at the intestinal smooth muscle neuromuscular junction. Studies were performed in guinea pig ileum.

Role of PSD95 in membrane association and catalytic activity of nNOSalpha in nitrergic varicosities in mice gut.

We have recently shown that membrane association of neuronal nitric oxide synthase-alpha (nNOSalpha) is critical in the regulation of synthesis of NO during nitrergic neurotransmission. The purpose of this study was to examine the role of the synapse-associated proteins (SAPs) in membrane association of nNOSalpha. Varicosities (swellings on terminal axons) were isolated from mice gastrointestinal tract and examined for nNOSalpha, postsynaptic density protein 95 (PSD95), and membrane interactions by coimmunoprecipitation and SDS-PAGE.

Pyloric sphincter dysfunction in nNOS-/- and W/Wv mutant mice: animal models of gastroparesis and duodenogastric reflux.

Background & Aims: Nitrergic nerves and interstitial cells of Cajal (ICC) have been implicated in the regulation of pyloric motility. The purpose of these studies was to define their roles in pyloric function in vivo.

Methods: Pyloric sphincter manometry was performed in wild-type controls, neuronal nitric oxide synthase-deficient (nNOS(-/-)) mice, and ICC-deficient W/W(v) mice, and the effect of deafferented cervical vagal stimulation was examined.

PIN/LC8 is associated with cytosolic but not membrane-bound nNOS in the nitrergic varicosities of mice gut: implications for nitrergic neurotransmission.

This investigation demonstrates the presence and binding of the protein LC8 (described as "protein inhibitor of nNOS" or PIN in some reports) to different components of neuronal nitric oxide synthase (nNOS) in nitrergic varicosities of mice gut. Whole varicosity extracts showed three (320-, 250-, and 155-kDa) nNOS bands with anti-nNOS(1422-1433) antibody and a 10-kDa band with anti-LC8 antibody. The LC8 immunoprecipitate (IP) showed three nNOS bands, suggesting that LC8 was bound with all three forms of nNOS but dissociated from them during SDS-PAGE.

Physiology of normal esophageal motility.

The esophagus consists of 2 different parts. In humans, the cervical esophagus is composed of striated muscles and the thoracic esophagus is composed of phasic smooth muscles. The striated muscle esophagus is innervated by the lower motor neurons and peristalsis in this segment is due to sequential activation of the motor neurons in the nucleus ambiguus.

Active and inactive pools of nNOS in the nerve terminals in mouse gut: implications for nitrergic neurotransmission.

Nitric oxide (NO) is responsible for nitrergic neurotransmission in the gut, and its release is dependent on its de novo synthesis by neuronal nitric oxide synthase (nNOS). The magnitude of NO synthesis and release during neurotransmission may be related to the fraction of catalytically active nNOS out of a larger pool of inactive nNOS in the nerve terminals. The purpose of the present study was to identify catalytically active and inactive pools of nNOS in the varicosities from mouse gut.

DNA index determination with Automated Cellular Imaging System (ACIS) in Barrett's esophagus: comparison with CAS 200.

Background: For solid tumors, image cytometry has been shown to be more sensitive for diagnosing DNA content abnormalities (aneuploidy) than flow cytometry. Image cytometry has often been performed using the semi-automated CAS 200 system. Recently, an Automated Cellular Imaging System (ACIS) was introduced to determine DNA content (DNA index), but it has not been validated.

Telomerase inhibition by siRNA causes senescence and apoptosis in Barrett's adenocarcinoma cells: mechanism and therapeutic potential.

Background: In cancer cells, telomerase induction helps maintain telomere length and thereby bypasses senescence and provides enhanced replicative potential. Chemical inhibitors of telomerase have been shown to reactivate telomere shortening and cause replicative senescence and apoptotic cell death of tumor cells while having little or no effect on normal diploid cells.

Results: We designed siRNAs against two different regions of telomerase gene and evaluated their effect on telomere length, proliferative potential, and gene expression in Barrett's adenocarcinoma SEG-1 cells.

Surveillance and screening for Barrett esophagus and adenocarcinoma.

Current recommendations for screening and surveillance of Barrett esophagus and related lesions are based on recent guidelines by the Practice Parameters Committee of the American College of Gastroenterology. The purpose of this review is to critically examine the rationale and evidence behind these recommendations. There is strong rationale for vigorous initial testing to document the baseline status and identify early adenocarcinoma, and for surveillance of high-grade dysplasia.

DNA abnormalities as marker of risk for progression of Barrett's esophagus to adenocarcinoma: image cytometric DNA analysis in formalin-fixed tissues.

Objectives: To examine DNA content abnormalities in patients with Barrett's esophagus (BE) who progress to esophageal adenocarcinoma, using image cytometric DNA analysis (ICDA) of formalin-fixed tissues.

Methods: Studies were performed on archived biopsies of BE patients' undergoing endoscopic surveillance before developing adenocarcinoma. A comparison group consisted of BE patients' free of cancer during a follow-up period of over 9 yr.

Phenotype of columnar-lined esophagus in rats with esophagogastroduodenal anastomosis: similarity to human Barrett's esophagus.

In rats, esophagogastroduodenal anastomosis (EGDA) without concomitant chemical carcinogen treatment can lead to columnar-lined esophagus (CLE) including metaplasia, dysplasia, and esophageal adenocarcinoma (EAC). This study describes the morphology and phenotypic features of CLE and EAC in the rat model and compares them with the corresponding lesions in human Barrett's esophagus (BE). Swiss roll preparations of esophagi of EGDA rats and biopsies from human BE containing specialized intestinal metaplasia (SIM) and EAC were examined.

Musings on the wanderer: what's new in our understanding of vago-vagal reflex? IV. Current concepts of vagal efferent projections to the gut.

Vagal efferents, consisting of distinct lower motor and preganglionic parasympathetic fibers, constitute the motor limb of vagally mediated reflexes. Arising from the nucleus ambiguus, vagal lower motor neurons (LMN) mediate reflexes involving striated muscles of the orad gut. LMNs provide cholinergic innervation to motor end plates that are inhibited by myenteric nitrergic neurons.

Neural circuits in swallowing and abdominal vagal afferent-mediated lower esophageal sphincter relaxation.

The purpose of this review is to identify the medullary subnuclei that house neural circuits for lower esophageal sphincter (LES) relaxation. LES relaxation may occur as a component of primary peristalsis elicited by superior laryngeal nerve (SLN) afferent stimulation, secondary peristalsis elicited by esophageal distention or as a component of belch reflex, and transient LES relaxation elicited by gastric vagal afferent stimulation. In mice, SLN stimulation at 10 Hz elicited complete swallowing reflex, including pharyngeal and esophageal peristalsis, and LES relaxation.

Differences in calmodulin and calmodulin-binding proteins in phasic and tonic smooth muscles.

To determine whether densities of calmodulin (CaM) and CaM-binding proteins are related to phasic and tonic behavior of smooth muscles, we quantified these proteins in the opossum esophageal body (EB) and lower esophageal sphincter (LES), which represent phasic and tonic smooth muscles, respectively. Gel electrophoresis, immunoprecipitation, Western blot, and hemagglutinin epitope-tagged CaM (HA-CaM) overlay assay with quantitative scanning densitometry and phosphorylation measurements were used. Total protein content in the two smooth muscles was similar (approximately 30 mg protein/g frozen tissue).

Lower esophageal sphincter is achalasic in nNOS(-/-) and hypotensive in W/W(v) mutant mice.

Background And Aims: It has been proposed that nitrergic nerves mediate lower esophageal sphincter (LES) relaxation with intramuscular interstitial cells of Cajal (ICC-IM) as an intermediary. Dysfunction of the nitrergic pathway has been shown to cause LES hypertension and impaired relaxation in achalasia. We determined whether mice with neuronal nitric oxide synthase gene disruption (nNOS(-/-)) and W/W(v) mice lacking ICC-IM have achalasia-like LES dysfunction.

Swallowing reflex and brain stem neurons activated by superior laryngeal nerve stimulation in the mouse.

The purpose of the present study was to identify vagal subnuclei that participate in reflex swallowing in response to electrical stimulation of the left superior laryngeal nerve (SLN). SLN stimulation at 10 Hz evoked primary peristalsis, including oropharyngeal and esophageal peristalsis, and LES relaxation. It also induced c-fos expression in interneurons in the interstitial (SolI), intermediate (SolIM), central (SolCe), dorsomedial (SolDM) and commissural (SolC) solitary subnuclei.

Lower esophageal sphincter relaxation and activation of medullary neurons by subdiaphragmatic vagal stimulation in the mouse.

Background & Aims: Isolated lower esophageal sphincter (LES) relaxation associated with belching and vomiting and the transient LES relaxation associated with gastroesophageal reflux are gastric afferent-mediated vagovagal reflexes. We aimed to identify the brain stem vagal subnuclei involved in these reflexes.

Methods: In anesthetized mice, LES pressures were recorded using a manometric technique and response to electrical stimulation of the ventral trunk of subdiaphragmatic vagus was investigated.

Effect of galanin and galanin antagonists on peristalsis in esophageal smooth muscle in the opossum.

Galanin, a neuropeptide that is widely distributed in the esophageal nerves, is known to exert a neuromodulatory action in the gut. These studies examined the effect of galanin and galanin antagonists on esophageal peristalsis in anesthetized opossums in vivo. Intraluminal esophageal pressures were recorded at 1, 3, 5, 7, and 9 cm above the lower esophageal sphincter.

Altered ion channel activity in murine colonic smooth muscle myocytes in an experimental colitis model.

We have investigated the activity of calcium and potassium channels in a murine model of experimental colitis. Colonic myocytes from dextran sulphate sodium (DSS)-treated mice were examined by whole cell patch clamp techniques. Myeloperoxidase activity was enhanced 3.

Functional anatomy and physiology of the upper esophageal sphincter.

Upper esophageal sphincter (UES) refers to the high-pressure zone located in between the pharynx and the cervical esophagus. The physiological role of this sphincter is to protect against reflux of food into the airways as well as prevent entry of air into the digestive tract. UES is a musculocartilaginous structure with its anterior wall being formed by the full extent of the posterior surface of the cricoid cartilage and arytenoid and interarytenoid muscles in the upper part.