Effects of simvastatin on serum lipids and atherosclerosis in WHHL rabbits.

Watanabe heritable hyperlipidemic rabbits aged three months (young group) or 10 months (adult group) received 10 mg/kg of simvastatin daily for 24 weeks. Serum levels of total cholesterol, triglycerides, and beta-lipoproteins were reduced significantly in the treated animals but not in untreated controls. The decreases were greater in the young than in the adult animals. Levels of high-density lipoprotein cholesterol were not affected by treatment. At 24 weeks, the extent of atheromatous lesions on the thoracic-abdominal aorta was lower in the treated animals than in the controls, but the difference was significant only in the young animals. The results indicate that simvastatin would be effective in the treatment of atherosclerosis.

Influences of supplementary dietary tungsten on methionine metabolism in rabbits fed a low-cholesterol plus methionine diet.

Hyperhomocysteinemia results from an impaired methionine metabolism. Sulfite oxidase, which is an important enzyme in methionine metabolism, contains molybdenum. In contrast, tungsten has a molybdenum-antagonistic effect. Thus, we hypothesized that dietary tungsten may decrease plasma homocysteine levels and influence methionine metabolism. Male New Zealand White rabbits (n=15) were fed a low-cholesterol basal diet and then placed on three different diets: 0.1% cholesterol (Chol), Chol plus 1% methionine (Met), and Chol plus Met plus 0.1% tungsten (W). The animals received these diets for 20 weeks. Biochemical tests of blood and urine were performed. Plasma homocysteine levels were significantly lower in the Chol+Met+W group than in the Chol+Met group. Plasma levels of total cholesterol, triglyceride, lipid peroxide, and urinary 24-h taurine concentrations were higher in the Chol + Met + W group than in the Chol + Met group. In comparison, concentrations of 2, 3-diphosphoglycerate (2, 3-DPG), reduced glutathione (GSH) in erythrocytes, and urinary 24-h SO4(2) were lower in the Chol+Met+W group than in the Chol+Met group. From these results, tungsten could be expected to exhibit an antiatherogenic effect. Conversely, it may have effects on atherogenic factors. Thus, tungsten may play a number of roles in the methionine metabolism.

Cross-species transplantation of photoreceptors with tacrolimus hydrate (FK506) treatment.

Photoreceptors from normal neonatal or transgenic neonatal mice with normally developing retinas were transplanted into the subretinal spaces of normal rats. The animals with transplants received either immunosuppressive treatment with tacrolimus hydrate for the first two weeks after transplantation or no treatment. At 4 weeks after transplantation, graft survival occurred only in rats treated with tacrolimus. In 7 of the 12 treated eyes, photoreceptors survived at least 4 weeks after transplantation. Relatively mature outer segments were found only in 2 eyes in which the retinal grafts formed rosettes.

Nondetectable cone and rod electroretinographic responses in a patient with Cockayne syndrome.

A 10-year-old girl complained or poor vision in both eyes. The patient showed progeria, physical and mental retardation, sensorineural hearing loss, cutaneous photosensitivity, hyperopia, poor pupillary dilation, exotropia, salt-and-pepper fundi, nondetectable cone and rod electroretinographic (ERG) responses, cerebral atrophy on computed tomography, and demyelination of periventricular white matter on magnetic resonance imaging. We believe that nondetectable cone and rod ERG responses in Cockayne syndrome, as demonstrated in our patient, may be uncommon.

Histological findings of capsular delamination of the lens.

Histological findings in a 75-year-old man with idiopathic capsular delamination were reported. The anterior capsules were obtained during extracapsular cataract extraction, and examined by light and electron microscope. The epithelial side of the anterior capsules protruded towards the anterior chamber at the edge of the delaminated areas. This finding has not been described previously, and the defect in this fragile region was thought to be the cause of capsular delamination.

On the presence and function of closed lymphatic stomata in the diaphragm of the golden hamster.

The peritoneal surface of the golden hamster diaphragm was examined for closed lymphatic stomata by scanning electron microscopy (SEM) and serial sectioning. Closed stomata were absent on SEM but present on serial sectioning. Some closed stomata in the serial sections were reconstructed using a computerized image analysis system. They were less than 10 microns in diameter and consisted of an outer mesothelial margin and an inner lymphatic wall. The lymphatic wall was formed by several endothelial cells adjoined with various junctional abutments. The discrepancy of results between SEM and serial sectioning, and the functional aspects of lymphatic stomata are discussed.

The postnatal development of the mouse pericardium; the time and mechanism of formation of pericardial pores.

The mouse pericardium is a continuous serous membrane, up to postnatal day 6 (P6), that consists of pericardial and pleural mesothelia with sparse connective tissue sandwiched in between. This study shows that on P7 the pericardium becomes fenestrated, and the pericardial and pleural cavities become continuous. We found that the number of pores per pericardium increased continuously with the advance of age and reached as many as 3000 on P21. Transmission electron microscopy of the pericardium revealed various structures of the pericardial and pleural mesothelia that may relate to the formation of the pericardial pores. The pericardial and pleural mesothelia were adjoined with cytoplasmic processes that extended toward the base of the opposing mesothelium. As a result of the adjoinment, a pair of U-shaped folds were formed. The two U-shaped folds were connected with tight junctions at their apices, and separation of these junctions may give rise to the pericardial pores.

[Effect of LDL-apheresis on a case of Cerebrotendinous Xanthomatosis].

Cerebrotendinous Xanthomatosis (CTX) is a rare familial disease characterized by tendon-xanthomas, cataracts, progressive cerebellar ataxia, dementia and an elevation of serum cholestanol with normal levels of cholesterol. Although the pathogenesis of CTX is not fully understood, increment of cholestanol is suggested one of the major metabolic derangements of the disease. Recently, the LDL-apheresis has been developed as a new therapeutical equipment in the field of hyperlipidemia and been widely used to reduce the levels of LDL-cholesterol by selective LDL adsorption. From the point of view that cholestanol is involved mainly in LDL-cholesterol (1.019 less than d less than 1.063), we used this LDL-apheresis in the aim of reducing the cholestanol in 58 years old woman with typical sign and symptoms of CTX. The levels of serum cholestanol and cholesterol before the treatment with LDL-apheresis, were 10.7 micrograms/ml and 175 mg/dl respectively. Also the ratio of cholestanol/cholesterol indicated 0.63. By the first procedure of apheresis, the level of cholestanol was markedly decreased to 5.2 micrograms/ml (50%). Several LDL-apheresis treatments were carried out once a month. During 5 months treatments, neurological deterioration was arrested, dementia which included disorientation and recent-memory loss, cleaned a little. Although the xanthomas did not decrease in size, this patients was better oriented to person, place, time and was able to speak rationally, 2nd her cerebellar dysfunction revealed improvement. From our new experiments-we believe that the LDL-apheresis offers the strong hope of preventing the progress on cerebrotendinous xanthomatosis.

[The effects of transcorneal administration of prostaglandin E2 on rabbit eyes].

The pharmacologic effects of prostaglandin E2 (PGE2) on the anterior ocular segment were investigated. PGE2 was administered with a glass cylinder attached to the cornea in concentrations ranging from 0.05 to 500 micrograms/ml. The intraocular inflammatory reaction was assessed according to the changes in the anterior chamber flare, ocular tension, and components of the aqueous humor. We also performed experiments designed to inhibit the reactions induced by PGE2 using anti-inflammatory agents. The PGE2 elicited a single peak reaction in the anterior chamber flare, which recovered after several hours, and a transient elevation in the ocular tension in the early stage after PGE2 administration. Quantitative analysis of these two reactions revealed that both were dependent on the dose of PGE2 administered. The concentrations of ascorbic acid and glutathione, particularly that of the reduced form of the latter, were transiently reduced in the aqueous humor. The anterior chamber flares were suppressed by agents that inhibit arachdonic acid metabolism. These findings suggest that the metabolism of arachdonic acid becomes newly activated as a result of stimulation by PGE2 of extrinsic origin.

[A clinical trial of cis-platinum (II) in combination with PSK and FT-207 in advanced stomach cancer].

A 69-year-old patient with advanced stomach cancer (Borrmann III) was treated with a combination chemotherapy regimen of cis-platinum administered one week after a course of PSK and FT-207. The maximum dosage of CDDP administered was gradually increased step by step from 20 mg/day to 40 mg/day every week. A remarkable decrease of tumor size was observed upon stomach x-ray and endoscopical examination. The cancer marker, serum CEA, determined by RIA also decreased from 59 ng/ml to 3.5 ng/ml. Moreover, no gastrointestinal disturbance was observed during this trial. From the results experienced, in this case, the combination therapy of PSK and FT-207 with CDDP was considered to be one of the most effective antineoplastic therapies available for stomach cancer, suppressing the gastrointestinal disturbances which are usually induced by CDDP administration alone.

[The correlation between the activity of tissue plasminogen activator (TPA), levels of tissue plasminogen activator inhibitor (PAI-1) antigen and serum lipids in healthy subjects].

It is well known that abnormality of the coagulation-fibrinolytic system and serum lipids plays an important role in the development of thrombi and atherosclerotic disease. In the present study, the correlation between the activity of tissue plasminogen activator (TPA), the levels of tissue plasminogen activator inhibitor (PAI-1) and serum lipids (TC, TG, beta-Lp, HDLC, LDLC and apolipoproteins) were studied in 102 healthy subjects. The activity of TPA showed negative correlation with the obesity rate (r = 0.21, p less than 0.05) but levels of PAI-1 antigen showed a positive correlation with the obesity rate (r = 0.182, p less than 0.1). The activity of TPA showed no correlation with serum lipids including apolipoproteins, while the levels of PAI-1 antigen showed a positive correlation between TG and beta-Lp (r = 0.292, p less than 0.01, r = 0.211, p less than 0.05). The levels of PAI-1 antigen showed a negative correlation with HDLC (r = -0.286, p less than 0.01). These results indicate that TPA and PAI-1 play an important role in the development of thrombotic disease and atherosclerotic disease.

[Changes in serum Lp(a) and apo(a)phenotype in patients with acute cerebral stroke].

33 patients with acute cerebral stroke (21 men and 12 women, averaged age 69.9 +/- 11.2 years) were examined for fluctuations in the level of serum Lp(a) 3, 7, 14, and 28 days after the onset of symptoms. The Lp(a) level was higher (p < 0.05, p < 0.001) on days 7 and 14 than on the day of onset. Higher values were associated with poorer outcomes and with larger abnormal densities on brain CT scans. In 33 of these patients, the apo(a)phenotype was determined. Diluted serum was electrophoresed with SDS-containing gel as a carrier, then transcribed on a nitrocellulose membrane, stained by Western blotting and then sensitizing-stained. The results were evaluated by the method of Utermann et al. Outcome was significantly poorer in patients with a double-band apo(a)phenotype than in those with a single-band (p < 0.05). Those with a double-band had significantly higher mean value of Lp(a), except on the day of onset, than did those with a single-band. Patients with large degrees of electrophoresis had significantly higher values of Lp(a) than did those with small degrees. These data suggest that serial measurement of Lp(a) can be of some value in predicting the outcome in patients with cerebral stroke. Determination of apo(a) phenotype may also be useful in the prevention and prognosis of cerebral stroke, especially when it is caused by cerebral infarction.

[The significance of determination of Lp(a) in health examinations].

Lp(a), an independent risk factor of thrombotic and arteriosclerotic diseases, was determined in subjects undergoing health examinations, and the significance of the determination of Lp(a) in such examinations was investigated by studying its relation wih other risk factors for arteriosclerosis, etc. The subjects were 838 individuals. Lp(a) was determined by latex immunoassay (LIA). The mean Lp(a) value for all of the subjects was 10.9 +/- 7.2 mg/dl. Both gender groups were compared by age, but no significant changes were observed. In a study of Lp(a) in accordance with complications, there was no significant difference between the DM group and the non-DM group. There was also no significant difference between the IHD group and the non-IHD group. In the hyperlipemia group, the value of Lp(a) tender to be higher than in the non-hyperlipemia group. In the abnormal ECG group, the Lp(a) value was significantly higher than in the normal ECG group. When the relation between Lp(a) and other factors was studied, there was positive correlation with TC, beta Lp and LDLC, and a significant negative correlation with TRG. There was significant negative correlation with GOT, GPT and TTT. When the incidence of disease was compared by cut-off value, the incidence of abnormal ECGs was significantly higher at Lp(a) values of 25 mgdl or higher. In this study, Lp(a) showed positive correlations with TC, beta Lp and LDLC, the atherogenic risk of Lp(a) was evident. Because of the significant incidence of abnormal ECGs at the Lp(a) cut-off value of 25 mg/dl or higher, the risk range for Lp(a) should probably be considered as 25 mg/dl or higher.(ABSTRACT TRUNCATED AT 250 WORDS)

SIRT1 gene, schizophrenia and bipolar disorder in the Japanese population: an association study.

Several lines of evidence suggest that alterations in circadian rhythms might be associated with the pathophysiology of psychiatric disorders such as schizophrenia and bipolar disorder (BP). A recent study reported that SIRT1 is a molecule that plays an important role in the circadian clock system. Therefore, to evaluate the association among the SIRT1 gene, schizophrenia and BP, we conducted a case-control study of Japanese population samples (1158 schizophrenia patients, 1008 BP patients and 2127 controls) with four tagging SNPs (rs12778366, rs2273773, rs4746720 and rs10997875) in the SIRT1 gene. Marker-trait association analysis was used to evaluate the allele and the genotype association with the χ(2) test, and haplotype association analysis was evaluated with a likelihood ratio test. We showed an association between rs4746720 in the SIRT1 gene and schizophrenia in the allele and the genotype analysis. However, the significance of these associations did not survive after Bonferroni's correction for multiple testing. On the other hand, the SIRT1 gene was associated with Japanese schizophrenia in a haplotype-wise analysis (global P(all markers) = 4.89 × 10(-15)). Also, four tagging SNPs in the SIRT1 gene were not associated with BP. In conclusion, the SIRT1 gene may play an important role in the pathophysiology of schizophrenia in the Japanese population.

Genetic Association Analysis of NOS3 and Methamphetamine-Induced Psychosis Among Japanese.

Endothelial nitric oxide synthase (NOS3) is one of the enzymes influencing nitric oxide (NO) function in the human brain. NO is a gaseous neurotransmitter that is involved in a variety of mechanisms in the central nervous system, such as N-methyl-D-aspartate receptor activation and oxidative stress. The evidence from animal pharmacological studies and postmortem studies supports an association between NO and psychotic disorders. Methamphetamine (METH) use disorder is a known psychotic disorder, and we therefore conducted a gene-based case-control study between tagging single nucleotide polymorphisms (SNPs) (rs2070744, rs1799983) in NOS3 and METH-induced psychosis in Japanese subjects (183 with METH-induced psychosis and 267 controls). Written informed consent was obtained from each subject. No significant association was found between any tagging SNP in NOS3 and METH-induced psychosis in the allele/genotype-wise or haplotype-wise analyses. In conclusion, we suggest that NOS3 might not contribute to the risk of METH-induced psychosis in the Japanese population.