Disproportion of economic impact, research achievements and research support in digestive diseases in Canada.

OBJECTIVES: To assess the economic impact, research output and research support of digestive diseases, and to compare them to those of other common disease entities, specifically mental, cardiovascular, respiratory, and central nervous system diseases. METHODS: Economic burden was assessed with the use of (a) published Canadian government data of direct cost from 1963 to 1993, (b) data from the Canadian Institute of Health Information and (c) recent Canadian economic studies. Research achievements were assessed on the basis of (a) research training in Canadian units, (b) individual achievements by Canadian investigators and (c) contribution to meetings and reception of awards. Research support was assessed by reviewing (a) Canadian government publications, (b) the Association of Canadian Medical Colleges, (c) the Medical Research Council (MRC) of Canada, (d) charitable organizations and (e) the Canadian Association of Gastroenterology (CAG). RESULTS: Digestive diseases are responsible for 15% of the total direct economic burden of Canadian health costs, and this figure exceeds those for mental, cardiovascular, respiratory and central nervous system diseases. Hospital discharges for digestive diseases contribute 12% of all hospitalizations and 20% of all neoplasias. Digestive diseases cause short-term loss of productivity, costing $1.14 billion/yr and exceeding the costs of mental, cardiovascular, respiratory and central nervous system diseases. Eighty-one percent of Research Fellows trained in Canadian units entered academic positions, and 63% obtained operating grants. Canadian investigators made important contributions in all areas of digestive science and received major international awards. Government support for digestive diseases was less than that for cardiovascular and neurologic research. In contrast to the highest economic burden, university staffing and residents were fewer for digestive than for mental, cardiovascular, respiratory and neurologic diseases. The number of MRC grants decreased, mainly because of organizational problems. Most charitable organizations support research specifically oriented to the disease of their interest. The CAG was the major supporter of non-specified research. CONCLUSIONS: Digestive diseases are responsible for a major economic burden. Scientists in this field have established international recognition, but research support lags behind the need to correct the economic burden and to provide future generations of scientists in the digestive sciences. There is need for government to readdress this shortcoming and to review its method of support.

Canadian research fellowship training programs in digestive sciences: achievements and challenges.

BACKGROUND: The Canadian Association of Gastroenterology (CAG) is committed to fostering the development of future Canadian investigators. Up to 1986, research fellowship support was obtained from the Medical Research Council (MRC) of Canada. Since that time, several peer-reviewed, industry-sponsored, CAG-supported research fellowships and a variety of independently funded awards have augmented this effort. In the same period, peer-reviewed operating grants (OGs) from the MRC and other agencies have been constrained. The aim of this study was to determine the success of CAG, MRC or any other Canadian research fellowships in the development of career investigators in digestive sciences and to identify factors influencing the outcomes of such training. METHODS: MRC records and the minutes of CAG annual meetings were reviewed to identify research fellowship support. Canadian program directors were requested to list research fellows affiliated with their groups between 1986 and 1997. Only fellowships providing at least 1 year of training were included. A 7-page questionnaire detailing biographic characteristics, the site and duration, and specific issues related to the quality of research training was sent to identified trainees. Significant associations between success in achieving an academic appointment or OG support and several variables of training were identified. RESULTS: Eighty-six research fellows were trained. Responses were obtained from 43 of them. The demographic characteristics of the whole group and the respondents were similar. Of the respondents, 81% of trainees obtained academic appointments. Fellowships longer than 1 year were associated with higher rates of academic posting, and MRC-funded fellows had greater success rates of academic appointments. Of eligible trainees 63% have obtained OG support. None of the other variables examined predicted success. Of the trainees responding, 85% valued the fellowship very highly. CONCLUSIONS: The establishment of the additional research fellowships has fostered the development of career investigators in digestive sciences. The high success rate of former trainees in obtaining academic appointments and OG support suggests that the fellowship programs are effective and appropriately oriented. The structure of the current programs does not require substantial revision. OG support for new investigators appears now to lag substantially.

The Second Canadian Consensus Conference on the Management of Patients with Gastroesophageal Reflux Disease.

The Second Canadian Consensus Conference on the Management of Patients with Gastroesophageal Reflux Disease (GERD) was organized by the Canadian Association of Gastroenterology to address major advances in the understanding of the pathophysiology of GERD, to review the new methods of investigation and therapy introduced since the first conference in 1992 and to examine the issue of relevant health economics. The changes that have taken place over the past four years have been sufficiently dramatic to necessitate reassessment of the recommendations made following the first conference. The second conference dealt with the investigation and treatment of uncomplicated GERD and the complex issues of esophageal and extraesophageal complications such as chest pain, Barrett's esophagus, and reflux-related pulmonary and laryngeal disorders. The role of laparoscopic surgery was also discussed. A decision tree for investigation and treatment of patients with GERD was developed. The 38 participants represented a broad spectrum of experience, location of practice and special interests. The distribution of participants conformed to the recommendations of the Canadian Medical Association guidelines for consensus documents in that there should be input from all possible interested parties. A list of the state-of-the-art lectures presented during the conference, the small group sessions, the session chairpersons and participants are appended to this document. CONCLUSIONS. UNCOMPLICATED GERD: GERD with alarm symptoms must be investigated immediately. There was no consensus about when to investigate uncomplicated GERD, ie, whether to perform endoscopy immediately or after initial therapy fails. There was controversy regarding 'step up' (H2 receptor antagonist [H2RA] or prokinetic [PK] first therapy) versus 'step down' therapy (proton pump inhibitor [PPI] first therapy). The majority decision was for short term 'step up' therapy and investigation if symptoms do not improve or recur. Maintenance therapy should be carried out with the initial therapy that was effective. H2RAs and PKs may suffice for maintenance therapy in milder GERD; however, for severe esophagitis, PPIs should be used. SURGERY: Indications for laparoscopic surgery should be the same as for conventional antireflux operations. NONCARDIAC ANGINA-LIKE CHEST PAIN: After exclusion of nonesophageal causes, the majority decided that eight weeks of therapy with a PPI should be performed, while some suggested work-up before a therapeutic test. In the absence of response or recurrence, esophagogastroduodenoscopy (EGD) and, depending on the circumstances, 24 h ambulatory pH/motility may be indicated. BARRETT'S ESOPHAGUS: Only patients who, in case of future discovery of cancer or dysplasia, are able or willing to undergo therapy should have surveillance. In the absence of dysplasia EGD should be performed every two years, and in the presence of mild dysplasia every three to six months. All agreed that for severe dysplasia, esophagectomy or poor risk patients, esophageal mucosal ablation is indicated. ESTRAESOPHAGEAL COMPLICATONS (EECs): Asthma, chronic cough and posterior laryngitis were considered EECs. Although PPIs may decrease symptoms, improvement alone is not diagnostic of the presence of EEC. Ambulatory pH studies with two pH probes or ambulatory pH/motility may be useful in establishing causation. HEALTH ECONOMICS: There are limited data for an economic comparison among the different drugs or between medical and surgical therapy.

Guidelines of the previous consensus conference and recent developments.

This article reviews the major changes that have occurred since the last Canadian consensus conference on gastroesophageal reflux disease (GERD), which was held four years ago. There were developments in the understanding of the pathophysiology of this disease and improvements in the methods of its investigation and management. Esophageal and extraesophageal complications have also been better defined. Since 1992 new knowledge on nitric oxide has been gained and several new inflammatory cytokines have been developed. Improved understanding of the mechanism of the hypersensitive esophagus helped to explain the presence of clinical symptoms with normal endoscopic findings. This also improved interpretation of the role of 24 h pH monitoring and 24 h pH with motility recording. There is better understanding of the role of H2 receptor antagonists and prokinetics and an increasing confidence in the long term safety of proton pump inhibitors (PPIs). The most important changes occurred in surgery with the introduction of laparoscopic fundoplication. Patients with Barrett's esophagus who are too ill for esophagectomy may now be enrolled in surveillance because it is possible to deal with dysplasia and small cancers with photodynamic therapy. As an introductory lecture to the consensus conference, this article also deals with the subject of health economics and discusses the necessity and the dangers involved in devising treatment guidelines. It indicates that guidelines change with advancing knowledge, and emphasizes that physicians' primary duty is toward their patients. Therefore, guidelines devised here should be adjusted to the individual needs of patients. Organizational aspects of the present conference are also described.

The effect of cisapride in patients with reflux esophagitis: an ambulatory esophageal manometry/pH-metry study.

OBJECTIVES: The mechanisms responsible for the efficacy of cisapride in gastroesophageal reflux disease remain unclear. The current study was designed to test the hypothesis that cisapride decreases esophageal acid exposure by augmenting esophageal motility and improving acid clearance. METHODS: Eighteen patients with reflux esophagitis underwent combined 24-h ambulatory esophageal manometry/pH-metry at baseline and then again after 2 wk of cisapride therapy (10 mg q.i.d.). RESULTS: Esophageal acid exposure was significantly decreased during cisapride therapy (total percentage of time pH was < 4: 8.3 +/- 2.0% at baseline vs 3.8 +/- 0.6% on cisapride). This was not associated with significant changes in contraction amplitude or duration, peristaltic velocity, or the proportion of peristaltic contractions. The number of reflux episodes per hour was unchanged by cisapride therapy; however, cisapride significantly decreased the number of prolonged duration reflux episodes as well as the duration of the longest reflux episode. Although the relative proportion of peristaltic versus nonperistaltic contractions occurring during reflux episodes was unchanged by cisapride therapy, there was a significant increase in the mean number of contractions per minute (both peristaltic and nonperistaltic combined) occurring during reflux episodes. CONCLUSIONS: These data suggest that cisapride decreases esophageal acid exposure by improving esophageal clearance and that this occurs because of an increase in the number of esophageal contractions rather than by augmenting contraction amplitude or duration or the proportion of peristaltic sequences.

Role of xanthine oxidase-derived oxidants and leukocytes in ethanol-induced jejunal mucosal injury.

Previous reports indicate that intestinal intraluminal ethanol increases mucosal permeability (an index of mucosal injury) and histamine release by mast cells, and that the released histamine plays a role in mediating the increased permeability. In the present study, we investigated whether reactive oxygen metabolites and their major sources (xanthine oxidase and leukocytes) were involved in these ethanol effects. In rabbits, segments of the jejunum were perfused with a control solution or with 6% ethanol. In these segments, mucosal permeability was assessed by determining jejunal clearance of i.v. administered 51Cr-ethylenediaminetetraacetate (51Cr-EDTA) and 125I-bovine serum albumin (125I-BSA), and mast cell histamine release was estimated from the histamine concentration of the gut effluent. Ethanol increased 51Cr-EDTA clearance, 125I-BSA clearance, and histamine release. These ethanol effects decreased when the animals were given superoxide dismutase plus catalase (scavenger of O2- and H2O2, respectively), allopurinol, or oxypurinol (xanthine oxidase inhibitors). Administration of a monoclonal antibody (R15.7) against leukocyte adhesion molecule, CD18, inhibited completely the ethanol-induced increased 51Cr-EDTA and 125I-BSA clearances and histamine release. These and supplementary data suggest that (a) ethanol-induced mucosal injury and mast cell histamine release are mediated primarily by leukocytes, and (b) oxy radicals, especially those generated by xanthine oxidase, mediate these ethanol effects mainly by promoting leukocyte infiltration.

Adaptive cytoprotection against ethanol-induced small intestinal mucosal injury.

Exposure of the small intestinal mucose to 6% ethanol (which is found in human jejunum during alcohol consumption) causes morphological alterations, and increased permeability of the mucosa and histamine release from intestinal mast cells. The released histamine is shown to mediate a significant component of the increased mucosal permeability (i.e., mucosal injury). In the present study, we have investigated whether adaptive cytoprotection occurs against the increased mucosal permeability and histamine release induced by 6% ethanol. Rabbits were used. In each animal, three adjacent segments of upper small intestine were pre-perfused for 30 min, and then perfused for 90 min in the following order control solution followed by control solution (control segment); control solution followed by 6% ethanol (ethanol segment); 1% ethanol followed by 6% ethanol (pretreated ethanol segment). During the 90-min perfusion, mucosal permeability of each segment was measured by analyzing the effluent for intraluminal clearance of i.v. administered 51Cr-labelled ethylenediaminetetraacetic acid (51Cr-EDTA) and 125I-labelled bovine serum albumin (125I-BSA). Mast cell histamine release was assessed by determining histamine concentration of the gut effluent. All measurements were higher in the ethanol segments than in the controls. These ethanol effects were significantly lower in the pretreated ethanol segments, indicating that adaptive cytoprotection occurs against the mucosal injury induced by 6% ethanol. These findings are discussed in relation to the literature on mucosal effects of intestinal intraluminal ethanol.

Reproducibility and physiological characteristics of 24-hour ambulatory esophangeal manometry/pH-metry.

OBJECTIVES: To assess the reproducibility and physiological characteristics of ambulatory esophageal manometry/pH-metry. METHODS: Ten healthy volunteers were studied on two separate occasions (2 wk apart) using the Synectics Microdigitrapper System. The pH recording failed in one subject; thus, pH data were analyzed in nine, and motility measurements in all 10 subjects. RESULTS: A high degree of reproducibility was established for the five pH and seven manometry variables assessed. Using the paired t test and Wilcoxon signed rank test to compare the two sets of data, all p values were >0.05. Narrow 95% confidence intervals containing the zero measures were also obtained on the differences of the data from both sessions for all variables. Better correlation coefficients were obtained for the motility parameters than for the pH parameters. As would be expected, reflux occurred more often in the upright than in the supine position. Furthermore, esophageal contractions were of higher amplitude and longer duration in the distal esophagus, and the frequency of propulsive contractions sequences was higher during meals and in the upright position than in the supine position. CONCLUSIONS: This study demonstrates the reproducibility of ambulatory esophageal manometry/pH-metry, suggesting that this technology may be useful in assessing the effect of pharmacological intervention on esophageal motor function.

Ambulatory esophageal manometry/pH-metry discriminates between patients with different esophageal symptoms.

Ambulatory esophageal manometry/pH-metry has been used primarily in patients with chest pain of presumed esophageal origin, and it is unclear whether the discriminating power of this test applies to other esophageal symptoms. In the present study, prolonged ambulatory manometry/pH recordings were compared in 17 healthy controls, 12 patients with atypical chest pain, and 11 patients with chest pain and nonstructural dysphagia using the Synectics microdigitrapper system. Chest pain patients tended to have higher values for all the pH variables, but their esophageal motility parameters were no different than controls. On the other hand, the chest pain plus dysphagia group was characterized by a significantly lower proportion of propagated contractions between 10 and 5 cm above the lower esophageal sphincter. This group also tended to have a higher frequency of high-amplitude or prolonged-duration contractions. In comparison to the results of standard stationary esophageal manometry, the prolonged ambulatory recordings were more sensitive in detecting esophageal motor dysfunction in the two patient groups. This study suggests that quantitative analysis of ambulatory pH/motility recordings is a sensitive method of evaluating patients with suspected esophageal dysfunction.

Studies on ethanol-induced subepithelial fluid accumulation and jejunal villus bleb formation. An in vitro video microscopic approach.

Jejunal intraluminal ethanol causes morphological and mucosal microvascular injury. The purpose of the present study was to understand the mechanism of the morphological alterations caused by ethanol without the influence of ethanol's effect on the microcirculation. Therefore, we have investigated the ethanol-induced morphological changes in the absence of blood flow (i.e., in the jejunum in vitro) and compared these changes with those reported to occur in the presence of microcirculation (i.e., in the jejunum in vivo). The mucosa of jejunal segments was exposed to a control solution and to solutions containing 0.8, 1.6, and 4.8% (w/v) ethanol, using a specially designed apparatus. The morphological response of the mucosa to these solutions was continuously examined employing a video microscopic technique, and the changes were morphometrically evaluated on subsequent playback of videotapes. Ethanol caused a concentration-dependent increase in the number of villi with subepithelial fluid accumulation, i.e., blebs, and a decrease in the height of the villus core (i.e., lamina propria). With 0.8 and 1.6% ethanol, the contracted core remained partially attached to the epithelium and the total villus height (villus core plus epithelial layer) decreased. With 4.8% ethanol, the villus core contraction was so rapid that the stroma fully separated from the epithelium. Thus, among other factors, the rapidity of the villus core contractions appears to play a role in the subepithelial bleb formation and in the appearance of the bleb. The ethanol-induced changes in vitro are similar to those reported to occur in the jejunum in vivo. Therefore, we conclude that the effect of ethanol on morphology is independent of its action on the microcirculation.

Ambulatory esophageal manometry, pH-metry, and Holter ECG monitoring in patients with atypical chest pain.

Standard Holter electrocardiographic (ECG) monitoring was combined with ambulatory esophageal manometry and pH-metry in 25 patients with atypical chest pain in order to determine whether an association could be found between spontaneous pain episodes and ischemic ECG changes or esophageal dysfunction. Results of ambulatory testing were compared to those obtained with standard esophageal manometry and provocative testing. Twenty-two of the 25 patients experienced a total of 88 pain episodes during ambulatory testing. Although 15 of the 22 patients (68%) experiencing pain during testing had at least one pain episode that correlated temporally with gastroesophageal reflux, esophageal dysmotility or ischemic ECG changes, 65% of all pain episodes were unrelated to abnormal esophageal events or ECG changes. Seventeen percent of pain episodes were associated with gastroesophageal reflux, 15% with esophageal dysmotility, and 2% with a combined acid reflux and esophageal dysmotility event. Only one pain episode was associated with ischemic ECG changes. Twelve of the 15 patients with chest pain episodes associated with reflux or esophageal dysmotility had other identical pain episodes in which there was no correlation. Reproduction of a patient's pain during standard manometry with provocative testing did not predict a strong correlation between the patient's spontaneous pain episodes and esophageal dysfunction during ambulatory recordings. In summary, patients with atypical chest pain have relatively few spontaneous pain episodes that correlate with gastroesophageal reflux, esophageal dysmotility, or ischemic ECG changes. It appears that different stimuli can trigger identical episodes of chest pain, which suggests that many of these patients may have dysfunction of their visceral pain sensory mechanisms.

The use of oximetry in determining intestinal blood flow.

The intraoperative evaluation of intestinal ischemia and viability is often subjective and unreliable. The results of recent reports of pulse and surface oximetry have suggested that these techniques may be useful in assessing intestinal blood flow. In the current study, we evaluated and compared the ability of intestinal tissue oxygen saturation (as measured by pulse oximetry) and intestinal surface oxygen tension (as measured by surface oximetry) to determine the actual intestinal tissue blood flow (as measured with a radiolabeled microsphere technique). In five dogs, tissue oxygen saturation, surface oxygen tension and blood flow of the proximal and distal parts of the small intestine were measured under basal conditions. A clamp placed around the root of the superior mesenteric artery was then tightened to decrease the blood flow through this artery (as measured by an ultrasonic flow probe) by 50 percent and then by 75 percent, repeating all measurements after each reduction. The two consecutive reductions in superior mesenteric artery blood flow resulted in an average 54 and 76 percent reduction in tissue blood flow, respectively. As a result of these reductions in tissue blood flow, the average intestinal tissue oxygen saturation (percentage), as determined by pulse oximetry, decreased significantly from a basal value of 93 +/- 1 to 83 +/- 1 (p < 0.05) and then to 76 +/- 1 (p < 0.05) with the two progressive blood flow reductions. Intestinal surface oxygen tension decreased more steeply, from a basal value of 97 +/- 1 to 80 +/- 6 (p < 0.05) and then to 64 +/- 7 millimeters of mercury (p < 0.05) with the same two reductions in tissue blood flow. Both techniques were capable of estimating tissue blood flow, but pulse oximetry was quicker and simpler to use. We conclude that the pulse oximeter has the potential to be of value in the intraoperative assessment of intestinal blood flow.

Ethanol-induced jejunal microvascular and morphological injury in relation to histamine release in rabbits.

BACKGROUND: To investigate the relation between ethanol-induced jejunal microvascular injury, morphological changes, and histamine release, the present study examined whether the attenuation of microvascular effect of ethanol by 16,16-dimethyl prostaglandin E2 (dmPGE2) (reported by us previously) was associated with an attenuation of epithelial damage and histamine release. METHODS: Rabbits were used. Mucosal microvascular injury was assessed by determining jejunal plasma protein loss (JPPL), histamine release by measuring histamine concentration of the gut effluent, and epithelial damage by routine histology. RESULTS: (1) During 90-minute jejunal ethanol perfusion, there was a direct relation between the time course of histamine release and that of JPPL. (2) dmPGE2 attenuated the ethanol-induced JPPL and histamine release, and the decrease in JPPL was directly proportional to the decrease in histamine release. (3) dmPGE2 did not alleviate ethanol-induced epithelial damage. (4) Ketotifen (a mast cell stabilizer), similar to dmPGE2, attenuated ethanol-induced JPPL and histamine release. (5) Ethanol caused histamine release by the jejunum in vitro; this was attenuated by dmPGE2 and also by phloretin (a mast cell stabilizer). CONCLUSIONS: It appears that (1) ethanol causes JPPL by inducing release of mediators from mucosal mast cells. (2) dmPGE2 attenuates JPPL by stabilizing mast cells. (3) The ethanol-induced mucosal microvascular injury is directly related to histamine release but not to epithelial damage.

The role of angiotensin in the intestinal vascular response to hypotension in a canine model.

It was previously shown that the vasoconstrictory response to hypotension was similar in the mucosa of the small bowel and the colon but was significantly higher in the muscularis of the latter than that of the former. To understand the mechanism of this differential response of the muscularis of the small bowel and the colon, the present study investigated the effect of an angiotensin II inhibitor (saralasin) on the hypotension-induced vasoconstriction of the mucosa and the muscularis of these two locations of the gastrointestinal tract. Dogs were used. Hypotension was induced by hemorrhage to reduce blood pressure by 40 mm Hg. Blood flow was measured by 15-microns radiolabeled microspheres. Saralasin was infused intravenously for 20 minutes at a rate of 0.05 mg.kg-1 bolus followed by 1 microgram.kg-1.min-1. Saralasin had no effect on the basal blood flow of the mucosa or the muscularis of the small bowel or on the hypotension-induced vasoconstriction of these two layers of the small bowel. In contrast, saralasin decreased blood flow to the mucosa (-28%; P less than 0.001) and increased blood flow to the muscularis (+140%; P less than 0.001) of the colon under basal conditions and also reduced the hypotension-induced vasoconstriction of the colonic muscularis (P less than 0.01). These and supplementary data indicate that there is a difference between the small bowel and the colon in local activity of vascular angiotensin system and that this system is most active in the colonic muscularis where it plays a significant role in the vasoconstrictory response to hypotension.

The role of histamine1 and histamine2 receptors in the ethanol-induced jejunal plasma protein loss.

Histamine and other mediators have been shown to be involved in the ethanol-induced jejunal plasma protein loss. In this study we have investigated whether the histamine (H)-related component of this protein loss is mediated by H1-receptors, H2-receptors or both. Four groups of dogs (n = 12 in each) were studied. They were: untreated, H1 + H2-receptor blockade, H1-receptor blockade and H2-receptor blockade. Chlorpheniramine and ranitidine were used to block H1 and H2-receptor blockade. Chlorpheniramine and ranitidine were used to block H1 and H2-receptors respectively. In all animals, jejunal protein loss was measured over 10 min periods for 90 min. Ethanol increased protein loss in all time periods (p less than 0.001). This protein loss was depressed by H1 + H2-receptors blockade throughout 90 min (p less than 0.01). H1-receptor blockade caused a similar depression of ethanol effect but only during 20 to 40 min (p less than 0.05). In contrast, H2-receptor blockade aggravated the protein losing effect of ethanol throughout 90 min (p less than 0.01). Analyses of data tend to suggest that the ethanol-induced protein loss is mediated principally by H1-receptors, and that a complete inhibition of the histamine-related ethanol-induced protein loss can be achieved only by a simultaneous blockade of both H1 and H2-receptors, and not by H1- or H2-receptor blockade alone.

The effect of pitressin on esophageal blood flow of the dog.

In a previous study on canine esophagus, we reported that intravenous infusion of isoproterenol caused mucosal (i.e., mucosal + submucosal) vasodilation only in the lower esophageal sphincter (but not in the body) and muscularis vasodilation only in the body (not in the lower esophageal sphincter). In the present study, we have investigated in dogs whether these esophageal tissues also exhibit a similar difference in their vasoconstrictory response to intravenous infusion of pitressin. All measurements were made before (basal) and after infusion of 0.02 U pitressin.min-1.kg-1 for 15 min. Pitressin significantly decreased portal venous pressure and blood flow, and increased vascular resistance of all tissues of the esophagus. This vasoconstriction of the tissues, however, was higher in the squamous mucosa of the body than in the columnar mucosa of the lower esophageal sphincter. In contrast, it was higher in the smooth muscle of the lower esophageal sphincter than in the striated muscle of the body. These data together with those of our previous report on isoproterenol demonstrate that pitressin causes a pronounced vasoconstriction in those esophageal tissues where isoproterenol had no effect. Conversely, pitressin causes least vasoconstriction in those tissues where isoproterenol produced a significant vasodilation. These differences could be the result of partial agonist actions or differences in receptor density or in receptor-effector coupling mechanism.

Transition from nutcracker esophagus to achalasia. A case report.

We report a middle-aged woman with nutcracker esophagus who progressed to classic achalasia in two years. Several previous reports have documented progression of nutcracker esophagus to diffuse esophageal spasm and diffuse esophageal spasm to achalasia, but the only previous report of nutcracker esophagus progressing to achalasia was in a child. Our case suggests that, in some instances, nutcracker esophagus and achalasia may share the same pathogenesis.

Microvascular permeability increases early in the course of acid-induced esophageal injury.

To test the hypothesis that microvascular injury is involved in the pathophysiology of acid-induced esophagitis, the effect of acid perfusion on intraluminal plasma protein loss was studied in relation to histological changes. Four groups of opossums (n = 6 in each) were perfused with either normal saline control) or 10, 20, or 100 mmol/L isoosmolar hydrochloric acid at 2 mL/min for 90 minutes using a midesophageal catheter. The distal esophagus was cannulated via a gastrostomy, and the effluent was collected and measured for intraluminal loss of IV injected 125I-bovine serum albumin. Plasma protein loss in the control group was constant with a total loss of 3.40 +/- 0.69 mg/g dry wt. Perfusion of 10, 20, and 100 mmol/L hydrochloric acid increased total protein loss to 8.06 +/- 2.62, 13.94 +/- 2.72, and 27.34 +/- 4.34 mg/g dry wt, respectively. The protein loss was not associated with intraluminal blood loss, as measured by previously injected 51Cr-labeled autologous red blood cells. Histological changes, scored by a blinded observer, were significant only between control animals and those perfused with 100 mmol/L hydrochloric acid. Separate studies using the vascular tracer monastral blue B demonstrated an increase in labeling of lamina propria blood vessels that varied directly with the concentration of acid perfusate, thereby providing direct morphological evidence of microvascular injury. These studies suggest that increased microvascular permeability occurs early in the course of acid-induced esophageal injury.