The role of the clinician in research.
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Crohn Disease↗
Biomedical subjects
D Y Graham
Publications and source records attributed to D Y Graham.
Rotaviruses code for two types of glycoprotein precursors.
Rotaviruses are nonenveloped viruses that code for two glycoproteins: a structural glycoprotein (VP7) and a nonstructural glycoprotein (NS29). The precursor to VP7 (37K) was shown to contain a 1.5K cleavable signal sequence. The 37K precursor was authentically processed (signal sequence cleaved and the polypeptide "core" glycosylated) when synthesized in a cell-free system supplemented with dog pancreatic microsomes. Similar experiments were performed with the nonstructural glycoprotein precursor (20K); however, the 20K precursor contained an integral (noncleavable) signal sequence. Both precursors were inserted into membranes cotranslationally and both glycosylated products underwent posttranslational oligosaccharide processing. The results suggest a morphogenetic scheme for the simian rotavirus SA11.
Glycoproteins↗
Comparison of phenolphthalein and phenolphthalein glucuronide on net water transport in rat ileum and colon.
Phenolphthalein is an odorless, tasteless compound, poorly soluble in water, but readily soluble in alcohol or ether. Although its laxative activity was discovered in 1902, the mechanism of action remains unclear. Phenolphthalein has been found to be an ineffective laxative in both jaundiced patients and in experimental animals with ligated common bile ducts. In contrast to the poor solubility of phenolphthalein, phenolphthalein glucuronide is highly water-soluble. In addition, phenolphthalein glucuronide is found in bile following oral phenolphthalein administration, suggesting an enterohepatic circulation. We compared the effect of phenolphthalein and phenolphthalein glucuronide on net water absorption of the ileum and colon of Sprague-Dawley rats using a single-pass perfusion technique. Perfusion of phenolphthalein (10 mg/dl in 154 mM NaCl with 0.5% ethanol and 0.1 g/l gum arabic) resulted in significantly reduced water absorption in both the ileum and colon (66% and 64%, respectively, P less than 0.05). In contrast, phenolphthalein glucuronide did not have a significant effect on net water flux compared to control perfusion in either the ileum or colon. In the ileum only 77 +/- 3% and colon 71 +/- 1.2% of the phenolphthalein infused was recovered, suggesting that much of the infused phenolphthalein was absorbed. In contrast there was no evidence of absorption of phenolphthalein glucuronide, as 98.9 +/- 1.2% was recovered from ileal and colon perfusions. Phenolphthalein glucuronide is not the active form of phenolphthalein, although it may be an effective laxative after deconjugation by colonic bacteria.
Animals↗
Double-blind comparison of liquid antacid and placebo in the treatment of symptomatic reflux esophagitis.
Although antacids have been the mainstay of pharmacologic therapy for reflux esophagitis, their effectiveness has not been tested in a placebo-controlled double-blind trial. We report a double-blind comparison of liquid antacid vs placebo in the treatment of reflux esophagitis in 32 patients with chronic heartburn. Entry criteria included the presence of symptomatic gastroesophageal reflux confirmed by both an acid perfusion (Bernstein) test and by intraesophageal pH probe. Drug treatment consisted of 15 ml (80 mEq) doses of antacid (Maalox Therapeutic Concentration, William H. Rorer) or placebo taken 7 times daily, ie, 1 and 3 hr after meals and at bedtime. Both groups showed significant improvement (P less than 0.05) in both frequency and severity of heartburn. The time to reproduce heartburn with the timed Bernstein test was increased with both active drug and placebo therapy. The mean increase was 402% (41 +/- 20 sec to 169 +/- 66 sec) for the placebo group and 286% (42 +/- 16 to 120 +/- 57 sec) in the antacid group. Both the antacid and placebo groups showed improvement in the degree of esophagitis as assessed endoscopically. The current study asked: does regular antacid therapy have a favorable influence on the natural history of symptomatic reflux esophagitis, ie, does therapy heal or otherwise change esophagitis so that painful episodes are either less frequent, less severe, or both? We found that the natural history of symptomatic reflux esophagitis was to improve with either antacid or placebo. There was no significant difference in antacid or placebo on the (short-term) natural history of the disease.
Aluminum Hydroxide↗
Solubility of calcium soaps of long-chain fatty acids in simulated intestinal environment.
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Bile Acids and Salts↗
Gastric adaptation occurs with aspirin administration in man.
Endoscopy has become a standard method to evaluate drug-induced damage to the gastroduodenal mucosa; however, studies defining the time course, extent, and duration of the injury in man are unavailable. We report a systematic endoscopic evaluation of the effect of aspirin administration on the gastric mucosa in normal volunteers. Aspirin (2.6 g/ day) or placebo was administered for 1 or 7 days. Gastroscopy was performed after 1, 2, 4, and 8 days, and every other day thereafter until the lesions resolved. Submocosal hemorrhages and/or focal erosions were present within 24 hr in all subjects. With continuous aspirin administration, injury was maximal within 3 days and then lessened, ie, damage present after 7 days of aspirin was significantly less than after 1 day of therapy. The time to resolution of the damage was also longer following 1 day than after 7 days of aspirin (median 8 days for 1 day of aspirin vs median 3 days for 7 days of aspirin). Thus, gastric mucosal adaptation occurred and was associated both with less damage and with an accelerated healing process. Acute administration of aspirin produced well-defined areas of submucosal hemorrhages within 2 hr of administration; additional doses increased the area of involvement but not necessarily the severity of involvement.
Adult↗
Two types of glycoprotein precursors are produced by the simian rotavirus SA11.
The rotavirus genome codes for two glycoproteins: an outer capsid structural glycoprotein (VP7, apparent molecular weight 38,000 (38K)) and a nonstructural glycoprotein (NS28K). The synthesis of these glycoproteins was analyzed in infected cells and in a cell-free system derived from rabbit reticulocyte lysates supplemented with dog pancreatic microsomes. The data showed a 37K product synthesized in the cell-free system is the precursor to the 38K glycoprotein and that the 37K polypeptide contains a cleavable signal sequence (apparent molecular weight 1.5K). The 37K polypeptide was glycosylated in vitro in the presence of microsomal membranes to a polypeptide of 38K that was immunoprecipitated by monospecific antiserum to VP7. Endo H digestion of the 38K polypeptides from either infected cells or the cell-free system produced polypeptides of identical molecular weight, 35.5K (the glycoprotein precursor lacking the signal sequence). These results were confirmed by comparative studies with a variant of SA11 that is defective in glycosylation of VP7. Similar experiments with the 20K precursor to the 29K nonstructural glycoprotein showed the 20K polypeptide contains a noncleavable signal sequence. Both glycoproteins were inserted into microsomal membranes and were processed via oligosaccharide trimming.
Amino Acid Sequence↗
What is the role of prosthesis insertion in esophageal carcinoma?
We review our experience with 13 patients in whom esophageal dilation was used for palliation of malignant esophageal obstruction and with five patients treated with esophageal prostheses for malignant esophagorespiratory fistula. Twelve of the 13 patients with dilation alone received satisfactory palliation and were able to eat a soft or regular diet. Four of five patients with esophagorespiratory fistulas had esophageal dilation followed by insertion of a esophageal prosthesis and received good palliation. Endoscopic insertion of esophageal prosthetic devices has become increasingly popular as a palliative procedure, despite lack of controlled trials either proving efficacy of this therapy or comparing it to radiation therapy with or without dilation of the esophagus. The reported mortality and morbidity rates for esophageal prosthesis insertion are higher than those reported for radiotherapy. There is little to suggest that prostheses are better than or even equal to radiotherapy alone or radiotherapy and bougienage. We review the reported series (greater than 2300 cases) of push-through prostheses insertions in esophageal cancer and compare prosthesis insertion to other therapy. The need for a carefully controlled trial of the different forms of therapy is emphasized, and guidelines for such a study are suggested.
Adenocarcinoma↗
There is no right way to do the wrong thing.
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Esophageal Neoplasms↗
Niacin hepatitis.
We report a case of severe liver injury occurring on two occasions in a patient ingesting large doses of nicotinic acid. The liver architecture was markedly distorted, with both massive and submassive lobular collapse and marked cholestasis. Complete resolution of biochemical and histologic abnormalities occurred after withdrawal of these drugs.
Adult↗
Detection of antigenically distinct rotaviruses from infants.
Antigenically distinct rotaviruses, i.e., viruses morphologically identical to conventional rotaviruses by electron microscopy, yet lacking the common group antigen(s) detected by an enzyme-linked immunosorbent assay, were found in 2 of 51 fecal samples from Bulgarian infants with rotavirus gastroenteritis. These antigenically distinct viruses contained 11 segments of double-stranded RNA, but they demonstrated a unique RNA migration profile after electrophoresis of the genome RNA in polyacrylamide gels. This report confirms the presence of a new group of rotaviruses in humans. The significance of these viruses is currently unknown, and specific diagnostic tests must be developed for epidemiological studies to determine their role as human and veterinary pathogens and to evaluate their impact on proposed vaccine development programs.
Antigens, Viral↗
Effects of tunicamycin on rotavirus morphogenesis and infectivity.
The functions of the two rotavirus glycoproteins were investigated by using tunicamycin and a variant of SA11 rotavirus having nonglycosylated VP7. Results showed that glycosylation of VP7 is not required for normal viral morphogenesis and infectivity and suggested that the nonstructural glycoprotein is involved in assembly of the outer capsid.
Glucosamine↗
Biochemical mapping of the simian rotavirus SA11 genome.
Biochemical mapping experiments of the simian rotavirus SA11 genome were performed to determine which double-stranded RNA segment coded for each of the viral polypeptides. Viral RNA transcripts were synthesized in vitro by using the endogenous viral RNA polymerase and fractionated by electrophoresis in acid-urea agarose gels. The fractionated transcripts were translated in two cell-free systems: micrococcal nuclease-treated reticulocyte lysates and wheat germ extracts. The polypeptide products were identified by polyacrylamide gel electrophoresis and partial peptide analysis and compared with polypeptides synthesized in infected cells or found in purified virus. The RNA segment that coded for each transcript was determined by hybridization of the fractionated transcripts to the double-stranded RNA genome and analysis of the hybrids by electrophoresis in polyacrylamide gels. Primary gene products were assigned for 10 of the rotavirus transcripts and 10 of the double-stranded RNA segments. The coding assignments are as follows: the inner-capsid polypeptides, VP1, VP2, and VP6, were assigned to segments 1, 2, and 6, respectively; the major outer-capsid polypeptides, VP3 and VP7, were assigned to segments 4 and 9, respectively; segments 5, 7, and 8 coded for nonstructural polypeptides with molecular weights of 53,000, 34,000, and 35,000, respectively; segment 10 coded for the 20,000-molecular-weight precursor to the 29,000-molecular-weight glycosylated nonstructural polypeptide; and segment 11 coded for a 26,000-molecular-weight polypeptide that may be the precursor to the minor outer-capsid polypeptide VP9. Several methods were used to determine the product of gene segment 3, and the problems associated with the identification of this gene product are discussed.
Animals↗
Double-blind comparison of bismuth subsalicylate and placebo in the prevention and treatment of enterotoxigenic Escherichia coli-induced diarrhea in volunteers.
Enterotoxigenic Escherichia coli cause most traveler's diarrhea in Third World countries. We tested bismuth subsalicylate as prophylactic therapy and as treatment for enterotoxigenic E. coli-induced diarrhea. Thirty-two healthy hospitalized volunteers were challenged orally with enterotoxigenic E. coli, strain H10407 (serotype 078:K80:H11). Administration of 600-mg doses of bismuth subsalicylate or placebo was begun 8 h before bacterial challenge. Doses were taken at 8 h and 2 h before, and at 2 h and 4 h after, the E. coli challenge and were continued four times a day for 3 additional days. The maximum prophylactic bismuth subsalicylate dose was 9.6 g. Those experiencing diarrhea were rerandomized to receive bismuth subsalicylate or placebo, given as 300 mg every 30 min for a total of 2.4 g of bismuth subsalicylate, in eight doses. Diarrhea occurred in 9 of the 16 (56%) subjects receiving placebo and in 2 of the 15 (13%) subjects receiving bismuth subsalicylate, p less than 0.03. This study confirms the effectiveness of bismuth subsalicylate in preventing traveler's (enterotoxigenic E. coli) diarrhea, and shows that bismuth subsalicylate in other than liquid form is effective. Enterotoxigenic E. coli were recovered less frequently from those receiving bismuth subsalicylate than from those receiving placebo, suggesting that bismuth subsalicylate prevents diarrhea by reducing the number or multiplication of enterotoxigenic E. coli. In vitro studies revealed that bismuth subsalicylate and its components each were bactericidal at concentrations possibly attained during the clinical trial.
Antidiarrheals↗
Why do apparently healthy people use antacid tablets?
Proprietary antacids represent a multimillion dollar business in this country. Marketing surveys have shown that approximately one-half of American adults have used antacids. Twenty-seven percent of adults take 2 or more doses per month. Seventy-five percent of total antacid consumption is by heavy users, defined as greater than 6 doses per week (less than 5% of adults). We investigated why apparently healthy people are heavy antacid users. Thirty-seven heavy users were evaluated. The median duration of antacid use was 20 years, and most took antacids 2-6 times per day, concentrated through the work week. The primary diagnosis was reflux esophagitis in 31 (84%), peptic ulcer disease in one, and nonulcer dyspepsia in five. Ninety-five percent had symptoms consistent with reflux esophagitis. Thirty-three completed a 1 month double-blind, randomized cross-over trial of antacid tablets (14 mEq neutralizing capacity per tablet) versus placebo. Twenty-nine correctly identified the antacid product (p less than 0.0001). Twenty-three subjects underwent Bernstein tests and endoscopy; 21 had positive Bernstein tests, 13 had definite esophagitis as determined endoscopically. We conclude 1) heavy proprietary antacid tablet use in the adult male is not an expression of functional disease but is due to reflux esophagitis, 2) tablet use can be effective symptomatic treatment, and 3) history is an adequate evaluation for most heavy antacid tablet users.
Antacids↗
Recurrent ulcers after gastric surgery: endoscopic localization to the gastric mucosa.
The traditional teaching has been that ulcers recurring after ulcer surgery occur at, or distal to, the anastomosis of the gastric and intestinal mucosa. These concepts predate the widespread availability of fiberoptic endoscopy. We noted that recurrent ulcers were frequently located in the gastric mucosa proximal to the gastrointestinal anastomosis. We analyzed our cases for the purpose of identifying the location of ulcers that occur after surgery for peptic ulcer disease and to investigate the possible relationship between indication for the original ulcer surgery and the presentation of the recurrent ulcer. Ulcers after peptic ulcer surgery were most frequently located in the gastric mucosa proximal to the intestinal anastomosis. The location of the recurrence was not found to be related to the original diagnosis, to the indication for the operation, or to the presentation of the recurrence. These findings may reflect either a change in the pattern of ulcer recurrence or an altered pattern of recognition related to the routine use of endoscopy.
Adult↗
DNA hybridization studies of the association of Pseudomonas maltophilia with inflammatory bowel diseases.
An infectious etiology has been suggested for the inflammatory bowel diseases, Crohn's disease and ulcerative colitis, and an association of cell wall-defective variants of Pseudomonas maltophilia and Pseudomonas-like group Va bacteria with Crohn's disease has been reported by Parent and Mitchell. Seven of the Parent-Mitchell isolates were compared by using DNA hybridization and six were identical and similar, but not identical, to a type strain of P. maltophilia. The seventh isolate showed extensive homology with VARC, a reference strain of group Va organism, but not with P. maltophilia. Pseudomonas DNAs were radiolabeled by nick translation and used as probes for homologous DNA in hybridization experiments involving 48 different tissues. The presence of DNA with sequences homologous to those of P. maltophilia was detected in three of 23 Crohn's disease samples, two of 10 ulcerative colitis samples, and none of 15 control samples. There was no hybridization with VARC or Pseudomonas aeruginosa probes. We were unable to culture cell wall-defective organisms from patients' tissues but have detected pleomorphic organisms in hypertonic cultures of 14 of 53 Crohn's disease specimens, none of six ulcerative colitis specimens, and none of 11 control specimens. None reverted to normal bacteria. These results do not support an exclusive association of P. maltophilia with Crohn's disease but rather suggest a possible association of P. maltophilia with IBD. Technical limitations currently preclude definitive conclusions regarding the significance of this association. Although we demonstrated the presence of DNA sequences with homology to P. maltophilia DNA in tissues of some patients with IBD, the role, if any, of these bacteria in the pathogenesis of IBD has yet to be established.
Base Sequence↗
Natural history of benign esophageal stricture treated by dilatation.
Although bougienage is widely used to treat benign esophageal stricture, the rate of stricture recurrence and the long-term effectiveness of bougienage are unknown. We studied the natural history of esophageal stricture in 154 patients in whom bougienage was used as primary therapy. Dilatations were considered successful in terms of relief or major improvement of dysphagia in 84.5% of 103 patients followed 6 mo or longer (median, 26 mo). The risk of requiring esophageal dilatation after the initial episode was greatest in the first year of follow-up; thereafter, a smaller fraction of patients required dilatation each year. Forty-three percent of patients required no further dilatations, and a life-table analysis showed that 36% of patients would require no further dilatation during a projected 4-yr follow-up. The median frequency of subsequent dilatation was less than once a year. We were unable to identify any significant factors, such as initial severity of stricture, cause of stricture, presence of active esophagitis, or initial caliber of dilatation, that could predict the need for subsequent dilatation. Our results suggest that patients with benign strictures fall into two groups. In one group, the natural history was to improve or become asymptomatic after an initial series of dilatations, and only a small proportion eventually developed recurrent symptoms. The second group (46% of patients) required further dilatations to treat dysphagia during the first year of follow-up. Two-thirds of these patients needed regular dilatations in subsequent years. We conclude that bougienage is effective treatment for benign esophageal strictures, and should be utilized as primary therapy for most strictures.
Adult↗