Forty-two patients with severe infection were treated with direct hemoperfusion (DHP) using polymyxin B immobilized fiber column (PMX) . Thirty-eights out of 42 suffered MOF. DHP was performed for 2 hours via femoral vein with double lumen catheter.
Blood endotoxin level was high in 35 patients, and in these patients were cured 19/35 (54%), but 3/8 (38%) in the patients with normal endotoxin level. The patients with pathogenic bacteria were cured 20/31 (61%), but patients without cultured bacteria showed significantly lower survival rate (23%) .
Blood endotoxin levels significantly decreased between the inlet and the outlet of column.
Cardiovascular parameter (blood pressure, C.I SVR, VO₂I) and body temperature were significantly improved after DHP in the patients with abnormal values.
PMX therapy on the MOF patients with systemic inflammatory response syndrome due to infection was demonstrated to be effective.

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Osteoporosis, especially the juxtaarticular osteoporosis of involved joints is characteristic to rheumatoid arthritis (RA) . Histomorphometric studies suggest the existence of increased bone turnover in RA: impaired bone formation and hightened osteoclastic bone resorption. Recent studies show that important mediators in the pathogenesis of RA, such as prostaglandin E, interleukin 1 (IL-1) or tumor necrosis factor α (TNF α), are also important in the bone remodelling and, more importantly, the signal transduction mediated by these IL-1 or TNF α is tightly associated with the activation of c-fos gene and related AP 1 regulated gene expression.
We have shown that constitutive expression of c-fos gene in transgenic mice results in the joint destruction solely by the synovial mesenchymal cells. A transfection study shows that constitutive expression of c-fos gene in rheumatoid synovial cells supports the growth and morphological transformation of these cells. Because c-fos expression is indeed enhanced in rheumatoid synovia, we studied the effects of c-fos on MC3T3-E1 osteoblasts by the transfection technique. The results show that the percent collagen synthesis as well as type I collagen mRNA expression was significantly depressed in c-fos-expressing transfectants. The culture supernatants of c-fos-expressing osteoblasts significantly enhanced the generation of mature osteoclasts from precursor cells and facilitated osteoclastic bone resorption as examined with the pit formation technique.
The results therefore suggest that constitutive expression of c-fos DNA facilitates synovial cell growth and interferes with bone formation by inhibiting collagen synthesis in osteoblasts and bone resorption by osteoclasts, and in this way a reminiscent feature to human RA is experimentally reproduced.

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We synthesized lecthinized superoxide dismutase (PC-SOD), recombinant human SOD covalently bound to a lecithin derivative. Next, we studied the pharmacological effect of PC-SOD and the mechanism of that.
PC-SOD inhibited the Forssman antiserum-induced respiratory resistance which is known to induce via actions of O₂- at a dose of 100-1, 000 U/kg, whereas unmodified SOD did not.
PC-SOD was more effective at 2.8 fold in inhibiting the superoxide generation of neutrophils than unmodified SOD. Superoxide generation of neutrophils washed after incubation with PC-SOD for 1 hr was inhibited but not with unmodified SOD.
These data suggest that PC-SOD protects lung injury by Forssman antiserum in guinea pigs by binding to neutrophils. PC-SOD would be expected as a useful drug delivery system preparation for SOD.

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In order to clarify the mechanism of pathophysiology of renal damage due to viral infection, we measured generation of superoxide anion (O^-₂) in isolated rat glomeruli under basal conditions, and also under inoculation with inactivated or live cox-sackievirus B4 (Cox. B4, 10² TCD₅₀/0.1 ml) in the presence of phytohemagglutinin (PHA) or concana-valin A (Con A) as a stimulant. Release of O^-₂from isolated rat glomeruli was determined spectroscopically on the basis of SOD-inhibitable reduction of ferricytochromec.
Generation of O^-₂stimulated by PHA or Con A was increased, and was dose-dependant. Live Cox. B4 enhanced O^-₂generation in isolated rat glomeruli, while inactivated Cox. B4 did not. Furthermore, O^-₂generation in isolated rat glomeruli cultured with live Cox. B4 for 24 hours was more increased than with only medium under stimulation with PHA.
These results suggest that the enhancement of O^-₂generation during Cox. B4 infection is an important factor in the pathophysiology of renal damage due to viral infection.

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Zaltoprofen, a novel nonsteroidal anti-inflammatory drug (NSAID), shows potent anti-inflammatory, analgesic and anti-pyretic effects. Although gastrointestinal dysfunction is a common side effect of NSAIDs, effects of zaltoprofen on the gastric functions have not yet fully clarified. In the present study, we report the effect of zaltoprofen on gastric blood flow (GBF) and on capacity to generate prostaglandin E₂ (PGE₂) in gastric mucosa of the rat. zaltoprofen (1 and 10 mg/kg, i.v.) showed no effect on the GBF, which was measured by the laser Doppler method. On the other hand, loxoprofen Na (1 mg/kg, i.v.) and diclofenac Na (10 mg/kg, i.v.) significantly decreased the GBF. Moreover loxoprofen Na (1 mg/ kg, p.o.), diclofenac Na (1 mg/kg, p.o.) and indomethacin (1 mg/kg, p.o.) significantly inhibited the gastric mucosal generation of PGE₂, which was measured by the radioimmunoassay method. On the contrary, zaltoprofen (1 mg/kg, p.o.) did not inhibit the PGE₂generation.
These results suggest that zaltoprofen may not cause marked gastric dysfunction comparing with loxoprofen Na, diclofenac Na and indomethacin. This characteristic of zaltoprofen may be beneficial for long-term use for therapy of chronic inflammatory diseases such as rheumatoid arthritis.

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We have studied levels of interleukin 6 (IL-6) in the cerebrospinal fluid (CSF) from children with aseptic meningitis, using an enzyme-linked immuno-sorbent assay. We have also studied whether cells in the CSF can produce IL-6 in vitro. The patients' CSF contained significantly higher levels of IL-6 than those of the controls, during the first two days of the illness. However, after the first two days, the IL-6 titer rapidly decreased, even in patients who had clinical symptoms of meningitis. Furthermore, when CSF mononuclear cells in the acute phase were cultivated for 24 hours, the culture supernatant contained IL-6. But we did not detect IL-6 in the patients' sera at the initial stage of the disease. IL-6 levels in the CSF correlated with both the number of cells in the CSF and the highest body temperature within the first two days of the illness.
These observations demonstrate that the IL-6 concentration of the CSF increases at the initial stage of aseptic meningitis, and that the IL-6 is derived, at least in part, from the CSF mononuclear cells.

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We have reported that the presence of a specific type of myeloid cell was found in the epiphyseal bone marrow of affected joints from patients with active severe rheumatoid arthritis (RA) .
In the bone marrow of 38 patients with RA involving three kinds of disease subset 10 least erosive (LES), 18 more erosive (MES), 10 mutilating disease (MUD), the absolute number of iliac pan-myelocytes (CD15⁺CD16^-cells) was 288/mm³, 528/mm³and 801/mm³ (median), respectively. These values were significantly increased as compared with 7 healthy subjects in whom CD15⁺CD16^-cells were 153/mm³ (P<0.01 for MES and MUD) but LES was not. And there was a marked correlation (γ_s=0.476 P < 0.05) between percentage of CD15⁺CD16^-cells in the affected tibial bone marrow and iliac bone marrow of RA. Furthermore, a higher percentage of iliac CD8-positive T-lymphocytes expressed HLA-DR (30.5%) from patients with RA than did those from normal subjects (14.4%) .
This novel findings of coordinate elevated levels of myelocytes and activated T-lymphocytes in bone marrow of RA suggests an immunological imbalance that may have implication in the disease.

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We investigated the effects of cationic protein, protamine sulfate, on pulmonary extravascular lung water and pulmonary capillary permeability in guinea pigs. Twenty mg/kg of protamine sulfate was injected intravenously followed by 5 mg/kg/hr continuous infusion. We used lung wet-dry weight ratio (W/D) as a parameter of extravascular lung water and ¹²⁵I- albumin lung tissue plasma ratio (albumin leak: AL) as a parameter of vascular permeability. Plasma total protein was decreased by 15 minutes after the protamine bolus injection and remained low until the end of the experiment. Hematocrit was increased by 60 minutes after protamine bolus and remained high. However, W/D and AL did not change significantly.
These findings suggest that protamine sulfate did not change pulmonary capillary permeability although it might increase systemic capillary permeability in guinea pigs.

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The role of superoxide in scar formation following renal infection caused by mannose-sensitive (MS) -piliated strains of bacteria was studied in the experimental pyclonephritis model using female Sprague-Dawley rats. The MS-piliated strain stimulated renal scarring to a significantly greater extent than either the non-piliated or mannose-resistant (MR) -piliated strains. Modification of leukocytes by administering cyclophosphamide to induce neutropenia and colchicine to inhibit leukocyte migration was effective in preventing renal scarring. Treatment with superoxide dismutase during the early stage of infection was also effective in preventing scar formation. Finally, the production of superoxide following stimulation by MS-piliated strain was larger amount than it following stimulation by either non-piliated or MR-piliated strains.
These observations suggest that superoxide released from leukocytes plays an important role in the development of renal scarring following infection by MS-piliated strains.

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The effects of new immunomodulators, KE-298, on the production of immunoglobulins and IgG- and IgM-rheumatoid factors (IgGRF, IgMRF) by mono-nuclear cells from patients with rheumatoid arthritis (RA) were studied.
KE-298 at the concentrations ranging from 3.13 to 200 μg/ml inhibited IgG, IgM and IgA production and IgGRF and IgMRF production by RA mononuclear cells. Mean % inhibition for IgG, IgM, IgA, IgGRF and IgMRF by 100 μg/ml KE-298 was 38.3%, 43.8%, 40.4%, 73.8% and 50.3%, respectively. Since enhanced RF production by RA mononuclear cells has an immunopathogenetic role in RA, the inhibitory action of KE-298 on RF production by RA mononuclear cells may be one of the mechanisms by which KE-298 exerts clinical efficacy in RA patients.

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This study had two purposes; to assess the results of 5-year administration of bucillamine (Bc), and to see the predictability of the continuous effect of Bc over 5 years on the basis of the clinical results obtained at the initial stage of administration.
68 patients with rheumatoid arthritis on Bc therapy from 1982 until 1985 were adopted as subjects. They consisted of 10 males and 58 females, with a mean age of 51.8±9.6 years and a mean disease duration of 9.2±8.2 years. Changes of Lansbury index were monitored, and the following results were obtained.
1) Bc was administered throughout 5 years in 14 patients (20.6%), Bc was discontinued in less than 5 years because of attenuation of effect in 8 patients (11.8%), because of absence of effect in 12 patients (17.6%), because of side effects in 16 patients (23.5%), and 18 patients (26.5%) dropped out of the study.
2) In patients who received Bc for 5 years, the Lansbury index improved significantly after 1 month of administration. This improvement was sustained over 5 years.
3) In patients who were withdrawn because of attenuation of effect, no improvement of Lansbury index was seen after 18 months of administration.
4) In patients who received Bc continuously over 5 years, the Lansbury index at month 18 demonstrated significant decrease below 55% of the level of the Lansbury index at the start of treatment.
5) In patients who received Bc continuously over 5 years and those who were withdrawn because of attenuation of effect, the Lansbury index decreased significantly below 90% of the initial value at month 1 and below 85% of that at month 2. However, in patients who were withdrawn because of absence of effect, no improvement of the Lansbury index was noted at either point.
Based on these results, the following conclusions may be drawn. The efficacy of Bc lasts for a long period in about 20% of patients. Unless the Lansbury index decrease below 90% of the initial value at month 1 and below 85% at month 2, Bc cannot be expected to be effective. Furthermore, unless the Lansbury index at month 18 decrease below 55% of the initial value, its effect will not be maintained over 5 years.

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