Gastroenterology's editors-in-chief: historical and personal perspectives of their editorships.

Fourteen editors-in-chiefs have steered Gastroenterologyto success since its inception in 1943. Five (Alvarez, Ivy, Aaron, Grossman, and Donaldson) are no longer with us. Their personalities and editorships, along with those of Marvin Sleisenger, are presented by their admirers. Fordtran, Ockner, Goyal, LaRusso, Podolsky, Brenner, Rustgi, and Omary describe their own backgrounds, experiences, and personal reflections on serving as editor-in-chief of Gastroenterology.

Gastroesophageal reflux disease: presentation and assessment of a common, challenging disorder.

Although gastroesophageal reflux disease (GERD) is frequently referred to as a continuous spectrum, it is more useful to consider GERD as 2 discrete entities with several subsets that differ in pathophysiology, clinical presentation, natural history, and therapy. One entity is classic severe acid reflux with erosive esophagitis and its complications. Barrett's esophagus is an important subset of this group, with markedly increased acid exposure and an increased risk of adenocarcinoma. The second entity is nonerosive reflux disease (NERD) with minimal or no esophagitis. Patients with NERD do not develop local mucosa complications, like stricture or Barrett's esophagus, but their symptom severity can equal that of erosive esophagitis. Acid is involved in the symptoms of many but not all NERD patients. This acid dependence is evident either as an increase in esophageal acid reflux or a hypersensitivity to acid, and both generally respond well to proton pump inhibitor (PPI) therapy. NERD patients who are not acid-dependent have what is called functional heartburn; GERD-like symptoms are present, but there is no obvious involvement of refluxed acid. An important subset of GERD is refractory GERD, which consists of patients who fail aggressive PPI therapy. Parallel findings with other refractory syndromes can be anticipated; however, there are indications that psychosocial factors play a major role in refractory GERD, and these patients may benefit more from an integrated biopsychosocial approach. Diagnosis of GERD is usually made on clinical grounds, often supplemented by a therapeutic trial with antisecretory agents. Endoscopy is reserved for patients with alarm symptoms, such as dysphagia, anemia, or weight loss, or to detect Barrett's esophagus. Endoscopy is not useful to exclude the diagnosis of GERD because it will be negative in 70% of cases in primary care. Ambulatory 24-hour esophageal pH monitoring is necessary only when the diagnosis is in doubt, the patient fails medical management, or surgery is contemplated.

Apical EGF receptors regulate epithelial barrier to gastric acid: endogenous TGF-alpha is an essential facilitator.

In previous studies, we found that apical and basolateral EGF receptors (EGFR) on primary canine gastric monolayers decreased paracellular permeability, evident by increased transepithelial electrical resistance (TER) and decreased flux of [(3)H]mannitol (MF). After studying monolayers in Ussing chambers, we now report that treatment with apical, but not basolateral, EGF enhanced tolerance to apical H(+), evident by a slower decay in TER and an attenuated rise in MF. Enhanced tolerance to apical acid was evident within 10 min of treatment with apical EGF. Immunoneutralization of endogenous transforming growth factor (TGF)-alpha accelerated the drop in TER and the rise in MF in response to apical acidification; apical EGF reversed these effects. Study of monolayers cultured in Transwell inserts showed that immunoblockade of basolateral, but not apical, EGFR also impaired the resistance to apical acidification and enhanced MF. We conclude that apical EGFR regulates the barrier to apical acidification via effects on paracellular resistance. Although exogenous basolateral EGF has a less apparent effect on the barrier to acid, endogenous ligand active at basolateral EGFR plays an important role in maintaining the barrier to apical acid. Our data implicate a role for an apical EGFR ligand, which may be EGF or another member of the EGF family.

Secretin regulates paracellular permeability in canine gastric monolayers by a Src kinase-dependent pathway.

Previous studies found that epidermal growth factor (EGF) decreased paracellular permeability in gastric mucosa, but the other physiological regulators and the molecular mechanisms mediating these responses remain undefined. We investigated the role of secretin and Src in regulating paracellular permeability because secretin regulates gastric chief cell function and Src mediates events involving the cytoskeletal-membrane interface, respectively. Confluent monolayers were formed from canine gastric epithelial cells in short-term culture on Transwell filter inserts. Resistance was monitored in the presence of secretin with or without specific kinase inhibitors. Tyrosine phosphorylation of Src at Tyr(416) was measured with a site-specific phosphotyrosine antibody. Basolateral, but not apical, secretin at concentrations from 1 to 100 nM dose dependently increased resistance; this response was rapid and sustained over hours. PP2 (10 microM), a selective Src tyrosine kinase inhibitor, but not the inactive isomer PP3, abolished the increase in resistance by secretin but only modestly attenuated apical EGF effects. AG-1478 (100 nM), a specific EGF receptor tyrosine kinase inhibitor, attenuated the resistance increase to EGF but not secretin. Secretin, but not EGF, induced tyrosine phosphorylation of Src at Tyr(416) in a dose-dependent fashion, with the maximal response observed at 1 min. PP2, but not PP3, dramatically inhibited this tyrosine phosphorylation. Secretin increases paracellular resistance in gastric mucosa through a Src-mediated pathway, while the effect of EGF is Src independent. Src appears to mediate the physiological effects of this G(s)-coupled receptor in primary epithelial cells.