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This study concerns a case of congenital homozygous deficiency in ??2-antiplasmin associated with a severe hemorrhagic diathesis. Heterozygous family members also show a mild bleeding tendency. The propositus is a 17-yr-old male born of white parents and showing a severe hemorrhagic diathesis characterized by spontaneous bleeding in the joints since his early childhood. He was originally suspected of having factor XIII deficiency but was found to have normal functions of the coagulation system and the platelets. Except for ??2-antiplasmin, all protease inhibitors showed normal plasma values. With the immediate plasmin inhibition test (synthetic substrate), only 2% of normal functional inhibition was detected, while no reaction with monospecific antisera for ??2-antiplasmin was observed. Inhibition of activator-induced fibrinolysis in vitro was reduced. No enhanced spontaneous in vitro fibrinolysis was detected nor were there signs of increased in vivo fibrinolysis during an asymptomatic period. During recovery from a hemorrhagic episode, signs of previous consumption of antithrombin III, ??2-macroglobulin, factor XIII, and inter-??-trypsin inhibitor were noted. After the diagnosis was made, treatment with tranexamic acid (4 daily doses of 1 g) was effective for about 2 yr. among the 37 family members studied, a separate group of 16 individuals (including the father and mother of the propositus) with approximately one-half normal plasma levels of ??2-antiplasmin both functionally (59% ?? 6%) and immunologically (48% ?? 8%) was discovered. The defect appeared to be inherited as an autosomal recessive gene; no ancestral consanguinity could be shown. The group of apparent heterozygotes as a whole showed increased levels of ??1-antitrypsin (142% ?? 39%; p < 0.01), indicating systemic consequences of the deficiency and reduced binding (?? 50%) of ??2-antiplasmin to fibrin. Six exhibited a mild hemorrhagic diathesis for which no explanation was provided by routine screening of coagulation and platelet functions; also, within the group of heterozygotes, the occurrence of the bleeding tendency did not correlate with differences in residual ??2-antiplasmin levels and functions. It is concluded that not only the absence of ??2-antiplasmin but also a reduction in its plasma level to ??60% of normal may predispose to a hemorrhagic diathesis. Chemicals/CAS: antithrombin, 9000-94-6; blood clotting factor 13, 9013-56-3; tranexamic acid, 1197-18-8, 701-54-2; alpha-Macroglobulins; Antiplasmin; Factor XIII, 9013-56-3; Plasminogen, 9001-91-6

Hormone-sensitive lipase (HSL) is a major enzyme for triglyceride (TG) lipolysis in adipose tissue. In HSL-knockout mice, plasma free fatty acid and TG levels are low, associated with low liver TG content. Because a decreased hepatic insulin sensitivity has been reported to be associated with high liver TG levels, our aim was to determine whether a hepatic TG content lower than normal, as observed in HSL-knockout mice, leads to increased hepatic insulin sensitivity. Therefore, hyperinsulinemic clamp experiments in combination with D-3H. glucose were used. Furthermore, hepatic insulin receptor and phosphorylated protein kinase B (PKB-P)/akt were analyzed by Western blotting. No significant differences where observed in insulin-mediated whole-body glucose uptake between HSL-knockout and control mice. Interestingly, hepatic insulin sensitivity of HSL-knockout mice was increased, because insulin caused a greater reduction in endogenous glucose production (∼71% compared with ∼31% in control mice; P < 0.05), despite decreased plasma adiponectin levels. PKB/akt phosphorylation and phosphatidylinositol-3-kinase activity was significantly higher in livers of HSL-knockout mice after insulin stimulation. In HSL-knockout mice, reduced hepatic TG stores result in an increased suppressive effect of insulin on hepatic glucose production, in line with an increased hepatic PKB-P/akt and phosphatidylinositol-3 kinase activity. Thus, hepatic insulin sensitivity is indeed increased after reducing hepatic TG stores below normal.

Only a few studies have addressed the cost-effectiveness of pharmacogenetics interventions in healthcare. Lack of health economics data on aspects of pharmacogenetics is perceived as one of the barriers hindering its implementation for improving drug safety. Thus, a recent Institute for Prospective Technological Studies (IPTS) study, entitled 'Pharmacogenetics and pharmacogenomics: state-of-the-art and potential socio-economic impact in the EU' included an explorative cost-effectiveness review for a pharmacogenetic treatment strategy compared with traditional medical practice. The selected case study examined the cost-effectiveness of thiopurine methyltransferase (TMPT) genotyping prior to thiopurine treatment in children with acute lymphoblastic leukemia (ALL). Information for the cost-effectiveness model parameters was collected from literature surveys and interviews with experts from four European countries (Germany, Ireland, the Netherlands and the UK). The model has established that TPMT testing in ALL patients has a favorable cost-effectiveness ratio. This conclusion was based on parameters collected for TPMT genotyping costs, estimates for frequency of TMPT deficiency, rates of thiopurine-mediated myelosuppression in TPMT-deficient individuals, and myelosuppression-related hospitalization costs in each of the four countries studied. The mean calculated cost per life-year gained by TPMT genotyping in ALL patients in the four study countries was €2100 (or €4800 after 3% discount) based on genotyping costs of €150 per patient. Cost per life-year gained is expected to further improve following the introduction of the wider use of TMPT genotyping and the availability of lower cost genotyping methods. Our analysis indicates that TPMT genotyping should be seriously considered as an integral part of healthcare prior to the initiation of therapy with thiopurine drugs. © 2006 Future Medicine Ltd. Chemicals / CAS: azathioprine, 446-86-6; mercaptopurine, 31441-78-8, 50-44-2, 6112-76-1; thiopurine methyltransferase, 67339-09-7; Antineoplastic Agents; Methyltransferases, EC 2.1.1.-; thiopurine methyltransferase, EC 2.1.1.67

CD36 (fatty acid translocase) is involved in high-affinity peripheral fatty acid uptake. Mice lacking CD36 exhibit increased plasma free fatty acid and triglyceride (TG) levels and decreased glucose levels. Studies in spontaneous hypertensive rats lacking functional CD36 link CD36 to the insulin-resistance syndrome. To clarify the relationship between CD36 and insulin sensitivity in more detail, we determined insulin-mediated whole-body and tissue-specific glucose uptake in CD36-deficient (CD36-/-) mice. Insulin-mediated whole-body and tissue-specific glucose uptake was measured by D-[3H]glucose and 2-deoxy-D-[1-3H]glucose during hyperinsulinemic clamp in CD36-/- and wild-type control littermates (CD36+/+) mice. Whole-body and muscle-specific insulin-mediated glucose uptake was significantly higher in CD36-/- compared with CD36+/+ mice. In contrast, insulin completely failed to suppress endogenous glucose production in CD36-/- mice compared with a 40% reduction in CD36+/+ mice. This insulin-resistant state of the liver was associated with increased hepatic TG content in CD36-/- mice compared with CD36+/+ mice (110.9 ± 12.0 and 68.9 ± 13.6 μg TG/mg protein, respectively). Moreover, hepatic activation of protein kinase B by insulin, measured by Western blot, was reduced by 54%. Our results show a dissociation between increased muscle and decreased liver insulin sensitivity in CD36-/- mice.

Objective-Cholesterol 7α-hydroxylase (cyp7a1) catalyzes the rate-limiting step in conversion of cholesterol to bile acids. To study the relationship between bile acid biosynthesis and triglyceride metabolism, we cross-bred mice lacking cyp7a1 on a hyperlipidemic APOE*3-Leiden background. Methods and Results-Female mice received a chow or lipogenic diet. On both diets, fecal bile acid excretion was 70% decreased concomitantly with a 2-fold increased neutral sterol output. The differences in bile acid biosynthesis did not change plasma cholesterol levels. However, plasma triglyceride levels decreased by 41% and 38% in the cyp7a1-/- APOE*3-Leiden mice as compared with APOE*3-Leiden mice on chow and lipogenic diet, respectively. Mechanistic studies showed that very-low-density lipoprotein (VLDL)-apolipoprotein B and VLDL-triglyceride production rates were reduced in cyp7a1-/-.APOE*3-Leiden mice as compared with APOE*3-Leiden mice (-34% and -35%, respectively). Cyp7a1 deficiency also increased the hepatic cholesteryl ester and triglyceride content (2.8-fold and 2.5-fold, respectively). In addition, hepatic anti-oxidative vitamin content, which can influence VLDL-production, was lower. Hepatic mRNA analysis showed decreased expression of genes involved in lipogenesis including srebf1. Conclusions-Cyp7a1 deficiency in APOE*3-Leiden mice decreases the VLDL particle production rate, as a consequence of a strongly reduced bile acid biosynthesis, leading to a decrease in plasma triglycerides. These data underscore the close relationship between bile acid biosynthesis and triglyceride levels. Chemicals / CAS: cholesterol 7alpha monooxygenase, 9037-53-0; cholesterol, 57-88-5; acyltransferase, 9012-30-0, 9054-54-0; alpha tocopherol, 1406-18-4, 1406-70-8, 52225-20-4, 58-95-7, 59-02-9; diacylglycerol acyltransferase, 9029-98-5; retinol, 68-26-8, 82445-97-4; Acyltransferases, EC 2.3.-; apolipoprotein E3 (Leidein); Apolipoprotein E3; Apolipoproteins B; Apolipoproteins E; Bile Acids and Salts; Cholesterol 7-alpha-Hydroxylase, EC 1.14.13.17; Cholesterol Esters; Dgat1 protein, mouse, EC 2.3.1.20; Diacylglycerol O-Acyltransferase, EC 2.3.1.20; Ketone Bodies; Lipoproteins, VLDL; RNA, Messenger; Sterols; Triglycerides; Vitamin A, 11103-57-4; Vitamin E, 1406-18-4