Duodenal ulcer disease: treatment by surgery, antibiotics, or both.

Peptic ulcer disease is a function of derangements in intraluminal aggressive factors and defects in endogenous defense mechanisms. Some of these previously described abnormalities may be caused by the presence of H pylori colonization of the antral mucosa and antral mucosal metaplasia of the proximal duodenum. In vivo and in vitro data are being accrued that support this concept, particularly with reference to the mechanisms of H pylori-induced aberrations in gastric and duodenal mucosal function. Standard medical therapy for PUD includes antisecretory medications as well as antibiotics designed to eradicate H pylori colonization. It is rare for patients with an asymptomatic but nonhealed DU to come to surgical attention. Those who do, along with those with a symptomatic DU refractory to all forms of medical therapy, should be offered a proximal gastric vagotomy. Life-threatening bleeding from a DU requires secure suture ligation of the base of the ulcer combined with truncal vagotomy and pyloroplasty. Those patients with non-life-threatening hemorrhage most likely will have been treated with intensive medical therapy, including antibiotics, and should be treated with truncal vagotomy and antrectomy. If H pylori is still present histologically in the antral specimen, sensitivity testing of the bacteria should lead to the use of appropriate antibiotic therapy. Both of these populations of patients with bleeding DU will likely have a lower rebleeding rate if H pylori is eradicated than if they are treated with surgery alone. Perforated DU should be treated with omental patch closure and antisecretory medications and antibiotics to eradicate H pylori, particularly when there are comorbid conditions such as shock, perforation for more than 24 hours, or if the patient has not had significant symptoms for 3 months preperforation. Those patients with perforated DU who are appropriate candidates for proximal gastric vagotomy in addition to omental patch closure and antibiotic therapy do well; however, the true benefit of proximal gastric vagotomy over omental patch closure with antibiotic therapy, in this population, has yet to be clearly demonstrated.

Giant fundic polyp complicating attenuated familial adenomatous polyposis.

This case details the development of a rapidly growing polypoid mass in the proximal stomach in a patient with known attenuated familial adenomatous polyposis. Surgical resection was required and histology showed hyperplasia with extensive areas of dysplastic adenomatous change. This case illustrates that patients with the attenuated form of familial adenomatous polyposis are at risk for multiple neoplasia distinct from those patients with the classic form of familial adenomatous polyposis.

Pretreatment with SR48692 has different effects on central neurotensin-induced gastric mucosal defense and inhibition of gastric acid secretion in rats.

Neurotensin is a tridecapeptide present in the brain and gastrointestinal tract. Administration of neurotensin into the brain results in responses in the gastrointestinal tract, suggesting a role for neurotensin in the interrelationships that comprise the brain-gut axis. Intracerebroventricular (i.c.v.) administration of neurotensin protects the gastric mucosa against injury caused by cold water restraint (CWR) and also inhibits gastrin-stimulated gastric acid secretion. The hypothesis tested was that these two actions of neurotensin are mediated via its high-affinity receptor. Rats were given neurotensin (60 microgram, i.c.v.) prior to CWR or pylorus ligation after pretreatment with SR48692, a nonpeptide antagonist of the high-affinity neurotensin receptor (0.25 or 2.5 microgram, i.c.v., or 10, 100, or 500 microgram kg-1, i.p.). Neurotensin reduced cold water restraint (CWR)-induced gastric mucosal injury and inhibited gastrin-stimulated acid secretion. Pretreatment with SR48692 (2.5 microgram, i.c.v., or 100 microgram kg-1, i.p.) prior to CWR blocked neurotensin's protection of the gastric mucosa against injury. In contrast, pretreatment with 2.5 microgram SR48692, i.c.v., did not block neurotensin-induced inhibition of acid secretion, whereas 500 microgram kg-1, i.p., partially blocked the inhibition. SR48692 (2.5 microgram, i.c.v.) inhibited acid secretion, suggesting that SR48692 has agonist activity in this system. These results suggest that central neurotensin protects the gastric mucosa against CWR-induced injury via its high-affinity receptor. The receptor that mediates central neurotensin-induced inhibition of gastric acid secretion does not appear to be the high-affinity receptor since the neurotensin receptor antagonist SR48692, when given i.c.v., had agonist activity, inhibiting stimulated acid secretion. High-affinity neurotensin receptors in the periphery appear to play a role in inhibition of stimulated gastric acid secretion.

Mesolimbic expression of neurotensin and neurotensin receptor during stress-induced gastric mucosal injury.

Neurotensin is a neurotransmitter present in the brain and gastrointestinal tract. Intracerebroventricular injection of neurotensin protects rats from gastric mucosal injury caused by cold water restraint (CWR). Direct injection of neurotensin into the nucleus accumbens (NACB), part of the mesolimbic dopamine system, reduces gastric mucosal injury, suggesting that neurotensin confers protection on the mucosa through interaction with the mesolimbic system. The hypothesis is that the concentration of neurotensin in the mesolimbic system decreases during CWR, affecting the expression of neurotensin and the neurotensin receptor. After 1 h of CWR, neurotensin concentration significantly decreased 41% in the NACB and returned toward control concentrations after 2 h of CWR. The concentration of neurotensin mRNA significantly decreased 46% after 1 h CWR and returned toward control after 2 h. In contrast, neurotensin binding sites in the NACB increased from 159 to 228 fmol/mg protein after 1 h of CWR and increased significantly to 280 fmol/mg protein after 2 h CWR, whereas the level of neurotensin receptor mRNA significantly decreased 51 and 50% at 1 and 2 h, respectively. These studies show that neurotensin concentration within the mesolimbic system is transiently reduced by CWR stress and that the number of neurotensin binding sites increases, presumably in response to the decrease in neurotensin.

Stress, the brain, and the gastric mucosa.

Exposure of rats to 2 hours of cold water restraint is associated with both macroscopic and microscopic gastric mucosal injury. Administration of neurotensin into the lateral ventricle or into the nucleus accumbens, one of the mesolimbic dopamine system nuclei, is associated with protection when given before exposure to cold water restraint. Under conditions of cold water restraint, pretreatment with central neurotensin is associated with maintenance of gastric mucosal blood flow and an increase in endogenous gastric mucosal PGE2 activity. In addition, pretreatment with 6-hydroxy dopamine into the mesolimbic nuclei, which depletes them of endogenous dopamine, prior to exposure to cold water restraint, ameliorates the protective effect of central neurotensin. Centrally administered neurotensin inhibits basal, pentagastrin-, carbachol-, and 2-deoxy-D-glucose-induced but not histamine-induced gastric acid secretion. This antisecretory effect is ameliorated by parenteral pretreatment with haloperidol and domperidone. Taken together, these observations support the hypothesis that centrally administered neurotensin, particularly into the nuclei of the mesolimbic dopamine system, confers protection against gastric mucosal injury produced by 2 hours of cold water restraint. This affect may be due, in part, to inhibition of acid secretion and maintenance of mucosal blood flow mediated by an increase in gastric mucosal PGE2 activity.

Increased intestinal permeability in rats with graft versus host disease.

BACKGROUND/AIMS: The study of graft versus host disease of the intestine has significant clinical relevance and may also be a model for other immune mediated intestinal diseases. There presently is no simple non-invasive test that can be used to evaluate graft versus host disease induced intestinal injury in humans or animal models. This study tested the hypothesis that graft versus host disease leads to an increase in host bowel permeability as assessed by the relative urinary excretion of orally administered lactulose and rhamnose. METHODS: The urinary excretion ratio of orally administered lactulose and rhamnose was determined daily for two weeks in (Lewis x Brown-Norway) F1 rats with graft versus host disease caused by either the transplantation of parental (Lewis) small bowel or the intraperitoneal injection of parental (Lewis) splenic lymphocytes. RESULTS: Significant twofold to fourfold increases in the lactulose to rhamnose ratio were seen in both small bowel transplant and splenic lymphocyte transfer animals suffering from graft versus host disease during the second postoperative week. This effect occurred sooner in small bowel transplant than in splenic lymphocyte transfer animals (postoperative day 7 versus 11, respectively). The signs of graft versus host disease, including splenomegaly and altered intestinal mucosal architecture, as well as the increased lactulose to rhamnose ratio were significantly attenuated in small bowel transplant animals treated with cyclosporine A (10 mg/kg/day). CONCLUSIONS: Graft versus host disease is associated with an increase in the lactulose to rhamnose clearance ratio reflecting an increase in host bowel permeability. This increase, along with the signs of systemic graft versus host disease, can be significantly ameliorated by cyclosporine A. The lactulose to rhamnose clearance ratio is a non-invasive technique that can be used to assess the intestinal effects of graft versus host disease and the associated increase in intestinal permeability.

Intracerebroventricular secretin enhances pancreatic volume and bicarbonate response in rats.

BACKGROUND: Although secretin has been found within the brain, its central role in pancreatic exocrine function has not been previously addressed. The hypothesis that intracerebroventricular secretin enhances pancreatic volume and bicarbonate output at doses that have no effect when given intravenously was tested. METHODS: Sprague-Dawley rats had a cannula stereotactically placed into the left lateral cerebral ventricle 24 hours before study. At laparotomy the bile and pancreatic ducts were separately cannulated and excluded for tared collections and bicarbonate assay. RESULTS: Increasing doses of intracerebroventricular secretin (0.005, 0.05, and 0.5 microgram/1.0 microliter) induced a significant dose-related increase in bicarbonate output (2.95, 3.32, and 4.02 microEq/30 min, respectively) above basal (2.62 microEq/30 min) compared with control or intracerebroventricular saline treated animals. Pancreatic volume increased to 59.7 microliters at the lowest intracerebroventricular dose and increased (p < 0.025) to 65.8 microliters at the 0.05 intracerebroventricular secretin dose when compared with basal (59.4 microliters). To show that this was not a systemic effect of secretin, intravenous infusion of secretin at 0.005 and 0.05 microgram/kg/hr failed to stimulate either volume or bicarbonate output compared with that observed with intracerebroventricular secretin over the same dose range. CONCLUSIONS: These observations indicate that intracerebroventricular secretin stimulates pancreatic volume and bicarbonate output and suggest that central secretin may play a role in the regulation of exocrine pancreatic secretion.

Awake epidural anesthesia is associated with improved natural killer cell cytotoxicity and a reduced stress response.

BACKGROUND: Laparotomy under general anesthesia is associated with depressed natural killer cell cytotoxicity (NKCC) and compromised clearance of tumor cells. We tested the hypothesis that awake epidural anesthesia (AEA) improves NKCC compared to conventional general endotracheal anesthesia (GEA). PATIENTS AND METHODS: Preoperative, perioperative, and postoperative (day 3) NKCC, plasma epinephrine, norepinephrine, cortisol levels, and 24-hour urinary cortisol levels were measured in 20 patients undergoing open colectomy under either AEA or GEA. RESULTS: Preoperative and postoperative measurements were not significantly different in the two groups. Patients receiving GEA had a significant reduction in NKCC from 36% +/- 4% preoperatively to 22% +/- 4% perioperatively (P = 0.02). Patients receiving AEA had no significant change in NKCC. Perioperative plasma epinephrine and cortisol levels were higher with GEA than AEA. The perioperative 24-hour urinary cortisol excretion values were significantly higher in the group receiving GEA, suggesting a greater stress hormone response in this group compared to AEA patients. CONCLUSIONS: Compared to GEA, AEA appears to preserve perioperative NKCC. This effect may be related to an attenuated stress hormone response associated with AEA. Cancer patients may have improved killing of embolized tumor cells during surgery performed under AEA.

Comparison of the costs associated with medical and surgical treatment of obesity.

BACKGROUND: We compared the long-term costs and outcomes of gastric bypass versus medical therapy (very low-calorie diet plus weekly behavioral modification) for obese patients. METHODS: A successful outcome was defined as the loss of at least one third of excess weight that was maintained for the duration of the study. A minimal cost was assigned: $3000 for medical and $24,000 for surgical treatment. A cost per pound of weight lost for all patients successfully monitored was calculated. The Federal Trade Commission recently asked all weight loss programs to report this cost for patients at least 2 years after therapy. RESULTS: A total of 201 patients entered surgical and 161 entered medical therapy. The surgical group was initially heavier (mean body mass index [kg/m2] +/- SE = 49.3 +/- 0.6 versus 41.2 +/- 0.7, p < 0.01), but each group's lowest mean body mass index was similar (31.8 versus 32.1, respectively). A significantly higher percentage of patients in the surgical versus the medical group were still successful at year 5: 89% versus 21%. The cost per pound lost for medical therapy exceeded the cost of surgical therapy in the sixth posttreatment year (both more than $250/pound). CONCLUSIONS: Surgical treatment appears to be more cost-effective at producing and maintaining weight loss. It is imperative that long-term follow-up studies be funded to definitely establish this finding.

Graft-versus-host disease after small bowel transplantation is associated with host colonic injury.

The present studies were undertaken to evaluate the histologic effects of graft-versus-host disease on the host colon after small bowel transplantation. Graft-versus-host disease was produced in six Lewis x Brown Norway F1 rats by performing vascularized, out-of-continuity small bowel transplants from parental Lewis donors. Host proximal and distal colon were sampled 14 days after operation when signs of graft-versus-host disease, including weight loss and splenomegaly, were present. Tissue was assessed histologically by blinded observer and compared to eight sham-operated controls. Three histologic features were noted to be statistically increased in diseased animals: (1) mucin loss; (2) crypt abscesses; and (3) large lymphoid aggregates in the mucosa and submucosa. These features were more commonly noted in the distal rather than the proximal colon. Another group of five grafted animals treated with cyclosporine A (10 mg/kg/day intramuscularly) still lost weight but did not display overt signs of graft-versus-host disease and had normal-sized spleens. There was normal mucin content and no evidence of crypt abscesses in these treated animals, although large lymphoid aggregates were present. It is concluded that mucin loss, crypt abscesses, and large lymphoid aggregates are characteristics of graft-versus-host disease-induced colonic injury in this model and that these changes are most evident in the distal colon. Cyclosporine A therapy does not completely reverse the histological changes of colonic graft-versus-host disease. This model may be useful in studying the mechanisms by which immune mediated colitides preferentially affect the distal colon.

The incidence, management, and outcome of patients with gastrointestinal carcinoids and second primary malignancies.

BACKGROUND: A higher than expected incidence of second primary malignancies in patients with gastrointestinal carcinoids has been reported. How patients with such concurrent neoplasms should be managed and whether or not the discovery of an incidental carcinoid at the time of operation for another malignancy affects patient management or outcome, has never been previously addressed. STUDY DESIGN: We retrospectively reviewed our 20-year experience with gastrointestinal carcinoid tumors with the purpose of determining the appropriate management and eventual outcome of patients with these multiple malignancies. RESULTS: Sixty-nine patients with carcinoids of the gastrointestinal tract were discovered, of whom 29 (42 percent) had second synchronous tumors and three (4 percent) had metachronous tumors. The gastrointestinal tract accounted for 42.9 percent of the tumors, and carcinoma of the colon and rectum was found in seven (21.9 percent) of 32 patients. None of the 29 patients with a second synchronous tumor presented with symptoms referable to their carcinoid, each of which was incidentally discovered: nine at autopsy and 20 at laparotomy for the treatment of other tumors. All of the 20 surgical patients had the gastrointestinal carcinoids resected for cure, although three had histopathologic criteria for invasion. None of the 29 patients died as a result of, had recurrence of, or had their postoperative therapy altered by the carcinoid diagnosis. CONCLUSIONS: Gastrointestinal carcinoid is associated with a high incidence of second primary malignancy, 46 percent in this study. The most common site for the second primary malignancy in these patients is the gastrointestinal tract, suggesting a site specific predisposition to malignant degeneration. Most gastrointestinal carcinoids are incidentally discovered at laparotomy or autopsy. The discovery of an asymptomatic gastrointestinal carcinoid during the operative treatment of another malignancy will usually only require resection without additional treatment and will have little affect on the prognosis of the individual.

The association between PGE2 activity and mucosal permeability in proximal small bowel.

Little is known about the ontogeny of cyclooxygenase activity and synthesis of prostaglandins in the developing gastrointestinal tract. We tested the hypothesis that an age-related increase in cyclooxygenase as reflected in production of PGE2 in the proximal small bowel (PSB) is associated with the maturation of the mucosal barrier as determined by 51Cr-EDTA permeability. Cyclooxygenase activity in PSB of rats at 10, 22, 36, and 63 (adult) days of age was determined by the generation of PGE2 using specific radioimmunoassay. Systemic 51Cr-EDTA clearance into the lumen was used to assess mucosal barrier function in PSB in 10- to 12-day-old and adult rats. Prostaglandin E2 generation rose significantly from 24.8 +/- 0.4 pg/mg/min in 10-day-old rats to 125.0 +/- 7.8 in adult rats. The 51Cr-EDTA clearance decreased significantly from 5.08 +/- 0.90 ml/min/100 g in 10- to 12-day-old rats to 0.43 +/- 0.18 ml/min/100 g in adult rats. To assess the possible role of endogenous PGE2 in directly mediating these observed changes in the mucosal permeability, a group of adult rats chronically received indomethacin (2.5 mg/kg/day) over a 3-day period, while another group of vehicle-treated rats served as controls. The 51Cr-EDTA clearance of the indomethacin-treated rats was significantly higher than the control rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Epidermal growth factor enhances intestinal mitotic activity and DNA content after acute abdominal radiation.

BACKGROUND: Mediators of radiation-induced enteritis and colitis remain undefined. Epidermal growth factor (EGF) is an endogenous peptide that is trophic to the gastrointestinal tract. We tested the hypothesis that EGF enhances DNA synthesis and mitotic activity and prevents acute radiation enteritis after total abdominal radiation. METHODS: Four equal groups (n = 6) of Sprague-Dawley rats were studied: I (control), II (radiation), III (EGF), and IV (radiation + EGF). Animals in groups III and IV received EGF (10 micrograms/kg) every 8 hours for 48 hours before radiation exposure and for 72 hours after radiation, and the remaining animals were given an equal volume of vehicle. Animals in groups II and IV were administered a single dose of abdominal radiation (1000 cGy) 48 hours after the start of either vehicle or EGF. Distal ileum and colon were harvested 72 hours after radiation, examined histologically, and assayed for total DNA content. RESULTS: Group II or radiated animals had diarrhea, significant weight loss (p < 0.05), and decreased food consumption consistent with acute clinical radiation enteritis. Mitotic activity and total DNA content were significantly reduced (p < 0.05) when compared with group I (nonradiated controls). Group IV animals treated with EGF and exposed to radiation did not suffer the acute clinical manifestations of radiation enteritis. In addition, total DNA content and mitotic activity of the terminal ileum increased significantly (p < 0.05), and a significant increase in mitotic activity occurred in the distal colon when compared with radiated controls. CONCLUSIONS: The results of this study suggest that (1) a decrease in mitotic activity and total DNA content occurs early and persists for at least 72 hours after acute radiation, (2) EGF treatment significantly increases small and large bowel mitogenicity in acutely radiated animals, and (3) EGF significantly decrease the acute clinical manifestations of radiation enteritis.

Stimulated pancreatic exocrine secretion does not require pancreatic hyperemia in rats. Potential cholinergic role.

Although blood flow and cholinergic tone influence gastric and salivary gland secretion, their role in pancreatic secretion is poorly defined. The purpose of the present study was: (1) to test the hypothesis that an increase in pancreatic blood flow accompanies stimulated pancreatic exocrine secretion, and (2) to examine the effects of cholinergic agents on basal and stimulated blood flow using hydrogen gas clearance. Stimulated pancreatic exocrine secretion (secretin 0.4, 0.8, 1.6 micrograms/kg/hr) resulted in a significant (P < 0.005) increase in secretory volume; however, pancreatic blood flow was not significantly changed, and a negative correlation between blood flow and secretion was observed. A pharmacologic dose of secretin (5.0 micrograms/kg/hr) resulted in a significant (P < 0.05) increase in pancreatic blood flow, which was inhibited by atropine (5.0 micrograms/kg/hr) infusion. Although 2-deoxyglucose caused a significant decrease (P < 0.03) in basal pancreatic blood flow, atropine had no effect on basal blood flow levels. These observations suggest that: (1) under physiologic conditions, secretin- or 2-deoxyglucose-stimulated pancreatic secretion does not require pancreatic hyperemia; (2) a pharmacologic dose of secretin does produce pancreatic hyperemia, perhaps through a local cholinergic mechanism; (3) peripheral cholinergic tone does not contribute significantly to basal pancreatic blood flow; and (4) basal pancreatic blood flow may be influenced by central mechanisms.

Gallbladder mucosal blood flow increases during early cholesterol gallstone formation.

Gallbladder absorption increases during early cholesterol gallstone formation and is influenced by the intraluminal presence of lithogenic bile. The effect of lithogenic bile on gallbladder mucosal blood flow is unknown. The current study tested the hypothesis that the presence of lithogenic gallbladder and hepatic bile enhances gallbladder mucosal blood flow in cholesterol-fed (0.4%) prairie dogs, as determined by hydrogen gas clearance. Gallbladder mucosal blood flow in control animals was 35.57 +/- 3.9 mL.min-1.100 g-1. In contrast, basal gallbladder mucosal blood flow in cholesterol-fed animals was significantly (P less than 0.01) increased to 64.94 +/- 8.7 mL.min-1.100 g-1. In crossover studies, the addition of lithogenic gallbladder bile to control animals (n = 6) resulted in a significant (P less than 0.025) 26% increase in gallbladder mucosal blood flow, whereas the addition of nonlithogenic gallbladder bile into gallbladders of cholesterol-fed prairie dogs resulted in a significant (P less than 0.025) 58% decrease in gallbladder mucosal blood flow. Similarly, hepatic bile crossover studies showed that the addition of lithogenic hepatic bile to control gallbladders significantly increased (P less than 0.025) gallbladder blood flow by 30%, whereas instillation of nonlithogenic hepatic bile in gallbladders of cholesterol-fed animals significantly (P less than 0.025) decreased gallbladder mucosal blood flow by 29%. These results suggest that alterations in gallbladder mucosal blood flow, influenced by the presence and absence of lithogenic bile, may play a role in cholesterol gallstone formation.

Mechanism of aggravation of mucosal injury by intravenous nicotine in rat stomach.

Endogenous prostaglandins and injury-induced hyperemia are important defense mechanisms in the gastric mucosa. In the rat stomach, we tested the hypotheses that an ulcer-promoting dose of intravenous nicotine 1) reduces ex vivo prostaglandin generation and 2) aggravates mucosal lesions by impairing injury-induced hyperemia. Anesthetized rats were given intravenous control or 4 or 40 micrograms.kg-1.min-1 nicotine infusion. In study 1, ex vivo generation of prostaglandin E2 and 6-ketoprostaglandin F1 alpha (stable metabolite of prostacyclin) was determined by vortexing the mucosal tissue, followed by radioimmunoassay. No significant difference in prostaglandin generation was found between the control and experimental groups. In study 2, intravenous nicotine (40 micrograms.kg-1.min-1) produced a significant rise (19 +/- 3%) in mean blood pressure and completely abolished the gastric hyperemia produced by intragastric saline (2 M). The extent of the associated gastric mucosal injury was significantly increased (from 5.3 +/- 0.8 to 17.4 +/- 5.2% of the corpus mucosa), while the maximum depth of the largest lesions was not affected by intravenous nicotine. The data confirm that the gastric hyperemia associated with gastric mucosal exposure to hypertonic saline plays an important role in limiting the extent of gastric mucosal damage. We conclude that in the rat stomach 1) an ulcer-promoting dose of intravenous nicotine does not significantly inhibit cyclooxygenase activity, and 2) the same does of intravenous nicotine exacerbates hypertonic saline-induced gastric mucosal injury by a mechanism that involves inhibition of injury-induced hyperemia.

Effect of neurotensin on regional cerebral glucose utilization in cold water-restrained rats.

Neurotensin (NT), given intracerebroventricularly (icv), attenuates cold water restraint (CWR)-induced gastric mucosal injury; however, it is not clear which brain nuclear group or groups are involved. These studies tested the hypothesis that neuronal function, as measured by regional cerebral metabolic rate for glucose (rCMRGlc), is altered by icv NT with or without CWR. CWR resulted in a reduced global glucose utilization of 72 and 65% in control and NT-treated rats, respectively. NT, given icv, protected against ulcer formation induced by CWR. In those rats given NT icv, rCMRGlc was elevated significantly in amygdala, nucleus accumbens, substantia nigra, tuberculum olfactrium, hypothalamus, and cerebellum compared with CWR rats without NT pretreatment. This rCMRGlc increase was observed in both unstressed and stressed rats given NT icv in the nucleus accumbens and amygdala. These observations suggest that the nucleus accumbens and amygdala, both components of the mesolimbic dopamine system, are involved in the central action of NT on the gastric mucosa.