Analysis of false-negative diagnoses on endoscopic brush cytology of biliary and pancreatic duct strictures: the experience at 2 university hospitals.

CONTEXT: Endoscopic brush cytology is a valuable technique for the diagnosis of pancreatobiliary malignancy. Despite its widespread use, the sensitivity of this method has been reported as approximately 50%. The specificity is usually higher than 95%. Few reports have systematically analyzed the reasons for this relatively low sensitivity. OBJECTIVES: To determine the rate and reasons for false-negative diagnoses in endoscopic brushing cytology of biliary and pancreatic ducts based on the results of sensitivity, specificity, accuracy, and positive and negative predictive values. DESIGN: Retrospective analysis of laboratory data and slide review of false-negative cases. SETTING: Two tertiary care state university hospitals. PATIENTS: A total of 183 pancreatobiliary brushing specimens obtained from patients undergoing endoscopic retrograde cholangiopancreatography for biliary or pancreatic duct disease for a 4- to 5-year period. INTERVENTION: Endoscopic retrograde cholangiopancreatography brushings. MAIN OUTCOME MEASURES: Determination of sensitivity, specificity, accuracy, and positive and negative predictive values. Analysis of false-negative results. RESULTS: The sensitivity, specificity, accuracy, and positive and negative predictive values, overall, were 48%, 98%, 79%, 92%, and 76%, respectively. Sampling error was a major cause of false-negative diagnoses (67%), followed by interpretive (17%) and technical errors (17%). CONCLUSIONS: Improvements in sensitivity and diagnostic accuracy for cancer of the pancreatobiliary tract can be achieved by optimizing slide preparatory techniques. Also, enhancement of the cytologist's diagnostic skills enables the identification of the morphologic features of premalignant lesions. Repeat brushings are indicated for suspicious or negative results not consistent with the clinical or radiologic findings.

Helicobacter pylori: a review.

Helicobacter pylori is a gram-negative bacterium that was first isolated in 1982. In the years following its discovery, H. pylori infection in humans has been shown to be associated with gastritis, peptic ulcer disease, and gastric carcinoma, as well as other, nongastrointestinal disorders. The epidemiology, transmission, and virulence factors of this bacteria have been an area of intense study. Successful treatment improves cure rates of gastritis and ulceration of the stomach and duodenum. Treatment with antimicrobials also decreases the recurrence rates of these diseases. Clinicians have numerous diagnostic tools and treatment options at their disposal. Vaccination in high-endemic areas may be available in the near future. Here, we review the pharmalogical basis of these treatment options, including their efficacy and economic considerations.

Mucinous ductal ectasia in an octogenarian: successful treatment with the Whipple procedure.

Mucinous ductal ectasia is a recently defined neoplasm of the pancreas characterized by excessive mucin production. The natural history of this entity is unknown, and only two cases in people over the age of 80 yr have appeared in the literature. In this report, we review the literature on mucinous ductal ectasia and present the first report of an octogenarian who was successfully treated by the Whipple procedure.

High levels of dietary amino and branched-chain alpha-keto acids alter plasma and brain amino acid concentrations in rats.

Plasma and brain amino acid and plasma branched-chain alpha-keto acid (BCKA) concentrations were measured in rats fed diets containing high levels of individual amino and alpha-keto acids. Consumption of a low-protein (9% casein) diet high in leucine or alpha-ketoisocaproate depressed plasma concentrations of isoleucine and valine and their respective keto acids, alpha-keto-beta-methylvalerate and alpha-ketoisovalerate. High dietary levels of alpha-keto-beta-methylvalerate or alpha-ketoisovalerate (but not of isoleucine or valine) depressed plasma concentrations of the other BCKA and their respective branched-chain amino acids (BCAA). Consumption of a low protein, high phenylalanine diet depressed plasma concentrations of both BCAA and BCKA. Brain large neutral amino acid pools of rats fed all low-protein, high-amino acid diets were depleted. Consumption of diets high in individual BCKA increased brain concentrations of aromatic amino acids. In this study of rats allowed to feed for only 6 h/d, elevated brain phenylalanine concentration was associated with a significant depression of food intake, whereas elevated brain BCAA concentrations were not. Also, elevated plasma BCKA concentrations, comparable with those observed in maple syrup urine disease, were accompanied by elevations in concentrations of aromatic amino acids in brain but not in plasma.

High branched-chain alpha-keto acid intake, branched-chain alpha-keto acid dehydrogenase activity, and plasma and brain amino acid and plasma keto acid concentrations in rats.

Diets containing high quantities of individual branched-chain alpha-keto acids (BCKAs) or a combination of BCKAs as used for treatment of renal disease were fed to rats. When the diet contained a single BCKA, its concentration was high in plasma and the concentration of its corresponding amino acid was high in plasma and brain. Liver BCKA dehydrogenase (BCKD) was 42% active in control rats. Consumption of diets containing 0.38 mol/kg diet of alpha-ketoisocaproate (KIC), alpha-keto-beta-methylvalerate (KMV), or alpha-ketoisovalerate (KIV) resulted in complete activation of liver BCKD. Consumption of the diet containing the combination of BCKAs increased basal BCKD activity of liver twofold. Muscle BCKD was activated after feeding the KIV diet (2-fold), the KIC diet (3-fold), and the KMV diet (15-fold). Total BCKD activity of liver and muscle was unaffected by dietary treatments. Activation of liver and muscle BCKD by dietary BCKA is consistent with their ability to inhibit BCKD kinase in vitro.

Regulation of rat liver branched-chain alpha-keto acid dehydrogenase activity by meal frequency and dietary protein.

Effects of feeding frequency on liver branched-chain alpha-keto acid dehydrogenase (BCKAD) activity are unknown. In the present study, rats were trained to consume their daily allotment of food in 6 h (meal-feeding). Rats were fed diets containing 0, 9, 25 or 50% casein and after 10 d were killed before or 3 h after the meal. The enzyme in rats fed diets containing 0, 9 and 25% casein was activated three- to sixfold after meal consumption. Previous studies showed that the liver enzyme is essentially fully activated in post-absorptive rats fed an adequate protein diet ad libitum. Meal-feeding an adequate protein (25% casein) diet resulted in a marked decrease in the postabsorptive percentage of active complex compared to ad libitum feeding of the same diet (29 +/- 6% vs. 93 +/- 6% active). Administration of alpha-ketoisocaproate (200 mumol/100 g body weight, an inhibitor of BCKAD kinase) reversed the meal-feeding-induced inactivation of the complex within 10 min. We conclude that the frequency of food intake, in addition to the level of dietary protein, influences the proportion of liver BCKAD in the active state. Inactivation of hepatic BCKAD in rats trained to feed once a day may be an adaptive mechanism that results in increased efficiency of branched-chain amino acid utilization between meals.

Glucocorticoid regulation of muscle branched-chain amino acid metabolism.

Branched-chain alpha-keto acid dehydrogenase (BCKAD) is a multisubunit complex regulated by phosphorylation and is considered to be rate-limiting for branched-chain amino acid (BCAA) metabolism in skeletal muscle. Glucocorticoids increase net protein degradation in muscle; associated with this increased breakdown of muscle protein is an elevated rate of BCAA oxidation. The effects of glucocorticoids on skeletal muscle BCKAD were investigated in different rat models. BCKAD was activated after glucocorticoid treatment (both acutely, within 2 h, and chronically). The amount of enzyme per muscle cell increased after 5 d of cortisone acetate treatment. Insulin administration partially blocked the acute effects of glucocorticoids on muscle BCKAD. Activation was also observed during metabolic acidosis, insulinopenic diabetes mellitus, and endotoxic shock, three conditions characterized by elevated circulating glucocorticoids, increased BCAA oxidation, and increased net protein breakdown. Activation of BCKAD may account for the increased oxidation of BCAA observed during hypercortisolemia. The sequelae of this accelerated catabolism may include increased glutamine and alanine production for gluconeogenesis and provision of ATP for muscle work.

Administration of endotoxin, tumor necrosis factor, or interleukin 1 to rats activates skeletal muscle branched-chain alpha-keto acid dehydrogenase.

Protein catabolic states (i.e., sepsis and trauma) are thought to be associated with accelerated oxidation of branched-chain amino acids (BCAA). Branched-chain alpha-keto acid dehydrogenase (BCKAD), the rate-limiting enzyme for BCAA oxidation by muscle, is regulated by phosphorylation/dephosphorylation. Skeletal muscle BCKAD was only 2-4% active in control rats. Intravenous injection of Salmonella enteritidis endotoxin (0.25-10 mg/kg) did not change total BCKAD activity, but increased the percent active enzyme in muscle three- to four-fold in 4-6 h. Identical results were observed in adrenalectomized rats pretreated with one dose of alpha-methylprednisolone (2.5 mg/kg i.p.) 30-60 min before saline or endotoxin injection, indicating that endotoxin's effect was not mediated by hypersecretion of adrenal hormones. Cortisone pretreatment of normal rats (100 mg/kg per d) for 2 d prevented endotoxin-induced activation of muscle BCKAD, suggesting that endogenous secretion products mediated BCKAD activation by endotoxin. Human recombinant tumor necrosis factor-alpha and/or IL-1 beta or alpha (50 micrograms/kg) increased muscle BCKAD activation two- to fourfold in normal rats 4-6 h after intravenous injection. We conclude that cytokine-mediated activation of muscle BCKAD may contribute to accelerated BCAA oxidation in septicemia.

Activities of branched-chain amino acid--degrading enzymes in liver from rats fed different dietary levels of protein.

The relationships among dietary protein intake, plasma branched-chain amino acid (BCAA) and keto acid (BCKA) concentrations, and liver BCAA-degrading enzyme activities were investigated in rats fed, for 5 h/d for 2, 6 or 9 d, diets containing from 0 to 50% casein. Plasma, liver and muscle BCAA concentrations were proportional to protein intake over the entire range tested; plasma BCKA concentration, however, was proportional only in the range from 0 to 20% casein, after which a plateau was reached. By d 2, liver cytosolic BCAA aminotransferase activity had increased in rats fed 50% casein; by d 9, activity had increased in rats fed 0 or 5% casein as well. Liver mitochondrial BCAA aminotransferase activity was unresponsive to dietary treatment. Basal liver BCKA dehydrogenase activity and the percent active complex were proportional to protein intake on d 2 and 6. On d 2, total BCKA dehydrogenase activity was the same in all groups; by d 6, total activity had increased in rats fed 30 or 50% casein. We conclude that although the adaptive changes in BCAA-degrading enzyme activities are small, they are sufficient to compensate for excessively high or low protein intakes, so that tolerable concentrations of BCAA and BCKA are maintained.

Branched-chain amino acid metabolism in rat muscle: abnormal regulation in acidosis.

Branched-chain amino acid (BCAA) metabolism is frequently abnormal in pathological conditions accompanied by chronic metabolic acidosis. To study how metabolic acidosis affects BCAA metabolism in muscle, rats were gavage fed a 14% protein diet with or without 4 mmol NH4Cl X 100 g body wt-1 X day-1. Epitrochlearis muscles were incubated with L-[1-14C]-valine and L-[1-14C]leucine, and rates of decarboxylation, net transamination, and incorporation into muscle protein were measured. Plasma and muscle BCAA levels were lower (P less than 0.05) in acidotic rats. Rates of valine and leucine decarboxylation and net transamination were higher (P less than 0.05) in muscles from acidotic rats; these differences were associated with a 79% increase in the total activity of branched-chain alpha-keto acid dehydrogenase and a 146% increase in the activated form of the enzyme. We conclude that acidosis affects the regulation of BCAA metabolism by enhancing flux through the transaminase and by directly stimulating oxidative catabolism through activation of branched-chain alpha-keto acid dehydrogenase.