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People with implantable cardiac defibrillators (ICDs) who are nearing the end of life are at risk for arrhythmias, which activate the ICD and may cause unnecessary shocks and suffering. Because ICDs have enabled more patients to live longer, they often succumb to noncardiac diseases and may be cared for by primary care physicians. Despite published recommendations 10 years ago regarding the management of ICDs during the end of life, over half of patients with ICDs who are dying still have not been offered the choice of deactivation. The Coronavirus disease 2019 (COVID-19) pandemic has complicated this issue and the need to discuss it because of practices that separate patients from loved ones and that modify the usual interactions of patients with doctors and nurses. We offer the following recommendations: (1) the management of ICDs at the end-of-life needs to be understood by all physicians who care for patients with ICDs; (2) discussions about deactivating the ICD should occur while patients have decision-making capacity and are clinically stable, beginning at the time of ICD implantation, then periodically at follow-up appointments, and certainly when a change in the patient's clinical status warrants a reconsideration of the goals of care; and (3) clinicians should compensate for the impediments to communication with patients and families associated with the COVID-19 pandemic, which includes patient isolation and restrictive visitor policies, by using devices that permit visual communication to reexamine goals of care, including defibrillator deactivation, in patients with ICDs who are expected to die., Competing Interests: Conflict of interest: None., (© Copyright 2021 by the American Board of Family Medicine.)

Ethical issues have become increasingly important in gastroenterology research. This is for several reasons, including (i) an understanding of how conflicts of interest might affect research, (ii) the influence of the drug and device industries on research, (iii) ghostwriting (taking credit for something you did not write), (iv) the occurrence of ethically inappropriate research and scientific misconduct, and (v) respect for the rights of research subjects. These include the rights (i) to give informed consent to participate after understanding the purposes, risks, and benefits of the research; (ii) to ask questions; and (iii) to withdraw from participation at any time. Notions of doing good (beneficence), avoiding harm (non-maleficence), confidentiality, and, most important, the primacy of the welfare of the patient or research subject can be traced to antiquity. In the modern era, the Nuremburg Code (1947), the Declaration of Helsinki (1964), the Belmont report (1979), and other events and reports have led to the refinement of ethical practices in both clinical and research domains, have reinforced those long observed principles, and have given rise to the newer principles of autonomy and justice. The ethical conduct of research not only promotes good research but also is in the best interests of research subjects, investigators, sponsors, patients, and the public., (© 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Physicians often are asked for advice about medical matters by relatives and friends. These range from requests for simple information to requests for medical opinion and judgment and more substantial involvement by the physician. I comment on the motivations and expectations of the requester and the physician, and the legal, ethical, and practical considerations related to such requests. I recommend: (1) Be clear about the expectations of the requester and yourself, including whether you are being asked for simple factual information, your medical judgment and opinion, or more substantial involvement in the situation. (2) Treat your interactions with relatives or friends with the same professional expertise and judgment as you would any patient. (3) Be aware that a physical examination and especially charging a fee strengthen the establishment of a legal relationship with the requester as your patient. (4) Respect the requester's autonomy and confidentiality and conform to HIPAA requirements where applicable. (5) Be aware of the potential conflict between your roles as a relative or friend and as a physician.

The pathogenesis of peptic ulcer disease is multifactorial, including the effects of Helicobacter pylori, gastric acid, pepsin, gastroduodenal motility, smoking and nicotine, and the complex interaction of an array of other so-called aggressive and protective factors. Since the discovery and acceptance of H. pylori as a major etiologic agent in peptic ulcer disease, the role of smoking has received less attention. Smokers are more likely to develop ulcers, ulcers in smokers are more difficult to heal, and ulcer relapse is more likely in smokers. These clinical observations may be explained by the adverse effects that smoking has on mucosal aggressive and protective factors. Of the aggressive factors, smoking appears to have no consistent effect on acid secretion. However, smoking impairs the therapeutic effects of histamine-2 antagonists, may stimulate pepsin secretion, promotes reflux of duodenal contents into the stomach, increases the risk for and harmful effects of H. pylori, and increases production of free radicals, vasopressin, secretion by the pituitary, secretion of endothelin by the gastric mucosa, and production of platelet activating factor. Smoking also affects the mucosal protective mechanisms. It decreases gastric mucosal blood flow and inhibits gastric mucous secretion, gastric prostaglandin generation, salivary epidermal growth factor secretion, duodenal mucosal bicarbonate secretion, and pancreatic bicarbonate secretion. These adverse effects of smoking on aggressive and protective factors quality it as an important contributor to the pathogenesis of peptic ulcer disease and indicate that smoking plays a significant facilitative role in the development and maintenance of peptic ulcer disease.

Dietary supplements of calcium, vitamins A, C, and E, carotenoids, and omega-3 fatty acids can reduce the yield of experimental cancers in animals and reverse the pattern of abnormal epithelial proliferation in animals and humans. Epidemiological studies indicate that diets containing high amounts of these agents convey a protective effect against the development of colon cancer. Moreover, regular aspirin use in humans appears to reduce the risk of colon cancer and sulindac causes regression of polyps in patients with familial polyposis. These agents are promising for the prevention of human colorectal cancer, but their efficacy has not yet been shown in prospective, controlled trials. Thus, although it is tempting to speculate that in the future we may treat our patients who have a predisposition to colon polyps and cancer, or even healthy people at average risk, with such ordinary supplements as calcium, vitamins, fish oil, or aspirin, such advice at this time is premature.

Renewal of the gastrointestinal (GI) epithelium fulfills the normal functions of maintaining the integrity of the mucosa, repairing mucosal injury, and replenishing the specialized cells of the epithelium. Alterations in epithelial renewal also are intimately involved in transformation of the epithelium to benign and malignant neoplasms. Certain abnormalities in epithelial proliferation, including an increase in the rate of proliferation and expansion of proliferating cells beyond the normal zone of proliferation, are closely linked to the predisposition for and frank development of GI cancer. These abnormalities are common to all human premalignant conditions studied, including Barrett's epithelium, chronic gastritis, inflammatory bowel disease, and colon polyps; they also occur in experimental carcinogenesis. The same proliferative abnormalities have also been observed in some relatives of patients with colon neoplasms who themselves do not have any colon polyps or cancer. Several agents, including calcium, vitamins A, C, and E, and omega-3 fatty acids, have been shown to reverse the abnormal proliferation under some laboratory and clinical conditions. Moreover, some nonsteroidal anti-inflammatory drugs appear to decrease the size of colon polyps in familial polyposis and to reduce the risk for colon cancer in the general population. We await further clinical trials that will indicate whether such ordinary supplements as calcium, vitamins, fish oil, or aspirin have a role in the treatment of patients with premalignant conditions of the gastrointestinal tract.

Previous studies have shown that cigarette smoking depresses prostaglandin generation by human gastric mucosa, but the component of smoke that is responsible for that action is not known. To investigate whether nicotine has a direct effect on gastric mucosal prostaglandin generation, we performed the following study. Eight rats were sacrificed and the stomachs removed. Using a biopsy forceps, small pieces of gastric mucosa were resected and placed in incubation vials containing either buffered Krebs solution alone (control), Krebs solution plus indomethacin (5 micrograms/ml), or Krebs solution plus one of several concentrations of nicotine ditartrate (10, 100, 500, 1000 ng/ml). The nicotine concentrations we used ranged below and above the plasma nicotine concentrations of smokers shortly after smoking cigarettes. Three separate incubations of gastric mucosa were performed per experimental group from each animal. After 30 min of incubation, prostaglandin E2 and 6-keto-prostaglandin F1 alpha concentrations in the incubation medium were measured by radioimmunoassay. We found that nicotine at any concentration tested had no effect on the generation of prostaglandin E2 and 6-keto-prostaglandin F1 alpha by rat gastric mucosa. Thus, this study indicates that, if nicotine is involved in the depression of prostaglandin generation in the gastric mucosa of smokers, its role is an indirect one and not by direct action on the gastric mucosa.

To determine the effect of different doses of hydrocortisone sodium succinate (HC) on rat gastric mucosal prostaglandin synthesis, two experiments were performed. In the first experiment, 20 male Lewis rats were divided into 4 groups of 5 rats each and gavaged either with 2 ml of water (control) or different concentrations of HC (10 mg/ml, 100 mg/ml and 500 mg/ml). In the second experiment in a similar design, lower doses of HC were used (water, 0.1 mg/ml, 0.50 mg/ml and 5.0 mg/ml). The rats were killed after 1 h and three 3 x 3 mm pieces of gastric tissue were removed from each rat and incubated for the determination of prostaglandin E2 and 6-keto-prostaglandin F1 alpha accumulation in the medium measured by radioimmunoassay. At low doses HC inhibits rat gastric mucosal prostaglandin synthesis whereas at higher doses HC stimulates it. This biphasic effect of HC on gastric mucosal prostaglandin synthesis may help explain its role in ulcerogenesis.

The constant rapid renewal of the epithelium of the gastrointestinal (GI) tract is important in the development of neoplasms that are derived from the epithelium as well as in maintaining the functional integrity of the mucosa. An abnormality of epithelial proliferation, characterized by an increase in numbers of proliferating cells and expansion of the proliferative zone, is common to all human premalignant conditions of the GI tract that have been studied, including Barrett's epithelium, chronic gastritis, ulcerative colitis, and colonic polyps, and is a consistent observation after the use of experimental carcinogens, such as N-methyl-N-amylnitrosamine and N-methyl-N'-nitro-N-nitrosoguanidine. These abnormalities also have been observed in some relatives of patients with colonic polyps or cancers who themselves do not have any demonstrable colonic lesion. Calcium, vitamins A, C, and E, and other agents have been shown to reverse the abnormalities in proliferation in some experimental and clinical conditions, which raises the question of whether some of these agents can be used to reduce the risk of development of cancer in patients with known premalignant conditions of the GI tract.

We have previously shown that chronic sucralfate ingestion stimulates gastric epithelial proliferation in rats, which may explain one of the beneficial effects of sucralfate in healing of peptic ulcers. In a separate study, we have found that chronic steroid administration delays the healing of experimental gastric ulcers in rats. This study was designed to test the beneficial effects of sucralfate, cimetidine, and lansoprazole (AG-1749, a new proton pump inhibitor), on the delayed healing by steroids in rat chronic gastric ulcers. Chronic gastric ulcers were produced in male Wistar rats, weighing 180 g, by the application of 100% acetic acid. The rats were randomly divided into five groups; (1) control, (2) vehicle alone, (3) 10 mg/kg lansoprazole, (4) 500 mg/kg sucralfate, and (5) 100 mg/kg cimetidine. Except for controls, all rats received daily intraperitoneal injections of 2.5 mg/kg hydrocortisone sodium phosphate. Tested drugs were administered intragastrically (lansoprazole and sucralfate) or intraperitoneally (cimetidine) twice a day for 2 weeks. Rats were sacrificed 14 days later and ulcer size was measured. Chronic administration of hydrocortisone sodium phosphate resulted in a significant delay of ulcer healing induced by acetic acid. Treatment with either lansoprazole or sucralfate abolished the deleterious effect of steroids, whereas cimetidine had no effect. These results indicate that lansoprazole and sucralfate overcome the delayed healing by steroids of chronic gastric ulcers in the rat.

To determine whether Helicobacter pylori has an effect on gastroduodenal mucosal prostaglandin generation, mucosal biopsies were obtained from the gastric body, antrum, and duodenal bulb of 30 patients who were undergoing upper gastrointestinal endoscopy for clinical indications. One biopsy from the gastric body and one from the antrum were tested for urease activity (urea broth) and one biopsy from each area including the duodenum was processed for histology. Two other biopsies form each area were incubated and the accumulation of prostaglandin E2 and 6-keto prostaglandin F1 alpha in the incubation medium was measured by radioimmunoassay. Twelve of the 17 H. pylori-positive patients and seven of the 13 H. pylori-negative patients agreed to take bismuth subsalicylate (Pepto-Bismol) two tablets four times a day for four weeks. One week after treatment, these patients again underwent endoscopy and the above studies. This study indicates that: (1) mucosal PGE2 generation may be increased in the duodenum, gastric body, and antrum in H. pylori-positive patients compared to H. pylori-negative patients, and (2) treatment with bismuth subsalicylate for four weeks results in reduction of mucosal PGE2 in the duodenum, gastric body, and antrum of H. pylori-positive patients and fails to eradicate H. pylori or reduce gastric inflammation.

The constant, rapid renewal of the gastroduodenal epithelium is an important mechanism of mucosal protection because it maintains the functional integrity of the epithelium. It also is necessary for the repair of mucosal injury. Aspirin, indomethacin, and ethanol all have been shown to stimulate epithelial proliferation in the experimental setting. The stimulatory effects of these agents may be a compensatory reaction to mild injury and may contribute to the process of mucosal adaptation. On the other hand, corticosteroids, physiologic stress, and smoking appear to depress epithelial proliferation, which could render the mucosa susceptible to the effects of other ulcerogens as well as retard the healing of existing mucosal lesions. Epithelial proliferation in mucosa adjacent to active duodenal ulcers as well as from nonulcerated duodenitis is increased when compared to normal-appearing mucosa. This stimulation of epithelial proliferation may be caused by inflammation; it is not known whether ulcer patients have a defect in epithelial proliferation that precedes ulceration. Although prostaglandins (PGs) protect ulceration. Although prostaglandins (PGs) protect the gastroduodenal mucosa, the weight of evidence indicates that PGs do not have a primary effect on epithelial proliferation but rather retard senescence and loss of epithelial cells. The result is thickening of the mucosa, which may contribute to the protective effects of PGs. Ulcerogenic agents or conditions may either depress epithelial proliferation, which predisposes to ulceration or the ulcerogenic effects of other ulcerogens, or result in a hyperproliferative response, which may contribute to the process of mucosal adaptation and protection.

We have previously shown that chronic steroid administration delays the healing of experimental gastric ulcers in rats. This study was designed to test the beneficial effects of 16,16-dimethylprostaglandin E2 or TRY-200, a stable prostaglandin I2 analogue, on the delayed healing by hydrocortisone (HC) of chronic gastric ulcers in rats. Chronic gastric ulcers were produced in male Wistar rats, weighing 180 g, by serosal application of 100% acetic acid. The rats were randomly divided into six groups: (1) saline, (2) saline, HC-treated, (3) 10 micrograms/kg of 16,16-dimethylprostaglandin E2, (4) TRY-200, a stable prostaglandin I2 analogue, at 5 micrograms/kg, or (5) 10 micrograms/kg, or (6) 30 micrograms/kg. All rats, except for control, were given daily intraperitoneal injection of 2.5 mg/kg of HC sodium phosphate. Tested drugs were administered intragastrically twice a day for 2 weeks. Rats were killed 14 days later and ulcer size was measured. Chronic administration of HC sodium phosphate resulted in a significant delay of ulcer healing induced by acetic acid. Treatment with TRY-200 at 10 or 30 micrograms/kg abolished the deleterious effect of steroids, whereas 16,16-dimethylprostaglandin E2 had no effect. These results indicate that prostaglandin I2 is more effective than prostaglandin E2 in reversing the delayed healing by steroids of chronic gastric ulcers in the rat.

To study the effects of a single parenteral dose of indomethacin on gastric epithelial proliferation, we performed the following study. Male Wistar rats weighing about 200 g were divided into two groups and given single intraperitoneal injections of indomethacin 5 mg/kg, either suspended in 0.5% carboxymethyl cellulose sodium salt or vehicle alone, after an overnight fast. After 6 h, all rats were injected by tail vein with tritiated thymidine, 1 microCi/g body weight, to label proliferating cells and were killed 1 h later. Sections from fundic and antral mucosae were processed for light autoradiography. Parenteral indomethacin resulted in spotty erosions in fundic mucosa. Histologically, there was congestion with or without epithelial disruption. These areas were excluded in the proliferation measurements. There was a significant decrease not only in the number of labeled cells but also in the thickness of the proliferative zone with the thinning of the entire mucosal thickness in the fundic mucosa. None of the measurements in antral mucosa showed significant difference. These results showed that a single parenteral injection of indomethacin inhibits epithelial proliferation and decreases mucosal thickness in fundic, but not antral mucosa of the rat.

Unlabelled: To study the effects of (a) cold restraint stress and (b) adrenalectomy in association with cold restraint stress on gastric mucosal ulceration and prostaglandin generation, we performed two experiments. In the first, 40 rats were divided into four groups of 10 rats each: (a) unstressed and (b) stressed for 0.5 h, (c) stressed for 2 h, and (d) stressed for 4 h. In the second experiment, another 80 rats were divided into four groups of 20 rats each: (a) adrenalectomy plus cold restraint stress for 2 h, (b) adrenalectomy plus no stress, (c) sham operated plus 2 h of stress, and (d) sham operated plus no stress. In both experiments we recorded an ulcer index and measured mucosal generation of prostaglandin E2 (PGE2) and prostaglandin I2 (6-keto-PGF1a)., In Conclusion: (a) Cold restraint stress is associated with a time-dependent decrease in gastric mucosal PGE2 generation, but no change in 6-keto-PGF1a generation, and an increase in mucosal injury that is maximal by 2 h. (b) Adrenalectomy augments the effects of stress on mucosal injury but has no effect on prostaglandin generation; thus, the ulcerogenic effect of adrenalectomy appears to be independent of an effect on prostaglandin generation.

We administered intravenous ergonovine maleate to 14 patients with chest pain resembling angina pectoris and to four healthy volunteers. Five of the patients experienced their typical chest pain after ergonovine, and manometric signs of esophageal spasm also developed. The remaining nine patients and the four volunteers did not experience chest pain, but all subjects except one had some symptomatic response to ergonovine, including chest warmth or heaviness, headache, mild choking sensation, facial numbness, flushing, or nausea. Two of the nine patients and one of the four volunteers developed manometric signs of esophageal spasm after ergonovine but experienced no chest pain. Intravenous ergonovine may be useful to identify esophageal spasm in selected patients with chest pain who have normal coronary arteries or in whom coronary artery disease is insufficient to explain symptoms. However, we believe that the potential risks of ergonovine do not justify its routine use as a provocative agent for esophageal spasm.

Acid-induced esophageal injury in the cat, produced by infusion of 0.1 N HCl (1 ml/min for 30 min) on 4 consecutive days, has been shown previously to adversely affect lower esophageal sphincter (LES) pressure. We studied the role of prostaglandins in acid-induced esophagitis and the associated LES hypotension by simultaneous treatment of some animals with indomethacin (150 micrograms/kg intravenous), a specific inhibitor of prostaglandin synthesis, either during production of esophagitis or during recovery. LES pressures and esophageal histology were compared to control groups which received acid alone. Indomethacin treatment resulted in more rapid healing of the esophageal inflammation and prevented or promptly corrected the esophagitis-associated LES hypotension. These studies provide further evidence that prostaglandins play an important role in the pathogenesis of acid-induced esophagitis and LES hypotension and raise the possibility that indomethacin, a prostaglandin synthetase inhibitor, may be of benefit in prevention or therapy of esophagitis.

Recent reports of the association of cimetidine treatment with the development of gastric carcinoma stimulated us to study the effect of chronic cimetidine ingestion on epithelial proliferation in the stomach of male Wistar/Lewis rats. One group of rats received cimetidine in the drinking water to deliver 150-200 mg/kg/day. Control rats received plain water. To label proliferating cells, the rats were injected by tail vein with tritiated thymidine 1 hr before sacrifice at 1, 6, and 12 months. Sections of fundus and antrum were processed for light autoradiography. We found no histological evidence for malignant change and no effect on the measurements of epithelial proliferation by cimetidine in either fundus or antrum at any of the times studied, with the possible exception of an upward shift in the distribution of labeled cells within the proliferative zone of the fundus after 6 months. Thus, under the conditions of our experiments we have been unable to identify an effect of cimetidine on epithelial proliferation which would implicate it as a chemical carcinogen.

Bile salts break the gastric mucosal barrier. To explain this, the suggestion has been made that bile salts may disrupt surface epithelial cell membranes or break the tight junctions between cells, but appropriate ultrastructural studies are lacking. We therefore instilled control and bile salt-containing solutions into the stomachs of fasted mice at pH, 1, 3, 5, AND 7. Taurocholate (pKa equals 1.8) caused mucosal injury only at pH 1, whereas glycochenodeoxycholate (pKa equals 4.2) injured the mucosa at pH 1 and 3. By electron microscopy, areas of mild mucosal injury were characterized by clumping of nuclear chromatin and loss of cytoplasmic density within surface mucous cells. The apical cell membranes and tight junctions remained intact. In areas of severe damage surface cells were ruptured but tight junctions still appeared unbroken. These studies indicate that acid pH markedly augments the damaging effects of bile salts on mouse gastric mucosa. Moreover, as an initial step in the mechanism of bile salt-induced gastric injury, the nonionized moiety of a given bile salt which exists below its pKa may be important in altering the gastric surface epithelial cell in a way which allows the ingress of bile salt and/or hydrogen ion to cause intracellular damage.

The natural history of peptic ulcer disease shows a high rate of recurrence over the short term, with the recurrence rate decreasing over a period of many years. Drug therapy does not appear to alter the natural history of the disease. Smoking increases the risk of ulcer recurrence by increasing the rate of gastric emptying, diminishing the secretion of pancreatic bicarbonate, decreasing duodenal luminal pH, reducing mucosal blood flow, and inhibiting mucosal prostaglandin synthesis. There is a probable role for routine maintenance therapy in patients with known recurrent ulcer disease.

Common GI disorders merit special attention when the patient is elderly. The author's recommendations for diagnosing and managing GI bleeding, swallowing disorders, ulcers, and other problems are tailored to the frail older patient. Follow-up guidelines stress the search for malignancy.

A 65-year-old woman suffered from both chronic gastroesophageal reflux, which was complicated by columnar metaplasia (Barrett's epithelium), and profound hypothyroidism. An esophageal motility tracing showed absence of peristalsis in the lower esophagus and the lower esophageal sphincter (LES) could not be identified. Thyroid replacement therapy, in conjunction with antacid and cimetidine treatment, was associated not only with improvement in the gastroesophageal reflux symptoms, but also with a return of esophageal peristalsis and LES pressure to normal. To support our clinical observations, we rendered four cats hypothyroid with 131I and documented a fall in LES pressure. We propose that abnormal smooth-muscle function of the esophagus may be another manifestation of the gastrointestinal motility disturbances which are associated with hypothyroidism.

The aim of this study was to determine whether parenteral administration of steroids affects epithelial renewal in hamster stomach. Male golden hamsters received either hydrocortisone sodium succinate or saline intraperitoneally for three days. In the first experiment, hamsters were sacrificed 1 hr after injection of tritiated thymidine [( 3H]TdR) to label proliferating cells. In the second experiment, hamsters were sacrificed hourly after a single [3H]TdR injection up to 48 hr in order to determine cell cycle time by the method of fraction of labeled mitoses. In the third experiment, hamsters were sacrificed 1, 24, and 72 hr after [3H]TdR injection for the study of epithelial migration and cell turnover time. Sections of fundic and antral mucosae were prepared for light autoradiography. Steroid treatment caused no gross or microscopic injury to gastric mucosa, but the number of [3H]TdR-labeled cells as well as the thickness of the proliferative zone were reduced significantly in fundic mucosa, but not in antral mucosa. The study of the fraction labeled mitoses indicated that steroid treatment lengthened the cell cycle time in fundic mucosa, which was due primarily to prolonged G1 and DNA synthesis phases. Furthermore, epithelial migration was significantly slower in fundic mucosa after steroid treatment, which was associated with a prolonged cell turnover time. Thus, parenteral steroids depress the entire process of epithelial renewal in hamster fundic mucosa.

Changes in the gastric mucosa after a partial gastrectomy may predispose to neoplasia, but epithelial proliferation in such patients has not been studied well. Therefore, we obtained one or more suction biopsies of fundic mucosa from 6 volunteers (controls), 5 patients in whom a duodenal ulcer had healed, and 6 patients with antrectomy and vagotomy. Biopsies were organ cultured over tritiated thymidine-containing medium to label proliferating cells, and processed for light microscopy and autoradiography. The measurements of proliferation that were used, namely, the total number of cells in the gastric pits, the number of cells in the proliferative zone, the number of labeled cells in the proliferative zone, and proliferation index (number of cells in the proliferative zone/total number of cells in the gastric pit) all indicated that epithelial proliferation is increased significantly in fundic mucosa of patients after antrectomy and vagotomy when compared with fundic mucosa from normal controls or patients with healed duodenal ulcer. Proliferation was increased most in biopsies that showed atrophic gastritis. The enhancement of epithelial proliferation after antrectomy and vagotomy may be due to the development of gastritic changes, but an additional effect of vagotomy cannot be excluded. Further, the expansion of the proliferative zone suggests a disorder of proliferation which may predispose to malignant transformation.

The effect of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) on gastroduodenal epithelial proliferation p]rior to the development of frank neoplasia was studied in inbred LEW rats with or without gastric ulcers. The rats received either MNNG (100 gm/liter) in the drinking water or plain water. After 4 weeks, some rats in the MNNG-treated and control groups were given injections of tritiated thymidine and killed 1 hour later. In other rats, either an ulcer of the fundic mucosa was formed by a suction biopsy tube at laparotomy or a sham operation was performed. At 2 and 4 weeks after the operation, these rats were given injections of tritiated thymidine and killed 1 hour later. Sections of fundus, antrum, and duodenum were prepared for light autoradiography. MNNG treatment stimulated gastroduodenal epithelial proliferation, expanded the proliferative zone (PZ), and in the duodenum caused marked villus blunting and elongation of the crypts. No additional effect of the fundic ulcer or sham operation on gastroduodenal proliferation could be determined. The MNNG-induced expansion of the PZ occurred in a downward direction. Thus theories of carcinogenesis should include not only the expansion of the PZ toward the mucosal surface but also the possibility of expansion of the PZ toward the base of the mucosa.

We correlated changes in the gastric transmucosal potential difference (PD), as an indicator of the integrity of the gastric mucosal barrier, with morphological evidence of injury in dogs which had received either intragastric saline or 5, 10, 15, or 30% ethanol. Increasing degrees of morphological damage were accompanied by greater, more rapid changes in PD. Furthermore, ultrastructural changes occurred within surface epithelial cells, not in the deeper parietal or zymogen cells, and initially did not involve disruption of the apical cell membrane. Typically, the tight junctions also were not affected, although in a minority of dogs small bleblike separations of the tight junctions were seen. We consider the gastric mucosal barrier to be represented morphologically by the interconnecting sheet of gastric epithelial cells and that ethanol breaks the barrier by first causing intracellular injury.

Pancreatic polypeptide was infused into obese-hyperglycemic (ob/ob) mice and lean littermates to determine its effect on weight gain. Obese mice continuously infused with 30, 60, or 100 micrograms/day for 7 days developed both diarrhea and weight loss in a dose dependent fashion. Lean littermates infused with 100 micrograms/day developed neither diarrhea nor weight loss. Light microscopic study of ileum and colon revealed no abnormalities. These studies indicate that the effects of pancreatic polypeptide are in part genetically determined since the obese and non-obese mice differ at only one gene locus.

Perfusion of 0.1 n HC1 5 cm above the lower esophageal sphincter (LES) in cats for 30 min on 4 consecutive days produced biopsy-documented esophagitis and marked decreases in LES pressure. Using this model the effects of experimental esophagitis on the LES response to edrophonium, pentagastrin, and bethanechol were determined. The sphincter response to both edrophonium and pentagastrin after esophagitis was induced was significantly less than preperfusion responses. When the esophagitis had resolved, the pressure response to edrophonium and pentagastrin returned to preperfusion levels. In contrast, the sphincter response to bethanechol during esophagitis was not different from the preperfusion response and remained unchanged after resolution of the esophagitis. Lower esophageal smooth muscle taken from cats with active esophagitis appeared normal by both light and electron microscopy. These studies indicate that besides decreasing resting LES tone, esophageal inflammation causes functional impairment of a cholinergic mechanism regulating LES pressure. In contrast, the smooth muscle appears to be unaffected by inflammation despite the LES hypotension.

We treated four patients who had early gastric carcinoma with weekly endoscopic local injections of 5-fluorouracil (5FU). In all four patients the lesions disappeared by endoscopic and biopsy examination within 12-18 weeks of treatment. None of the patients experienced side effects which are usually associated with oral or intravenous administration of 5FU. Two patients eventually underwent surgery. In one, a small focus of carcinoma was identified within the resected stomach; no evidence of carcinoma was found in the other. The remaining two patients have not submitted to surgery and are free of carcinoma by endoscopy for over 1 1/2 years. In this uncontrolled study, endoscopic local injection of 5FU appeared to be effective in treating early gastric carcinoma as assessed by endoscopic and histological criteria. Surgery remains the treatment of choice for early gastric carcinoma. However, further studies of endoscopic injection therapy are needed to determine whether this treatment is appropriate for patients with early gastric carcinoma who are not surgical candidates.

To determine the effect of smoking on gastroduodenal mucosal prostaglandin synthesis, endoscopies were done after an overnight fast on 10 nonsmokers, 12 active smokers who smoked four cigarettes in the hour before endoscopy, and then 11 of the smokers who refrained from smoking for 12 hours. Biopsy samples of fundic, antral, and duodenal mucosae were incubated, and the accumulation of prostaglandin E2 and 6-keto-prostaglandin F1 alpha in the incubation medium was measured by radioimmunoassay. We assumed that accumulation of prostaglandins in the medium reflected mucosal synthesis. Comparison of active and inactive smoking showed that active smoking significantly depressed 6-keto-prostaglandin F1 alpha synthesis in antral and fundic mucosa and prostaglandin E2 synthesis in antral mucosa. Comparison of nonsmokers and inactive smokers showed no difference in prostaglandin synthesis. Active smoking causes a transient decrease in prostaglandin synthesis in fundic and antral mucosae. This depression of prostaglandin synthesis may help explain slower ulcer healing and predisposition to ulcer recurrence in smokers.