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Biomedical subjects

I M Modlin

Publications and source records attributed to I M Modlin.

At least 91 records · Page 5Linked to original sources
PubMed1995

To repair the fault or end the acid reign?

BACKGROUND: Despite the vast effort and expense devoted to the elucidation of the cause of esophagogastro-duodenal ulcer disease, relatively minimal progress has been made towards the understanding of causation. Since earliest times, it has been recognized that milk, chalk powder, or charcoal ameliorate the disease process and its symptoms. In addition, the avoidance of acidic or spicy foods provides some relief. Thus ulcer disease has been ascribed to acid or the consequences of hyperacidity. Reams of data and countless meetings have purported to confirm and support this viewpoint. Surprisingly, the co-secretion in the stomach of the powerful proteolytic enzyme pepsin has been virtually ignored as a pathogenetic agent. Marshalling distant antipodean resources, a novel bacteria, H. pylori, was identified as a significant causative agent in ulcer disease. To the amazement of nobody but gastroenterologists, it became apparent that there might be more than one cause for ulcer disease. Subsequently, both corporations and physicians seized the reins of multi-variant antibiotic therapy as a panacea for the third millennium treatment of peptic ulcer disease. Only a brave few have raised the issues of possible abnormalities in intrinsic mucosal function which might generate a locus minoris resistentiae. Defective mucosal repair mechanisms have barely been evaluated, since the regulation of normal mucosal healing is so poorly understood. Nevertheless, consideration of the therapeutic potential of mucosal protection has found support at both an intellectual and a clinical level. The more exciting recent possibility of the local delivery of growth factors which might promote healing has provided a unique opportunity for further therapeutic advance. CONCLUSIONS: Indeed in the future the exogenous regulation of mucosal repair may provide a milieu conductive to the resolution of an old but ill-understood problem. It is certainly apparent that processes beyond parietal cell proton secretion are critical and require both delineation and management. The acid reign may be in decline but the site of the fault and its repair remain to be defined.

Esophagitis, Peptic↗
PubMed1995

Critical reappraisal of mucosal repair mechanisms.

The repair of the mucosal surface of the stomach is a complex process involving a number of different cell systems. These include mucosal enterocytes, matrix proteins, and cells responsible for angiogenesis. The regulation of each of these systems is as yet poorly defined and the interaction between the different components remains to be characterized. The signal system involved in recognition of damage initiates a cascade of events which broadly comprise cell migration, cell proliferation, lineage determination, matrix reconfiguration, and angiogenesis. Critical regulators of this process include the trefoil peptides, specific adhesion molecules, and the modulators of cell lineage. The utility of specific pharmacotherapeutic probes, whether responsible for surface protection, growth factor delivery, acid inhibition, or growth factor amplification, remains to be rigorously defined. The repair of the mucosal defect is critical in establishing the functional integrity of the gastric luminal surface. In order to facilitate rapid and long-lasting repair of mucosal injury, a precise understanding of the specific biological events participant in the repair process is required. At this time, there is only a paucity of such information available.

Extracellular Matrix↗
PubMed1995

Gastric carcinoid tumors: the biology and therapy of an enigmatic and controversial lesion.

Gastric carcinoid tumors were previously believed to be rare lesions, representing less than 2% of all carcinoid tumors and less than 1% of all stomach neoplasms. More recent studies have demonstrated that they may constitute as much as 10-30% of carcinoid tumors. Patients with conditions associated with hypergastrinemia, such as chronic atrophic gastritis, Zollinger-Ellison syndrome with multiple endocrine neoplasia type 1 (ZES-MEN-1), and pernicious anemia, display a markedly elevated incidence of gastric carcinoid tumor formation. A classification system distinguishing three types of gastric carcinoid tumor has been proposed: 1) tumors associated with chronic atrophic gastritis, 2) tumors associated with Zollinger-Ellison syndrome, and 3) sporadic lesions. Tumors that develop in association with hypergastrinemia are usually composed of enterochromaffin-like (ECL) cells, in contrast to sporadic lesions that contain a variety of endocrine cell types (enterochromaffin, ECL, X). In both intact animal models such as the rat and Praomys (mastomys) natalensis and in isolated purified ECL cell preparations, gastrin has been demonstrated to exert a powerful trophic effect on ECL cells, in addition to stimulating histamine secretion. It is apparent that hypergastrinemia-associated gastric carcinoids display relatively benign biological behavior. Sporadic lesions require aggressive surgical management on diagnosis. Type I and type II (hypergastrinemia-associated) lesions can be managed initially by endoscopic excision of accessible tumors, followed by endoscopic surveillance. If tumors recur, antrectomy and local excision may be used to remove the source gastrin, resulting in cure in the vast majority of patients.

Animals↗
PubMed1994

Unusual permeability properties of gastric gland cells.

Physiologists have long pondered the riddle of why the stomach is itself not digested by the very juice it secretes. One explanation is that a mucus-bicarbonate barrier, coating the stomach lumen as well as superficial portions of gastric glands, prevents autodigestion. However, this leaves unanswered the question of what protects cells deeper in the glands, which seem to lack a mucus barrier. These are the parietal and chief cells, which secrete acid and pepsin. Using perfused single gastric glands from rabbit, we recently found that intracellular pH is uniquely resistant to extreme degrees of luminal acidification, suggesting that the apical (luminal) barrier might also exclude ammonia and carbon dioxide, to which cell membranes are generally highly permeable. We now show that this is indeed the case. There are three reports of membranes with very low permeabilities to NH3 (refs 5-7), and none of membranes impermeable to CO2.

Ammonia↗
PubMed1994

Oddi: the paradox of the man and the sphincter.

Ruggero Oddi was born of a modest family in the small town of Perugia, Italy, in 1866. While still a young medical student, he identified the sphincter and in addition characterized its physiological properties. At the early age of 29 years, he was appointed as the director of the Physiological Institute at Genoa, but a dalliance with drugs and fiscal improprieties resulted in his being relieved of this eminent position in Italian Physiology. He subsequently sought employment as a physician in the Belgian colonial medical service and briefly spent time in the Congo. The deterioration of his physical status and his use of Vitaline, a homeopathic preparation, led to the demise of his medical career. For reasons that are unclear, he then traveled to Africa where he died in Tunisia. In the last 50 years, the use of sophisticated methodology has allowed delineation of aspects of the neural and hormonal regulatory mechanisms of the sphincter. Its exact role in disease has not been determined, although its relationship to the putative entity of biliary dyskinesia has been suggested. The paradox of both the sphincter and its original discoverer remain to be resolved.

History, 19th Century↗
PubMed1994

Effect of tyrosine kinase inhibition on basal and epidermal growth factor-stimulated human Caco-2 enterocyte sheet migration and proliferation.

Mucosal healing requires enterocyte migration (restitution) supplemented by proliferation. Proliferation and migration may be studied independently by thymidine uptake and proliferation-blocked cell migration using human Caco-2 enterocyte monolayers in culture. Since epidermal growth factor (EGF) promotes mucosal healing and the EGF receptor is a tyrosine kinase, we hypothesized that tyrosine kinases might therefore modulate enterocyte migration and proliferation. The tyrosine kinase inhibitors genistein and 2,5-dihydroxymethylcinnamate, which block kinase ATP-binding and substrate-binding sites, respectively, were studied alone and with EGF. Proliferation was blocked with mitomycin. Although each inhibitor decreased basal and EGF-stimulated monolayer expansion when cell proliferation occurred, neither genistein nor 2,5-dihydroxymethylcinnamate decreased migration when proliferation was blocked. However, each inhibitor prevented EGF stimulation of proliferation-blocked migration and thymidine uptake. More substantial inhibition of basal proliferation by genistein correlated with increased protein-linked DNA breaks, which may reflect nonspecific inhibition of DNA topoisomerase activity by genistein. The more specific 2,5-dihydroxymethylcinnamate blocked changes in the alpha 2 integrin subunit organization which may modulate EGF-stimulated migration. Antiproliferative effects of tyrosine kinase inhibitors decrease basal monolayer expansion but true basal enterocyte migration appears independent of tyrosine kinase regulation. However, a specific tyrosine kinase-dependent modulation of cell-matrix interaction inhibits EGF-stimulated migration.

Cell Division↗
PubMed1994

Effect of buprenorphine on pancreatic enzyme synthesis and secretion in normal rats and rats with acute edematous pancreatitis.

Pancreatic enzyme secretion is inhibited during acute pancreatitis, resulting in an increase in acinar zymogen content. Since the premature activation of zymogens has been assigned a central role in the pathogenesis of acute pancreatitis, minimizing the amount of stored zymogens might lead to less severe acute pancreatitis. Inhibition of enzyme synthesis or stimulation of enzyme secretion would result in reduction of zymogen stores. Opiates have a varying effect on pancreatic secretion, depending on the dosage, site of administration, and presence of pancreatic stimulants. The effect of opiates and acute pancreatitis on individual pancreatic enzyme synthesis is unknown. The following study was undertaken in order to examine the effects of an opiate on pancreatic enzyme secretion and synthesis during experimental acute pancreatitis. Four groups of rats were studied. Group I received cerulein (25 micrograms/kg); group II received an opiate, buprenorphine (BPN, 0.5 mg/kg); and group III received cerulein and BPN. Drugs were dissolved in gelatin/saline and injected subcutaneously. A control group (group IV) received only gelatin/saline. Rats were sacrificed 4 hr after injection, and pancreatic mass was measured. Pancreatic acini were prepared and assayed for amylase and DNA content. Amylase, trypsinogen, chymotrypsinogen and lipase synthesis, and amylase secretion were measured for 2 hr. Results showed that, compared to controls, acini of rats with AP had increased amylase content, a finding consistent with decreased in vivo amylase secretion. Total protein and individual enzyme synthesis rates were significantly lower in the acini of the rats with AP than in those of the controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1994

Histamine as an intermediate growth factor in genesis of gastric ECLomas associated with hypergastrinemia in mastomys.

Profound and sustained inhibition of gastric acid secretion has been associated with development of carcinoid tumors of the fundic enterochromaffin-like (ECL) cells in rodents. While ECL cell hyperplasia has been recognized in humans, the development of carcinoid tumors is rare and often confined to patients under treatment for gastrinoma related to the multiple endocrine neoplasia type I (MEN1) syndrome. The Mastomys was utilized as a model for the rapid induction of ECLomas by insurmountable acid secretory blockade induced by the pharmacologically irreversible H2-receptor antagonist, loxtidine. Loxtidine-induced ECL cell hyperplasia and neoplasia were compared in the absence of presence of cyproheptadine (0.5 mg/kg), an H1-receptor antagonist. Loxtidine administration resulted in a significant increase in ECL cell hyperplasia and neoplasia as well as an increase in ECL cell number, mucosal thickness, plasma gastrin levels, and stomach weight. Cyproheptadine ameliorated loxtidine-induced ECL cell hyperplasia and neoplasia and significantly decreased loxtidine-stimulated increases in ECL cell number. Nevertheless, cyproheptadine failed to alter the loxtidine-induced increase in plasma gastrin, stomach weight or mucosal height. The results indicate that cyproheptadine, an H1-receptor antagonist, inhibits loxtidine-induced ECL cell hyperplasia independent of any effects on serum gastrin.

Animals↗
PubMed1994

Acid suppression and gastric mucosal cell biology.

This review examines recent concepts of gastric mucosal cell biology in relation to acid inhibition. Powerful acid-inhibitory drugs have been associated with the production of enterochromaffin-like (ECL) cell proliferation and the induction of ECL-cell carcinoids in rats. The ECL-cell lineage and its renewal is discussed, and the factors that regulate ECL-cell proliferation are reviewed. Current methods in use for assessing genotoxicity in gastric mucosa are scrutinized; the much discussed claim that antisecretory drugs induce unscheduled DNA synthesis is examined, and the methodology that is the basis for these claims is found defective and wanting. The nature of ECL-cell proliferation in rats receiving lifelong treatment with H2-receptor antagonists or acid pump inhibitors is explored, and their relationship to ECL-cell proliferation and ECL-cell carcinoids discussed. It is concluded that aged rats are very prone to developing endocrine proliferations, and this may be related to the multiple endocrine neoplasia syndrome found in humans. There is no evidence at present that long-term antisecretory therapy causes significant ECL-cell proliferation in humans.

Animals↗
PubMed1994

Lester R. Dragstedt and his role in the evolution of therapeutic vagotomy in the United States.

The date October 22, 1993, marks the centenary of the birth of Lester R. Dragstedt. He emerged from humble roots of Swedish immigrant parents to become one of the pre-eminent surgical innovators of the twentieth century. Early in his scientific career, Dragstedt was profoundly influenced by another Swede, A. J. Carlson, who was initially employed as a Lutheran minister in Dragstedt's hometown of Anaconda, Montana. Carlson left the ministry for graduate school and later became chairman of The Department of Physiology at the University of Chicago. When Dragstedt finished his schooling, Carlson convinced him to attend the University of Chicago. In addition to Carlson, Dragstedt's research was influenced by many prominent physiologists and surgeons, including Pavlov and Latarjet. Their work, along with his own investigations, helped him both to formulate his hypotheses on the regulation of gastric acid secretion and to formalize the operation of truncal vagotomy. In 1943, Dragstedt initiated the clinical use of this procedure in North America. Although he studied his patients carefully and documented his results meticulously, the operation initially met with considerable resistance from both his medical and surgical colleagues. Over time, many other surgeons accepted vagotomy as a viable procedure and further modified his technique. The unique ability of Dragstedt to transfer his research studies to the development and implementation of rational surgical therapy remains an enduring example for the surgical profession.

History, 19th Century↗
PubMed1994

Laparoscopic local excision of a proximal rectal carcinoid.

Early carcinoids of the distal rectum have been treated effectively by transanal local excision. Unfortunately, small carcinoids of the proximal rectum may be unreachable by transanal approaches, and as a result patients have been subjected to more extensive, transabdominal colorectal resections. The recent introduction of minimally invasive techniques for treatment of colorectal diseases has opened new approaches for the treatment of proximal rectal carcinoids. We describe a patient with a 0.5 cm rectal carcinoid located just above the peritoneal reflection in whom transanal local excision was not feasible. We report the first laparoscopic, full-thickness excision of a proximal rectal carcinoid. Intraoperative colonoscopy was used to localize the lesion. This combined laparoscopic and colonoscopic approach spared the patient from the potential morbidity of a low anterior resection and anastomosis.

Aged↗
PubMed1994

Duodenal gastrinoma: the solution to the pancreatic paradox.

There has been a recent focus of attention on the duodenum as a major source of gastrinomas. The question has often arisen as to why the pancreas should give rise to gastrinomas because, in the adult, it contains no gastrin-producing (G) cells. However, the numerous G cells of the duodenum may proliferate and function as a "carcinoid" lesion, producing a relatively indolent tumor, much like a papillary carcinoma of the thyroid. On the contrary, islet cells of the pancreas, which do not produce gastrin, may behave much like a neuroendocrine carcinoma and may be defined as a "pancreatic gastrinoma" because they produce an ectopic hormone (gastrin). These lesions are capable of behaving much more aggressively, as do many other ectopic hormone-producing neoplasms. The recognition of the difference between these two types of gastrinoma is of considerable clinical and biological significance.

Diagnostic Imaging↗
PubMed1994

Laparoscopic cholecystectomy: from gimmick to gold standard.

Laparoscopic cholecystectomy was first performed in 1987, and within 2 years had become widespread. Its rapid growth was due in part to a perceived reduction in postoperative morbidity and shorter convalescence than with open cholecystectomy. Although these perceptions were shared both by surgeons and the lay public, no controlled study has documented them conclusively, but now, because of its popularity, it is unlikely that such a study will ever be undertaken. Nevertheless, a wealth of information has been accumulated on open cholecystectomy, and a large body of data is being generated regarding laparoscopic cholecystectomy. We examine selected reports of both laparoscopic and open cholecystectomy in terms of incidence and outcome. Our review supports the notion that laparoscopic cholecystectomy is safe and effective, has an acceptable complication rate, and a considerably shorter convalescence. Thus, laparoscopic cholecystectomy is now the treatment of choice for symptomatic cholelithiasis, and is becoming the new gold standard against which other procedures should be judged.

Cholecystectomy, Laparoscopic↗
PubMed1994

Luminal perfusion of isolated gastric glands.

We have extended to rabbit gastric glands the technique for perfusing single isolated renal tubules. We isolated glands by hand dissection and used concentric glass pipettes to hold them and perfuse their lumina. Parietal cells (PCs), which tended to be located toward the gland opening, were identified by their pyramidal shape, large size, and autofluorescence. Chief cells (CCs) were identified by their round shape and smaller size. In some experiments, we perfused the lumen with hydroxypyrenetrisulfonate, a pH-sensitive fluorophore, at pH 7.4 and used digital image processing to monitor luminal pH (pH1). Solutions were buffered with N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid to pH 7.4 at 37 degrees C. With fast perfusion, we found no evidence of decreased pH1, even with stimulation by 10 microM carbachol. With slow perfusion, pH1 often fell below the dye's sensitive range (pH < 5), especially at low perfusate buffering power. In other experiments, we loaded cells with the pH-sensitive dye 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein and monitored intracellular pH (pHi) in multiple individual PCs and CCs in a single gland. Mean pHi was 7.21 +/- 0.02 (n = 136 cells) for PCs and 7.27 +/- 0.03 (n = 103) for CCs. To examine the response to decreased pH1 and basolateral pH (pHb), we lowered pHb to 6.4 or lowered pH1 to 3.4 or 1.4. Lowering pHb to 6.4 for approximately 1 min caused pHi to fall reversibly by 0.39 +/- 0.05 (n = 53) in PCs and 0.58 +/- 0.03 (n = 50) in CCs. Lowering pH1 to 3.4 or 1.4 caused no significant pHi changes in PCs (n = 38 and 82) or in CCs (n = 44 and 77). Carbachol did not affect the response to changes in pH1 or pHb. We conclude that the apical surfaces of PCs and CCs are unusually resistant to extreme pH gradients.

Ammonia↗
PubMed1994

Enrichment of rab11, a small GTP-binding protein, in gastric parietal cells.

Parietal cell secretion of acid requires the coordinated fusion of H(+)-K(+)-adenosinetriphosphatase (ATPase)-containing tubulovesicles with a secretory canalicular target membrane. We have previously reported the presence of rab2 on parietal cell tubulovesicles (L. H. Tang, S. A. Stoch, I. M. Modlin, and J. R. Goldenring. Biochem. J. 285: 715-719, 1992). Since 60% of the small GTP-binding protein sequences obtained from parietal cells were > 95% homologous with human rab11 (J. R. Goldenring, K. R. Shen, H. D. Vaughan, and I.M. Modlin. J. Biol. Chem. 268: 18419-18422, 1993), we sought to study rab11 in gastric parietal cells. A complete rab11 sequence was obtained, and the deduced amino acid sequence of rabbit rab11 was identical to that for human. Rab11 mRNA was present throughout the gastrointestinal mucosa. mRNA for both rab11 and rab2 were enriched in isolated parietal cells compared with chief cells. A polyclonal antiserum against rab11 labeled a single 25-kDa band in isolated parietal cells. Immunostaining of rat fundic tissue demonstrated prominent staining of parietal cells. Rab11 staining cosegregated with alpha-H(+)-K(+)-ATPase staining in enriched preparations of rabbit parietal cell tubulovesicles. These results suggest that rab11 is enriched in parietal cells and is associated with intracellular tubulovesicles.

Amino Acid Sequence↗
PubMed1994

The mastomys gastric carcinoid: aspects of enterochromaffin-like cell function.

The mastomys rodent exhibits a genetic propensity to develop gastric carcinoid tumors. Utilizing acid inhibitory pharmacotherapy (histamine-2 receptor antagonists and proton pump inhibitors), we have demonstrated transformation from normal to neoplastic enterochromaffin-like (ECL) cells in a well-defined fashion over a period of 4 months. In addition, we have demonstrated inhibition of tumor growth with either somatostatin or histamine-1 receptor antagonists (terfenadine and cyproheptadine). In order to define the regulation of growth and secretion of transformed ECL cells, we developed an isolated pure ECL cell system. ECL cells secrete histamine in response to gastrinergic (gastrin), muscarinic (carbachol), and beta-adrenergic (isoproterenol) stimulation. Both cAMP and intracellular calcium-dependent mechanisms are involved in the process of histamine secretion.

Animals↗