Rapid decrease in N-hydroxy-2-acetylaminofluorene sulfotransferase activity of liver cytosols from rats fed carcinogen

Sulfation of N-hydroxy-2-acetylaminofluorene (N-OH-AAF) by N-OH-AAF sulfotransferase yields a candidate for ultimate carcinogen in hepatocarcinogenesis in rats. We have monitored this pathway during the initial phase(s) of hepatocarcinogenesis produced by feeding male Holtzman rats a diet containing 0.05% 2-acetylaminofluorene (AAF). Our studies revealed an immediate and precipitous decrease in N-OH-AAF sulfotransferase activity beginning after 1 day on the AAF diet and decreasing 4- to 5-fold after 5 days on the AAF diet. This decrease in activity remained at low values during continuous administration of AAF throughout 4 weeks but was shown to be both reversible and AAF dose dependent. Parallel monitoring of rat serum glutamic oxaloacetic acid transaminase activity during the administration of AAF indicated that no appreciable hepatocellular toxicity occurred during the period of sulfotransferase activity lowering. Other known carcinogenes, i.e. 3′-methyl- and 4′-fluoro-4-dimethylaminoazobenzene, aflatoxin B₁, thioacetamide, ethionine, and diethylnitrosamine, and the hepatotoxin α-naphthylisothiocyanate, also caused decreases in N-OH-AAF sulfotransferase activity after 7 and 28 days of administration. In contrast, very weak or non-carcinogens, i.e. p-aminoazobenzene, fluorene, and barbital, failed to reduce N-OH-AAF sulfotransferase activity during 28 days of feeding. Data from these studies on the short-term chronic administration of xenobiotics suggest (a) reduced likelihood for the direct involvement of the sulfotransferase pathway in providing sufficient cytotoxic AAF metabolites to cause compensatory hyperplasia and its putative promotion-effect for AAF-mediated carcinogenesis, and (b) the possible use of the rapid loss in sulfotransferase activity as an early indicator of hepatocarcinogenesis.     

Assessment of rat liver microsomal epoxide hydrolase as a marker of hepatocarcinogenesis

The influence of eleven xenobiotics on the activity and amount of hepatic microsomal epoxide hydrolase was determined. Activity was assayed using three different substrates after rats were fed, throughout 3 weeks, diets containing one of six hepatocarcinogens, viz. 2-acetylaminofluorene, 3'-methyl-4-dimethylaminoazobenzene, 4'-fluoro-4-dimethylaminoazobenzene, thioacetamide, aflatoxin B1 and ethionine. Five hepatocarcinogens induced activity 4- to 10-fold; ethionine was relatively ineffective as an inducer. Two non-carcinogenic analogues of hepatocarcinogens, viz. fluorene and p-aminoazobenzene, caused no appreciable increase in enzyme activity, but phenobarbital, barbital and 1-naphthylisothiocyanate induced activity 2- to 3-fold. All eleven xenobiotics increased the amount of microsomal epoxide hydrolase 2- to 9-fold when examined immunochemically using either a radial diffusion assay or an enzyme-linked immunosorbent assay (ELISA). Serum glutamic oxaloacetic acid transaminase activity was not appreciably elevated by feeding ten of the xenobiotics, suggesting that inductions were not owing to toxicity. Using ELISA, microsomal epoxide hydrolase was detected in post-microsomal (PM) supernatant fractions from control rat liver, thus confirming an earlier report by Gill et al. [Carcinogenesis 3, 1307 (1982)]. The eleven xenobiotics induced the amount of ELISA-detectable antigen in PM supernatant fractions by 3- to 34-fold. Longer centrifugation of PM supernatant fractions yielded a pellet fraction that contained 92 +/- 1.2% of the ELISA-detectable antigen irrespective of the xenobiotic regimen. Relationships between xenobiotic induction of microsomal epoxide hydrolase activity and amount and hepatocarcinogenesis are discussed.     

Medical problems in whitewater sports

Overall, whitewater sports are relatively free of serious medical problems, with submersion accidents, trauma, and overuse syndromes being the most commonly encountered afflictions. Various infectious diseases and environmental exposure problems may occur, but serious illness or injury from such causes is infrequent. Nonetheless, the growing popularity of whitewater sports, along with increasing attempts by less experienced persons to navigate more difficult rivers, underscores the need for physicians to be aware of the medical problems likely to be encountered in these activities so that they may appropriately counsel and prepare persons for these invigorating yet potentially dangerous pastimes.     

Cardiogenic and aortogenic brain embolism

Cardioaortic brain embolism is a potentially devastating condition that presents frequent diagnostic and therapeutic challenges. In this report, we review key aspects of the etiology, clinical presentation, diagnosis, prognosis, and treatment of cardiogenic and aortogenic stroke. Emphasis is on advances in diagnostic imaging capabilities and on recent literature addressing secondary prevention for specific cardioembolic sources, upon which diagnosis and prognosis primarily depend. While early evaluation with modern neuroimaging techniques offers to enhance diagnostic accuracy, additional study is required to define optimal utilization. Appropriate imaging of the heart and aorta is paramount to identifying potential sources of embolism. Secondary prevention for high-risk embolic sources generally involves anticoagulation, but immediate initiation of anticoagulation is not routinely indicated. Medium-risk sources have more modest or undefined risks and little randomized comparative evidence to guide management, but antiplatelet therapy is generally favored. One possible exception is patent foramen ovale, for which high-risk features may warrant anticoagulation or mechanical closure. Definitive recommendations for this and other findings await completion of ongoing clinical trials.     

Platelet dysfunction in Noonan's syndrome. A case with a platelet cyclooxygenase-like deficiency and chronic idiopathic thrombocytopenic purpura

Individuals with Noonan's syndrome are likely to have one or more coagulation abnormalities: complex platelet function defects, partial Factor XI deficiency, or von Willebrand's disease. A distinctive platelet function defect has not been identified. The authors describe a 24-year-old women with Noonan's syndrome, chronic idiopathic thrombocytopenic purpura (ITP), and a platelet function defect characterized by a greater than 15-minute bleeding time, failure of aggregation and release with 10 microM ADP, 10 microM epinephrine, 750 microM arachidonic acid or 0.019 g/L collagen. A mixture of aspirin-treated platelets with the patient's platelets failed to correct the defect. Addition of 2.5 microM U46619 (a PGG2 analogue) corrected the aggregation and release defect. An electron microscopic analysis failed to reveal structural abnormalities. Thus, the platelet function defect in this patient appears to be a functional deficiency of cyclooxygenase. The presence of autoantiplatelet antibodies in a clinical setting consistent with chronic ITP raises the possibility that the defect may be acquired.