Fas-independent and nonapoptotic cytotoxicity mediated by a human CD4(+) T-cell clone directed against an acute myelogenous leukemia-associated DEK-CAN fusion peptide

The mechanism underlying the cytotoxicity mediated by a human CD4(+) cytotoxic T-lymphocyte (CTL) clone directed against a peptide derived from the acute myelogenous leukemia-associated fusion protein, DEK-CAN, was investigated. A DEK-CAN fusion peptide-specific CD4(+) Th0 CTL clone, designated HO-1, was established from the peripheral blood lymphocytes of a healthy individual. HO-1 exerted direct but not "innocent bystander" cytotoxicity within 2 hours. The cytotoxicity mediated by HO-1 was completely Ca2+-dependent. Because HO-1 lysed peptide-loaded Fas-deficient target cells derived from a patient with a homozygous Fas gene mutation, its cytotoxicity appeared to be mediated by a Fas-independent pathway. In addition, its cytotoxicity was only partially inhibited by treatment with concanamycin A and strontium ions, which are inhibitors of the perforin-based cytotoxic pathway. Although membrane-bound type of tumor necrosis factor-alpha (TNF-alpha) was expressed on HO-1, an anti-TNF-alpha antibody had no effect on HO-1-mediated cytotoxicity. HO-1 expressed mRNA for apoptosis-inducing mediators, including perforin, granzyme B, Fas ligand, TNF-alpha, and lymphotoxin; however, no DNA fragmentation was detected in target cells incubated with HO-1 by 5-[125I]Iodo-2'-deoxyuridine release assay and agarose gel electrophoresis of DNA. Although it has been suggested that the Fas/Fas ligand system is the main pathway by which CD4(+) CTL-mediated cytotoxicity is exerted in murine systems, HO-1 produced peptide-specific and HLA-restricted cytotoxicity via a Fas-independent and nonapoptotic pathway. The present study thus describes a novel mechanism of cytotoxicity mediated by CD4(+) CTL.     

Serotonin inhibits the induction of long-term potentiation in rat primary visual cortex

1. The effect of serotonin (5-hydroxytryptamine; 5-HT) on the induction of long-term potentiation (LTP) in rat visual cortex was investigated by using slice preparations in vitro. 2. Bath application of 5-HT (0.1-10 microM) did not affect the baseline synaptic potentials evoked by single-pulse test stimulation, but inhibited the induction of LTP in a concentration-dependent manner. 3. The effect of 5-HT was blocked by the 5-HT1 receptor antagonist pindolol or the 5-HT2,7 receptor antagonist ritanserin, but not by the 5-HT3,4 receptor antagonist MDL72222. 4. These results suggest that 5-HT plays a role in suppressing the induction of LTP in the rat visual cortex.     

Modeling Party Support of Japanese Voters in the Early 1996

This article investigates factors that influenced Japanese voters in the early 1996 in determining which political party to support. Proportional-odds model, a model which retains ordinal nature of political hues or ideologies of the Japanese political parties, is fitted to the data. Samples with answers “I do not know” to the questions are treated as missing. The EM algorithm enables us to incorporate the samples with missing-values. We found that determining which party to support is a purely political decision for Japanese voters based solely on their ideologies and attitude towards the current cabinet, not to be influenced by their geographical profiles nor financial situations. Missing-value problem were found not to be ignored in the sense that marginally significant or insignificant explanatory variables can easily turn otherwise when the same model is fitted only for the data with no missing-values.

     

Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in HTLV-I-associated myelopathy

Matrix metalloproteinases (MMPs) have been reported to be involved in inflammatory disorders of the central nervous system (CNS). However, little is known about the role of MMPs in the pathogenesis of HTLV-I-associated myelopathy (HAM)/Tropical spastic paraparesis (TSP). To address this issue, we examined the tissue expression and localization of MMPs and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs) in the spinal cord lesions of HAM/TSP using immunohistochemistry. In addition, the blood and cerebrospinal fluid (CSF) levels of MMPs and TIMPs of the patients with HAM/TSP were determined using sandwich enzyme immunoassays (SIA) and gelatin zymography. Immunohistochemical studies revealed that collagen IV and decorin immunoreactivity on the basement membrane of CNS parenchymal vessels was partially disrupted where inflammatory mononuclear cells infiltrated in active-chronic lesions of HAM/TSP. In these lesions, MMP-2 (gelatinase A) was immunostained mainly on the surface of foamy macrophages and lymphocytes, whereas MMP-9 (gelatinase B) expression was positive in the intravascular and perivascular mononuclear cells but not on foamy macrophages. In contrast, inactive chronic lesions of the spinal cords of the HAM/TSP contained fewer MMP-2-positive or MMP-9-positive mononuclear cells than active-chronic lesions. Many parenchymal vessels had thickened vascular walls which showed increased immunoreactivity to decorin. SIA revealed that production levels of MMP-2 and MMP-9 in both blood and CSF were higher in the patients with HAM/TSP than those in non-inflammatory other neurological disease controls (ONDs). Using zymography, proMMP-9 was detected more frequently in the CSF of patients with HAM/TSP than those in ONDs. Taken together, our data indicate that MMP-2 and MMP-9 may play an important role in the blood-brain barrier breakdown and tissue remodeling in the CNS of HAM/TSP.     

Use of bronchopulmonary lavage for eliminating inhaled fume particles from a patient with arc welder's lung

A 42-year-old man, who had worked as a welder for 20 years, was admitted to our hospital complaining of a dry cough. A chest radiograph showed diffuse small nodular shadows and chest computed tomography revealed small patchy opacities. A transbronchial lung biopsy specimen showed welding fume particles mainly located in alveolar space with mild fibrosis of alveolar septa. In order to prevent further fibrosis, bronchopulmonary lavage (BPL) was performed to eliminate the fume particles. The amount of iron particles derived from the total lavage fluid was 911.7 mg.     

Experimental glaucoma model in the rat induced by laser trabecular photocoagulation after an intracameral injection of India ink

A combined hemostatic defect consisting of a reduction in certain procoagulants, anticoagulants (antithrombin III-ATIII-, protein C-PC-) and components of the fibrinolytic system (plasminogen-Plg-) was demonstrated in very-low-birth-weight infants (VLBW <1,500 g) with gestational age 26-32 weeks. Sixteen of them were healthy, 28 were suffering from RDS and 24 from septicemia. The hemostatic defect was more profound in the RDS group, nevertheless increased TAT (thrombin + ATIII complex) and/or PAP values (plasmin + a2-antiplasmin complex) was a more frequent finding in the septicemic group of infants (91.8 vs. 17.9%). Moderate-to-severe thrombocytopenia was detected in a higher percentage in the septicemic (70.8%) than in the RDS group (50%), and increased D-dimers were demonstrated in 34.8 and 28.6% of the infants, respectively. Elevated TAT or PAP values were not always associated with gross coagulation abnormalities, and advanced disseminated intravascular coagulation (DIC) was only documented in 16.7% of the septicemic and 7.1% of the RDS infants. None of the VLBW neonates presented with clinical evidence of thrombosis, although hemorrhagic manifestations were apparent in 34.8 and 14.3% of the neonates with septicemia or RDS, respectively, mainly due to DIC or severe thrombocytopenia. In conclusion, increased TAT and/or PAP values are good indicators of the in vivo activation of the hemostatic system, but still their impact on sick neonates morbidity and mortality remains unknown.     

ONO-5046 is a potent inhibitor of neutrophil elastase in human pleural effusion after lobectomy

The imbalance of neutrophil elastase and alpha1-antitrypsin in pleural effusion after lobectomy and the effects of the neutrophil elastase inhibitors, sodium N-[2-[4-(2,2-Dimethylpropionyloxy)phenyl-sulfonylamino]benzo yl]aminoacetic acid (ONO-5046) and purified alpha1-antitrypsin, on neutrophil elastase activity were determined. The amount of neutrophil elastase complexed to alpha1-antitrypsin, measured by an enzyme-linked immunosorbent assay, was 170 times higher in pleural effusion than in blood 3 h after lobectomy. The alpha1-antitrypsin levels measured by laser nephelometry did not increase in either blood or pleural effusion. Although neutrophil elastase activity, measured by the hydrolysis of succinyl-(Ala)3-p-nitroanilide, was not detected in blood, it was increased in pleural effusion 3 h and 24 h after lobectomy. ONO-5046, but not alpha1-antitrypsin, reduced the neutrophil elastase activity in pleural effusion. There is an imbalance of neutrophil elastase and alpha1-antitrypsin in pleural effusion after lobectomy. ONO-5046 is a potent inhibitor of neutrophil elastase activity in human pleural effusion.