It is clinically usefull to divide the location of infarction into the cortical and perforating arterial system. Computerized tomography (CT) and magnetic resonance imaging (MRI) now make the point of infarction a simple and useful task in daily practice. The diagnostic modality has also demonstrated that risk factors and clinical manifestations are different for infarction in the cortical as opposed to the perforating system.
In this paper, we present various aspects of images of cerebral ischemia according to CT and/or MRI findings. With the advance of imaging mechanics, diagnostic capability of CT or/and MRI for cerebral infarction has markedly been improved. We must consider these points on evaluating the previously reported results. In addition, we always consider the pathological background of these image-findings for the precise interpretation of their clinical significance. In some instances, dynamic study such as PET or SPECT is needed for real interpretations of CT and/or MRI images. We paid special reference to lacunar stroke and striatocapsular infarct. In addition, “branch atheromatous disease (Caplan)” was considered, in particular, for their specific clinical significances. Large striatocapsular infarcts frequently show cortical signs and symptoms such as aphasia or agnosia in spite of their subcortical localization. These facts, although have previously been known, should be re-considered for their pathoanatomical mechanism.

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ApoE, as well as apoB100, is a major component of mammalian lipoproteins and functions in metabolism of plasma lipoproteins through its interaction with LDL receptor mainly in the liver. ApoE is also thought to be a specific ligand for putative hepatic chylomicron remnant receptor (apoE receptor). Several lines of evidence suggest that lipoproteins with several molecules of apoE have a higher affinity for LDL receptors than those without apoE, suggesting that apoE functions in determining the metabolic fate of lipoproteins containing apoB100. In transgenic mouse lines with integrated rat apoE gene under control of metallothionein promotor, the plasma level of rat apoE in homozygotes for the transgene was 17.4mg/dl after zinc induction. Overexpression of apoE enhanced the clearance of lipoproteins containing apoB100, resulting in reduced plasma triglycerides levels. To investigate the role of apoE in hepatic uptake of chylomicron remnants, kinetics of chylomicrons were studied in transgenic mouse lines. Plasma clearance of injected ¹²⁵I-labeled human chylomicrons was five-fold faster in transgenic mice than in controls. Immunohistochemistry demonstrated that apoE was specifically localized at the basolateral surface of hepatocytes of fasted transgenic mice. After injection of a large amount of chylomicrons, the density of the cell-surface apoE was markedly reduced and vesicular staining was observed in the cytoplasm, suggesting that the cell-surface apoE was used for hepatic endocytosis of chylomicron remnants.

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Natriuretic peptide family, which possesses potent diuretic, natriuretic and vasorelaxing properties, is now recognized to be composed of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP). We have elucidated that ANP and BNP are the cardiac hormone mainly secreted from the atrium, and the ventricle, respectively. We have also discovered that CNP first recognized as the neuropeptide is produced in endothelial cells and considered to be an autocrine/paracrine regulator in the vascular wall. The aim of this study is to elucidate clinical significance of natriuretic peptide family using molecular biology and developmental biotechnology technique and seek for the clinical application of natriuretic peptide family for cardiovascular disorders.
To elucidate the significance of natriuretic peptide family in chronic regulation of blood pressure and body fluid homeostasis, we isolated mouse BNP gene and cDNA and tried to generate BNP gene overexpressing transgenic mice. Mouse BNP gene contains three exons and two introns. Typical TATAAA sequence exists about 100 base pairs upstream of the translation initiation site. By microinjecting the expression vector which contained cloned mouse BNP gene linked to human serum amyloid P promoter into mouse male pronucleus of fertilized egg, we succeed in obtaining several F1 transgenic mice with various copy numbers of BNP gene (15∼50 copies). Northern blot analysis revealed that mouse BNP mRNA was abundantly expressed in the liver in the BNP transgenic mice. The BNP mRNA concentration in the liver was ten-times higher than that in the ventricle. We established the radioimmunoassay specific to mouse BNP and examined the plasma level of BNP in the transgenic mice. The plasma BNP concentration in the transgenic mice was 2-15pmol/ml, which was at least 10 to 100 times higher than the control mice (less than 0.16pmol/ml). Blood pressure of the transgenic mice determined by the direct measurement was 106±1mmHg, which was significantly lower than that of the control mice (126±2mmHg). These findings indicate that BNP can chronically exert biological action to modulate blood pressure and body fluid homeostasis, and support the long term effectiveness of natriuretic peptide family for clinical application. The significance of natriuretic peptide family is now under investigation, using the transgenic mice. We also succeeded in cloning mouse CNP gene. The mouse CNP gene is composed of at least two exons and one intron. The 5'-flanking region contains an array of cis-acting regulatory elemnts, including TATA box, Y box, GC box and CRE-like sequence, and a dinucleotide CA repeat (microsatellite). CNP mRNA expression was observed widely in mouse tissues, suggesting the role of CNP as a local regulator. On the basis of the polymerase chain reaction-analyzed microsatellite length polymorphisms among recombinant inbred strains of mice, the CNP gene (Nppc) was assigned to mouse chromosome 1. This is well contrast to the fact that the genes of ANP and BNP, which act as the cardiac hormone, are tightly linked on chromosome 4. CNP gene over-expressing transgenic mice and CNP knock-out mice have been now under development for the investigation of the significance of CNP in cardiovascular homeostasis.

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To clarify the process of atherosclerosis, the mechanism of cholesteryl ester accumulation in macrophages must be elucidated. Many drugs, hormones and cytokines are known to affect this process. Glibenclamide is widely used for the treatment of diabetes mellitus. However, the effects of this drug on cholesterol metabolism are not well known. In this study, we examined the effect of glibenclamide on cholesteryl ester synthesis and cellular cholesterol contents in macrophages. Glibenclamide enhanced cholesteryl ester synthesis in a concentrationdependent manner. This effect was observed both in the presence and absence of LDL. Degradation and association of ¹²⁵I-LDL were not changed by glibenclamide. However, glibenclamide inhibited cholesteryl ester accumulation. These findings suggest that glibenclamide did not change the metabolism of LDL and that cholesteryl ester hydrolysis and efflux may be enhanced by glibenclamide. To study the involvement of ATP-sensitive potassium channel in the action of glibenclamide, the effect of lemakalim and nicorandil, potassium channel openers, on cholesteryl ester synthesis was examined. Neither nicorandil nor lemakalim had any effects on cellular cholesteryl ester synthesis. In addition, nicorandil did not alleviate the action of glibenclamide. These findings suggest that a factor other than the ATP-sensitive potassium channel is involved in the inhibition of cholesteryl ester accumulation by glibenclamide.

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We examined the association of LDL subclass with coronary risk factors and angiographically defined CAD. Studies were performed on 213 patients. Patients with diabetes mellitus and hypercholesterolemia (TC>220mg/dl) were excluded. The presence of CAD was defined as ≥50% stenosis of at least one of 15 segments according to AHA Committee Report. LDL subclasses were classified into small LDL (diameter<25.5nm) and normal LDL based on LDL particle size by nondenaturing 2.5 to 16% polyacrylamide gradient gel electrophoresis. In all subjects, small LDL was significantly associated with increased plasma levels of triglyceride, apolipoprotein B, E and insulin compared with normal LDL. Small LDL was also more likely to have a high body mass index and hypertension. In addition, small LDL was significantly associated with decreased plasma levels of HDL cholesterol and apolipoprotein A-I than normal LDL. These alterations and hyperinsulinemia in small LDL are consistent with disturbances in insulin resistance. The prevalence of CAD was significantly higher in small LDL than in normal LDL (75.7% vs 43.2% p<0.01). The percentage of small LDL was significantly increased in proportion to the increase in vessel disease (zero vessel disease: 18.6%, one vessel disease: 32.6%, multi (2∼3) vessel disease: 58.6% p<0.01). These findings suggest that small LDL is significantly associated with high triglyceride, low HDL-cholesterol, hypertention, obesity and hyperinsulinemia and could be a marked discriminator for CAD in non-diabetic and normocholesterolemic subjects.

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Lipoprotein (a) (Lp(a)) is an independent risk factor for coronary atherosclerosis. However, few investigations have been reported concerning the treatment of high plasma Lp(a).
The sex hormones, especially estrogen or a combination of estrogen and progesterone, have been reported to lower the plasma Lp(a) in the females. On the other hand, progesterone alone has attracted much less attention.
We examined the effect of allylestrenol (AE), a synthetic progesterone, on the plasma Lp(a) level. We administered 25mg AE twice daily to 16 male patients with both benign prostate hypertrophy and high plasma Lp(a), and measured the plasma levels of Lp(a), total cholesterol (TC), triglyceride (TG), HDL cholesterol (HDL-C), and other parameters, before and after one month of treatment. Lp(a) was measured by an enzyme-linked immunoassay. LDL cholesterol (LDL-C) was calculated according to Friedewald's formula. The values were expressed as mean±SD.
AE was tolerated well and there was no clinical or laboratory evidence of adverse effects. Plasma Lp(a) decreased from 57±37 to 39±24mg/dl. The mean decrease was 32%. Especially in patients with the top 6 highest plasma Lp(a) levels, the reduction of Lp(a) was marked (145→85, 131→97, 98→66, 65→31, 62→38, 50→33mg/dl: -37%). TC decreased from 199±34 to 185±32mg/dl, and HDL-C also decreased from 45±11 to 37±10mg/dl, and there was no change in the LDL-C. TG slightly decreased from 107±54 to 95±44mg/dl.
Our findings suggest that progesterone alone, even without estrogen, could reduce the plasma Lp(a) levels. The mechanism by which Lp(a) decreased in our study is not clear at present. However, Lp(a) appears to be under some hormonal control. Further investigations are necessary to justify the clinical use of progesterone for patients with high plasma Lp(a) levels and to clarify the mechanisms in its lowering of Lp(a). We should also be careful about the lipid profile including Lp(a) in different types of hormone therapy.

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