[Evaluating the efficacy and tolerance of atorvastatin in hyperlipidemia in general practice (SWITCH Study)]. / Prüfung der Wirksamkeit und Verträglichkeit von Atorvastatin bei Hyperlipidämie unter Praxisbedingungen (SWITCH-Studie).

Elevated levels of serum lipids and lipoproteins are known to play a major role in the development of atherosclerosis and subsequent coronary heart disease (CHD). In controlled clinical studies, atorvastatin (Sortis), a new 3-hydroxy-3-methyl-glutaryl-coenzyme-A (HMG-CoA)-reductase inhibitor, proved to be a very effective and safe lipid-lowering agent. The aim of this open-label, multicentre study (without a control group) was to confirm the efficacy and safety of atorvastatin in a private practice group, including 181 Swiss cardiologists, internists, and general practitioners. A total of 877 hyperlipidaemic patients requiring treatment participated in this study. To evaluate the effectiveness of the treatment with atorvastatin over a period of 12 weeks, total plasma cholesterol (TC), HDL cholesterol, LDL cholesterol and triglycerides (TG) were determined every 4 weeks. The initial atorvastatin dose was 10 mg in 78% of patients and 20 mg in 22%. The dose was doubled every 4 weeks until the target values of TC < or = 5.2 mmol/l and TC/HDL < or = 5 were reached. After 12 weeks of treatment with atorvastatin the mean reduction in TC, TC/HDL, LDL and TG compared to baseline levels was 33, 37, 42, and 25% respectively. At the same time the HDL concentration was increased by 9%. These results were evidenced in patients with existing coronary heart disease, in high risk patients without manifest coronary heart disease and in patients with significantly elevated lipid levels (TC > 7.8 mmol/l, TC/HDL > 6.5). After treatment with atorvastatin for 12 weeks, 59% of patients had reached the therapeutic target of TC < or = 5.2 mmol/l. The target of TC/HDL < or = 5 was reached by 79%. Atorvastatin was almost without exception well tolerated, the most frequently reported side effects being nausea, myalgia, and headache. In this open-label multicentre study atorvastatin was found to be effective and well tolerated. The observed reduction in the lipid and lipoprotein concentration is in accordance with the results of published controlled studies. The lipid and lipoprotein concentrations were decreased significantly in patients with slight to moderate elevation of lipid levels as well as in those with significantly raised values.

Epithelial mesenchymal transition by c-Fos estrogen receptor activation involves nuclear translocation of beta-catenin and upregulation of beta-catenin/lymphoid enhancer binding factor-1 transcriptional activity.

Mouse mammary epithelial cells expressing a fusion protein of c-Fos and the estrogen receptor (FosER) formed highly polarized epithelial cell sheets in the absence of estradiol. Beta-catenin and p120(ctn) were exclusively located at the lateral plasma membrane in a tight complex with the adherens junction protein, E-cadherin. Upon activation of FosER by estradiol addition, cells lost epithelial polarity within two days, giving rise to a uniform distribution of junctional proteins along the entire plasma membrane. Most of the beta-catenin and p120(ctn) remained in a complex with E-cadherin at the membrane, but a minor fraction of uncomplexed cytoplasmic beta-catenin increased significantly. The epithelial-mesenchymal cell conversion induced by prolonged estradiol treatment was accompanied by a complete loss of E-cadherin expression, a 70% reduction in beta-catenin protein level, and a change in the expression pattern of p120(ctn) isoforms. In these mesenchymal cells, beta-catenin and p120(ctn) were localized in the cytoplasm and in defined intranuclear structures. Furthermore, beta-catenin colocalized with transcription factor LEF-1 in the nucleus, and coprecipitated with LEF-1-related proteins from cell extracts. Accordingly, beta-catenin- dependent reporter activity was upregulated in mesenchymal cells and could be reduced by transient expression of exogenous E-cadherin. Thus, epithelial mesenchymal conversion in FosER cells may involve beta-catenin signaling.