AND IGOR KLATZO. Testing of a hypothesis for osmotic opening of the blood-brain barrier. Am.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The SCN1A gene encodes the α subunit of the neuronal voltage‐gated sodium channel, which is a target for carbamazepine and other antiepileptic drugs (AEDs). • Recent studies have demonstrated that a common polymorphism of SCN1A IVS5‐91 G > A was associated with carbamazepine and phenytoin use in daily practice. • However, it has not been determined whether the polymorphism affects carbamazepine or other AED responsiveness. WHAT THIS STUDY ADDS • This study demonstrated a significant association between the SCN1A IVS5‐91 AA genotype and carbamazepine‐resistant epilepsy, while the AA genotype did not affect carbamazepine use. AIMS To establish whether the SCN1A IVS5‐91 G > A polymorphism of the SCN1A gene, which encodes the neuronal sodium channel α subunit, affects responsivenss to the antiepileptic drugs (AEDS) carbamazepine and/or phenytoin. METHODS SCN1A IVS5‐91 G > A polymorphism was genotyped in 228 Japanese epileptic patients treated with AEDs. The association between AED responsiveness and the polymorphism was estimated by logistic regression analysis, adjusting for clinical factors affecting the outcome of AED therapy. RESULTS The frequency of the AA genotype was significantly higher in carbamazepine‐resistant patients (odds ratio, 2.7; 95% confidence interval (CI), 1.1, 7.1) and was insignificantly higher in AED‐resistant patients. CONCLUSIONS This is the first report demonstrating an association between the SCN1A polymorphism and carbamazepine‐resistant epilepsy.
Ductectatic‐type mutinous cystic neoplasms of the pancreas constitute a recently recognized new human pancreatic tumor entity. Examination for the presence of point mutations at codon 12 of K‐ras by oligonucleotide hybridization in 5 adenomas and 3 carcinomas revealed alteration in 3 and 2, respectively. In 4 of these positive cases, the transition was GGT–GAT (Gly–Asp) with the remaining one, found in a cancer, being GGT–GTT (Gly–Val). In two carcinoma cases, the same point mutation was detected both in the carcinoma area and in a coexisting adenoma component. Thus K‐ras point mutation appears to be associated with this particular type of neoplasm in the same manner as observed for typical exocrine pancreas carcinomas. Our study also indicates the possible existence of an adenoma‐carcinoma sequence in the evolution of this type of neoplasm and we suggest that K‐ras activation may be an important event in the phase of adenoma development.
Objective-We recently identified esculeoside A, a new spirosolane-type glycoside, with a content in tomatoes that is 4-fold higher than that of lycopene. In the present study, we examined the effects of esculeoside A and esculeogenin A, a new aglycon of esculeoside A, on foam cell formation in vitro and atherogenesis in apoE-deficient mice. Methods and Results-Esculeogenin A significantly inhibited the accumulation of cholesterol ester (CE) induced by acetylated low density lipoprotein (acetyl-LDL) in human monocyte-derived macrophages (HMDM) in a dosedependent manner without inhibiting triglyceride accumulation, however, it did not inhibit the association of acetyl-LDL to the cells. Esculeogenin A also inhibited CE formation in Chinese hamster ovary cells overexpressing acyl-coenzymeA (CoA): cholesterol acyl-transferase (ACAT)-1 or ACAT-2, suggesting that esculeogenin A suppresses the activity of both ACAT-1 and ACAT-2. Furthermore, esculeogenin A prevented the expression of ACAT-1 protein, whereas that of SR-A and SR-BI was not suppressed. Oral administration of esculeoside A to apoE-deficient mice significantly reduced the levels of serum cholesterol, triglycerides, LDL-cholesterol, and the areas of atherosclerotic lesions without any detectable side effects. Conclusions-Our study provides the first evidence that purified esculeogenin A significantly suppresses the activity of ACAT protein and leads to reduction of atherogenesis. T he presence of a large cluster of macrophage-derived foam cells in situ in the subendothelial spaces is one of the characteristic features of early stage atherosclerotic lesions. 1 Macrophages take up chemically-modified lowdensity lipoproteins (LDL), such as oxidized LDL (Ox-LDL) and acetylated LDL (acetyl-LDL) through the scavenger receptors 2 such as class A scavenger receptor (SR-A), 3 class B scavenger receptor (CD36), 4 and class B scavenger receptor type-I (SR-BI). 5 Because free cholesterol, which is incorporated into the cells with modified LDL through the scavenger receptors, is toxic to the cells, it is esterified to the cholesterol ester (CE) by acyl CoA: cholesterol acyltransferase (ACAT), an intracellular enzyme located in the rough endoplasmic reticulum. 6 These reactions change the macrophages to foam cells that are characterized by intracellular accumulation of CE. To date, 2 human ACAT isozymes (ACAT-1 and ACAT-2) are known. 7,8 ACAT-1 is highly expressed by macrophage-derived foam cells in atherosclerotic lesions and upregulated during monocytic differentiation into macrophages. 9 In addition, ACAT-1 is located in the Kuppfer cells of the liver, kidney, and adrenal cortical cells, whereas ACAT-2 is mainly located in hepatocytes and intestinal mucosal cells. 9 These findings are consistent with the notion that ACAT-1 plays a critical role in foam cell formation in macrophages; whereas ACAT-2 is responsible for the cholesterol absorption process in intestinal mucosal cells. 9 Because foam cell formation by these mechanisms is believed to play an essential role...
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