Peptic Ulcer

Peptic Ulcer

GASTROENTEROLOGY Vol. 49, No. I Printed in U.S.A. Copyright © 1964 by The Williams & Wilkins Co. PROGRESS IN GASTROENTEROLOGY PEPTIC ULCER Review ...

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GASTROENTEROLOGY

Vol. 49, No. I Printed in U.S.A.

Copyright © 1964 by The Williams & Wilkins Co.

PROGRESS IN GASTROENTEROLOGY

PEPTIC ULCER Review of the literature for 1964 JosEPH B. KIRSNER, M.D., PH.D.

Department of Medicine, University of Chicago, Chicago, Illinois

The vast literature on peptic ulcer available for review each year attests to the continuing challenge and interest of this subject. The physiological and biochemical studies of gastric secretion, including the isolation and initial clinical application of gastrin represent perhaps the most significant feature of this review. These ingenious observations, together with anatomic (ultrastructural) studies of the gastric epithelium, promise eventually to unravel the mystery of the secretion of hydrochloric acid; although they do not yet provide the key to the control of gastric acid secretion, applicable to the management of peptic ulcer. There has been less progress in elucidating the nature of the tissue vulnerability that must play a role in the development of peptic ulcer; although occasional biochemical studies provide a glimpse of future advances in this area. There have been no striking therapeutic developments during the past year. Many studies now clearly reveal the limitations and the potential hazards of gastric freezing. The nutritional and metabolic consequences of gastric resection, often apparent only years later, have received renewed attention. Vagotomy and hemigastrectomy, although apparently effective, seem not to have achieved the now widespread popularity of vagotomy and either pyloroplasty or gastroenterostomy. Although the causes and the cure of peptic

ulcer remain elusive, the increasing fundamental knowledge of the stomach and the duodenum sustains hope for the eventual resolution of this fascinating problem. Gastric Secretion Frog gastric secretion . The continuing interest in gastric secretion relates not only to the expectation that its elucidation may help solve the problem of peptic ulcer and possibly other gastroduodenal diseases, but also to the clarification of one of the fascinating biological phenomena of the living organism . In recent years, the frog has achieved scientific status as a productive source of information on the biochemical and bioelectrical events involved in the elaboration of hydrochloric acid. Measurements of the respiration directly associated with acid secretion by the isolated bullfrog gastric mucosa, utilizing histamine to increase and sodium thiocyanate to decrease acid secretion and oxygen consumption, appeared to invalidate a simple redox pump hypothesis of hydrogen ion transport by the gastric mucosa. 1 Of interest was the decrease in acid secretion preceding the fall in respiration. The current necessary to establish the electrical potential difference between the two surfaces of the gastric mucosa of the frog in vitro is equivalent to the net chloride moved in excess of that secreted as hydrochloric acid. 2 This electrical activity is greatly depressed after removal of the external oxygen. Electron microscope studies of the structure of the parietal cells demonstrated, during sup-

Address requests for reprints to: Dr. J. B. Kirsner, Univ. of Chicago, Dept. of Medicine, Chicago, Ill. 60637. 79

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pression of the external oxygen supply, increased volume, and low electron density of the cytoplasm, producing a swollen appearance of the microvillus, extending from the apical cell border and into the glandular lumen. The gastric mucosa of the frog can transport Cl-, H+, and K+ from the submucosal to the mucosal side of the gastric epithelium against electrochemical potential gradients. 3 Chloride flux from the nutrient to secretory surface of frog gastric mucosa was observed to be maximal with isotonic sodium chloride as the secretory solution; and was depressed in varying degree by the replacement of sodium chloride with other sodium salts or nonelectrolytes. The rate of acid secretion has been described as a reaction velocity, depending on chloride concentration, in a manner closely resembling Michaelis-Menten kinetics. 4 • 5 The Rana pipiens stomach does not actively transport so4- and is able to secrete H+ without concomitant transport of anion.6 In Rana esculenta, "spontaneous" secretion of gastric juice is negligible, compared with mechanically induced secretion.7 The response is not influenced by section of the stomachal branch of the splanchnic nerve or by double vagotomy, although pepsin secretion is reduced approximately 40 % by vagotomy. Histamine. Refeeding fasted rats or the injection of an extract of gastrin mobilized histamine and concurrently elevated the histamine forming capacity (HFC) in the gastric mucosa containing parietal cells ;8 such changes were not observed in the pyloric region. Similar alterations were observed also in cats, mice, and frogs. Mucosal histamine-forming capacity did not increase when acid secretion was stimulated by the injection of histamine. When the mucosal histamine content had been lowered to approximately 5 % of normal by inhibiting the formation of histamine, the injection of gastrin elevated mucosal HFC and produced an acid secretory response of normal magnitude. A correlation between HFC and the density of parietal cells was found in most instances. The concept linking mucosal histamine to the process of stimulation of the parietal cell is reinforced by the demon-

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stration that circumstances known to inhibit natural activation of acid secretion, such as oil and high acidity in the stomach, also suppress the changes in mucosal histamine. However, the crucial test of mucosal histamine as a final link in the stimulation of the parietal cells awaits the development of a method to inhibit completely the release and synthesis of mucosal histamine. Histamine stimulation increases dehydrogenase activity in the parietal cells in dogs, rats, and frogs, and also produces vesicular changes in the parietal cell, studied with electron microscopy . Simultaneous measurements of the radioactivity of the blood, gastric (fundic) duodenal, and rectal mucosa and gastric juice, in dogs with Heidenhain pouches, given C 14-histamine intravenously indicated lower levels of radioactivity in the serum than in the mucosa. 9 The acid output initially paralleled the level of radioactivity in the gastric mucosa; but when gastric secretion had ceased, the level of radioactivity in the gastric mucosa and serum remained moderately high. The level of radioactivity in the gastric juice was curiously low. After the C 14 -histamine-induced secretion had ceased for 1 hr, stimulation with the same dose of unlabeled histamine increased the radioactivity of the juice above previous levels; suggesting a "washout" phenomenon. Studies such as these, on the role of histamine in gastric secretion, will be facilitated by identification of the metabolic products of histamine in serum, gastric mucosa, and gastric juice. Gastric blood flow. Inhibition of gastric secretion in dogs with Heidenhain pouches after the injection of epinephrine and norepinephrine, has been ascribed to decreased gastric mucosal blood flow; and this view appeared substantiated by studies measuring gastric blood flow directly in the large gastric artery or indirectly in the epiploic arteries, in adult dogs, following the intravenous injection of catecholamines and the feeding of a cooked meat meal. 10 Mucosal flow was reduced more by epinephrine than by norepinephrine. Low frequency stimulation of the anterior hypothalamus resulted in a parasympathetic

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vascular and secretory pattern characterized by increased gastric secretion and blood flow and associated with decreased systemic pressure.U This effect on gastric and mesenteric blood flow was abolished by vagotomy and increased by direct stimulation of the distal end of the vagal nerve. High frequency stimulation of the anterior hypothalamus was associated with depressed gastric secretion ; perhaps from the spread of current to activate the posterior hypothalamus and the sympathetic centers. Direct stimulation of the posterior hypothalamus greatly decreased gastric mesenteric blood flow; this pattern was reproduced by direct stimulation of the celiac ganglion and was abolished by ganglionectomy. Total gastric blood flow as estimated by the K 42 clearance t echnique, agreed within 5 % of the measured total venous outflow.l2 By comparison with the radioactive microsphere method, the K 42 clearance t echnique also was reasonably accurate for determining the distribution of total blood flow within the organ. Mean total gastric blood flow in intact dogs, unoperated upon except for femoral arterial and venous catheterization, was 49 ml per min per organ, or 0.54 ml per min per g; this flow was distributed 80 % to the corpus and 20 % to the antrum. The corpus flow was partitioned among the mural tissues, as follows: mucosa, 72 %; submucosa, 13 %; and muscle and serosa, 15 %. Vagal influen ces. In dogs with gastric pouches constructed by transforming a Pavlov pouch into a Heidenhain pouch with a resultant vagotomy, the submaximal secretory response to exogenous gastrin was markedly reduced ; whereas the sub maximal secretory response to histamine was unaffected in t hree or four animals and lowered in one ;13 suggesting that continuous subthreshold vagal impulses on the acid-secreting glands maintain the sensitivity of these glands to gastrin. Vagotomy significantly reduced the secretory responses of monanesthetized cats to histamine and to gastrin; and reserpine did not produce the usual increase in basal secretion; or the secretory responses to histamine and gastrin; indicating the need for an intact vagal mechanism

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in mediating the gastric hypersecretory effects of reserpine.14 Reserpine increased the sensitivity of the parietal cells to histamine and gastrin only in the vagally innervated stomach, presumably by central enhancement of vagal tone. In six H eidenhain pouch dogs with "selective vagotomy" (severing the branches of the left anterior vagal trunk to the stomach and only the gastric branches of the right post erior vagal trunk), total gastrectomy (aside from the pouch), and esophagoduodenostomy, the output of acid from the pouch increased after total abdominal vagal denervation.15 The possible explanations include augmentation of the intestinal phase of gastric secretion as a consequence of intestinal stasis following vagotomy. Acidification and cocainization of isolated innervated pyloric pouches inhibited the intestinal phase of gastric secretion in innervated and denervated fundic pouches; 16 probably as a result of decreased liberation of endogenous gastrin, rather than from release of an inhibitory hormone. Pronounced increases in Heidenhain pouch secretion were observed in four dogs immediately after removal of much of the small intestine. 17 A similar trend was noted in two dogs after bypass of the small bowel; with prompt return to control levels of gastric secretion following restoration of normal intestinal continuity. Only one of four dogs with antrectomy manifested a similar rise in pouch secretion after massive intestinal resection. The gastric hypersecretion may be attributed to a loss of inhibitory influences, rather than an augmentation of stimulating mechanisms. Effects of secretin on gastric secretion . Rapid intravenous inj ections of secretin and of cholecystokinin (Vitrum) inhibited the acid response of H eidenhain pouch dogs to the continuous intravenous administration of a gastrin extract. 18 Cholecystokinin caused greater inhibition than secretin and responses to small doses of histamine were inhibited by cholecystokinin but not by secretin. Histamine appeared more resistant to these inhibitory influences than gastrin. The possibility thus arises that the humoral substance released by duodenal

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acidification is contained in preparations of secretin and cholecystokinin. In similar experiments, secretin intravenously decreased the gastric acid response to meat but not to histamine; the inhibitory effect was not affected by ligation of the pancreatic duct. 19 A secretin extract given intravenously inhibited acid secretion by the main stomach stimulated by histamine or by gastrin. 20 The secretory response of the Heidenhain pouch to stimulation with either gastrin or histamine was less when the gastric fistula was closed than when it was open, indicating, presumably, inhibition of acid secretion from the Heidenhain pouch, when acid secreted by the main stomach entered the duodenum rather than being drained to the exterior. The mechanism whereby vagal innervation promoted the inhibitory action of secretin is not known, but inhibition dependent upon vagal innervation is not necessarily due to direct vagal reflex activity. A highly purified preparation of secretin (Jorpes) produced the same degree of inhibition of gastric secretion as a commercial secretin extract (Vitrum); suggesting that secretin itself, rather than some other constituent of the extract, was responsible for the inhibition of gastric secretion. To determine whether other active substances were present in commercial preparations of secretin, two secretin preparations, different in weight per unit of pancreatic secretogogic activity (Vitrum and Boots), were tested for their relative abilities to stimulate pancreatic secretion in dogs with Thomas cannulae, and to inhibit gastric secretion of Heidenhain pouches stimulated by exogenous gastrin.21 The results supported the concept that the same factor, either secretin or a closely related substance, effective in the absence of the pancreas, accounted for both of these effects. In other experiments, the inhibitory effect of intravenously administered secretin upon gastric secretion in dogs appeared ascribable to drug toxicity. 22 In 10 adult patients free of gastrointestinal disease, except for one person with a healed antral ulcer, two different preparations of secretin intravenously significantly inhibited gastric acid output for at least 30 min ;23 these observations thus

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suggest that secretin may have a physiological role in the inhibition of gastric secretion, possibly via its release after the entrance of acid gastric content into the duodenum. Pancreatic influences. The pancreas has been shown capable of influencing secretion of hydrochloric acid, both clinically and experimentally. Clinically, the ZollingerEllison type of pancreatic islet cell tumor is associated with gastric hypersecretion and intractable peptic ulceration. Experimentally, total ligation of the pancreatic duct, total pancreatic fistula, and pancreatitis increase acid secretion from an isolated denervated gastric pouch. To obtain further information on the relative influences of endocrine and exocrine portions of the pancreas in these secretory relationships, mongrel dogs were given DL-methionine, the ethyl analogue of methionine, in doses of 10 to 50 mg per kg per day.24 This drug causes pancreatic exocrine damage (acinar portion) and decreases enzymatic output, without producing histological changes in the pancreatic islets; it also induces hepatic damage; but does not alter the gastric parietal cells. In eight of nine dogs with Heidenhain pouches, acid secretion was unchanged or decreased, in spite of substantial pancreatic and hepatic injury. These results tend to support the concept of release of a gastric secretogogue from the nonexocrine portion of the pancreas as the cause of the increased gastric secretion following pancreatitis and total ligation of the pancreatic duct. Glucagon, a polypeptide produced by the a-cells of pancreatic islets of Langerhans and capable of provoking hyperglycemia, also inhibits the secretory response of gastric pouches in dogs to meat, sham feeding, distension of the antrum, exogenous gastrin, insulin, and to cholinergic drugs, but not to histamine. Insulin-free glucagon, given in small doses into the portal venous system via the spleen, inhibited the secretion by vagally innervated and vagally denervated pouches of dogs in response to meat and to exogenous gastrin as effectively as when given intravenously.25 There was no correlation between the degree of inhibition of

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gastric secretion and the increments in blood glucose after the injection of glucagon. Antrum and gastrin. Simultaneous studies of the secretion of acid and pepsin from a vagally innervated and a vagally denervated portion of the dog's stomach in response to gastrin, histamine, and Urecholine indicated that in the vagally innervated part of the stomach, the maximal rate of secretion of acid was the same with histamine and with gastrin stimulation.26 Hovvever, in the vagally denervated portion, the maximal rate of secretion was significantly lower in response to gastrin than to histamine, suggesting that vagotomy reduces the response to gastrin more than that to histamine. Studies from the same laboratory had established the existence of true potentiation between U recholine and gastrin and between Urecholine and histamine in the stimulation of acid and pepsin secretion in dogs with Heidenhain pouches. 27 The degree of augmentation of maximal response by urecholine was greater for gastrin than for histamine. Since these observations in dogs do not necessarily apply to man, the differential inhibitory effect of vagotomy in man upon the response to gastrin and to histamine will require studies with purified preparations of gastrin. The secretory response of pouches to injected gastrin, after diversion of the secretion of the main stomach to the exterior, supports the hypothesis that the augmentation is caused by prevention of entry of acid from the main stomach into the duodenum. A similar effect has been observed following resection of the main stomach.28 Food was employed to elicit the vagalantral-gastrin secretory response in three dogs with Heidenhain pouches; direct antral stimulation by food was avoided by creating a double-mucosal diaphragm isolating the antrum from the gastric contents, without interfering with its vagal innervation. In acute and chronic experiments, changes in antral pH markedly influenced pouch secretions, presumably by modifying gastrin output subsequent to vagal stimulation of the antrum. 29 In similar studies by other investigators, the nervous phase of gastric

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acid secretion was studied in sham-fed Pavlov pouch dogs with an isolated, innervated antrum. 30 The sham feeding response was not inhibited by antral acidification to pH > 2.5. A slight but highly significant inhibition occurred at antral pH 2.0 and a substantial inhibition was apparent at antral pH 1 to 1.5. The results suggest that, on vagal stimulation, gastrin is released from the antrum at antral pH > 2, in amounts sufficient to augment significantly the nervous secretory response. Inhibition of the sham-feeding response by antral acidification was eliminated by a very low dose of intravenously administered gastrin, in accord with the hypothesis that depression of vagal release of gastrin is the main inhibitory mechanism elicited by antral acidification during the nervous phase of gastric acid secretion. An opposing point of view is emphasized in experiments in female mongrel dogs equipped with a denervated fundic (Heidenhain) pouch and an isolated denervated antral pouch. 31 The slow intravenous administration of a dilute solution of an extract of gastrin over a 3-hr period resulted in sustained gastric secretion. However, the rapid single intravenous injection of 2 ml of the gastrin extract (representing 20 g wet weight of hog antral mucosa), in 10 tests on four dogs, induced approximately 67 % inhibition of the histamine-stimulated gastric secretion, confirming previous observations by Gillespie and Grossman, and by Gregory on the inhibitory influence of large doses of gastrin. Acid perfusion of the isolated antrum in Heidenhain pouch dogs uniformly inhibited acid secretion stimulated by the exogenous administration of hog gastrin. Simultaneous and intermittent antral acidification also suppressed gastrinstimulated gastric secretion. These observations are interpreted as evidence for the action of an antral inhibitory hormone, since they cannot be ascribed to suppression of endogenous release of gastrin. Irrigation of isolated antral pouches with a suspension of liver in dogs with Heidenhain pouches induced vigorous secretion of gastric juice, continuing undiminished for 24 hr, 32 without apparent fatigue in the

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tides (gastrins I and II) ; both many times more potent than histamine in stimulating gastric acid secretion, when given in low concentration, but inhibiting acid secretion when given in high concentrations. Gregory and Tracy, 35 - 37 utilizing a new improved and less costly method of preparation, have now described two almost identical peptides, each in an apparently pure state. The final product obtained from 600 hog antrums contained 17 mg of gastrin I and 22 mg of gastrin II. Both gastrins were found to have the same amino acid constitution: aspartic acid (1), glutamic acid (6), glycine (2), alanine (1), methionine (2), tyrosine (1), tryptophane (2), proline (1), and phenyl alanine (1) . The minimal molecular weight for each gastrin is approximately 2114; but ultracentrifugal analysis gave values for both g-I and g-Il of approxi- . mately 1335. The conclusion that both gastrins are pure is based upon the findings that: (1) the quantitative amino acid composition of each is consistent with that of a single molecule; (2) the quantitative amino acid composition of each remains unchanged after successive high voltage electrophoresis in alkaline and acid buffer systems; (3) ultracentrifugal analysis shows no evidence of nonhomogeneity in either; and (4) neither has an NH2-terminal group demonstrable with fluorodinitrobenzene. The possible physiological differences between gastrin I and gastrin II and their precise role in gastric secretion remain to be determined; but clarification of these and other problems, such as development of an accurate technique for the measurement of gastrin in the blood and gastric content, should now be facilitated greatly by this significant research accomplishment. Both gastrins are many times more potent than histamine in stimulating gastric acid secretion in conscious pouch dogs, when injected ~ubcutaneously in appropriate doses. Both gastrins stimulate pepsin secretion, volume of pancreatic secretion and enzymatic output, and gastrointestinal Gastrin motility. Both gastrins have little effect on After many years devoted to physiological gall bladder tone or hepatic blood flow. A studies of gastrin, the final product has steady acid secretion evoked by the subbeen identified as two nearly identical pep- cutaneous injection of gastrin I or II or

gastrin mechanism. Presumably, in the pathogenesis of peptic ulcer, some defect in the normal acid "cutoff" mechanism allows gastrin to be liberated continuously, until the gastric content becomes sufficiently acid to break down the mucosa and produce a gastric ulcer. Insulin hypoglycemia in dogs with vagally denervated pouches inhibited gastric secretion resulting from endogenous gastrin released by mechanical and chemical stimulation of the pyloric gland area, and also lowered the gastric secretion resulting from inj ection of exogenous gastrin. 33 Prevention of hypoglycemia by the infusion of glucose eliminated insulin inhibition of gastric secretion. Sudden reduction of elevated blood glucose to normoglycemic levels inhibited gastric secretion, even though hypoglycemia apparently inhibits the stimulating effect of gastrin on the parietal cells in both innervated and denervated fundic pouches. In nine Pavlov pouch dogs, with antrum and duodenum previously excluded from gastrointestinal continuity, the antrum was resected; additional resections of the duodenal bulb and distal 3 to 4 em of corpus were performed in five of the dogs. 34 Following these resections, the acid response to sham feeding was reduced greatly, but was increased by subthreshold quantities of gastrin, suggesting that physiological vagal excitation of the acid secreting glands by sham feeding requires the presence of gastrin. These interesting observations derived from ingenious experimentation increasingly demonstrate the complex interrelationships involved in the mechanism of gastric secretion and the fascinating role of gastrin. Among the problem;; awaiting clarification is the mechanism of release of gastrin from the antrum, including the question of specific chemoreceptors and mechanical receptors and the possibility of other humoral influences, yet to be identified, from the stomach and perhaps from the duodenum.

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histamine is inhibited by the rapid intravenous injection of a small amount (5 to 50 ~.~-g) of gastrin I or gastrin II. The effects of increasing doses of gastrin II administered intravenously in continuous and single infusions were studied in a healthy male volunteer. 38 Doses between 5 and 50 ~.~-g inj ected over a period of 5 min were not accompanied by symptoms beyond that of vague epigastric fullness. On one occasion, when a dose of 20 J..tg was injected rapidly intravenously on a background of continuous maximal infusion, the subject collapsed for a period of 10 min, without loss of consciousness. The peak acid outputs, as well as the plateau acid outputs and secretory rates following continuous infusion plotted against the corresponding log-dose, were fitted to a logistic function. A relationship between the peak acid output and log-dose following single intravenous injections also was demonstrated. The latency after intravenous administration of gastrin II appeared to be very brief. There was a preliminary indication that the maximal acid response to gastrin II resembled the maximal acid response to histamine. In six patients with duodenal ulcer, the acid outputs to gastrin II, 0.5 ~.~-g per kg and histamine, 40 ~.~-g per kg, were sinular. 39 Doses of 2 ~.~-g per kg gastrin II appeared to be the "maximal" subcutaneous dose; with a "peak hour" output exceeding 4:~ meq. The intravenous or intramuscular inj ection of gastrin in appropriate doses evoked acid outputs essentially similar to the subcutaneous dose. In 16 patients (ulcer, 11; normal, 4; and pernicious anemia, 1), the response to this dose of gastrin exceeded the acid output to 40 ~.~-g per kg of histamine acid phosphate. No side effects were observed with gastrin II. Gastrin-stimulated secretion may last for as long as 3Yz hr; the rapid establishment of a maximal secretory rate after its injection presumably reflects an equally rapid distribution of gastrin in the body. Studies of an extract made from a primary pancreatic tumor indicated responses virtually identical with those described for pure gastrin .40 A method of biological assay of gastrin using the anesthetized rat is described,

estimating the mean rates of acid secretion in response to graded intravenous doses of gastrin extracts. 41 The effects of t est preparations were compared with those of an arbitrary standard, according to the balanced incomplete block design of Youden. 42 Utilizing this method, gastrinlike activity was present in the highest concentration in the antral mucosa and decreased at various levels along the gut. 43 No activity could be detected in normal pancreatic tissue. Gastrinlike activity was smaller in uncomplicated duodenal ulcer compared with stenosing duodenal ulcer. Gastrinlike activity in benign gastric ulcer and gastric carcinoma resembled or exceeded that in the average uncomplicated duodenal ulcer. There was no definite correlation between total gastrinlike activity and either basal or augmented histamine acid secretion. The use of a porcine gastrin, whose preparation had been described previously, when adn1inistered in doses of 1.5 to 2.5 mg per kg subcutaneously to Heidenhain and Gregory pouch dogs, produced an excellent acid secretory response, inhibited only partially by atropine.44 • 45 This preparation now has been tested in five men and one woman given Benadryl (50 mg) or chlortrimetron (4 to 8 mg); with injections of 180 to 500 mg of gastrin per kg body weight subcutaneously, and collections of gastric secretion for 2 to 3 hr. Acid secretion was stimulated by 350 mg per kg of gastrin or more. The peak response occurred in 30 to 60 min and disappeared within another hour. There was no change in pepsin output. Since malaise and mild febrile reactions occurred uniformly, further experiments await the availability of a more purified compound. The same investigators also have described the isolation and assay of ovine gastrin 46 from the sheep abomasal antrum and of bovine gastrin .47 Other observations. The normal gastric mucosa of man, dogs, cats, and rats provides a nearly complete barrier to the passage of sodium ions. 48 To det ermine the consequences of disrupting this barrier, t est solutions containing acid or glycine and labeled water and sodium were placed in separated Heidenhain pouches of healthy dogs before

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and after irrigation of the pouches with a solution of eugenol. The barrier to the transmucosal movement of Na and H ions offered by the resting and secreting intact gastric mucosa was confirmed. Eugenol disrupted the barrier, so that after irrigation of the pouches, H ions quickly disappeared from the contents and N a entered. Mter application of eugenol, juice collected from the pouches during stimulation by histamine was rich in Na and poor in H ions. Maintenance of the transmucosal potential differences was dependent upon preservation of the barrier to Na, whereas the ability of the membrane to secrete acid was not. Study of the secretory activity of 80 canine stomachs isolated from mongrel dogs indicated that approximately 35 % of the perfused organs secrete small amounts of acid and pepsin for periods ranging from 1 to 6.5 hr; pepsin may be produced in the absence of acid secretion.49 Improvements in the perfusion solution, flow rate, anticoagulation, maintenance of electrolyte, pH, and glucose levels probably will increase the success rate of this preparation. Anatomic observations. Peroral suction biopsies and surgical specimens of human gastric mucosa, examined by light and electron microscopy, demonstrated that the mucous cell contains characteristic dense, stippled granules in the region above the nucleus. 50 The density and stippling increases progressively in cells nearer the neck region. The base of mucou" cells located in the upper foveola and on the surface contains diffuse fibrillar material and only sparse particle-coated endoplasmic reticulum. Numerous cells of the neck region have numerous short, irregularly arranged cisternae of the particle-coated endoplasmic reticulum, but few fibrils. Between the mucous cells of the surface and upper foveola are basally located spaces, bridged by slender cytoplasmic processes. The upper half of the zymogenic cell is filled with pepsinogen granules, consisting of pale homogeneous material within membrane envelopes. The base of the zymogenic cell is filled with long, closely stacked cisternae of the particle-coated endoplasmic reticulum. The fine structure of the parietal cell is char-

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acterized by numerous oval mitochondria and a myriad of fine tubules. Some of the tubules appear to communicate with the lumen of the intracellular canaliculi via openings between the microvilli; profiles of typical Golgi apparatus also were seen. Noteworthy in this comprehensive and careful study is the characteristic appearance of the granules in different types of cells within the human gastric fundic glands, and the distinctive fine structure of each cell type. Pepsins and pepsinogens. Fractionation of human gastric mucosal extracts on diethylaminoethyl (DEAE)-cellulose yields pepsinogens I, II, and III. 51 Acidification of these components to pH 2 for 8 min, followed by incubation at varied pH levels (1.1 to 7.3) for 45 min and subsequent alkalinization by dialysis versus buffer at pH 7.8, leads to the formation of compounds intermediate in behavior between pepsinogen and pepsins, designated as human pepsin-pepsin inhibitor (HPPI) complexes. These observations have practical implications in quantitative studies of the conversion of pepsinogen to pepsin . Similar chemical methods have demonstrated the presence of three pepsin fractions with the same chromatographic mobility as the three pepsin fractions described in acidified whole gastric mucosal extracts, also in acid gastric juice from healthy individuals and from patients with peptic ucler and gastritis. Gastric juice from one patient with pernicious anemia was found to contain only pepsinogen I. A satisfactory chromatographic separation of pepsins is possible from as little as 4 ml of gastric juice. 52 Gastric secretion: clinical observations. The augmented histamine or histalog test currently is preferred to submaximal stimulatory tests of gastric secretory activity. 53 Furthermore, in evaluating normal or excessive gastric secretion, the artificial concept of "free" and "total" acid should be replaced with the determination of one value for gastric acid output, by titration to pH 7, with phenol red or by glass electrode. In a study of 20 male and 20 female subjects without digestive symptoms, 20 male and 20 female patients with gastric ulcer, and 40 male and 20 female subjects with duodenal ulcer, the peak acid output of the

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augmented histamine test could not be correlated with body weight, surface area or linearity.54 The intramuscular injection of 1.7 mg of histalog per kg body weight provided the maximal gastric responses (peak, 30 min; the peak 60-min responses were higher than those obtained with 0.9 mg and not statistically different from the results with 2.6 mg per kg body weight). 55 In 45 patients the gastric secretory response to a continuous intravenous infusion of histamine acid phosphate (0.04 mg per kg per hr) was significantly higher than the response to the augmented histamine test. 56 . Among 47 patients with active thyrotoxicosis the augmented histamine test revealed only one with achlorhydria. 57 In a~o~her study of 32 patients with hyperthyrOidism, the augmented histamine test demonstrated achlorhydria in 5 patients; and the mean levels of basal and posthistamine acid secretion were considerably lower than normal; 58 posthistamine pepsin secretion also was creased. This series differs from the precedmg in the larger proportion of older age patients. A reduction in acid secretion without structural changes in the gastric mucosa also was noted in rats given L-thyroxine. In five of nine patients with primary hyperparathyroidism, the basal secretion .of acid was elevated, but the augmented histamine secretion was normal. The basal secretion was lowered by parathyroidectomy.59 In dogs with Heidenhain pouches, single and daily injections of parathormone and daily injection of vitamin D tended to stimulate the basal secretion of acid, but inconstantly and transiently; observatio~s that have been noted also in man by this reviewer. Intravenous injections of the calcium lactate reduced the volume of basal secretion; and lowering of the serum calcium by the chelating agent, edathimil, reduced the output of acid in response to histamine. The relationships between parathormone, serum calcium, and gastric secretion obviously are complex and appear to depend upon the species studied, the presence or absence of vagal innervation of the stomach, and the rapidity with which the serum calcium is altered, among other factors.

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Histamine and reserpine did not induce ulcers in nine dogs with pyloric pouches free of acid, as they do in dogs with acid-secreting pouches; reaffirming the indispensable role of hydrochloric acid in the development of experimental peptic ulcer. 60 Inclusion of the duodenum in an isolated, circular intestinal loop, and transplantation of the orifices of the biliary and pancreatic ducts to the jejunum adjacent to the gastroenterostomy, regularly resulted in fatal gastrojejunal ulceration in dogs, an observation indirectly suggesting a duodenal mechanism for inhibition of gastric secretion. 61 Ulceration did not appear to result from a failure of duodenal inhibition of gastric secretion, since ulceration does not regularly follow duodenectomy_ Studies in dogs prepared with duodenoileal and coloileal implants in the antrum and then given inj ections of histamine in beeswax, again indicated that the duodenum was most resistant to experimental ulceration, followed by ileum and colon; reaffirming the concept of a gradient of susceptibility to histamine-induced peptic ulceration. 62 The 6 hr "on" and 6 hr "off" schedule of conditioned avoidance in the rhesus monkey does not necessarily result in gastrointestinal ulceration, as repon:ed previously. 63 Six rhesus monkeys, tramed to conditioned avoidance, failed to develop gastrointestinal ulceration over periods of 64 to 128 days of performance on such a schedule in a behavioral laboratory in which the environmental conditions were kept reasonably constant. 64 Peptic ulceration occurred in control animals who had not been trained to conditioned avoidance, implying as yet unidentified factors in the environment. Fatal intussusception developed in five monkeys. 65 Observations on experimental modification of gastric vascular dynamics are interpreted as implicating decreased gastric mucosal blood flow as one of the factors responsible for the development of "stress" ulcers of gastric lesions accompanying disease of the central nervous system. 66

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Since active peptic ulcer is uncommon during pregnancy and pregnancy is thought to influence beneficially the course of peptic ulcer, studies were undertaken on the nature of the protective mechanism. 67 In nonpregnant rats, injection of the histamine liberator, polymixin B, produced hemorrhagic erosions and necrosis of the glandular mucosa of the stomach. In the later stages of pregnancy, injection of polymixin B rarely caused gastric lesions; despite maintenance of the response of the maternal acid-secreting cells to stimulation by histamine. Protection of the mother is associated with the presence of the fetus; since surgical removal of the fetus restores the susceptibility to induction of gastric lesions. The protective agent is blood borne, as shown in experimental parabiosis, and is present in sufficient concentrations to protect the nonpregnant partner against gastric lesions. These interesting observations, if confirmed, may renew interest in the intriguing possibility of hormonal influences in the mechanisms of protection against experimental and human peptic ulcer. · Gastric Ulcer Experimental. Chronic gastric ulcers developed in three of seven dogs with gastric stasis produced by wrapping cellophane tape around the pylorus. 68 Histamine in beeswax induced gastric ulcers in four of seven animals with experimental pyloric stenosis; usually in the upper part of the stomach, adjacent to the esophagus. Confirming the work of Van Y zeren 69 and others, chronic gastric ulcers were found in 3 of 10 rabbits examined 90 days after complete division of the vagus nerves to the stomach.70 Partially healed gastric ulcers were found in two other rabbits; no gastric lesions were found in rabbits treated by vagotomy and gastroenterostomy or pyloroplasty. Division of the vagal nerves to the main stomach in the rabbit increased Heidenhain pouch secretion. These data are interpreted as supporting the concept that chronic gastric ulcers sometimes occur because of a hypersecretion of gastric juice caused by gastrin, produced in a stomach with decreased motility or with atony.

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Similarly, gastric ulcers may develop in patients with stenosing duodenal ulcer. 71 The "secondary" gastric ulcers heal rapidly after vagotomy and a drainage operation. These and other observations, including the rarity of gastrojejunal ulcer after antrum resection for gastric ulcer, and the beneficial effect of the Kelling-Madlener operation on the healing of gastric ulcer, are in accord with the view that prolonged elaboration of gastrin is the cause of these lesions. 72 The evidence accumulated by Dragstedt and his colleagues is impressive. However, the possibility exists that the gastrin pathogenesis of gastric ulcer is an oversimplification of a complex problem. Gastric ulcers develop in the absence of "hypersecretion" of acid gastric juice, as ordinarily defined. Gastric ulcers are not invariably associated with gastric stasis and distension of the antrum, or with decreased gastric motility. Some observers have emphasized the frequency of gastric ulceration in an area of the lesser curvature, lacking the usual rich submucosal plexus of blood vessels, and, therefore, vulnerable to ischemia. Clinical. In a series of 4201 cases of gastric ulcer, collected from London, other areas in England and northern Ireland, gastric ulcers were classified into two principal types: one associated with hypersecretion and pronounced blood group 0 predominance; and the other with hyposecretion, without group 0 preponderance, but strong evidence for an excess of group A. 73 Hypersecretion ulcers were divided further: ulcers occurring in the body of the stomach, secondary to duodenal ulcer; and prepyloric, resembling more closely duodenal ulcer than ulcers elsewhere in the stomach. Hypersecretion ulcers constituted about half of all surgically treated gastric ulcers. A study of 4185 individuals over the age of 50, including 29:) patients with chronic benign gastric ulcer, 1704 controls and 188 patients with gastric cancer, indicated a higher incidence and more pronounced calcification of the abdominal aorta among those with gastric ulcer (65 %) than in the control group (23.4 %) and among those with cancer (1.9 %). 74 On the basis of these data, the assumption is made that calcified

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plaques in the central blood supply of the stomach may lead to arterial insufficiency or obstruction, increasing the vulnerability of the gastric mucosa to ulceration. In addition to possible imperfections in the design of this study (for example, dependence solely upon lateral X-rays of the abdomen, raising question as to the precise location of the calcification in the abdominal aorta or one of its branches; and the absence of organic disease in the control subjects), extrapolation of gross roentgenographic evidence of vascular calcification to possible limitations in the ultimate blood supply to the gastric mucosa seems unwarranted. The analogy with renal or cerebral arteries is not necessarily appropriate; for in contrast to these locations, the gastric vessels are not end arteries. As has been demonstrated repeatedly, occlusion of a major vessel to the stomach, such as the left gastric artery, fails to impair gastric circulation. The complexity of this problem is emphasized in the following study. The histological features of blood vessels around 42 chronic peptic ulcers, in comparison with vessels at some distance from the ulcer, differed in degree rather than in type. 75 Mild arterial changes in the vicinity of the ulcer were similar histologically to those in control material. More advanced lesions were consistent with the more severe degree of diffuse hyperplastic sclerosis, usually associated with hypertension. Lipid deposition in the arteries and arterioles of chronic peptic ulcer also resembled atherosclerosis, diffuse hyperplastic sclerosis, and arteriolosclerosis, and was noted also in the control material. The vascular changes were not those of arteritis and all the layers of the vascular wall were involved, not merely the intima. Neighboring vessels often were affected unequally, with daughter branches having little or no thickening, in the presence of greater thickening in the parent vessel; nor was eccentric thickening always on the side nearest the ulcer crater. Among 515 patients with gastric ulcer, only 36 (7 %) were found eventually to represent malignant lesions; thus confirming the accuracy of diagnosis, utilizing X-ray,

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gastroscopy, and cytology. 76 Of 236 patients treated medically, complete and continued healing was noted in 57 %. The medical mortality was 3.4 %, as compared to a surgical mortality of 5 %. Duodenal Ulcer General observations. The serum pepsino-

gen levels were determined for 100 healthy young subjects (aged 18 to 35 years) in each of eight phenotypic classes (male and female, blood groups 0 and A, salivary ABH secretor, and nonsecretor status) in a total of 800 subjects.77 Analysis of variance revealed significantly higher serum pepsinogen levels in males than in females and in group 0 than in group A subjects; the blood group effect was more evident in males than in females. The mean serum pepsinogen level was not significantly higher in salivary ABH nonsecretors than in salivary ABH secretors. A study of the usefulness of various radiological techniques, in a series of 107 patients, indicated that fluoroscopy alone would fail to indicate one-third of demonstrable craters by experienced examiners; and more than 50 % of the ulcers would be missed by less experienced fluoroscopists. 78 Approximately 60 % of the ulcer craters were not demonstrated on the ordinary roentgenograms of the stomach and duodenum, made in the erect, prone oblique, and supine oblique positions. Erect spot roentgenograms demonstrated only 42 % of demonstrable craters. Multiple prone roentgenograms of the cap without compression revealed only 30 % of ulcer craters. The supine, oblique, air contrast spot exposure demonstrated 75 % of all craters. The prone oblique roentgenograms of the duodenum with compression were adequate for demonstrating 63 % of the ulcer craters; about 12 % were seen only in this position. More than 98 % of the craters were demonstrated by exposure in these two positions. Significant differences were found between gastric ulcer (34 patients) and duodenal ulcer patients (68) for taste sensitivity to 6-n propylthiouracil-a bitter tasting, antithyroid, phenylthiourea-type compound .79 The duodenal ulcer patients were more

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sensitive tasters than those with gastric ulcer or nonpatient volunteers. Patients with both gastric and duodenal ulcers resembled the duodenal ulcer group, although the number of cases was small . No significant differences were observed regarding taste sensitivity to l-quinine and to hydrochloric acid. Since taste threshold for PROP and other phenylthiourea-type compounds is based primarily on genetic factors, this difference in taste sensation presumably may involve a genetic influence. Peptic Ulcer in Children

A total of 184 patients under 15 years of age with peptic ulcer were identi_fied in the pediatric medical departments m Sweden during the years 1953 and 1962.80 In. 168 patients, the diagnosis had bee~ venfied by the radiographic demonstratiOn of a crater. The disease appeared to be more common in city than in country districts; but was approximately equally distributed in different parts of Sweden. The disease was commoner among boys (66 %) than girls (34 %). Duodenal ulcer accounted for 85 % of cases, gastric ulcer for 14 % and combined gastric and duodenal ulcers, 1 %. Peptic ulcer was noted in the family in 47 % of cases. A questionnaire survey among 29 pediatric roentgenologists in the United States indicated a total of 419 peptic ulcers among children; an average case proportion per hospital of 1.9 per year. 81 This survey suggested that, contrary to other r~ports, peptic ulcer was uncommon among ch1ldre~. Among 50 children with documented pept1c ulcer, peptic ulceration was associate~ with steroid therapy or a serious underlying Illness in 7 of 10 infants and in 9 of 40 older children.s2 In children with duodenal ulcer, visible craters are similar to those found in adults. 83 The diagnosis of peptic ulcer with perforation in children with brain disease is difficult in that vomiting, a common symptom in intracranial disease, also is an early symptom of ulcer in children. 84 Only 39 of 143 infants with neonatal gastric perforation survived; the most frequent site of perforation was the greater curvature of the stomach.85 Interesting case reports

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document the successful surgical treatment of ulcer perforations in infants. 86 · 87 Peptic Ulcer and Obstructive Pulmonary Disease

A prospective study of ambulatory patients with proven chronic obstructive bronchopulmonary disease demonstrated a higher than usual incidence of chronic duodenal ulcer.8s The high prevalence (22 % of 94 men) was independent of the presence or absence of other associated pulmonary lung disease or the administration of steroids. Studies in 48 patients, including 9 normal controls, 14 with severe emphysema, 5 with emphysema and peptic ulcer, 6 with hypoxia without obstructive pulmonary disease, and 14 patients with peptic ulc~r and normal lungs, 89 indicated that gastnc acidity is enhanced by the hypercapnia and hypoxia characterizing emphysema. In another study, hypercapnia induced by inspiring 7.5 % of C02 in air for 40 min was associated with a significant decrease in the rate of acid secretion. 9° Changes in the accompanying 0 2 tension, over a range of 67 to 138 mm Hg, did not appear to influence histamine-stimulated secretion, nor modify secretory responses associated with high, normal, or low C02 tension . The findings thus indicate that the effects of hypercapnia on gastric acid secretion depend upon the nature of the secretory studies. Comparisons of pituitary cell counts indicated a significant association among pituitary hyaline basophil increased (Crooke's) cells, pulmonary emphysema, and either peptic ulcer, lung carcinoma, or both .91 The findings were not correlated with the type of lung carcinoma or the presence of adrenocortical hyperplasia. Peptic Ulcer and Liver Disease

The over-all incidence of peptic ulcer in 290 patients with portal cirrhosis was 11.3 %.92 The incidence was the same in male and female patients, whether or not the patient had an alcoholic history and whether or not they had a portacaval anastomosis. No abnormality of gastric secretion was observed in patients with hepatic cirrhosis, except aft.flr a portacaval

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anastomosis, when the basal secretion increased; but the response to maximal histamine stimulation was not elevated. In a study of 23 older men and three women with hepatic cirrhosis, basal and maximal histamine acid outputs were reduced ;93 and the secretory response to stimulation with peptone was subnormal. Gastric hyposecretion was not related to the etiology or severity of the hepatic disease nor to the extent or presence of a portal-collateral circulation. Increased gastric production of ammonia in cirrhosis did not influence acid output significantly. Since a significant relationship was demonstrated between hypokalemia and hyposecretion, and since the volume of gastric juice appeared more greatly reduced than acid concentration, the possibility arose of a relationship between gastric hyposecretion and disorders of fluid and electrolyte metabolism. In female dogs with portacaval transposition, hydrochloric acid was present more often in the basal secretion and the output of acid in response to ingestion of meat and to the injection of histamine was higher than in female dogs also with separated (corpus) pouches, but without portacaval transposition. 94 Urinary excretion of free histamine during fasting and after a meat meal did not differ significantly from normal limits, indicating that increased quantities of circulating histamine are not implicat ed in the elevat ed secretion of acid .

periulcer mucus was secreted by actively proliferating mucous cells and was interpreted as a local protective mechanism. Iron (Prussian blue) was trapped by antral and periulcer mucus, but not by corpus mucus, suggesting structural differences of mucus, depending upon its source. In healthy dogs, short chain fatty acids (acetic, proprionic, or butyric) and acetylsalicylic acid damage the mucosa under circumstances facilitating penetration of the compound into the mucosa. 96 Under the condition of these experiments, fat solubility was the determining factor in the penetrating ability of the compounds. Once in or through the mucosal barrier, the toxic compounds damage it, possibly by interfering with the underlying metabolic processes that maintain the barrier. For acetic, propionic, and butyric acids, the rapid transport of hydrogen ions into the cells may overwhelm the local buffers. Acetylsalicylic acid may be a protein precipitator or enzymatic inhibitor. The administration of aspirin and soluble aspirin to cats with completely innervated total gastric pouches produced erosion and bleeding from the stomach.97 Similar gastric changes were observed when aspirin was administered directly into the duodenum, thereby avoiding direct contact with the stomach. The mechanism of injury appeared to be a direct toxic action upon gastric epit helium, whether contact with the drug is from the lumen or via the circulation.

Drugs and P eptic Ulcer

Zollinger-Ellison Syndrome

In a study of prednisolone-induced multiple gastric ulcers in rats, ferric chloride was given orally 1 hr before sacrifice, and at autopsy the st omach was submerged in potassium ferracyanide.95 Instantaneously, Prussian blue appeared at the sites of the ulcerations only, leaving the intact areas unstained. The ulcers were present only in the corpus and at a time when gastric mucus (as shown by the periodic Schiff reagent) was markedly depleted by the steroid. The antrum, richer in mucus th an the corpus, did not ulcerate. On the sides of the ulcers, there was always a group of glands containing newly formed mucus. This

The review of 260 registered cases of the Zollinger-Ellison syndrome, including 190 reported cases by Ellison and Wilson, revealed that 144 (57 %) patients are dead and 111 (43 %) are living; 98 24 patients came to autopsy without operation . Of the 230 patients operated upon for gastric hypersecretion, or islet cell tumors of the pancreas, or both, 111 (49 %) died, usually as a result of complications arising from recurrent ulceration, including perforation and peritonitis, obstruction, and hemorrhage. The sex incidence now is predominantly male, 6:4. Pain was a predominant symptom in most patients, and was related :to peptic

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ulceration in at least four of five; and to diarrhea in 15 %. About one in four ulcers occurred in the distal duodenum or proximal jejunum. Only 10 (6 %) of the 149 single ulcerations occurred in the stomach. Eight of the 17 multiple ulcerations were gastric and six of these had an associated duodenal ulcer. Three-fourths of the primary ulcers were not abnormally located. Although associated endocrine disease was noted in 56 of the 260 patients (21 %), the syndrome of multipe endocrine adenomatosis (Wermer's disease) was recorded in only eight patients (3 %). A pituitary tumor was manifest in 17 of the 56 patients and a parathyroid adenoma was recorded in more than one-half of the total. Diarrhea is an important manifestation of the syndrome and may occur without ulceration. The Zollinger-Ellison syndrome has occurred in at least 12 families. Resection of tumor alone and subtotal gastrectomy do not provide sufficient protection if there has been inadequate removal of tumor tissue. Total gastrectomy is the preferred initial definitive therapeutic procedure. If resection of tumor is feasible, short of total pancreatectomy, then gastrectomy can be combined with tumor resection. According to Zollinger and Grant, ulcerogenic tumors of the pancreas may be implicated in approximately 10 % of "intractable" ulcers. 99 Total gastrectomy is the most effective treatment. Approximately 85 % of patients will produce 2000 ml or more of gastric juice in a 12-hr overnight aspiration, in contrast to a normal volume of 350 cc. Among 86 reported cases of the Zollinger-Ellison syndrome, the diagnosis was suspected clinically in only 22 % and the mortality exceeded 50 %.100 Diarrhea was a persistent symptom in 25 % of patients. The duodenum was the most common site of ulceration; although ulcers also were noted from the esophagus to the ileum, and were multiple in 20 % of cases. Palpable tumor nodules within the pancreas were found in 78 % of cases; especially in the head of the pancreas. Extrapancreatic islet cell tumors were present in 62 % of patients ; more often in regional lymph nodes than in other tissues, indicating the

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need for biopsy of the peri-pancreatic nodes when no tumor is palpated in the pancreas. Associated tumors of other endocrine glands were present in 37 % of all cases and in 50 % of the cases autopsied. In a 65-year-old man with the ZollingerEllison syndrome, the islet cell tumors were found in the submucosa of the duodenal stump following previous partial gastrectomy .101 There was hyperplasia of the pancreatic islets, but no adenomas were found in the gland; there were no metastases from the duodenal tumors. This experience reemphasizes the importance of careful examination of the duodenum since, if an adenoma is found without evidence of metastasis, simple removal may prevent recurrent ulceration. In two patients with the Zollinger-Ellison syndrome, a gastric secretagogue, resembling gastrin and differing from histamine, was present in the gastric content and in the venous blood; 102 in one, th e presence of gastrinlike activity in the serum was confirmed also by the rat bioassay method.52 In a 49-year-old man with an isolated retained antrum after partial gastrectomy, the output of acid resembled that in the Zollinger-Ellison syndrome. 103 The ratio of basal secretion to maximal histamine secretion was 85 % and 109 (;;, on two occasions. A likely explanation for the hypersecretion is that th e gastric antrum, when isolat ed, is released from the inhibitory effects of acid gastric juice. Thus, in a patient with recurrent ulceration after prev ious parti al gastrectomy, antral retention should be excluded before pancreatectomy or total gastrectomy is considered for a presumed Zollinger-Ellison syndrome. In a :H-year-old farmer, profuse di arrhea with hypokalemia and hypercalcemia were associated with parathyroid and pancreatic adenomas. 104 The output of hydrochloric acid was not excessive and peptic ulcer was not demonstrable. Temporary remissions followed two operations on the parathyroids. However, subtotal pancreatectomy led to complete remission. Among 1;~ paternal relatives, !i had histories of intrac table ulcer, 6 of renal stones, 2 had pancreatic and other endocrine adenomas, and 1 had a

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proved pancreatic malignancy. Another icant findings include benign and maliginstance of severe watery diarrhea asso- nant tumors of the adrenal cortex; benign ciated with hypokalemia is reported in a and malignant bronchial and intestinal man of 29 with a pancreatic islet cell carcinoids; multiple lipomas; giant rugal adenoma, in whom an augmented histamine hypertrophy of the stomach; steatorrhea, or test on two occasions failed to demonstrate intractable diarrhea or both. The MEAhydrochloric acid in the stomach.105 Gastric peptic ulcer complex appears to be inherited biopsy indicated a normal mucosa with as an autosomal dominant with variable parietal cells present; jejunal biopsy also expressivity, high penetrance, and notable was normal. Operation demonstrated a pleiotropism. On the basis of present infortumor in the pancreas with enlarged lymph mation, the authors conclude that many of nodes and nodules in the liver. The patient the reported cases of the Zollinger-Ellison subsequently developed a convulsive state 'syndrome represent special variants of the and died. Autopsy demonstrated extensive more inclusive MEA. tumor tissue in the abdomen, with an Ulcer Complications undifferentiated small spindle cell carcinoma of the pancreas. Secondary carcinoma was Obstruction . Episodic vomiting, rather present in the dura adherent to the brain, than abdominal pain, was the characteristic the liver, retroperitoneal tissues, testes, and symptom in four patients (two men and lung. Extracts of portions of the pancreatic two women) with nonobstructing duodenal and omental tumor tissue failed to yield ulcer; 108 the reviewer has encountered any gastrinlike activity. Adenomatous dis- similar instances. Obstruction was found ease involving both the pancreas and the in 885 of 8451 consecutive patients with parathyroid glands was demonstrated in a peptic ulcer hospitalized at Cook County 52-year-old Negro woman with persistent Hospital during 1936 to 1955 ;109 82 % were hyperparathyroidism and intractable peptic in men. The mortality rate was 10.6 % ulceration. 106 Extracts of the pancreatic among those with gastric ulcer and 7.3 % tumor possessed gastrinlike activity. for those with duodenal ulcer and obstrucThe syndrome of multiple endocrine tion. adenomatosis (MEA) is a familial disorder On the basis of a study of patients with characterized by the concomitant occurrence pyloric stenosis and metabolic alkalosis of multiple tumors or hyperplasia involving caused by the continued loss of hydrochloric various endocrine glands. The parathyroids, acid, three stages of alkalosis are identified.110 pancreatic islets and pituitary are the Stage 1 is characterized by raised plasma glands most often affected, with less frequent bicarbonate, slightly increased Pc 02 and involvement of the adrenals and the thyroid. alkaline urine. Sodium loss through vomitPeptic ulcer has been present in more than ing and urinary excretion with excess bi50 % of the reported cases. The clinical carbonate leads to dehydration and renal and pathological features of this syndrome conservation of sodium. Renal compensaas presented by members of a Negro family tion of alkalosis is impaired because the arc reviewed; including analysis of six retention of sodium limits excretion of excess generations of this family ;107 this informa- bicarbonate. The urine becomes less alkaline tion is supplemented by a detailed review and clinical manifestations become apparent. of 74 additional cases of MEA reported in In Stage 2, increased values of pH and P co 2 the literature. The family studied comprises are accompanied by hypokalemia and acid 42 members; the husband and 24 members urine. Dehydration, weakness, irritability, are living, while 17 are deceased. The and slow cerebration become evident. Stage clinical manifestations of MEA reflect the 3 is characterized by severe dehydration, functioning states of the affected endocrine gross alkalosis, extreme potassium defiglands. In addition to pituitary, parathyroid, ciency, hypochloremia, pronounced weight and pancreatic involvement, with intracta- loss, mental confusion, and tetany. In the extracellular alkalosis induced ble peptic inflammatory disease, other signif-

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experimentally by loss of gastric juice in dogs, and associated with dehydration and deficits of sodium chloride and cellular potassium, neither sodium nor hydrogen ions accumulated within the cells, as measured in samples of sartorious muscle.m Total body chloride decreased 43 %, with direct correlation between the decreases in plasma chloride and total body chloride concentrations.112 Body sodium decreased 21 %, with no change in plasma sodium concentration. Body potassium diminished 20 %, but was not significantly related to the decline in plasma potassium concentration . Sodium chloride alone corrected the alkalosis and acidified the urine. Deficits of potassium, sodium, and water are not primary in the development of the metabolic alkalosis induced by loss of gastric hydrochloric acid. 113 The administration of sodium chloride, plus a potassium-free diet, quickly induced an alkali diuresis and restored the normal acid-base equilibrium. To the extent that cation and water deficits develop, they do so as a result of secondary renal adjustments. These several studies confirm earlier observations by Kirsner and his colleagues, emphasizing repair of hypochloremia and total body chloride deficits in the treatment of metabolic alkalosis in patients with obstructing duodenal ulcer and vomiting, with loss of acid gastric content, in individuals subjected to frequent gastric aspiration, and in patients with alkalosis during "Sippy" treatment with calcium carbonate.114 - 11 6 Massive Hemorrhage At the Cook County Hospital (Chicago), the mortality rate for 395 medically treated patients with massive bleeding from gastric ulcer was 36.3 % and for 230 surgically treated cases, 20.8 %Jl 7 Emergency surgical treatment i1icreased the mortality rate for gastric resection from 13 to 37 % and for duodenal ulcer from 4.8 to 33 %. At the Peter Bent Brigham Hospital (Boston), during the 10-year period from January 1951 to 31 December 1960, 339 patients underwent subtotal gastrectomy for peptic ulcer.I 18 Of these, 235 had elective subtotal gastrectomy for complications, with a mortality

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of 0.4 %. During the same period 104 cases of massive gastrointestinal bleeding secondary to peptic ulcer were treated by subtotal gastrectomy. Three of 28 patients classified as severe, uncompensated hemorrhage, died; whereas 16 of 76 classified as exsanguinating hemorrhage succumbed. The mortality rate was highest in elderly patients and was related closely to reduced cardiac, renal and especially pulmonary reserve. A mortality rate of 36% among patients undergoing emergency gastric resection for massive upper gastrointestinal hemorrhage led to a change to the procedure of vagotomy, pyloroplasty, and ligation of the bleeding area, with striking reduction in the mortality rate, especially among the elderly and poor risk patients. 119 A more aggressive surgical approach, embodied in the administration of 3 or 4 units of blood over a short period, with immediate operation in the presence of sweating, tachycardia, or other objective evidence of bleeding, was proposed for the massive bleeding from duodenal ulcer.l 20 Immediate barium study of the upper gastrointestinal tract to identify the cause of hemorrhage has been disappointing; because of inability of the patient to cooperate, the presence of blood clots in the stomach and the frequency with which small craters and superficial ulcerations in the stomach and duodenum are not detected; these observations are in accord with the experience of this reviewer. Among 21!i patients with duodenal ulcer treated by operation, usually partial or subtotal gastric resection, from 1938 to 1962, 18 (8.4 %) subsequently had one or more hemorrhages from the upper gastrointestinal tract. 121 Gastric hypothermia controlled bleeding in 22 of 2fi poor surgical risk patients with massive upper gastrointestinal bleeding, 122 including six with duodenal ulcer and four with gastric ulcer, and in a series of 18 severely ill patients. 123 Pmjoration. In a series of 147 cases of perforated gastric and duodenal ulcer, the usual operation consisted of simple closure, with gastrectomy reserved for hemorrhage, stenosis, and difficult closures. 124 More than one-half of the simple closure patients re-

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quired additional treatment for ulcer complications. Primary gastric resection was performed in 607 of 681 consecutive cases of acute perforated peptic ulcer at National Taiwan University Hospital between January 1950 and D ecember 1961 (Billroth I in 121 cases, Billroth II in 486; duodenal ulcers 533, gastric ulcers 74) .1 25 There were 11 deaths: 8 with duodenal ulcer and 3 with gastric ulcer. Simple closure and other methods were performed in 74 poor risk cases, with a mortality of 31.8 %. These statistics indicate that primary gastric resection is a safe and effective procedure for perforated peptic ulcer in patients otherwise · in good general condition . General observations. Over a period of 15 years, 265 persons with peptic ulcer were observed in a general practice of more than 6000 patients in Kent, England; comprising 212 with duodenal (176 males and 36 females) and 53 with gastric ulcers (28 males and 25 females). 126 The usual course consisted of a period of activity, with frequent episodes of pain. The severity of symptoms reached a peak after 5 to 10 years, followed by a period of progressive remission a nd eventual complete recovery. Surgical treatment was required in 16 % of duodenal ulcers and in 19 % of gastric ulcers. Onethird of those who had a gastrectomy developed anemia 5 to 10 years after the operation. Males with duodenal ulcers were five times more likely to develop pulmonary tuberculosis, three times more likely to suffer neuroses, and twice as likely to develop coronary heart disease. The author concludes: "The warmth of clinical art rather than cold science is still required to manage the patient with a peptic ulcer." M edical Treatment of Peptic Ulcer Diet. No characteristic patterns of food intolerance were encountered in patients with peptic ulcer in interviews with hospitalized patients at the Boston Veterans Administration Hospital. 127 The conventional dietary management of peptic ulcer, as emphasized originally by Sippy, has been liberalized in recent years. 128 However, the concept of neutralization of acid gastric

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juice with the aid of food continues to be an important consideration in ulcer therapy. An earlier investigation demonstrated an apparent association between a relatively high incidence of myocardial infarction and the consumption of "Sippy" diets and diets high in milk content, both in the United States and Great Britain; this relationship has been reaffirmed. 129 To reduce the lipemia but retain the therapeutic efficacy of multiple feedings in peptic ulcer, a polyunsaturated fat nutritional preparation was utilized in place of milk and cream.l30 The blood lipid responses to single and hourly feedings of this preparation were lower than to a milk and cream "Sippy" mixture in patients with peptic ulcer.m . 1a2 Miscellaneous drugs and gastric irradiation. In 14 patients with peptic ulcer, detailed study of cardiodynamics indicated that the anticholinergic drugs, poldine, and !-hyoscyamine, placed no increased load on the circulation, when administered for long periods.133 Doses of 3 to 5 g of acetazolamide by mouth (approximately 45 to 70 mg per kg) were required to inhibit the secretion of hydrochloric acid for periods of 1 hr. 134 This compound, therefore, does not appear to be therapeutically useful for controlling acid secretion in peptic ulcer. A synthetic polysaccharide, amylopectin sulfate (SN -263), inhibited the proteolytic activity of pepsin in vitro. 135 Its oral administration decreased the ulcerations in pyloric-ligated rats, the gastric ulcerations induced in rats by starvation and cortisol, and the frequency and severity of histamineinduced duodenal ulceration in guinea pigs. In these capacities, amylopectin sulfate resembles the naturally occurring sulfated polysaccharides such as carrageenin . Mild roentgen irradiation of the acidsecreting portions of the stomach remains a valuable adjunct in the medical management of peptic ulcer.l 36 The inhibition of gastric secretion is variable in degree and duration, with a transitory or permanent anacidity in 10 % of cases and a greater than 50 % reduction in 40 % of patients. Extract liquorice. Extract of liquorice has been used in the treatment of peptic ulcer for many years, but did not attract atten-

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tion until Revers 137 in Holland observed that patients who had taken a proprietary preparation containing succus liquiritiae, seemed to respond unusually well; gastric ulcers responded more readily than duodenal ulcer. The extract causes water retention in approximately 20 % of cases and has antiinflammatory activity, at least in animals. The activity of liquorice extract is believed to be associated with glycoside, glycyrrhizinic acid. Hydrolysis of this acid yields the pentacyclic triterpenoid hydroxyketo acid, 3-hydroxy-11-oxo-18 f)-olean-12-en 30oic acid, whose 3-0 (f)-carboxypropionyl) derivative, "Biogastrone acid" and the derived desodium salt, Biogastrone (disodium salt) have been prescribed in the management of gastric and duodenal ulcer, in doses of 100 mg three times daily. 138 After 5 weeks of treatment, of 28 patients with duodenal ulcer, the crater disappeared in five and the average number of days with pain was 7.7, not significantly different from a control series of 14 patients. Of 30 patients with gastric ulcer, the ulcer crater disappeared radiologically in 11 and the number of days with pain was 5.3. Of 20 control patients, the ulcer crater disappeared radiologically in 1 and the average number of days with pain was 6.8. Of the 58 patients on Biogastrone, 10 developed edema, amounting in two cases to congestive heart failure; 4 patients complained of heartburn and 2 of headaches. The data are interpreted as indicating a nil effect for duodenal ulcer, but a significantly beneficial result for gastric ulcer. The mechanism whereby the drug influences the healing of gastric ulcer is unknown. Additional studies would seem indicated to confi rm these observations. Gastric "freezing"- animal observations. In 13 dogs with gastrostomies, gastric freezing for 1 hr at -20 C inflow and -12 C outflow did not reduce signifi cantly the response to betazole hydrochloride (histalog), insulin or peptone. 139 Light and electron microscopy indicated transient and erratic damage to the superficial layers of the mucosa, with no effect upon the glandular layers. Tritiated thymidine studies demonstrated normal cell renewal within 1 week after freezing . After seven 1-hr freezes, the

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gastric mucosa appeared normal histologically and acid secretion was demonstrable. Similar results were obtained by other investigators.l 40 · 141 In dogs subjected to gastric freezing with submucous temperatures of -8 C, complete necrosis of the stomach ensued, with death within 2 to 4 days. 142 Actual gastric freezing of the fundus or corpus was accomplished in 27 dogs, with the uniform development of hemorrhagic necrosis at the site of freezing. 143 In eight dogs, death resulted from massive hemorrhage from these sites within 24 hr. By contrast, the esophagus and antrum proved relatively resistant to freezing at the temperature employed. Gastric freezing-clinical observations. Gastric freezing induced temporary clinical improvement in patients with duodenal ulcer. 144 · 145 Approximately 70 % of 168 patients with duodenal ulcer noted symptomatic improvement for short periods after gastric freezing. 146 Symptoms then recurred in a progressively large percentage of patients evaluated at 6 weeks to 9 months postfreeze. Among 42 patients accepting a second gastric freezing, about half experienced return of symptoms in 6 to 12 weeks after refreeze. Although histologica l evidence of nerve damage could not be identified in biopsies of the stomach after gastric freezing, the temporary improvement has been attributed to temporary partial vagotomy and sympathectomy, owing to the effects of low temperatures on terminal nerve fibrils in the gastric wall. 147 As others have noted, the psychological reinforcement inherent in gastric freezing complicates objective evaluation.148 Among 100 patients with duodenal ulcer treated with gastric "freezing," 82 were failures 9 months after treatment and only seven \\"ere totally asymptomatic. 149 In a group of 40 patients with pain due to active duodenal ulcer, gastric freezing, in a double-blind study, had no beneficial effects. 150 There was no significant depressant effect on gastric secretion. In a group of 36 patients, 17 controls and 19 submitted to gastric freezing, the number of patients with relief or improvement of symptoms was high in both groups. 151 At 6 months,

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75 % of patients with freezing were relieved completely or substantially; whereas only 29 % of patients with sham freezing fell into these categories. Similar trends were noted in a series of 55 patients with duodenal ulcer.l 52 The striking observation in many of the gastric freezing studies has been the dramatic relief of pain, not correlated with sustained decrease in acid secretion. Gastric freezing-harmful effects. The problems and complications of gastric freezing have aroused increasing concern. In a group of 120 patients, 63 presented varied significant clinical manifestations, including a shocklike state in 5, abdominal cramping in 21, a transient febrile reaction in 18 and bleeding in 19; 3 of the latter group required blood transfusions.153 Among six patients with peptic ulcer treated by freezing, gastric biopsies revealed mucosal inflammations, cellular degeneration, edema and hemorrhage during the first 2 weeks after gastric freezing. 154 There was no evidence of significant damage to the parietal cells. Gastric ulcer with confined perforation developing after freezing in a patient with duodenal ulcer required subtotal gastric resection. 15 5 Postfreezing mucosal injury usually occurs on the anterior wall of the stomach, at the junction of the proximal and middle thirds. The elimination of mucosal injury requires attention to (1) the force of delivery of the coolant; (2) degree and duration of the cold temperature ; (::~) the size of the stomach and thickness of its wall; (4) the position of the inflow apparatus relative to th e gastric wall; and (5) the material used for the gastric balloon. 156 A special infusion device diffuses alcohol uniformly throughout the balloon; centers the infusion tip away from the wall of the stomach; and permits a 60-min freeze interval at -17 C inflow and -10 C outflow, safely. Data from a collected series of 1484 gastric freezes performed by others, supplemented with personal observations in 120 gastric freezes, reemphasize the problems of this procedure. 157 Some of the technical difficulties include obstruction of the airway, rupture of the esophagus and stomach, and rupture of the intragastric balloon . The

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complications of the hypothermia include perforation of the stomach, gastric ret ention, postfreeze edema of the gastric wall, ulceration, and hemorrhage. The systemic difficulties include onset of a shocklike state and temporary alterations in the electrocardiogram. A questionnaire indicated that 18 % of physicians or institutions did not require radiological evidence of peptic ulcer, 40 % did not require the presence of an ulcer crater, and 9 % did not require a history of medical intractability. In addition, 9 % of the replies indicated that the gastric freeze was being utilized as an office procedure. These figures are disturbing and clearly reflect a serious lack of the indispensable critical and informed approach to a complicated, potentially hazardous, and unproven therapeutic procedure for peptic ulcer. Present evidence provides no justification for the widespread clinical use of gastric freezing. 158 According to Wangensteen et al., 159 the position of gastric freezing will depend ultimately in great measure upon hO\\" closely the desired depression of gastric mucosal t emperature can be made to approximate that necessary to attain protracted achlorhydria. No hospital deaths have occurred among 605 patients submitted to 810 episodes of gastric freezing. Postfreeze melena was observed in 3.8 % and gastric ulcer in 2.8 % of the entire freeze group of patients. A 30-min gastric freeze in the dog with inflow temperature of -20 C with premedication of intravenous 10\Y molecular weight dextran exerted a protective action against gastric ulceration and necrosis.160 At inflow temperatures greater than - 30 C, use of low molecular weight dextran provided little protective action. It is now known that the t emperatures of the coolant as it leaves and returns to the freezing machine bear little relationship to balloon-mucosal interface t emperatures or to temperatures within the gastric mucosa. 161 The temperature at the balloon-mucosal interface seldom decreases below 0 C and usually exceeds 5 C. Observations in laboratory animals and, to a lesser extent, in man, indicate that with the gastric "freezing" procedure, as performed currently, either

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none or only a small part of the stomach in contact with the cold balloon actuallv freezes solidly .162 The total evidence t~ date, therefore, indicates that gastric freezing is not an acceptable method of treatment for peptic ulcer. Gastric " heating." The effects of gastric hyperthermia upon gastric acid secretion were studied in adult dogs prepared with gastrostomies. 163 Heating at 10 C above the normal gastric temperature produced a fall in acid secretion. The inhibitory effect was temporary in dogs heated for 10 min and prolonged when heating was maintained for 20 min. In dogs heated at 50 C for 45 min acid production decreased, with achlorhy~ dria during the 1st week; 164 in two dogs the inhibitory effect has continued for almost 1 year. Comment on the medical treatment of peptic ulcer. The objectivity of doubl e-blind therapeutic trials is a welcome addition to the scientific climate of gastroenterology. However, as so often is the case, extrapolation may reach unwarranted proportions. While recognizing the limitations of current medical therapy in the long term course of peptic ulcer, the negative attitude appears also to have resulted in the rejection of most, if not all, of the hitherto accepted methods of treatment for active peptic ulcer. Individual adjustments in the diet facilitate relief of symptoms and frequent feedings can aid in neutralizing and buffering gastric acidity. Antacids can neutralize and anticholinergic drugs can lower acid secretion significantly when potent compounds are administered in adequate amounts . These measures, combined with modification of difficult life situations and the elimination of ulcerogenic agents, often provide effective ulcer control. The many failures of surgery, and now the denouement of gastric freezing, to mention only the latest in an impressively long list of "successful medical failures," should perhaps renew interest in th~ albeit simple, and possibly scientifically na1ve, yet useful therapeutic approach comprising acid control and improvement in the general health of the patients. Peptic ulcer remains an enigmatie disorder; but it is not incurable.

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Surgical Aspects of Peptic Ulcer Although subtotal gastric resection remains an accepted, albeit less popular approach in the surgical treatment of duodenal ulc~r, the complications continue to present senous problems. Experimental investigation of the effect of duodenal contents upon the gastric mucosa in dogs subjected to Billroth I and P6lya gastrectomies demonstrated a severe gastritis around the stoma.16 5 When reflux was prevented by long loop r~construction of the Roux-Y type, gastritis d1d not occur. Partial gastrectomy is followed by a decline in serum vitamin B 12 concentration in approximately 15 % of ?ases, but clinical signs of deficiency develop m only 1 to 5 % of patients. 166 The suggested mechanisms include (1) intrinsic factor ?eficiency, ow.ing to mucosal atrophy; (2) madequate stimulation of intrinsic factor secretion; (:3) failure of binding of vitamin B,2 to intrinsic factor; (4) abnormal flora in blind afferent loops; and (5) activation of previously latent jejunoileal lesions that cause the malabsorptive syndrome. After partial gastrectomy for peptic ulcer, nine patients were found to have developed mega loblastic anemia and low serum B 12 levels; achlorhydria and increased fecal fat outputs were noted in seven of the nine and low urinary or seru m pepsinogen leve l~ in five cases. The absorption of radioactively tagged vita n1in B 12 was decreased in al l nine patients. Intrinsic factor restored the absorption of vitamin B, 2 to normal in eight of the nine patients. The ninth patient with a blind intestinal loop improved after the administration of chlortetracycline. Defici ency of folic acid was noted in 12 % of randomly selected patients after partial gastrectomy. 167 Rarefaction of the bones was twice as frequent in 100 patients 2 to l!i years after partial gastrectomy (48 patients) in co mparison with 100 control subjects conlparable in age, sex, and social class (19 patients) .1 68 The skeletal abnormality also was more severe, as evidenced by the number of crush fractures of the vertebrae, the incidence of fractures after minimal trauma and by the presence of pain in the bones.

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Loss of weight, anemia, the dumping syndrome, and diarrhea were more frequent in the patients with skeletal changes than in individuals with normal bones. Clinically, 11 patients appeared to have spinal osteoporosis and 18 patients a syndrome resemling osteomalacia. Inadequate intake of calcium and protein in the diet, steatorrhea, and possibly a deficiency of vitamin D appeared important in the pathogenesis of the osseous disorder. 169 In another study, spinal rarefaction was greater in patients examined six or more years after a partial gastrectomy than in matched controls.l1° The bone lesion after operation was mainly osteoporosis, but there also was some biochemical and histological evidence of osteomalacia, judged by the serum chemistry, the response to calcium infusion and the histology of the bone, as studied in biopsies. Disordered calcium metabolism was found in 28 % of .~3 patients who had undergone P6lya partial gastrectomy, 7 to 16 years earlier. 171 Osteomalacia was the major problem, combined in some patients with osteoporosis. Vagotomy and drainage operation. The surgical treatment of choice for duodenal ulcer is transabdominal supradiaphragmatic vagotomy, pyloroplasty, and temporary gastrostomy .172 The added operative risk associated with hemigastrectomy does not warrant its performance, despite a potential slight in1provement in the ulcer recurrence rate. Vagotomy was utilized effectively in Hi of 1\) pati ents developing gastrojejunal ulceration after subtotal gastrectomy. 173 The return of acid after complete vagotomy is ascribed to collateral nerve fibers which begin to function as a result of transection of the vagus nerves. Division of all vagal branches to the stomach probably decreases the incidence of recurrent ulceration, hut it does not protect completely against this complication. 174 Among 100 patients with chronic duodenal ulcer treated hy vagotomy, the gastric secretory response to insulin was negative in G2 and positive in :~8. 175 Of the "positive" :{8, 9 manifested a positive response within -lfi min, and 29 a positive response from 4.~ min to 2 hr after the administration of in-

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sulin. The "early positives," in comparison with the "late positives," demonstrated significantly higher levels of basal secretion and larger responses to both insulin and the augmented histamine test. Anastomotic ulcers developed in three of the nine patients with early positive responses, but in none of the late positive group, during a follow-up period up to 3 years. These observations suggest that a positive response to insulin within 2 hr does not necessarily reflect an inadequate vagotomy. The early reduction in acid output following vagotomy with either gastrojejunostomy or pyloroplasty is maintained for at least 3 years after operation. 176 · 177 Study of the bowel habit of 100 patients, approximately 4 years after vagotomy and gastrojejunostomy, disclosed an increase in daily bowel frequency in 71, episodic diarrhea in 2:3, transient diarrhea in 10, and a tendency to constipation in 5 cases. 17S The incidence of troublesome diarrhea approximated fi % ; but disabling diarrhea was rare. Among 66 male patients who had a vagotomy and drainage operation between 1 and 2 years earlier, diarrhea and steatorrhea occurred independently of each other and probably were attributable to the vagotomy rather than to the drainage procedure. 179 Among 9!) patients, approximately 4 years after vagotomy and gastrojejunostomy, the serum concentration of iron and absorption of vitamin B12 were lowered; fecal fat excre· tion was increased slightly .18° Because of the occurrence of postoperative gastric atony, vagotomy and gastric drainage were rejected in the surgical management of patients with obstructing duodenal ulcer, in favor of gastric resection.181 In the experience of the reviewer, however, patients with obstructing duodenal ulcer can he treated by vagotomy and a drainage procedure, provided appropriate preoperative preparation, including adequate gastric decompression, is undertaken. Among 200 patients with chronic duodenal ulcer treated with vagotomy and simple drainage, in whom the electrical stimulation test was used at the time of operation to prove complete nerve section, after 1 to 7 years of follow-up, one case came to opera-

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Vol. 49, No.1

tion for recurrent ulceration and was shown and antrectomy (126), and subtotal gasto have an incomplete nerve section by the trectomy (112 patients) .188 There were no test at the second operation. 182 Another postoperative fatalities and no later deaths patient developed a gastrojejunal ulcer associated with the operation or the ulcer. from severe antral retention between the The follow-up indicated excellent and good stenosed duodenum and the stoma. results in 74.8, 79.3, and 80.3 %, respecThe etiology of recurrent ulcer after tively. Early dumping was significantly vagotomy and a gastric drainage procedure is more common after subtotal gastrectomy, not entirely clear. In many instances, in- and diarrhea (usually mild and episodic), adequate vagotomy can be demonstrated more frequent after vagotomy and gastroby the insulin test and confirmed at opera- enterostomy. tion by identification of a large individual Acknowledgment. This review was supported in nerve trunk. 183 In other cases, no such confirmation is found and the recurrence may part by the Wallach Fund for Gastrointestinal be attributed to collateral nerve sprouting, Research. impossible to recognize grossly. Electrical REFERENCES stimulation of the vagus nerves results in 1. Forte , J. G., and R. E. Davies . 1964. Relaan increase in intragastric pressure dependtion between hydrogen ion secretion and ing upon the initial degree of gastric disoxygen uptake by gastric mucos a . Amer. tension and the frequency and voltage of J. Physiol. 206 : 218. the stimulus. 184 In cats subjected to a 2. Villegas, L . 1964. Anoxia in parietal cells of standardized method of incomplete vagotthe frog gastric mucosa. Biochem. Bi oomy, stimulation of the right cervical vagus phys. Acta 88: 227. distal to the excised segment produced no 3. Harris, J. B., and I. S. Edelman. 1964. Chemical concentration gradients and electrical response. On stimulation of the left cervical properties of gastric mucosa. Amer. J. vagus, the result depended upon the interval Physiol. 206: 769. after operation. One week after incomplete 4. Durbin, R . P. 1964. Anion requirements for vagotomy, the result was a revival of the gastric acid secretion. J . Gen . Physiol. 47 : normal response, relaxation predominating. 735. At 4 and at 6 weeks, however, the changes 5. Durbin, R. P ., S. K oto ba ra, K. Stahlmanne, in intragastric pressure greatly exceeded a nd E. Heinz . 1964. Exchange diffusi on of those of control animals and cmresponded chloride in frog gastric mucosa. A mer. J. to the responses obtained when all the gastric Physiol. 207: 1177. motor fibers from the left cervical vagus were 6. Sackiko, K. M., and C. A.M. Hogben. 1964. Ioni c flux es of H.ana pipiens stomach intact. bathed by sulfate solutions. Amer . J. The results among Hi7 patients with Physiol. 207 : 1173. duodenal ulcer treated by 70 % Billroth I 7. Smit, H. 1964. The regulation of pepsin gastric resection were compared with 110 secretion in the edible frog. H.ana esculenta patients treated by hemigastrectomy, vagot(L). J. Comp. Biochem. Physiol. 13: 129. omy, and gastroduodenostomy. Ulcer re8. K ahlson, G., E. Rosengren, D. Svahn, and currenres were 1.2 % in the resection gmup R . Thunbe rg. 19li4. Mobilization and and 0.9 ?(. in the combined operation group; functi on of hi stamine in the gastric mucosa operative mortality rates were 4.4 % and as related to acid sec retion. J. Physiol. 124: 400. 0.9 %, respectively. 18 5 The over-all mortality 9. Ragins , H ., M. Dittbrenne r, P . Labay, and rate of hemigastrectomy and vagotomy D. State. 1964. Observations on the pat happroximates 1.6 to 2.0 %.18 6 • 187 way of exogenous C 14 -histamine in stimuIn a well conceived, controlled trial underlating gast ric secretion. J. Surg. Res. 4: taken in Leeds, 360 patients with duodenal 164. ulcer coming to elective surgery without 10. Nicoloff, D . M., E. T . Peter, N. H. Stone, specific contraindications for any procedure and 0. H. Wangensteen. 1964. The efTect were distributed randomly among vagotomy of catecholamines on gastric secretion a nd and gastroenterostomy (122), vagotomy blood flow. Ann. Surg. 159: 32.

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11. Leona rd, A. S., D. Long, L.A. French, E. T. Peter, and 0. H. Wangensteen. 1964. Pendular patte rn in gas tric secretion and blood flow following hypothalamic stimulation-origin of stress ulcer? Surgery 56: 109. 12. Delaney, J . P., and E . Grim. 1964. Canine gastric blood flow and its dist ribution. Amer. J. Physiol. 207: 1195. 13. Andersson, S., and L. Olbe . 1964. Gastric acid secretory responses to gastrin and histamine in dogs before and after vagal stimulation of the vagal pouch. Acta Physiol. Scand. 60: 51. 14. Emas, S. 1964. Gastric acid secretion in gast ric fistula cats before and after vagotomy and in vagotomized gastric fistula cats during reserpine treatment. Acta Physiol. Scand. 61: 255. 15. Kelly, K. A., L . M. Nyhus, and H . N. Harkins . 1964. The vagal nerve and the intestinal phase of gastric secretion . Gastroenterology 46: 163. 16. Jordan, P. H. , Jr. , a nd C. De L a Rosa. 1964. The regulatory effect of t he pyloric gland area of the stomach on the intestinal phase of gastric secretion. Surgery 56: 121. 17. La ndor, J. H ., a nd W. K. Baker. 1964. Gastric hy persecretion produced by massive small bowel resection in dogs. J. Surg . Res. 4: 518. 18. Gillespie, I. E., and M. I. Grossman. 1964. Inhibi tory etTect of secretin and cholecystokinin on Heidenhain pouch responses to gastrin extract and hist.amine. Gut 5: 342. 19. Grybuski, W. A., and R . Menguy . Effects of secretin on gastric secretion . Amer. J . Dig. Dis. 9:87. 20. Wormsley, K. G ., and M. I. Grossman. 1964. Inhibition of gastric acid secretion by secretin and by endogenous acid in the duodenum. Gastroenterology 47: 72. 21. Mcilrath, D. C., and G. A. Hallenbeck. 1964. Comparison of gastric inhibitory properties of two secretin prepa rations. Amer. J. Physiol. 206 : 1077. 22. Jordan, P. H., Jr., and C. De La H.osa. 1964. Inhibition of gastric secretion by duodenal mucosal extracts. Ann. Su rg. 160: 978. 23. Kamionkowski, M., S. Grossman, and B. F leshier. 1964. The inhibitory effect of sec retin on broth-stimulated gastric secretion in human subjects. Gut 5: 237. 24. Mason, G. R ., E. H. Eigenbrodt, H. A. Oberhelman, Jr., and T. S. Nelsen. 1964. Ethionine-induced alteration in gastric secretion. Arch. Surg. 88: 1063.

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25. Von Heimburg, R. L., and G. A. Hallenbeck. 1964. Inhibition of gastric secretin in dogs by glucagon given intraportally. Gastroenterology 47: 531. 26. Passaro, E. P., Jr., and M. I. Grossman. 1964. Effect of vagal innervation on acid and pepsin response to histamine and gastrin . Amer. J. Physiol. 206: 1068. 27. Gillespie, I. E. , and M. I. Grossman. 1964. Potentiation between urecholine and gastrin extract and between urecholine and histamine in the stimulation of Heidenhain pouches. Gut 5: 71. 28. Mcilrath, D. C., and G. A. Hallenbeck. 1963. Increased sensitivity of Heidenhain pouches to exogenous gastrin after removal of main stomach. Proc. Soc. Exp. Bioi. Med. 112: 909. 29. O'Callaghan, W. J. , N. N. Kubota, and R. C. H a rrison. 1964. Acid control by the a ntrumeffect of antral pH on vagally stimulated antral response. Amer. J. Physiol. 206: 1065. 30. Andersson, S., and L. Olbe. 1964. Inhibition of gastric acid response to sham feeding in Pavlov pouch dogs by acidification of antrum. Acta Physiol. Scand . 61 : 55. 31. Thompson, J. C., W. D. Davidson, J . H . Miller, and R. E. D a vies . 1964. Suppression of gastrin-stimulated gastric secretion by the antral chalone. Su rgery 56: 861. 32. Dragstedt, L. R., R . B . Quintana, C. De La Rose, and C. Linares . 1964. The question of fa tigue in the gastrin mechanism. Arch. Surg. 89: 1042. 33. Jordan, P. H., Jr. , and R.. Quintana. 1964. Insulin inhibition of gastrin-stimulated gastric secretion. Gastroenterology 47: 617. 34. Olbe, L . 1964. Effect of resection of gastrinreleasing regions on acid response to sham fe eding and insulin hypoglycemia in Pavlov pouch dogs. Acta Physiol. Scand. 62: 169. 35. Grego ry, R . A., and H. J. Tracy. 1964. The constitution a nd properties of two gastrins extracted from hog antral mucos a. I. The isolation of two gastrins from hog antral mucosa. Gut 5: 103. 36. Gregory, R . A., and H. J. Tracy. 1964. The constitution a nd properties of two gastrins extracted from hog antra l mucosa . II. The properties of two gastrins isolated from hog antral mucosa. Gut 5: 107. 37 . Taylor, W. H . 1964. Ultracentrifugal analysis of gastrin I and II . Gut 5: 115. 38. Makhlouf, G . M., J. P. A. McManus, and W. I. Card. 1964. Dose-response curves

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53. Sparberg, M ., and J. B. Kirsner. 1964 . Gast ri c secretory act ivi ty with reference to 1-I Cl-clini cal in terpretations. Arch. Inte rn. Med. 114: 508 . 54. Baron, J. I-I. 1964. Peptic ul cer, gastric sec retion and body build. Gut 5: 83. 55. Zate rka, S., and D.P. Neves . 1964. Maximal gastric secretion in human subjects after histalog st imulation. Gastroenterology 47: 251. 56. L awrie, J. H. , G. M. R. Smit h, and A. P.M. Forrest. 1964. The histamine-infusion test. Lancet 2: 270. 57. J3 ock, 0. A. A., and L . J . Wi tts. 1963. Gastric acidi ty in t hyrotoxicosis. Bri t. Med. J . 2: 20. 58. Willi ams, M. J. , a nd D. W. Blair. 1964. Gas tri c sec ret ion 111 hy per t hy roidi sm. Brit. Med. J . 1:940. 59. Wa rd , J. T. , A. 0. Adeso la , and R. B. Weibourn. 1964. The parathyroids, calcium and gast ri c sec retion in man and t he dog. Gu t 5: 173. 60. Smith , G. \'. , a nd E. L . Howes. 1964. Absence of hi stamin e -reserpin e ul ce rs in py lori c pouches free of acid. Surgery 55 : 2G2. 61. Stafford , E . S., an d L. Schnaufer . 19G4. An invest iga tion in dogs of gastro-jejunal ul cerat ion subsequ en t t o a new met hod of duodena l s timul a tion. Ann . Surg. 159:802 . G2. Guest, J . L ., .Jr. 1!Jii4 . New evide nce support ing t.he co nce p t. of a ·gradient nf suscept ibility to peptic ul ceration in t he gas tro int est in a l tract. Surge ry 56: 383. 6:3 . Brady, J . V. , ll. W. Port er, D. G. Conrad , an d J. W . i\lason. 1!l58. Avoidance be havior an d th e developmen t. of gastroduodenal ul ce r . J . Exp. Ana l. Behav . 1: (i\J . (i~. FollY- , E. L. , and F. E. Millett. , Jr . 1\Hi.J. Experimenta l psyc hosomati c di sease states in monk eys. 1. P epti c ul ce r- "execut.ivc" monkeys. J. 1-'urg. ll es. 4: 445. 1\5. Folt.z, E. L. , F. E. Millet.(., Jr., D. E. Webe r, and J. F . Alksne. 191i4. Experimental psyc hosorna t ic di sease s t.at.es in monkeys. If. Uut h~· p c rnwti lit y. J. f:lurg. ll es. 4: .J5.J . 1\G. Leona rd , A. S., .J. C . Engle, E . T . l'et.e r, 1> . Lon g, a nd 0. I f. Wangensteen. 19ti4. Uast ri c blood How a nd inhibit.ion of hi stamin es timulat ed gas tri c sec retion. J. A. M. A. 187 : 58\J. G7. 1\:a hlson , G. , B. Lilja , and R. E. Svensson. 19ti4. Physiological protect,ion against gastric ulceration durin g pregnancy a nd lac ta t ion. Lancet. 2 : 12u!J . 68 . de Ia Rosa , C., C. A. Linares, E. R. Wood -

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ulce rs in children . S. Afr. Clin. Hadiol. 15: 267. 84. Walker, E. E . 1964. Gast roduodenal ulcers in

chi ldren with brain disease. Arch. Su rg. 89: 559. 85. Inouye, W. Y. 1964. Neonatal gastric perforation . Arch. Surg . 88: 471. 86. Pertsemlidis, D. 1964. Neonatal gastric perforation. J. Mount Si nai Hosp. N. Y. 31: 97. 87. Sly, R. M . 1964. Perforation of a gastric

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conve n t.iona l roen \ genographic \ echn iques for demonstra\ ion of duodenal ulcer craters. Amer. J. Hoentgenol. 91: 801. Kap lan , A. H. , H. Fischer, E. (;!anville, W. Powell, M. J"amionkowsk i, and B. FleshIer. HHi4. Ditierential taste sensitiviti es in duodenal and gast rie ulcer patients. Cast.roen terology 47: liO-l. Karl strom, F. l!llicl . Peptic ulcer in children in Sweden during the _,·ears HJ53- 1962. Ann. Paediat. (Basel) 202: 218. ~ ing;l eto n, E. B., a nd M. H. Faykus. 19G4. Incidence of peptic ulcer as det ermined by radiologic examina tio ns in t he pediatric age group. J. Pediat. 65: 859. Thomson, N . 13., Jr. , and T. C. J ewett, Jr. 19G4. Peptic ul ce rs in infancy and childhood. J. A.M. A. 189: 539. Berman, \ .. 19li4. Detection of duodenal

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115. Kirsner , J . B ., and W. L . P almer. 1943. Arch . Inte rn . Med. 71 : 415. 116. Kirsner , J. B. , W. L. P almer , a nd K. Knowlt on. 1943. J . Clin. Invest . 22: 95 . 117. Kozoll, D. D . 1964. Massivel y bleeding gas t roduodenal ul cer . Effect of trea tment on morbidi ty and mortali ty . Arch . Surg. 89: 250. 118. Brooks, J . R., and A. J . Eraklis. 1964. Fac tors affecting t he mortali ty fr om pep tic ul cer. The bleeding ulcer and ul cer in t he aged . New E ngl. J . Med. 271: 803. ll9. F oster , J . H ., T . K. Hunt, and J . E. D unphy. 1964. E mergency operation for massive upper gastroin tes tinal hemorrhage . Bri t. J. Surg . 51 : 757. 120. H erringt on , J . L . 1964. A more aggressive surgi cal attit ude in the management of t he massively bleeding duodenal ul cer. Surgery 56: 349. 121. Coe, J . D. , C. W. McLa ughlin , Jr ., a nd E. Walker. 1964. Rec urrent gastrointestinal bleedin g after definitive gastri c surgery . Arch. Surg . 88: 888. 122. Cramp ton , R. S. , J . R . Cali , P . Yerys, G . W. Bur tow, and J . P. Gla ubi tz. 1964. E xperience with gastri c hypothermi a for active uppe r gastrointestinal trac t hemorrh age. Surge ry 55: 607 . 123. He rmann , G ., H . B. K a rsh , and A. J. K a uva r. 1964. Gas t rie cooling in the managemen t of massive uppe r gastrointestinal hemorrh age . Gas troente rology 47: 513. 124. Krippaehne, W. W., W. S. Fletche r, and J. E. D unphy. 1964 . F acto rs influencing mortali ty following ae ute perforation of duodenal and gastri c ul cer. Arch. Surg. 88: 874 . 125. 1\ao, T . C., S. C. Hsu, a nd C . S. Hsieh. 1964. Prima ry gas t rectomy for perfo rate d pep t ic ul ce r. Su rge r:v 56: 487. 12(). Fry , J. 1964 . P eptic ul ce r: a profile . Bri t . Med. J . 2: 809. 127. Koch, J .P., and H. M. Donaldson , Jr. 1964 . A survey of food intole ran ces in hospitali zed patients. New E ngl. J . Met!. 271: 657 . 128 . Moelle r, H . C. 1964. Conven tion al di etary t rea tmen t, of peptic ul cer . Amer. J . Clin . Nu t r. 15: 194. 129. Ha r t roft, W. S. 1964 . The incidence of co rona ry a rtery di sease in patien ts t reated with t he Sippy diet. Amer. J . Clin. Nu tr. 15: 205 . 130. La ure ta, H. C ., C . C. Chou, and E. C . T exter , Jr . 1964. An appraisal of t he managemen t of pept ic ul cer including compa rative

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174. Clark, C. G . 1964. Com plete vagotomy and its consequences . Brit.. Med. J. 2: 900. 175. Ross, B., and A. W. Kay. 1964. Assessmen t of vagotomy. Gastroenterology 46: 379. 176. Bell, P. R . F. 1964. The long-term effect of vagotomy on t he maximal acid response to histamine in man. Gast roe ntero logy 46: 387. 177 . Gelb, A. M. , and H. D. J anowitz , 1964. Note on the late effect of vagotomy an d pyloroplasty on t he maximal acid response to histamine. Gut 5: 400. 178. Cox, A. G., a nd M. R. Bond . 1964. Bowel hab i t after va gotomy and gast rojej unos tomy. Brit. Med. J. 1: 460. 179 . Logan, H. 1964. Steatorrhea and diarrhea a fter vagotomy: A comparison of drainage procedure. Gut 5: 188. 180. Cox, A. G., M. H. Bond , D. A. P odmore, and D . P. Hose . 19G4. Aspects of nutrition after vagot.omy an d gastrojejunostomy. Brit. Med. J . 1: 465. 181. Kraft , 11. 0., W. J. Fry , a nd M.S . DeWeese. 1964 . Post-vagotomy gastric atony. Arch. f:i urg. 88: 865. 182. Burge, I-1., A. :\·1. C: ill , and H. H . Lewis. 19()4. Hesult s of vagoto my with t he elect ri cal stimul at ion test: an int erim repor t. Brit. Med. J . 2: 17. 183. Clark , C. G. H)(i4. Hecove ry of gastric fun ction after ineo mpl ete vagotomy . Brit.. ,J. l:'urg. 51: 539. 184. P aton , W . D . i\1. , and J. H . Va ne. 105(i. Proc. 20t h Int erna tion a l Physiol. Cong ress. 709 p. 185 . Havage, L. E., L. S. Stavney, II. N. Har kin s , an d L . i\ 1. :\' y hus. 1!)(i-l . Compari so n oft he co mbi ned operation an d llillroth I gastrectomy in the trea tm ent. of chroni c duod enal ul ce r . Amer . J . Hurg. 107: 283 . 18G. Thoroughma n, J. C., L . U. Walker, Jr ., and D . Haft. 1!)(i-l. A revi ew of 504 patients with pept ic ulcer treated by hemigas t.recto my and vago tom y. Surg. Gynec. Ohs tet.. 119 : 257. 187. J ohnston, H . H ., Jr. , D . C . qu ast, and(:. L. J ord an , Jr . HJG-1. H emigastrect.omy a nd vagotomy for duodenal ulce r. Arch. Surg. 88: 860. 188. Go ligher , J. C ., C. N. Pulve rtaft, and G. Watkinson . 1!)(i4. Co n t rolled t rial of vagotomy and gast.roen te ros to my, vagotomy and at.rectomy, and sub total gastrect.omy in elective t reat ment of duodena l u lce r: interim report. Brit. Meet. J. 1: 455.