We followed 828 nondemented residents of Hisayama Town, Kyushu, Japan, aged 65 years or older (88.3% of the elderly population) for 7 years starting in 1985 in order to determine the type-specific incidence of dementia and its risk factors in the general Japanese population. Only two subjects were lost to the follow-up, during which period 103 subjects developed dementia. Morphologic examination of the brains of 89 subjects (86.4%) was made by autopsy or CT. We made the initial diagnosis of dementia based on the DSM-III-R criteria, with the diagnoses of vascular dementia (VD) being based on the NINDS-AIREN criteria and Alzheimer's disease (AD) on the NINCDS-ADRDA criteria. The incidence of VD and AD increased with age for both sexes. The age-adjusted total incidence (per 1,000 person-years) of dementia was 19.3 for men and 20.9 for women. The corresponding rates for VD were 12.2 for men and 9.0 for women, and for AD, 5.1 for men and 10.9 for women. Among the VD subjects whose brain morphology we examined, the most frequent type of stroke was multiple lacunar infarcts (42%), but half these subjects lacked a stroke episode in their histories. Multivariate analysis showed that age, prior stroke episodes, systolic blood pressure, and alcohol consumption were significant independent risk factors for the occurrence of VD. In contrast, age and a low score on Hasegawa's dementia scale were significant risk factors for AD, and physical activity was a significant preventive factor for AD.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract-Primary pulmonary hypertension is a fatal disease characterized by endothelial dysfunction, hypercontraction and proliferation of vascular smooth muscle cells (VSMCs), and migration of inflammatory cells, for which no satisfactory treatment has yet been developed. We have recently demonstrated that intracellular signaling pathway mediated by Rho-kinase, an effector of the small GTPase Rho, is involved in the pathogenesis of arteriosclerosis. In the present study, we examined whether the Rho-kinase-mediated pathway is also involved in the pathogenesis of fatal pulmonary hypertension in rats. Animals received a subcutaneous injection of monocrotaline, which resulted in the development of severe pulmonary hypertension, right ventricular hypertrophy, and pulmonary vascular lesions in 3 weeks associated with subsequent high mortality rate. The long-term blockade of Rho-kinase with fasudil, which is metabolized to a specific Rho-kinase inhibitor hydroxyfasudil after oral administration, markedly improved survival when started concomitantly with monocrotaline and even when started after development of pulmonary hypertension. The fasudil treatment improved pulmonary hypertension, right ventricular hypertrophy, and pulmonary vascular lesions with suppression of VSMC proliferation and macrophage infiltration, enhanced VSMC apoptosis, and amelioration of endothelial dysfunction and VSMC hypercontraction. These results indicate that Rho-kinase-mediated pathway is substantially involved in the pathogenesis of pulmonary hypertension, suggesting that the molecule could be a novel therapeutic target for the fatal disorder. Key Words: pulmonary hypertension Ⅲ Rho-kinase Ⅲ vascular smooth muscle cells Ⅲ endothelial nitric oxide synthase Ⅲ macrophages P rimary pulmonary hypertension (PPH) is a lifethreatening disease characterized by a marked and sustained elevation of pulmonary artery pressure. The disease has no obvious causes and ultimately results in right ventricular (RV) failure and death. The pathological changes of hypertensive pulmonary arteries include endothelial injury, proliferation and hypercontraction of vascular smooth muscle cells (VSMCs), and migration of macrophages. 1-3 PPH continues to be a serious clinical problem with high morbidity and mortality. 4 In 1990s, Rho-kinase/ROK/ROCK was identified as an effector of the small GTPase Rho, 5-7 which plays an important role in various cellular functions, including smooth muscle contraction, actin cytoskeleton organization, cell adhesion and motility, cytokinesis, and gene expression. 8 -10 In a series of experimental and clinical studies, we have demonstrated that Rho-kinase-mediated pathway is substantially involved in the pathogenesis of arteriosclerosis. 11-17 These Rho-kinase-mediated alterations in blood vessels also may be involved in the pathogenesis of pulmonary hypertension (PH). In this study, we examined whether Rho-kinasemediated pathway is involved in the pathogenesis of rat model of fatal PH in vivo. Materials and MethodsThe present study was...

The long-term administration of N -nitro-L -arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthesis, produces coronary vascular remodeling and myocardial hypertrophy in animals. This study used a rat model to investigate the role of angiotensin I converting enzyme (ACE) in the pathogenesis of such changes. We studied the following groups, all of which received drug treatment in their drinking water: untreated controls, and those administered L-NAME, L-NAME, and an ACE inhibitor (ACEI), and L-NAME and hydralazine. Cardiovascular structural changes and tissue ACE activities were evaluated after the first, fourth, and eighth week of treatment. In rats treated with L-NAME alone, vascular remodeling was evident at the fourth and eighth week, and myocardial hypertrophy was present at the eighth week of treatment. The vascular and myocardial remodeling were characterized by increased tissue ACE activities and immunodetectable ACE in those tissues. These changes were markedly reduced by ACEI, but not by hydralazine treatment.

This review attempts to define the early events that lead to lesions of human atherosclerosis based on careful morphological studies in human autopsy specimens. In contrast to most small laboratory animals, diffuse intimal thickening (DIT) is present in human arteries before atherosclerosis develops, particularly in the atherosclerosis-prone arteries such as coronary arteries and abdominal aorta. In the earliest stage of atherosclerosis, lipids deposit eccentrically in the deep layer of DIT to form Type I lesions. These layers are enriched in extracellular matrix (ECM) proteoglycans such as biglycan. Following lipid deposition, macrophages appear in these regions and foam cells are observed (Type II lesions). Such observations support the 'response-to-retention' hypothesis that states that a principle early event in the pathogenesis of human atherosclerosis is the trapping and retention of lipoproteins by ECM proteoglycans followed by infiltration and accumulation of macrophages.

Objective. To investigate the effects of pulse methylprednisolone acetate on bone and bone marrow tissues and to clarify the causal factors of corticosteroidinduced osteonecrosis (ON) by using an experimental animal model.Methods. Male adult Japanese white rabbits were injected once with 20 mg/kg of methylprednisolone into the right gluteus medius muscle. Seven rabbits were killed at 4 weeks, 4 at 6 weeks, 4 at 8 weeks, and 6 at 10 weeks. Both histopathologic and hematologic studies were performed every week.Results. By 4 weeks after the steroid injection, 43% of the rabbits studied had developed multifocal ON lesions in the femur and/or humerus. In 1 rabbit, a thrombus was detected in an arteriole adjacent to the necrotic area at 4 weeks. After 6 weeks, there was also progressive histologic evidence of revascularization, with granulation tissue, and osteoblastic repair, with appositional bone formation. Hyperlipemia, fatty liver, and intraosseous fat embolism were observed in conjunction with thrombocytopenia and hypofibrinogenemia.Conclusion. A single injection of high-dose corticosteroids was found to be capable of inducing thrombocytopenia, hypofibrinogenemia, and hyperlipemia with multifocal ON in several bones.

Cerebral infarction is the most common type of stroke and often causes long-term disability. To investigate the genetic contribution to cerebral infarction, we conducted a case-control study using 52,608 gene-based tag SNPs selected from the JSNP database. Here we report that a nonsynonymous SNP in a member of protein kinase C (PKC) family, PRKCH, was significantly associated with lacunar infarction in two independent Japanese samples (P = 5.1 x 10(-7), crude odds ratio of 1.40). This SNP is likely to affect PKC activity. Furthermore, a 14-year follow-up cohort study in Hisayama (Fukuoka, Japan) supported involvement of this SNP in the development of cerebral infarction (P = 0.03, age- and sex-adjusted hazard ratio of 2.83). We also found that PKCeta was expressed mainly in vascular endothelial cells and foamy macrophages in human atherosclerotic lesions, and its expression increased as the lesion type progressed. Our results support a role for PRKCH in the pathogenesis of cerebral infarction.

Objective-The present study was designed to clarify the morphological features of early human atherosclerosis and to determine whether specific extracellular matrix proteoglycans play a role in early atherogenesis. Methods and Results-Step and serial sections were obtained from right coronary arteries with no or early atherosclerosis.Atherosclerosis was classified into 4 grades according to the amount of lipid deposition. Coronary arteries with Grade 0 showed diffuse intimal thickening (DIT) with no lipid deposits. The extracellular matrix proteoglycans, biglycan and decorin, were localized in the outer layer of DIT. Most cases of Grade 1 and Grade 2 exhibited fatty streaks with extracellular lipids colocalizing with biglycan and decorin in the outer layer of the intima. As lipid grades increased, macrophages increased in number and were present in the deeper layers. Most cases of Grade 3 exhibited pathologic intimal thickening (PIT) with extracellular lipids underneath a layer of foam cell macrophages. Key Words: early human atherosclerosis Ⅲ diffuse intimal thickening Ⅲ fatty streak Ⅲ lipid retention Ⅲ biglycan L ittle is known as to how early human atherosclerosis develops. We previously reported that diffuse intimal thickening (DIT) develops from an early age in human arteries before atherosclerosis evolves. 1 DIT, also known as "nonatherosclerotic" intimal thickening, 2 is a thickened intima mainly composed of smooth muscle cells (SMCs), elastin, and proteoglycans, and devoid of lipid deposition. As DIT is strongly expressed in atherosclerosis-prone arteries, such as coronary arteries and abdominal aorta, we suggested that DIT plays an important role in human atherogenesis. In the classic pathological study, Holman et al showed that the fatty streak, a nonraised sudanophilic lesion, is the earliest lesion that appears in the aorta of children and adolescents and some fatty streaks convert into the advanced raised lesion in later life. 3 This fact was also recently confirmed in the coronary artery by McGill et al in The Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study. 4 However, as microscopic examinations were not performed in these studies, it is not clear how fatty streaks develop in normal arteries and covert into advanced lesions. Based on microscopic findings, Virmani et al defined the pathologic intimal thickening (PIT) as a preatheromatous lesion that is composed of extracellular lipid pools with an overlying layer of SMCs and lipid-laden macrophages. 2,5 These studies have contributed to our understanding of the microscopic features of human atherosclerosis before the stage of advanced lesions. Thus, PIT is thought to be an intermediate stage that represents the link from early to advanced lesions, 5 but the nature of the early lesion and how the early lesion is converted into PIT are yet to be clarified. Furthermore, Williams and Tabas proposed the response-to-retention hypothesis in early atherogenesis in 1995, which states that atherogenic lipoproteins are retained in the...

Moyamoya disease is a specific chronic cerebrovascular occlusive disease first reported by Japanese surgeons in 1957. The disease is characterized by stenosis or occlusion of the terminal portions of the bilateral internal carotid arteries and abnormal vascular network in the vicinity of the arterial occlusion. It may cause ischemic attacks or cerebral infarction, which is more frequent in children than in adults. In adults, cerebral hemorrhage may occur. The disease is distributed in all age groups, but the highest peak is in childhood at less than 10 years of age. The characteristic histopathologic features of the steno-occlusive arteries are fibrocellular thickening of the intima containing proliferated smooth muscle cells and prominently tortuous and often duplicated internal elastic lamina. There is usually no atheromatous plaque in the arterial wall. Etiology of the disease is still unknown; however, multifactorial inheritance is considered possible because of a higher incidence of the disease in Japanese and Koreans and approximately 10% of familial occurrence among the Japanese. Recent genetic studies suggest some responsible genetic foci in chromosomes 3, 6 and 17.