Showing papers in "Digestive Diseases and Sciences in 1985"
TL;DR: In the final paragraph of that classical volume, "Peptic Ulcer" (1) published in 1951, three of the most eminent gastrointestinal physicians, namely A. C. Ivy, Morton Grossman and William Bachrach, predicted that "future research will reveal orally-active innocuous substances for specifically preventing the formation of acid by the parietal cells and/or rendering the gastric and duodenal mucosa less susceptible to injury".
Abstract: In the final paragraph of that classical volume, \"Peptic Ulcer\" (1) published in 1951, during an era when medical treatment consisted only of special diet and antacids, three of the most eminent gastrointestinal physicians the world has ever known, namely A. C. Ivy, Morton Grossman and William Bachrach, looked towards the future treatment of ulcer. They expressed the hope that \"mutilating operations will be unnecessary\" and predicted that \"future research will reveal orally-active innocuous substances for specifically preventing the formation of acid by the parietal cells and/or rendering the gastric and duodenal mucosa less susceptible to injury\". Over the thirty years which have elapsed since these postulates were put forward many of their requirements have been fulfilled. Certainly, fewer and less mutilating operations are being performed with minimal mortalities but there are still significant and irreversible complications and the chances of ulcer recurrence are appreciable. In the last two decades pharmacological research has achieved the first postulate by developing orally administered agents, now given once daily, which are capable of \"specifically preventing the formation of acid by the parietal cell\". Initially, vagal blockage was attempted with anticholinergics but these were only partially effective and they produced unpleasant side-effects. This state of affairs has been much improved by the development of new muscarine M 1-receptor antagonists such as pirenzepine, which are capable of healing ulcers and have minimal side-effects. There was widespread disappointment when the antihistamine drugs developed in the 1950s were
872 citations
TL;DR: Pulmonary complications, including pulmonary edema and congestion, appeared to be the most significant factor contributing to death and occurred even in those cases where the pancreatic damage appears to be only moderate in extent, which should contribute significantly to an increase in survival in this disease.
Abstract: A large retrospective autopsy study of patients was analyzed to evaluate the major etiologic and pathologic factors contributing to fatal acute pancreatitis (AP). From an autopsy population of 50,227 patients, 405 cases were identified where AP was defined as the official primary cause of death. AP was classified according to morphological and histological, but not biochemical, criteria. Patients with AP died significantly earlier than a control autopsy population of 38,259 patients. Sixty percent of the AP patients died within 7 days of admission. Pulmonary edema and congestion were significantly more prevalent in this group, as was the presence of hemorrhagic pancreatitis. In the remaining 40% of patients surviving longer than 7 days, infection was the major factor contributing to death. Major etiologic groups in AP were chronic alcoholism; postabdominal surgery; common duct stones; a small miscellaneous group including viral hepatitis, drug, and postpartum cases; and a large idiopathic group comprising patients with cholelithiasis, diabetes mellitus, and ischemia. The prevalence of established diabetes mellitus in the AP group was significantly higher than that observed in the autopsy control series, suggesting that this disease should be considered as an additional risk factor influencing survival in AP. Pulmonary complications, including pulmonary edema and congestion, appeared to be the most significant factor contributing to death and occurred even in those cases where the pancreatic damage appeared to be only moderate in extent. Emphasis placed on the early recognition and treatment of pulmonary edema in all cases of moderate and severe AP should contribute significantly to an increase in survival in this disease.
442 citations
TL;DR: Electromyography of the striated pelvic floor muscles during attempts at expulsion of the balloon in the constipated patients showed failure of the normal inhibition of resting activity, which may contribute to the symptoms of some patients who complain of constipation.
Abstract: Among patients complaining of constipation, a group can be defined in which there is slow whole gut transit shown by retention of radiopaque markers but a rectum and colon of normal width judged by measurements of barium enema radiographs compared with control observations. It is not known whether their symptoms are due to an abnormality of colonic motility or to a failure of the defecatory mechanism. Defecation was simulated experimentally in a group of these patients by asking them to expel a water-filled rectal balloon. The constipated patients were not able to expel the balloon, whereas normal subjects could do so. Electromyography of the striated pelvic floor muscles during attempts at expulsion of the balloon in the constipated patients showed failure of the normal inhibition of resting activity. Failure of external anal sphincter relaxation on attempted defecation may contribute to the symptoms of some patients who complain of constipation.
401 citations
TL;DR: The site of intestinal involvement with Crohn's disease did not appear to play a significant role in the frequency or degree of response to 6-MP, but patients without prior resection and fistulae did better than those with fists occurring after surgery.
Abstract: Fistulae are distressing chronic complications of Crohn's disease which have served as one of the most common indications for surgical resection. While steroids and sulfasalazine have not been successful in closing fistulae, in a previous double-blind study 6-mercaptopurine (6-MP) was more effective than placebo in accomplishing this goal (31% vs 6%). Thirty-four patients with Crohn's disease fistulae were treated with 6-MP for a minimum period of 6 months. In 13 patients (39%) the fistulae closed completely, and in another 9 (26%) there was obvious improvement. All types of fistulae responded to 6-MP with the most impressive closures occurring in patients with fistulae of the abdominal wall and enteroenteric fistulae. The mean time to respond was 3.1 months, with 23% of patients taking longer than 4 months to show any response. Response was not related to other drugs (steroids, sulfasalazine) used in conjunction with the 6-MP. The site of intestinal involvement with Crohn's disease did not appear to play a significant role in the frequency or degree of response to 6-MP, but patients without prior resection and fistulae did better than those with fistulae occurring after surgery. The long-term response to fistulae was good if 6-MP was maintained, whereas exacerbation eventually followed discontinuation of 6-MP. 6-Mercaptopurine is an effective and useful drug in the treatment of fistulae, as it is in other manifestations of chronic unrelenting Crohn's disease.
243 citations
TL;DR: Gastric emptying was studied with a double radioisotopic method in 12 patients with insulin-dependent diabetes mellitus complicated by autonomic neuropathy and in 22 control subjects, and symptoms of gastroparesis were less after domperidone.
Abstract: Gastric emptying was studied with a double radioisotopic method in 12 patients with insulin-dependent diabetes mellitus complicated by autonomic neuropathy and in 22 control subjects. In the diabetics, the acute and chronic effects of oral domperidone on gastric emptying, symptoms of gastroparesis, and glycemic control were assessed. Gastric emptying of solid and liquid was slower in diabetics than controls (P less than 0.001). Acute administration of domperidone increased the rate of both solid and liquid emptying (P less than 0.005). Domperidone was most effective in those patients with the greatest delay in gastric emptying. After chronic administration (35-51 days), domperidone had no significant effect on solid emptying (P greater than 0.05), but was still effective in increasing liquid emptying (P less than 0.025). Symptoms of gastroparesis were less after domperidone (P less than 0.001).
217 citations
TL;DR: In healthy controls habituation reduces the stress-related increase in colonic motility, and in patients with the irritable colon syndrome, chlordiazepoxide decreases the stress to increase colonic Motility.
Abstract: Colonic smooth muscle spike potentials and contractility were recorded during the periods of stress by a bipolar electrode-perfused catheter apparatus placed in the rectosigmoid colon. Healthy subjects and patients with the irritable colon syndrome (ICS) were exposed to three standardized stressful conditions: (1) ice-water immersion, (2) Stroop stimulus differentiation test, and (3) ball sorting. In healthy controls, colonic motility. An increase in colonic motility occurred in patients with the irritable colon <0.5), or ball sorting. Respiratory frequency also increased after exposure to the stressful stimuli. However, repeat exposures to the stress tests did not stimulate colonic motility. An increase in colonic motility occurred in patients with the irritable colon syndrome pretreated with a placebo after exposure to ice water (P<0.05), Stroop Test, or ball sorting (P<0.05). However, after exposure to the stressful situations patients pretreated with chlordiazepoxide had a diminished increase in colonic motility or in respiratory frequency. These studies suggest: (1) in healthy controls habituation reduces the stress-related increase in colonic motility, and (2) in patients with the irritable colon syndrome, chlordiazepoxide decreases the stress-related increase in colonic motility.
173 citations
TL;DR: In this paper, the authors used ursodeoxycholic acid (UDCA) to dissolve cholesterol gallstones in six patients with histologically confirmed HBsAg-negative chronic active hepatitis.
Abstract: Chemical dissolution of cholesterol gallstones using ursodeoxycholic acid (UDCA) in six patients with histologically confirmed HBsAg-negative chronic active hepatitis was started after a minimum of one year of therapy with steroids, azathioprine, or chloroquine and a treatment-free period of 8–15 months. The treatment with UDCA lasted 3–20 months with a daily dose of 8–11 mg/kg. Four patients served as controls. A decrease in transaminases (P<0.05) occurred in all patients during the UDCA therapy. After completion of the treatment, the figures rose again, but did not return to the initial value. The stones dissolved in five patients. A second liver biopsy was carried out in two patients after UDCA therapy, and this showed no detectable deterioration. Four patients refused biopsy because the laboratory parameters had improved under UDCA. A stone recurred in one patient six months after the end of therapy; the others have remained free of stones for up to 24 months.
170 citations
TL;DR: It is obvious from the above discussion that, whereas no really clear-cut animal model of IBD has been established, a number of specific insights into the nature of the human illness can be derived from the study of naturally occurring and induced gastrointestinal inflammations occurring in animals.
Abstract: It is obvious from the above discussion that, whereas no really clear-cut animal model of IBD has been established, a number of specific insights into the nature of the human illness can be derived from the study of naturally occurring and induced gastrointestinal inflammations occurring in animals. One of the most important emerges from the finding that both immune complex deposition in the gastrointestinal tract as well as stimulation of the mucosal T-cell system results in an ulcerative colitis-like gastrointestinal inflammation. The simplest explanation of the fact that vastly different methods of inducing immune-mediated injury in the gastrointestinal tract can lead to a similar kind of gastrointestinal inflammation is that the inflammatory response in the gastrointestinal tract is rather restricted in its overall pathologic appearance and that the histologic lesions characteristic of ulcerative colitis and Crohn's disease can arise from primary disturbance of the B-cell system, the T-cell system, or both. Another explanation of this fact, however, is that no matter what the initial immunological disorder may be, the mechanism underlying the gastrointestinal inflammation ultimately comes to involve a response to materials in the mucosal environment so that pathologic events are inevitably channeled into an inflammatory pathway that is either ulcerative colitis-like or Crohn's disease-like in its final configuration. This second explanation is buttressed by other findings derived from the study of animal models which, in general, suggest that no matter what the initial result, an immunologic interaction against a constituent of the bowel flora determines the ultimate course of the gastrointestinal inflammation.(ABSTRACT TRUNCATED AT 250 WORDS)
137 citations
TL;DR: In anorexia nervosa patients who are symptomatic and seeking medical care, gastric emptying of solids is significantly delayed when compared with female subjects of similar age and normal body weight and with patients of less than 90% ideal body weight but without psychiatric disorder.
Abstract: Upper gastrointestinal symptoms may be prominent in anorexia nervosa. This study is an investigation of the gastric emptying of solid and liquid meal components in 16 female patients (mean age 20.0 years, range 14–40 years) who met accepted psychiatric diagnostic criteria for anorexia nervosa. The results were compared with those of gastric emptying studies in 10 normal females of ideal body weight (mean age 25.4 years, range 20–35), 13 normal persons (12 males), and six patients (mean age 12 years, range 9–14 years) with weight loss (<90 percent ideal body weight) secondary to Crohn's disease with no psychiatric symptoms. A dual-isotope technique using chicken liver intracellularly labeled with technetium-99m (99mTc) bound to sulfur colloid as the solid-phase marker, and indium-111 (111In)-labeled water as the liquid-phase marker was used. Gastric emptying was monitored for 2 hr by gamma camera. In 13 of the 16 anorexia nervosa patients (80%), gastric emptying of solids was slower than the range in the two groups of normal subjects, and mean gastric emptying was significantly slower (P<0.05) than in the weight-loss patients. Liquid emptying (water) in anorexia nervosa was normal and similar to the control groups studied. In 11 of the anorexia nervosa patients with delayed gastric emptying, intramuscular metoclopramide, 10 mg, significantly (P<0.05) accelerated the mean gastric emptying from 60 through 120 min after the meal. We conclude that in anorexia nervosa patients who are symptomatic and seeking medical care: (1) gastric emptying of solids is significantly delayed when compared with female subjects of similar age and normal body weight and with patients of less than 90% ideal body weight but without psychiatric disorder; (2) these data are consistent with an antral motility disturbance, either primary or secondary; and (3) metoclopramide, a gastric prokinetic agent, accelerates (delayed) gastric emptying.
125 citations
TL;DR: Ulastructural and histological similarities between Whipple's disease and M. avium infection suggest that both are manifestations of immune deficits limiting macrophage destruction of particular bacteria after phagocytosis.
Abstract: At endoscopy, a 30-year-old man with acquired immune deficiency syndrome (AIDS), Kaposi's sarcoma, diarrhea, and unexplained malabsorption showed erythematous macular duodenal lesions consistent with Whipple's disease by histology and electron microscopy Symptoms did not respond to tetracycline Subsequent cultures revealed systemicMycobacterium avium (M avium) infection Tissue from this patient, from patients with Whipple's disease and from a macaque withM avium were compared All contained PAS-positive macrophages butM avium could be distinguished by positive acid-fast stains and a difference in pattern of indirect immunofluorescence staining with bacterial typing antisera PAS-positive macrophages in the intestinal lamina propria are no longer pathognomonic of Whipple's disease Ultrastructural and histological similarities between Whipple's disease andM avium infection suggest that both are manifestations of immune deficits limiting macrophage destruction of particular bacteria after phagocytosisM avium must be considered in the differential diagnosis of diarrhea in patients with AIDS and other immunosuppressed conditions
116 citations
TL;DR: It is found that liquid emptying in 12 diabetic patients with symptoms of stasis was abnormal, as determined by residue area determination when compared to normal volunteers, suggesting that chronic oral administration of metoclopramide may result in a loss of the gastrokinetic properties of this drug.
Abstract: Metoclopramide tablets have been approved for use in the acute and chronic management of diabetic gastroparesis. Its efficacy as an antiemetic has been well documented. We measured the acute and chronic effects of oral metoclopramide on gastric liquid emptying in 12 diabetic patients with symptoms of stasis using scintiscanning techniques. We found that liquid emptying in these subjects was abnormal, as determined by residue area determination when compared to normal volunteers (P<0.01). Metoclopramide 10 mg orally acutely enhanced emptying, restoring it to control values (P<0.01). In contrast, when gastric emptying was evaluated following one month of chronic liquid metoclopramide use, 10 mg before each meal, the acute effect of the drug on emptying could no longer be demonstrated and residue areas returned to baseline values, suggesting that chronic oral administration of metoclopramide may result in a loss of the gastrokinetic properties of this drug.
TL;DR: The resting motility of the pelvic colon was studied in 28 patients with constipation and compared with control subjects and patients with diarrhea and it is possible that the relative inactivity of the colon in the latter group is due to a disorder of the myenteric plexus.
Abstract: The resting motility of the pelvic colon was studied in 28 patients with constipation and compared with control subjects and patients with diarrhea. Colonic activity in patients who had been shown to have slow colonic transit was not significantly different from controls. In contrast, activity in patients who complained of constipation but who were found to have normal colonic transit time was increased (P<0.02). The response of the pelvic colon to the introduction of a surface-acting laxative was studied in 18 patients with slow-transit constipation. Eleven patients developed progressive peristaltic waves, while in 7 there was no response. It is possible that the relative inactivity of the colon in the latter group is due to a disorder of the myenteric plexus. If so, the bisacodyl stimulation test may distinguish patients with an abnormal myenteric plexus from those in whom it is normal.
TL;DR: Six cases of unexplained pancreatitis associated with inflammatory bowel disease (five patients with Crohn's disease, one with indeterminate colitis) emphasize the existence of a probably nonfortuitous association ofinflammatory bowel disease with pancreatitis.
Abstract: The list of extraintestinal manifestations of inflammatory bowel diseases does not classically include pancreatitis and pancreatic insufficiency. We report here six cases of unexplained pancreatitis associated with inflammatory bowel disease (five patients with Crohn's disease, one with indeterminate colitis). None of the classical etiologies for pancreatitis was found in our patients; moreover none of them had duodenal localization of Crohn's disease or sclerosing cholangitis, two conditions in which pancreatitis associated with inflammatory bowel disease has been previously described. Pancreatitis was painless (or was associated with moderate and atypical abdominal pain) in four of our six cases; no pancreatic calcification was found in any case; in three patients a total or subtotal exocrine pancreatic insufficiency was evidenced. Endoscopic retrograde pancreatography performed in four subjects showed normal or minimally altered pancreatic ducts even in those with severe pancreatic insufficiency. These cases emphasize the existence of a probably nonfortuitous association of inflammatory bowel disease with pancreatitis. Its recognition could make a significant contribution in the management of inflammatory bowel disease.
TL;DR: In vivo, adherent mucus forms a thin but continuous cover of variable thickness over the gastroduodenal mucosa, which can be active up to luminal pH values of 5.5 and increases in luminal mucus can occur independently of increased gel thickness.
Abstract: Gastroduodenal mucus is present as a water insoluble gel adherent to the mucosal surface and as a viscous mobile solution in the lumen. The protective properties of the mucus against acid (with bicarbonate), pepsin (diffusion barrier) and mechanical damage depend on the quality (structure) and quantity (thickness) of the adherent mucus gel layer. Adherent mucus is a viscoelastic gel which is 95% (v/v) water. It is permeable to ions and smaller molecules (Mr c. 1000), but is impermeable to large proteins (Mr,c. 17,000) including pepsins. However, mucus is solubilized rapidly by pepsin, more slowly (>-1 h) by thiol agents, and is unchanged following exposure to bile, acid and ethanol (<40%). Glycoprotein macromolecules (Mr≥2×106) are the structural components of the mucus gel and have a polymeric, structure of glycoprotein subunits (Mrc. 5×105, for gastric mucus) joined by disulphide bridges between their protein cores. This glycoprotein polymerization, which is essential for gel formation and hence function, is the site of action of proteolytic enzymes and thiol agents. The glycoprotein polymeric structure is deficient in antral mucus from patients with peptic ulcer disease.In vivo, adherent mucus forms a thin but continuous cover of variable thickness (50–450 μm in man, about two-fold less in rat) over the gastroduodenal mucosa. Pepsin in gastric juice will rapidly dissolve this mucus cover and can be active up to luminal pH values of 5. Mucus erosion by pepsin or by abrasion must be balanced by its secretion. Prostaglandins and carbachol stimulate a rapid increase (within minutes) in mucus thickness of up to two-fold. Soluble luminal mucus can be increased by mucus secretagogues, mucosal damaging agents, or peptic degradation of adherent mucus. Increases in luminal mucus can occur independently of increased gel thickness.
TL;DR: The findings suggest that the denervation in the majority of cases is located in the Auerbach plexus, with complete absence of ganglion cells and, therefore, absence of postganglionic nerve fibers.
Abstract: A prospective study was performed in 17 patients with achalasia of the esophagus determining the manometric characteristics of the gastroesophageal sphincter, correlating in with hisotological analysis by biopsies taken during surgery at the distal narrowed segment of the esophagus, at the location of the sphincter. The histological findings were compared to 10 control cases. Presence or absence of ganglion cells at the Auerbach's plexuses and appearance of smooth muscle fibers were evaluated. Only one case (6%) had Chagas' disease. The mean sphincter pressure was 41 mm Hg, with incomplete relaxation in all patients. Histological analysis showed a complete disappearance of ganglion cells in 94% of the cases and a decrease in the number of neurons with marked chronic inflammatory cells in one case (6%). In all control cases, the ganglion cells were normal. Smooth muscle fibers were normal on light microscopy. No relationship was found between resting gastroesophageal sphincter pressure, length and relaxation, and histological findings at the distal esophagus. These findings suggest that the denervation in the majority of cases is located in the Auerbach plexus, with complete absence of ganglion cells and, therefore, absence of postganglionic nerve fibers.
TL;DR: Active inflammation of the gastroduodenal mucosa likely accounts for the symptoms in patients with non-ulcer dyspepsia and an endoscopically normal mucosa was more likely to be associated with a normal neutrophil count.
Abstract: Proper control and quantitation are important in the accurate evaluation of gastroduodenal inflammation in dyspeptic patients without ulcers or erosions as proved by endoscopy. The endoscopic findings and the gastroduodenal mucosal inflammatory cell count in 31 patients with nonulcer dyspepsia were compared with an age-matched group of 32 healthy controls. Endoscopy revealed similar mucosal changes and in similar frequency in both groups. Differential mucosal inflammatory cell count showed a statistically significant (P<0.001) increase in the neutrophil count in the gastric body, antrum, and duodenal cap of the dyspeptic group, as well as a slight but significant (P<0.05) increase in the round cell and eosinophil count of the duodenal mucosa alone. No correlation was found between the endoscopic changes and an increase in neutrophil count above a normal level determined by the healthy controls. However, an endoscopically normal mucosa was more likely to be associated with a normal neutrophil count. Active inflammation of the gastroduodenal mucosa likely accounts for the symptoms in patients with nonulcer dyspepsia.
TL;DR: It is demonstrated that intrarectal administration of dmPGE2 can protect the colonic mucosa from damage induced by direct application of a potent topical irritant.
Abstract: The effects of pretreatment with 16,16-dimethyl prostaglandin E2 (dmPGE2) on ethanol-induced colonic damage were studied in the rat. Colonic damage was assessed macroscopically, histologically, and using cytoplasmic (lactate dehydrogenase) and lysosomal (acid phosphatase) enzyme markers of cell disruption. Intrarectal administration of 30% ethanol produced grossly visible regions of hyperemia and hemorrhage. Histologically, the ethanol injury was characterized by complete destruction of the surface epithelium and necrosis extending throughout most of the mucosal layer. When incubatedin vitro after challenge with ethanolin vivo, the colons released significantly more acid phosphatase and lactate dehydrogenase than did controls. Intrarectal pretreatment with dmPGE2 caused a dose-dependent reduction in ethanol-induced damage, as measured by all three parameters. A significant (P<0.05) reduction of macroscopically visible damage was observed with 0.2 μg/kg dmPGE2, while at higher doses (20 μg/kg) the histological signs of damage, including that to the colonic epithelium, were reduced or completely prevented. This dose of dmPGE2 also reduced (P<0.01) the release of the enzymemarkers to control levels. The possibility that this protection was mediated by increased colonic fluid secretion was studied. Pretreatment with dmPGE2 had no effect on net colonic fluid secretion (measured using the nonabsorbable marker [3H]inulin) or on the absorption of ethanol by the colon. This study demonstrates that intrarectal administration of dmPGE2 can protect the colonic mucosa from damage induced by direct application of a potent topical irritant. With the highest dose of dmPGE2 tested (20 μg/kg), protection of the colonic epithelium from ethanol injury was observed.
TL;DR: It is suggested that chronic alcohol abuse in man results in complex, nonparallel alterations in the synthesis and secretory kinetics of specific pancreatic exocrine proteins.
Abstract: The effect of chronic alcohol abuse on the secretion of pancreatic exocrine proteins was studied. Pure pancreatic juice (PPJ) was obtained by endoscopic cannulation of the pancreatic duct from 21 healthy, nonalcoholic volunteers and 25 chronic alcoholics. Peak concentration and output of total proteins after sequential stimulation with secretin and cholecystokinin was elevated significantly in chronic alcoholics when compared to nonalcoholic subjects. The most striking change in the secretory proteins investigated was exhibited by the trypsinogens. Although the concentrations of all three trypsinogen variants were elevated significantly in PPJ of chronic alcoholics, most of the increase resulted from an approximately fivefold increase of the anionic variant, suggesting nonparallel alterations in the synthesis of pancreatic exocrine proteins. Whereas the ratio of cationic-anionic trypsinogen in the control group was consistently greater than one, it was, without exception, below one in the chronic alcoholics group. As there was no significant increase in trypsin inhibitor in PPJ of alcoholics, the ratio of trypsinogen-trypsin inhibitor showed a highly significant increase in this group. This distortion of the normal ratio in favor of trypsinogen may facilitate premature activation of pancreatic zymogens as postulated in acute pancreatitis. The concentrations of other zymogens and lysosomal hydrolases in PPJ of chronic alcoholics showed small, but not significant, increases, with the exception of leucine naphthylamidase which was significantly elevated. Nonparallel secretion of some exocrine proteins previously described in healthy nonalcoholic subjects was affected selectively by chronic ethanol ingestion. Thus, in chronic alcoholics the secretory kinetics of trypsinogen and chymotrypsinogen were altered, but trypsin inhibitor secretion remained apparently unaffected.(ABSTRACT TRUNCATED AT 250 WORDS)
TL;DR: Misoprostol, a synthetic analog of prostaglandin E1, inhibits gastric acid production and is cytoprotective at doses well tolerated by patients in preliminary trials as discussed by the authors.
Abstract: Misoprostol, a synthetic analog of prostaglandin E1, inhibits gastric acid production and is cytoprotective at doses well tolerated by patients in preliminary trials. This multicenter double-blind study was performed in out-patients with endoscopically demonstrated duodenal ulcers, to compare the efficacy in ulcer healing and the safety of two dosages of misoprostol and placebo. Up to six antacid tablets daily were permitted for pain. 308 patients enrolled and were randomized to three treatment groups: placebo, misoprostol 50 micrograms and misoprostol 200 micrograms. After two weeks of treatment, the three groups had similar percentages of patients with complete ulcer healing. However, after four weeks, 76.6% of patients taking misoprostol 200 micrograms q.i.d. had complete healing, compared with 42.6% on misoprostol 50 micrograms q.i.d. and 51% on placebo (P less than 0.001, 200 micrograms versus placebo). Patients taking misoprostol 200 micrograms used less antacid than the others. Diarrhea, mild and self-limiting, was present in 13% of the 200 micrograms group versus 5% on placebo. We conclude that misoprostol 200 micrograms q.i.d. is effective, safe and well tolerated in the treatment of duodenal ulcers.
TL;DR: Rodent models for colon cancer have contributed information on many aspects of the disease that may be applicable to prevention and treatment, and major questions, such as the controversies over the role of dietary fat and fiber, will be resolved only if investigators use comparable, consistent regimens and protocols.
Abstract: Rodent models for colon cancer have contributed information on many aspects of the disease that may be applicable to prevention and treatment. Data of major importance on factors that retard or enhance tumorigenesis are now within reach. There are several basic research needs in the further development of animal models. Major questions, such as the controversies over the role of dietary fat and fiber, will be resolved only if investigators use comparable, consistent regimens and protocols, report full results, and use comparable endpoint and statistical analyses. If the deceptively simple controversies in the animal models can be resolved, we shall have powerful tools for further investigation of carcinogenesis in the intestine.
TL;DR: In this article, the effects of 16-dimethyl prostaglandin E2 (16-dmPGE2) and necrotizing agents on gastric motility and gastric mucosa were studied in conscious rats.
Abstract: Effects of 16-dimethyl prostaglandin E2 (16-dmPGE2) and necrotizing agents on gastric motility and gastric mucosa were studied in conscious rats. Gastric motility was determined using a miniature balloon positioned in the glandular part of the stomach, which was connected to a pressure transducer and polygraph. Necrotizing agents, such as absolute ethanol, 0.6 N HCl, 0.2 N NaOH, or 4 M NaCl, were instilled into the stomach through a small fistula prepared in the forestomach. One milliliter of these agents produced streak lesions in the glandular part of the stomach within 1 hr, which were preceded by violent gastric contraction in every case. An intragastric administration of 16-dmPGE2 (0.3–3 μg/kg) by itself increased a tonus of the gastric wall but dosedependently lessened the number and the amplitude of contractions. In those rats treated with 16-dmPGE2 (3 μg/kg), necrotizing agents failed to enhance the motility or to induce streak lesions. Pretreatment with 1 M NaCl as a mild irritant also inhibited gastric motility and lesion formation, but those actions were significantly antagonized by indomethacin (5 mg/kg). These results indicate that necrotizing agents induce a violent gastric contraction, followed by development of lesions in the stomach, and that the inhibition of gastric hypercontraction may be involved in a cytoprotective action of a prostaglandin against those induced gastric lesions in rats.
TL;DR: Investigation of the effects of sulfasalazine and its moieties on synthesis of individual products of arachidonic acid metabolism by human colonic mucosa found that inhibition of synthesis of lipoxygenases products and modulation of the profile of cyclooxygenase products could reduce inflammation and enhance mucosal resistance to damage in ulcerative colitis.
Abstract: The effects of sulfasalazine and its moieties on synthesis of individual products of arachidonic acid metabolism by human colonic mucosa have been investigated. Sulfasalazine inhibited synthesis of the lipoxygenase products. Sulfasalazine and sulfapyridine also inhibited synthesis of thromboxane B2 while enhancing synthesis of prostaglandin (PG) F2 alpha or PGE2, respectively. Inhibition of synthesis of lipoxygenase products and modulation of the profile of cyclooxygenase products could reduce inflammation and enhance mucosal resistance to damage in ulcerative colitis.
TL;DR: In this article, the authors show that in the absence of alcohol consumption, low-dose weekly methotrexate treatment rarely causes clinically significant liver damage, even in the presence of liver fibrosis.
Abstract: Thirty patients with psoriasis or other nonmalignant diseases had liver biopsies done before treatment with low-dose methotrexate, 15 mg/week, and then at one- to two-year intervals as long as they continued the methotrexate. All patients were symptomatically improved on this regimen. The 15 patients who had normal liver biopsies at the start of the study had normal biopsies after methotrexate. Fifteen others had minor hepatic histologic abnormalities before treatment. Eleven patients had fatty infiltration. Ten showed no significant change after treatment while one had increased fat and portal fibrosis on a fourth liver biopsy done seven years after MTX was begun. This last patient, a former alcohol abuser, continued methotrexate and showed no further worsening at 8 years. The remaining four had portal fibrosis before treatment. One patient had less fibrosis after methotrexate, two patients slightly more fibrosis, and one a marked increase in portal fibrosis. No patient developed cirrhosis or clinical liver disease. Our results suggest that in the absence of alcohol consumption, low-dose weekly methotrexate treatment rarely causes clinically significant liver damage.
TL;DR: It is shown that serum gamma-glutamyl transpeptidase is persistently elevated in patients with clinically obvious liver injury, but only in 22% of chronic alcoholics without significant liver disease.
Abstract: Serum gamma-glutamyl transpeptidase was determined in 123 alcoholic patients and found elevated in all patients with liver disease but in only 52% of patients without significant liver disease. In patients without clinically obvious liver disease, the elevations were two to three times the upper limit of normal and decreased to normal in 80% of patients, eight weeks after abstinence. By contrast, in patients with liver disease, the elevations of serum gamma-glutamyl transpeptidase were of the order of eight to 10 times above normal and persisted at these high levels following eight weeks of abstinence. The degree of abnormality of the serum enzyme did not correlate with the daily amount of alcohol ingested or with the total length of time of alcohol consumption in these alcoholic patients. This study shows that serum gamma-glutamyl transpeptidase is persistently elevated in patients with clinically obvious liver injury, but only in 22% of chronic alcoholics without significant liver disease.
TL;DR: In this double-blind parallel group multicenter international study, patients with endoscopically proven acute duodenal ulcers were allocated randomly to treatment for four weeks with either misoprostol 50 μg, misopostol 200 μg or cimetidine 300 mg.
Abstract: In this double-blind parallel group multicenter international study, patients with endoscopically proven acute duodenal ulcers were allocated randomly to treatment for four weeks with either misoprostol 50 μg, misoprostol 200 μg or cimetidine 300 mg, each given q.i.d.. Endoscopic, clinical and laboratory assessments were made prior to and after four weeks' treatment. A clinical assessment was also made at two weeks. 703 patients were recruited. The three treatment groups were similar with regard to age, sex and occupation. Therapeutic success was defined as complete healing of all ulcers on the basis of an endoscopic examination. On an intent to treat basis, which includes all losses to follow-up and withdrawals as treatment failures, the cure rates in the misoprostol 50 μg, misoprostol 200 μg and cimetidine groups were 41%, 60% and 67% respectively. There was no statistically significant difference between the misoprostol 200 μg and the cimetidine 300 mg groups (P=0.11). Both were significantly better than the low dose misoprostol group (P<0.001). All three treatments were well tolerated and severe adverse events were rare.
TL;DR: It remains to be seen whether prostaglandins, mucus secretion, or gastric mucosal blood flow are impaired in chronic ulcer disease, and it is also becoming clear that of all the abnormal functions noted, few are present in all subjects and many are clustered in subgroups.
Abstract: Heterogeneity is the most important consideration in the pathophysiology of peptic ulcer disease. Acute ulcers and erosions present clinically with gastrointestinal bleeding or perforation. If they heal there is no predictable recurrence. Factors concerned with mucosal defense are relatively more important than aggressive factors such as acid and pepsin. Local ischemia is the earliest recognizable gross lesion. The gastric mucosa is at least as vulnerable as the duodenal mucosa and probably more so. Most drug-induced ulcers occur in the stomach. Chronic or recurrent true peptic ulcers (penetrating the muscularis mucosae) usually present with abdominal pain. Many duodenal ulcer patients report that the pain occurs when the stomach is empty or is relieved by food, and follows a pattern of relatively long periods of freedom from symptoms between recurrences. Approximately 50% of patients experience a recurrence within a year if anti-ulcer medication is stopped. In most western countries recurrent duodenal ulcer is more common than gastric ulcer. Peptic ulcer disease is also more common in men. Recent evidence indicates genetic and familial factors in duodenal ulcer and increased acid-pepsin secretion in response to a variety of stimuli. However, it is also becoming clear that of all the abnormal functions noted, few are present in all subjects and many are clustered in subgroups. In chronic gastric ulcer of the corpus, defective defense mechanisms, such as duodenogastric reflux and atrophic gastritis, seem to be more important than aggressive factors. Nevertheless, antisecretory medications accelerate the healing of such ulcers. It remains to be seen whether prostaglandins, mucus secretion, or gastric mucosal blood flow are impaired in chronic ulcer disease.
Abstract: Selenium deficiency has been implicated as a cause of hepatic injury, possibly from accentuated lipoperoxidation due to decreased activity of the selenoenzyme, glutathione peroxidase. Because of possible clinical and biochemical links between selenium and alcohol, we performed nutritional assessment and assayed red blood cell, plasma, and whole blood selenium by spectrofluorometry in 27 normals (group I), 30 asymptomatic alcoholics on admission to a detox unit (group II), and 16 alcoholics with severe liver disease (group III). We found a mean (±sd) whole blood selenium of 0.109 μg/ml±0.014 for group I vs 0.076±0.010 for group II (P<0.001), and 0.047±0.006 for group III (P<0.001 vs group I and II). For plasma, the mean (±sd) selenium was 0.095 μg/ml±0.016 for group I versus 0.065 μg/ml±0.012 in group II and 0.038 μg/ml± 0.007 in group III (AllP<0.001). Calculated red blood selenium levels were also significantly reduced in alcoholics versus controls. Whole blood and plasma selenium correlated directly with serum albumin. For whole blood selenium versus albumin,r=0.73 (P<0.01), and for plasma selenium versus albumin,r=0.71 (P<0.01). A significant inverse correlation was noted between whole blood selenium and the height of the total serum bilirubin (r=−0.46), alkaline phosphatase (r=−0.50), and AST (r=−0.51) (P<0.01 for all). Among alcoholics admitted for detoxification, selenium was diminished despite the absence of severe malnutrition, as determined by standard nutrition assessment parameters. We conclude that blood selenium levels are diminished in alcoholics, even in the absence of severe liver disease or malnutrition. This abnormality is markedly accentuated in the presence of severe liver disease and correlates directly with albumin and inversely with bilirubin. Associations between this finding and its role in liver disease, as well as other pathologic states attributed to alcoholism, deserves further consideration.
TL;DR: PYY has been shown to inhibit gastric acid secretion and emptying, at plasma concentrations similar to those seen after glucose, in patients with the dumping syndrome, and may be a factor involved in the pathophysiological changes associated with this condition.
Abstract: The newly isolated hormonal peptide PYY is mainly localized to endocrine cells of the lower intestinal mucosa. The release of PYY by oral glucose was studied in six patients with the dumping syndrome to ascertain the effect of this condition on PYY release. Plasma PYY concentrations were greatly increased following oral glucose in patients with the dumping syndrome compared with healthy controls. In a separate series of experiments, the effect of somatostatin infusion on the PYY release by glucose in these patients was investigated. The release of PYY was completely blocked by infusion of somatostatin, and its release from the bowel in normal subjects may therefore be modulated by local somatostatin in the gut. PYY has been shown to inhibit gastric acid secretion and emptying, at plasma concentrations similar to those seen after glucose, in patients with the dumping syndrome. PYY may therefore be a factor involved in the pathophysiological changes associated with this condition.
TL;DR: The authors' observations are consistent with the previously described localization of neurological areas controlling swallowing and micturition and favor the pons as the possible level of supraspinal control of colonic and anorectal motility.
Abstract: The supraspinal control of colonic motility and anorectal motility is poorly documented. We had the opportunity to study colonic function, esophageal function, and urinary bladder function in three patients who presented with vascular lesions limited to the anterior (case 1) or the posterior area (cases 2 and 3) of the pons. Esophageal manometry, urodynamic examination, whole and segmental transit time measurements (using radiopaque markers) and anorectal motility were systematically performed. The results were the following: (1) in the first case esophageal motility was not altered, whereas abnormal micturition, right colonic inertia, and absence of rectoanal inhibitor reflex were observed; (2) in cases 2 and 3, there was a poor esophageal coordination, the micturition and rectoanal inhibitor reflex were normal, and the transit time of the left colon was increased. Our observations are consistent with the previously described localization of neurological areas controlling swallowing and micturition; they also favor the pons as the possible level of supraspinal control of colonic and anorectal motility.
TL;DR: In this paper, spinal cord injury patients had significantly more spike wave activity in the basal state than did the controls (12.6 spikes per 10 min vs 3.3) while meal stimulation did not lead to an increase in spike activity.
Abstract: Colonic myoelectric activity was recorded from six para- or quadriplegic subjects with spinal cord injury and seven normal controls via bipolar electrodes in contact with the rectal mucosa. Recordings were carried out in the fasting (basal) state and after stimulation by a standard meal and by 1.0 mg neostigmine intramuscularly. The recordings were visually analyzed for spike activity, average slow wave frequency, and percentage occurrence of subsets of slow wave frequency (2–4 and 5–12 cycles/min). The spinal-cord-injured subjects had significantly more spike wave activity in the basal state than did the controls (12.6 spikes per 10 min vs 3.3). However, meal stimulation did not lead to an increase in spike activity in the spinal-cord-injured subjects (13.7 spikes per 10 min vs 12.6) while it did in the controls (6.4 vs 3.3 spikes per 10 min). Neostigmine significantly increased spike activity in both groups. There was no difference in average slow wave frequency nor any slow wave subsets between the two groups studied. Thus persons with spinal cord injuries have higher basal colonic myoelectric activity than normals but lack a demonstrable gastrocolic reflex. We conclude that the central nervous system exerts a tonic inhibitory influence on basal colonic motility and appears to participate in the gastrocolic reflex.