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Biomedical subjects

W G Paterson

Publications and source records attributed to W G Paterson.

At least 19 recordsLinked to original sources
PubMed2006

Clinical diagnosis of achalasia: how reliable is the barium x-ray?

Manometry is considered to be the gold standard for the diagnosis of achalasia. However, many physicians believe that contrast radiography, classically showing esophageal dilation with bird-beak narrowing of the gastroesophageal junction, is also accurate in either diagnosing or excluding the disorder. The aim of the current study was to determine the accuracy of barium x-ray in the diagnosis of achalasia. The radiological diagnosis of all patients manometrically diagnosed with achalasia (using conventional criteria) between January 1994 and June 1998 were reviewed. A total of 51 cases of achalasia were identified. Thirteen patients were excluded because they either did not have contrast radiography before a manometric diagnosis or had their x-rays performed more than six months previously. Of the remaining 38 patients, achalasia was stated as a diagnostic possibility in the radiologists report in only 22 (58%) of those patients. Achalasia was not considered in the remaining 16 patients: two were reported as normal, four as having stenosis/narrowing in distal esophagus, two as having presbyesophagus, one as having mild gastroesophageal reflux and seven as having nonspecific dysmotility. To determine the reason for the diagnostic failure of the barium x-ray, an expert gastrointestinal radiologist reviewed 12 of the nondiagnostic x-rays in a blinded fashion, interspersed with 10 randomly selected esophageal-contrast radiographs from control subjects to avoid bias. Of these initially nondiagnostic x-rays in achalasia patients, typical radiological features of achalasia were deemed to be present in 50%. The present study indicates that contrast radiography lacks sensitivity in the diagnosis of achalasia. This is not only due to radiologist oversight but also because of the absence of the characteristic radiological features in many cases. This reinforces the important role of esophageal manometry in patients with persistent nonstructural dysphagia.

Administration, Oral↗
PubMed2003

Effects of acid-induced esophagitis on esophageal smooth muscle.

Acid-induced esophagitis is associated with sustained longitudinal smooth muscle (LSM) contraction and consequent esophageal shortening. In addition, LSM strips from opossums with esophagitis are hyper-responsive, while the circular smooth muscle (CSM) contractility is impaired. To determine the origin of these changes, studies were performed on esophageal smooth muscle cells isolated from opossum esophagi perfused intraluminally on 3 consecutive days with either saline (control; n = 8) or HCl (n = 9). CSM and LSM cells, obtained by enzymatic digestion, were exposed to various concentrations of carbachol (CCh) and fixed. CCh induced concentration-dependent contraction of both LSM and CSM cells. CCh-induced LSM cell contraction was not different between control and esophagitis animals; however, there was marked attenuation in the CCh-induced contraction of CSM cells from esophagitis animals. Morphological studies revealed significant hypertrophy of the CSM cells. These findings suggest that impaired CSM contractility can be attributed at least in part to alterations to the CSM cell itself. In contrast, hyper-contractility demonstrated in LSM strips is likely related to factors in the surrounding tissue.

Animals↗
PubMed2001

Nitric oxide contracts longitudinal smooth muscle of opossum oesophagus via excitation-contraction coupling.

1. The effects of sodium nitroprusside (SNP) and diethylenetriamine/nitric oxide adduct (DETA/NO), putative nitric oxide (NO) donors, on opossum oesophageal longitudinal smooth muscle were investigated using isometric tension and intracellular micro-electrode recordings. 2. SNP produced concentration-dependent contractions of oesophageal longitudinal smooth muscle with an EC(50) of 239.6 +/- 78.2 microM (mean +/- S.E.M., n = 10). Maximal contraction induced by SNP (1 mM) was about 75.5 +/- 8.5 % (n = 10) of the 60 mM KCl-induced contraction. The SNP-induced contraction was resistant to tetrodotoxin (TTX; 1 microM), but abolished by nifedipine (1 microM), as well as by niflumic acid (300 microM) and 9-anthroic acid (9-AC; 1 mM), Ca(2+)-activated Cl(-) channel blockers. 3. DETA/NO at concentrations of 100 and 500 microM induced 83.1 +/- 24.4 and 104.1 +/- 34.9 % of the 60 mM KCl-induced contraction (n = 4), respectively, which was abolished by nifedipine (1 microM), niflumic acid (300 microM) and 9-AC (1 mM). 4. Pre-application of 1H-[1,2,4]oxidiazolo[4,3,-alpha]quinoxalin-1-one (ODQ) (10 microM), a guanylate cyclase inhibitor, significantly inhibited the SNP-induced contraction, whereas 8-bromo-cGMP (1 mM), a membrane-permeable analogue of cGMP, mimicked the SNP-induced contraction. 5. Intracellular recordings revealed that SNP (300 microM) depolarized resting membrane potentials (RMPs) and increased the frequency of spontaneous spike-like action potentials. However, these electrical alterations were eliminated by pretreatment with niflumic acid (300 microM). 6. These results suggest that NO produces an excitation-contraction coupling in opossum oesophageal longitudinal smooth muscle via a cGMP-dependent signalling pathway. This contraction depends on extracellular Ca(2+) entry through activation of L-type Ca(2+) channels.

Anesthetics, Local↗
PubMed2001

Role of substance P and calcitonin gene-related peptide in acid-induced augmentation of opossum esophageal blood flow.

Increased esophageal blood flow may protect against damaging refluxed gastric juices. We have shown that mast cells, histamine, and nitric oxide increase esophageal blood flow in the opossum during acid perfusion. This study examined the roles of substance P and calcitonin gene-related peptide on acid-induced hyperemia and whether the effects of substance P are mediated by mast cells. The opossum distal esophagus was perfused with saline, acid, or capsaicin while blood flow and histamine release were determined. Neuropeptides and neurokinin antagonists were administered parenterally. Only acid or calcitonin gene-related peptide (not substance P or capsaicin) significantly increased blood flow, which was prevented by neurokinin or calcitonin-gene-related peptide antagonists. Acid, substance P, and capsaicin all increased histamine release. Pretreatment with neurokinin antagonists did not affect acid-induced histamine release. We conclude that calcitonin-gene-related peptide is an important mediator of acid-induced esophageal hyperemia, while substance P plays an indirect role.

Animals↗
PubMed2001

Impairment of deglutition reflex by acid-induced esophageal mucosal injury.

Swallowing is an important defense mechanism against reflux esophagitis as it helps clear refluxed gastric contents from the esophagus, while bicarbonate in the saliva acts to neutralize acid. The purpose of the present study was to examine the effect of esophagitis on the deglutition reflex in anesthetized opossums. Animals perfused with either an acidified pepsin solution for 45 min or with 100 mM hydrochloric acid for 45 min on each of three consecutive days exhibited a significantly impaired deglutition reflex in comparison to baseline. Control animals perfused with 0.9% saline showed no impairment. Bilateral cervical vagotomy in animals perfused with acidified pepsin attenuated the impaired deglutition reflex. Taken together, these results suggest that esophagitis causes an impairment in the deglutition reflex that is mediated by vagal afferent pathways.

Animals↗
PubMed2001

Initiation of distension-induced descending peristaltic reflex in opossum esophagus: role of muscle contractility.

The balloon distension (BD)-induced descending peristaltic reflex in the opossum smooth muscle esophagus is abolished in vitro when a Ca(2+)-free Krebs solution is placed at the site of distension, suggesting that either synaptic transmission occurs at the origin of the reflex or initiation of the reflex requires the development of muscle tension in response to BD. To test the latter possibility, an 8- to 10-cm length of smooth muscle esophagus was placed in a dual-chamber organ bath, isolating the stimulating (orad) from the recording site (aborad). Nifedipine addition to the orad chamber (i.e., site of distension) inhibited the BD-induced "off" contractions in both chambers in a concentration-dependent manner. However, the aborad response to electrical field stimulation (EFS) was unaffected. Atropine addition to the orad chamber had no effect on BD or EFS responses in either chamber. To examine the effects of these agents on tonic contractility, an isobaric barostat was employed. Pressure-volume curves were not altered by Ca(2+)-free Krebs solution, nifedipine, or TTX, suggesting that resting esophageal tone is not dependent on neural factors or muscle contractility. However, both Ca(2+)-free Krebs solution and nifedipine markedly decreased phasic contractions over the top of the distending bag. These observations suggest that local, stretch-induced phasic muscle contraction is required for initiation of the BD-induced descending peristaltic reflex.

Animals↗
PubMed2001

Esophagitis-related esophageal shortening in opossum is associated with longitudinal muscle hyperresponsiveness.

Acute intraluminal acid perfusion induces esophageal shortening in humans and opossums. Lower esophageal sphincter (LES) hypotension and peristaltic dysfunction occur in patients and animal models of reflux esophagitis. This study examined whether similar shortening and motor dysfunction occur in anesthetized opossums after repeated esophageal acid exposure and whether this is associated with longitudinal muscle (LM) hyperresponsiveness. Manometry used before and after 3 consecutive days of 45-min perfusion with 100 mmol/l HCl or normal saline measured esophageal length and motor responses to induced swallows. LM electrical and mechanical responses were assessed using standard isometric tension and intracellular recording techniques. Compared with controls, repeated acid perfusion induced erosive esophagitis and significant esophageal shortening, associated with enhanced LM responses to carbachol, a significantly depolarized resting membrane potential, and abnormal spike patterns. LES resting pressure and swallow-induced peristalsis were unaffected. In this model of reflux esophagitis, marked persistent esophageal shortening and associated LM hyperresponsiveness occur before significant LES or peristaltic dysfunction, suggesting that esophageal shortening is the earliest motor disorder induced by acid injury.

Animals↗
PubMed2001

Etiology and pathogenesis of achalasia.

The primary pathophysiologic abnormality in achalasia is loss of intrinsic inhibitory innervation of the lower esophageal sphincter and smooth muscle segment of the esophageal body. Disease of the extrinsic (vagal) nervous system and esophageal musculature may also be present, but these are less consistent findings and could represent secondary phenomena. Inflammation within the esophageal myenteric plexus is pathognomonic of the disease, but the cause of this inflammation is uncertain. Autoimmunity and previous viral infection have been hypothesized, but remain unproven.

Autoimmune Diseases↗
PubMed2001

Diversity of K+ channels in circular smooth muscle of opossum lower esophageal sphincter.

We previously demonstrated that a balance of K+ and Ca2+-activated Cl- channel activity maintained the basal tone of circular smooth muscle of opossum lower esophageal sphincter (LES). In the current studies, the contribution of major K+ channels to the LES basal tone was investigated in circular smooth muscle of opossum LES in vitro. K+ channel activity was recorded in dispersed single cells at room temperature using patch-clamp recordings. Whole-cell patch-clamp recordings displayed an outward current beginning to activate at -60 mV by step test pulses lasting 400 ms (-120 mV to +100 mV) with increments of 20 mV from holding potential of -80 mV ([K+]I = 150 mM, [K+]o = 2.5 mM). However, no inward rectification was observed. The outward current peaked within 50 ms and showed little or no inactivation. It was significantly decreased by bath application of nifedipine, tetraethylammonium (TEA), 4-aminopyridine (4-AP), and iberiotoxin (IBTN). Further combination of TEA with 4-AP, nifedipine with 4-AP, and IBTN with TEA, or vice versa, blocked more than 90% of the outward current. Ca2+-sensitive single channels were recorded at asymetrical K+ gradients in cell-attached patch-clamp configurations (100.8+/-3.2 pS, n = 8). Open probability of the single channels recorded in inside-out patch-clamp configurations were greatly decreased by bath application of IBTN (100 nM) (Vh = -14.4+/-4.8 mV in control vs. 27.3+/-0.1 mV, n = 3, P < 0.05). These data suggest that large conductance Ca2+-activated K+ and delayed rectifier K+ channels contribute to the membrane potential, and thereby regulate the basal tone of opossum LES circular smooth muscle.

Animals↗
PubMed2001

The normal antireflux mechanism.

The normal antireflux mechanism consists of several components, any one of which may malfunction and render an individual prone to the development of GERD. The LES is clearly the most important component because gastroesophageal reflux almost always occurs when the sphincter pressure equals that of the stomach. Usually, an LES pressure of just 2 to 3 mm Hg above intragastric pressure is sufficient to prevent reflux. Other factors certainly play significant ancillary roles in preventing reflux. In the absence of a hiatal hernia, the crural fibers of the diaphragm serve as an "extrinsic" sphincter. Furthermore, the unique anatomy of the proximal stomach (e.g., the angle of His, mucosal flap valve, posterolateral location of the fundus) serves to keep gastric contents away from the gastroesophageal junction, making it less likely for reflux to occur when the LES relaxes. When a hiatal hernia is present, these factors are lost, and the hernia sac provides a reservoir for gastric juices with ready access to the LES. Finally, some degree of reflux occurs in all individuals, but esophageal clearance and acid neutralization provide an important last line of defense.

Esophagogastric Junction↗
PubMed2001

Extraesophageal manifestations of reflux disease: myths and reality.

Because of the anatomic proximity of the esophagus and the upper respiratory tract, it is not surprising that, in some patients with GERD, symptoms attributable to the respiratory and upper aerodigestive tract may occur. The prevalence of respiratory or other extraesophageal manifestations of GERD remains unknown, however, primarily because in any given patient it is often difficult to determine whether GERD is causing the extraesophageal condition or whether the two conditions are coexisting independently. Acid can reflux into the hypopharynx or trachea in some patients with GERD, thereby causing a variety of respiratory tract symptoms. Additionally, vagovagal reflexes triggered by acid that comes in contact with the esophageal or tracheal mucosa may contribute to the pathogenesis of GERD-related respiratory symptoms, particularly wheezing and coughing. The clinician should be particularly suspicious of underlying GERD in patients with unexplained dental caries, posterior laryngitis, chronic unexplained cough, and intrinsic asthma that does not respond to (or worsens with) bronchodilator therapy. Intensive medical antireflux therapy should be instituted in patients with a suspected extraesophageal manifestation of GERD. Failure to respond to this should not lead automatically to antireflux surgery; the clinician should use 24-hour pH monitoring to document the relationship between GERD and extraesophageal complications and to demonstrate that intensive medical therapy has indeed failed to eliminate acid reflux.

Arrhythmias, Cardiac↗
PubMed2000

Upper gastrointestinal toxicity of alendronate.

OBJECTIVE: Alendronate is rapidly gaining widespread use in the treatment of osteoporosis. However, recent postmarketing surveys and endoscopic studies suggest that its use may be associated with significant predictable esophageal and gastric mucosal toxicity, similar to that of aspirin and nonsteroidal anti-inflammatory drugs. Because treatment of osteoporosis may be needed in as many as 30% of all postmenopausal women, and considering that alendronate could be used in all postmenopausal women as prevention, definition of potential mucosal toxicity is crucial. Our aim was to study the upper gastrointestinal toxicity of alendronate in an age-appropriate female population using a clinically applicable dose (10 mg/day) to determine whether it causes predictable damage in the proximal gastrointestinal mucosa in a fashion similar to that seen with aspirin and nonsteroidal anti-inflammatory drugs. METHODS: We conducted a double-blind, randomized, placebo-controlled trial in 32 healthy female volunteers between the ages of 40 and 65 yr recruited by newspaper advertisement. Endoscopic mucosal abnormalities in the esophagus, stomach, and duodenum both before and after 1 month of treatment were scored and compared using validated endoscopic grading systems. Symptom scores before and after treatment were determined. Noninvasive measurements of gastrointestinal permeability were obtained before, during, and after treatment using sucrose and mannitol/lactulose urinary excretions. RESULTS: Endoscopic scores before and after treatment with alendronate were not significantly different. Similarly, mean symptom scores in the alendronate group did not change significantly after treatment. There were no significant mucosal permeability changes in the stomach or small intestine after treatment. CONCLUSION: Alendronate does not cause predictable esophageal, gastric, or duodenal mucosal damage when used as directed.

Adult↗
PubMed2000

Opposing roles of K(+) and Cl(-) channels in maintenance of opossum lower esophageal sphincter tone.

The ionic basis underlying the maintenance of myogenic tone of lower esophageal sphincter circular muscle (LES) was investigated in opossum with the use of standard isometric tension and conventional intracellular microelectrode recordings in vitro. In tension recording studies, nifedipine (1 microM) reduced basal tone to 27.7 +/- 3.8% of control. The K(+) channel blockers tetraethylammonium (TEA, 2 mM), charybdotoxin (100 nM), and 4-aminopyridine (4-AP, 2 mM) enhanced resting tone, whereas apamin and glibenclamide were without affect. Cl(-) channel blockers DIDS (500 microM) and 5-nitro-2-(3-phenylpropylamino)-benzoic acid (500 microM), as well as niflumic acid (0.1-300 microM), decreased basal tone, but tamoxifen was without effect. Intracellular microelectrode recordings revealed ongoing, spontaneous, spike-like action potentials (APs). Nifedipine abolished APs and depolarized resting membrane potential (RMP). Both TEA and 4-AP significantly depolarized RMP and augmented APs, whereas niflumic acid dose-dependently hyperpolarized RMP and abolished APs. These data suggest that, in the opossum, basal tone is associated with continuous APs and that K(+) and Ca(2+)-activated Cl(-) channels have important opposing roles in the genesis of LES tone.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed2000

Acid-induced esophageal shortening in humans: a cause of hiatus hernia?

BACKGROUND: Hiatus hernia and gastroesophageal reflux disease commonly coexist, and there is pathophysiological evidence that the presence of a hiatus hernia contributes to abnormal acid reflux. However, the cause of hiatus hernia remains unclear. In an animal model, it has been shown that acute acid injury to the esophagus results in esophageal shortening, raising the possibility that reflux esophagitis per se can contribute to the formation of hiatus hernia by inducing esophageal shortening. AIM: To determine whether luminal acid produces esophageal shortening in humans. METHODS: Twelve volunteers were each studied on two occasions, one week apart, in a double-blind, crossover trial. The location of the lower esophageal sphincter (LES), as well as the LES resting pressure and axial length were determined at baseline and then again after 20 min of either acid or saline perfusion. RESULTS: Acid perfusion did not induce significant changes in resting LES pressure but resulted in proximal migration of the LES (ie, esophageal shortening) by an average of 0.5 cm, with the largest proximal migration being 1.8 cm. In contrast, saline perfusion resulted in slight distal migration of the LES (ie, esophageal lengthening). CONCLUSIONS: Intraluminal acid perfusion causes longitudinal axis shortening of the esophagus and suggests that gastroesophageal acid reflux may contribute to the cause of hiatus hernia.

Adult↗
PubMed1999

Recommendations for the management of irritable bowel syndrome in family practice. IBS Consensus Conference Participants.

To help family physicians manage patients with irritable bowel syndrome (IBS), a consensus conference was convened in June 1997 at which 5 internationally recognized experts in IBS presented position papers on selected topics previously circulated to the conference participants. Five working groups comprising family physicians, gastroenterologists and allied health care professionals from across Canada were then charged with developing recommendations for the diagnosis, patient education, psychosocial management, dietary advice and pharmacotherapy, respectively. An evidence-based approach was used where possible; otherwise, recommendations were made by consensus. The participants concluded that family physicians can make a positive diagnosis of IBS using symptom criteria. The pathophysiology is poorly understood, but motility and sensory disturbances appear to play a role. Neither psychological nor specific dietary factors cause IBS, but both can trigger symptoms. Drug therapy is not recommended for the routine treatment of IBS, but short-term trials of drug therapy may be targeted to predominant symptoms in selected patients. A step-wise, patient-centred approach to management is outlined.

Colonic Diseases, Functional↗
PubMed1999

Alteration of swallowing and oesophageal peristalsis by different initiators of deglutition.

It has long been believed that once initiated, the involuntary phase of deglutition follows a stereotypical pattern, that is modified only by ongoing sensory input from the transported bolus. To test the hypothesis that the mode of sensory activation of deglutition can modify the motor response irrespective of bolus characteristics, the mylohyoid, lower oesophageal sphincter (LES) and oesophageal body response to swallows induced in anaesthetized opossums by pharyngeal stroking or superior laryngeal nerve (SLN) stimulation (unilateral and bilateral) were compared. In comparison with unilateral SLN stimulation, swallows triggered by pharyngeal stroking resulted in a greater mylohyoid spike burst and LES relaxation. There was no significant difference in the oesophageal and LES motor response to pharyngeal stroking vs bilateral SLN stimulation, although the mylohyoid response was of greater magnitude with pharyngeal stroking. These studies demonstrate that the motor component of deglutition can be altered by different sensory initiators of swallowing, and provides a possible link between oropharyngeal and oesophageal motor disorders.

Animals↗
PubMed1999

Predictive value of the Rome criteria for diagnosing the irritable bowel syndrome.

OBJECTIVE: Our aim was to examine the predictive value of the Rome criteria and absence of so-called "red flags" of clinical practice for diagnosing irritable bowel syndrome. Red flags were relevant abnormalities on physical examination, documented weight loss, nocturnal symptoms, blood in stools, history of antibiotic use, and family history of colon cancer. METHODS: In retrospective studies, 98 patients who had one or more Rome criteria and lacked red flags were identified by chart review of a 1-yr period. In prospective studies, 95 patients were identified who met the Rome criteria and lacked red flags. Sensitivity, specificity, predictive value of Rome criteria, and absence of red flags were determined. Consultant's final diagnosis was the gold standard. Investigations before and after referral were recorded and reason for referral was determined in prospective studies. RESULTS: In the retrospective series, the Rome criteria and absence of red flags had a sensitivity of 65%, specificity of 100%, and positive predictive value of 100%. None of these patients required revision of their diagnosis during a 2-yr follow-up. In the prospective study, the positive predictive value was 98%. More than 50% of the patients in this group had been referred because of diagnostic uncertainty and 24% had had an abdominal ultrasound; 66% of those <45 yr old underwent at least partial colonic evaluation. CONCLUSIONS: These findings suggest that the Rome criteria combined with a lack of red flags have a very high predictive value for diagnosing irritable bowel syndrome. Application of these diagnostic criteria has the potential to alter utilization of health care resources.

Adolescent↗