永井 良三

It has been established that patients with chronic kidney disease (CKD) suffer from frequent cardiovascular events. On the other hand, recent studies suggest that renal damage tends to worsen in patients with cardiovascular diseases (CVD). Although the mechanisms for the cardiorenal association are unclear, the presence of arteriosclerotic risk factors common to both CVD and CKD is important. In arteriosclerosis, vascular derangement progresses not only in the heart but also in the kidney. In addition, heart failure, cardiac catheterization and hesitation of medical treatments due to renal dysfunction may explain the progression of renal damage. Therefore, the goal of treatments is a total control of arteriosclerotic risk factors. Medication should be selected among agents with protective effects on both heart and kidney. It is important to always consider the presence of CKD for the treatment of the cardiovascular disease and strictly control the risk factors.

Insulin receptor substrate (Irs) mediates metabolic actions of insulin. Here, we show that hepatic Irs1 and Irs2 function in a distinct manner in the regulation of glucose homeostasis. The PI3K activity associated with Irs2 began to increase during fasting, reached its peak immediately after refeeding, and decreased rapidly thereafter. By contrast, the PI3K activity associated with Irs1 began to increase a few hours after refeeding and reached its peak thereafter. The data indicate that Irs2 mainly functions during fasting and immediately after refeeding, and Irs1 functions primarily after refeeding. In fact, liver-specific Irs1-knockout mice failed to exhibit insulin resistance during fasting, but showed insulin resistance after refeeding; conversely, liver-specific Irs2-knockout mice displayed insulin resistance during fasting but not after refeeding. We propose the concept of the existence of a dynamic relay between Irs1 and Irs2 in hepatic insulin signaling during fasting and feeding.

AIMS: The early diagnosis of acute aortic dissection (AD) remains challenging. We sought to determine the utility of the troponin-like protein of smooth muscle, calponin, as a diagnostic biomarker of acute AD. METHODS AND RESULTS: Immunoassays against calponin (acidic, basic, and neutral isoforms) were developed and the levels were compared in a convenience sample of 59 patients with radiographically proven AD [34 males, age 59 +/- 15 (SD) years] vs. 158 patients suspected of having AD at presentation (116 males, age 63 +/- 15 years) but whose final diagnosis was not AD. Basic calponin, which is the most specific and abundant in smooth muscle, and acidic calponin, respectively, showed greater than two-fold and three-fold elevations in patients with acute AD. Diagnostic performance as determined by receiver-operating characteristics curve analysis showed that both acidic and basic calponin have the potential to detect AD in the first 24 h [respective areas under the curve (AUCs) 0.63 and 0.58], with superior performance of basic calponin (when compared with acidic) in the initial 6 h (respective AUCs 0.63 and 0.67). CONCLUSION: Circulating calponin levels were elevated in acute AD compared with controls. These biomarkers have the potential for use as an early diagnostic biomarker for acute AD.

医学教育は社会のさまざまな面と接点があり，多様な価値観が含まれる．最新の医学知識を身につけるだけでなく，職業専門人としての教育も求められる．とくに学生時代に学ぶ知識や技能と，現場で求められる知識·技能の解離の大きいことが，多くの混乱を招いている．しかし知識不足だけが，混乱の原因ではない．医療のあり方や，医学研究の進む方向が十分に議論されてこなかったことも一因と思われる．医療安全の問題は，近代化をめざす医療システムの根本に関わる問題であり，医学教育，なかんずく生涯教育の恰好の課題である．また，近年の臨床研究の停滞は，これまでの実験医学のあり方を基本から見直す機会を与えた．医療者の生涯教育で取り組むべき重要な課題であることが明らかになったと言える．本稿では，我が国の生涯教育の現状と課題，さらに今変わりつつある医療と医学の考え方について紹介した．<br>

Cardiovascular diseases are closely related to circadian rhythm, which is under the control of an internal biological clock mechanism. Although a biological clock exists not only in the hypothalamus but also in each peripheral tissue, the biological relevance of the peripheral clock remains to be elucidated. In this study we searched for clock-controlled genes in vascular endothelial cells using microarray technology. The expression of a total of 229 genes was up-regulated by CLOCK/BMAL2. Among the genes that we identified, we examined the thrombomodulin (TM) gene further, because TM is an integral membrane glycoprotein that is expressed primarily in vascular endothelial cells and plays a major role in the regulation of intravascular coagulation. TM mRNA and protein expression showed a clear circadian oscillation in the mouse lung and heart. Reporter analyses, gel shift assays, and chromatin immunoprecipitation analyses using the TM promoter revealed that a heterodimer of CLOCK and BMAL2 binds directly to the E-box of the TM promoter, resulting in TM promoter transactivation. Indeed, the oscillation of TM gene expression was abolished in clock mutant mice, suggesting that TM expression is regulated by the clock gene in vivo. Finally, the phase of circadian oscillation of TM mRNA expression was altered by temporal feeding restriction, suggesting TM gene expression is regulated by the peripheral clock system. In conclusion, these data suggest that the peripheral clock in vascular endothelial cells regulates TM gene expression and that the oscillation of TM expression may contribute to the circadian variation of cardiovascular events.