High dose of fluvastatin sodium (XU62-320), a new inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, lowers plasma cholesterol levels in homozygous Watanabe-heritable hyperlipidemic rabbits.

The effects of fluvastatin sodium (XU62-320), a new type of inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on plasma cholesterol and triacylglycerol levels were investigated using homozygous Watanabe-heritable hyperlipidemic (WHHL) rabbit, an LDL-receptor-deficient animal which expresses a hepatic LDL receptor activity less than 5% that of control rabbits. Plasma levels of total, VLDL- and LDL-cholesterol were decreased profoundly after oral administration of fluvastatin at a dose of 50 mg/kg per day for 4 weeks. Plasma triacylglycerol levels were not affected by fluvastatin. Hepatic HMG-CoA reductase activity increased by 3-fold and hepatic LDL receptor activity increased by only 3.7-fold, as calculated by Scatchard plot analysis, with fluvastatin administration for 4 weeks, and the hepatic mRNA level for the rabbit LDL receptor was increased by 3-fold. Combined administration of fluvastatin (50 mg/kg per day) and cholestyramine, a bile acid sequestrant resin, at a level of 2% of the diet for 4 weeks more profoundly decreased plasma total, VLDL- and LDL-cholesterol levels with induction of hepatic cholesterol 7 alpha-hydroxylase and no further induction of the hepatic LDL receptor. Plasma triacylglycerol levels were increased by the combination treatment. These results suggest that high dose of fluvastatin sodium is effective in lowering plasma cholesterol levels in homozygous WHHL rabbits through the shared mechanisms involving decrease in production and secretion of cholesterol from the liver and the induction of hepatic LDL receptor. Additional effect of cholestyramine on decrease in plasma cholesterol levels seems to be due to the further decrease in hepatic cholesterol secretion by up-regulation of hepatic cholesterol 7 alpha-hydroxylase.

Opposite effects on cholesterol metabolism and their mechanisms induced by dietary oleic acid and palmitic acid in hamsters.

The effects of dietary oleic acid on cholesterol metabolism were investigated and compared with those of palmitic acid in hamsters. Addition of 5% oleic acid to a 0.1% cholesterol-supplemented diet decreased plasma total cholesterol, very low density lipoprotein (VLDL) cholesterol, and low density lipoprotein (LDL) cholesterol, increased hepatic LDL receptor activity, and decreased plasma cholesteryl ester transfer protein (CETP) activity in comparison with 0.1% cholesterol alone. In contrast, addition of 5% palmitic acid to a 0.1% cholesterol-supplemented diet increased total cholesterol and LDL-cholesterol, increased plasma CETP activity, and suppressed hepatic LDL receptor activity to a greater extent than 0.1% cholesterol alone. Neither oleic acid nor palmitic acid altered hepatic microsomal 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity, but oleic acid increased hepatic microsomal cholesterol 7 alpha-hydroxylase activity. These results suggest that dietary oleic acid inhibits the increases in total, VLDL-, and LDL-cholesterol induced by dietary cholesterol by preventing both LDL receptor suppression and increased CETP activity, whereas dietary palmitic acid augments the cholesterol-induced increases in total and LDL-cholesterol by both further suppression of LDL receptor activity and further stimulation of CETP activity.

Angiotensin I-converting enzyme gene polymorphism and salt sensitivity in essential hypertension.

We undertook the present study in 66 Japanese patients with essential hypertension to identify genetic factors associated with salt sensitivity. Patients were classified into salt-sensitive or salt-resistant groups on the basis of changes in their mean blood pressures from a week of a low salt diet (50 mmol/d) to a week of a high salt diet (340 mmol/d). Salt sensitivity and resistance were studied in relation to a 287-bp insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme gene detected by a polymerase chain reaction method and the haptoglobin phenotype determined by polyacrylamide gel electrophoresis. Patients with the angiotensin I-converting enzyme gene genotype II were more apt to be salt sensitive than patients with the ID and DD genotypes, although plasma renin activity was similar in each group. The frequency of the I allele in the salt-sensitive group was significantly higher than that in the salt-resistant group (chi2 = 7.4, odds ratio = 2.78). However, there was no significant relationship between haptoglobin phenotype and salt sensitivity. These data suggest that an I/D polymorphism of the angiotensin I-converting enzyme gene is a genetic factor associated with salt sensitivity of blood pressure independently of plasma renin activity in Japanese patients with essential hypertension.

Coronary atherosclerosis and oxidative stress as reflected by autoantibodies against oxidized low-density lipoprotein and oxysterols.

Clinical studies and animal experiments have demonstrated that oxidized low-density lipoprotein (oxLDL) and oxysterols play important roles in atherogenesis. OxLDL is immunogenic, and autoantibodies (Ab) against oxLDL are detectable in serum. We investigated the relevance of oxysterols and Ab against-oxLDL to coronary artery disease (CAD) in 183 patients undergoing coronary angiography. Patient groups included angiographically normal subjects (< 75% stenosis), others with spasm (> 75% narrowing in response to acetylcholine), and some others with fixed stenosis (> 75%). The group with stenosis was subdivided into patients with stable and unstable angina. Serum concentrations of autoantibodies and 25-, 27-, and 7-beta-hydroxycholesterols were significantly higher in the stenotic group than in the normal group (P < 0.01, P < 0.05, P < 0.05, and P < 0.05, respectively). Antibodies, but not oxysterol concentrations, were significantly greater in subjects with unstable than with stable angina (P < 0.01). We conclude that anti-oxLDL antibody and oxysterol concentrations are associated with coronary artery stenosis, and that oxidative stress may be greatly increased in unstable angina.

Significance of intracellular free calcium and magnesium and calcium-regulating hormones with sodium chloride loading in patients with essential hypertension.

This study was designed: (1) to test the hypothesis that the pressor response to sodium chloride loading in patients with essential hypertension is associated with disorder of divalent cations (calcium and magnesium); and (2) to clarify the relationship between intracellular free calcium concentration and serum levels of calcium-regulating factors and intracellular magnesium concentration. With sodium chloride loading, mean blood pressure, urinary calcium and magnesium excretions and platelet calcium concentration were increased, and serum total and ionized calcium, magnesium concentrations and erythrocyte magnesium concentration were decreased. Change in mean blood pressure was correlated with changes in parathyroid hormone (r = 0.49, P less than 0.05), serum total and ionized calcium (r = -0.50, P less than 0.05) and erythrocyte magnesium (r = -0.56, P less than 0.05) and platelet calcium concentrations (r = 0.46, P less than 0.05). In addition, change in platelet calcium concentration was related to changes in parathyroid hormone (r = 0.44, P = 0.05), serum total and ionized calcium (r = -0.66, P less than 0.01) and erythrocyte magnesium concentration (r = -0.49, P less than 0.05). It is concluded that the pressor effect of excessive sodium chloride intake on blood pressure in patients with essential hypertension is associated with a disorder of divalent cations and that alteration of the intracellular free calcium concentration with sodium chloride loading may occur through handling of serum total and ionized calcium, parathyroid hormone and/or intracellular magnesium concentration.

Factors determining sodium chloride sensitivity of patients with essential hypertension: evaluation by multivariate analysis.

Factors which determine sodium chloride sensitivity, defined as the difference between the mean blood pressure after 1 week of a low sodium chloride diet (3 g/day) and that after 1 week of a high sodium chloride diet (20 g/day), were studied in 60 inpatients with essential hypertension using a multivariate analysis. The sodium chloride sensitivity was independently correlated with the change in erythrocyte sodium concentration (r = 0.47) and with the change in plasma renin activity (r = 0.29); but it was not related to basal blood pressure, the change in plasma volume of the change in plasma norepinephrine concentration. These data suggest that both intracellular sodium accumulation and inadequate suppression of the renin-angiotensin system may be independently involved in the elevation of blood pressure after sodium chloride loading. We could not find the independent importance of volume retention, hyperadrenergic activity or basal blood pressure in the sodium chloride sensitivity.

Effect of prostacyclin on platelet intracellular free calcium concentration of hypertensive and normotensive humans.

Platelet intracellular free calcium concentration ([Ca2+]i) has been reported to be increased in essential hypertensive patients (EHT) as compared with normotensive controls (NT). Prostacyclin (PGI2), which influences cellular Ca2+, has been reported to be reduced in EHT. This study tested the hypothesis that the resting level of platelet [Ca2+]i in humans is influenced by PGI2. We also investigated the role of PGI2 in regulating platelet [Ca2+]i of 28 EHT subjects compared to 28 NT controls. Platelet [Ca2+]i was measured using the fluorescent Ca2+ probe fura-2 under control conditions and a 10-min preincubation with PGI2. Simultaneous measurement of platelet cyclic-adenosine 3':5'-monophosphate (cAMP) was performed by radioimmunoassay. The resting level of platelet [Ca2+]i was significantly higher in EHT than in NT (32.7 +/- 1.4 v 28.3 +/- 0.9 nmol/L; P < .01). PGI2 from 30 nM to 1 mumol/L lowered the resting level of platelet [Ca2+]i in a dose-dependent manner (EHT -22.2 +/- 2.4, NT -22.9 +/- 2.3%, 1 mumol/L PGI2); however, no significant difference in platelet [Ca2+]i was observed between NT and EHT. While prostacyclin induced a transient rise in platelet cAMP, the magnitude of PGI2-induced cAMP level was similar between the two groups. These results do not support the hypothesis that endogenous PGI2 activity contributes to the increased level of platelet [Ca2+]i in EHT, although PGI2 incubation lowered the resting level of platelet [Ca2+]i.

Plasma renin activity and norepinephrine as predictors for antihypertensive effects of nifedipine and captopril.

To examine predictors for the efficacy of antihypertensive agents, we investigated the effects of nifedipine and captopril on blood pressure (BP) and humoral factors in patients with essential hypertension. Eleven essential hypertensive patients (mean age: 54) were treated with long acting nifedipine at 20 to 40 mg/day for 8 weeks and 25 essential hypertensives (mean age: 51) were treated with captopril at 37.5 to 75 mg/day. Blood pressure was measured every 2 weeks. Plasma renin activity (PRA), and plasma concentrations of aldosterone, epinephrine and norepinephrine were determined before and at the end of treatment. Both nifedipine and captopril decreased BP (nifedipine: mean BP 119 +/- 3 to 101 +/- 2 mm Hg, captopril: 124 +/- 2 to 100 +/- 2, P less than .01 for each), whereas neither of them affected heart rate. The 8-week treatment of nifedipine showed no significant effect on humoral factors. Captopril increased PRA by 63% (P less than .05) and decreased plasma epinephrine by 42% (P less than .01) and norepinephrine by 35% (P less than .01). The change in mean BP was positively correlated with pretreatment PRA (r = 0.68, P less than .01) in nifedipine-treated patients and inversely with pretreatment norepinephrine (r = -0.53, P less than .01) in captopril treatment. The results suggest that both nifedipine and captopril were effective antihypertensive agents and that the long term treatment of nifedipine is more effective in essential hypertensives with lower PRA, while captopril is more effective in those with higher plasma norepinephrine concentration.

Pentaerythritol tetranicotinate (niceritrol) decreases plasma lipoprotein(a) levels.

We determined the most effective dosage of pentaerythritol tetranicotinate (niceritrol) to reduce plasma lipoprotein(a) [Lp(a)] levels in 44 Japanese patients (16 men and 28 women; mean age, 59.2 +/- 10.8 years) with hyperlipidemia types IIa, IIb, and IV. Patients received oral niceritrol at a dosage of 750 mg (3 tablets)/d for 8 weeks, followed by 1,500 mg (6 tablets)/d for 8 weeks. Administration of niceritrol 750 mg/d for 8 weeks decreased total and low-density lipoprotein (LDL) cholesterol in patients with type IIa hyperlipidemia and decreased triglycerides in patients with type IV hyperlipidemia, but did not affect Lp(a). However, niceritrol 1,500 mg/d for 8 weeks decreased Lp(a) in patients with initial Lp(a) levels greater than 30 mg/dL in addition to decreasing total and LDL cholesterol and triglycerides. These results suggest that the effective dosage of niceritrol to reduce the serum Lp(a) concentration in Japanese hyperlipidemic patients with a high Lp(a) level (> or = 30 mg/dL) is greater than 1,500 mg/d.

New method for assaying free and total cholesterol in cultured cells by high-pressure liquid chromatography.

We developed a simple, sensitive and accurate method for assaying cellular free and total cholesterol by monitoring 4-cholesten-3-one, a conversion product of the cholesterol oxidase-catalyzed oxidation of the free cholesterol that has a strong chromophoric alpha, beta-unsaturated ketone at 240 nm, using a high-pressure liquid chromatographic system. This method measured picomole quantities of free and total cholesterol and precisely determined their concentrations in cells (10(4) range) in culture using 7 beta-hydroxycholesterol as an internal standard.

An acetophenone glycoside from Exacum affine.

A new acetophenone glycoside, affinoside, was isolated from the aerial parts of Exacum affine and its structure was determined as 2-O-primeverosylpaenol. The known glucosides, gentiopicroside, 2'-O-E/Z-p-coumaroylloganin and glucopaeonol, were also identified.

Meningioma with hypergammaglobulinemia. Case report.

The case of a 14-year-old boy presenting with hypergammaglobulinemia (immunoglobulin (Ig)G and IgA) and a cerebellopontine angle tumor is reported. The tumor was histologically confirmed as meningioma infiltrated with plasma cells, lymphocytes, and histiocytes. Immunohistochemical studies showed that the infiltrating plasma cells were stained by antibodies to IgG and IgA. After total tumor removal, the hypergammaglobulinemia immediately resolved. A plausible interpretation of this sequence of events is that the inflammatory cell reaction to the meningioma caused the immunological response followed by an unusual hypergammaglobulinemia.

Antipsychotic-induced life-threatening 'esophageal dyskinesia'.

We report two patients with lingual dyskinesia and complaints of food regurgitation following long-term antipsychotic therapy. Esophageal contrast radiography revealed dyskinetic movements extending from the pharynx to the upper portion of the esophagus. The elevation of intraesophageal pressure was confirmed by esophageal manometry. The dyskinetic movements almost disappeared along with improvement of lingual dyskinesia following the administration of sulpiride in one patient. Another patient suddenly died due to asphyxiation of foods before the beginning of treatment. We termed this life-threatening movement, 'esophageal dyskinesia'. It should be emphasized that 'esophageal dyskinesia' associated with lingual dyskinesia is a potentially fatal adverse reaction to antipsychotic therapy.

Low prevalence of hepatitis C virus infection among hospital staff and acupuncturists in Kyushu, Japan.

During 1987 and 1988, samples of serum were collected from 1097 members of the staff of four prefectural hospitals in Miyazaki prefecture and from 183 acupuncturists in Fukuoka City, Japan. The staff included both surgical and non-surgical doctors, radiographers, physiotherapists, nurses, laboratory technicians and others. The samples were tested for the following hepatitis C virus (HCV) markers; antibodies to c100 (anti-c100) by means of enzyme-linked immunosorbent assay (ELISA) with supplementary recombinant immunoblot assay as well as antibodies to the GOR epitope (anti-GOR), also by means of ELISA. Anti-c100 was present in 1.7% of the doctors, radiographers and physiotherapists, in 1.3% of the nurses and in 2.2% of the acupuncturists. These prevalences were slightly higher than those in the controls but the differences were not statistically significant. Anti-c100 was not detected in any laboratory technician or other member of the hospital staff. For an accurate determination of the prevalence of HCV infection, the combined rate of anti-c100 and/or anti-GOR was also calculated. The combined prevalence of HCV infection was 4.3% in medical staff, 2.2% in nurses and 5.5% in acupuncturists. The prevalence of HCV infection among those with direct contact with patients was higher than that of the controls but without statistical significance. In the cohort we examined, the occupational risk of HCV infection was low.

Leptosins I and J, cytotoxic substances produced by a Leptosphaeria sp. Physico-chemical properties and structures.

Leptosins I and J, belonging to a series of epipolythiodioxopiperazines, have been isolated from the mycelium of a strain of Leptosphaeria sp. OUPS-4 attached to the marine alga Sargasssum tortile. Their relative stereostructures have been elucidated by chemical and spectral evidence. These compounds exhibited significant cytotoxic activity against cultured P388 cells.

Spontaneous subperiosteal hematoma of the orbit--case report.

A 62-year-old female was admitted with complaints of sudden proptosis of the left eye and severe left orbital pain without history of trauma or previous illness. Computed tomography and magnetic resonance imaging demonstrated a biconvex extraconal hematoma in the upper part of the left orbit. Surgical exploration of the orbit revealed the presence of a subperiosteal hematoma without a causative lesion. Such spontaneous subperiosteal hematoma of the orbit is extremely rare, but may result from an occult vascular disorder.

[An epidemiologic study of anti-HTLV-I (antibody to human T cell lymphotropic virus type I) by category of disease in the Kushima district of Miyazaki prefecture].

HTLV-I seroprevalence in the southern part of Miyazaki prefecture was reported to be high in many seroepidemiological surveys. In order to determine the distribution of antibody to Human T-cell lymphotropic virus type I (anti-HTLV-I) in the Kushima district of Miyazaki prefecture and evaluate the relation between the HLTV-I carrier and disease, determination of anti-HTLV-I status of patients in a hospital in Kushima City, Miyazaki prefecture was carried out from March to July, 1985. Sera from 542 patients was tested for presence of anti-HTLV-I by particle agglutination (PA) and indirect immunofluorescence (IF). Results obtained area as follows 1) Overall prevalence of anti-HTLV-I was 31.2 per cent (169 of 542 individuals). It increased gradually with age and elevated remarkably in the 60-69 age group, showing the highest rate of 39.6 per cent. 2) Prevalence of anti-HTLV-I was 28.6 per cent (65 of 227) in males and 33.0 per cent (104 of 315) in females. A significant difference by sex was not recognized. 3) No significant difference was found in the geographical distribution of anti-HTLV-I, but prevalence in the Toi area was relatively low. 4) Anti-HTLV-I was prevalent in the patients with tuberculosis (46.2 per cent), most of whom had a history of blood transfusion. In this study, the relation between HTLV-I carriers and diseases was not analysed. 5) Seroprevalence of anti-HTLV-I in the patients who had had blood transfusions was significantly higher than that of those who had not had blood transfusions (p less than 0.01).

[A four year follow-up study of recombinant HB vaccine--comparisons between three doses of subcutaneous injections and additional low dose intradermal injection].

To determine the efficacy of an additional low dose of intradermal injection of recombinant HB vaccine administered to nonresponders in addition to the standard three injections, we investigated the anti-HBs positive rate and titer of anti-HBs after four years among 58 subjects who did not develop antibodies after three doses of subcutaneous injections and who did develop the antibody after an additional low dose intradermal injection (Nonresponders), and compared them with 150 subjects who developed anti-HBs after three doses of subcutaneous injections (Responders). Fifty four subjects who were negative after four years were revaccinated with one or three doses of the subcutaneous injection. Anti-HBs positive rates after four years were 56.0 percent in Responders and 56.9 percent in Nonresponders, showing no differences. Eighty eight percent of 54 subjects who were given one or three doses of the vaccine developed anti-HBs. There were no differences in the antibody rates or titer of the antibody between the one and three doses groups. The decrease in titer of antibody was related to the levels initially having the most marked decrease in the level four years later. From these findings, we concluded that there were no differences of anti-HBs positive rates or antibody titer after four years in Responders and Nonresponders, and that one additional dose of the vaccine may be effective four years after initial administration among both groups.

[A case of pituitary apoplexy: remarkable improvement of visual acuity and field by surgical intervention at the subchronic stage].

A case is reported of a pituitary apoplexy which shows remarkable improvement of visual acuity and field by transsphenoidal surgery performed 33 days after hemorrhage. Possible factors contributing to this excellent surgical outcome are speculated about as follows; atrophic brain (wide suprasellar cistern), destruction of the sella floor by the tumor (infrasellar/extracranial decompression), no vasospasm (pure intracapsular hemorrhage), no hypopituitarism, less invasive operation (transsphenoidal surgery), and so on. Transsphenoidal surgery is thought to be worth performing for pituitary apoplexy, even if timing for the operation is later than the acute stage and even if initial visual impairment is severe.

[Traumatic anterior cerebral artery aneurysm difficult to distinguish from congenital cerebral aneurysm: case report].

We report the case of a 29-year-old woman in whom a saccular aneurysm of the distal anterior cerebral artery developed following head trauma due to a car accident. She was semicomatose on admission but had no lateralizing motor signs. Reflexes were symmetrical, with bilateral extensor toe sign. X-ray of the skull showed no fracture but CT scans demonstrated a large frontal hematoma and interhemispheric bleeding. Initial cerebral angiography performed within 12 hours of trauma showed a small protrusion on the pericallosal portion of the left pericallosal artery with no branching point nearby. Angiography was repeated on the 9th day after admission and confirmed the presence of a saccular aneurysm of the pericallosal artery, which had been visible as a small protrusion on the initial angiogram. Traumatic aneurysm was suspected and successful neck clipping of the aneurysm was performed on the 14th day. Preoperative CT and angiographic findings could not rule out a congenital aneurysm but the histological study of the specimen confirmed that it was a traumatic false aneurysm. We discussed the diagnosis and the etiology of posttraumatic aneurysm.