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The Significance of the Gastric Acidity in the Surgical Therapy of Peptic Ulcer
**'"
THE SIGMFICANCE OF THE GASTRIC ACIDITY IN THE SURGICAL THERAPY OF PEPTIC ULCER ASHER WINKELSTEIN,
M.D. ~
THE ultimate cause of peptic ulcer is, as yet, unknown. Ulcer in our opinion is probably not a disease with a unitary etiology. However, the important etiologic agent in most of the cases seems to be a psychosomatic disturbance. 1 Whatever the ultimate cause of ulcer may be, the idea is generally accepted that the actual mechanism of ulcer production is the so-called "acid-pepsin" factor. The following facts attest strongly to the striking importance of the acid-pepsin factor in the mechanism; the location; and in the medical and surgical treatment of peptic ulcers. Peptic ulcer occurs only in acid-pepsin areas. It does not exist actively in the presence of an achlorhydria. Medical measures which best control the acidity throughout the twenty-four hours of the day, such as the author's continuous intra gastric drip therapy, are the most efficient in healing the lesion. 2 • 3 Recurrent jejunal ulcers are not seen after surgical procedures which are followed by achlorhydria such as subtotal gastrectomy with or without vagotomy. Because of these considerations, the medical and surgical gastrointestinal group at The Mount Sinai Hospital has concerned itself largely with this "acid-pepsin" factor during the past twenty-five years. We have carried out numerous clinical, physiologic, statistical and surgical studies in an attempt to elucidate this problem more fully. It is the purpose of this publication to summarize briefly these studies and to emphasize again the central importance of the acidpeptic factor in the problem of the therapy of peptic ulcer. PREOPERATIVE ACIDITY STUDIES
In a series of earlier studies 4 we had found that there is a striking difference in the preoperative gastric acidity in gastric and duodenal ulcer. While it is possible that gastric ulcer at the angle commences in a hyperchlorhydric, hypersecretory milieux, fractional test meal studies have demonstrated that the majority of the cases of chronic From the Medical Department, Mount Sinai Hospital, New York City. ~ Associate Physician, in charge of the Gastrointestinal Clinic, Mount Sinai Hospital, New York, and Associate in Medicine, College of Physicians and Surgeons, Columbia University.
255
256
ASHER WlNKELSTEIN
gastric ulcer exhibit a normal or a low free acidity. Occasionally, there is a transient achlorhydria which is not present in subsequent tests or disappears after a short period of medical therapy. We have been at a loss to explain this somewhat diminished acidity in gastric ulcer. It is probably the result of a gastritis which, located about the ulcer and in the adjacent secretory tissue, acts as an inhibitor to secretion. The gastritis may precede or follow the ulcer. Thus, gastritis plus the retention of the acid-depressant function of the normal duodenum and upper jejunum (due to enterogastrone) seems a sufficient explanation of the lowered acidity in gastric ulcer. Duodenal ulcer, on the other hand, offers a strong contrast in this respect to gastric ulcer. Our earlier studies had revealed the remarkable fact that 80 per cent of our duodenal ulcers exhibited a marked "clinical" hyperchlorhydria and hypersecretion. The other 20 per cent was normal. Achlorhydria in duodenal ulcer has not been encountered. What is the explanation of the marked increase in acidity in duodenal ulcer? As a result of numerous studies, we think that it is permissible to conclude that the primary, cephalic or nervous (vagal) phase of gastric secretion is greatly increased in duodenal ulcer and not in gastric ulcer. When we subject unoperated duodenal ulcer patients to sham feeding (the chewing of an orange), or to insulin hypoglycemia (15 units of insulin intravenously usually induces a blood sugar under 50 mg. per 100 cc., which is a powerful stimulus to the vagus nucleus), there is a very high acidity response. This is not the case in gastric ulcer, at least in respect to sham feeding. Add to this the probability that the presence of a duodenal ulcer disrupts the normal inhibitory mechanism (due to enterogastrone) of the duodenum and upper jejunum and the explanation of duodenal ulcer hyperchlorhydria seems clear. In fact, it is much more easily understandable than is the hyposecretion in gastric ulcer. We shall see that this difference is of fundamental importance in the problem of the surgical therapy of peptic ulcer. POSTOPERATIVE STUDIES
Today, leaving aside for the present a discussion of the operation of complete vagotomy, it is generally conceded that the operation of choice for gastric and duodenal ulcer is subtotal gastrectomy with terminolateral gastrojejunostomy. It is a good operation since it removes the lesion and the associated antrum gastritis; it gives an optimum motor effect; and it abolishes or lowers greatly the gastric acidity. The last, of course, is the sine qua non for the surgical cure of
~
SURGICAL THERAPY OF PEPTIC ULCER
257
ulcer. In an experience of twenty-three years, I have not seen a recurrent jejunal ulcer after a subtotal gastrectomy in which there was an absence of free hydrochloric acid postoperatively. Nor does it seem to matter whether this postoperative achlorhydria is due to neutralization or is a complete achlorhydria. In our earlier studies, in fifty-seven cases of corporeal ulcer (gastric ulcer at the angle) in all but three cases there was a postoperative achlorhydria. In the three cases, there was merely a trace of free acid late after the test meal. A long follow-up of many of these cases has not brought to light a single recurrent jejunal ulcer. "No acid-no ulcer" has long been a dictum. We may paraphrase it by stating "no postoperative free acid-no recurrent ulcer." We may, therefore, safely conclude that subtotal gastrectomy seems to be a complete cure for gastric ulcer at the incisura angularis. With reference to duodenal ulcer, the postoperative acidity, unfortunately, does not present such a bright picture. In our earlier studies we quickly found, to our dismay, that only 55 per cent of our duodenal ulcers revealed a postoperative achlorhydria. In the other 45 per cent, free acidity of varying degrees persisted. In some recent studies which will be published elsewhere in detail, Drs. Albert Cornell, Franklin Hollander and I found that practically the same postoperative acidity figures held true in Dr. Ralph Colp·s more recent series. We found, for example, in one period, in eighteen of twenty cases (90 per cent) of gastric ulcers at the angle, achlorhydria was present. In the same period, thirty-two of fifty-two patients (59 per cent) with duodenal ulcers developed a postoperative achlorhydria. It is quite striking that these percentages practically agree with the earlier series, already cited. Colp and Druckerman also found that the Madlener-Florcken's palliative resection for ulcer high on the lesser curvature is followed by an achlorhydria without recurrences. 5 In the duodenal ulcers with retained free acidity, a not inconsiderable number developed a recurrent jejunal ulcer. The percentage as given by Mage and Hollander was as high as "in the neighborhood of" 9 per cent. 6 While this figure represents probably only one-third of the incidence of jejunal ulcer seen after simple gastroenterostomy, it is, nevertheless, far too high when we consider the magnitude of the operation of subtotal gastrectomy. It seemed to us that a careful study of the preoperative and postoperative acidity in these two groups of patients might prove rewarding in that we might find some technical method of abolishing the
258
ASHER WINKELSTEIN
free acidity after subtotal gastrectomy for duodenal ulcer. Our studies revealed the following: 1. Gastric ulcer exhibits a low acidity preoperatively and postoperatively because of the presumable gastritis, duodenal inhibition, and low vagal tone. 2. Duodenal ulcer exhibits a high pre-operative acidity due to excessive vagal irritability and a lack of normal intestinal inhibition. 3. Persistent postoperative free acidity is found most often in the duodenal ulcer patients with a high preoperative acidity. 4. Recurrent jejunal ulcer occurs practically entirely in the group of duodenal ulcers with a very high preop>erative acidity. 7 5. The postoperative free acidity in duodenal ulcer is completely abolished by atropine sulfate. 6. The addition of vagotomy to subtotal gastrectomy abolishes the postoperative acidity in the majority of the cases.7, S Comment.-It seems apparent that the future attack in the problem of surgical therapy of peptic ulcer should include a careful consideration of the role of the vagus nerves. Supradiaphragmatic bilateral vagotomy alone does not seem to be the answer. Time, experimentation and experience will probably lead us to a combination of subtotal gastrectomy (or even gastroenterostomy) with subdiaphragmatic vagotomy as the operation of choice for duodenal ulcer. s,9 However, supradiaphragmatic vagotomy may be of value in the therapy of recurrent jejunal ulcers. MISCELLANEOUS OBSERVATIONS
Night Secretion.-In over 200 studies of the night secretion in ulcer patients, as contrasted with normals, we have found a hyperchlorhydria and hypersecretion. 1O This observation has been amply confirmed by Henning, Valdez and Dragstedt. We reject Sandweiss' conclusions l l that the night secretion in ulcer patients is no higher than in normals since (1) he used mild ambulatory cases; (2) he aspirated the stomach completely all night, thus interfering with the duodenal regulatory (inhibitory) mechanism, and (3) his test meal was too heavy and too stimulating (containing meat soup, 200 cc. of orange juice, and coHee). It is of interest to note that we found in the patients with subtotal gastrectomy with postoperative achlorhydria that they did not secrete free acid during the night. The Nature of the Postoperative Achlorhydrias.-If one tests the achlorhydrias after a subtotal gastrectomy for gastric ulcer with neutral red and histamine, one finds a failure of the dye's appearance
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j,
I
1 I,
I
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SURGICAL THERAPY OF PEPTIC ULCER
259
and no free acid. This apparently implies a complete achlorhydria. Since ~he fundic secretory tissue with its vagal supply is intact, there must be an inhibition of the secretory cell itself. In the light of our present knowledge, the most logical explanation is a gastritis, whether due to preoperative or postoperative causes. Most of the achlorhydrias following operation for duodenal ulcer, however, show a neutral red secretion and free acid with the above test. This is, therefore, a neutralization achlorhydria. Nevertheless, it is a striking fact that it seems sufficient, in our experience, to prevent recurrent ulcers. SUMMARY AND CONCLUSIONS
1. Peptic ulcer is probably a psychosomatic disease. 2. The immediate mechanism is the acid-pepsin factor. 3. The acidity in gastric ulcer at the angle is usually normal or low. 4. The acidity in duodenal ulcer is high in the majority of duodenal ulcer patients. 5. The low acidity in gastric ulcer is probably due to gastritis and duodenal inhibition. 6. The high acidity in duodenal ulcer is due to the vagus nerves and interference with the duodenal regulatory mechanism. 7. Subtotal gastrectomy is today the operation of choice for both gastric and duodenal ulcer. 8. After subtotal gastrectomy for "angle" gastric ulcer there is practically 100 per cent postoperative achlorhydria. After the palliative operation for high lesser curvature gastric ulcer, there is also an achlorhydria without recurrences. 9. No recurrences are seen in the presence of this achlorhydria. 10. Mter subtotal gastrectomy for duodenal ulcer, achlorhydria occurs only in 55 per cent of cases. 11. Recurrences are frequent (9 per cent) after subtotal gastrectomy for duodenal ulcer with retained free acidity. 12. This retained acidity is probably due to the vagus nerves. 13. Subtotal gastrectomy (or even gastroenterostomy) combined with subdiaphragmatic vagotomy seems to be indicated in the future surgical therapy of duodenal ulcer. 14. There is a; marked nocturnal hypersecretion in peptic ulcer patients. 15. After subtotal gastrectomy, if there is an achlorhydria, the nocturnal acid secretion is also absent. 16. While the postoperative achlorhydria is a complete one in
~
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Ii :11
260
ASHER WINKELSTEIN
gastric ulcer and a neutralization one in duodenal ulcer, either one is sufficient to prevent recurrent ulcer.
REFERENCES 1. Winkelstein, A. and Rothschild, L.: Some Clinical Studies on the Psychosomatic Background of Peptic Ulcer. Am. J. Digest Dis. & Nutrition, 10:99102 (March) 1943. 2. Winkelstein, Asher: Studies in Gastric Secretion During the Night with a Preliminary Note on a New Therapy for Peptic Ulcer. Am. J. Surg., 15:523-528, 1932. 3. Winkelstein, A., Cornell, A. and Hollander, F.: Intragastric Drip Therapy for Peptic Ulcer. A Summary of Ten Years' Experience. J.A.M.A., 120: 743-745, 1942. 4. Winkelstein, Asher: Some Physiological and Pharmacological Aspects of the Gastric Secretory Changes in Peptic Ulcer Before and After Partial Gastrectomy. Tr. Am. Gastroenterol. A. 1933. 5. Colp, Rand Druckerman, L.: A Rational Approach to the Surgery of High Gastric Ulcer. Ann. Surg., 124:675-687. (Oct.) 1946. 6. Hollander, F. and Mage, S.: A Statistical Method for Evaluating the Results of Treatment for Peptic Ulcer. Surg., Gynec. & Obst., 76:533-546 (May) 1943. 7. Winkelstein, A. and Berg, A. A.: Vagotomy Plus Partial Gastrectomy for Duodenal Ulcer. Am. J. Digest Dis. & Nutrition, 5:497-501 ( Oct. 19). 8. Winkelstein, Asher: Vagotomy Plus Subtotal Gastrectomy for Peptic Ulcer. Tr. Am. Gastroenterol. A., 1046. (In press.) 9. Weinstein, V. A., Colp, R, Hollander, F. and Jemerin, E. E.: Vagotomy in the Therapy of Peptic Ulcer. Surg., Gynec. & Obst., 79:297-305. (Sept.) 1944. 10. Winkelstein, Asher: One Hundred and Sixty-nine Studies in Gastric Secretion During the Night. Am. J. Digest Dis. & Nutrition, 1:778-782, 1946. 11. Sandweiss, David, et al.: Nocturnal Gastric Secretion. Gastroenterology, 7:38-55 (July) 1946.
1
!
THE SIGMFICANCE OF THE GASTRIC ACIDITY IN THE SURGICAL THERAPY OF PEPTIC ULCER ASHER WINKELSTEIN,
M.D. ~
THE ultimate cause of peptic ulcer is, as yet, unknown. Ulcer in our opinion is probably not a disease with a unitary etiology. However, the important etiologic agent in most of the cases seems to be a psychosomatic disturbance. 1 Whatever the ultimate cause of ulcer may be, the idea is generally accepted that the actual mechanism of ulcer production is the so-called "acid-pepsin" factor. The following facts attest strongly to the striking importance of the acid-pepsin factor in the mechanism; the location; and in the medical and surgical treatment of peptic ulcers. Peptic ulcer occurs only in acid-pepsin areas. It does not exist actively in the presence of an achlorhydria. Medical measures which best control the acidity throughout the twenty-four hours of the day, such as the author's continuous intra gastric drip therapy, are the most efficient in healing the lesion. 2 • 3 Recurrent jejunal ulcers are not seen after surgical procedures which are followed by achlorhydria such as subtotal gastrectomy with or without vagotomy. Because of these considerations, the medical and surgical gastrointestinal group at The Mount Sinai Hospital has concerned itself largely with this "acid-pepsin" factor during the past twenty-five years. We have carried out numerous clinical, physiologic, statistical and surgical studies in an attempt to elucidate this problem more fully. It is the purpose of this publication to summarize briefly these studies and to emphasize again the central importance of the acidpeptic factor in the problem of the therapy of peptic ulcer. PREOPERATIVE ACIDITY STUDIES
In a series of earlier studies 4 we had found that there is a striking difference in the preoperative gastric acidity in gastric and duodenal ulcer. While it is possible that gastric ulcer at the angle commences in a hyperchlorhydric, hypersecretory milieux, fractional test meal studies have demonstrated that the majority of the cases of chronic From the Medical Department, Mount Sinai Hospital, New York City. ~ Associate Physician, in charge of the Gastrointestinal Clinic, Mount Sinai Hospital, New York, and Associate in Medicine, College of Physicians and Surgeons, Columbia University.
255
256
ASHER WlNKELSTEIN
gastric ulcer exhibit a normal or a low free acidity. Occasionally, there is a transient achlorhydria which is not present in subsequent tests or disappears after a short period of medical therapy. We have been at a loss to explain this somewhat diminished acidity in gastric ulcer. It is probably the result of a gastritis which, located about the ulcer and in the adjacent secretory tissue, acts as an inhibitor to secretion. The gastritis may precede or follow the ulcer. Thus, gastritis plus the retention of the acid-depressant function of the normal duodenum and upper jejunum (due to enterogastrone) seems a sufficient explanation of the lowered acidity in gastric ulcer. Duodenal ulcer, on the other hand, offers a strong contrast in this respect to gastric ulcer. Our earlier studies had revealed the remarkable fact that 80 per cent of our duodenal ulcers exhibited a marked "clinical" hyperchlorhydria and hypersecretion. The other 20 per cent was normal. Achlorhydria in duodenal ulcer has not been encountered. What is the explanation of the marked increase in acidity in duodenal ulcer? As a result of numerous studies, we think that it is permissible to conclude that the primary, cephalic or nervous (vagal) phase of gastric secretion is greatly increased in duodenal ulcer and not in gastric ulcer. When we subject unoperated duodenal ulcer patients to sham feeding (the chewing of an orange), or to insulin hypoglycemia (15 units of insulin intravenously usually induces a blood sugar under 50 mg. per 100 cc., which is a powerful stimulus to the vagus nucleus), there is a very high acidity response. This is not the case in gastric ulcer, at least in respect to sham feeding. Add to this the probability that the presence of a duodenal ulcer disrupts the normal inhibitory mechanism (due to enterogastrone) of the duodenum and upper jejunum and the explanation of duodenal ulcer hyperchlorhydria seems clear. In fact, it is much more easily understandable than is the hyposecretion in gastric ulcer. We shall see that this difference is of fundamental importance in the problem of the surgical therapy of peptic ulcer. POSTOPERATIVE STUDIES
Today, leaving aside for the present a discussion of the operation of complete vagotomy, it is generally conceded that the operation of choice for gastric and duodenal ulcer is subtotal gastrectomy with terminolateral gastrojejunostomy. It is a good operation since it removes the lesion and the associated antrum gastritis; it gives an optimum motor effect; and it abolishes or lowers greatly the gastric acidity. The last, of course, is the sine qua non for the surgical cure of
~
SURGICAL THERAPY OF PEPTIC ULCER
257
ulcer. In an experience of twenty-three years, I have not seen a recurrent jejunal ulcer after a subtotal gastrectomy in which there was an absence of free hydrochloric acid postoperatively. Nor does it seem to matter whether this postoperative achlorhydria is due to neutralization or is a complete achlorhydria. In our earlier studies, in fifty-seven cases of corporeal ulcer (gastric ulcer at the angle) in all but three cases there was a postoperative achlorhydria. In the three cases, there was merely a trace of free acid late after the test meal. A long follow-up of many of these cases has not brought to light a single recurrent jejunal ulcer. "No acid-no ulcer" has long been a dictum. We may paraphrase it by stating "no postoperative free acid-no recurrent ulcer." We may, therefore, safely conclude that subtotal gastrectomy seems to be a complete cure for gastric ulcer at the incisura angularis. With reference to duodenal ulcer, the postoperative acidity, unfortunately, does not present such a bright picture. In our earlier studies we quickly found, to our dismay, that only 55 per cent of our duodenal ulcers revealed a postoperative achlorhydria. In the other 45 per cent, free acidity of varying degrees persisted. In some recent studies which will be published elsewhere in detail, Drs. Albert Cornell, Franklin Hollander and I found that practically the same postoperative acidity figures held true in Dr. Ralph Colp·s more recent series. We found, for example, in one period, in eighteen of twenty cases (90 per cent) of gastric ulcers at the angle, achlorhydria was present. In the same period, thirty-two of fifty-two patients (59 per cent) with duodenal ulcers developed a postoperative achlorhydria. It is quite striking that these percentages practically agree with the earlier series, already cited. Colp and Druckerman also found that the Madlener-Florcken's palliative resection for ulcer high on the lesser curvature is followed by an achlorhydria without recurrences. 5 In the duodenal ulcers with retained free acidity, a not inconsiderable number developed a recurrent jejunal ulcer. The percentage as given by Mage and Hollander was as high as "in the neighborhood of" 9 per cent. 6 While this figure represents probably only one-third of the incidence of jejunal ulcer seen after simple gastroenterostomy, it is, nevertheless, far too high when we consider the magnitude of the operation of subtotal gastrectomy. It seemed to us that a careful study of the preoperative and postoperative acidity in these two groups of patients might prove rewarding in that we might find some technical method of abolishing the
258
ASHER WINKELSTEIN
free acidity after subtotal gastrectomy for duodenal ulcer. Our studies revealed the following: 1. Gastric ulcer exhibits a low acidity preoperatively and postoperatively because of the presumable gastritis, duodenal inhibition, and low vagal tone. 2. Duodenal ulcer exhibits a high pre-operative acidity due to excessive vagal irritability and a lack of normal intestinal inhibition. 3. Persistent postoperative free acidity is found most often in the duodenal ulcer patients with a high preoperative acidity. 4. Recurrent jejunal ulcer occurs practically entirely in the group of duodenal ulcers with a very high preop>erative acidity. 7 5. The postoperative free acidity in duodenal ulcer is completely abolished by atropine sulfate. 6. The addition of vagotomy to subtotal gastrectomy abolishes the postoperative acidity in the majority of the cases.7, S Comment.-It seems apparent that the future attack in the problem of surgical therapy of peptic ulcer should include a careful consideration of the role of the vagus nerves. Supradiaphragmatic bilateral vagotomy alone does not seem to be the answer. Time, experimentation and experience will probably lead us to a combination of subtotal gastrectomy (or even gastroenterostomy) with subdiaphragmatic vagotomy as the operation of choice for duodenal ulcer. s,9 However, supradiaphragmatic vagotomy may be of value in the therapy of recurrent jejunal ulcers. MISCELLANEOUS OBSERVATIONS
Night Secretion.-In over 200 studies of the night secretion in ulcer patients, as contrasted with normals, we have found a hyperchlorhydria and hypersecretion. 1O This observation has been amply confirmed by Henning, Valdez and Dragstedt. We reject Sandweiss' conclusions l l that the night secretion in ulcer patients is no higher than in normals since (1) he used mild ambulatory cases; (2) he aspirated the stomach completely all night, thus interfering with the duodenal regulatory (inhibitory) mechanism, and (3) his test meal was too heavy and too stimulating (containing meat soup, 200 cc. of orange juice, and coHee). It is of interest to note that we found in the patients with subtotal gastrectomy with postoperative achlorhydria that they did not secrete free acid during the night. The Nature of the Postoperative Achlorhydrias.-If one tests the achlorhydrias after a subtotal gastrectomy for gastric ulcer with neutral red and histamine, one finds a failure of the dye's appearance
ii
Ii
"
I:
I
,r
j,
I
1 I,
I
I
SURGICAL THERAPY OF PEPTIC ULCER
259
and no free acid. This apparently implies a complete achlorhydria. Since ~he fundic secretory tissue with its vagal supply is intact, there must be an inhibition of the secretory cell itself. In the light of our present knowledge, the most logical explanation is a gastritis, whether due to preoperative or postoperative causes. Most of the achlorhydrias following operation for duodenal ulcer, however, show a neutral red secretion and free acid with the above test. This is, therefore, a neutralization achlorhydria. Nevertheless, it is a striking fact that it seems sufficient, in our experience, to prevent recurrent ulcers. SUMMARY AND CONCLUSIONS
1. Peptic ulcer is probably a psychosomatic disease. 2. The immediate mechanism is the acid-pepsin factor. 3. The acidity in gastric ulcer at the angle is usually normal or low. 4. The acidity in duodenal ulcer is high in the majority of duodenal ulcer patients. 5. The low acidity in gastric ulcer is probably due to gastritis and duodenal inhibition. 6. The high acidity in duodenal ulcer is due to the vagus nerves and interference with the duodenal regulatory mechanism. 7. Subtotal gastrectomy is today the operation of choice for both gastric and duodenal ulcer. 8. After subtotal gastrectomy for "angle" gastric ulcer there is practically 100 per cent postoperative achlorhydria. After the palliative operation for high lesser curvature gastric ulcer, there is also an achlorhydria without recurrences. 9. No recurrences are seen in the presence of this achlorhydria. 10. Mter subtotal gastrectomy for duodenal ulcer, achlorhydria occurs only in 55 per cent of cases. 11. Recurrences are frequent (9 per cent) after subtotal gastrectomy for duodenal ulcer with retained free acidity. 12. This retained acidity is probably due to the vagus nerves. 13. Subtotal gastrectomy (or even gastroenterostomy) combined with subdiaphragmatic vagotomy seems to be indicated in the future surgical therapy of duodenal ulcer. 14. There is a; marked nocturnal hypersecretion in peptic ulcer patients. 15. After subtotal gastrectomy, if there is an achlorhydria, the nocturnal acid secretion is also absent. 16. While the postoperative achlorhydria is a complete one in
~
:
Ii :11
260
ASHER WINKELSTEIN
gastric ulcer and a neutralization one in duodenal ulcer, either one is sufficient to prevent recurrent ulcer.
REFERENCES 1. Winkelstein, A. and Rothschild, L.: Some Clinical Studies on the Psychosomatic Background of Peptic Ulcer. Am. J. Digest Dis. & Nutrition, 10:99102 (March) 1943. 2. Winkelstein, Asher: Studies in Gastric Secretion During the Night with a Preliminary Note on a New Therapy for Peptic Ulcer. Am. J. Surg., 15:523-528, 1932. 3. Winkelstein, A., Cornell, A. and Hollander, F.: Intragastric Drip Therapy for Peptic Ulcer. A Summary of Ten Years' Experience. J.A.M.A., 120: 743-745, 1942. 4. Winkelstein, Asher: Some Physiological and Pharmacological Aspects of the Gastric Secretory Changes in Peptic Ulcer Before and After Partial Gastrectomy. Tr. Am. Gastroenterol. A. 1933. 5. Colp, Rand Druckerman, L.: A Rational Approach to the Surgery of High Gastric Ulcer. Ann. Surg., 124:675-687. (Oct.) 1946. 6. Hollander, F. and Mage, S.: A Statistical Method for Evaluating the Results of Treatment for Peptic Ulcer. Surg., Gynec. & Obst., 76:533-546 (May) 1943. 7. Winkelstein, A. and Berg, A. A.: Vagotomy Plus Partial Gastrectomy for Duodenal Ulcer. Am. J. Digest Dis. & Nutrition, 5:497-501 ( Oct. 19). 8. Winkelstein, Asher: Vagotomy Plus Subtotal Gastrectomy for Peptic Ulcer. Tr. Am. Gastroenterol. A., 1046. (In press.) 9. Weinstein, V. A., Colp, R, Hollander, F. and Jemerin, E. E.: Vagotomy in the Therapy of Peptic Ulcer. Surg., Gynec. & Obst., 79:297-305. (Sept.) 1944. 10. Winkelstein, Asher: One Hundred and Sixty-nine Studies in Gastric Secretion During the Night. Am. J. Digest Dis. & Nutrition, 1:778-782, 1946. 11. Sandweiss, David, et al.: Nocturnal Gastric Secretion. Gastroenterology, 7:38-55 (July) 1946.
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