Up-Regulation by Cyclosporine (CsA) of the In Vitro Release of Soluble CD23 (sCD23) and of the In Vitro Production of IL-6 and IgM

In the present study, we examined the effect of CsA on the in vitro production of Ig and on the in vitro production of molecules known to have B-cell growth and differentiation activities, such as IL-6 and sCD23. For the purpose of this study, we developed an experimental In vitro system closely resembling an In vivo model of ongoing B-cell activation. Pre-activated B cells proliferated and produced IgM optimally when they were re-cultured in the presence of IL-2/IL-6. CsA down-regulated the IL-2/IL-6-induced proliferative responses of pre activated B cells by at least 50%., but it up-regulated IgM production in the same experiments. This up regulating effect was not cytokine-related since it was also seen when cells were re-cultured in the absence of any cytokines. Optimal release of sCD23 was observed when SAC-pre-activated B cells were re cultured in the presence of IL-4 or IL-4 plus IL-2 and CsA up-regulated significantly the release of this molecule in these cultures. Finally, CsA was shown to inhibit PHA-induced cell proliferation of PBMC and to up-rcgulate IL-6 production in the same cultures. We conclude that CsA can amplify in vitro both the production of Ig and the release of sCD23 by pre activated B cells. This finding, in combination with the CsA-induced up-regulation of lectin-induced IL-6 production, may have clinical implications in disease states with an ongoing immune activation, where prolonged administration of CsA might be anticipated.     

Monoclonal antibody analysis of glomerular, tubulo-interstitial infiltrating immune cells in various glomerulonephritis

To investigate the role of cell-mediated immunity (CMI) in glomerulonephritis (GN), we identified the infiltrating immune cells both within the glomerulus and in the interstitium. Frozen sections from 103 patients with various forms of GN: 10 with minor glomerular abnormality (MGA) as control, 10 with minimal change nephrotic syndrome (MCNS), 10 with membranous nephropathy (MN), 9 with focal glomerulosclerosis (FGS), 30 with IgA nephropathy (IgAN), 22 with acute post streptococcal glomerulonephritis (APSGN), and 2 with rapidly progressive glomerulonephritis (RPGN) were examined using monoclonal antibodies (MoAb) by indirect immunoalkaline-phosphatase labelling. In most glomerulonephritis, monocyte/M phi and helper/inducer T cells were predominantly infiltrating in the interstitium, but intraglomerular infiltration was rare, except for APSGN. This interstitial infiltration increased proportionally to the level of serum creatinine, and was most prominent in RPGN. Apparently different distribution was seen in APSGN, that is, prominent increase in total number of intra-glomerular monocyte/M phi infiltration with slightly increased T cells. The change was correlated with time after onset; namely the more leucocytic infiltration was observed when the tissue was taken earlier. These data suggest that in APSGN, monocyte/M phi accumulate in glomeruli via cell mediated immunity in addition to humoral immune mechanism resulting in glomerular hypercellularity, whereas in most chronic glomerulonephritis interstitial leucocyte infiltration, particularly helper T cells and monocyte/M phi may play an important role in the progression of glomerulonephritis.     

The experimental pharmacotherapy of the liver lesion induced by indomethacin

In experiments on albino rats it was established that three administrations of indomethacin in a dose of 0.01 g/kg body weight induced a severe damage of the liver characterized by disturbances of hepatocytic membranes, bile-producing and protein-producing functions of the liver, an enhancement of lipid peroxidation, a decrease of reduced glutathione pool. Antioxidants (tocopherol acetate, essentiale, legalon, flacumin) limit manifestations of indomethacin, hepatotoxicity, as a result of which tha functional-biochemical disorders in the liver show up to a lesser degree. During the combined use of antioxidants in indomethacin-induced lesions of the liver their hepatoprotective activity increases.     

A chemically defined medium for the culture of mature oligodendrocytes

A new chemically defined medium consisting of equal parts of Dulbecco modified Eagle's and Ham's F-12 media supplemented with insulin, sodium selenite, putrescine, and D+ galactose, which allows the long-term survival of mature oligodendrocyte pure cultures, is described. Immunohistochemical staining has shown that over 90% of the cells become positive for myelin proteins shortly following subculture. Contaminating astrocytes (2%) do not survive in this medium. Biochemical data have indicated that these purified oligodendrocytes express 2'3'-cyclic nucleotide 3'-phosphohydrolase and UDP-galactose ceramide galactosyltransferase activities. Electron microscopical examination revealed that the oligodendrocytes were mostly of medium-dark type and appeared to be identical to cells cultured in serum-containing medium. The ability to maintain pure oligodendrocyte cultures in such a defined medium will allow investigations concerning exogenous and endogenous factors involved in oligodendrocyte metabolism.     

Reduction of reticulata neuronal activity by zolpidem and alpidem, two imidazopyridines with high affinity for type I benzodiazepine receptors

Zolpidem and alpidem, two imidazopyridines with high affinity for the type I benzodiazepine recognition site, have recently been proposed as preferential hypnotic (zolpidem) and anxiolytic (alpidem) drugs notable for the minor incidence of side-effects. To further characterize the molecular mechanism involved in the action of these drugs, we studied their effects in comparison with those of diazepam on the spontaneous electrical activity of substantia nigra pars reticulata (SNR) neurons. These cells have been shown to be extremely sensitive to various positive and negative modulators of GABAergic transmission. All three drugs consistently produced a dose-dependent (0.03-8.0 mg/kg i.v.) inhibition of the firing of SNR cells when administered as a single bolus. However, zolpidem was more potent and efficacious than diazepam or alpidem. The ID50s were 0.076, 0.492 and 0.821 mg/kg, respectively. When the drugs were injected in exponentially (ratio 2) increasing doses up to 8.0 mg/kg, the rank order for tachyphylaxis was zolpidem much greater than diazepam greater than alpidem. Since the effects of the drugs were abolished and prevented by a small dose (0.5 mg/kg i.v.) of flumazenil (Ro 15-1788), it is likely that the effects were mediated through activation of benzodiazepine receptors. The results indicate that the hypnotic, zolpidem, has a more potent inhibitory action on SNR cell activity than the anxiolytics, alpidem and diazepam.     

Pharmacological studies of 6-amidino-2-naphthyl 4-[(4,5-dihydro-1H-imidazol-2-yl)amino]benzoate dimethanesulfonate. Effects on experimental pancreatitis

The effects of FUT-187 (6-amidino-2-naphthyl 4-[(4,5-dihydro-1H-imidazol-2-yl)amino]benzoate dimethanesulfonate, CAS 103926-82-5), a novel synthetic protease inhibitor, were examined in experimental rat and canine models of pancreatitis. 1. FUT-187 significantly increased the survival of rats with trypsin- and phospholipase A2-induced pancreatitis in a dose-dependent manner (10-100 mg/kg, p.o.). 2. FUT-187 decreased plasma enzymatic activity reflecting the degree of pancreatitis in rats with ethionine-induced pancreatitis, and showed a tendency to ameliorate histopathological changes in the pancreas (10-100 mg/kg p.o.). 3. FUT-187 (10 mg/kg) produced an obvious improvement of various biochemical parameters of pancreatitis and also reduced histopathological changes in the pancreas in animals with experimental pancreatitis produced by the closed duodenal loop method. In addition, FUT-187 significantly increased the survival of dogs when given by direct administration into the lumen of the closed duodenal loop. The therapeutic effects of FUT-187 in experimental pancreatitis were nearly equal in most instances to those of camostat mesilate. Thus, FUT-187 would appear to be an effective new agent for the treatment of pancreatitis.     

A case of a small hepatoma with multicentric development in precirrhotic fibrosis

Multicentricity of hepatocellular carcinoma (HCC) is considered, especially in patients with liver cirrhosis. This paper describes an operative case of a male patient with probable multicentric development of HCC in precirrhotic fibrosis. The main tumors inside the capsule were completely necrotic due to transarterial embolization (TAE). Histologic examination disclosed discrete tiny nodules of HCC that were not detected grossly. They showed highly differentiated trabecular arrangements: Edmondson I. A scirrhous type was noted in the center of the tumors. At the borders of the tumors the carcinoma cells exhibited replacing growth patterns and it was thought that they developed multicentrically. Partial resection must be performed as extensively as possible in a case such as the present one.     

Population screening and referral for hypercholesterolemia

To determine the potential effect of screening on referral patterns, an adult population sample (4,404 men, 5,164 women, 20-69 years of age) was systematically recruited and screened for hypercholesterolemia and then analyzed by different cholesterol referral recommendations. Using levels suggested by the Lipid Research Clinics Coronary Primary Prevention Trial (greater than or equal to 265 mg/dL), 7.3% of men and 5.8% of women would be referred for follow-up. With the suggested recommendations of the National Cholesterol Education Program (NCEP), (greater than or equal to 200 mg/dL), 49.2% of men and 40.2% of women would be referred. The use of age-related definitions of the NIH Consensus Conference on Lipid Lowering results in 28.0% referrals in men and 21.8% in women. From this population, hypercholesterolemia subjects (greater than or equal to 265 mg/dL at screening; n = 624) were invited for a second cholesterol determination (58% returned), which found 36% below the 265 mg/dL level. Population screening for cholesterol is likely to produce large numbers of patients for follow-up, with the actual numbers strongly dependent on cutoff levels and age-sex distributions. Referral and follow-up of these patients may place a significant load on an unprepared health care community.