Randomised clinical trial: the safety and tolerability of Trichuris suis ova in patients with Crohn's disease.

BACKGROUND: Recent evidence suggests that embryonated eggs of the porcine whipworm Trichuris suis ova (TSO) may be an effective treatment for inflammatory bowel disease (IBD). AIM: To assess the safety and tolerability of TSO following a single dose in patients with Crohn's disease. METHODS: This was a sequential dose-escalation (500, 2500 and 7500 viable embryonated TSO), randomised, double-blind, placebo-controlled study to evaluate the safety of a single dose of oral suspension TSO in patients with Crohn's disease. Twelve patients were randomised into each of three cohorts. Patients were assessed 1, 3, 5, 7, 9, 11 and 14 days following dosing (via a telephone call and diary symptom collection through 14 days postdose) for adverse events, changes to concomitant medications and gastrointestinal (GI) signs and symptoms. Patients were again assessed at Months 1, 2 and 6. RESULTS: Eighteen males and 18 females were enrolled, ages 20 to 54 years. All patients were dosed and completed the initial 2-month follow-up period (five patients did not attend their 6-month study visit). GI disorders were reported with the highest frequency; 7 (25.9%) TSO-treated patients and 3 (33.3%) placebo-treated patients. No dose-dependent relationship was observed, with 3 (33.3%) placebo, 4 (44.4%) TSO 500, 0 (0.0%) TSO 2500 and 3 (33.3%) TSO 7500 patients experiencing at least one GI event, and no clinically meaningful changes in GI signs and symptoms. CONCLUSIONS: A single dose of Trichuris suis ova up to 7500 ova was well tolerated and did not result in short- or long-term treatment-related side effects. Clinicaltrials.gov NCT01576461.

Oral rehydration for viral gastroenteritis in adults: a randomized, controlled trial of 3 solutions.

BACKGROUND: Pedialyte and Gatorade are advocated for the treatment of dehydration in viral gastroenteritis, but there is limited evidence to support their use. We examine the efficacy, safety, and palatability of Pedialyte, Gatorade, and a New Oral Rehydration Solution (N-ORS). This was a randomized double-blind trial conducted in an inpatient, community hospital. Seventy-five consecutive adult patients (male, 42; female, 33) admitted with viral gastroenteritis were randomized to receive Gatorade, Pedialyte, or N-ORS for 48 hours. A yogurt/rice diet was allowed ad libitum. Stool and urine output, electrolytes, fluid intake, body weight, hematocrit, and palatability of solutions were measured. RESULTS: Sixty completed the study. Stool frequency, consistency, and body weight improved (p < .001) in all 3 groups, but there was no difference between groups. Likewise, urine output, hematocrit, and correlations between fluid ingested, stool weight, or urine output were similar. At admission and 24 and 48 hours later, hypokalemia was observed in 7, 10, and 8 patients with Gatorade; 3, 2, and 1 with N-ORS; and 2, 2, and 1 with Pedialyte, respectively. Similarly, hyponatremia was observed in 6, 9, and 3 patients with Gatorade; 5, 3, and 4 with N-ORS; and 4, 5, and 4 with Pedialyte. Tastewise, Gatorade and N-ORS were rated higher (p < .05) than Pedialyte. Limitations were a smaller sample size and higher dropout (20%). CONCLUSIONS: Gatorade and N-ORS seem to be as effective as Pedialyte in correcting dehydration and in improving bowel symptoms. All 3 solutions were safe. Unlike other groups, hypokalemia persisted in the Gatorade group. Gatorade and N-ORS may be effective in the treatment of dehydration associated with mild viral gastroenteritis.

Trichuris suis therapy in Crohn's disease.

BACKGROUND: Crohn's disease is common in highly industrialised Western countries where helminths are rare and uncommon in less developed areas of the world where most people carry worms. Helminths diminish immune responsiveness in naturally colonised humans and reduce inflammation in experimental colitis. Thus exposure to helminths may help prevent or even ameliorate Crohn's disease. AIMS: The aim of the study was to determine the safety and possible efficacy of the intestinal helminth Trichuris suis in the treatment of patients with active Crohn's disease. PATIENTS: Twenty nine patients with active Crohn's disease, defined by a Crohn's disease activity index (CDAI) > or =220 were enrolled in this open label study. METHODS: All patients ingested 2500 live T suis ova every three weeks for 24 weeks, and disease activity was monitored by CDAI. Remission was defined as a decrease in CDAI to less than 150 while a response was defined as a decrease in CDAI of greater than 100. RESULTS: At week 24, 23 patients (79.3%) responded (decrease in CDAI >100 points or CDAI <150) and 21/29 (72.4%) remitted (CDAI <150). Mean CDAI of responders decreased 177.1 points below baseline. Analysis at week 12 yielded similar results. There were no adverse events. CONCLUSIONS: This new therapy may offer a unique, safe, and efficacious alternative for Crohn's disease management. These findings also support the premise that natural exposure to helminths such as T suis affords protection from immunological diseases like Crohn's disease.

Functional chest pain of esophageal origin: hyperalgesia or motor dysfunction.

OBJECTIVE: Many patients with functional (noncardiac) chest pain exhibit both hypersensitivity and motor dysfunction of the esophageal wall. We aimed to determine whether the sensory or motor dysfunction plays an important role in the pathogenesis of chest pain. METHODS: We performed graded balloon distentions of the esophagus using impedance planimetry in 16 consecutive patients with chest pain and otherwise normal cardiac and esophageal evaluations and in 13 healthy controls. In those patients who experienced chest pain with balloon distention, the test was repeated after atropine was given. Sensory and biomechanical parameters were measured. RESULTS: Balloon distention reproduced typical chest pain in 13/16 patients (81%) and at lower (p < 0.01) sensory thresholds than controls. Pain was reproduced in all 13 patients and at lower (p < 0.05) sensory thresholds after atropine. Also, after atropine, the esophageal cross-sectional area and wall tension increased (p < 0.05), the tension/strain association shifted to the right (p < 0.05), and reactivity decreased (p < 0.002) relative to results before atropine or in healthy controls (i.e., the esophageal wall relaxed and became more deformable). CONCLUSIONS: Even after relaxing the esophageal wall, most patients experienced chest pain and at lower sensory thresholds. Hence, hyperalgesia rather than motor dysfunction appears to be the predominant mechanism for functional chest pain of esophageal origin.

Behavioural responses of red deer to fences of five different designs.

Capercaillie, a large species of grouse, are sometimes killed when they fly into high-tensile deer fences. A fence design which is lower or has a less rigid top section than conventional designs would reduce bird deaths, but such fences would still have to be deer-proof. The short-term behavioural responses of farmed red deer (Cervus elaphus) to fences of five designs, including four that were designed to be less damaging to capercaillie, were measured. Five deer were located on one side of a fence with a larger group (20 animals), from which they had been recently separated, on the other. The efficacy of fences in preventing deer from the small group from rejoining the larger group was also recorded. In addition to a conventional deer fence (C) the four new designs were, an inverted "L" shape (L), a fence with offset electric wire (E), a double fence (D) and a fence with four webbing tapes above (W). Four replicate groups of deer were each tested for 3 days with each fence design. Deer paced the test fence line relatively frequently (a proportion of 0.09 scan observations overall) but significantly less when deer were separated by fences E or C compared to L, W or D (overall difference between fence types, P<0.001). Deer separated by fence E spent significantly more time pacing perimeter fences than deer separated by fences of other types (overall difference between fence types, P<0.01) but deer separated by fence C maintained a low level of fence pacing overall. Analysis of behaviour patterns across the first day and the 3 days of exposure suggested that the novelty of the test fences, rather than the designs per se, influenced the behaviour of the deer. Over the course of the study, no deer crossed either C or L. Three deer crossed E and two deer crossed both W and D. On this basis, field testing, particularly of fence L, would be a useful next step.

Intestinal fluid absorption during exercise: role of sport drink osmolality and [Na+].

The purpose of this study was to evaluate the effects of modifying the osmolality and [Na+] of orally ingested rehydration beverages during exercise on intestinal absorption in the duodenum and upper jejunum. Six subjects randomly ingested (23 mL.kg-1 BW) the following 6% carbohydrate solutions with and without Na+ during 85-min of cycle exercise (65% VO2 peak) in a cool (22 degrees C, 40% RH) environment: a) 0 Na+, 245 mOsm.kg-1; b) 20 mEq Na+, 283 mOsm.kg-1; c) 20 mEq Na+, 169 mOsm.kg-1; d) 50 mEq Na+, 275 mOsm.kg-1; and e) 50 mEq Na+, 176 mOsm.kg-1. To alter solution osmolality and maintain carbohydrate concentration constant, glucose, sucrose, fructose, and maltodextrin were used in different combinations. Nasogastric and multilumen tubes were fluoroscopically placed in the stomach and intestine, respectively, to simultaneously determine gastric emptying and intestinal absorption as previously described (Lambert et al., Int. J. Sports Med.17:48, 1996). Gastric emptying was not different among solutions and averaged 13 +/- 0.5 mL.min-1. Net fluid absorption was not different among beverages nor between duodenum and jejunum (x = 10.8 +/- 1.6 and 7.9 +/- 1.1 mL.cm-1.h-1, respectively). Mean osmolality increased significantly (P < 0.05) from the duodenum to the jejunum (242 +/- 6 and 293 +/- 7 mOsm.kg-1, respectively) but did not differ among solutions. These data provide evidence that a hypotonic 6% carbohydrate beverage with 50 mEq.L-1 Na+ did not enhance intestinal fluid absorption or attenuate the decline in plasma volume during exercise more than an isotonic carbohydrate-electrolyte solution or a hypotonic carbohydrate solution without sodium.

Direct genetic testing for Smad4 mutations in patients at risk for juvenile polyposis.

BACKGROUND: The identification of germline mutations in juvenile polyposis (JP) families has made presymptomatic genetic testing possible. In this study we report the results of genetic testing in two large JP families and develop an algorithm for the clinical management of these patients. METHODS: DNA was extracted from 55 members of 2 JP kindreds, and the Smad4 mutations in the germline were determined by direct sequencing. All family members were then tested for mutations with use of single-strand conformational polymorphism analysis and were invited for genetic counseling. RESULTS: All 18 affected members of both kindreds had a 4-bp deletion in exon 9 of the Smad4 gene. In 30 patients at risk for JP, 17 had previously had negative endoscopic screening results and 13 had never been screened. Five patients at risk had inherited germline Smad4 mutations. Two carriers have had hematochezia but have not been screened, whereas 3 were asymptomatic. The mean age of carriers was 29.8 years (range 9.1-49.5 years), whereas that of noncarriers was 41.0 years (range 8.1-76.5 years). CONCLUSIONS: Compliance has been a problem with endoscopic screening for JP. With genetic testing non-carriers may no longer require frequent screening endoscopy, whereas gene carriers can be targeted for close endoscopic surveillance and early intervention to prevent the development of gastrointestinal cancers. Direct genetic testing significantly improves the presymptomatic diagnosis of gene carriers in JP families with Smad4 mutations.

Calcium supplements for the prevention of colorectal adenomas. Calcium Polyp Prevention Study Group.

BACKGROUND AND METHODS: Laboratory, clinical, and epidemiologic evidence suggests that calcium may help prevent colorectal adenomas. We conducted a randomized, double-blind trial of the effect of supplementation with calcium carbonate on the recurrence of colorectal adenomas. We randomly assigned 930 subjects (mean age, 61 years; 72 percent men) with a recent history of colorectal adenomas to receive either calcium carbonate (3 g [1200 mg of elemental calcium] daily) or placebo, with follow-up colonoscopies one and four years after the qualifying examination. The primary end point was the proportion of subjects in whom at least one adenoma was detected after the first follow-up endoscopy but up to (and including) the second follow-up examination. Risk ratios for the recurrence of adenomas were adjusted for age, sex, lifetime number of adenomas before the study, clinical center, and length of the surveillance period. RESULTS: The subjects in the calcium group had a lower risk of recurrent adenomas. Among the 913 subjects who underwent at least one study colonoscopy, the adjusted risk ratio for any recurrence of adenoma with calcium as compared with placebo was 0.85 (95 percent confidence interval, 0.74 to 0.98; P=0.03). The main analysis was based on the 832 subjects (409 in the calcium group and 423 in the placebo group) who completed both follow-up examinations. At least one adenoma was diagnosed between the first and second follow-up endoscopies in 127 subjects in the calcium group (31 percent) and 159 subjects in the placebo group (38 percent); the adjusted risk ratio was 0.81 (95 percent confidence interval, 0.67 to 0.99; P=0.04). The adjusted ratio of the average number of adenomas in the calcium group to that in the placebo group was 0.76 (95 percent confidence interval, 0.60 to 0.96; P=0.02). The effect of calcium was independent of initial dietary fat and calcium intake. CONCLUSIONS: Calcium supplementation is associated with a significant - though moderate - reduction in the risk of recurrent colorectal adenomas.

Calcium supplements and colorectal adenomas. Polyp Prevention Study Group.

Experimental and observational findings suggest that calcium intake may protect against colorectal neoplasia. To investigate this hypothesis, we conducted a randomized, double-blind trial of colorectal adenoma recurrence. Nine hundred thirty patients with a recent history of colorectal adenomas were randomly given calcium carbonate (3 gm daily; 1200 mg elemental calcium) or placebo, with follow-up colonoscopies one and four years after the qualifying examination. The main analysis focused on new adenomas found after the first follow-up endoscopy, up to (and including) the second follow-up examination. Risk ratios of at least one recurrent adenoma and ratios of the average numbers of adenomas were calculated as measures of calcium effect. There was a lower risk of recurrent adenomas in subjects assigned calcium. Eight hundred thirty-two patients had two follow-up examinations and were included in the main analysis; the adjusted risk ratio of one or more adenomas was 0.81 (95% CI 0.67 to 0.99); the adjusted ratio of the average numbers of adenomas was 0.76 (95% CI 0.60 to 0.96). Among subjects who had at least one follow-up colonoscopy, the adjusted risk ratio of one or more recurrent adenomas was 0.85 (95% CI 0.74 to 0.98). The effect of calcium seemed independent of initial dietary fat and calcium intake. No toxicity was associated with supplementation. These findings indicate that calcium supplementation has a modest protective effect against colorectal adenomas, precursors of most colorectal cancers.

The risk of gastrointestinal carcinoma in familial juvenile polyposis.

BACKGROUND: Familial juvenile polyposis (JP) is an autosomal dominant condition in which affected individuals develop upper or lower gastrointestinal (GI) juvenile polyps, or both, and have a predisposition to cancer of the gastrointestinal tract. The risk of GI cancer has not been well defined because of the small number of these families and the lack of follow-up. The objective of this study was to determine the prevalence and age at diagnosis of GI polyposis and cancer in a large JP kindred. METHODS: Medical records were reviewed, patients were interviewed, and histories were taken. Pathology reports and slides were reviewed by our pathologists. A database was created for analysis of clinical and pathologic factors. RESULTS: This kindred contains 117 members, 29 of whom have had upper or lower GI polyps or cancer, or both. All those affected have had colonic juvenile polyps or cancer, except for two who died of advanced gastric cancer and never had colonic evaluation. Nine individuals have had both upper and lower GI polyps or cancer. Sixteen of 29 (55%) affected patients have developed gastrointestinal cancer. Eleven (38%) have had colon cancer, and six (21%) have had upper GI cancers. CONCLUSIONS: The risk of gastrointestinal malignancy in affected members of this JP kindred exceeds 50%. The high risk of GI cancer warrants frequent endoscopic screening of both affected and at-risk family members. Screening will soon be facilitated by presymptomatic genetic testing for the identification of gene carriers.

Effect of beverage osmolality on intestinal fluid absorption during exercise.

To determine how osmolality of an orally ingested fluid-replacement beverage would alter intestinal fluid absorption from the duodenum and/or jejunum during 85 min of cycle exercise (63.3 +/- 0.9% peak O2 uptake) in a cool environment (22 degreesC), seven subjects (5 men, 2 women, peak O2 uptake = 54.5 +/- 3.8 ml . kg-1 . min-1) participated in four experiments separated by 1 wk in which they ingested a water placebo (WP) or one of three 6% carbohydrate (CHO) beverages formulated to give mean osmolalities of 197, 295, or 414 mosmol/kgH2O. CHO solutions also contained 17-18 meq Na+ and 3.2 meq K+. Nasogastric and multilumen tubes were fluoroscopically positioned in the gastric antrum and duodenojejunum, respectively. Subjects ingested a total of 23 ml/kg body mass of the test solution, 20% (370 +/- 9 ml) of this volume 5 min before exercise and 10% (185 +/- 4 ml) every 10 min thereafter. By using the rate of gastric emptying as the rate of intestinal perfusion (G. P. Lambert, R. T. Chang, D. Joensen, X. Shi, R. W. Summers, H. P. Schedl, and C. V. Gisolfi. Int. J. Sports Med. 17: 48-55, 1996), intestinal absorption was determined by segmental perfusion from the duodenum (0-25 cm) and jejunum (25-50 cm). There were no differences (P > 0.05) in gastric emptying (mean 18.1 +/- 1.3 ml/min) or total fluid absorption (802 +/- 109, 650 +/- 52, 674 +/- 62, and 633 +/- 74 ml . 50 cm-1 . h-1 for WP, hypo-, iso-, and hypertonic solutions, respectively) among beverages; but WP was absorbed faster (P < 0.05) from the duodenum than in the jejunum. Of the total volume of fluid ingested, 82 +/- 14, 74 +/- 6, 76 +/- 5, and 68 +/- 7% were absorbed for WP, hypo-, iso-, and hypertonic beverages, respectively. There were no differences in urine production or percent change in plasma volume among solutions. We conclude that total fluid absorption of 6% CHO-electrolyte beverages from the duodenojejunum during exercise, within the osmotic range studied, is not different from WP.

Effect of hypohydration on gastric emptying and intestinal absorption during exercise.

Dehydration and hyperthermia may impair gastric emptying (GE) during exercise; the effect of these alterations on intestinal water flux (WF) is unknown. Thus the purpose of this study was to determine the effect of hypohydration ( approximately 2.7% body weight) on GE and WF of a water placebo (WP) during cycling exercise (85 min, 65% maximal oxygen uptake) in a cool environment (22 degrees C) and to also compare GE and WF of three carbohydrate-electrolyte solutions (CES) while the subjects were hypohydrated. GE and WF were determined simultaneously by a nasogastric tube placed in the gastric antrum and via a multilumen tube that spanned the duodenum and the first 25 cm of jejunum. Hypohydration was attained 12-16 h before experiments by low-intensity exercise in a hot (45 degrees C), humid (relative humidity 50%) environment. Seven healthy subjects (age 26.7 +/- 1.7 yr, maximal oxygen uptake 55.9 +/- 8.2 ml . kg-1 . min-1) ingested either WP or a 6% (330 mosmol), 8% (400 mosmol), or a 9% (590 mosmol) CES the morning following hypohydration. For comparison, subjects ingested WP after a euhydration protocol. Solutions ( approximately 2.0 liters total) were ingested as a large bolus (4.6 ml/kg body wt) 5 min before exercise and as small serial feedings (2.3 ml/kg body wt) every 10 min of exercise. Average GE rates were not different among conditions (P > 0.05). Mean (+/-SE) values for WF were also similar (P > 0.05) for the euhydration (15.3 +/- 1.7 ml . cm-1 . h-1) and hypohydration (18.3 +/- 2.6 ml . cm-1 . h-1) experiments. During exercise after hypohydration, water absorption was greater (P < 0.05) with ingestion of WP (18.3 +/- 2. 6) and the 6% CES (16.5 +/- 3.7), compared with the 8% CES (6.9 +/- 1.5) and the 9% CES (1.8 +/- 1.7). Mean values for final core temperature (38.6 +/- 0.1 degrees C), heart rate (152 +/- 1 beats/min), and change in plasma volume (-5.7 +/- 0.7%) were similar among experimental trials. We conclude that 1) hypohydration to approximately 3% body weight does not impair GE or fluid absorption during moderate exercise when ingesting WP, and 2) hyperosmolality (>400 mosmol) reduced WF in the proximal intestine.

Mutations in the SMAD4/DPC4 gene in juvenile polyposis.

Familial juvenile polyposis is an autosomal dominant disease characterized by a predisposition to hamartomatous polyps and gastrointestinal cancer. Here it is shown that a subset of juvenile polyposis families carry germ line mutations in the gene SMAD4 (also known as DPC4), located on chromosome 18q21.1, that encodes a critical cytoplasmic mediator in the transforming growth factor-beta signaling pathway. The mutant SMAD4 proteins are predicted to be truncated at the carboxyl-terminus and lack sequences required for normal function. These results confirm an important role for SMAD4 in the development of gastrointestinal tumors.

A gene for familial juvenile polyposis maps to chromosome 18q21.1.

Familial juvenile polyposis (FJP) is a hamartomatouspolyposis syndrome in which affected family members develop upper and lower gastrointestinal juvenile polyps and are at increased risk for gastrointestinal cancer. A genetic locus for FJP has not yet been identified by linkage; therefore, the objective of this study was to perform a focused genome screen in a large family segregating FJP. No evidence for linkage was found with markers near MSH2, MLH1, MCC, APC, HMPS, CDKN2A, JP1, PTEN, KRAS2, TP53, or LKB1. Linkage to FJP was established with several markers from chromosome 18q21.1. The maximum LOD score was 5.00, with marker D18S1099 (recombination fraction of .001). Analysis of critical recombinants places the FJP gene in an 11.9-cM interval bounded by D18S1118 and D18S487, a region that also contains the tumor-suppressor genes DCC and DPC4. These data demonstrate localization of a gene for FJP to chromosome 18q21.1 by linkage, and they raise the possibility that either DCC or DPC4 could be responsible for FJP.

Absorption from different intestinal segments during exercise.

This study evaluated intestinal absorption from the first 75 cm of the proximal small intestine during 85 min of cycle exercise [63.6 +/- 0.7% peak O2 consumption (VO2 peak)] while subjects ingested either an isotonic carbohydrate-electrolyte beverage (CHO-E) or a water placebo (WP). The CHO-E beverage contained 117 mM (4%) sucrose, 111 mM (2%) glucose, 18 meq Na+, and 3 meq K+. The two experiments were performed a week apart by seven subjects (6 men and 1 woman; mean VO2 peak = 53.5 +/- 6.5 ml . kg-1 . min-1). Nasogastric and multilumen tubes were fluoroscopically positioned in the gastric antrum and duodenojejunum, respectively. Subjects ingested 23 ml/kg body weight of the test solution, 20% (383 +/- 11 ml) of this volume 5 min before exercise and 10% (191 +/- 5 ml) every 10 min thereafter. By using the rate of gastric emptying (18.1 +/- 1.1 vs. 19.2 +/- 0. 7 ml/min for WP and CHO-E, respectively) as the rate of intestinal perfusion, intestinal absorption was determined by segmental perfusion from the duodenum (0-25 cm) and jejunum (25-50 and 50-75 cm). Water flux was different (P < 0.05) between solutions in the 0- to 25- and 25- to 50-cm segments for WP vs. CHO-E (30.7 +/- 2.7 vs. 15.0 +/- 2.9 and 3.8 +/- 1.1 vs. 11.9 +/- 3.3 ml . cm-1 . h-1, respectively). Furthermore, water flux differed (P < 0.05) for WP in a comparison of the 0- to 25- to the 25- to 50-cm segment. Total solute flux (TSF) was not significantly different among segments for a given solution or between solutions for a given segment. There was no difference between trials for percent change in plasma volume. These results indicate that 1) fluid absorption in the proximal small intestine depends on the segment studied and 2) solution composition can significantly effect water absorption rate in different intestinal segments.

Upper limit for intestinal absorption of a dilute glucose solution in men at rest.

We studied gastric and intestinal function by gastric intubation/intestinal perfusion in six healthy male volunteers to evaluate optimal use of a 6% glucose-electrolyte (GES) solution. Gastric volume, residual volume, emptying rate, and secretion were measured for an initial 763 +/- 19 ml gastric load of GES and at the beginning and end of four additional gastric loads (2.2 ml.kg-1; approximately 180 ml) given at 10-min intervals. The relatively high gastric (713 +/- 58 ml) and residual (507 +/- 26 ml) volumes maintained a high gastric emptying rate (19.5 +/- 1.4 ml.min-1). Composition of the GES emptied into the duodenum was also measured in this first experiment. In a second experiment, this modified solution was infused (triple lumen tube) into the duodenum at a rate equal to gastric emptying rate, or at 38 or 77% greater rates. Absorption of water (11.3-12.9 ml.h-1.cm-1) and glucose 4.3-5.6 mmol.h-1.cm-1) were similar at all perfusion rates during the second experiment. We conclude that duodenojejunal segmental absorption rates of water and glucose produced by a rapid, sustained gastric emptying rate cannot be increased by delivering a greater load of glucose and water by intestinal perfusion.

Unexplained chest pain: the hypersensitive, hyperreactive, and poorly compliant esophagus.

OBJECTIVE: To determine whether neuromuscular dysfunction of the esophagus causes chest pain in patients in whom no disease is found on cardiac work-up, upper gastrointestinal endoscopy, esophageal manometry, and 24-hour pH studies. DESIGN: Prospective study. SETTING: Tertiary referral center. PATIENTS: 24 consecutive patients and 12 healthy controls. MEASUREMENTS: A new technique, impedance planimetry, was used to measure the sensory, motor, and biomechanical properties of the human esophagus. The impendance planimeter, which consists of a probe with four ring electrodes, three pressure sensors, and a balloon, simultaneously measures intraluminal pressure and cross-sectional areas. This allows calculation of the biomechanical variables of the esophageal wall. RESULTS: Stepwise balloon distentions from 5 to 50 cm H2O induced a first sensation at a mean pressure (+/- SD) of 15 +/- 9 cm H2O in patients and 30 +/- 11 cm H2O in controls (P < 0.001). Moderate discomfort and pain were reported by 20 of 24 patients (83%) at 26 +/- 9 cm H2O and at 36 +/- 9 cm H2O, respectively, but by none of the controls (P < 0.001). Typical chest pain was reproduced in 20 of 24 patients (83%). In patients, the reactivity of the esophagus to balloon distention was greater (P = 0.01), the pressure elastic modulus was higher (P = 0.02), and the tension-strain association showed that the esophageal wall was less distensible (P = 0.02). Distention excited tertiary contractions and secondary peristalsis at a lower threshold of pressure (P = 0.05) and with a higher motility index in patients than in controls (P = 0.04). CONCLUSION: In patients with chest pain and normal cardiac and esophageal evaluations, impedance planimetry of the esophagus reproduces pain and is associated with a 50% lower sensory threshold for pain, a 50% lower threshold for reactive contractions, and reduced esophageal compliance.