Effects of an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme a reductase on serum lipoproteins and ubiquinone-10 levels in patients with familial hypercholesterolemia

We studied the effects of ML-236B, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (KMG-CoA) reductase, on serum levels of lipoproteins and ubiquinone-10 in seven heterozygous patients with familial hypercholesterolemia. ML-236B was given at doses of 30 to 60 mg per day for 24 weeks. Serum cholesterol decreased from 390 ± 9 to 303 ± 8 mg per deciliter (10.1 ± 0.2 to 7.88 ± 0.2 mmol per liter, mean ± S.E.M.; P<0.001), and serum triglyceride decreased from 137 ± 18 to 87 ± 9 mg per deciliter (1.55 ± 0.20 to 0.98 ± 0.1 mmol per liter; P<0.05). Intermediate-density-lipoprotein (IDL) cholesterol, IDL triglyceride, low-density-lipoprotein (LDL) cholesterol, and LDL triglyceride decreased significantly (P<0.01, P<0.02, P<0.001, and P<0.001, respectively). However, there were no significant changes in very-low-density-lipoprotein (VLDL) cholesterol and triglyceride or high-density-lipoprotein (HDL) cholesterol. Serum ubiquinone-10 levels did not change, and LDL levels of ubiquinone-10 decreased by 50 per cent, from 0.39 ± 0.07 to 0.20 ± 0.01 μg per milliliter (P<0.05). No adverse effects were observed. We conclude that ML-236B is effective in lowering serum cholesterol without lowering serum ubiquinone-10 in heterozygous patients with familial hypercholesterolemia

Effects of ML-236B (compactin) on sterol synthesis and low density lipoprotein receptor activities in fibroblasts of patients with homozygous familial hypercholesterolemia

金沢大学大学院医学系研究科　We studied biochemical genetics of low density lipoprotein (LDL) receptor mutations in fibroblasts from six homozygous and five heterozygous patients with familial hypercholesterolemia (FH). Three of six homozygotes are receptor-negative type and the other three homozygotes are receptor-defective type. In the cells from three receptor-negative homozygotes, the receptor binding, internalization, and degradation of 125I-LDL were 0.5 ± 0.3 ng/mg protein (mean ± SEM), 14 ± 8 and 8 ± 6 ng/mg protein per 6 h (four normal cells; 44 ± 3, 386 ± 32, and 1,335 ± 214 ng/mg protein per 6 h), respectively. In the cells from three receptor-defective homozygotes, the receptor binding, internalization, and degradation of 12:5I-LDL were 6 ± 2, 29 ± 8, and 90 ± 32 ng/mg protein per 6 h, respectively. In these six homozygotes, two pairs of siblings are included. Two siblings in the same family were classified as receptor-negative and two siblings in another family were classified as receptor-defective. The receptor-negative phenotypes and the receptor-defective phenotypes bred true in individual families. The cells from five heterozygotes showed ~46% of the normal activities of receptor. ML-236B, competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), completely inhibited the incorporation of [14C]acetate into digitonin-precipitable sterols in fibroblasts from normal subjects and heterozygous and homozygous patients with FH with the concentration of 0.5 μg/ml. However, at 0.05 μg/ml of ML-236 B sterol synthesis in fibroblasts from homozygotes was not completely suppressed in contrast to normal and heterozygous cells. Moreover, after preincubation with 0.05 μg/ml of ML-236B for 24 h in medium containing lipoproteins, sterol synthesis in the cells from receptor-negative homozygote showed 75% of the initial activity compared with that of 25% without preincubation. In the cells from a normal subject and heterozygote, sterol synthesis was inhibited even after preincubation. These results suggest that (a) the inhibitory effect of ML-236B is overcome in homozygote cells by their high intracellular levels of HMG-CoA reductase and (b) that a higher dose of ML-236B may be required to lower serum cholesterol levels in FH homozygotes than in heterozygotes

Electrochemical Epitaxial Growth of a Pt(111) Phase on an Au(111) Electrode

The electrochemical deposition of platinum on an Au(111) single-crystal electrode in acidic solutions containing H2PtCl6 was studied using an electrochemical scanning tunneling microscope (STM) and electrochemical quartz crystal microbalance (EQCM). The STM investigation showed an ordered adlayer of PtCl6^[2-] on the electrode surface during the electrochemical deposition of platinum and a Pt(111)-(1x1) structure on the electrode surface after the electrode was rinsed with a Pt complex-free solution. Formations of the Pt(111) bulk phase and surface structure of Pt(111)-(1x1) were confirmed by X-ray diffraction (XRD) and the underpotential deposition of copper and hydrogen, respectively

身体運動時の下肢機能軸の変化に関する文献調査

[目的]　下肢機能軸(MA: Mechanical Axis)は膝関節の変形の指標として利用されている。本研究では身体運動時のMA についての文献調査を行うことで，MA の動作分析への利用に資する可能性を考察することとした。[方法]　「下肢機能軸」，「Mechanical axis」を検索語とし，日本語および英語のデータベースにおいて1983年～2020年の期間で検索した。対象論文は身体運動時のMA またはMA が垂線と成す角度に関連する評価項目があるものとした。[結果]　124編の文献が抽出され，著者らの採択基準を満たした10編を分析対象とした。身体運動の分類では片脚立位が2編と歩行が7編であり，MAが垂線と成す角度の報告は静止立位時の1 編であった。身体運動時のMA についてはすべての論文がMA の膝関節通過点についての報告であり，荷重や歩行様式の違いと関連する変化を認めていた。[結論]　身体運動時のMAを報告している論文は少なかったが，膝関節の変形，片脚立位や歩行などの身体運動においてMA が変化することを考慮すると，身体運動時のMA が垂線と成す角度を生体力学的に分析することは動作分析を行う上で有用であると考えられた。[Objective] Mechanical axis (MA) is used as an index of knee joint deformation. The present reviewaimed to provide the usefulness of MA for a motion analysis based on a literature search about MA during a motion.[Methods]The literature review was undertaken using Japanese and English databases. The key words were "Mechanical axis", "Mikulicz line", and "Load bearing axis". The literatures searched in this review involved an evaluation item related to MA during a motion or the angle between MA and a perpendicular line.[Results] After selected 124 literatures, 10 literatures were evaluated. The literatures of MA during the motion were consisted of 2 literatures on one-leg-standing and 7 literatures on walking. There was only one literature on the angle between MA and a perpendicular line while an upright position.[Conclusions] Although there were few literatures about MA during the motion, it was suggested that MA changed during the motion, including knee joint deformation, one-leg-standing, and walking. The biomechanical analysis of the angle between MA and the perpendicular line during motions may be contributed as the useful tool for the motion analysis

Effects of ML-236b (compactin) on sterol synthesis and low density lipoprotein receptor activities in fibroblasts of patients with homozygous familial hypercholesterolemia. J Clin Invest

A B S T R A C T We studied biochemical genetics of low density lipoprotein (LDL) receptor mutations in fibroblasts from six homozygous and five heterozygous patients with familial hypercholesterolemia (FH 29 December 1980. 1532 tion of 0.5 Ag/ml. However, at 0.05 ,ug/ml of sterol synthesis in fibroblasts from homozygotes was not completely suppressed in contrast to normal and heterozygous cells. Moreover, after preincubation with 0.05 ,ug/ml of ML-236B for 24 h in medium containing lipoproteins, sterol synthesis in the cells from receptornegative homozygote showed 75% of the initial activity compared with that of 25% without preincubation. In the cells from a normal subject and a heterozygote, sterol synthesis was inhibited even after preincubation. These results suggest that (a) the inhibitory effect of ML-236B is overcome in homozygote cells by their high intracellular levels of HMG-CoA reductase and (b) that a higher dose of ML-236B may be required to lower serum cholesterol levels in FH homozygotes than in heterozygotes