Search

Objective: To evaluate whether climate change is associated with male:female ratios (sex ratios) of fetal deaths and births in Japan., Design: A population-based cohort study., Setting: Not applicable., Patient(s): Newborn infants and fetuses spontaneously aborted after 12 weeks of gestation., Intervention(s): None., Main Outcome Measure(s): Yearly sex ratios of fetal deaths and newborn infants and monthly fetal death rates and sex ratios of newborn infants., Result(s): A statistically significant positive association was found between yearly temperature differences and sex ratios of fetal deaths; a statistically significant negative association was found between temperature differences and sex ratios of newborn infants from 1968 to 2012, and between sex ratios of births and of fetal deaths. The sex ratios of fetal deaths have been increasing steadily along with temperature differences, whereas the sex ratios of newborn infants have been decreasing since the 1970s. Two climate extremes, a very hot summer in 2010 and a very cold winter in January 2011, showed not only statistically significant declines in sex ratios of newborn infants 9 months later in June 2011 and October 2011 but also statistically significant increases of fetal death rates immediately, in September 2010 and January 2011., Conclusion(s): The recent temperature fluctuations in Japan seem to be linked to a lower male:female sex ratio of newborn infants, partly via increased male fetal deaths. Male concepti seem to be especially vulnerable to external stress factors, including climate changes., (Copyright © 2014. Published by Elsevier Inc.)

The present study assessed whether the smoking habits of fathers around the time of conception affected the period in which daughters experienced menstrual cycles (i.e., the reproductive life span). The study revealed that the smoking habits of the farther shortened the daughters' reproductive life span compared with daughters whose fathers did not smoke., (Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Identification of the ovary at the time of ovulation during three consecutive menstrual cycles results in one of eight ovulation patterns, left-left-right, right-left-right, left-right-right, and right-right-right of right-sided ovulation and right-right-left, left-right-left, right-left-left, and left-left-left of left-sided ovulation. Our data suggest that IVF and IUI treatment in cycles in which development of the preovulatory follicle(s) occurs in the right-sided ovary-and ovulations took place from the left-sided ovary in the preceding two cycles (left-left-right)-is likely to show the best pregnancy potential and high offspring sex ratio., (Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

We conducted a 52-week clinical study of iguratimod in 394 Japanese patients with rheumatoid arthritis to evaluate the long-term safety of the drug. Iguratimod was administered orally at a daily dose of 25 mg for the first 4 weeks and 50 mg for the subsequent 48 weeks. Some of the patients continued the treatment for 100 weeks for their benefit. The cumulative incidence of adverse events for 100 weeks was 97.6%. The cumulative incidence of adverse reactions was 65.3%; unfavorable symptoms and signs (excluding abnormal laboratory data changes) accounted for 33.2% of the reactions, and abnormal laboratory data changes accounted for 50.4%. The continued treatment rate was 66.8% at week 28 and 53.6% at week 52. For reference, the American College of Rheumatology (ACR) 20 response rate was calculated for the patients who had assessable disease activity, who did not violate the study protocol, and who continued the study treatment at weeks 28 and 52. The rate was 46.9% at week 28 and 41.0% at week 52. To use iguratimod safely for a long time, patients should be observed closely for adverse reactions such as increased hepatic enzymes.

We conducted a 28-week, randomized, double-blind, parallel-group study of iguratimod in 376 Japanese patients with active rheumatoid arthritis to compare the efficacy and safety of the drug with those of placebo and salazosulfapyridine. In the American College of Rheumatology (ACR) 20 response rate, iguratimod was superior to placebo (53.8% versus 17.2%; Fisher's exact test, P < 0.001) and was not inferior to salazosulfapyridine (63.1% versus 57.7%, 95% confidence interval for the rate difference, -7.9% to 18.7%). Iguratimod began exhibiting its therapeutic effect within 8 weeks after the initiation of treatment and was effective even in patients who had a poor response to previous treatment with disease-modifying antirheumatic drugs. No statistically significant difference was noted in the incidence of adverse reactions between iguratimod and salazosulfapyridine. The study results suggest that iguratimod could become a new option for the treatment of rheumatoid arthritis.

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 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.

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.

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.

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.

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)

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.

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.

Objective: To better understand the immunoglobulin variable (V) region repertoire of rheumatoid factors (RF)., Methods: We characterized the heavy (H) and light (L) chain gene segments utilized in a monospecific IgG RF secreting hybridoma (AEE111F) which were derived from a patient with rheumatoid arthritis (RA). The hybridoma was established by fusion of a mouse myeloma cell line with bone marrow derived mononuclear cells from a patient with RA. First strand complementary DNA (cDNA) was generated and used for a polymerase chain reaction amplification of the H and L chain V domains. The amplified V domains were sequenced and compared with an extensive database of germline and cDNA V gene segments., Results: The VH sequence was found to be 96% homologous to a previously described fetal VH3 cDNA (60P2). The VL sequence was also highly homologous to the previously described V lambda II gene (96%) derived from a patient with systemic lupus erythematosus which correlated with an 8.12 idiotype (Id), and to an antibacterial antibody against the Haemophilus influenzae type b capsular polysaccharide (94.7%)., Conclusion: The overlap among this RF VL gene and the 2 reported V lambda sequences of antibodies that expressed anti-DNA related Id and an environmental pathogen specificity suggests that a part of the IgG RF isolated from patients with RA may thus be derived from the physiological natural antibody repertoire during an abnormal immune response and then develop high affinity, monospecific RF by the selection of an antigen driven mechanism.

Humoral and cellular immune mechanisms are thought to be involved in various forms of vasculitis and glomerulonephritis. Recent clinical and experimental results point to a role of cytokines in ANCA-positive vasculitides. In patients with malignant rheumatoid arthritis (MRA) which is characteristically induced by vasculitis in extra-articular lesions, serum soluble IL-2 receptor level was significantly higher than in rheumatoid arthritis patients without vasculitis. In Wegener's granulomatosis, TNF-alpha, IL-1 beta and IL-2 receptor positive infiltrating cells were observed in the kidneys of these patients, and in these patients, plasma levels of TNF-alpha and soluble IL-2 receptor were markedly increased. These results suggest that in ANCA-positive vasculitis TNF-alpha and IL-1 beta are produced in situ by activated infiltrating mononuclear cells and resident renal cells. In patients with giant cell arteritis and Kawasaki disease, increased levels of leukaemic inhibitory factor (LIF) and TNF-alpha were observed, respectively. These inflammatory cytokines increased in the vascular tissues and circulation may be a result of increased production by infiltrated cells or vascular cells such as endothelial cells or may be a result of endothelial cell lysis.

We treated a patient with severe aplastic anemia with long-term administration of recombinant human granulocyte-colony stimulating factor (rhG-CSF). When a trilineage response of hematopoiesis was obtained after the first treatment, a chromosomal change [45XX, -7] was observed in 20 of the 20 metaphases examined. Later, we were able to show a monoclonal X inactivation pattern in the phosphoglycerate kinase (PGK) gene in the peripheral blood polymorphonuclear leukocytes and mononuclear cells, indicating the presence of clonal hematopoiesis regardless of the disappearance of the karyotype abnormality. We suggest that it is important to pay close attention to the appearance of clonal hematopoiesis during the administration of G-CSF to patients with idiopathic severe bone marrow aplasia.

Clinical features between 69 early RA patients (within a year duration) and 79 established RA patients (more than 3 years duration) were compared retrospectively. There were no significant differences about frequencies of morning stiffness (68.2% vs 54.4%) and rheumatoid nodules (20.2% vs 15.2%) between early RA and established RA. There were also no significant differences between two groups about elevation of ESR (92.8% vs 97.4%), positivity of CRP (97.1% vs 94.9%) and rheumatoid factor (RF) (82.6% vs 93.7%), and Lansbury activity index (AI) (mean 68.8% vs 78.8%). After hospitalization and treatment, all clinical indices (ESR, CRP, RF, AI) improved significantly in both groups. There, however, were clinically more "marked improvement" (39.1% vs 16.4%) and "remission" (8.7% vs none) in early RA group. We conclude that by hospitalization and treatment, clinical improvement can be expected in both early and established RA, but to secure satisfactory improvement, early detection and intervention of RA would be recommended.

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.

To clarify the pathophysiological changes of pre-eclampsia, we investigated the injurious effect of sera from women with pre-eclampsia on cultured endothelial cells, vascular smooth muscle cells and fibroblasts. We obtained serum samples from 32 Japanese women, including 10 healthy nonpregnant women, 12 normal pregnant women and 10 women with pre-eclampsia. Cell injury was measured by the release of radiolabelled chromium from the cells into the culture medium. The mean values +/- SD of percentage chromium release from endothelial cells in normal nonpregnant, normal pregnant and pre-eclamptic subjects were 8.5 +/- 2.4, 8.8 +/- 2.1 and 19.7 +/- 3.6%, respectively. Sera from women with pre-eclampsia demonstrated significantly greater endothelial cell injury than did sera from normal pregnant and nonpregnant subjects. However, normal pregnant and pre-eclamptic subjects did not differ with respect to both vascular smooth muscle cell injury and fibroblast injury. These results indicate that a serum cytotoxic to endothelial cells is present in pre-eclampsia and that this activity has a cellular specificity for endothelial cells.

The symptoms of myasthenia gravis (MG) reflect the loss of neuromuscular transmission due to the functional loss of the acetylcholine receptor. We reviewed the reported association of MG and connective tissue diseases including rheumatoid arthritis, systemic lupus erythematosus, progressive systemic sclerosis (PSS), polymyositis and dermatomyositis, mixed connective tissue disease (MCTD) and Sjøgren's syndrome (SjS). We found that the association of MG and MCTD or PSS is rare. We also reviewed the role of D-penicillamine, thymus abnormalities and the coexistence of SjS as one of the underlying pathological conditions for the association of MG and various connective tissue diseases.

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.

Objective: We investigated whether mononuclear cells (MNC) from patients with seronegative rheumatoid arthritis (SNRA) are able to produce rheumatoid factor (RF) in response to lectin stimulation, Staphylococcus aureus Cowan I (SAC) or pokeweed mitogen (PWM), and also we investigated the role of CD5+ B cells in the pathogenesis of in vitro IgM RF production., Methods: IgM RF production was measured by enzyme linked immunosorbent assay and CD5+ B cells by flow cytometry. Also, the effects of monocyte depletion and the inhibition of prostaglandin (PG) were compared in SNRA, seropositive RA (SPRA) and healthy controls., Results: Peripheral blood MNC of patients with SNRA were able to produce the same amount of IgM RF as patients with SPRA following stimulation and SAC. CD5+ B cells also increased in patients with SNRA as well as patients with SPRA compared to healthy controls. However, a definite contribution of the CD5+ B cells to SAC-induced IgM RF production could not be demonstrated. The role of macrophage and PG on in vitro IgM RF synthesis were insignificant., Conclusion: MNC of patients with SNRA were able to produce IgM and IgG RF in response to SAC stimulation as well as that of the healthy controls. However, we could not find a significant role of CD5+ B cells and monocytes on in vitro IgM RF synthesis by MNC of patients with SNRA.

We herein describe a 41-year-old female patient with an association of myasthenia gravis (MG) with anti-acetylcholine receptor (AcR) antibody, mixed connective tissue disease (MCTD) and Sjögren's syndrome (SjS). We reviewed the reported association of MG and MCTD, systemic lupus erythematosus, progressive systemic sclerosis, polymyositis and dermatomyositis, and SjS. Since we could find only two patients who fulfilled the diagnostic criteria for MCTD in the previous literature, we concluded that the association of MG and MCTD is rare. We also discuss the coexistence of SjS as one of the underlying pathological conditions for the association of MG and various connective tissue diseases including MCTD.

We have encountered 2 patients with mixed connective tissue disease (MCTD) associated with lymphadenopathy at the outset. Biopsy specimens of enlarged lymph nodes showed massive necrotizing lesions with follicular hyperplasia, which are occasionally observed in the involved lymph nodes of patients with systemic lupus erythematosus (SLE) and called lupus lymphadenitis. Usually, the only histologic finding of an involved lymph node in MCTD is lymphoid hyperplasia. These are the 2nd and 3rd cases of MCTD associated with lupus lymphadenitis. Our cases suggest that histologic studies of the swollen lymph nodes are not helpful in distinguishing MCTD from SLE.

In a multicentre double blind study, it was demonstrated that bucillamine (Bu) 100 mg was more effective than placebo in patients with rheumatoid arthritis who are partially remitted by gold injections for more than six months. Global effectiveness and usefulness rates of 100 mg Bu in the combination therapy were almost the same as those of 3200 mg Bu in single administration. Side effects were also similar in the two regimens.

Objective: To clarify the role of endothelial cells in pregnancy-related hypertensive disorders, we studied the cytotoxic effect of sera from normal pregnant women and from gravidas with various hypertensive complications of pregnancy., Methods: We obtained serum samples from 84 Japanese women: 17 with preeclampsia, ten with gestational hypertension, six with chronic hypertension, five with chronic hypertension with superimposed preeclampsia, 21 normal gravidas, and 25 healthy nonpregnant women. Endothelial cell injury was measured by the release of radiolabeled chromium from the cells into the culture medium., Results: The mean (+/- standard error of the mean) values of chromium 51 release in preeclampsia, gestational hypertension, chronic hypertension, chronic hypertension with superimposed preeclampsia, normal pregnancy, and healthy nonpregnant women were: 21.9 +/- 2.1, 10.0 +/- 2.0, 9.2 +/- 2.3, 12.9 +/- 0.8, 8.4 +/- 1.4, and 7.3 +/- 1.6%, respectively. Normal pregnant and nonpregnant subjects did not differ with respect to endothelial cell injury. Sera from women with preeclampsia demonstrated significantly greater endothelial cell injury than did sera from normal gravidas. Subjects with the three other categories of hypertensive disorders did not differ significantly from normal gravidas., Conclusion: Preeclampsia is characterized by the presence of a serum factor cytotoxic to endothelial cells. Therefore, the mechanism responsible for the increase in blood pressure differs between women with preeclampsia and those with other hypertensive disorders in pregnancy.

We investigated the clinical significance of the close association of Sjögren's syndrome (SS) with mixed connective tissue disease (MCTD) by analyzing the clinical manifestations, sialographic findings and immunological parameters of MCTD and primary SS. The prevalence of sialectasia or SS in MCTD was significantly higher than in any other connective tissue diseases. The prevalence of Raynaud's phenomenon, swollen fingers, arthralgias, lymphadenopathy, sclerodactyly, muscle weakness, fever and erythema was significantly higher in MCTD than in primary SS. There were no significant differences between these manifestations in MCTD patients with sialectasia or SS, and those in MCTD patients without sialectasia or SS. Although the levels or prevalence of the erythrocyte sedimentation rate, CRP, antinuclear factor, anti-DNA antibody and anti-RNP antibody were significantly greater in MCTD than in primary SS, there were no significant differences in the levels or the prevalence of laboratory abnormalities between MCTD with sialectasia or SS, and MCTD without sialectasia or SS. Moreover, there was a strict dissociation between the occurrence of anti-RNP antibody and anti-SS-B antibody both in MCTD and primary SS. These results suggest that the association of secondary SS or sialectasia in MCTD, although more common than in other connective tissue diseases, is merely a consequence of MCTD and does not influence the clinical course of MCTD.

Malignant rheumatoid arthritis (MRA) is a name for rheumatoid arthritis (RA) complicated with systemic vasculitis or other severe extra-articular manifestations, which can cause a fatal outcome. MRA is found in 4-5% of inpatients with RA. The male to female ratio is 1:1.45. Histologically, 3 main types are recognised in rheumatoid vasculitis; RA type (vasculitis with rheumatoid nodule-like appearance), PN type (fibrinoid vasculitis similar to PN), and EA type (endoarteritis obliterans). High titers of rheumatoid factor, immune complexes, hypocomplementemia, hypoproteinemia, decreased choline esterase activity, elevated alkaline phosphatase activity and leukocytosis are characteristic laboratory features of MRA. Recently, it appears that MRA is becoming less and the prognosis is getting better, perhaps due to the advancement in treatment.

Leukotriene B4 (LTB4) was measured in synovial fluid from 20 patients with rheumatoid arthritis and 15 patients with osteoarthritis. The level of LTB4 was significantly higher in synovial fluid from rheumatoid arthritis patients as compared with synovial fluid from osteoarthritis patients. LTB4 levels also significantly correlated with cell numbers, rheumatoid factor, and immune complexes in synovial fluid from rheumatoid arthritis patients. There was an inverse correlation between LTB4 levels and complement components. The high-pressure liquid chromatography peak of immunoreactivity extracted from the synovial fluid occurred at a retention volume identical to that of authentic LTB4. These results suggest that the increased level of this mediator in synovial fluid may contribute to perpetuation of inflammation and tissue destruction in rheumatoid arthritis.

The effects of recombinant human IL-1 beta on the production of prostaglandin E2 (PGE2), leukotriene B4 (LTB4), N-acetyl-beta-D-glucosaminidase (NAG), and superoxide by synovial cells and chondrocytes derived from osteoarthritis patients were determined. IL-1 beta markedly enhanced PGE2 production in chondrocytes and, to the lesser extent, in synovial cells. Synovial cells and chondrocytes spontaneously released LTB4 into culture medium and IL-1 beta significantly inhibited LTB4 production by these cells. IL-1 beta significantly suppressed the release of NAG and superoxide by synovial cells, whereas it significantly enhanced the production of NAG and superoxide by chondrocytes. Production of intracellular superoxide dismutase by synovial cells was significantly enhanced on incubation with IL-1 beta, but that of chondrocytes was not altered. IL-6, unlike IL-1 beta, significantly suppressed the production of NAG and superoxide by synovial cells and chondrocytes. These results suggest that IL-1 has differing effects on the release of mediators by synovial cells and chondrocytes and that these cells also vary in their responses to IL-1 beta and IL-6.

The complete nucleotide sequences of the variable region genes of the heavy and light polypeptide chains of a human monoclonal rheumatoid factor (RF) produced from a human-mouse heterohybridoma were determined. The antibody, designated YES8c, contained V kappa III, J kappa 2, VH1, JH4, and a D gene segment of 9 amino acids. The nucleotide sequences and the deduced amino acid sequences of the light chain variable region were remarkably homologous (97-98%) to previously described RF of the Wa idiotypic family (PAY, GLO, CUR, FLO, and GAR) and to that of a V kappa III germline gene (Humkv325). The YES8c heavy chain variable region gene was most closely related to the VH1 gene of the restricted human fetal repertoire, designated 51p1, and also to 3 rearranged VH1 genes that were recently isolated from patients with chronic lymphocytic leukemia. These results suggest that variable region genes of RFs are highly conserved and that YES8c VH, as well as V kappa, may be identical to heavy and light chains expressed during early B cell development.

Vascular endothelial cells (EC) produced IL-1 alpha but not IL-1 beta into extracellular fluids. Vascular smooth muscle cells (SMC), on the other hand, produced both IL-1 alpha and IL-1 beta, and IL-1 beta produced was much higher than IL-1 alpha. The addition of recombinant human IL-1 beta or recombinant human TNF-alpha significantly enhanced IL-1 alpha production in EC, and IL-1 alpha and IL-1 beta production in SMC. IL-1 beta release was not observed even when EC were stimulated with TNF-alpha. These results suggest that the species of released form of IL-1 are different in different cell types and that cytokines enhance IL-1 alpha and IL-1 beta production in SMC and IL-1 alpha production in EC.

Serum antibodies to cytoskeletal systems were detected, using indirect immunofluorescence in patients with adult T-cell leukemia (ATL), healthy carriers of human T cell lymphotropic virus 1 (HTLV-1), patients with infectious mononucleosis and healthy adults. Healthy carriers of HTLV-1 had IgG antibodies to cytoskeletal systems as evidenced by an increased incidence of IgG antibodies to actin and vimentin. Decreased IgG antibody levels to Epstein-Barr virus nucleic acid (EBNA) were also evident. In patients with ATL, the titers of IgM antibodies to vimentin and cytokeratin showed a positive correlation with decreased serum levels of IgM, despite the fact that serum concentrations of IgM were significantly decreased in patients with ATL. The IgM antibody titer divided by the IgM concentration (the antibody ratio) was nigher than that of healthy carriers and healthy adults, suggesting that the IgM antibody response to cytoskeletal systems was preferentially preserved in these cases. There was also a suggestion of the presence of polyclonal as well as specific antibody responses to cytoskeletal systems in patients with infectious mononucleosis. As a result of these findings we suggest that there is some difference in the mechanisms responsible for the production of autoantibodies to cytoskeletal systems following HTLV-1 infection and Epstein-Barr virus infection.

Metal-binding proteins (ceruloplasmin, transferrin, ferritin, and lactoferrin), proteinase inhibitors (alpha 1-antitrypsin, alpha 2-macroglobulin and inter-alpha-trypsin inhibitors), and albumin were assayed in synovial fluid obtained from 20 patients with rheumatoid arthritis (RA) and 15 with osteoarthritis (OA). The levels of proteinase inhibitors and metal-binding proteins, except transferrin, were significantly increased in synovial fluid from RA patients as compared with synovial fluid from OA patients. Metal-binding proteins significantly correlated with rheumatoid factor and immune complexes in synovial fluid from RA patients. Proteinase inhibitor levels also significantly correlated with C-reactive protein, and complement components. These results suggest that the raised level of metal-binding proteins and proteinase inhibitors in synovial fluid from RA patients reflect inflammatory activity, and hence may play an important role in the pathogenesis of inflammatory joint diseases.

Serum antibodies to cytoskeletal systems were measured by indirect immunofluorescence using human skin fibroblasts as the substrate for actin and vimentin, and HEp2 cells for cytokeratin. IgM concentration in 12 umbilical cord blood was less than 20 mg/dl, but antibody to cytokeratin was detected in samples that contained more than 10 mg/dl of IgM. Sera from 8-year-old pupils had elevated antibody titer to vimentin of IgG, IgM and IgA class and to cytokeratin of IgG and IgM class. Healthy adults had IgM anti-vimentin and anti-cytokeratin antibody at 60 times serum dilution, but other antibodies were lower than 10 times serum dilution. IgG and IgA concentration did not have any correlation with anti-cytoskeletal system antibodies. IgM concentration tended to correlate with IgM antibody titer to vimentin and cytokeratin. With increasing age in adults, antibody to actin of IgG class appeared.

We studied the effect of recombinant tumor necrosis factor-alpha (rTNF-alpha) on the production of superoxide and metalloproteinase by rheumatoid synovial cells or osteoarthritis chondrocytes. rTNF-alpha significantly inhibited superoxide generation by osteoarthritis chondrocytes and rheumatoid synovial cells at a concentration of 23 U/ml. On the other hand, rTNF-alpha at a concentration of 1500 U/ml significantly enhanced superoxide production by rheumatoid synovial cells, osteoarthritis synovial cells and osteoarthritis chondrocytes, respectively. Metalloproteinase released by rheumatoid synovial cells and chondrocytes derived from osteoarthritis patients were stimulated by rTNF-alpha at a concentration of 94 U/ml. rTNF-alpha at the highest concentration (15000 U/ml) significantly inhibited metalloproteinase release by rheumatoid synovial cells. The enhancing effect of rTNF-alpha at higher concentrations on superoxide production by rheumatoid synovial cells and osteoarthritis chondrocytes was time dependent. These results suggest that rTNF-alpha has a biphasic effect on superoxide and metalloproteinase production, and hence may play an important role in the pathogenesis of inflammatory joint diseases.