Hepatosplenic T-cell lymphoma: an unusual case of a gamma delta T-cell lymphoma with a blast-like terminal transformation.

We describe a case of a middle-aged women who presented with anemia and mild hepatosplenomegaly and who was found to have an unusual peripheral T-cell lymphoma with only subtle morphologically abnormal but mature-appearing cells noted in the blood and bone marrow. Less than 2 years after diagnosis the patient presented with an increasing white blood cell count to 26 x 10(9)/L, and numerous blasts were noted in the periphery. Flow cytometry studies showed cells with an unusual T-cell phenotype expressing the gamma delta T-cell receptor and restricted expression of the V delta 1 but not the V delta 2 protein, indicating the clonal nature of the proliferation. A clonal T-cell receptor gene rearrangement was seen with a V delta 1 probe. The patient died and was found at autopsy to have extensive hepatic sinusoidal infiltration by abnormal cells. The histopathologic, immunophenotypic, and molecular findings are those of "hepatosplenic T-cell lymphoma." In spite of the striking morphologic change during the course of the patient's disease the same phenotype and clonal rearrangement were found both at initial diagnosis and during terminal phase, indicating that this change represented a blast-like transformation of the patient's original lymphoproliferative disorder.

Reductive metabolism of 1,1,1,2-tetrachloroethane and related chloroethanes by rat liver microsomes.

The susceptibility of polychlorinated ethanes to reductive metabolism was evaluated by measuring the amount of each compound consumed during anaerobic incubations with rat live microsomes; 1,1,1,2-tetrachloroethane, pentachloroethane and hexachloroethane were metabolized extensively, 1,1,1,2-tetrachloroethane and the trichloroethanes were metabolized very slowly and the dichloroethanes were not metabolized at a detectable rate. The electron affinity of the chloroethanes was determined by measuring electrochemical half-wave reduction potentials. Chloroethanes with an E1/2 of - 1.35 V or less negative were reduced readily in microsomes while those with an E1/2 equal to or more negative than -1.90 V were not good substrates for enzymatic reduction. Metabolites produced from 1,1,1,2-tetrachloroethane in vitro were 1,1-dichloroethylene (DCE) and 1,1,2-trichloroethane (TCEA) and the ratio DCE/TCEA was about 25:1. These conversions were NADPH-dependent and were inhibited by air, CO and metyrapone. In the presence of SKF 525-A, DCE formation was inhibited by 47%. Microsomes from untreated or beta-naphthoflavone-treated rats were 70-90% less active than microsomes from phenobarbital-treated rats. The Km was 0.50 mM and the Vmax was 66 nmol min-1 mg-1 protein for DCE formation. The results are consistent with the proposal that 1,1,1,2-tetrachloroethane is reduced by hepatic cytochrome(s) P-450 to a free radical intermediate which, for the most part, remains closely associated with the enzyme, is reduced further and undergoes beta-elimination of a chloride ion to form DCE. The occurrence of this reductive pathway in vivo was demonstrated by the quantitation of DCE and TCEA in blood from rats treated with 1,1,1,2-tetrachloroethane.

Hereditary protein C deficiency: a review of the genetics, clinical presentation, diagnosis and treatment.

Protein C (PC) is the central component of a major antithrombotic regulatory system with both anticoagulant and profibrinolytic properties. A deficiency of PC is one of several hereditary abnormalities of haemostatic proteins that have been described in patients with a propensity for thromboembolic complications. Major morbidity is often seen in these patients. The various aspects of hereditary PC deficiency in terms of clinical presentation, genetics, diagnosis and treatment of both homozygous and heterozygous states will be presented. In heterozygous deficiency, the levels of plasma PC are usually between 35% and 65% of normal, whereas the majority of normal individuals have levels between 70% and 130%. PC-deficient patients usually develop venous thrombotic complications between the ages of 15 and 40 years with a high incidence of DVT and pulmonary embolism. The majority of thrombotic lesions appear to develop spontaneously; others are associated with trauma, surgery or pregnancy. Treatment of symptomatic patients is initial heparin therapy followed by coumadin. After multiple thrombotic events, lifelong oral anticoagulant therapy is necessary. The potential complications of treatment are coumadin-induced skin necrosis, heparin-induced thrombocytopenia and bleeding. Homozygous PC deficiency, a rare but fatal hereditary condition, manifests itself with massive DIC and purpura fulminans in the newborn period. Effective treatment for these infants can be instituted with either oral anticoagulant therapy or PC replacement. The heterozygous deficiency of PC is similar to that found in other inherited disorders in that several genetic mechanisms are responsible for the expression of the disease. Both quantitative and qualitative decreases in PC exist, the former being type I deficiency and the latter, type II. The best initial diagnosis of either form involves a clotting (functional) assay while differentiation between the two also requires an antigenic (immunological) assay. Autosomal inheritance with significant variable penetrance is found with profound clinical implications. In summary, PC deficiency is one of a group of inherited disorders termed hereditary thrombotic disease, which may have serious implications for patient morbidity and mortality.

Dynamic headspace analysis of volatile metabolites from the reductive dehalogenation of trichloro- and tetrachloroethanes by hepatic microsomes.

A dynamic headspace technique was developed to facilitate the identification and quantitation of low levels of volatile metabolites produced in vitro by subcellular preparations. The method is complementary to commonly used static headspace and solvent-extraction techniques, and involves purging the compounds from microsomal suspensions with an inert gas, trapping them on a short column of adsorbant resin, and transferring the metabolites to a gas chromatograph. An apparatus was designed to facilitate the incubations and isolations of volatile compounds. Recoveries of several chlorinated hydrocarbons with boiling points in the range 12 to 186 degrees C were 85% or higher, and the recovery of vinyl chloride (boiling point -13 degrees C) was 25%. The quantitative precision of the method was determined and calibration curves were established for each metabolite, demonstrating that no discrimination occurred over a wide range of concentrations. This technique was employed to investigate the reductive metabolism of 1,1,1-trichloroethane, 1,1,2-trichloroethane, and 1,1,2,2-tetrachloroethane by rat liver microsomes. The metabolites from these substrates were 1,1-dichloroethane, vinyl chloride, and 1,2-dichloroethylene, respectively. These conversions were NADPH-dependent, occurred only under anaerobic conditions, and indicate that chloroethanes with relatively low electron affinities can be reduced slowly by microsomal cytochrome P-450. The rates of formation of vinyl chloride, 1,1-dichloroethane, and 1,2-dichloroethylene with 1.0 mM substrate were 12.5 +/- 2.0, 122 +/- 14, and 147 +/- 12 pmol/min/mg of protein, respectively. The results show that there are distinct advantages of the purge/trap method over the static headspace method for studying volatile metabolites when high sensitivity is required.

Oxidative metabolism of butylated hydroxytoluene by hepatic and pulmonary microsomes from rats and mice.

Metabolism of the antioxidant butylated hydroxytoluene (BHT; 2,6-di-tert-butyl-4-methylphenol) has been studied with liver and lung microsomes from rats and mice. The structures of several previously reported metabolites were confirmed, the identities of four new metabolites were determined, pathways of oxidation were investigated, and quantitative data were obtained for several of the products. Two main metabolic processes occur, hydroxylation of alkyl substituents and oxidation of the aromatic pi electron system. The former leads to the 4-hydroxymethyl product (BHT-BzOH) and a primary alcohol resulting from hydroxylation of a t-butyl group (BHT-tBuOH). Additional metabolites were produced by oxidation of BHT-BzOH to the corresponding benzaldehyde and benzoic acid derivatives. Hydroxylation of BHT-tBuOH occurs at the benzylic methyl position, and the resulting diol is oxidized further to the hydroxybenzaldehyde derivative. Oxidation of the pi system leads to the quinol, 2,6-di-t-butyl-4-hydroxy-4-methyl-2,5-cyclohexadienone, the quinone, 2,6-di-t-butyl-4-benzoquinone, and the quinone methide, 2,6-di-t-butyl-4-methylene-2,5-cyclohexadienone. Derivatives of the quinol and quinone with a hydroxylated t-butyl group were also formed. Quantitative data demonstrate that BHT-BzOH is the principal metabolite in rat liver and lung microsomes. On the other hand, mice produce large amounts of both BHT-BzOH and BHT-tBuOH in these tissues. The metabolite profile was similar in rat liver and lung. Mouse lung, however, produced more quinone relative to other metabolites than mouse liver.(ABSTRACT TRUNCATED AT 250 WORDS)