永井 良三

大動脈瘤ならびに大動脈解離は成人でみられる代表的な大血管の疾患である．ともに急性発症するため，迅速な診断法の開発は急務である．本稿では，バイオマーカーによるこれら大血管疾患の診断法の研究開発の現状と今後の可能性について概説する．<br>

Neutral cholesterol ester hydrolase (NCEH) accounts for a large part of the nCEH activity in macrophage foam cells, a hallmark of atherosclerosis, but its subcellular localization and structure-function relationship are unknown. Here, we determined subcellular localization, glycosylation, and nCEH activity of a series of NCEH mutants expressed in macrophages. NCEH is a single-membrane-spanning type II membrane protein comprising three domains: N-terminal, catalytic, and lipid-binding domains. The N-terminal domain serves as a type II signal anchor sequence to recruit NCEH to the endoplasmic reticulum (ER) with its catalytic domain within the lumen. All of the putative N-linked glycosylation sites (Asn(270), Asn(367), and Asn(389)) of NCEH are glycosylated. Glycosylation at Asn(270), which is located closest to the catalytic serine motif, is important for the enzymatic activity. Cholesterol loading by incubation with acetyl-LDL does not change the ER localization of NCEH. In conclusion, NCEH is targeted to the ER of macrophages, where it hydrolyzes CE to deliver cholesterol for efflux out of the cells.

今回われわれは, 両側腎動脈狭窄症 (RAS) による再発性の心不全と急性腎不全, あるいは治療抵抗性高血圧をきたした2症例を経験した.<BR>症例1: 72歳, 女性. 僧帽弁置換術後の低左心機能症例で心不全入院を繰り返していた. 今回心不全加療中に急性腎前性腎不全を発症して血液透析導入となり, その後両側RASの存在が判明した. 両腎とも8.5cm大と軽度萎縮していたが, 透析から離脱困難だったこともあり腎機能と血行動態の改善を目指してステント留置による経皮的腎動脈形成術 (PTRA) を施行した. 術直後より著明な腎機能の改善が得られ, 透析から離脱できるとともに慢性期の心不全の管理も容易となった.<BR>症例2: 63歳, 女性. 冠動脈3枝病変に対するバイパス術直前に, 両側RASによる難治性高血圧が顕在化した. 腎動脈エコー上, 腎硬化症の指標である腎抵抗係数は両側とも1.0と著明高値であったが, 薬物治療抵抗性の高血圧であったため両側RASに対してPTRA (ステント留置によるPTRA) を施行した. 術後血圧は著明に改善して降圧薬の減量が可能となり, その後冠動脈バイパス術が無事に施行された. 以上の2症例はいずれも症候性RASに対してPTRAが有効であった. 特異的な臨床徴候に乏しく見逃されることの多いRASとその病態, および適応をめぐっていまだ議論の多いPTRAを考えるうえで示唆に富む2症例であり, ここに報告する.

It has long been a matter of debate whether the hormone-sensitive lipase (HSL)-mediated lipolysis in pancreatic beta-cells can affect insulin secretion through the alteration of lipotoxicity. We generated mice lacking both leptin and HSL Lep(ob/ob)/HSL(-/-) and explored the role of HSL in pancreatic beta-cells in the setting of obesity. Lep(ob/ob)/HSL(-/-) developed elevated blood glucose levels and reduced plasma insulin levels compared with Lep(ob/ob)/HSL(+/+) in a fed state, while the deficiency of HSL did not affect glucose homeostasis in Lep(+/+) background. The deficiency of HSL exacerbated the accumulation of triglycerides in Lep(ob/ob) islets, leading to reduced glucose-stimulated insulin secretion. The deficiency of HSL also diminished the islet mass in Lep(ob/ob) mice due to decreased cell proliferation. In conclusion, HSL affects insulin secretary capacity especially in the setting of obesity.

Metabolic syndrome is a major risk factor for cardiovascular and metabolic diseases. Playing a central role in the development of metabolic syndrome and in its clinical consequences is visceral obesity. Adipose tissue is now considered to be an active endocrine organ that secretes various humoral factors (adipokines), and its shift to production of proinflammatory cytokines in obesity likely contributes to the low-level systemic inflammation that is seen in metabolic syndrome-associated chronic pathologies such as atherosclerosis. Recent studies have shown that obesity induces chronic local inflammation in adipose tissue, and that cells of the innate immune system, particularly macrophages, are crucially involved in adipose inflammation and systemic metabolic abnormalities. Moreover, we and others recently revealed that T cells are key regulators of adipose inflammation, and that the adaptive immune system is also crucially important. In mouse models modulation of T cell function ameliorated not only adipose inflammation but also systemic insulin resistance induced by obesity. Thus clarification of the inflammatory processes ongoing in obese adipose tissue would seem essential for the understanding of metabolic syndrome and for developing novel therapeutic strategies to treat it.

BACKGROUND: D-dimer has been reported to be elevated in acute aortic dissection. Potential use as a "rule-out" marker has been suggested, but concerns remain given that it is elevated in other acute chest diseases, including pulmonary embolism and ischemic heart disease. We evaluated the diagnostic performance of D-dimer testing in a study population of patients with suspected aortic dissection. METHODS AND RESULTS: In this prospective multicenter study, 220 patients with initial suspicion of having acute aortic dissection were enrolled, of whom 87 were diagnosed with acute aortic dissection and 133 with other final diagnoses, including myocardial infarction, angina, pulmonary embolism, and other uncertain diagnoses. D-dimer was markedly elevated in patients with acute aortic dissection. Analysis according to control disease, type of dissection, and time course showed that the widely used cutoff level of 500 ng/mL for ruling out pulmonary embolism also can reliably rule out aortic dissection, with a negative likelihood ratio of 0.07 throughout the first 24 hours. CONCLUSIONS: D-dimer levels may be useful in risk stratifying patients with suspected aortic dissection to rule out aortic dissection if used within the first 24 hours after symptom onset.