Abnormal expression of heparan sulfate proteoglycan on basal lamina of muscle fibers in two Japanese patients with adhalin deficiency

We recently reported the selective reduction of the BI subunit of laminin in two Japanese patients with adhalin deficiency. We here investigated immunohistochemically the expression of other components of the extracellular matrix (ECM), including collagen type IV, heparan sulfate proteoglycan (HSPG), chondroitin-4-sulfate proteoglycan, decorin, and fibronectin in adhalin deficiency, compared with other types of muscular dystrophy. We found a reduction of HSPG on the basal lamina surrounding each muscle fiber in adhalin deficiency compared with HSPG in other diseases. This finding may be characteristic evidence of the disturbance of the sarcolemma-ECM interaction and the sarcolemmal instability in adhalin deficiency. Recently, a direct role of HSPG in fibroblast growth factor (FGF) signal transduction was demonstrated. Further investigation is required to determine if the dysfunction of FGF is relevant to the pathogenesis of adhalin deficiency.     

Effect of flunitrazepam on sleep and memory

Flunitrazepam's (FNZ) effect on sleep and memory 1 mg and 2 mg was investigated in 6 healthy volunteers (mean age 21.5 ± 0.8 years) by polysomnography (PSG) and memory testing. A PSG was recorded on each study night. Memory testing was done before sleep (40 min after taking FNZ or placebo), and after waking (560 min after medication). Rapid eye movement (REM) latency was found to be prolonged on the FNZ 2 mg night (FNZ2N) compared to the baseline night (BN). Percentage of stage 2 sleep was increased in the FNZ2N as compared to BN, while REM percentage on both FNZ nights did not significantly differ from BN. The number of total REM and REM density were decreased in the FNZ2N compared to BN. Memory testing showed significant differences between before sleep and after waking on the FNZ2N. There was a significant correlation between the degree of impairment on memory testing and the rate of reduced REM density, but there was no significant correlation between degree of impairment on memory testing and the rate of increased non-REM sleep on the FNZ2N. The results of this study suggest that impairments in memory result from the dose of FNZ, and that there is a possibility of a relationship between memory disturbance and REM sleep suppression caused by this benzodiazepine.     

Interferon-α reduces catecholamine secretion from bovine adrenal chromaffin cells stimulated by acetylcholine

A long-term pretreatment (72h) of bovine adrenal chromaffin cells with recombinant human interferon (IFN)-α-2b (1500 units/ml) produced a decrease in the secretion of catecholamines from the cells stimulated by acetylcholine (ACh) (25μmol/l) but not that with human fibloblast IFN-β (3000 units/ml) or recombinant human IFN-γ (3000 units/ml). IFN-α-2b inhibited the ACh-induced secretion in a concentration- (30–1500 units/ml) and time-dependent manner (18–72h). The content of catecholamines in the cells treated with IFN-α-2b for 72h did not change. The inhibitory effect of IFN-α-2b on the secretion was abolished when the cells were simultaneously treated with anti-IFN-α antibody, and it was overcome by the increase in the external ACh concentration. IFN-α-2b also inhibited ACh-induced Ca²⁺ influx into the cells in a concentration-dependent manner similar to that of the IFN-α-2b inhibiting ACh-induced secretion. On the other hand, IFN-α-2b failed to reduce the secretion from the cells induced by high K⁺. These results strongly suggest that IFN-α-2b reduces the ACh-induced secretion of catecholamines from bovine adrenal chromaffin cells due to modulating the gene expression of the nicotinic ACh receptor-operated cation channels rather than due to directly affecting the channels. The results further indicate that the IFN-α-2b inhibition may be associated with the psychiatric side effects of IFN-α (depression, neurasthenica and somnolence, etc.), and that immune systems may regulate the function of (autonomic) nervous systems or adrenal medulla via IFN-α in vivo. Received: 6 March 1997 / Accepted: 31 July 1997     

In vivo growth of Epstein-Barr virus transformed B cells with mutations in latent membrane protein 2 (LMP2)

Summary.  Epstein-Barr virus (EBV) causes infectious mononucleosis in adolescents and is associated with malignant B lymphocyte proliferation in AIDS patients, patients undergoing immune suppression for organ transplantation, and SCID mice. In vitro, EBV transformed, latently infected lymphoblastoid B cell lines (LCLs) contain EBV episomes and express nine virus encoded proteins. Six are nuclear proteins (EBNAs) and three are the integral membrane proteins, LMP1, LMP2A, and LMP2B. To determine if LMP2 was essential for in vivo growth, SCID mice were injected with LCLs containing wild-type EBV (LMP2⁺) or with LCLs transformed with EBV containing mutations in either LMP2A or LMP2B (LMP2⁻). SCID mice injected with the LMP2⁺ or LMP2⁻ LCLs were monitored for tumor development, length of time to tumor development, and phenotypic characterization of the resulting tumors. No difference was observed in any of the above parameters between LMP2⁺ and LMP2⁻ LCLs demonstrating that LMP2 is not essential for the in vivo growth of EBV transformed B lymphocytes in SCID mice. Received July 19, 1996 Accepted October 15, 1996     

Additive beneficial effects of the combination of a calcium channel blocker and an angiotensin blocker on a hypertensive rat-heart failure model.

The present study was undertaken to examine the effects of a calcium channel blocker, azelnidipine (1 mg/kg/day), an angiotensin converting enzyme (ACE) inhibitor, temocapril (10 mg/kg/day), an angiotensin II type 1 (AT1) receptor blocker (ARB), olmesartan (5 mg/kg/day), and their combination on Dahl salt-sensitive rats (DS rats) developing heart failure with preserved systolic function. DS rats were fed a high-salt diet (8% NaCl) from 7 weeks of age and progressively developed hypertension. Although monotherapy with azelnidipine lowered the blood pressure of DS rats to a greater extent than monotherapy with temocapril or olmesartan, the three drugs had similar effects on cardiac hypertrophy, cardiac fibrosis, the expressions of brain natriuretic peptide, transforming growth factor-beta1, collagen I, collagen III and monocyte chemoattractant protein-1 mRNA (as estimated by Northern blot analysis), and cardiac diastolic dysfunction (as estimated by echocardiography). These results show that ACE and AT1 receptor, as well as hypertension, are involved in the development of heart failure with preserved systolic function in DS rats. The combination of azelnidipine with olmesartan or temocapril produced no additive hypotensive effect in DS rats and no additive effect on cardiac hypertrophy or gene expressions. However, the combination therapy prolonged the survival rate of DS rats more than azelnidipine (p <0.01) or temocapril alone (p <0.05), and this additive beneficial effect by the combination therapy was associated with a greater reduction of cardiac fibrosis, urinary albumin excretion and serum creatinine. Our results thus showed that the combination of a calcium channel blocker with an ARB or an ACE inhibitor had additive preventive effects on a rat model of hypertensive heart failure with preserved systolic function. Thus, combination therapy with these agents seems to be a useful therapeutic strategy for the prevention of hypertensive heart failure.     

Effects of antiepileptic drugs on delivery and early childhood--comparison among mono-therapies of valproic acid, phenytoin, carbamazepine and phenobarbital

The effects of antiepileptic drugs (AED) on infants during pregnancy and delivery were studied in a total of 82 epileptic mothers on various monotherapies; 29 cases receiving valproic acid (VPA), 20 receiving phenytoin (PHT), 18 on carbamazepine (CBZ) and 15 on phenobarbital (PB). While AED serum concentrations were low in most cases of VPA, PHT and PB except for one case of VPA which exceeded therapeutic limits, concentrations were within therapeutic levels in many cases of CBZ. Conclusion: When compared with normal controls, abnormal deliveries such as caesarian section were seen more frequently in epileptic mothers under AED treatment. In addition, infants in PB cases were shown to have significantly lower mean birth length, weight and head circumference, suggesting that PB may retard fetal growth. The incidence of malformation in cases of VPA, PHT, CBZ and PB, was 10.3%, 5.0%, 0% and 6.7%, respectively. There were five types of malformation: in VPA cases, spina bifida, Siamese twins and ventricular septal defect tended to be severe, while in PHT and PB cases, cor biloculare and hypospadias respectively were observed. In cases of VPA, serum levels in the umbilical cord were found to be 150% higher than those in the mother.     

Clinicopathological study of midbrain corectopia

A clinicopathological study was conducted in 19 cases (including 9 autopsied) of midbrain corectopia (oval pupil) occurring in the acute stage of cerebrovascular disorders. This ocular symptom manifested itself in conjunction with severe impairment of consciousness invariably in all instances, unilaterally in 11 and bilaterally in 8 cases, with the shape of the pupil and the direction of its displacement varying from case to case. In 17 cases, this patients died several hours to several days after the appearance of this sign. On autopsy were noted small hemorrhagic lesion of the upper mesencephalic tegmentum in 2 cases and conspicuous cerebral herniation in 7 cases. In this study, it was thought that all cases had diffuse lesions including nuclear, infra- and/or supra-nuclear parts of the midbrain. Clinicopathologically, it was difficult to define the corresponding lesion for corectopia. We suggested that this ocular symptom which appeared transiently was the sign of poor prognosis.     

A clinical study of testicular tumors

Fifty-eight of the 44,698 patients seen at our Department, between 1972 and 1984 had a testicular tumor. The incidence rate was 0.13%. The mean age of these 58 cases was 28.6 years and two peak distributions, one in the 0 to 5 year and another in 26 to 30 year age group were observed. Among them, 54 patients (93.1%) had chief complaints of painless testicular swelling at initial examination. The vast majority of them had unilateral tumors; 28 in the right and 29 in the left. Only one patient had bilateral seminomas. Histologically, 30 of them (51.7%) were seminoma, 8 were embryonal carcinoma (13.8%), 2 were teratoma (3.5%) and the remaining 18 had tumors of double or multiple histological type. Most of the seminomas were treated by a combination of high orchiectomy and radiotherapy, and chemotherapy was done mainly for non-seminomatous cases. The 5-year survival rate calculated by the Kaplan-Meier method was 100% for patients with low stage (I, II) seminomas and 62% for those with non-seminomatous tumors.