A comparison of three fingerstick, whole blood antibody tests for Helicobacter pylori infection: a United States, multicenter trial.

OBJECTIVE: We compared three whole blood antibody tests for Helicobacter pylori (H. pylori) in a United States, multicenter trial. METHODS: Patients referred for EGD at three medical centers were recruited. During EGD, biopsies were taken for histology and rapid urease testing (RUT). Immediately after endoscopy, patients underwent the antibody tests (FlexPack HP, Abbott Diagnostics; QuikVue, Quidel Corporation; AccuMeter, ChemTrak) using whole blood obtained by two to three fingersticks. Performance characteristics were calculated for each antibody test using the biopsy-based methods as a gold standard. RESULTS: A total of 131 patients participated; 50 (38%) patients had histological evidence of H. pylori infection. Using histology as a gold standard, the sensitivities of FlexPack HP, QuikVue, and Accumeter were 76%, 78%, and 84%, respectively. Specificity was 79% with FlexPack HP and 90% with QuikVue and Accumeter. There were no significant differences in the performance of the three antibody tests though there was a trend toward superior performance for AccuMeter compared to FlexPack HP (p = 0.019). However, RUT proved superior to FlexPack HP using histology as a gold standard (p = 0.008). Using either concordant histology and RUT results or a positive histology or RUT to define active H. pylori infection, there was no statistically significant difference between the antibody tests. CONCLUSIONS: There were no statistically significant differences in the performance of the three antibody tests. These tests proved only marginally sensitive in detecting patients infected with H. pylori. Clinicians should be aware of the limitations of these tests, particularly when using them as a sole means of testing for H. pylori.

Induction of an ATPase inhibitor protein by propylthiouracil and protection against paracetamol (acetaminophen) hepatotoxicity in the rat.

1. The purpose of the present study was to test the following hypothesis: propylthiouracil (PTU) treatments of rats induces an increase in the concentration and activity of the mitochondrial ATPase (m-ATPase) inhibitor protein (IF1). The PTU-induced elevated baseline levels of this inhibitor protein inactivated m-ATPase, and prevented hepatotoxicity by a toxic dose of acetaminophen (AAP) (paracetamol), by maintaining hepatic adenosine 5'-triphosphate (ATP) levels. 2. Male Wistar rats were either gavaged with a toxic dose of AAP alone, or after pretreatment with PTU for periods of 3 and 12 days. 3. Twenty four hours after acetaminophen treatment alone, toxicity was manifested by: an approximately 10 fold increase in serum transaminase levels (serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase); depletion of hepatic reduced glutathione (GSH) and ATP levels; loss of inhibitor protein activity, and extensive pericentral necrosis of the hepatocytes. Propylthiouracil pretreatment for 12 days enhanced the concentration of the following metabolites in the liver: ATP (1.5 fold), ATPase inhibitor protein (IF1) (4.5 fold), and reduced glutathione (1.3 fold), while the activity of the inhibitor protein increased 2 fold. When the PTU treated rats were challenged with AAP, transaminases were not elevated, and only sporadic areas of necrosis were detected by histological examination of the liver tissue. In contrast to the 12 day treatment with PTU the 3 day treatment had no protection against AAP. No histological evidence of protection was manifested and the transaminases were not different from AAP treated controls. Most of the protective metabolites were depleted. 4. Our findings suggest that PTU-induced increased concentration of inhibitor protein and GSH, are contributing factors in the prevention of hepatotoxicity by maintaining hepatic m-ATP levels and reducing the harmful effect of the toxic metabolite of AAP.

The ChemTrak Hp Chek fingerstick whole blood serology test for the detection of Helicobacter pylori infection.

OBJECTIVE: To evaluate a new whole blood serology test (Hp Chek; ChemTrak) that detects IgG antibodies to Helicobacter pylori. METHODS: The study was conducted at 10 sites within the United States. Patients undergoing upper endoscopy for dyspepsia were recruited for enrollment. Those treated for H. pylori infection within a year of endoscopy and those who had regularly used proton pump inhibitors, bismuth compounds, or antibiotics within a month of endoscopy were not eligible. During endoscopy, specimens were obtained from the corpus and antrum for histological examination, which was performed by a single experienced pathologist. The Hp Chek was tested using whole blood and serum. Serum was also tested with a reference enzyme-linked immunosorbent assay (ELISA) at a centralized location. Test characteristics for the Hp Chek and ELISA were calculated using histology as the "gold standard." RESULTS: Two hundred eighty-seven patients (140 women and 147 men; mean age 53 +/- 6 yr) were enrolled. The Hp Chek was easy to perform and yielded results 9 min after inoculation of the test cassette with whole blood or serum. When the Hp Chek used with whole blood was compared with histology as the gold standard, the sensitivity was 88%, specificity 85%, positive predictive value 83%, negative predictive value 90%, and percent agreement 86%. There were no statistically significant differences among the results obtained with the Hp Chek using whole blood, the Hp Chek using serum, or reference ELISA. CONCLUSIONS: The Hp Chek whole blood serology test was easy to perform and rapid and yielded performance characteristics comparable to those of a reference ELISA or the Hp Chek used with serum.

Lovastatin induces synthesis of cholesterol, which acts as a secretagogue of biliary phospholipids in rats.

The effects of treatment with lovastatin (LS), a hypocholesterolemic drug, on hepatic metabolism of cholesterol (CH) and phosphatidylcholine (PC) were studied in rats. Hepatic synthesis of CH was increased, as previously reported by our laboratory. Total plasma CH was increased, and biliary secretion of CH was raised fourfold, but biliary secretion of bile salts was not affected. Because CH is practically insoluble in an aqueous milieu, we tested the hypothesis that excessive CH is solubilized and secreted into bile as cholesterol-phospholipid (CH-PL) vesicles. The effects of LS-induced increase in CH synthesis on hepatic metabolism of PC after 7 days of oral LS treatment (17.5 mg/day) were studied. Our results showed accelerated synthesis of PC and increased biliary secretion of newly formed PC into bile, as evidenced by the following. 1) Phosphocholine cytidylyltransferase (EC 2.7.7.15) activity, the rate limiting enzyme in the synthesis of PC, increased 2.5-fold in the hepatic microsomes of the hepatocytes. 2) After intravenous administration of [14C]choline, a precursor of PC, [14C]PC increased significantly in bile. 3) Biliary output of PC increased twofold. 4) Quasi-elastic light scattering measurements of bile showed a 3.5-fold increase in intensity of the CH-PL vesicles, indicating higher concentrations of CH-PL vesicles, but there was no change in the intensity of the micelles. These observations support the hypothesis that PC synthesis was enhanced as a transport mechanism for secretion of the excessive amounts of cholesterol from the hepatocytes into bile as CH-PC vesicles.

Effects of PEG-electrolyte (Colyte) lavage on serum acetaminophen concentrations. A model for treatment of acetaminophen overdose.

The purpose of this study was to evaluate whole gut lavage with polyethylene glycol electrolyte solution (Colyte), as a potentially adjunctive measure in lowering serum acetaminophen levels. The effect of bowel lavage was evaluated on serial serum acetaminophen concentrations after 2-g and 4-g doses in 7 and 12 male patients, respectively. Mean peak level of serum acetaminophen after 2 g (60 min after intake) was not significantly lowered by bowel lavage. After 4 g, peak acetaminophen serum levels were significantly lower after bowel lavage (65.4% of controls, P < 0.001). Urinary concentrations of the mercapturic acid conjugate of the toxic metabolite were also significantly reduced by lavage (55% after 2 g and 45% after 4 g, P < 0.01). Activated charcoal given orally after administration of 4 g of acetaminophen had no significant effect on peak serum levels and had no additive effect on lavage. These studies suggest that rapid, complete bowel lavage with a polyethylene glycol electrolyte solution may be beneficial as an adjunct to the treatment of the acetaminophen intoxication.

Increase in serum and bile cholesterol and HMG-CoA reductase by lovastatin in rats.

Lovastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, is effective in the treatment of hypercholesterolemic patients and is currently being evaluated as a potential agent for dissolving gallstones. We therefore evaluated its effect on cholesterol metabolism in a rat model. A low-cholesterol diet containing 0.1% lovastatin was fed 15 h and 7 and 21 days. Microsomal HMG-CoA reductase activity, hepatic cholesterol synthesis, blood cholesterol, and biliary lipid output were determined and compared with control rats. Hepatic cholesterol synthesis increased ninefold after 7 days and levels of HMG-CoA reductase activity sevenfold. Biliary cholesterol excretion maximally increased fourfold. Biliary lipid output was still elevated after 21 days of treatment (cholesterol 3-fold and phospholipid 2-fold, P less than 0.01). Bile salt output did not change. Augmented responses to lovastatin were present but less on the high-cholesterol diet. The data are consistent with the hypothesis that lovastatin increases HMG-CoA reductase activity through a feedback mechanism that promoted increased cholesterol synthesis, biliary lipid secretion, and elevated blood cholesterol. There was an apparent coupling of biliary cholesterol output with phospholipids but not with bile salts. Although lovastatin also increased microsomal HMG-CoA reductase activity in humans, cholesterol synthesis is not stimulated but is inhibited. This may be explained by higher permeability of the microsomal membranes for lovastatin. Thus the effect of HMG-CoA reductase inhibitors on cholesterol synthesis in different species should then depend on the properties of microsomal membranes.

Modulation of gastric pH by continuous gastric and jejunal infusion of cimetidine.

We studied the effect of gastric versus jejunal tube feedings on gastric pH and evaluated the acid-inhibiting effects of continuous gastric and jejunal infusions of cimetidine. pH was monitored by an intragastric pH probe in 19 gastrostomy and 13 jejunostomy patients during fasting, continuous infusions of Osmolyte, cimetidine, and simultaneously Osmolyte and cimetidine. Gastric Osmolyte increased fasting pH from a mean of 1.32 to 2.78 (P less than 0.01), while jejunal Osmolyte did not (pH 1.02). Continuous gastric infusion of cimetidine maintained a high gastric pH (5.06) in 17 of 19 patients. Jejunal cimetidine also achieved therapeutic serum levels and raised gastric pH to 4.81 in nine of 13 patients. We conclude that the persistently low gastric pH during jejunostomy tube feeding may play a major role in the upper gastrointestinal bleeding previously observed in such patients and that continuous gastric and jejunal cimetidine infusions effectively raise and sustain a high gastric pH.

Percutaneous endoscopic jejunostomy: long-term follow-up of 23 patients.

This study reports our experience with the placement and long-term follow-up of 26 percutaneous endoscopic jejunostomy (PEJ) tubes in 23 patients over a 2-year period. Eighty-four percent of the PEJ tubes failed and were functional for an average of only 39.5 days. The reasons for failure were: (1) separation of the inner PEJ tube from the outer gastrostomy tube (59%); (2) clogging (32%) due to small PEJ tube diameter; and (3) kinking and knotting (9%). Upper gastrointestinal bleeding occurred in 30% of the patients (7 of 23). Only one patient required blood transfusions (2 units). The etiology of the bleeding was not determined. These patients had a previous history of acid-peptic disease and bleeding occurred despite cimetidine treatment. In contrast, only 1 of the 16 nonbleeding patients had acid-peptic disease (p less than 0.0001) and none were on cimetidine. The frequency of aspiration pneumonia decreased from 13 episodes during nasogastric tube feedings to 5 episodes during PEJ tube feedings. Improvement in the design of the PEJ tubes may increase the longevity and effectiveness of the tubes.

Mechanism of pH effect on oleic acid and cholesterol absorption in the rat.

Previous experiments [K. Chijiiwa and W. G. Linscheer, Am. J. Physiol. 246 (Gastrointest. Liver Physiol. 9): G492-G499, 1984] have shown higher rates of absorption of oleic acid (OA) and cholesterol (CH) from micellar solutions perfused through segments of small bowel at pH 5.5 than at pH 6.5. Both solutions contained equal amounts of these lipids in addition to sodium taurocholate (30 mM). It was hypothesized that there may be two reasons to explain this observation. First, the micelles of one of the two solutions (pH 6.5) became depleted of these lipids during the perfusion procedure, while the micelles of the other solution (pH 5.5) were kept saturated with these lipids by the presence of emulsified particles in the perfusate. Second, the pH difference resulted in a much lower ratio of protonated vs. ionized OA in the pH 6.5 solution. Most investigators assume that primarily protonated fatty acid (FA) is absorbed and very little ionized FA is absorbed. The purposes of the present study are to evaluate further the factor of lipid saturation of the micelles by comparison of rates of absorption from two partially lipid-depleted micellar solutions containing equal amounts of OA and CH, in which the micelles of one solution were much more lipid depleted than the micelles of the other. This was caused by the pH difference. The second purpose is to evaluate the effect of the pH-related difference in protonate vs. ionized OA on absorption of OA from nonmicellar aqueous solutions.(ABSTRACT TRUNCATED AT 250 WORDS)

Distribution and monomer activity of cholesterol in micellar bile salt: effect of cholesterol level.

Despite the fact that uptake of cholesterol by the enterocyte occurs as a monomer from the intermicellar aqueous phase in equilibrium with micelle, the cholesterol monomer concentration in the aqueous phase and the partition coefficient between intermicellar aqueous phase and micellar aggregate have not been clarified. The present study deals with the distribution of cholesterol and monomer activity in constant bile salt-fatty acid micellar solutions with different cholesterol concentrations. In addition, uptake of cholesterol from these micellar solutions into rat jejunum was studied using everted sacs. Cholesterol monomer concentration in the aqueous phase increased linearly with the concentration of cholesterol in the micellar solution. Partition coefficient of cholesterol between the aqueous phase surrounding micelle and micellar aggregate was essentially constant at any cholesterol level (K = 3 X 10(-2)). Cholesterol monomer activities were linearly proportional to the cholesterol concentrations in the micellar solutions and correlated well with the rate of cholesterol uptake. It is concluded from these experiments that a partitioning phenomenon determines cholesterol monomer concentrations in the intermicellar aqueous phase from which the cholesterol is absorbed. After disappearance of the cholesterol monomers from the aqueous phase, these monomers are replaced by a shift of monomers from the intramicelle to intermicellar aqueous phase, under constant partition coefficient between extra- and intramicelle. The bile salt micelle provides a huge reservoir for partitioning of cholesterol monomers.

Possible role of pancreatic insulin and glucagon in the hyperlipidemia and obesity of obese strain of chicken.

Circulating levels of insulin, glucagon, thyroid hormones as well as lipid levels were determined in an obese strain of chicken and their lean controls. Hepatic and muscle glycogen and lipids were also measured. Obese birds had higher plasma lipids accompanied by significantly higher insulin and lower glucagon levels compared to lean controls. Hepatic and muscle triglycerides were also higher in obese birds. Plasma T4 level was significantly higher in obese but T3 was not different in the two groups. Results suggest that genetically obese birds have significantly increased insulin/glucagon ratios as previously reported in the PTU induced hypothyroid-obese chicks (Horm. Metab. Res. 12: 51, 1980) and this could have causal relationship to hyperlipidemia and obesity observed in these birds.

Propylthiouracil-induced hypothyroid hyperlipidemic chick: a model for clofibrate-induced toxicity.

An animal model for clinically observed clofibrate (p-chlorophenoxy isobutyrate, CPIB)-induced toxicity has been tested. It is demonstrated that propylthiouracil-induced hypothyroid-hyperlipidemic chick develops severe toxic manifestations following clofibrate administration. Toxic symptoms are characterized by listlessness, drowziness, and extreme muscular weakness. This is associated with elevation of blood urea nitrogen, creatine phosphokinase, uric acid and glutamic oxaloacetic transaminase. Histological examination of muscle specimen from chicks exhibiting toxic syndrome showed degeneration and vacuolization of muscle fibers. The biochemical and histological changes observed are quite similar to those reported in clinical practice in some patients given clofibrate. It is suggested that this chick model could be used to investigate the biochemical basis of clofibrate toxicity.

Failure of exogenous prostaglandin to afford complete protection against acetaminophen-induced hepatotoxicity in the rat.

The protective effect of 16, 16-dimethylprostaglandin E2 (dm-PGE2) against acetaminophen-induced hepatotoxicity was determined in the rat. The dm-PGE2 was administered at two dose levels both before and after acetaminophen administration. The hepatotoxicity was evaluated by a rise in serum transaminases 24 h after acetaminophen administration and by histological examination of liver preparations. The urinary acetaminophen and its metabolites were determined by high-pressure liquid chromatography. The results suggest that exogenous dm-PGE2 administration had a modest protection against acetaminophen-induced hepatotoxicity, in contrast to its well established cytoprotective effect against many noxious agents in the gastrointestinal tract. Prostaglandin treatment had little effect on acetaminophen metabolites excretion in the urine, suggesting that it did not affect the cytochrome P-450-dependent mixed-function oxidase drug-metabolizing enzyme system. The livers from dm-PGE2-acetaminophen-treated rats showed less advanced necrosis compared to those from saline-acetaminophen-treated rats. Whereas only 2 of 13 rats died in the prostaglandin-treated group, 4 of 13 rats died in the saline-treated group.

Inhibitory effect of propylthiouracil-induced hypothyroidism in rat on oxidative drug metabolism.

The effect of propylthiouracil (PTU) pretreatment on in vivo and in vitro oxidative drug metabolism was determined in the rat. Whereas pentobarbital sleeping time (PBST) and zoxazolamine paralysis time (ZZPT) were used as indices of in vivo drug metabolizing activity, biotransformation of aminopyrine and aniline by hepatic microsomal preparations were used as indices of in vitro drug metabolizing enzymes activities. PTU pretreatment significantly prolonged both PBST and ZZPT. Whereas PTU did not affect microsomal protein concentration or cytochrome P-450 content, it significantly decreased microsomal cytochrome c reductase and aniline hydroxylase activities. These changes in enzymatic activities were observed in microsomal preparations from either non-fasted or 24-hr fasted rats. Our results suggest that PTU-induced hypothyroidism modifies the metabolism and effectiveness or toxicity of concomitantly administered drugs.

Sarcoidlike granulomas as an early manifestation of Whipple's disease.

Whipple's disease is often accompanied by a long, preintestinal phase of vague symptoms, such as weight loss, fever, and migratory arthralgia, which may delay diagnosis and proper treatment. We report a patient who presented with sarcoidlike granulomas in the lung 1.5 yr before the development of gastrointestinal symptoms. He was treated with prednisone and his lung lesions improved dramatically. However, steroids could not be discontinued until the diagnosis of Whipple's disease was made and he was started on antibiotic treatment. Whipple's disease was diagnosed from a small intestinal biopsy specimen by electron microscopic demonstration of characteristic bacillary bodies. Liver biopsy specimens also demonstrated a few Kupffer cells containing degenerative bacillary bodies. Based on this case and other reported cases of Whipple's disease with sarcoidlike lesions in various organs, we suggest that sarcoidlike tissue reaction can be an early manifestation of Whipple's disease, recognition of which may have practical value in facilitating an early diagnosis and treatment.

Effect of intraluminal pH on cholesterol and oleic acid absorption from micellar solutions in the rat.

We have studied the effects of intraluminal pH on micellar solubilization and on absorption rate of oleic acid (OA) and cholesterol in proximal small bowel segments and the total small bowel in rats. In addition, pH effect on fecal excretion of [3H]cholesterol was studied over a period of 4 days after duodenal administration of cholesterol in solutions at different pH using beta-sitosterol as a nonabsorbable marker. Rates of absorption of OA and cholesterol were, respectively, 1.8 and 1.9 times higher at pH 5.5 in both proximal bowel segments as compared with pH 6.5 (P less than 0.001). Similar observations were made when the whole small bowel was perfused. At pH 5.5, 1.8 times more OA was absorbed and 1.5 times more cholesterol than at pH 6.5 (P less than 0.001). Also, fecal output of radioisotope following administration of pH 5.5 solution was only 47% of the excretion using the pH 6.5 solution. Excretion of beta-sitosterol, which serves as a nonabsorbable marker, was not affected by pH differences. In vitro measurements of micellar solubility at the two pH levels by ultracentrifugation showed that an increase of one pH unit resulted in a decreased number of particles in the oil phase (oleic acid and cholesterol in the emulsified particles in pH 6.5 solution is 37 and 34%, respectively, of that in the pH 5.5 solution) due to increased solubilization into the micellar phase. Measurements of monomer activities of OA and cholesterol using a polyethylene disk technique showed a significantly higher activity at the lower pH.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of acetaminophen toxicity on erythrocyte osmotic fragility in the Fisher rat.

The protective effect of propylthiouracil (PTU) pretreatment against acetaminophen-induced erythrocyte osmotic fragility was determined in the male Fisher rat. Hepatotoxicity was assessed for comparative purposes. PTU (0.15%) was fed in chow for a period of 12 days. Acetaminophen (1 g/kg body wt) was then administered orally by a stomach tube after an overnight fast. The rats were killed either 4 or 24 hr later. Erythrocyte osmotic fragility was determined by the extent of hemolysis in various concentrations of NaCl solutions. Hepatotoxicity was assessed by a rise in serum transaminases and by histological examination of hepatic tissue. PTU treatment when compared with control not only protected rats against acetaminophen-induced hepatotoxicity as reported before, but also protected against erythrocyte osmotic fragility. The time course of acetaminophen toxicity seems to be similar for liver and erythrocyte since both showed damage after 24 hr but not after 4 hr of acetaminophen administration. The data show that PTU pretreatment affords protection against acetaminophen-induced increased erythrocyte osmotic fragility even when their glutathione concentrations were not significantly different, suggesting that PTU per se has a protective effect.

Effects of propylthiouracil on urinary metabolites of cyclophosphamide in rats.

Our previous studies have shown a protective effect of propylthiouracil (PTU) pretreatment against the toxicity of cyclophosphamide (CP). The present study was undertaken to investigate the mechanism of the PTU protection. CP is metabolized by the cytochrome P-450 drug-metabolizing enzyme system in the liver to alkylating metabolites, to active antineoplastic agents, and to acrolein, the most toxic and least antineoplastic metabolite. Measurements of CP metabolites in blood and urine during a 4-hr i.v. infusion of CP (50 mg/kg body weight/hr) showed urinary acrolein excretion to be 2.5 times higher in control rats as compared to PTU-treated rats. Since it has been reported that urinary acrolein levels are directly related to the frequency and severity of hemorrhagic cystitis, it is concluded from our observations that prevention of hemorrhagic cystitis is probably mediated by the PTU effect on lowering urinary acrolein concentration and excretion. Serum alkylating activity was significantly higher in the PTU-pretreated rats, which may enhance the antineoplastic potential of CP.