Biomedical subjects
Publications and source records attributed to M Nobunaga.
The authors present a pair of identical twins with congenital diaphragmatic hernia (CDH) diagnosed prenatally, who underwent successful surgical repair. They were diagnosed as having CDH at 32 weeks' gestation and showed respiratory distress soon after cesarean section at 33 weeks' gestation. Both survived after scheduled perinatal management followed by surgery, for which the prenatal diagnosis of CDH was valuable.
The value of measuring soluble interleukin-2 receptor (sIL-2R) in the sera of patients with joint pain as a predicting parameter for the future development of rheumatoid arthritis (RA) was examined. sIL-2R was measured by the ELISA method. Sixty-four patients with joint pain (suspected RA: sus-RA) but no bone or joint destruction were enrolled over 2 years and 47 were selected for the study. Eleven patients whose diagnosis was sus-RA after a year of observation were successively followed-up for 5 years. Two-thirds of the patients whose sIL-2R levels were higher than those of normal healthy adults (< 82 pmol/l; mean +2SD) developed RA within a year. On the other hand, one-quarter of the patients with normal levels of sIL-2R also developed RA within a year. The presence of two or three of the following three items in patients with joint pain without any bone and joint destruction was thus indicated to be useful for the early diagnosis of RA: elevated CRP level (> or = 1.0 mg/dl), positive rheumatoid factor (RF) (> or = 30 IU/ml) and an elevated sIL-2R level (> or = 100 pmol/l). Sensitivity and specificity were 72.7% and 96.0%, respectively. The probability of development of RA is expressed as P = 1/[1 + exp(2.673 - 0.01784 x sIL-2R - 0.4398 x CRP - 0.004835 x RF)], with R2 = 0.3083 and p<0.0005. On the other hand, the sIL-2R levels did not correlate with any future bone or joint changes within a year of observation. The above criteria may therefore hopefully justify the early treatment of patients with joint pain using drugs that can modify the patients' immune function. However, the validity of these criteria still need to be examined more thoroughly in the future.
The expression of metallothionein, an intracellular heavy-metal-binding protein, and p-glycoprotein, an energy-dependent drug efflux pump, was examined to study the mechanism of cell resistance to gold sodium thiomalate (GST). THP-1, one of the monocyte-derived cell lines, was cultured for 6 months and resistance to 25 microg/ml of GST (GST-resistant cells) was thus induced. The GST-resistant cells were then cultured with bucillamine to examine the presence of cross-resistance. The intracellular GST concentration was examined by flameless atomic absorption spectroscopy. The cell viability was determined by the uptake of 3-4,5 dimethylthiazole-2,5 diphenyl tetrazolium bromide (MTT). The expression of p-glycoprotein was detected by Western blotting using monoclonal anti-p-glycoprotein antibody. The expression of metallothionein was detected using the indirect immunofluorescence technique. GST-resistant cells did not show any cross-resistance to bucillamine. The rate of cytoplasmic GST accumulation decreased in the GST-resistant cells, while the rate of GST efflux also decreased. The expression of p-glycoprotein in the GST-resistant cells was not significantly different from that in the cells not treated with GST. On the other hand, the GST-resistant cells showed a higher expression of metallothionein than cells not treated with GST. These findings suggest that the induced resistance to GST might partly be due to an induction of metallothionein.
The problem of nonsteroidal anti-inflammatory drug (NSAID)-induced gastrointestinal toxicity was reviewed by members of the Asia Pacific League of Associations for Rheumatology (APLAR) in a consensus conference in September 1992. This paper by the participants presents the consensus conclusions incorporating knowledge from recent publications. There had been a high level of concern that much of the toxicity had resulted from extensive and indiscriminate prescribing of NSAIDs. The implementation of evidence-based guidelines was considered likely to be able to effect a substantial reduction in toxicity without significant loss of overall therapeutic benefit. The evidence from which such guidelines could be developed is critically appraised.
In order to investigate the in vivo role of rheumatoid factor (RF), the effects of the administration of human monoclonal (m) IgM-RF and IgG-RF on the development of arthritis in mice were examined. The administration of human mRFs into mice immunized with type II collagen (CII) markedly enhanced the clinical score and paw swelling. The severity of arthritic joint disease with a marked infiltration of lymphoid cells, proliferation of synovial membrane, pannus formation and destruction of articular cartilage was significantly enhanced in both groups receiving RF (RF-enhanced arthritis). Skin ulcers were also observed in some of these RF-enhanced arthritis mice, whereas no such signs were observed in CII-immunized mice without mRFs. Both IgM-RF and IgG-RF increased CII-specific IgG antibodies in circulation, and the severity of arthritis correlated with the production of high titres of anti-CII antibodies. In vivo treatment of RF-enhanced arthritis mice with an anti-CD4 MoAb or an anti-CD8 MoAb inhibited the induction and progression of arthritis in these mice. Administration of RF to severe combined immunodeficient (SCID) mice with arthritis developed by the transfer of spleen cells from CII-immunized mice, prolonged the arthritis and enhanced the severity. This murine model of RF-enhanced arthritis may provide a useful tool for analysing the pathogenesis of rheumatoid arthritis in RF-positive patients.
Two rheumatoid arthritis (RA) patients with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) during the course of infection are herein reported. One patient developed SIADH during the course of a localized cutaneous herpes zoster infection while the other developed SIADH in conjunction with Staphylococcus simulans septicemia. We consider that the development of SIADH was strongly associated with superimposed infections in the underlying RA. This is the first report discussing the association of SIADH and infections in RA patients in which SIADH is diagnosed by measurement of plasma ADH.
The clinical features of 134 consecutive hospitalized patients with rheumatoid arthritis in the northeastern area of the People's Republic of China and 251 consecutive hospitalized patients from western Japan were compared. A total of 91.8% of the Chinese patients were of Han nationality, while all of the patients from Japan were Japanese. The patients in the People's Republic of China showed more inflammatory articular disease and more frequent subcutaneous nodules than did the Japanese patients in the presence of a less elevated ESR value and less radiographic joint destruction. The clinical features of the patients of Han nationality and the Japanese did not change even after adjusting the patients' age and disease duration. The reasons for the contradictory features in the Chinese patients still remain to be clarified. This study is hopefully a first step in promoting more precise studies on rheumatoid arthritis in the People's Republic of China.
In order to investigate the possible role of IL-1 receptor antagonist (IL-1ra) in patients with rheumatoid arthritis (RA), this study was undertaken to measure the amounts of IL-1ra and interleukin-1 beta (IL-1 beta) protein produced by mononuclear cells (MNC) and to investigate the relationship between production of these cytokines and clinical parameters. The MNC were cultured for 24 h and the supernatants were measured for IL-1ra and IL-1 beta by ELISA kits. MNC from peripheral blood (PB) and synovial fluid of RA patients produced significantly higher amounts of IL-1ra than normal PBMNC (P < 0.01 and P < 0.05, respectively). When the IL-1 beta/IL-1ra ratio was calculated, IL-1 beta/IL-1ra ratios of RA PBMNC were significantly lower than those of normal PBMNC (P < 0.001). The IL-1 beta/IL-1ra ratio of RA PBMNC was significantly higher in active RA patients than in RA patients in remission (P < 0.02). The amounts of IL-1ra produced by stimulated RA PBMNC positively correlated with the joint score (P < 0.05), serum CRP levels (P < 0.05) and the amounts of IL-1 beta produced (P < 0.01). The amounts of IL-1ra produced by unstimulated RA PBMNC did not correlate with any of the clinical parameters studied. Gold sodium thiomalate (GST), but not auranofin, increased IL-1ra production in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)
We here report fourteen patients diagnosed as adult-onset Still's disease (AOSD) in our hospital. Seven patients were males (mean age at onset was 26.6 years), and seven were females (30.6 years). All of the cases had spiking fever ( > 39 degrees C) and joint symptoms. Hepatomegaly, splenomegaly, and lymphadenopathy were noted in 50% of the patients, respectively. Skin eruption was seen in twelve patients (85.7%). Among them, nine patients (64.3%) exhibited typical rash. Pleuritis or pericarditis was seen in one case each. Only one patient revealed neurological disorder. Abdominal pain was present in 50% of the cases. The ratio of occurrence of secondary amyloidosis was 14.3%. Four patients (28.6%) were diagnosed to have the apophyseal narrowing at the cervical spine (C2-C3). Two patients (14.3%) accompanied by Sjögren's syndrome were women over 40 years of age. The levels of soluble interleukin-2 receptor were significantly elevated in the sera obtained from seven patients with AOSD and four patients with juvenile-onset Still's disease, compared with normal controls. It seems to support the notion that immunopathologic processes via T cell activation play an important role in the pathogenesis of AOSD.
The effects of the extract of Tripterygium wilfordii. (TWE) on experimental adjuvant arthritis (AA) in the rat was studied. Lewis rats induced with AA were administered with TWE at 50 mg/kg/day for 10 weeks. The paw volume, its ratio to the body weight (paw ratio) and the radiologic changes in the feet of the rats with AA taking TWE were compared with those in the rats taking indomethacin (0.5 mg/kg/day) and no additional drugs. The rats taking TWE showed a smaller paw volume, a lower paw ratio and milder radiologic changes than the rats taking no drugs, however, the beneficial effects were weaker than those of indomethacin. We concluded that the beneficial effects of TWE on rats with AA was suggested. However, these results still need to be further confirmed by additional experiments.
We herein report two cases of gastrointestinal amyloidosis, secondary to juvenile rheumatoid arthritis (JRA) in one, and rheumatoid arthritis (RA) in the other. A 21-year-old woman, who has been suffering from JRA for the past 12 years, was transferred to our hospital due to intense pain in the epigastrium and back, diarrhea, high fever, and paralytic ileus. Treatment by corticosteroid, antibiotics, protease inhibitor, and total parenteral nutrition was not effective. The laparoscopic surgery was performed because of repeated melena followed by an episode of hypovolemic shock. The resected specimen of the ileum showed histologically marked amyloid deposition in the arteriolar walls. A 83-year-old man with RA for 14 years, was admitted to our hospital with complaints of abdominal pain, nausea, and diarrhea. He underwent an emergency operation for perforation of the ileum. The resected specimen revealed amyloid deposition and non-caseating granulomas. The fragility and impaired blood supply caused by amyloid deposition in the vascular walls may have terminated in the severe intestinal lesion. Further clinicopathological studies along this line are keenly desired in order to establish therapeutic modalities for gastrointestinal amyloidosis.
Stromelysin-1 (MMP-3) is a metalloproteinase that degrades articular cartilage matrix in patients with rheumatoid arthritis (RA). We measured MMP-3 in the sera from patients with RA and other connective tissue diseases using specific sandwich EIA and studied its clinical significance in early onset RA. MMP-3 level in healthy control (n = 170) was significantly higher in male than in female. The level of MMP-3 in RA was significantly and dramatically higher than in healthy control, osteoarthritis, systemic lupus erythematosus, progressive systemic sclerosis, primary sjogren's syndrome, mixed connective tissue disease, gouty arthritis and traumatic arthritis. Serum MMP-3 significantly correlated with serum BUN or serum creatinine levels in SLE patients but not in RA patients. In early onset RA, serum MMP-3 level was significantly elevated. Furthermore, when the relationship between the serum MMP-3 level and X-ray findings of the joints in RA was studied, it was found that MMP-3 level was elevated even in stage I or II and that there was no statistical differences between stage I or II and stage III or IV, suggesting that serum MMP-3 level is elevated in the early stage of initial inflammatory process when only mild cartilage degradation is seen. These results suggest that measurements of serum MMP-3 is an important tool for establishing diagnosis of early onset RA, and that serum MMP-3 level may be a marker of cartilage destruction and of estimating therapeutic efficacy in early onset RA.
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The anti-inflammatory effects of recombinant human manganese superoxide dismutase on adjuvant arthritis was investigated. Local application of this manganese superoxide dismutase given every 2 days not only significantly reduced foot swelling but also retarded radiological bone destruction in adjuvant arthritis. Copper zinc superoxide dismutase had little effect on foot swelling.
The present study was designed to establish the effects of cytokines on soluble ICAM-1 (sICAM-1) production by human endothelial cells (EC) and ICAM-1 expression on these cells and the effects of purified sICAM-1 on lymphocyte-EC adhesion. Expression of ICAM-1 and production of sICAM-1 were measured by a specific ELISA method. ICAM-1 expression was enhanced by IL-1 beta, TNF-alpha, and most effectively by IFN-gamma. IL-4, IL-6, M-CSF, or GM-CSF showed no effects on ICAM-1 expression. IL-4 (100 units/ml) or IL-6(100 units/ml) abolished the enhancing effect of IL-1 beta, while TNF-alpha (1, 10, 100 units/ml) synergized with IL-1 beta to promote ICAM-1 expression in EC. In contrast with the transient increase of cell-associated ICAM-1 expression after activation by IL-1 beta, which peaked 40 h poststimulation and declined thereafter, sICAM-1 continued to accumulate in culture supernatants even after 48 h poststimulation in IL-1 beta-stimulated EC. IL-1 beta treatment resulted in an increase in adhesion. sICAM-1, purified from cell-free supernatants obtained after a 48-h culture of EC in IL-1 beta by affinity chromatography using monoclonal ICAM-1 antibody coupled to Sepharose beads, significantly inhibited lymphocyte EC adhesion. Preincubation of lymphocytes with conditioned medium of EC cultured with 100 units/ml IL-1 beta for 48 h, which contained a considerable amount of sICAM-1, resulted in a significant inhibition of lymphocyte adhesion to IL-1 beta-stimulated EC. These results suggest that there is a cumulative increase in sICAM-1 concentration in the vicinity of cytokine-stimulated EC and that this sICAM-1 modulates ICAM-1-mediated cell to cell interaction.
The present study was designed to quantify the level of the soluble form of ICAM-1 (sICAM-1) produced by mononuclear cells (MNC) of rheumatoid arthritis (RA) patients, and to correlate these levels with the disease activity and with the amounts of cytokines or rheumatoid factors (RF) produced by MNC. Unstimulated synovial fluid (SF) MNC produced higher amounts of sICAM-1 than peripheral blood (PB) MNC in RA patients (P < 0.01). sICAM-1 production by PHA-stimulated MNC was higher in RA SF MNC than RA or normal PB MNC (P < 0.01). The amounts of SICAM-1 produced correlated with the amounts of soluble IL-2 receptor produced (P < 0.02) but not with IL-1B or the Lansbury activity index in RA PB MNC. sICAM-1 correlated with the amounts of soluble CD23 and IL-4 produced by normal PB MNC (P < 0.01). The amounts of sICAM-1 correlated with IgG-RF (P < 0.02) and IgM-RF (P < 0.01) produced by unstimulated MNC obtained from the bone marrow (BM) of RA patients. ICAM-1 expression of T-lymphocyte subsets, B lymphocytes, and monocytes obtained from RA PB and RA BM assayed by two-color flow cytometry ranged from 0.1 to 6%, which was not appreciably different from that of normal controls. The monocyte fraction of RA PB MNC produced significantly higher amounts of sICAM-1 than lymphocyte fraction. These results suggest that sICAM-1 produced by MNC may be a marker of cell activation in T and B lymphocytes, in contrast to the transient increase of ICAM-1 expression.
It has been suggested that IL-1 produces cartilage matrix degradation by metalloproteinases such as collagenase and that such degradation is regulated by metalloproteinase inhibitors. In the present study, the effects of IL-6 and oxygen radical scavengers on cartilage matrix degradation were studied. Superoxide dismutase, catalase, or methionine all significantly inhibited cartilage matrix degradation both in IL-1 beta-stimulated and unstimulated experimental conditions. Both 10 mM EDTA and 100 nM tissue inhibitor of metalloproteinase (TIMP) significantly inhibited cartilage matrix degradation. The addition of methionine significantly inhibited collagenase activity produced in the culture supernatants of chondrocytes stimulated with IL-1 beta. IL-6 significantly suppressed cartilage matrix degradation produced spontaneously or by IL-1 beta stimulation in chondrocytes. IL-6 inhibited superoxide production by chondrocytes both in IL-1 beta-stimulated or unstimulated conditions. These results suggest that oxygen radicals are involved in cartilage matrix degradation mediated by both paracrine and autocrine IL-1 mechanisms and that oxygen radical-mediated activation of collagenase in chondrocytes may explain the mechanisms of how oxygen radicals are involved in cartilage matrix degradation. IL-6 inhibited superoxide production in chondrocytes and thus inhibited cartilage matrix degradation.
We describe a 64-year-old female patient with ochronosis and rheumatoid arthritis. Magnetic resonance imaging of the spinal column disclosed the destruction of vertebral disks, and a bony bridging in Th12 to L2. In addition, we observed joint space narrowing in the wrists as well as among the carpal bones, positive rheumatoid factor and the presence of rheumatoid nodules, in which the histological findings were compatible with those of rheumatoid arthritis. The co-existence of these two diseases has not yet been previously reported. Pre-existing ochronotic arthropathy might have masked the manifestation of rheumatoid arthritis and made the diagnosis of rheumatoid arthritis rather difficult.