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.     

TNF-α, nitric oxide and IFN-γ are all critical for development of necrosis in the small intestine and early mortality in genetically susceptible mice infected perorally with Toxoplasma gondii

We previously reported that genetic susceptibility of mice to peroral infection with T. gondii is associated with CD4+ T cell-dependent, interferon (IFN)-gamma-mediated necrosis of their small intestine. We examined the role of tumour necrosis factor (TNF)-alpha and nitric oxide (NO), in addition to IFN-gamma. At 7 days after infection, a marked increase in CD4+ T cells was observed in lamina propria mononuclear cells (LPC) of the small intestine as compared with normal mice, and significantly greater amounts of mRNA for IFN-gamma, TNF-alpha, and inducible NO synthase (iNOS) were detected in LPC of the small intestine of infected than uninfected animals. Treatment of infected mice with anti-TNF-alpha monoclonal antibody (mAb) or the iNOS inhibitor, aminoguanidine, prevented necrosis and prolonged time to death. Infected iNOS-targeted mutant mice did not develop the disease whereas infected, control mice did. Treatment with anti-TNF-alpha mAb did not affect the expression of IFN-gamma in the LPC but inhibited expression of iNOS in the infected mice, indicating the role of TNF-alpha in the induction of iNOS. These results suggest that NO induced by a combination of IFN-gamma and TNF-alpha through activation of iNOS is a critical mediator of intestinal pathology and contributes to early mortality in genetically susceptible mice.     

Phase II Study of UFT in Patients With Advanced Non-Small Cell Lung Cancer

A phase II study of UFT (a mixture of uracil and tegafur; molarratio of uracil to tegafur = 4) was undertaken in 21 patientswith advanced non-small cell lung cancer (NSCLC). UFT was administeredorally at a dose of 400 mg/m² every day, for more than fourweeks. Of 16 adequately treated patients, one (6.3%) showed a partialresponse. Toxic effects included minimal myelosuppression, anorexia,nausea, vomiting and epigastralgia. Gastrointestinal toxicitywas well tolerated. Considering the poor response and mild toxicity,a further phase II study of higher-dose UFT is necessary forpatients without prior therapy.     

Beneficial Effects of Cervical Spinal Cord Stimulation (cSCS) on Patients with Impaired Consciousness: A Preliminary Report

Electrical stimulation of the spinal cord can be used for treatment of intractabie pain and spasticity. Based on our experimental findings cervical spinal cord stimulation (cSCS) was performed on eight patients with severe brain dysfunction due to traffic accidents, pronounced vasospasm caused by subarachnoid hemorrhage or surgery of huge cerebral tumors (chordoma). After a 1 to 2 month period of stimulation, two patients became conscious and began to speak. It remains unclear whether cSCS induced the restoration of consciousness and improved neurological deficits. Although the successful results might be due to chance, cSCS might have stimulated brain function. This preliminary report shows such excellent results that further studies are warranted.     

Pathogenesis of centrilobular necrosis following congestion of the liver

The exact pathogenesis of centrilobular necrosis following congestion of the liver is still unknown. We reviewed the clinical data related to systemic circulatory disturbance and histopathology of the liver and the gut in 320 autopsy subjects. Congestion of the liver alone was associated only with atrophy and loss of hepatocytes in centrilobular areas, but not with hepatocellular coagulative necrosis. In many patients with coagulative necrosis of centrilobular hepatocytes and congestion of the liver, fibrin thrombi and neutrophil infiltration in the sinusoids, which are the characteristic histopathological features of the liver in endotoxaemia, were found in and around the necrotic area. Congestion, erosion or haemorrhage of the intestinal mucosa, which may allow entrance of endotoxin into the liver through the portal vein, was seen in such patients. Prolonged hypotension or shock, which may lead to portal endotoxaemia, was present in half the patients with centrilobular necrosis and congestion of the liver. These results suggest that not only congestion of the liver but also portal endotoxaemia may be involved in the pathogenesis of centrilobular necrosis in patients with congestion of the liver.     

Structure-activity studies on C-terminal hirudin peptides containing sulfated tyrosine residues

To clarify the role of the negative charge of the C-terminal region of hirudin, we chemically synthesized the C-terminal peptide of hirudin variant-1 (HV-1), HV-1-(54-65), and its analogs, [E61Y,E62Y]HV-1-(54-65) and [E62Y]HV-1-(54-65), and then sulfated the Tyr residue(s) in these peptides by both enzymic and chemical methods. Enzymic O-sulfation of Tyr residues in the peptides by use of sulfotransferase isolated from Eubacterium A-44 allowed us to produce four kinds of the sulfated peptide, whose C-terminal sequences were -PEY(SO₃H)YLQ, -PYY(SO₃H)YLQ, -PYYY(SO₃H)LQ and -PYY(SO₃H)Y(SO₃H)LQ. On the other hand, all Tyr residues in the peptides were successfully sulfated by chemical reaction with N, N′-dicyclohexylcarbodiimide in the presence of sulfuric acid. Based on the analysis of structure-activity relationships of these sulfated peptides for thrombin inhibition, the Tyr62 and Tyr63 bisulfated peptide GDFEEIPEY(SO₃H)Y(SO₃H)LQ was found to be the most potent inhibitor of thrombin among the products tested. No increase in potency was observed by further substitution of Glu61 with Tyr(SO₃H). The inhibitory activity by substitution with Tyr(SO₃H) at position 63 was greater than that obtained by the substitution at position 62. © Munksgaard 1996.     

Experience of the treatment with gemcitabine, docetaxel, and carboplatin (GDC) chemotherapy for patients with small-cell carcinoma of the prostate

Small-cell carcinoma of the prostate (SCCP) is a rare entity. Many treatment modalities have been done, but thus far no uniform treatment has been clearly established. We carried out combination chemotherapy with gemcitabine, docetaxel, and carboplatin (GDC) regimen (for two patients with refractory SCCP. Case 1 involved a 53-year-old man diagnosed with SCCP after receiving hormone therapy for prostate cancer (stage D1). Six cycles of GDC chemotherapy was applied. Initially the primary site reduced according with a decline of neuro-specific enolase and with relief of the symptoms; however, bone disease occurred and he died of cancer 13 months after diagnosis of SCCP. Case 2 involved a 69-year-old man complaining of severe anal pain. He underwent a biopsy and a huge prostate tumor showing SCCP was showed. He had pelvic node metastases but no distant lesions, and received four cycles of GDC chemotherapy. He was discharged after receiving subsequent radiotherapy and remained stable for a while; however, he died of possible drug-induced hepatitis. This is the first report of chemotherapy with GDC against patients with SCCP. This regimen raised the possibility that it would intensify the outcome, which had been poorly achieved.     

Asthenozoospermia: Possible association with long-term exposure to an anti-epileptic drug of carbamazepine

Little attention has been paid to infertility in men with epilepsy and little information exists about the mechanisms by which anti-epileptic drugs affect spermatogenesis or sperm function. We report a case of a male infertility patient with asthenozoospermia during long-term treatment with anti-epileptic drugs. A 29-year-old man had continued treatment with anti-epileptic drugs under the diagnosis of epilepsy for 13 years. He and his wife had been examined and treated as an infertile couple for 3 years. The patient was found to have no motile sperm with a normal sperm count, while taking a dose of 400 mg/day of carbamazepine. On suspicion of an adverse effect of carbamazepine, he was switched to phenytoin monotherapy. One month after that, sperm motility was vastly improved (65%) and they conceived a child 5 months after that. One must be cautious in extrapolating from a case report, but these findings strongly suggest a direct effect of carbamazepine on spermatic function.     

Impact of adjuvant systemic chemotherapy on postoperative survival in patients with high-risk urothelial cancer

BACKGROUND: The objective of this study was to retrospectively investigate the effectiveness of adjuvant combination chemotherapy for locally advanced urothelial cancer. METHODS: Between 1987 and 1998, 56 patients with locally advanced bladder (n = 27) or upper urinary tract (n = 29) cancer (pathological stage T3, T4 or N1, N2 and M0) were treated by radical cystectomy or radical nephroureterectomy and regional lymphadenectomy. Thirty-one patients had lymph node-positive disease and 25 patients did not. Twenty patients underwent adjuvant chemotherapy and 36 patients were observed after surgery. Cox proportional hazards models were used to determine the impact of numerous clinicopathological findings on survival. A subgroup analysis of patients with lymph node-positive disease was conducted to evaluate disease-free survival and overall survival rates. RESULTS: In this series, the median follow-up period was 39 months (range, 4-163) after surgery. Disease-free and overall survival rates of all 56 patients were 45% and 58%, respectively, at 3 years. Only lymph node status was significantly associated with disease-free and overall survival in the multivariate analyses. In a subgroup analysis of patients with lymph node-positive disease, 16 patients who underwent adjuvant chemotherapy had superior disease-free survival compared to 15 patients with no adjuvant chemotherapy (P = 0.0376). CONCLUSION: These findings show that the prognosis of advanced urothelial cancer is significantly associated with nodal status. Furthermore, adjuvant combination chemotherapy has a positive impact on survival in patients with lymph node-positive disease.