The role of protein tyrosine kinase activity in ErbB3-mediated signal transduction was investigated. ErbB3 was phosphorylated in vivo in response to either heregulin (HRG) in cells expressing both ErbB3 and ErbB2, or epidermal growth factor (EGF) in cells expressing both ErbB3 and EGF receptor. A recombinant receptor protein (ErbB3-K/M, in which K/M stands for Lys-->Met amino acid substitution) containing an inactivating mutation in the putative ATP-binding site was also phosphorylated in response to HRG and EGF. Both the wild-type ErbB3 and mutant ErbB3-K/M proteins transduced signals to phosphatidylinositol 3-kinase, Shc and mitogen-activated protein kinases. Separate kinase-inactivating mutations in the EGF receptor and ErbB2 proteins abolished ErbB3 phosphorylation and signal transduction activated by EGF and HRG respectively. Hence the protein tyrosine kinase activity necessary for growth factor signalling via the ErbB3 protein seems to be provided by coexpressed EGF and ErbB2 receptor proteins.

In a double-blind, placebo-controlled, randomized crossover study, 15 stable mild hyperglycemic patients without treatment and with features of metabolic syndrome were treated with cerivastatin (0.4 mg/day) or placebo for 3 months. The insulin sensitivity index during the euglycemic-hyperinsulinemic clamp (EHC; 5.4 mmol/l; 80 mU ⅐ m ؊2 ⅐ min ؊1 ) was increased by cerivastatin treatment (66.39 ؎ 3.9 nmol ⅐ lean body , 0.91 ؎ 0.01; P < 0.01 and P < 0.05, respectively). During statin treatment, the first-phase insulin response increased from 2.07 ؎ 0.28 to 2.82 ؎ 0.38 pmol ⅐ l ؊1 ⅐ pmol ؊1 (P < 0.05). The second phase of insulin responses examined by C-peptide and insulin levels averaged during the hyperglycemic clamp (20 mmol/l) was unchanged. In conclusion, this study demonstrates that 0.4 mg cerivastatin therapy improves first-phase insulin secretion and increases insulin-mediated glucose uptake and respiratory quotient in the early state of obese type 2 diabetes. Diabetes 51:2596 -2603, 2002 T ype 2 diabetes represents the final stage of a progressive syndrome characterized by targettissue resistance to insulin that cannot be overcome by ␤-cell hypersecretion (1). In the initial period, some subjects accumulate a constellation of major risk factors such as central (intra-abdominal) obesity, hypertriglyceridemia, low HDL cholesterol, raised blood pressure, and insulin resistance associated with proinflammatory states (2). In this state, patients receive primary care from their physicians with a recommendation for lifestyle changes (3). However, most people do not adequately maintain weight loss after participating in weightcontrol programs (4), and some subjects develop late micro-and macrovascular complications of diabetes. Approaches to reduce coronary heart disease have been focused on statins therapy (5,6). Several pleiotropic effects of statins could represent a potential means for controlling multifactorial atherosclerosis observed in diabetes. A post hoc analysis in the West of Scotland Coronary Prevention Study database provided evidence for the protective treatment effect of Pravastatin on the development of diabetes (7). However, whether statin treatment is beneficial in glucose metabolism of diabetes still remains to be seen. Suppression with high doses of statins on VLDL production of patients with type 2 diabetic hypertriglyceridemia could effect the release of fatty acids (FAs) from the liver (8). It is now recognized that plasma FA concentrations have profound effects on insulin action and glucose metabolism (9,10). Finally, cholesterol is a key component in the regulation of signal transduction through membrane lipid-ordered microdomains and in the regulation of gene expression through cholesterol-activated transcription factors (11). Intracellular cholesterol might serve as a link between fat cell size, glucose metabolism, and adipocyte metabolic activity (12). Sterol regulatory element-binding protein is implicated as a major mediator of insulin action (13). The major aim of the present study w...

One hundred and twelve consecutive Child Class A and B cirrhotic patients were included in a prospective controlled trial aimed at investigating the efficacy and safety of endoscopic sclerotherapy vs. distal splenorenal shunt in the elective treatment of hemorrhage from esophagogastric varices. Fifty-seven patients were randomly allocated to splenorenal shunt and 55 to endoscopic sclerotherapy. Since only 4 of the 55 patients assigned to endoscopic sclerotherapy had to be excluded after randomization and before treatment as compared to 14 of the 57 patients assigned to splenorenal shunt, it is suggested that the applicability of endoscopic sclerotherapy is greater than that of splenorenal shunt. One patient in each group died within 30 days of the procedure and two in the endoscopic sclerotherapy group were lost to follow-up just after discharge. Variceal rebleeding during follow-up occurred in 37.5% (18/48) of patients in the endoscopic sclerotherapy group and in 14.3% of those in the splenorenal shunt group (6/42) (p less than 0.02), whereas hepatic encephalopathy was more frequent in patients submitted to splenorenal shunt (10/42, 24%) than in those treated by endoscopic sclerotherapy (4/48, 8%) (p less than 0.05). The therapeutic modality was the only variable with independent predictive value for rebleeding during follow-up, whereas for hepatic encephalopathy, the therapeutic modality, and the presence of encephalopathy related to the bleeding episode each showed independent predictive value. Early and long-term mortality, did not differ between the two therapeutic groups, being the 2-year survival was 71% for splenorenal shunt and 68% for endoscopic sclerotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Background:The fatty acid composition of the diet can modulate the effect of dietary cholesterol on plasma lipoproteins. However, HDL composition and its capacity to promote cholesterol efflux can be influenced by the diet. Objective: Modifications in plasma lipids and in the capacity of serum to stimulate the cholesterol efflux induced by a low-fat diet [National Cholesterol Education Program (NCEP) Step I diet], by a monounsaturated fatty acid (MUFA)-rich diet, and by addition of cholesterol to both diets was studied. Design: Fifteen young, healthy men followed 2 NCEP Step I diets (< 30% of fat as energy, with < 10% saturated fat and 14% MUFAs) for 24 d, providing 0.027 or 0.068 mg cholesterol · kJ Ϫ1 · d Ϫ1 , and 2 oleic acid-enriched diets (38% of energy as fat, with 24% MUFAs) providing the same amount of dietary cholesterol as the NCEP Step I diets. Results: Total cholesterol, LDL cholesterol, apolipoprotein (apo) B, and apo A-I concentrations decreased after the NCEP Step I and MUFA diets compared with the usual diet. HDL cholesterol also decreased after the NCEP Step I diet. Total:HDL cholesterol, apo B, and apo B:apo A-I were lower after the MUFA diets than after the NCEP Step I diets. There were no significant differences between the lipid profiles obtained after the NCEP Step I and MUFA diets were enriched with cholesterol. The capacity of serum to promote cholesterol efflux was significantly higher after the cholesterol-enriched NCEP Step I diet than after the NCEP Step I diet. Conclusions:The MUFA diet induced a better lipid profile than the NCEP Step I diet; however, the increase in the cholesterol content of both diets produced similar plasma lipid changes. The cholesterol in the NCEP Step I diet increased the cholesterol efflux induced by total serum.Am J Clin Nutr 1998;68:1028-33. KEY WORDS Cholesterol efflux, National Cholesterol Education ProgramStep I diet, monounsaturated fatty acids, dietary cholesterol, Fu5AH cells, lipoproteins, men INTRODUCTIONCoronary artery disease is still the most important cause of death and morbidity in the Western world. One of the major factors associated with its development relates to diet-induced elevations in plasma LDL concentrations. For this reason, the National Cholesterol Education Program (NCEP) has recommended a reduction in dietary fat intake to < 30% of daily energy consumption (1). The Mediterranean region has been characterized by a low prevalence of coronary artery disease (2) and it has been postulated that this apparent protection may be due in part to the relatively high proportion of monounsaturated fatty acids (MUFAs) in the traditional diet of this region (3). Therefore, some researchers consider a MUFA-rich diet to be as beneficial as a low-fat diet in the prevention of atherosclerosis (4).Reduction of dietary saturated fats is usually accompanied by a reduction in cholesterol consumption, although some foods, such as liver and eggs, are rich in cholesterol and relatively poor in saturated fats. It has also been suggested that die...

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