Neurogenic pathways mediating ascending and descending reflexes at the porcine ileocolonic junction.

We studied the pharmacology of the neural pathways mediating the responses of ileo- and coloileo-colonic junction (ICJ) to regional distension in ten anaesthetized pigs. Using manometric pullthroughs and a sleeve sensor, we found the ICJ demonstrated sustained tone that was resistant to tetrodotoxin. Ileal distension decreased ICJ pressure by 22.2 ¿ 10.1% (11.9 ¿ 2.7-10.1 ¿ 2.6 mmHg; P=0.002) and colonic distension augmented ICJ pressure by 23.5 ¿ 8.6% (12.8 ¿ 1.5-15.6 ¿ 2.1 mmHg; P=0.02). Bethanecol and Nw-nitro-L-arginine methyl ester (L-NAME) increased ICJ pressure (P=0.002, P=0.01, respectively). Sodium nitroprusside and isoproterenol reduced ICJ pressure (P=0.004, P=0.02, respectively). In the presence of L-NAME, the early inhibitory ileo-ICJ response was abolished, while early and late inhibitory responses were abolished by further addition of propranolol but not by the addition of hexamethonium, atropine, prazosin or yohimbine. The excitatory colo-ICJ response was replaced by inhibition in the presence of L-NAME. We concluded that: (1) the porcine ICJ displays myogenic tone which is influenced by excitatory muscarinic and inhibitory nitrergic and beta adrenergic pathways (2) an inhibitory ileo-sphincteric reflex mediated by nitrergic and beta adrenergic postganglionic neural pathways (3) both excitatory and inhibitory neurogenic colo-sphincteric reflexes exist, and the excitatory pathway involves nitrergic neurotransmission.

The role of brushing cytology in the diagnosis of gastric malignancy.

The results of endoscopic biopsy and brushing cytology in 234 consecutive patients with established histologic diagnoses of discrete gastric lesions were analyzed. A histopathologic diagnosis of malignancy, established by independent means, was made in 74 patients. Brushing cytology was positive for malignancy in 63, a diagnostic sensitivity of 85%. Endoscopic biopsy was positive in 64, a diagnostic sensitivity of 86%. The sensitivity for combined cytology and biopsy was 91%, which was not significantly greater than for biopsy alone (P = .6). Cytology yielded false-positive results in 5 of 160 patients (3.1%) with confirmed benign disease. There were no false-positive biopsy reports. Although both brushing cytology and biopsy have high diagnostic sensitivities, based on the findings of this study, the routine addition of cytology to biopsy in the endoscopic evaluation of gastric lesions is not recommended. Cytology could be reserved for situations in which difficulty is encountered in obtaining adequate tissue for histologic examination and for cases with a high suspicion of malignancy that have yielded negative biopsies.

Long-term outcome following pneumatic dilatation as initial therapy for idiopathic achalasia: an 18-year single-centre experience.

BACKGROUND: Relapse after treatment for idiopathic achalasia is common and long-term outcome data are limited. AIM: To determine the cumulative relapse rate and long-term outcome after pneumatic dilatation (PD) for achalasia in a tertiary referral centre. METHODS: A retrospective study of 301 patients with achalasia treated with PD as first-line therapy. Short-term outcome was measured at 12 months. Long-term outcome was assessed in those who were in remission at 12 months by cumulative relapse rate and cross-sectional analysis of long-term remission rate regardless of any interval therapy, using a validated achalasia-specific questionnaire. RESULTS: Eighty-two percent of patients were in remission 12 months following initial PD. Relapse rates thereafter were 18% by 2 years; 41% by 5 years and 60% by 10 years. Whilst 43% patients underwent additional treatments [PD (29%), myotomy (11%) or botulinum toxin (3%)] beyond 12 months, 32% of those who had not received interval therapy had relapsed at cross-sectional analysis. After a mean follow-up of 9.3 years, regardless of nature, timing or frequency of any interval therapy, 71% (79/111) patients were in remission. The perforation rate from PD was 2%. Chest pain had a poor predictive value (24%) for perforation. CONCLUSIONS: Long-term relapse is common following pneumatic dilatation. While on-demand pneumatic dilatation for relapse yields a good response, one-third of relapsers neither seek medical attention nor receive interval therapy. Close follow-up with timely repeat dilatation is necessary for a good long-term outcome. Given the poor predictive value of chest pain for perforation, routine gastrografin swallow is recommended postdilatation.

Experimental gastroesophageal reflux in the Australian brush-tailed possum.

It has been suggested that the lower esophageal sphincter (LES) plays an important role in preventing gastroesophageal reflux. This study was designed to determine if abolition of the LES alone is sufficient to induce gastroesophageal reflux and esophagitis. Studies were performed in the Australian brush-tailed possum (Trichosurus vulpecula) which has a lower esophagus resembling that of man. Esophageal manometry, esophagoscopy, and contrast radiography of the lower esophagus and stomach were performed before and after surgery in a group of animals undergoing cardioplasty and in a group of sham operated control animals. In the animals undergoing cardioplasty, LES pressure fell from a preoperative level of 12.6 +/- 1.3 mm Hg to 0 mm Hg. This was followed by the development of gastroesophageal reflux and esophagitis. Sham operation did not alter LES pressure or result in either gastroesophageal reflux or esophagitis. In 4 of 5 animals undergoing cardioplasty, LES activity returned after 10 weeks, and this time gastroesophageal reflux ceased and esophagitis healed. It is concluded that abolition of the LES alone can induce gastroesophageal reflux and esophagitis.

Gastro-oesophageal reflux disease.

Gastro-oesophageal reflux disease is the most common cause of indigestion in the community, and is usually chronic. Typical symptoms are recurrent retrosternal burning (heartburn) and regurgitation of sour or bitter fluid. In patients with typical symptoms and no alarm symptoms (pain on swallowing, dysphagia, weight loss or anaemia), treatment may be instituted without investigation. Patients with alarm symptoms and those who respond poorly or relapse after initial treatment require investigation (endoscopy and possibly pH monitoring). About 60% of reflux sufferers have no evidence of mucosal injury; their management aims to relieve symptoms. About 40% of reflux sufferers have oesophagitis and/or complications such as Barrett's oesophagus or oesophageal stricture at endoscopy. Drug therapy consists of H2-receptor antagonists, cisapride or proton-pump inhibitors.

A dopamine receptor in esophageal smooth muscle of the opossum.

We examined the possibility that dopamine may play a role in nerve-mediated "off" responses of esophageal body (EB) and relaxations of lower esophageal spincter (LES) smooth muscle. The effects of dopamine, epinine, and dopamine antagonists on EB and LES smooth muscle were studied on these responses. Dopamine and epinine caused a dose-related fall in basal LES muscle tension and in amplitude of EB muscle "off" responses. Threshold dose for both was about 10(-7) M, and maximal dose was about 10(-4) M. At high concentrations, they also caused repetitive transient contractions of both LES and EB muscle after the period of inhibition. These effects were antagonized by haloperidol, 10(-5) M, and bulbocapnine, 10(-5) M, but were not influenced by propranolol, 10(-5) M, nor by phenoxybenzamine, 10(-5) M. Neither haloperidol nor bulbocapnine influenced responses to electrical field stimulation. Tetrodotoxin 10(-7) M abolished the responses to electrical field stimulation but did not antagonize the effects of dopamine and epinine. EB and LES smooth muscle contain a dopamine receptor. It is unlikely that dopamine is involved in responses to electrical field stimulation.

Pneumatic dilatation for the treatment of achalasia.

Pneumatic dilatation is an accepted treatment for achalasia. However, in Australia, its use is limited, with oesophagomyotomy being the usual treatment. Since April, 1977, pneumatic dilatation has been used as the initial treatment for achalasia at The St George Hospital. Ten patients have been treated, with a successful result in seven. There were no complications. These results are in agreement with those published previously and compare favourably with those of oesophagomyotomy. They support the view that pneumatic dilatation is a safe, simple and effective means of treating achalasia.

Temperature dependence of responses of esophageal smooth muscle to electrical field stimulation.

Strips of smooth muscle, cut transversely from the smooth-muscle segment of opossum esophagus, were superfused with oxygenated Krebs-Ringer solution at 37 degrees C in a system that allowed electrical field stimulation of the intrinsic nerves. Three-to-five-second trains of rectangular pulses (0.5 ms long at 10 Hz) were delivered at 30-s intervals at supramaximal maximal current strength. In strips from the esophageal body, each train resulted in a twitch which followed after the end of train with a particular latency, the off-response. Strips from the esophagogastric sphincter relaxed during the train. Temperature was varied above and below 37 degrees C to observe the temperature dependence of the responses. Latency of the off-response varied exponentially with temperature. Amplitude of the off-response showed a linear decline with changes in temperature, both above and below 35 degrees C, the zero-intercepts being 19.6 and 42.3 degrees C, respectively. Amplitude of relaxation of strips from the junction varied little between 20 and 37 degree C but declined sharply beyond those limits, the zero-intercepts being 14.2 and 42 degrees C, respectively.

Arterial vasoconstrictor therapy for bleeding oesophageal varices.

Upper gastrointestinal bleeding in patients with hepatic cirrhosis carries considerable mortality. Difficulties are encountered both in determining the source of bleeding and in controlling blood loss. The techniques of selective visceral angiography not only supply diagnostic information, but can be used to administer selective intra-arterial vasoconstrictor therapy to control blood loss. We report our experience with 28 patients in whom angiography was performed with particular reference to six patients treated with selective vasoconstrictor therapy. Although the precise role of the technique is not yet established, early experience is most promising. We believe it will play an important role in a difficult group of patients in the future and may well supplant present methods of controlling bleeding.

The effect of dopamine on human gastric smooth muscle.

Dopamine had inhibitory effects on contractions of human gastric smooth muscle strips. Inhibition of spontaneous contractions occurred at high concentrations only, the mean maximum inhibition being 17% at a concentration of 4.7 X 10(-4) M. It was unaffected by haloperidol (10(-5) M) or tetrodotoxin (10(-6) M) but was abolished by a combination of phenoxybenzamine (10(-5) M) and propranolol (10(-5) M). Isoprenaline caused a dose-dependent inhibition of spontaneous contractions with mean maximal inhibition at a concentration of 4.6 X 10(-6) M. These results suggest that there are no specific dopamine receptors in human gastric smooth muscle and that dopamine-induced inhibitory effects are due to stimulation of adrenergic receptors.

Histamine receptors in esophageal smooth muscle of the opossum.

Esophageal smooth muscle was examined for histamine receptors. The effects of histamine, the histamine analogs 4-methylhistamine (4-MH) and 2-(2-pyridyl) ethylamine (PEA), the histamine receptor antagonists mepyramine and metiamide, and the histamine-releasing substance compound 48/80, on lower esophageal sphincter (LES) and esophageal body (EB) smooth muscle of the opossum were studied in a superfused tissue bath. Histamine, PEA, an H1 receptor agonist, and compound 48/80 caused a dose-related increase in LES basal tension and in EB off response amplitude, the threshold for histamine being 6.7 X 10(-8) M and that for PEA being 6.7 X 10(-7) M. In the presence of mepyramine, and H1 receptor antagonist, the effects of histamine and compound 48/80 were reversed to inhibition of both LES basal tension and EB off response amplitude, while the effect of PEA was abolished. Metiamide, an H2 receptor antagonist, did not alter responses to histamine, PEA, or compound 48/80. The H2 receptor agonist 4-methylhistamine caused a reduction of LES tension and EB off response amplitude, but caused an increase in those parameters in the presence of metiamide. A combination of mepyramine and metiamide abolished responses to all agonist drugs. The results indicate that LES and EB smooth muscle contain both excitatory H1 and inhibitory H2 receptors for histamine. Endogenous histamine released from storage sites in LES and EB and exogenous histamine both preferentially activate H1 receptors.

Chronic excessive acetaminophen use and liver damage.

Severe, often fatal liver damage results from extreme overdosage with acetaminophen. In usual dosage, it is considered harmless. We describe three cases of toxic hepatitis associated with the chronic ingestion of excessive doses of acetaminophen. Each patient took approximately 5 to 8 g of acetaminophen per day during a period of several weeks. The transient elevations of serum hepatocellular enzyme concentrations and the histologic evidence of a toxic hepatitis suggest the liver damage was related to the use of acetaminophen. Alcohol abuse in one patient and negative nitrogen balance in another may have increased the susceptibility to acetaminophen toxicity. With the increasing popularity of acetaminophen for mild pain relief, hepatotoxicity from acute or chronic ingestion may be more common than previously recognized, especially in those patients with predisposing conditions.

Shigella dysenteriae type 1 enterocolitis.

Shigella dysenteriae type 1 is much more virulent than Shigella flexneri and sonnei which are endemic in Australia. This report describes a 22 year old woman who acquired Shigella dysenteriae type 1 whilst travelling in India. During the course of her illness, she developed severe enterocolitis for which a subtotal colectomy was performed. The illness resembled fulminant ulcerative colitis and its infectious nature was difficult to establish because several fecal cultures failed to grow the pathogen. Her infection was complicated by shigella bacteremia, disseminated intravascular coagulation, and renal cortical necrosis which requires continued hemodialysis.

Influence of altered tongue contour and position on deglutitive pharyngeal and UES function.

The potential influence of altered lingual position and contour during the bolus loading phase of the swallow in mediating the swallowed bolus volume-dependent regulation of upper esophageal sphincter (UES) relaxation and opening was studied in 15 healthy volunteers using simultaneous videoradiography and manometry. A maxillary dental splint modulated tongue deformity during the early oral phase of deglutition. We examined the effect of the splint and swallowed bolus density on bolus volume-dependent changes in the timing of events in the swallow sequence and on hypopharyngeal intrabolus and midpharyngeal pressures. Peak mid-pharyngeal pressure (P = 0.001) and hypopharyngeal intrabolus pressure (P = 0.04) were significantly reduced by the splint. The normal volume-dependent earlier onset of sphincter relaxation and opening was preserved with the splint in situ. The splint significantly delayed the onset of hyoid motion and UES relaxation and opening without influencing transit times or total swallow duration. Alterations in tongue contour and position reduce intrabolus pressure and pharyngeal contraction without influencing normal bolus volume-dependent regulation of timing of UES relaxation and opening.

Esophageal pneumatic dilation for postfundoplication dysphagia: safety, efficacy, and predictors of outcome.

OBJECTIVE: Persistent dysphagia occurs in 5-10% of patients after fundoplication. The cause is obscure in most cases, and the management has not been well established. The aim of this study is to evaluate the clinical outcomes and the predictors of success for esophageal pneumatic dilations in patients with dysphagia after fundoplication. METHODS: We retrospectively reviewed 14 patients who underwent pneumatic dilation for persistent postfundoplication dysphagia. All patients had esophageal manometry before dilations. RESULTS: There were nine responders to pneumatic dilations (30-40-mm balloons). The nadir lower esophageal sphincter (LES) relaxation pressure was the only significant predictor for successful dilation and was higher among the responders than nonresponders (median 10 mm Hg vs 5 mm Hg). All six of 14 patients with nadir LES pressure > or = 10 mm Hg had a good response. There was no significant difference in the LES basal pressure between the responders and nonresponders (median 20 mm Hg vs 12 mm Hg). The median distal peristaltic amplitude (74 mm Hg vs 69 mm Hg), percent of failed peristalsis (8% vs 45%), and ramp pressure (19 mm Hg vs 17 mm Hg) did not differ significantly between the responders and nonresponders. No perforations occurred. CONCLUSIONS: Pneumatic dilation is a reasonably safe and effective treatment for patients with postfundoplication dysphagia. Raised nadir LES relaxation pressure seems to be a useful predictor of successful outcome.

Calcium dependence of neuromuscular events in esophageal smooth muscle of the opossum.

Intramural nerves in smooth muscle strips from opossum esophagus were stimulated electrically to cause contractions of longitudinal body muscle, off responses of transverse body muscle and relaxations of sphincter muscle. Krebs solution was modified by calcium removal by strontium substitution for calcium, by adding magnesium, and by adding nitroprusside. Longitudinal muscle contractions were abolished by calcium removal and by excess magnesium; they were unaffected by nitroprusside; strontium could not replace calcium. Off responses were abolished by calcium removal and by excess magnesium; they were depressed by nitroprusside; strontium effectively replaced calcium. Resting active tension in sphincter strips was partly reduced by calcium removal and by excess magnesium; it was abolished by nitroprusside; strontium could not replace calcium. Relaxations in sphincter strips were unaffected by all experimental conditions. Longitudinal contractions, off responses, and resting active tension of the sphincter represent different kinds of calcium activation of muscle. The excitatory nerves (which are cholinergic) in longitudinal muscle are calcium dependent, the nerves that produce off responses may not be, and the nerves that relax the sphincter are not.

Small bowel mucosa from celiac patients generates 15-hydroxyeicosatetraenoic acid (15-HETE) after in vitro challenge with gluten.

Celiac disease (gluten-sensitive enteropathy [GSE]) is a disorder characterized by small intestinal mucosal injury caused by dietary exposure to wheat gluten and similar proteins. There is evidence that the mucosal injury is immunologically mediated and there is an inflammatory infiltrate present in the mucosa. It is postulated that release of lipid-derived inflammatory mediators may be involved in the pathogenesis of the mucosal injury. Jejunal mucosal biopsy samples from patients with GSE and from a group of patients who were subsequently shown to have normal jejunal mucosa were incubated with tritiated arachidonate and a peptic/tryptic digest of either gluten or casein. Generation of lipid-derived inflammatory mediators was measured by beta-scintillation counting after separation of metabolites by reverse-phase high performance liquid chromatography with two different buffer systems. The predominant arachidonic acid metabolite generated was 15-hydroxyeicosatetraenoic acid (15-HETE). Mucosa from newly diagnosed GSE patients on a normal diet generated more 15-HETE than either control patients or GSE patients maintained on a gluten-free diet. In addition, gluten acted as a specific stimulus to 15-HETE production by mucosa from the GSE patients on a normal diet. 15-HETE has a number of biologic effects that could contribute to the mucosal changes seen in GSE, and the specific release of 15-HETE by gluten suggests involvement in the pathogenesis of the disorder.

Basal pressure patterns and reflexive motor responses in the human ileocolonic junction.

This study aimed to determine whether a sustained high-pressure zone exists at the human ileocolonic junction (ICJ) and whether the motor responses of ICJ are consistent with sphincteric function. In 10 subjects with temporary ileostomies, a high-pressure zone was identified using a manometric pull-through with a mean pressure of 9. 7 +/- 3.2 mmHg and length of 4.8 +/- 1.2 cm. Prolonged recordings using a sleeve sensor confirmed sustained tone in the ICJ and superimposed phasic pressure waves (4-8 counts/min) occupying 35% of fasted state. A meal increased ICJ tone (P = 0.0001) and the proportion of time occupied by phasic activity to 50% (P = 0.013). Terminal ileal propagating pressure wave sequences inhibited ICJ phasic activity, and sequences not extending to the cecum reduced ICJ tone (9.0 +/- 7.2 to 5.6 +/- 6.3 mmHg; P = 0.04). Cecal distension increased ICJ tone (8.9 +/- 4.4 mmHg to 11.7 +/- 4.9 mmHg; P = 0.005). The ICJ response to ileal distension was variable and depended on resting tone at the time of distension. We conclude that the human ICJ has sustained tone with superimposed phasic activity. Tone is augmented by cecal distension or a meal and is inhibited by ileal propagating pressure waves. Response to ileal distension is variable but suggests control by descending excitatory and inhibitory pathways.

Esophagopharyngeal acid regurgitation: dual pH monitoring criteria for its detection and insights into mechanisms.

BACKGROUND & AIMS: A valid technique for the detection of esophagopharyngeal acid regurgitation would be valuable to evaluate suspected reflux-related otolaryngologic and respiratory disorders. The aim of this study was to derive pH criteria that optimally define esophagopharyngeal acid regurgitation and to examine patterns of regurgitation. METHODS: In 19 healthy controls and 15 patients with suspected regurgitation, dual or quadruple pH sensors were used to monitor pharyngeal and esophageal pH. For each combination of the 2 variables, DeltapH and nadir pH, proportions of pH decreases that occurred during or independent of esophageal acidification were calculated to determine the likelihood that an individual pharyngeal pH decrease was a candidate regurgitation event or a definite artifact. RESULTS: Overall, 92% of pharyngeal pH decreases of 1-2 pH units and 66% of pH decreases of this magnitude reaching a nadir pH of <4 were artifactual. Optimal criteria defining a pharyngeal acid regurgitation event were a pH decrease that occurred during esophageal acidification, had a DeltapH of >2 units, and reached a nadir of <4 units in less than 30 seconds. Regurgitation occurred more frequently in subjects in an upright (32 of 35) than in a supine (3 of 35 events; P