Development of a scoring system to predict mortality from upper gastrointestinal bleeding.

Despite the widespread application of endoscopy in acute upper gastrointestinal bleeding, there is little evidence of improved survival among those who undergo the procedure. To select high-risk patients who might benefit most from diagnostic and therapeutic endoscopy, the authors developed and validated a scoring system based on prognostic indicators of increased mortality. The scoring system was developed from the best clinical predictors of mortality, determined in a prospective study of consecutive bleeding patients. The model was then tested in a prospective validation phase at three hospitals. Three main factors in the model predict mortality: bleeding, including hematochezia, drop in hematocrit of 5%, short duration of bleeding, absence of melena, and hypotension; liver disease, manifested by prolonged prothrombin time and encephalopathy; and renal disease. Patients determined to be at high risk for death using the scoring system might be candidates for aggressive management and for therapeutic endoscopy.

Multiple actions of a novel vaginal contraceptive compound, ORF 13904.

ORF 13904, a sulfonated polystyrene polymer possessing potent vaginal contraceptive activity, was tested in vitro and in vivo to investigate its mechanism of action. Observations of rabbit spermatozoa when mixed with the compound in buffered saline confirmed that the compound is not spermicidal and showed that the cells rapidly and irreversibly agglutinate. Seminal plasma did not compromise the effects of the drug, but rather enhanced them. When spermatozoa were suspended in solutions containing ORF 13904 and then washed thoroughly to remove excess drug, human spermatozoa could not penetrate bovine cervical mucus in vitro and rabbit spermatozoa could not achieve fertilization after artificial insemination in vivo, suggesting that the drug either adheres to the sperm surface or irreversibly compromises sperm function. Biochemical analysis showed that ORF 13904 is also a potent acrosin inhibitor. These experiments suggest that ORF 13904 has several mechanisms of action, including the ability to agglutinate spermatozoa, alter sperm-cervical mucus interaction, and inhibit sperm acrosin.

Peptidoleukotriene binding in guinea pig uterine membrane preparations.

Peptidoleukotrienes are known to be potent smooth muscle contractile agents in many tissues, including guinea pig uterus. In order to characterize the receptors at which the leukotrienes interact, guinea pig uteri were homogenized in 50mM Tris-HCl, pH 7.4 at 4 degrees C and centrifuged at 1000xg for 10 min. The supernatant was centrifuged at 40,000 xg and the washed pellet was used to measure the binding of 3H-LTC4 and 3H-LTD4. Specific binding of 3H-LTD4 was not detected, but specific, saturable binding of 3H-LTC4 was measured at 4 degrees C, was complete in 10 min. and was rapidly reversible on addition of unlabeled LTC4. Binding was linear with protein concentration and stimulated by CaCl2 and L-serine borate. Scatchard and kinetic analysis of binding in the presence of calcium suggested a Kd of 10-12 nM. LTC4 was a more potent competitor of binding than LTD4 (IC50 - 40nM and 30 microM, respectively). FPL 55712 inhibited binding from 10-100 microM but stimulated binding at lower concentrations. Thus, the guinea pig uterus has specific receptors for LTC4, but not LTD4, that can be demonstrated by radioligand binding.

Evaluation of calcium entry blockers in several models of immediate hypersensitivity.

Several calcium-entry blockers, i.e., verapamil, nifedipine, flunarizine and diltiazem, were evaluated for their effects in models of immediate hypersensitivity disease. Verapamil, flunarizine and diltiazem were all effective in inhibiting antigen-induced bronchospasm in the guinea pig; however, the effects seen were at relatively high doses compared to the doses known to cause cardiovascular effects. Nifedipine caused no significant inhibition of resistance or compliance changes induced by antigen. Flunarizine, verapamil and diltiazem were ineffective in inhibiting antigen-induced histamine release from rat peritoneal mast cells in vitro. Although these compounds were active inhibitors of 5-D-[5,6,8,9,H,12,14,15-3H(N)]-hydroxy-6,8,11,14-eicosatetraenoic acid production in rat basophilic leukemia-1 cells, only flunarizine and verapamil showed effects on the 5-lipoxygenase enzyme when assayed directly. Also, these compounds were ineffective on SRS-A mediated bronchospasm in vivo. These data suggest that the currently available calcium entry blockers have little potential use in immediate hypersensitivity reactions.

Tissue selectivity and variability of effects of acetaminophen on arachidonic acid metabolism.

Acetaminophen has variable effects on prostaglandin synthesis depending on the tissue preparation used. The present study was designed to determine the effects of acetaminophen on arachidonic acid metabolism in different tissues simultaneously removed from the same animals treated with the compound. The ex vivo conversion of 14C-arachidonic acid into 14C-prostaglandins was monitored in homogenates or slices of tissues to which no exogenous cofactors were supplied. Administered orally at doses of 100-300 mg/kg to guinea pigs, acetaminophen stimulated prostaglandin production by cell-free preparations of stomach, but had no effect in lung or kidney medulla. At doses ranging from 25-300 mg/kg, p.o., to rats, acetaminophen stimulated stomach, but inhibited cerebral cortex prostaglandin production. These same effects were mimicked qualitatively when acetaminophen was added in vitro at 10(-4)M to 10(-2)M to similar preparations. In addition, at these same high concentrations, acetaminophen inhibited 5-lipoxygenase activity in cultured RBL-1 cells. It is speculated that the multiple and tissue variable effects that acetaminophen had on arachidonic acid metabolism depend on the inherent cofactors associated with each tissue type.

Effect of intravenous fat emulsion on experimental acute pancreatitis.

The known relationship of hyperlipidemia and pancreatitis raises the question whether intravenous fat emulsion is detrimental in acute pancreatitis. Pancreatitis was induced in 52 male Sprague-Dawley rats followed by placement of a jugular catheter which was anchored to the back with a Teflon button. The animals were placed NPO in metabolic cages and continuously infused, initially with normal saline. The 37 animals surviving 24 hr were randomly assigned to group I (mean iv intake: glucose 222 kcal/kg/day; amino acids 13.1 g/kg/day) or group II (glucose 191 kcal/kg/day; intravenous fat emulsion 10% 47 kcal/kg/day; amino acids 12.9 g/kg/day). Nine animals were eliminated from the study because of mechanical problems leaving 14 in each group for analysis. Per cent survival on days 3, 5, and 7 was 64, 50 and 36 in group I, and 50, 36 and 36 in group II. Mean urinary amylase excretion was 244 +/- 185 units/day in group I and 262 +/- 127 units/day in group II. There was no significant difference in survival or urine amylase excretion nor in pancreatic histology or gross appearance of the animals between the two groups. In this model of acute pancreatitis, intravenous fat emulsion was not detrimental as measured by survival, urinary amylase excretion, and pancreatic histology.

Double-blind controlled trial of bethanechol and antacid versus placebo and antacid in the treatment of erosive esophagitis.

To determine the value of bethanechol in the treatment of erosive esophagitis, a double-blind study was undertaken in which 28 patients were randomized to either bethanechol and antacid, or placebo and antacid. Patients were evaluated clinically, endoscopically, and by esophageal manometry before and after 8 wk of therapy. After treatment both groups showed significant improvement in heartburn and in healing of esophageal lesions. Patients who received bethanechol plus antacids did not show a greater improvement than patients who received placebo plus antacids in any category, nor did patients in the bethanechol-treated group have a greater incidence of complete healing. In addition, pretreatment mean lower esophageal sphincter pressure was normal in approximately 30% of patients with erosive esophagitis and this finding was associated with a greater chance for complete healing of esophageal lesions. These results fail to show that the addition of bethanechol to an intensive antacid regimen is more effective than the antacid regimen alone in the treatment of erosive esophagitis and that patients with esophagitis and normal lower esophageal sphincter pressures respond more favorably to medical treatment.

A current approach to acute upper gastrointestinal bleeding.

The mortality in patients with upper gastrointestinal bleeding has not changed in the past quarter century in spite of the introduction of new modes of therapy and treatment. In this review we address the possible reasons for a lack of change in mortality and the implications raised for the use of new techniques. We review the factors that affect the mortality of acute upper gastrointestinal hemorrhage and the diagnostic accuracy of upper gastrointestinal endoscopy. Based on this information, we present guidelines for the therapy of the major causes of upper gastrointestinal bleeding. These guidelines should be useful until new therapies have been assessed and become generally available.

A current approach to rectal bleeding.

The source of bleeding from the rectum is extremely difficult to specify in many patients with moderate to severe bleeding. Lesions may be located anywhere along the gastrointestinal tract. On the basis of the available literature and reported clinical data, we conclude that moderate to severe rectal bleeding originates from the upper gut in up to 10% of patients, from the small bowel in up to 5%, and from the colon in the remaining 85%. Diverticulosis and vascular dysplasia account for 30-50% of colonic bleeding, and inflammatory bowel disease and ischemic colitis for another 5-15%. No diagnosis is made in 20-30% of patients with moderate to severe rectal bleeding. Patients with rectal bleeding can be classified as those whose bleeding stops spontaneously, those whose bleeding stops and then recurs, and those whose bleeding continues despite conventional treatment. Based on these classifications, we present an approach to the diagnosis and therapy of rectal bleeding.

Occult dental infection as a cause of fever of obscure origin.

Three patients with prolonged unexplained fevers were ultimately found to have deep-seated dental infection. After initial examination failed to elicit symptoms or signs of dental infection, and extensive in-hospital evaluation was nonproductive, dental consultation with roentgenograms provided the diagnosis. All three patients underwent dental extractions with periapical or peridontal debridement; following a brief postoperative febrile period, all three responded with defervescence, without subsequent recurrence of fever. These cases emphasize the importance of periapical and peridontal infection as causes of fever of obscure origin. The pathogenesis, characteristics and bacteriology of periapical abscess are discussed.

Metabolism of L-rhamnose in Arthrobacter pyridinolis.

In Arthrobacter pyridinolis, a respiration-coupled transport system for L-rhamnose caused accumulation of free L-rhamnose, while a phosphoenolpyruvate: L-rhamnose phosphotransferase system caused accumulation of L-rhamnose I-phosphate (Levinson & Krulwich, 1974). The pathways for subsequent metabolism of L-rhamnose and L-rhamose I-phosphate have now been investigated. Arthrobacter pyridinolis contains an inducible L-rhamnose isomerase and L-rhamnulokinase, as well as a constitutive L-rhamnulose I-phosphate aldolase. Results with mutants which are unable to metabolize L-rhamnose suggest the presence of an L-rhamnose I-phosphate phosphatase, which forms free L-rhamnose by hydrolysis of L-rhamnose I-phosphate produced by the phosphotransferase system. Mutants which lack this enzyme exhibited severe inhibition of growth in the presence of L-rhamnose plus any of a variety of carbon sources. There is some evidence that this inhibition was due to accumulation of L-rhamnose I-phosphate at toxic concentrations within the bacteria. The metabolism of L-rhamnose transported by the phosphotransferase system therefore appears to occur by hydrolysis of L-rhamnose I-phosphate to free L-rhamnose by a phosphatase. Metabolism of the L-rhamnose thus produced, and of that accumulated by the respiration-coupled transport system, the proceeds by the sequence of reactions: L-rhamnose leads to L-rhamnulose leads to L=rhamnulose I-phosphate leads to dihydroxyacetone phosphate plus L-lactaldehyde.