James C. Reynolds

Barrett's metaplasia and adenocarcinoma of the esophagus in scleroderma

Gastroesophageal reflux is well documented in scleroderma, but the complications of Barretts metaplasia and adenocarcinoma are not well described. The records of 75 patients with scleroderma seen over a four-year period at the Hospital of the University of Pennsylvania were retrospectively reviewed to determine the prevalence of Barretts metaplasia and adenocarcinoma of the esophagus and to identify clinical, manometric, laboratory, or radiographic criteria that might predict the presence of these lesions. Twenty-four of these patients underwent endoscopy. In this group, the prevalence of Barretts metaplasia was 37 percent (nine patients) and adenocarcinoma was also present in two of these patients. The patients with and without Barretts metaplasia were similar in age (range, 22 to 64 compared with 28 to 79, respectively), sex (six of nine compared with 12 of 15 female, respectively), frequency of esophageal motility disorders, presence of proximal skin involvement, digital ulceration, and pulmonary involvement as measured by diffusion capacity. Barretts metaplasia was diagnosed on the basis of double-contrast esophagographic results in only one of eight patients with Barretts metaplasia so-studied. Patients with Barretts metaplasia tended to have longer duration of heartburn (90 +/- 40 months compared with 11 +/- 35 months) and dysphagia (39 +/- 22 months compared with 7 +/- 3 months). Patients with Barretts metaplasia also tended to have greater impairment of lower esophageal sphincter pressure either at end-expiration (4.0 +/- 2.1 compared with 6.1 +/- 1.8 mm Hg) or mid-respiration (13.0 +/- 3.0 compared with 16.9 +/- 2.5 mm Hg). Using chi-square analysis, however, none of these differences reached statistical significance. Discrimination did occur on the basis of the presence of the CREST (calcinosis, Raynauds phenomenon, esophageal manifestations of scleroderma, sclerodactyly, and telangiectasis) variant (55 percent compared with 7 percent, p less than 0.01), a duration of dysphagia of more than five months (p less than 0.03), and mid-respiratory lower esophageal sphincter pressure of less than 10 mm Hg (p less than 0.05). It is suggested that: Barretts metaplasia of the esophagus occurs in one third of patients with scleroderma; clinical, manometric, laboratory, and radiographic features are poor predictors of the presence of Barretts metaplasia; patients with CREST syndrome, prolonged dysphagia, or a very low lower esophageal sphincter pressure may have an increased risk for the development of metaplasia; patients with scleroderma and Barretts metaplasia have an increased risk of complications such as stricture or adenocarcinoma.(ABSTRACT TRUNCATED AT 400 WORDS)

Barrett's esophagus in scleroderma: Increased prevalence and radiographic findings

Ten of 27 patients (37%) with scleroderma who underwent endoscopy at our hospital between 1980 and 1984 for symptoms of reflux esophagitis had biopsy-proven Barretts esophagus. Two of those 10 patients had esophageal adenocarcinomas. In a blinded review of esophagrams (all but 2 using double-contrast technique) from 16 of the 27 patients, only 1 patient was thought to be at high risk for Barretts esophagus due to a high esophageal stricture with an adjacent reticular pattern of the mucosa. The latter patient had biopsy-proven Barretts mucosa. Eight patients were thought to be at moderate risk for Barretts esophagus due to reflux esophagitis and/or distal strictures in 6 and polypoid intraluminal masses in 2. Three of the 6 patients with esophagitis and/or strictures had Barretts esophagus, and both patients with masses had adenocarcinomas arising in Barretts mucosa. Finally, 7 patients who had no esophagitis or strictures were thought to be at low risk for Barretts esophagus. None of those 7 had histologic evidence of Barretts mucosa. Thus, the major value of double-contrast esophagography is its ability to classify patients into high-, moderate-, and low-risk for Barretts esophagus to determine the relative need for endoscopy and biopsy in these patients.

Interactions of bombesin and substance P at the feline lower esophageal sphincter.

The purpose of this study was to determine the interactions between bombesin and substance P at the feline lower esophageal sphincter (LES). Intraluminal pressures were recorded using a fixed, perfused catheter assembly. Myoelectrical activity was recorded using bipolar Ag-AgCl serosal electrodes. Bombesin, i.v., gave a dose-dependent increase in LES pressure and electronically counted spike activity. The threshold dose was 10(-7) g/kg, while the maximal dose, 10(-5) g/kg, increased LES pressure by 65.5 +/- 14.8 mmHg. The neuroantagonist, tetrodotoxin, decreased the LES response to bombesin by 74.1% +/- 7.9% (P less than 0.05), but had no significant effect on the LES response to substance P. The sphincteric response to bombesin was not inhibited by bilateral cervical vagotomy, atropine, propranolol, or phentolamine (P less than 0.10). Bombesin tachyphylaxis abolished the LES response to bombesin but had no effect on the response to substance P. Conversely, substance P tachyphylaxis completely abolished the LES response to bombesin (P less than 0.001). The substance P antagonist [D-Pro2, D-Trp7,9]substance P also significantly inhibited the LES response to bombesin (P less than 0.05). Acidification of the distal esophagus with 2.0 ml of 0.1 N HCl increased LES pressure by 32.5 +/- 5.2 mmHg (P less than 0.02). The LES response to acid was inhibited by bombesin tachyphylaxis (maximal pressure response, 4.7 +/- 2.1 mmHg, P less than 0.01 compared with control acid response). The tachyphylaxis techniques were specific for the peptides giving no effect on the LES responses to phenylephrine, bethanechol, or pentagastrin. We drew the following conclusions: (a) bombesin increased feline LES pressure via nonvagal neural pathways that were insensitive to adrenergic or cholinergic antagonists; (b) bombesin may be involved in the enteric pathways that mediate the feline LES response to distal esophageal acidification; and (c) substance P mediates the effect of bombesin at the LES and is a neurotransmitter in the LES response to acidification.

Properties of the feline pyloric sphincter in vitro.

The purpose of this study was to determine the intrinsic functions of the feline pylorus in vitro. The myoelectric and pressure characteristics of the intact pylorus, antrum, and duodenum, free of extrinsic hormonal or neural influences, were studied in an in vitro bath that allowed separation of the bathing medium surrounding the different bowel segments. Basal recordings revealed a zone of tonic high pressure of 28.4 +/- 3.5 mmHg (mean +/- SEM) at the pylorus. The basal slow wave frequencies in the pylorus and duodenum were 2.8 +/- 1.4 and 12.6 +/- 0.6 cycles/min, respectively. Spontaneous action potential-associated phasic contractions of the pylorus were noted in 38% of preparations. Enteric nerve stimulation with direct electric current (10 Hz, 1 ms, 10-50 V) applied proximal to the pylorus gave relaxation of the pylorus at the lower voltages and rebound excitation at higher voltages. Electrical stimulation distal to the pylorus yielded phasic contractile pyloric response during the entire stimulus. The duodenal instillation of 0.5 N HCl produced action potential-associated phasic contractions of the pylorus and duodenum but not the antrum. Pyloric responses to electrical stimulation or acidification were abolished by tetrodotoxin (10(-5) M). Bethanechol (10(-6) M) or substance P (10(-7) M) produced a contractile response at the site of stimulation but this response was not transmitted to include adjacent bowel segments. These studies suggest that the pyloric sphincter with its intrinsic reflex properties can be studied in vitro.

Effect of celiac ganglionectomy on tachykinin innervation, receptor distribution and intestinal responses in the rat

Substance P (SP) is an important neurotransmitter in the control of intestinal motility and is found in both the enteric and sympathetic nervous systems. This study examined the effect of celiac ganglionectomy on (1) mechanical properties of the circular muscles of the duodenum, ileum and proximal colon, (2) circular muscle responses to SP and neurokinin A. (3) distribution of substance P-like immunoreactive nerves, and (4) the distribution of neurokinin 1 and neurokinin 2 receptors. Celiac ganglionectomy resulted in an effective sympathectomy as evidenced by a marked decrease in norepinephrine content and tyrosine hydroxylase staining in the duodenum, ileum and proximal colon. The in vitro length/tension characteristics of the circular muscle of the duodenum, ileum and colon were unchanged after ganglionectomy. In all regions of the gut studied, substance P and neurokinin A caused dose-dependent contractions that were unaltered by celiac ganglionectomy. Immunohistochemistry revealed moderate substance P-like immunoreactive fibers in the myenteric plexus, submucosal plexus and circular muscle of the ileum, while in the colon, substance P-like immunoreactivity was intense in the myenteric plexus, and moderate in the circular muscle. In vitro autoradiography showed minimal binding of SP (NK1 receptor) or neurokinin A (NK2 receptor) in the ileum and significantly greater binding in the circular muscle layer of the colon. Celiac ganglionectomy did not affect substance P-like immunoreactivity, or NK1 or NK2 receptor binding. A greater contractile response to neurokinins was seen in the colon than in the duodenum or ileum, which paralleled the receptor density. The studies demonstrate that surgical celiac ganglionectomy, unlike chemical sympathectomy, does not affect the substance P innervation, receptor density or physiological responses of the intestine. The greater contractile response of the colon than the ileum parallels the greater receptor density rather than the peptide content as determined by immunhistochemistry.

Innovative endoscopic mapping technique of barrett’s mucosa

Barretts esophagus is the most common premalignant lesion of the upper gastrointestinal tract. This metaplastic change in the normal esophageal epithelium occurs in 10% to 15% of patients with chronic reflux esophagitis and is associated with a 30- to 40-fold increased risk of developing esophageal cancer. Cancers of the esophagus and gastroesophageal junction are increasing in incidence faster than any other cancer in the Western world. Despite the importance of this cancer epidemic and its well-known precursor lesion, most investigators have taken a subjective approach to quantifying the extent of disease, the location of abnormal tissues, and the effect of ablation techniques. Our ability to impact on this epidemic may be dependent on our ability to apply modern technologies to document quantitatively both the extent of disease and the severity of molecular derangement of the intrinsic growth regulatory mechanism of the metaplastic cells. This review will focus on the challenge of addressing the quantitative endoscopic findings in Barretts esophagus.

Colonic slow-wave analysis

The fast Fourier transform (FFT) has been used to determine frequency components of colonic slow-wave activity. We studied the effect of (1) recorder filter characteristics, (2) number of data points and, (3) data window overlap technique and ingestion of a 1000-kcal meal on the resulting power spectrum. Human rectosigmoid slow-wave activity was recorded in nine normal subjects and stored on FM tape for computer analysis. The dynograph filter characteristics were tested using square wave signals, and derived compensation factors were applied to the FFT before viewing. The dynograph filter, when set to optimize visualization of slow waves, attenuates low frequencies nonlinearly. Failure to compensate for the dynograph filter results in inaccurate detection of slow-wave frequencies. FFT of 1-min data gives a different power spectrum than an FFT of 4 min data, indicating a rapidly changing waveform. FFTs of 1 min of data when examined over time fail to demonstrate a consistent frequency spectrum, confirming this conclusion. The lower frequencies in the normal human rectosigmoid are present at the greatest power. These studies indicate that the colon has slow waves of irregular frequencies, in contrast to the stomach or small intestine. No change in the dominant frequency was seen following the ingestion of a 1000-kcal meal.

Mechanisms and Management of Chronic Constipation

The mechanisms of chronic constipation are complex and vary in severity from a dietary deficiency of fiber to a diffuse systemic neuropathy. Most patients with milder degrees of constipation will respond promptly to an increase in dietary fiber.1–3 In fact, epidemiologic studies indicate that many colonic disorders that are endemic to Western nations, including the irritable bowel syndrome (IBS), constipation, and colon cancer, occur rarely in societies that injest higher quantities of dietary fiber.4,5 In contrast, there are increasing reports about the medical and surgical treatment of more intractable forms of constipation.6–12 Figure 1 shows the abdominal x-rays of a patient with severe constipation due to anal sphincter dysfunction. The diagnosis went unrecognized for over a decade, and thus led to years of discomfort that could have been avoided by earlier treatment. Data from several centers suggest that in a subset of patients, constipation may be the presenting symptom of a diffuse disorder of enteric and autonomic nerves.7,10 An increased understanding of the mechanisms of constipation will lead to a more rational approach to the diagnosis and treatment of patients suffering from this condition.