Mucosal Schwann cell hamartoma of the gastroesophageal junction: A series of 6 cases and comparison with colorectal counterpart.

Mucosal Schwann cell hamartoma (MSCH) is an uncommon neural lesion characterized by an ill-defined proliferation of S100-positive Schwann cells in the lamina propria, with reported cases exclusively occurring in the colorectum. Here we describe the first series of MSCHs arising in the gastroesophageal junction (GEJ) and discuss their clinicopathologic features in comparison with their colorectal counterparts. We searched the UCLA pathology database from 01/2014 to 12/2018 to identify cases carrying the diagnosis of MSCH. A total of 48 cases (45 in-house, 3 consults) of colorectal MSCHs and 6 cases (1 in-house, 5 consults) of GEJ MSCHs were identified. For GEJ MSCHs, there were 4 males and 2 females with an average age of 70.2 years (range: 57-76 years). Clinical indications for endoscopy included history of gastroesophageal reflux disease (n = 2), heartburn (n = 2), dysphagia (n = 1), and iron deficiency anemia (n = 1). Endoscopic findings at the GEJ were available for 5 patients including irregular Z-line (n = 3), mild nodular carditis (n = 1), and normal (n = 1). None of them showed a polyp or nodule. The mean size of the lesion was 2.8 mm (range: 2-4 mm) microscopically. None of the colorectal or GEJ MSCH cases had an association with inherited syndromes. In conclusion, MSCH of the gastrointestinal tract is predominantly seen in the colorectum, but also infrequently seen in the GEJ. GEJ MSCH shares histologic and immunohistochemical features with its colorectal counterpart, but is usually an incidental finding with no endoscopically visible lesion. As there is no syndromic association with MSCH, additional treatment, work-up and follow-up are unnecessary.

The Contribution of the Left Phrenic Nerve to Innervation of the Esophagogastric Junction.

The contribution of the left phrenic nerve to innervation of the esophagogastric junction. The esophagogastric junction is part of the barrier preventing gastroesophageal reflux. We have investigated the contribution of the phrenic nerves to innervation of the esophagogastric junction in humans and piglets by dissecting 30 embalmed human specimens and 14 piglets. Samples were microdissected and nerves were stained and examined by light and electron microscopy. In 76.6% of the human specimens, the left phrenic nerve participated in the innervation of the esophagogastric junction by forming a neural network together with the celiac plexus (46.6%) or by sending off a distinct phrenic branch, which joined the anterior vagal trunk (20%). Distinct left phrenic branches were always accompanied by small branches of the left inferior phrenic artery. In 10% there were indirect connections with a distinct phrenic nerve branch joining the celiac ganglion, from which celiac plexus branches to the esophagogastric junction emerged. Morphological examination of phrenic branches revealed strong similarities to autonomic celiac plexus branches. There was no contribution of the left phrenic nerve or accompanying arteries from the caudal phrenic artery in any of the piglets. The right phrenic nerve made no contribution in any of the human or piglet samples. We conclude that the left phrenic nerve in humans contributes to the innervation of the esophagogastric junction by providing ancillary autonomic nerve fibers. Experimental studies of the innervation in pigs should consider that neither of the phrenic nerves was found to contribute. Clin. Anat. 33:265-274, 2020. © 2019 Wiley Periodicals, Inc.

[The pathophysiology of motor disorders of cardioesophageal transition in children].

The review highlighted some issues on ontogeny of the nervous system of the esophagus. Data on burdened heredity role and gestosis risk of the pregnancy interruption in the development of GERD in childhood are presented. The role of nitrergic and serotoninergic systems and prostaglandins in the development of GERD in children is discussed.

Roles of gastro-oesophageal afferents in the mechanisms and symptoms of reflux disease.

Oesophageal pain is one of the most common reasons for physician consultation and/or seeking medication. It is most often caused by acid reflux from the stomach, but can also result from contractions of the oesophageal muscle. Different forms of pain are evoked by oesophageal acid, including heartburn and non-cardiac chest pain, but the basic mechanisms and pathways by which these are generated remain to be elucidated. Both vagal and spinal afferent pathways are implicated by basic research. The sensitivity of afferent fibres within these pathways may become altered after acid-induced inflammation and damage, but the severity of symptoms in humans does not necessarily correlate with the degree of inflammation. Gastro-oesophageal reflux disease (GORD) is caused by transient relaxations of the lower oesophageal sphincter, which are triggered by activation of gastric vagal mechanoreceptors. Vagal afferents are therefore an emerging therapeutic target for GORD. Pain in the absence of excess acid reflux remains a major challenge for treatment.

Jackhammer esophagus with and without esophagogastric junction outflow obstruction demonstrates altered neural control resembling type 3 achalasia.

BACKGROUND: Esophageal hypercontractility can manifest with and without esophagogastric junction (EGJ) outflow obstruction. We investigated clinical presentations and motility patterns in patients with esophageal hypercontractile disorders. METHODS: Esophageal HRM studies fulfilling Chicago Classification 3.0 criteria for jackhammer esophagus (distal contractile integral, DCI >8000 mmHg.cm.s in ≥ 20% swallows) with (n = 30) and without (n = 83) EGJ obstruction (integrated relaxation pressure, IRP > 15 mm Hg) were retrospectively reviewed from five centers (4 in Europe, 1 in US). Single swallows (SS) and multiple rapid swallows (MRS) were analyzed using HRM software tools (IRP, DCI, distal latency, DL); MRS: SS DCI ratio >1 defined contraction reserve. Comparison groups were achalasia type 3 (n = 72, positive control for abnormal inhibition and EGJ obstruction) and healthy controls (n = 18). Symptoms, HRM metrics, and MRS contraction reserve were analyzed within jackhammer subgroups and comparison groups. KEY RESULTS: The esophageal smooth muscle was excessively stimulated at baseline in jackhammer subgroups, with lack of augmentation following MRS identified more often compared with controls (P = .003) and type 3 achalasia (P = .07). Consistently abnormal inhibition was identified in type 3 achalasia (47%), and to a lower extent in jackhammer with obstruction (37%, P = .33), jackhammer esophagus (28%, P = .01), and controls (11%, P < .01 compared with type 3 achalasia). Perceptive symptoms (heartburn, chest pain) were common in jackhammer esophagus (P < .01 compared with type 3 achalasia), while transit symptoms (dysphagia) were more frequent with presence of EGJ obstruction (P ≤ .01 compared with jackhammer without obstruction). CONCLUSIONS AND INFERENCES: The balance of excessive excitation and abnormal inhibition defines clinical and manometric manifestations in esophageal hypercontractile disorders.

Reduction of interstitial cells of Cajal (ICC) associated with neuronal nitric oxide synthase (n-NOS) in patients with achalasia.

BACKGROUND: The etiology of achalasia is still unknown. The current theories of chronic inflammation leading to autoimmune response with destruction and loss of the inhibitory myenteric ganglion cells enlighten its pathogenesis in a limited way only. Interstitial cells of Cajal (ICC) have been shown to be involved in nitrergic neurotransmission of the lower esophageal sphincter (LES). AIM: To investigate the significance of ICC and neuronal nitric oxide synthase (n-NOS) in esophageal wall tissue of patients undergoing surgery for achalasia. METHODS: In 53 patients with a median age of 45 (6-78) yr undergoing surgery for achalasia, the immunoreactivity of ICC (CD117/c-kit) and n-NOS was assessed. In 42 patients, biopsies were taken from the LES high-pressure zone during Heller myotomy, whereas in 11 patients with end-stage achalasia and a decompensated megaesophagus, the complete esophagus was resected. A semiquantitative analysis was carried out and ICC and n-NOS impairments were classified into four grades. Staining intensity was correlated with preoperative clinical, radiologic, and manometric findings and with long-term postoperative Eckardt score. RESULTS: Grade III/IV ICC reduction (severe reduction to complete loss) was seen in 59.5% of all biopsy specimens of the LES high-pressure zone. Patients with grade III/IV ICC reduction had a significantly longer duration of achalasia symptoms (3 [0-43] yr) than patients with minor to marked (grade I/II) impairment (1 [0-16] yr, P= 0.028). A majority (72.5%) of tissue samples revealed severe reduction to complete loss of n-NOS immunoreactivity. The preoperative Eckardt score was statistically significantly different between patients with grade I/II and those with grade III/IV n-NOS reductions (P= 0.031). CD117 (c-kit) positivity was statistically significantly correlated with n-NOS staining intensity (correlation coefficient r= 0.781, P < 0.0001). CONCLUSION: The present results suggest that in the pathogenesis of achalasia, especially in the development of the LES high-pressure zone, depletion of ICC networks and potential changes in the electrical activity of smooth muscle cells may play a crucial role. The reduction in CD117-positive ICC in a few patients also seemed to be of relevance, even if the cells of Auerbach's plexus were unscathed. The associated reduced NOS release might underlie the profound ICC impairment and could possibly be responsible for the lack of LES relaxation, because of missing inhibitory neurotransmission. It is unclear, however, whether the ICC loss is primarily caused by the accelerated attrition of mature cells or their impaired regeneration.

The microscopic anatomy of the esophagus including the individual layers, specialized tissues, and unique components and their responses to injury.

The esophagus, a straight tube that connects the pharynx to the stomach, has the complex architecture common to the rest of the gastrointestinal tract with special differences that relate to its function as a conduit of ingested substances. For instance, it has submucosal glands that are unique and have a specific protective function. It has a squamous lining that exists nowhere else in the gut except the anus and it has a different submucosal nerve plexus when compared to the stomach and intestines. All of the layers of the esophageal wall and the specialized structures including blood and lymphatic vessels and nerves have specific responses to injury. The esophagus also has unique features such as patches of gastric mucosa called inlet patches at the very proximal part and it has a special sphincter mechanism at the most distal aspect. This review covers the normal microscopic anatomy of the esophagus and the patterns of reaction to stress and injury of each layer and each special structure.

Experimental induction of isolated lower esophageal sphincter relaxation in anesthetized opossums.

Isolated lower esophageal sphincter (LES) relaxation, defined as a transient sphincteric relaxation unaccompanied by esophageal peristalsis, has been shown to precede most episodes of gastroesophageal reflux in humans. We studied the genesis of isolated LES relaxation in anesthetized opossums by observing the response of four components of the deglutition reflex (mylohyoid electrical activity, pharyngeal contraction, esophageal peristalsis, and LES relaxation) to pharyngeal tactile stimulation, electrical stimulation of superior laryngeal nerve (SLN) afferents or cervical vagal efferents, and to balloon distention of the esophageal body. A single pharyngeal stroking evoked isolated LES relaxation in 56% of 160 instances. The proportion of isolated relaxations in response to SLN electrical stimulation varied inversely with the stimulus frequency, occurring in 64% of the responses at 5 Hz and 4% of the responses at 30 Hz. A full four-component deglutition sequence was most likely to occur at the higher frequencies of SLN electrical stimulation. Esophageal balloon distention elicited isolated LES relaxations or no response at low distending volumes, whereas at higher volumes LES relaxation and esophageal contraction predominated. Isolated LES relaxation had significantly less magnitude than relaxations accompanied by esophageal contractions. Bilateral cervical vagotomy abolished all LES and esophageal body responses induced by pharyngeal stroking and SLN stimulation, and rendered the esophageal body and LES less responsive to small volumes of distention. Vagal efferent stimulation produced isolated LES relaxation at lower frequency stimulation and LES relaxation with esophageal contractions at higher frequency stimulation. These studies show that isolated LES relaxation represents incomplete expression of either the deglutitive reflex or the peripheral reflex mediating secondary peristalsis.

Modulation of esophageal peristalsis by vagal efferent stimulation in opossum.

Experiments were performed on anesthetized opossums to study the influence of vagal efferent stimulation on peristalsis in the esophageal smooth muscle using various stimulus parameters. Current intensity, pulse duration, frequency, and train duration were varied systematically. Electrical and mechanical activities were recorded simultaneously at 5, 3, and 1 cm above the lower esophageal sphincter (LES). Vagal efferent stimulation produced a spike burst and contraction with a latency after the termination of the stimulus. This latency varied at different sites with the same stimulus parameters. For example, a stimulus of 5 mA, 0.5 ms, 10 Hz, and 1-s train produced latencies for the electrical response of 1.48 +/- 0.04, 2.2 +/- 0.12, and 3.5 +/- 0.09 s (+/- SEM) at 5, 3, and 1 cm above LES, respectively. The differences in latency were statistically significant (P less than 0.01). The latency of response at any one site also changed with different stimulus parameters; e.g. at 1 cm above LES, the latency of electrical response at 10 Hz was 3.5 +/- 0.09 s, but at 20 Hz the latency was 2.01 +/- 0.06 s when current intensity, pulse, and train duration remained at 5 mA, 0.5 ms, and 1 s. This decrease in latency with increasing frequency was statistically significant (P less than 0.01). By changing stimulus parameters, antiperistalsis or peristalsis with different speeds of propagation could be induced. Antiperistalsis or simultaneous responses occurred near threshold stimulus parameters. Suprathreshold stimuli produced peristaltic responses. Speed of peristalsis in the distal esophagus was 1.82 +/- 0.08 cm/s with swallowing, which was not different from 1.98 +/- 0.14 cm/s (P greater than 0.05) with vagal stimulation of 5 mA, 0.5 ms, 10 Hz, and 1-s train. These studies suggest that: (a) peristalsis in the smooth muscle part of the esophagus can be explained entirely on the basis of peripheral mechanisms, and (b) the central nervous system may modulate the occurrence, polarity, and speed of propagation by modifying the intensity and frequency of vagal activation.

Vasoactive intestinal polypeptide. A neurotransmitter for lower esophageal sphincter relaxation.

The effect of rabbit vasoactive intestinal polypeptide (VIP) antiserum on in vitro relaxation of the lower esophageal sphincter (LES) was studied in 10 cats. The stomach and esophagus were opened along the lesser curvature of the stomach and stripped of mucosa. Consecutive strips were cut and mounted in a 2.5-ml muscle chamber. They were perfused with Tyrode's solution and oxygenated continuously. After equilibration for 1 h, perfusion was stopped and one strip from the lower esophageal sphincter region was incubated in solution that contained 12-25 parts of VIP antiserum per 1,000 to Tyrode's solution, while a second strip was incubated in a solution of normal rabbit serum at the same concentration. A third strip was maintained in Tyrode's solution for the duration of the experiment. After a 1-h incubation, the strips were stimulated with 6-s square wave trains of 0.1-, 0.2-, 0.4-, and 0.8-ms pulses at 1, 2, and 5 Hz. These stimulation parameters produced LES relaxation that was completely blocked by tetrodotoxin but not by atropine or phentolamine. The strips incubated in Tyrode's solution or in normal serum relaxed reliably and consistently at all levels of stimulation. In the antiserum-treated strips, LES relaxation in response to all stimuli was significantly inhibited. Strips treated with normal serum were relaxed in a dose-dependent fashion by 10(-7) and 10(-6) M VIP, whereas the antiserum inhibited the relaxation induced by 10(-7) M, but not by 10(-6) M, VIP. Stimulation with two successive 15-min trains of electrical pulses (2 ms, 5 Hz) separated by 30 min of rest released increasing amounts of VIP into the bathing solution. VIP released during the second train of electrical stimulation was significantly (P less than 0.05) greater than in control conditions. In the cat LES, VIP antiserum inhibits the relaxation induced by exogenous VIP or by electric stimulation of nonadrenergic, noncholinergic inhibitory nerves at a level that causes the release of VIP. These findings are consistent with the hypothesis that VIP may be an inhibitory neurotransmitter responsible for LES relaxation.

Sympathetic control of lower esophageal sphincter function in the cat. Action of direct cervical and splanchnic nerve stimulation.

The purpose of this study was to determine the effect of direct stimulation of the sympathetic nerves on the lower esophageal sphincter (LES) in the anesthetized cat. Neither unilateral nor bilateral cervical sympathectomy, or splanchnicectomy significantly modified basal LES pressure in animals with intact vagi, or animals having undergone bilateral cervical vagotomy. Electrical stimulation of the cut, peripheral, cervical sympathetic trunk increased mean arterial blood pressure, but had no effect on LES pressure or LES relaxation as induced by vagal stimulation. Stimulation of the central end of the cervical sympathetic trunk had no effect on LES pressure. Stimulation of the central end of the cut splanchnic nerve produced a decrease in LES pressure with a maximal response of 69.1+/-16.0% (mean+/-SEM). This inhibitory response was not modified by either propranolol or bilateral cervical vagotomy. Stimulation of the peripheral end of the cut, greater splanchnic nerve gave an increase in LES pressure with a maximal response of 38.2+/-7.19 mm Hg. Guanethidine, in the presence or absence of the adrenal glands, significantly augmented this excitatory response. This response was also slightly increased by phentolamine alone at 10 V, 1 Hz, but was not altered by propranolol. The excitatory response was completely antagonized by atropine or by trimethaphan camsylate. Stimulation of the peripheral end of the splanchnic nerve inhibited LES relaxation as induced by vagal stimulation. The results of this study suggest that: (a) the LES in the cat is not affected by either central or peripheral stimulation of the cervical sympathetic trunk; (b) the central portion of the splanchnic nerve carries an afferent inhibitory response to the LES through yet unknown pathways; (c) the peripheral splanchnic nerve carries an atropine-sensitive excitatory response to the LES; and (d) the splanchnic nerves may modulate LES relaxation as induced by vagal stimulation.

Experimental human pain models in gastro-esophageal reflux disease and unexplained chest pain.

Methods related to experimental human pain research aim at activating different nociceptors, evoke pain from different organs and activate specific pathways and mechanisms. The different possibilities for using mechanical, electrical, thermal and chemical methods in visceral pain research are discussed with emphasis of combinations (e.g., the multimodal approach). The methods have been used widely in assessment of pain mechanisms in the esophagus and have contributed to our understanding of the symptoms reported in these patients. Hence abnormal activation and plastic changes of central pain pathways seem to play a major role in the symptoms in some patients with gastro-esophageal reflux disease and in patients with functional chest pain of esophageal origin. These findings may lead to an alternative approach for treatment in patients that does not respond to conventional medical or surgical therapy.

Functional oesophago-gastric junction imaging.

Despite its role in disease there is still no definitive method to assess oesophago-gastric junction competence (OGJ). Traditionally the OGJ has been assessed using manometry with lower oesophageal sphincter pressure as the indicator. More recently this has been shown not to be a very reliable marker of sphincter function and competence against reflux. Disorders such as gastro-oesophageal reflux disease and to a lesser extend achalasia still effects a significant number of patients. This review looks at using a new technique known as impedance planimetry to profile the geometry and pressure in the OGJ during distension of a bag. The data gathered can be reconstructed into a dynamic representation of OGJ action. This has been shown to provide a useful representation of the OGJ and to show changes to the competence of the OGJ in terms of compliance and distensibility as a result of endoluminal therapy.

A novel surgical procedure of vagal nerve, lower esophageal sphincter, and pyloric sphincter-preserving nearly total gastrectomy reconstructed by single jejunal interposition, and postoperative quality of life.

BACKGROUND/AIMS: For early gastric cancer total gastrectomy (TG) has so far been essentially unavoidable. We performed the nearly TG reconstructed by single jejunal interposition preservation of the vagal nerve, lower esophageal sphincter (LES) and pyloric sphincter (D1 or D2 lymph node dissection, curability A) as a function-preserving surgical technique (i.e. NTG) to improve postoperative quality of life (QOL). In this report, the application criteria and points of the technique are outlined. QOL in patients after NTG was also compared with those after TG. METHODOLOGY: Sixteen subjects who underwent NTG (12 men and 4 women subjects at age 30 to 70 years, mean 55.6 years) were interviewed to inquire about abdominal symptoms and compared with 20 patients after conventional TG (excision with D2 lymph node, radical curability A) reconstructed by single jejunal interposition without preserving the vagal nerve, LES, and pyloric sphincter (i.e. TGI; 14 men and 6 women at age 26 to 70 years, mean 54.8 years). The former was named group A and the latter group B. Included were cases with early cancer localizing at the upper third and middle stomach, 2cm or further in distance from oral-side margin of the cancer to esophagogastric mucosal junction; and 3.5cm or further in distance from anal-side margin of the cancer to the pyloric sphincter. In excision with the lymph node, hepatic and celiac branches were preserved. To preserve LES, the abdominal esophagus was completely preserved. The pyloric antrum was also preserved at 1.5cm from the pyloric sphincter. The substitute stomach was created as a 30-cm-long single jejunal segment having orthodromic peristaltic movement. RESULTS: The operative procedure in group A significantly improved postoperative gastrointestinal symptoms such as appetite loss (p=0.0004), weight loss (p=0.0369), reflux esophagitis (RE) (p=0.0163), early dumping syndrome (p=0.0163), endoscopic RE (p=0.0311), and postgastrectomy cholecystolithiasis (p=0.0163) compared with group B. Oral intake per one meal 5 years after operation compared with that before operation was better in group A than in group B (p=0.0703). Postoperative epigastric fullness was significantly detected in group A compared with group B (p=0.0072). CONCLUSIONS: The proposed surgical technique of NTG is a function-preserving surgery appropriate to improve QOL of subjects with early gastric cancer. There was a defect in this technique of postprandial feeling of epigastric fullness. We think that a gut motility improvement agent is necessary to improve postprandial epigastric fullness after NTG.

Innervation of the larynx, pharynx, and upper esophageal sphincter of the rat.

We identified a 'semicircular' compartment of the rat thyropharyngeus muscle at the pharyngoesophageal junction and used the glycogen depletion method to determine how the fibers of this muscle (as well as all others of the pharynx and larynx) are innervated by different cranial nerve branches. The semicircular compartment appears anatomically homologous to the human cricopharyngeus muscle, an important component of the upper esophageal sphincter. While we found very little overlap in the muscle targets of the pharyngeal, superior laryngeal and recurrent laryngeal nerves within the pharynx and larynx, the semicircular muscle receives a dual, interdigitating innervation from two vagal branches: the pharyngeal nerve and a branch of the superior laryngeal nerve we call the dorsal accessory branch. After applying horseradish peroxidase to either of these two nerves, we compared the distribution and number of cells labeled in the brainstem. The dorsal accessory branch conveys a more heterogeneous set of efferent fibers than does the pharyngeal nerve, including the axons of pharyngeal and esophageal motor neurons and parasympathetic preganglionic neurons. The observed distribution of labeled motor neurons in nucleus ambiguus also leads us to suggest that the semicircular compartment is innervated by two subsets of motor neurons, one of which is displaced ventrolateral to the main pharyngeal motor column. This arrangement raises the possibility of functional differences among semicircular compartment motor neurons correlated with the observed differences in brainstem location of cell bodies.

Innervation of the esophagus in mice that lack MASH1.

The striated muscle of the esophagus differs from other striated muscle, because it develops by the transdifferentiation of smooth muscle, and the motor end plates receive a dual innervation from vagal (cholinergic) motor neurons and nitric oxide synthase (NOS)-containing enteric neurons. Mash1-/- mice have no enteric neurons in their esophagus and die within 48 hours of birth without milk in their stomachs (Guillemot et al. [1993] Cell 75:463-476). In this study, the innervation of the esophagus of newborn Mash1-/-, Mash1+/- and wild type mice was examined. There was no difference between Mash1-/-, Mash1+/-, and wild type mice in the transdifferentiation of the muscle and the development of nicotinic receptor clusters. However, there were significantly more cholinergic nerve terminals per motor end plate in Mash1-/- mice than Mash1+/- or wild type mice. Each of the Mash1-/- mice had fewer than 50 NOS neurons per esophagus, compared with approximately 3,000 in wild type mice. Newborn Mash1+/- mice also contained significantly fewer NOS neurons than wild type mice. In Mash1-/- mice, NOS nerve fibers were virtually absent from the external muscle but were present at the myenteric plexus. Unlike that of newborn wild type mice, the lower esophageal sphincter of Mash 1-/- mice lacked NOS nerve fibers; this may explain the absence of milk in the stomach. We conclude that 1) the transdifferentiation of the esophageal muscle and the development of the extrinsic innervation do not require enteric neurons or MASH1, 2) extrinsic NOS neurons only innervate the myenteric plexus.

Organization and neurochemistry of vagal preganglionic neurons innervating the lower esophageal sphincter in ferrets.

The motor control of the lower esophageal sphincter (LES) is critical for normal swallowing and emesis, as well as for the prevention of gastroesophageal reflux. However, there are surprisingly few data on the central organization and neurochemistry of LES-projecting preganglionic neurons. There are no such data in ferrets, which are increasingly being used to study LES relaxation. Therefore, we determined the location of preganglionic neurons innervating the ferret LES, with special attention to their relationship with gastric fundus-projecting neurons. The neurochemistry of LES-projecting neurons was also investigated using two markers of "nontraditional" neurotransmitters in vagal preganglionic neurons, nitric oxide synthase (NOS), and dopamine (tyrosine hydroxylase: TH). Injection of cholera toxin B subunit (CTB)-horseradish peroxidase (HRP) into the muscular wall of the LES-labeled profiles throughout the rostrocaudal extent of the dorsal motor nucleus of the vagus (DMN) The relative numbers of profiles in three regions of the DMN from caudal to rostral are, 43 +/- 5, 67 +/- 11, and 113 +/- 30). A similar rostrocaudal distribution occurred after injection into the gastric fundus. When CTB conjugated with different fluorescent tags was injected into the LES and fundus both labels were noted in 56 +/- 3% of LES-labeled profiles overall. This finding suggests an extensive coinnervation of both regions by vagal motor neurons. There were significantly fewer LES-labeled profiles that innervated the antrum (16 +/- 9%). In the rostral DMN, 15 +/- 4% of LES-projecting neurons also contained NADPH-diaphorase activity; however, TH immunoreactivity was never identified in LES-projecting neurons. This finding suggests that NO, but not catecholamine (probably dopamine), is synthesized by a population of LES-projecting neurons. We conclude that there are striking similarities between LES- and fundic-projecting preganglionic neurons in terms of their organization in the DMN, presence of NOS activity and absence of TH immunoreactivity. Coinnervation of the LES and gastric fundus is logical, because the LES has similar functions to the fundus, which relaxes to accommodate food during ingestion and preceding emesis, but has quite different functions from the antrum, which provides mixing and propulsion of contents for gastric emptying. The presence of NOS in some LES-projecting neurons may contribute to LES relaxation, as it does in the case of fundic relaxation. The neurologic linkage of vagal fundic and LES relaxation may have clinical relevance, because it helps explain why motor disorders of the LES and fundus frequently occur together.

Neuronal control of the gastric sling muscle of the guinea pig.

The gastric sling (oblique) muscle (GSM), located close to the lower esophageal sphincter (LES), is involved in gastric motor function and may cooperate with the LES in controlling propulsion between the esophagus and stomach. Neuronal pathways and transmission to the GSM were investigated in isolated esophagus-stomach preparations by using intracellular recording with the focal electrical stimulation and neuroanatomical tracing method. Focal stimulation on the GSM evoked inhibitory junction potentials (IJPs) that were reduced to 45% by 100 microM N-nitro-L-arginine and subsequently blocked by 0.5 microM apamin, thereby unmasking excitatory junction potentials (EJPs), which were abolished by 1 microM hyoscine. Vagal and esophageal stimulation evoked IJPs that were blocked by 100 microM hexamethonium. Vagal stimulation also evoked EJPs after blockade of IJPs. Application of 1,1'-didodecyl-3,3,3',3'-tetramethyl indocarbocyanine perchlorate to the GSM labeled muscle motor neurons located in the stomach mainly close to the GSM, with a few neurons (2%) in the esophagus. The majority (79%) of labeled neurons were immunoreactive for choline acetyltransferase and, hence, excitatory motor neurons. Inhibitory motor neurons (nitric oxide synthase immunoreactive; 15%) were clustered in the midline near the gastroesophageal region. These results demonstrate that the GSM is innervated primarily by gastric excitatory and inhibitory motor neurons and some esophageal neurons. Both excitatory (acetylcholine) and inhibitory (nitric oxide and apamin-sensitive component) transmission can be activated via vagal-enteric pathways.

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. SLN stimulation at 5 Hz elicited pharyngeal contractions and isolated LES relaxation, which is not accompanied by esophageal peristalsis. Electric stimulation of afferents in the ventral branch of the subdiaphragmatic vagus (vSDV) at 10 Hz also elicited isolated LES relaxation. Using these defined stimuli, c-fos expression was examined in the entire craniocaudal extent of the medullary nuclei. SLN stimulation at 10 Hz induced c-fos expression in neurons in: (1) interstitial (SolI), intermediate (SolIM), central (SolCe), occasional medial (SolM), and dorsomedial (SolDM) solitary subnuclei; (2) motor neurons in the nucleus ambiguus, including its semicompact (NAsc), loose (NAl), and compact (NAc) formations; and (3) dorsal motor nucleus of vagus, including its rostral (DMVr) and caudal (DMVc) parts. The activated neurons represent neurons involved with afferent SLN-mediated reflexes, including swallowing. SLN stimulation at 5 Hz evoked c-fos expression in neurons in SolI, SolIM, SolM, and SolDM but not in SolCe; and motor neurons in NAsc, NAl, and DMVc but not in NAc or DMVr. Stimulation of vSDV induced c-fos expression in neurons in SolM and SolDM and in motoneurons in DMVc. When considered with published reports in other animal species, these data support the speculation that (1) swallow-evoked primary peristalsis involves the following neural circuits: SolI/SolIM --> NAsc/NAl for pharyngeal and SolCe --> NAc for esophageal (striated muscle) peristalsis, SolM/SolDM --> preganglionic neurons in DMVc and DMVr and nitrergic and cholinergic neurons in myenteric plexus for esophageal (smooth muscle) peristalsis, and SolM/SolDM --> preganglionic neurons in DMVc --> postganglionic nitrergic neurons in the myenteric plexus for LES relaxation; and (2) abdominal vagus-stimulated isolated LES relaxation may involve neurons in SolM and SolDM --> preganglionic motor neurons in DMVc --> postganglionic nitrergic neurons in the myenteric plexus.

Overview of the mechanisms of gastroesophageal reflux.

Reflux of acidic gastric contents through the esophagogastric junction into the esophageal lumen occurs in everyone nearly every day. The esophagogastric junction is composed of several structural components that contribute to its function as the primary antireflux barrier. Only when 1 or more of these components fail does reflux esophagitis develop. The initial focus of this review is on transient lower esophageal sphincter relaxations, a vagally mediated reflex arc that accounts for almost all reflux events in healthy individuals and the majority of reflux events in those with reflux esophagitis. The association of erosive esophagitis with low or absent (incompetent) lower esophageal sphincter (LES) pressure and anatomic disruptions of the esophagogastric junction, such as hiatal hernia, are also important, especially with respect to whether the LES dysfunction and hernia are the cause or the consequence of erosive disease.