調査業務の質を安定・向上させるために，業務標準書の作成を始め，ヒアリングシートと調査報告書フォーマットの新設，ダイセル版検索式リストの作成に取り組んできた。作成を通して，これらの取り組みが調査担当者のスキルの共有化・伝承にもつながることが見えてきた。また，調査担当者に求められる新たな役割に対応していくためには，個々人のスキルだけでなくチームとしてのスキルを上げていくことが必要である。

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糖尿病では動脈硬化性疾患の危険因子の一つとしてLp (a) が挙げられている.しかし, 糖尿病でLP (a) が上昇するか否かについては疑問がある.そこで高脂血症未治療のインスリン非依存性糖尿病患者83例における血清Lp (a) 濃度を測定し, 危険因子としての意義をApoB/ApoA1比やatherogenic index (A.I.) と比較検討した.合併症のない糖尿病患者22名のLp (a) は14.8±14.9 (±SD)) mg/dlで健常者の文献値と不変であった.Lp (a) と空腹時血糖やHbA₁cとの関係は認められなかった.網膜症, 蛋白尿, 虚血性心疾患合併例のLp (a) は合併症のない糖尿病より有意に高値を示したが, 重回帰分析では蛋白尿のみが重要であった.Lp (a) は他の脂質諸量とは独立しており, ApoB/ApoA1やA.I.と比較すると大血管合併症例で有意に異常値検出率が高いことから, 糖尿病の大血管合併症に対してもよりよい指標と考えられた.以上より, Lp (a) は糖尿病自体では高値とならないが, 蛋白尿と強く関係し, ApoB/ApoA1やA.I.よりも優れた糖尿病性大血管合併症の危険因子と考えられた.

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A high concentration of plasma Lp (a) is a risk factor of ischemic heart disease, and the Lp (a) level is genetically determined. Recently, it has been shown that in patients with NIDDM, high Lp (a) levels (high-Lp (a)) are observed more frequently than in the normal population. However, the cause of this phenomenon has not yet been fully investigated. Therefore, we determined the Lp (a) concentrations in 195 patients with NIDDM, 20 patients with IDDM and 195 normal subjects, to examine the correlation of Lp (a) concentration with clinical characteristics, fibrinolytic factors, and the levels of lipids and apolipoproteins. The results showed that the Lp (a) concentrations in patients with NIDDM (the mean±SD: 177±73mg/l) were significantly higher than those in normal subjects (115±101mg/l). The incidence of high-Lp (a) (≥250mg/l) in these patients (27%) was also higher than that in the normal group (11%). Between the two groups of high-Lp (a) (143 cases) and low-Lp (a) (<250mg/l, 52 cases) in patients with NIDDM, there were no differences in the plasma glucose level, HbA_1c, type of therapy or fibrinolytic factors. Meanwhile, in patients with NIDDM, the Lp (a) concentrations were correlated with the levels of total cholesterol, LDL-C and apo B, and the incidence of high-Lp (a) increased with the grade of proteinuria. Furthermore, the Lp (a) concentration was in no way correlated with the creatinine serum level, but was significantly correlated with the amount of urinary protein (r=0.508, p<0.01). In follow-up studies on 81 NIDDM and of IDDM patients over 1-19 months, the Lp (a) concentrations of most of the patients did not change significantly. However, the Lp (a) levels in 6 patients with nephrotic syndrome were higher (447±356mg/l), although these levels were lowered (294±187mg/l) when the proteinuria was improved by the treatment. We suggest that there may be a secondary high-Lp (a) besides the inherited high-Lp (a) in patients with NIDDM. On the basis of the relationships between Lp (a) and total cholesterol, LDL-C, apo B or urinary protein, we believe that this secondary high-Lp (a) may result from the hyperproduction of protein in the liver compensating for the loss of protein into the urine. The studies of 14 families (53 members), whose probands had NIDDM and high-Lp (a), showed that six families had no members with high-Lp (a) except the proband, and that five of the six probands were associated with proteinuria. This family study also noted the existence of high-Lp (a) secondary to proteinurua. In the diabetic patients with cerebrovascular disease and coronary heart disease, high-Lp (a) was more frequent than in those without these complications. In diabetics, not only inherited high-Lp (a), but also secondary high-Lp (a) may be risk factor leading to atherosclerosis.

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The detective sensitivity of apolipoprotein(a) [apo(a)] isoform measurement by immunoblotting was determined and the prevalence of apo(a) isoform in patients with diabetes mellitus or with coronary artery stenosis was examined. The detective limit was from 4 to 6ng of lipoprotein(a) [Lp(a)] loaded per lane in electrophoresis. There was no cross-reactivity with plasminogen of the anti-apo(a) antibody used in our immunoblotting system. Apo(a) isoform containing a smaller size of apo(a) was detected more frequently in cases with high Lp(a) concentration, and was more frequent in patients with non-insulin independent diabetes mellitus (NIDDM) of a higher Lp(a) concentration than in other disease groups. The frequency of higher Lp (a) concentration cases in patients with coronary artery stenosis was larger than that in normal controls among each identical apo(a) isoform group, suggesting that mechanisms other than genetic factor was involved in the Lp(a) increase in the patients with coronary artery stenosis.

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Serum Lp(a) lipoprotein [Lp(a)] levels in non-insulin dependent diabetics (NIDDM) were determined by a sensitive enzyme-linked immunosorbent assay (FLISA).
The Lp(a) concentration in NIDDM was significantly higher than in normal subjects. However, the Lp(a) was not correlated with fasting blood sugar (FBS), hemoglobin A₁C (HbA₁C) and the obesity index. The serum levels of TC, TG, LDL-C and Apo B significantly increased and those of HDL-C, Apo A-I and Apo A-II significantly decreased in NIDDM.
According to Hayashi's multidimensional quantification theory (type I analysis), a positive correlation was observed between the Lp(a) and diabetic retinopathy, but there was no correlation between the Lp(a) and diabetic nephropathy or nephropathy.
These results suggest that the Lp(a) plays some role in the development of diabetic retinopathy.

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Serum lipoprotein(a) {Lp(a)} is accepted as a potent risk factor for atherosclerotic disease. C_4b binding protein (C₄bp), a regulatory protein in complement system, plays important roles in blood coagulation and fibrinolysis, and is identical with proline-rich protein. Our previous study showed a positive correlation between serum Lp(a) and C₄bp levels (Nagata et al., J. Jpn. Atheroscler. Soc., 20: 651-655, 1992). Both the serum amyloid A (SAA) and serum amyloid P (SAP) components are precursors of the amyloid A and P proteins, which are the main amyloid components deposited in the tissue of secondary amyloidosis. In human blood, SAP binds with C₄bp, and SAA binds with HDL lipoprotein.
We examined effects of oral administration of niceritrol (750mg/day, for 16 weeks) on serum lipids, apolipoproteins, Lp(a), C₄bp, SAP, and SAA in 26 patients (12 males and 14 females) who had high serum Lp(a) levels (>30mg/dl) and the following cerebrovascular diseases: cerebral infarction (16 patients), cerebral bleeding (8 patients), and subarachinoidal hemorrhage (2 patients).
Niceritrol therapy decreased total cholesterol and triglyceride levels, confirming previous reports. HDL-cholesterol levels had increased 4 weeks after administration, but the increases after 16 weeks were not significant. Apolipoproteins B and C-III levels had decreased after 16 weeks, but other apolipoproteins showed no significant change.
Niceritrol obviously lowered serum Lp(a) levels; the percentage decrease from the pre-treatment level was 22±8% (12±4mg/dl) after administration for 16 weeks. Lp(a) levels rebounded to pre-treatment levels 4 weeks after niceritrol therapy was discontinued. C₄bp levels had also decreased after 4 weeks, but the decreases after 16 weeks were not significant. However, the percentage decreased in Lp(a) and C₄bp levels showed a positive correlation. In addition, both SAA and SAP levels decreased after 16 weeks, and the decreases, in percentage terms, percentage were positively correlated. Niceritorol therapy lowered the serum levels of C₄bp, SAA, and SAP as well as Lp(a). We speculate that niceritrol suppressed the production of these proteins in the liver.

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We examined serum lipids, lipoproteins including lipoprotein(a) (Lp(a)), apolipoproteins, and C_4b binding protein (C₄bp) in 262 patients (130 males and 132 females) with cerebrovascular diseases (CVD), consisting of cerebral infarction of cortical artery (16 males/13 females, age; 68.4±11.3 years), cerebral infarction of the perforated artery (12/11, 70.2±8.2), multiple infarctions (39/38, 75.5±8.1), vascular dementia (16/13, 72.9±4.7), cerebral embolism (5/10, 70.1±13.6), cerebral bleeding (35/34, 66.3±11.0), and subarachnoideal bleeding (7/13, 64.9±12.1).
Total serum cholesterol and/or LDL-cholesterol levels increased in cerebral infarction, multiple infarction, cerebral embolism and cerebral bleeding, compared with the control subjects. Serum triglycerides levels increased in cerebral infarction, multiple infarction and cerebral bleeding, and subarachnoideal bleeding. Serum HDL-cholesterol levels were low in cerebral infarction, multiple infarction, vascular dementia, cerebral bleeding, and subarachnoideal bleeding.
Serum Lp(a) levels were significantly higher in all types of CVD, especially in multiple infarctions and vascular dementia, except cerebral infarction of the perforated artery.
C₄bp, a regulatory protein in the complement system, has an important role in both the blood coagulation and the fibrinolysis system. Recently, it has been reported that C₄bp is identical to prolinerich protein, which has an affinity with several serum lipids. In this study, there was no significant difference in the serum C₄bp levels of the control subjects and of the patients with CVD.
Serum Lp(a) levels are genetically regulated, and serum Lp(a) is accepted as an independent risk factor of atherosclerotic disease. However, our study showed a positive correlation between serum Lp(a) and C₄bp levels. Both proteins were involved in the change in serum lipids, blood coagulation, fibrinolysis, and inflammation. Serum Lp(a) and C₄bp levels were probably correlated with each other according to these similarities.

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最近, 虚血性心疾患のみならず, 糖尿病においても血中Lp (a) が高値を示すことが報告されている. そこで我々は, 糖尿病における高Lp (a) 血症発現の一因を究明するため, 血中Lp (a) 濃度と血糖コントロールおよび糖尿病性合併症との関連性について検討した. NIDDM患者114名 (男性60名, 女性54名), 腎不全合併NIDDM患者20名 (男性14名, 女性6名) および健常人56名 (男性40名, 女性16名) を対象とした. ELISAキットを用いて測定した血中Lp (a) 濃度は, コントロール群の10.8±1.1mg/dlに比し, NIDDM群では, 20.2±1.7mg/dlと有意に高値を示したが, 性差, 年齢差はなかった. NIDDM患者75名において, 1～12ヵ月間における血中Lp (a) 濃度の変化とHbA₁cの変化の間には, rs=0.292 (p<0.01) と有意な正の相関を認め, 高血糖が糖尿病における高Lp (a) 血症の一因となっている可能性が示唆された. 合併症との関係では, 腎症の程度との間に相関性が認められ, 腎不全合併NIDDM群では血中Lp (a) 濃度はさらに高値を示した.

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冠動脈疾患 (coronary artery disease, CAD) の発症頻度が慢性血液透析 (hemodialysis, HD) 症例で高いことが問題になっている. HD症例では中性脂肪 (triglyceride, TG) の上昇とHDL-コレステロール (high density lipoprotein cholesterol, HDL-C) の低下が脂質代謝異常の特徴と考えられてきたが, 近年, lipoprotein (a) 〔Lp(a)〕 の上昇しているHD症例の多いことが報告されるようになり, なかでもCADとの関連が注目されるようになった. また, apolipoprotein (a) 〔apo(a)〕 phenotypeのうちlow molecular weight (LMW) がHD症例でのCAD発症に関与していることが報告されるようになった. このような背景をもとに本研究では冠動脈疾患の既往が明らかでないHD症例を5年間, 前向きに (prospective) に経過観察し, Lp(a) ならびにLMWがHD症例でのCAD発症の危険因子となるかを検討した.
268名のHD症例のうち37名 (13.8%) にCADが発症した. その内訳は心筋梗塞22名, 狭心症7名, 無症状であったが何らかの機会に冠動脈造影 (coronary angiography, CAG) が施行され, 75%以上の有意狭窄を認めたもの8名であった. また今回の検討では年齢が高く, 基礎疾患が糖尿病性腎症 (diabetic nephropathy, DN) であり, LMWでLp(a) が高値を示すHD症例にCADが多く出現した. 多変量解析による検討からはLp(a) が30mg/dl以上, DN, LMW, 年齢65歳以上がCADの独立した危険因子であった.
以上により, HD症例では年齢, DNという基礎疾患を背景に, 遺伝的に決定されているapo(a) phenotypeのLMWならびにLp(a) が高値を示す症例でCADの発症する可能性の高いことが示唆された.

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血液透析 (HD) 患者の死因の大部分は動脈硬化症を基盤とした脳血管障害や虚血性心疾患 (IHD) などの心血管系合併症であるが, これらの病態と脂質代謝異常の因果関係については十分解明されていないのが現状である. 今回, 我々はHD患者で高値を示すことが多く, IHDの危険因子の一つと考えられているLp(a) リポタンパク〔Lp(a)〕とアポ (a) アイソフォームを測定し, IHDの発症とHD患者の生命予後について, 主としてLp(a) の観点から検討した.
健常者212名 (平均年齢32.9歳) とHD患者317名 (平均年齢53.2歳) を対象に総コレステロール (TC), LDL-コレステロール (LDL-C), HDL-コレステロール (HDL-C), Lp(a), アポ (a) アイソフォームを測定した. またHD患者においては心筋タリウムシンチグラムにより心筋虚血の有無について検討した.
以下の結論が得られた. 1) HD患者のLp(a) は高値を示したが, 基礎疾患別による差異は認められなかった. 2) HD患者でのアポ (a) アイソフォームの検討からS₂, ならびにS₂/S₃のdouble bandが多く認められた. 3) IHDで死亡した症例の脂質代謝異常の特徴としてHDL-Cが低く, Lp(a), LDL-Cが高く, アポ (a) アイソフォームでdouble bandを呈している症例が多く認められた.
以上よりLp(a) ならびにアポ (a) アイソフォームはHD患者でのIHDの危険因子となる可能性が示唆された.

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糖尿病患者では腎症の進展とともに血清Lp (a) が上昇することが知られているが, 糖尿病透析患者における血清Lp (a) 代謝の変化については十分に検討されていない. 我々は血清Lp (a) について糖尿病透析患者 (DM/HD群, n=30), 非糖尿病透析患者 (nonDM/HD群, n=139) および健常者 (control群, n=39) の血清Lp (a) について比較検討した. 各群の血清Lp (a) 濃度はcontrol群, nonDM/HD群およびDM/HD群の順に14.4±1.7 (11.4) mg/dl {平均値±SE (中央値)}, 21.1±1.3 (18.5) mg/dl, 21.1±2.5 (15.0) mg/dlであり, control群と比較しnonDM/HD群では有意に高値を示したが, DM/HD群では高値の傾向は示すものの統計学的には有意ではなかった. 血清Lp (a) 濃度はHDL-コレステロール, アポリポタンパク (アポ) A-IおよびA-IIとの間に相関関係は認められなかったが, LDL-コレステロールおよびアポBと正の相関を示し, Lp (a) とアポB含有リポ蛋白との代謝の関連が示唆された. 糖尿病透析患老においては血清Lp (a) 濃度の高値が認められなかったことより, 糖尿病性腎症保存期にみられる肝でのアポB含有リポ蛋白およびLp (a) の産生促進が透析導入により改善することが考察された.

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