Inhibitory Effect of MK-801 on Amantadine-Induced Dopamine Release in the Rat Striatum

In the present study, we examined the effect of amantadine on extracellular dopamine levels in the rat striatum using an in vivo microdialysis. Perfusion of amantadine (0.1–1 mM) through the microdialysis probe caused an increase both in extracellular dopamine and glutamate levels in rat striatum. Amantadine was found to increase extracellular dopamine concentration in Ca²⁺-dependent manner, but the effect was not abolished by ω-conotoxin. Although intraperitoneal administration of MK-801 [(+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)cyclohepten-5,10-imine] alone could not significantly alter the concentration of dopamine, it attenuated amantadine-induced increase in dopamine level. These findings suggest that an interaction between dopaminergic and glutamatergic neurotransmission is an important component in the regulation of striatal dopamine levels. Copyright © 1996 Elsevier Science Inc.     

Modulation of Fas-mediated apoptosis of human thyroid epithelial cells by IgG from patients with Graves' disease (GD) and idiopathic myxoedema

The expression of two autoimmune thyroid diseases, GD and idiopathic myxoedema, is associated with antibodies to the thyroid-stimulating hormone (TSH) receptor. Thyroid stimulating antibodies (TSAb) in GD are TSH agonists and cause hyperthyroidism as well as goitre, whereas thyroid stimulation blocking antibodies (TSBAb) in idiopathic myxoedema are TSH antagonists and cause hypothyroidism and thyroid atrophy. We investigated the effect of antibodies to TSH receptor on Fas-mediated apoptosis of thyroid epithelial cells (thyrocytes). Human IgG was isolated from healthy donors, patients with GD and idiopathic myxoedema. Human thyrocytes were obtained from surgical specimens. Thyrocytes were cultured in the presence or absence of human IgG with or without interferon-gamma (IFN-γ) or IL-1β for a specified time. After incubation, we examined the level of cAMP in cultured supernatants and both Fas and Bcl-2 expression on thyrocytes. In addition, we examined anti-Fas-mediated apoptosis of thyrocytes. Fas expression on thyrocytes was significantly down-regulated by Graves' IgG and TSH, although idiopathic myxoedema IgG did not affect Fas expression on thyrocytes. Idiopathic myxoedema IgG abrogated the effect of TSH on both cAMP production and inhibition of Fas expression on thyrocytes. Treatment of thyrocytes with IL-1β or IFN-γ caused a marked augmentation of Fas expression on thyrocytes. The increase of Fas expression of thyrocytes induced by IL-1β or IFN-γ was significantly suppressed in the presence of TSH or Graves' IgG. Anti-Fas-induced apoptosis of thyrocytes was observed in thyrocytes treated with IL-1β or IFN-γ, but was markedly inhibited in the presence of TSH or Graves' IgG. Furthermore, idiopathic myxoedema IgG abrogated most of the inhibitory effect of TSH on Fas-mediated apoptosis of thyrocytes treated with IL-1β or IFN-γ. Bcl-2 expression of thyrocytes did not change after stimulation with TSH, Graves' IgG, idiopathic myxoedema IgG, IL-1β or IFN-γ. These results suggest that TSAb found in Graves' patients may be potentially involved in the development of goitre by inhibition of Fas-mediated apoptosis of thyrocytes. In addition, TSBAb inhibit the action of TSH and increase the sensitivity toward Fas-mediated apoptosis of thyrocytes, inducing thyroid atrophy seen in patients with idiopathic myxoedema.     

International cooperation with Islamabad Children's Hospital,Pakistan: The JICA project

The experience gained during 7 years of cooperation between the Japan International Cooperation Agency (JICA) and the Islamabad Children's Hospital (JICA-ICH project, July 1986-June 1993) is described. Islamabad Children's Hospital achieved the goals of the project and became a centre for excellence in health care, education and research for children, fulfilling the objectives of the project. This achievement was evaluated as one of the most successful projects in medical cooperation ever performed by JICA by a third party evaluation team. The problems arising and the lessons experienced through the process are discussed. The importance of the role which should be undertaken by pediatricians in international cooperation with developing countries is emphasized.     

Synovial cells are potent antigen-presenting cells for superantigen,staphylococcal enterotoxin B (SEB)

There is ample evidence suggesting that superantigens may act as a triggering factor in the pathogenesis of rheumatoid arthritis (RA). We investigated whether superantigen could activate T cells in the presence of synovial cells. T cells were cultured with SEB in the presence of interferongamma (IFN-γ)-treated synovial cells. T cell proliferation and activation were assessed by ³H-thymidine incorporation and IL-2 production. The expression of HLA class II antigens and adhesion molecules on synovial ceils was detected by flow cytometer. In the presence of IFN-γ-treated synovial cells, T cells proliferated vigorously and produced IL-2 in response to SEB. A low SEB-induced T cell response was noticed in the presence of untreated synovial cells. Allogeneic as well as autologous IFN-γ-treated synovial cells markedly enhanced SEB-induced T cell proliferation. IFN-γ-treated synovial cells had increased expression of HLA class II antigens and intercellular adhesion molecule-1 (ICAM-1) adhesion molecules. MoAbs towards these antigens markedly inhibited the SEB-induced T cell response. These results indicate that activated synovial cells are potent antigen-presenting cells for SEB to T cells, and that superantigens may play a critical role in the pathogenesis of RA through activated synovial cells.     

METHIMAZOLE-INDUCED AGRANULOCYTOSIS IN JAPANESE PATIENTS WITH GRAVES'' DISEASE

We reviewed the records of approximately 7000 Japanese patients whose hyperthyroidism was treated with methimazole (MMI) alone. Four patients (Group I) developed agranulocytosis during a second course of MMI therapy and eight patients (Group II) during an initial course. Six patients (three in each group) received less than 30 mg MMI daily. Agranulocytosis occurred after more than 2 months of therapy (12 weeks-1 year) in five patients. Seven patients were less than 40 years of age. One patient displayed a gradual protracted development of agranulocytosis. These results indicate that agranulocytosis after MMI may occur irrespective of dose, age, duration of treatment, and with a second exposure.     

Plasma endotoxin concentration and endotoxin binding capacity of plasma acute phase proteins in cirrhotics with variceal bleeding: An analysis by new methods

Plasma endotoxin levels in 12 cirrhotics with bleeding from oesophageal varices and 50 cirrhotics without bleeding were measured by the chromogenic assay after the pretreatment of sample by perchloric acid (HClO₄) and triethylamine. Endotoxin in cirrhotics with bleeding from varices was significantly higher than those without bleeding. In patients with bleeding, endotoxin increased for 3 days after the bleeding, first in the supernatant fraction and then in the precipitate fraction by HClO₄ treatment. Peak plasma α₁-acid glycoprotein and haptoglobin were observed 3 days after the bleeding. Alpha 1-antitrypsin gradually increased for 14 days. Transferrin did not markedly change. The endotoxin-binding capacity of transferrin and α₁-acid glycoprotein increased immediately after bleeding and thereafter decreased, but that of α₁-antitrypsin tended to increase in the recovery period. In summary, the plasma endotoxin concentration and endotoxin-binding capacity of α₁-acid glycoprotein and transferrin were shown to have increased after bleeding from varices by this new method. There may be a close relationship between endotoxaemia and acute phase reaction in this situation.     

Association between activity level and changes in bodyweight in dementia patients

Introduction: Bodyweight is routinely used as an important health assessment measure in care facilities. Recently, the integrated circuit (IC) tag monitoring system became available for measuring the distance walked by patients with dementia (PsWD) over an extended period. The main objective of the present study was to examine an association between the distance walked and changes in bodyweight in PsWD. Methods: Monitoring was conducted in a semi‐acute dementia care unit in Japan between November 2006 and March 2007. All patients had been diagnosed with dementia and were able to walk independently. Demographic and food intake data were obtained from medical records. Bodyweight was measured weekly. The monitoring system calculated the distance walked. The study was approved by the Ethics Committees of Osaka University and Asakayama Hospital and written informed consent was obtained from authorized proxies. Results: In total, 23 patients were monitored. The median distance walked per day for all subjects was 1042.7 m (range 136–7781m) and the mean rate of weight change per month was ?0.1 kg (range ?1.5 to 2.4 kg). The mean food intake per day was 97 ± 5% (range 79–100%). There was a significant negative correlation between median distance walked per day and rate of weight change per month (r = ?0.52; P < 0.05). Distance walked per day was divided into three groups (<1 km, 1–2 km and ≥ 2 km), but there was no change in mean food intake between the three groups. However, PsWD who walked ≥ 2 km/day tended to have higher total Neuropsychiatric Inventory–Nursing Home Version (NPI‐NH) scores and a higher number of symptoms than those who walked < 2 km/day. The former tended to have aberrant motor activity compared with the latter. Conclusion: The present study shows that the distance walked per day seems to play a major role in weight change. Because the IC tag monitoring system can measure the distance walked accurately over an extended period, it could be used to estimate the calorie expenditure for each patient and to reduce the various risks related to weight loss.     

Inhibitory effect of clarithromycin on costimulatory molecule expression and cytokine production by synovial fibroblast-like cells

This study was undertaken to investigate the immunomodulatory effect of clarithromycin against synovial fibroblast-like cells (synoviocytes). Synovial tissue obtained from rheumatoid arthritis (RA) or osteoarthritis (OA) patients was enzymatically digested to separate synoviocytes. The synoviocytes were cultured with or without cytokines in the presence of various concentrations of clarithromycin. The expression of costimulatory molecules was examined on the surface of the synoviocytes, using specific MoAbs and flow cytometry. The production of cytokines by synoviocytes was also measured using an immunoenzymatic assay. Finally, autologous T cells were stimulated by interferon-gamma (IFN-γ)-treated synoviocytes in response to purified protein derivative (PPD). In some experiments, MoAbs specific for costimulatory molecules or clarithromycin were added and ³H-thymidine incorporation was counted. Intercellular adhesion molecule-1 (ICAM-1), LFA-3 and vascular cell adhesion molecule-1 (VCAM-1) were detected on the surface of both RA and OA synoviocytes. However, ICAM-2, B7–1 and B7–2 were not detected, and cytokines failed to induce these molecules. Both spontaneous and up-regulated expression of ICAM-1, LFA-3 and VCAM-1 by IFN-γ, IL-1β or 12-o-tetradecanoyl phorbol 13-acetate (TPA) were markedly suppressed by clarithromycin in a dose-dependent manner at concentrations between 0.1 and 10 μg/ml. The production of IL-1β, IL-6, IL-8, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) but not IL-1α and tumour necrosis factor-alpha (TNF-α) by synoviocytes was detected. Clarithromycin significantly suppressed the production of these cytokines, but did not enhance IL-10 production. Finally, autologous T cells were stimulated by IFN-γ-treated synoviocytes in response to PPD. As clarithromycin suppressed HLA-DR and costimulatory molecule expression was enhanced by IFN-γ, autologous T cell proliferation was markedly inhibited by clarithromycin. Clarithromycin has a considerable immunosuppressive effect on synoviocytes by inhibiting costimulatory molecule expression, cytokine production and antigen-specific T cell proliferation induced by synoviocytes.